Review Oncology (Williston Park)
. 2019 Aug 23;33(8):683730.
Targeting the Sanctuary Site: Options When Breast Cancer Metastasizes to the Brain
Mridula Krishnan, Jairam Krishnamurthy, Nicole Shonka
PMID: 31469897
Free article
Abstract
Brain metastasis is a poor prognostic factor in breast cancer progression, and traditional treatment options have shown minimal response with overall low median survival rates. The incidence of brain metastasis has been increasing despite and, in part, due to advancements in treatment as a result of prolongation of survival. Targeted therapy such anti-HER2 agents have a lower efficacy in this setting compared to metastases elsewhere; however, novel therapies are emerging in this regard. In this comprehensive review, we discuss risk per subtype, special considerations for therapy selection, current focal and systemic treatments, and recent advancements and potential future targets for success. We present our treatment paradigm and multidisciplinary approach to brain metastases arising from breast cancer based on the available evidence, incorporating molecular characteristics.

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Review Curr Oncol
. 2019 Nov;26(Suppl 1):S43-S52. doi: 10.3747/co.26.5605. Epub 2019 Nov 1.
Adjuvant Therapy for Stages II and III Colon Cancer: Risk Stratification, Treatment Duration, and Future Directions
U Bender 1, Y S Rho 2, I Barrera 1, S Aghajanyan 1, J Acoba 2 3, P Kavan 1
Affiliations expand
PMID: 31819709 PMCID: PMC6878933 DOI: 10.3747/co.26.5605
Free PMC article
Abstract
Background: To date, the role of adjuvant systemic therapy in stages ii and iii colon cancer remains a topic of interest and debate. The objective of the present review was to assess the most recent data, specifically addressing methods of risk stratification, duration of therapy, and future directions.

Methods: PubMed and medline were searched for literature pertinent to adjuvant chemotherapy in either stage ii or stage iii colorectal cancer.

Summary: Locoregional disease, histopathology, age, laterality, and a number of other biologic and molecular markers appear to have a role in disease risk stratification. The duration of adjuvant therapy for stage iii disease can vary based on risk factors, but use of adjuvant therapy and duration of therapy in stage ii disease remain controversial. Future directions should include genomic assays and improved study design to provide concrete evidence about the duration of adjuvant folfox or capox and about other types of chemotherapy and immunotherapy.

Keywords: Adjuvant chemotherapy; colorectal cancer; risk stratification; treatment duration.

2019 Multimed Inc.

Conflict of interest statement
CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

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3
Oncologist
. 2019 Jun;24(6):e312-e317. doi: 10.1634/theoncologist.2018-0465. Epub 2019 Apr 2.
Hypomagnesemia and Survival in Patients With Ovarian Cancer Who Received Chemotherapy With Carboplatin
Wenli Liu 1, Aiham Qdaisat 2, Pamela T Soliman 3, Lois Ramondetta 3, Gabriel Lopez 1, Santhosshi Narayanan 1, Shouhao Zhou 4, Lorenzo Cohen 1, Eduardo Bruera 1, Sai-Ching J Yeung 5 6
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PMID: 30940743 PMCID: PMC6656478 DOI: 10.1634/theoncologist.2018-0465
Free PMC article
Abstract in English , Chinese
Background: Hypomagnesemia is a known side effect of several antineoplastic agents, but its impact on outcomes of patients with cancer is not well understood. We examined whether magnesium abnormalities affect survival in patients with ovarian cancer who receive chemotherapy containing carboplatin.

Materials and methods: We included patients with advanced ovarian cancer who had undergone surgery and chemotherapy between January 1, 2004, and December 31, 2014, at our institution. Inclusion criteria were age 18 years or older, pathology of high-grade serous carcinoma, first treatment (surgery or chemotherapy) within 60 days of diagnosis, and chemotherapy containing carboplatin. The final cohort consisted of 229 patients. Vital signs and laboratory tests were recorded at baseline and during the treatment course. The associations between magnesium abnormalities (and other clinical characteristics) and survival were analyzed.

Results: The median patient age was 64 years. Higher baseline heart rate (beats per minute; hazard ratio [HR] = 1.02, p = .002) and greater frequency of hypomagnesemia during the treatment course (HR = 1.05, p = .002) were significantly associated with shorter survival independent of completeness of tumor reduction (HR = 1.60, p = .02), and International Federation of Gynecology and Obstetrics stage (HR = 1.63, p = .01).

Conclusion: Baseline heart rate and the frequency of hypomagnesemia episodes during treatment are prognostic of survival for patients with advanced ovarian cancer receiving carboplatin-containing chemotherapy and tumor reductive surgery. Future research is needed for strategies to detect and prevent hypomagnesemia in this patient population.

Implications for practice: Despite standard laboratory tests and intravenous magnesium replacement prior to each cycle of chemotherapy, hypomagnesemia remains a common side effect of platinum-based chemotherapy. This study revealed that frequent occurrence of hypomagnesemia during the course of treatment including carboplatin-containing chemotherapy and tumor reductive surgery was strongly predictive of shorter survival in patients with advanced ovarian cancer. Strategies to effectively mitigate hypomagnesemia, such as more frequent detection, dietary recommendations, and timely replacement, should be considered in the overall cancer treatment plan for these patients.

Keywords: Carboplatin; Hypomagnesemia; Ovarian cancer; Survival.

© AlphaMed Press 2019.

Conflict of interest statement
Disclosures of potential conflicts of interest may be found at the end of this article.

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4
Review Photodiagnosis Photodyn Ther
. 2019 Dec;28:308-317. doi: 10.1016/j.pdpdt.2019.10.005. Epub 2019 Oct 7.
History and Future Perspectives for the Use of Fluorescence Visualization to Detect Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders
Saygo Tomo 1, Glauco Issamu Miyahara 2, Luciana Estevam Simonato 3
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PMID: 31600576 DOI: 10.1016/j.pdpdt.2019.10.005
Abstract
The early diagnosis of oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMD) is challenging. The use of fluorescence visualization (FV) has been improved as an auxiliary method to early detect alterations in the oral mucosa suggestive of malignancy or pre-malignancy. However, perhaps due to some misinterpretation regarding the clinical purpose of this method, its applicability may have been underestimated. The purpose of this review is to comment on the challenges within the prevention and early diagnosis of OSCC and OPMDs; to contextualize the use of fluorescence-based methods in the diagnosis of human cancers; and to critically analyze the methods and results of studies that evaluated the FV to detect OSCC and OPMDs, and how this method might be applicable in the clinical practice. The current evidence available in the scientific literature indicates that the FV has the potential to improve the early detection of OSCC and OPMDs. Its use in primary healthcare by general practice dentists, oral hygienists, and oral health therapists is recommended, although more research in the population screening scenario is still required.

Keywords: Autofluorescence; Optical fluorescence imaging; Oral cancer; Oral diagnosis; Oral potentially malignant disorders.

Copyright © 2019 Elsevier B.V. All rights reserved.

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5
Review Neuro Oncol
. 2019 Nov 4;21(11):1357-1375. doi: 10.1093/neuonc/noz123.
Risk Factors for Childhood and Adult Primary Brain Tumors
Quinn T Ostrom 1, Maral Adel Fahmideh 2 3, David J Cote 4 5, Ivo S Muskens 6, Jeremy M Schraw 1, Michael E Scheurer 7, Melissa L Bondy 1
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PMID: 31301133 PMCID: PMC6827837 (available on 2020-11-04) DOI: 10.1093/neuonc/noz123
Free PMC article
Abstract
Primary brain tumors account for ~1% of new cancer cases and ~2% of cancer deaths in the United States; however, they are the most commonly occurring solid tumors in children. These tumors are very heterogeneous and can be broadly classified into malignant and benign (or non-malignant), and specific histologies vary in frequency by age, sex, and race/ethnicity. Epidemiological studies have explored numerous potential risk factors, and thus far the only validated associations for brain tumors are ionizing radiation (which increases risk in both adults and children) and history of allergies (which decreases risk in adults). Studies of genetic risk factors have identified 32 germline variants associated with increased risk for these tumors in adults (25 in glioma, 2 in meningioma, 3 in pituitary adenoma, and 2 in primary CNS lymphoma), and further studies are currently under way for other histologic subtypes, as well as for various childhood brain tumors. While identifying risk factors for these tumors is difficult due to their rarity, many existing datasets can be leveraged for future discoveries in multi-institutional collaborations. Many institutions are continuing to develop large clinical databases including pre-diagnostic risk factor data, and developments in molecular characterization of tumor subtypes continue to allow for investigation of more refined phenotypes. Key Point 1. Brain tumors are a heterogeneous group of tumors that vary significantly in incidence by age, sex, and race/ethnicity.2. The only well-validated risk factors for brain tumors are ionizing radiation (which increases risk in adults and children) and history of allergies (which decreases risk).3. Genome-wide association studies have identified 32 histology-specific inherited genetic variants associated with increased risk of these tumors.

Keywords: epidemiology; glioma; meningioma; pediatric brain tumors; risk factors.

© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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6
Clin Genitourin Cancer
. 2019 Dec;17(6):e1171-e1180. doi: 10.1016/j.clgc.2019.08.005. Epub 2019 Aug 20.
Implications of Cystectomy Travel Distance for Hospital Readmission and Survival
Nathan E Hale 1, Liam C Macleod 2, Jonathan G Yabes 3, Robert M Turner 2nd 4, Mina M Fam 5, Jeffrey R Gingrich 6, Ted A Skolarus 7, Tudor Borza 8, Lindsay M Sabik 9, Benjamin J Davies 4, Bruce L Jacobs 4
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PMID: 31543443 DOI: 10.1016/j.clgc.2019.08.005
Abstract
Background: Regionalization of complex surgical care results in increasing need for patients to travel for complex oncologic procedures such as cystectomy in bladder cancer. We examined the association between travel distance to a cystectomy center, readmission, and survival.

Patients and methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified bladder cancer patients undergoing radical cystectomy during 2004-2011. Patients were grouped into quartiles of distance to cystectomy center in miles (< 6 [close], 6-16.9 [moderately close], 17-47.9 [moderately far], ≥ 48 [far]). Multivariable logistic regression, accounting for clustering within hospitals, was used to assess the association between travel distance and readmission. A secondary analysis examined the association between travel distance and survival using multivariable proportional hazard regression.

Results: Among 4556 patients who underwent cystectomy, 1857 (41%) were readmitted, and 1251 (67%) of readmissions were to the index hospital. With increasing travel distance there was no significant difference in the overall rate of 90-day readmission. However, the farther a patient traveled, the lower the odds of being readmitted to the index hospital (adjusted odds ratio [95% confidence interval] as follows: moderately close, 0.43 miles [0.29-0.63]; moderately far, 0.14 miles [0.10-0.19]; and far, 0.07 [0.05-0.11]). Increasing travel distance was associated with improved survival.

Conclusion: With greater distance traveled to a cystectomy center, rates of readmission to nonindex centers increased. Survival differences may be explained by the impact of travel burden on processes of care and case mix. Future efforts should focus on improving care coordination between index and nonindex hospitals and ensuring equitable access to cystectomy and other critical cancer services.

Keywords: Bladder cancer; Health services research; Medicare; Regionalization; SEER Program.

Copyright © 2019 Elsevier Inc. All rights reserved.

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7
Oncologist
. 2019 Jul;24(7):e559-e564. doi: 10.1634/theoncologist.2018-0641. Epub 2019 Apr 23.
Outcome of Patients With Soft-Tissue Sarcomas: An Age-Specific Conditional Survival Analysis
Kevin Bourcier 1, Derek Dinart 2, Axel Le Cesne 3, Charles Honoré 4, Pierre Meeus 5, Jean-Yves Blay 6, Audrey Michot 7, François Le Loarer 8, Antoine Italiano 9 10
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PMID: 31015315 PMCID: PMC6656454 DOI: 10.1634/theoncologist.2018-0641
Free PMC article
Abstract
Background: Soft-tissue sarcomas (STSs) are a group of rare cancers that can occur at any age. Prognostic outcomes of patients with STS are usually established at the time of the patient's initial disease presentation. Conditional survival affords a dynamic prediction of prognosis for patients surviving a given period after diagnosis. Estimates of conditional survival can provide crucial prognostic information for patients and caregivers, guide subsequent cancer follow-up schedules, and impact decisions regarding management. This study aims to estimate conditional survival and prognostic factors in patients with STS according to age at diagnosis (≤75 years and ≥75 years).

Subjects, materials, and methods: A total of 6,043 patients with nonmetastatic STS at first diagnosis who underwent complete surgical resection (R0 or R1) were assessed. Cox proportional hazards regression was used to establish prognostic factors of conditional metastasis-free survival and overall survival at 1, 2, and 5 years after diagnosis.

Results: Elderly patients have more adverse prognostic features at presentation and tend to receive less aggressive treatment than do younger patients. However, at baseline as well as at each conditional survival time point, the 5-year estimated probability of metastatic relapse decreases in both young and elderly patients and is almost identical in both groups at 2 years and 5 years after initial diagnosis. Prognostic factors for metastatic relapse and death change as patient survival time increases in both young and elderly patients. Grade, the strongest prognostic factor for metastatic relapse and death at baseline, is no longer predictive of metastatic relapse in patients surviving 5 years after initial diagnosis. Leiomyosarcoma is the histological subtype associated with the highest risk of metastatic relapse and death in young patients surviving 5 years after initial diagnosis. The positive impact on the outcome of peri-operative treatments tends to decrease and disappears in patients surviving 5 years after initial diagnosis.

Conclusion: Conditional survival estimates show clinically relevant variations according to time since first diagnosis in both young and elderly patients with STS. These results can help STS survivors adjust their view of the future and STS care providers plan patient follow-up.

Implications for practice: For patients with sarcoma who are followed up years after being treated for their disease, a common scenario is for the patient and caregivers to ask practitioners what the longer-term prognosis may be. The question posed to practitioners may be, "Doc, am I now cured? It's been 5 years since we finished treatment." Survival probability changes for patients who survive a given period of time after diagnosis, and their prognosis is more accurately described using conditional survival. By analyzing more than 6,000 sarcoma patients, an overall improvement was found in the risk of relapse as patients conditionally survive. Prognostic factors for metastatic relapse and death change as patient survival time increases in both young and elderly patients.

Keywords: Conditional survival; Elderly; Prognosis; Sarcoma.

© AlphaMed Press 2019.

Conflict of interest statement
Disclosures of potential conflicts of interest may be found at the end of this article.

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8
Biochem Biophys Res Commun
. 2019 Nov 12;519(3):597-604. doi: 10.1016/j.bbrc.2019.08.163. Epub 2019 Sep 17.
Sequential Combination of Bortezomib and WEE1 Inhibitor, MK-1775, Induced Apoptosis in Multiple Myeloma Cell Lines
Rebecca S S Barbosa 1, Paola M Dantonio 1, Taís Guimarães 1, Mariana B de Oliveira 1, Veruska L Fook Alves 1, Alex Freire Sandes 1, Rodrigo Carlini Fernando 1, Gisele W B Colleoni 2
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PMID: 31540690 DOI: 10.1016/j.bbrc.2019.08.163
Abstract
Introduction: Multiple myeloma (MM) remains incurable due to high rates of relapse after various treatment regimens. WEE1 is a cell cycle related gene that regulates the G2/M checkpoint and promotes cell cycle suspension for consequent DNA repair. To date, there are clinical studies for the evaluation of WEE1 inhibitors in the treatment of solid tumors and studies on cell lines of non-MM hematological tumors.

Objectives: To perform in vitro functional studies to verify the effect of the inhibition of WEE1 on MM cell lines viability and its potential as therapeutic target.

Material and methods: WEE1 expression was evaluated in 22 newly diagnosed MM patients and in four MM cell lines, RPMI-8226, U266 and SKO-007 and SK-MM2, by quantitative real-time PCR (qPCR). After treatment with the WEE1 inhibitor (MK-1775), with or without proteasome inhibitor (bortezomib) pretreatment, we assessed cell viability through Prestoblue functional test, microspheres formation in soft agar, and induction of apoptosis and cell cycle alterations by flow cytometry.

Results: All MM cell lines showed WEE1 expression by qPCR. RPMI-8226 and U266 showed a 50% reduction in cell viability after 24 h of incubation with MK-1775, at concentrations of 5 μM and 20 μM, respectively. SKO-007 showed dose and time dependence to this drug. Combination therapy with bortezomib and MK-1775 abolished the formation of soft agar microspheres in the RPMI-8226 cell line (also responsive to the use of both drugs) and U266, but SKO-007 was resistant to all drugs, isolated and combined. However, treatment of bortezomib followed by MK-1775 (sequential treatment) versus bortezomib alone showed statistically significant impact on cell lines total apoptosis: 88.8% vs 74.1% in RPMI-8222 (confirmed by cell cycle experiments); 92.5% vs 86.6% in U266; and 60.2% 30.9% on SKO-007 (p < 0.05).

Conclusion: The sequential combination of bortezomib and WEE1 inhibitor, MK-1775, induced apoptosis in RPMI-8226, U266, and especially SKO-007 cell lines, more efficiently than the use of the same isolated drugs, highlighting its effect in inhibition of proliferation of tumor cells in MM cell lines. Our data suggest that WEE1 can figure as a MM target and that the sequential combination of bortezomib and MK-1775 may be explored in future clinical trials.

Keywords: MK-1775; Myeloma; WEE1.

Copyright © 2019 Elsevier Inc. All rights reserved.

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9
Neuro Oncol
. 2019 Nov 4;21(11):1470-1479. doi: 10.1093/neuonc/noz130.
Cognitive and Brain Structural Changes in Long-Term Oligodendroglial Tumor Survivors
Nuria Cayuela 1, Esteban Jaramillo-Jiménez 2, Estela Càmara 3, Carles Majós 1, Noemi Vidal 1, Anna Lucas 1, Miguel Gil-Gil 1, Francesc Graus 4, Jordi Bruna 1 5, Marta Simó 1 3
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PMID: 31549152 PMCID: PMC6827827 (available on 2020-11-04) DOI: 10.1093/neuonc/noz130
Free PMC article
Abstract
Background: We identify cognitive impairment and MRI structural brain changes in long-term oligodendroglial tumor survivors treated with radiation therapy (RT) alone (21%) or with chemotherapy (CT) (79%).

Methods: Oligodendroglial tumor patients (based on the World Health Organization [WHO] 2007 classification) who completed RT ± CT at least 2 years before the study initiation, were classified into 3 groups according to the time treatment was completed: Group 1 = 2-5 years (n = 22), Group 2 = 6-10 years (n = 13), and Group 3 >10 years (n = 13). All patients had a cross-sectional neuropsychological evaluation (n = 48) and a longitudinal volumetric analysis (gray matter [GM; n = 34]) between postsurgical and last follow-up MRI. White matter (WM) changes on MRI were assessed using a qualitative scale.

Results: There were no differences regarding tumor or treatment-related characteristics between groups. Six of 22 patients (27.3%) in Group 1; 5/13 (38.5%) in Group 2; and 9/13 (69.2%) in Group 3 had cognitive impairment that was considered severe in 3/22 patients (13.6%) in Group 1; 4/13 (30.8%) in Group 2; and 6/13 (46.2%) in Group 3. Patients in Groups 2 and 3 showed significant GM atrophy and more leukoencephalopathy than Group 1. Cognitive deficits were associated with brain atrophy and WM changes.

Conclusions: Long-term oligodendroglial tumor survivors who underwent standard RT ± CT treatment, mainly >5 years of its completion, present cognitive impairment, especially on memory and executive functions, associated with late GM and WM damage, thus highlighting the need of developing future strategies in patients with oligodendroglial tumor and long expected survival.

Keywords: cognition; long-term survivors; neurotoxicity; oligodendroglioma; radiotherapy.

© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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10
J Nucl Med
. 2019 Dec;60(12):1825-1832. doi: 10.2967/jnumed.118.224568. Epub 2019 May 30.
89 Zr-Immuno-PET: Toward a Noninvasive Clinical Tool to Measure Target Engagement of Therapeutic Antibodies In Vivo
Yvonne W S Jauw 1 2, Joseph A O'Donoghue 3, Josée M Zijlstra 4, Otto S Hoekstra 2, C Willemien Menke-van der Houven van Oordt 5, Franck Morschhauser 6, Jorge A Carrasquillo 7 8, Sonja Zweegman 4, Neeta Pandit-Taskar 7 8, Adriaan A Lammertsma 2, Guus A M S van Dongen 2, Ronald Boellaard 2, Wolfgang A Weber 7 8, Marc C Huisman 2
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PMID: 31147401 DOI: 10.2967/jnumed.118.224568
Abstract
89Zr-immuno-PET is a promising noninvasive clinical tool that measures target engagement of monoclonal antibodies (mAbs) to predict toxicity in normal tissues and efficacy in tumors. Quantification of 89Zr-immuno-PET will need to move beyond SUVs, since total uptake may contain a significant non-target-specific contribution. Nonspecific uptake is reversible (e.g., blood volume) or irreversible (due to 89Zr-residualization after mAb degradation). The aim of this study was to assess nonspecific uptake in normal tissues as a first critical step toward quantification of target engagement in normal tissues and tumors using 89Zr-immuno-PET. Methods: Data from clinical studies with 4 89Zr-labeled intact IgG1 antibodies were collected, resulting in a total of 128 PET scans (1-7 d after injection from 36 patients: 89Zr-obinutuzumab [n = 9], 89Zr-cetuximab [n = 7], 89Zr-huJ591 [n = 10], and 89Zr-trastuzumab [n = 10] [denoted as 89Zr-anti-CD20, 89Zr-anti-EGFR, 89Zr-anti-PSMA and 89Zr-anti-HER2, respectively]). Nonspecific uptake was defined as uptake measured in tissues without known target expression. Patlak graphical evaluation of transfer constants was used to estimate the reversible (V t ) and irreversible (K i ) contributions to the total measured uptake for the kidney, liver, lung, and spleen. Baseline values were calculated per tissue combining all mAbs without target expression (kidney: 89Zr-anti-CD20, 89Zr-anti-EGFR, and 89Zr-anti-HER2; liver: 89Zr-anti-CD20; lung: 89Zr-anti-CD20, 89Zr-anti-EGFR, and 89Zr-anti-PSMA; spleen: 89Zr-anti-EGFR and 89Zr-anti-HER2). Results: For the kidney, liver, lung, and spleen, baseline V t was 0.20, 0.24, 0.09, and 0.24 mL⋅cm-3, respectively, and baseline K i was 0.7, 1.1, 0.2 and 0.5 μL⋅g-1⋅h-1, respectively. For 89Zr-anti-PSMA, a 4-fold higher K i was observed for the kidney, indicating target engagement. In this case, nonspecific uptake accounted for 66%, 34%, and 22% of the total signal in the kidney at 1, 3, and 7 d after injection, respectively. Conclusion: This study shows that nonspecific uptake of mAbs for tissues without target expression can be quantified using 89Zr-immuno-PET at multiple time points. These results form a crucial base for measurement of target engagement by therapeutic antibodies in vivo with 89Zr-immuno-PET. For future studies, a pilot phase including at least 3 scans at 1 or more days after injection is required to assess nonspecific uptake as a function of time, to optimize study design for detection of target engagement.

Keywords: 89Zr; immuno-PET; molecular imaging; monoclonal antibodies; positron emission tomography.

© 2019 by the Society of Nuclear Medicine and Molecular Imaging.

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11
Stem Cells Dev
. 2019 Nov 1;28(21):1424-1433. doi: 10.1089/scd.2019.0049. Epub 2019 Oct 7.
Characterization of Adult Canine Kidney Epithelial Stem Cells That Give Rise to Dome-Forming Tubular Cells
Te-Chuan Chen 1, Manish Neupane 2, Shao-Ju Chien 3, Feng-Rong Chuang 1, Robert B Crawford 4, Norbert E Kaminski 4, Chia-Cheng Chang 5
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PMID: 31495275 DOI: 10.1089/scd.2019.0049
Abstract
Dome formation can occur in cultured tubular epithelial cells originating from various tissues, including the mammary gland and the kidney. The isolation and characterization of normal kidney epithelial stem cells that give rise to dome-forming tubular cells have never been reported. We attempted to isolate and characterize canine kidney epithelial stem cells using a simple cell culture method that we have previously used to isolate other adult human stem cells. Dome-forming kidney epithelial cells were derived from dissociated adult canine kidney tissues that were cultured in a modified keratinocyte serum-free medium supplemented with N-acetyl-l-cysteine, l-ascorbic acid 2-phosphate, nicotinamide, and fetal bovine serum. These cells exhibited high self-renewal capacity in long-term culture (growth for >13 months and 30 cumulative population doublings) and exhibited characteristics of stem cells, including (1) deficiency in gap junctional intercellular communication, (2) anchorage-independent growth, (3) expression of stem cell markers octamer-binding transcription factor 4 and SRY (sex determining region Y)-box 2, (4) expression of cell surface markers CD24 and CD133, and (5) multipotent differentiation into osteoblasts, adipocytes, chondrocytes, and dome-forming tubular cells. Most of these characteristics are shared by the well-known canine renal tubule-derived immortalized Madin-Darby Canine Kidney cell line. Furthermore, the putative canine kidney stem cells developed in this study formed budding tubule-like organoids on Matrigel and required high cell density (>4,000 cells/cm2) for sustained growth and confluency for dome formation. The signal transducer and activator of transcription-3 (STAT3) phosphorylation inhibitor, AG490, inhibited colony-forming efficiency and dome formation, whereas lipopolysaccharide, an activator of STAT3, increased colony-forming efficiency in a dose-dependent manner. These results are consistent with the hypothesis that high cell density induces STAT3 expression, which promotes both stem cell self-renewal and differentiation into tubular cells. Our novel cell culture method should be useful for the future development of normal human kidney stem cells for clinical applications and for studying mechanisms of nephrotoxicity.

Keywords: STAT3; dome-forming tubular cells; kidney multipotent stem cells.

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12
Review Open Biol
. 2019 Nov 29;9(11):190187. doi: 10.1098/rsob.190187. Epub 2019 Nov 6.
Notch Signalling in T Cell Homeostasis and Differentiation
Joshua D Brandstadter 1, Ivan Maillard 1
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PMID: 31690218 PMCID: PMC6893402 DOI: 10.1098/rsob.190187
Free PMC article
Abstract
The evolutionarily conserved Notch signalling pathway regulates the differentiation and function of mature T lymphocytes with major context-dependent consequences in host defence, autoimmunity and alloimmunity. The emerging effects of Notch signalling in T cell responses build upon a more established role for Notch in T cell development. Here, we provide a critical review of this burgeoning literature to make sense of what has been learned so far and highlight the experimental strategies that have been most useful in gleaning physiologically relevant information. We outline the functional consequences of Notch signalling in mature T cells in addition to key specific Notch ligand-receptor interactions and downstream molecular signalling pathways. Our goal is to help clarify future directions for this expanding body of work and the best approaches to answer important open questions.

Keywords: Notch; T cell; alloimmunity; autoimmunity; infection; transplantation.

Conflict of interest statement
The authors have no competing interests to declare.

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13
Ter Arkh
. 2019 Jul 15;91(7):83-92. doi: 10.26442/00403660.2019.07.000305.
[Epidemiology of Multiple Myeloma in City Moscow]
[Article in Russian]
O Y Vinogradova 1 2 3, V V Ptushkin 1 2 3, M V Chernikov 4, Y B Kochkareva 1, V A Zherebtsova 1
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PMID: 32598740 DOI: 10.26442/00403660.2019.07.000305
Abstract in English , Russian
Aim: To study the epidemiology of multiple myeloma in the city of Moscow and compare the results obtained with data from similar studies in other countries.

Materials and methods: The study is based on information from a database of case histories of 3942 patients suffering from symptomatic MM, residents of the city of Moscow, which is maintained at the Hematologic Moscow City Center of S.P. Botkin Municipal Clinical Hospital. The control of the completeness of inclusion was carried out by cross - comparison with the data of the Moscow Cancer Register and the Register of Program 7 (beginning in 2019 - 12) of Highly Expensive Nosologies. The assessment was made according to data as of January 1, 2019. The calculations were carried out taking into account the data of Rosstat at the beginning of 2019 on the population of Moscow in different gender and age categories.

Results: Among the 3942 patients with active MM 1707 men - 43% and 2241 women - 57%, the median of the current age was 68 (28-94) years. The median time of observation of patients since the diagnosis of the disease 34 (1-423) months. The peak incidence was in the age range of more than 60 years. There were no significant differences in gender ratio in different age strata with a breakdown of 10 years. The number of cases of newly diagnosed MM per year for the period from 2009 (n=219) to 2018 (n=385) increased by 75.8%. At the same time, the demonstrated increase in the incidence rate for the described period turned out to be fair only for groups of patients over 50 years old, with the maximum increase in this indicator over the described period in the age range of 60-69 years. This is mainly due to the increase in life expectancy in Moscow in recent years. The study demonstrated that over the past 10 years, the average annual mortality rate from MM has decreased in Moscow, and as a result, its prevalence has increased. The rate of 2-year overall survival of patients with MM was 76%, 5-year - old - 49%, 10-year - old - 27%. The median overall survival of patients under the age of 65 when diagnosing the disease was 79 months, and 48 months. The distribution of patients within international classifications was consistent with international data.

Conclusions: The study revealed a significant dynamic of the epidemiological situation concerning MM in Moscow. Over the past 10 years there has been an increase in the incidence of MM, as a result of an increase in the life expectancy of the population. The use of modern diagnostics and therapy of MM in real clinical practice has led to a significant reduction in mortality. Due to these factors, an increase in the prevalence of MM in Moscow has taken place, and this process will no doubt progress in the future.

Keywords: epidemiology; incidence; multiple myeloma; prevalence; survival.

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14
Review Adv Drug Deliv Rev
. 2020 Jun 25;S0169-409X(20)30068-5. doi: 10.1016/j.addr.2020.06.022. Online ahead of print.
Recent Advancements in Liposome Technology
Nina Filipczak 1, Jiayi Pan 1, Satya Siva Kishan Yalamarty 1, Vladimir P Torchilin 2
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PMID: 32593642 DOI: 10.1016/j.addr.2020.06.022
Abstract
The liposomes have continued to be well-recognized as an important nano-sized drug delivery system with attractive properties, such a characteristic bilayer structure assembling the cellular membrane, easy-to-prepare and high bio-compatibility. Extensive effort has been devoted to the development of liposome-based drug delivery systems during the past few decades. Many drug candidates have been encapsulated in liposomes and investigated for reduced toxicity and extended duration of therapeutic effect. The liposomal encapsulation of hydrophilic and hydrophobic small molecule therapeutics as well as other large molecule biologics have been established among different academic and industrial research groups. To date, there has been an increasing number of FDA-approved liposomal-based therapeutics together with more and more undergoing clinical trials, which involve a wide range of applications in anticancer, antibacterial, and antiviral therapies. In order to meet the continuing demand for new drugs in clinics, more recent advancements have been investigated for optimizing liposomal-based drug delivery system with more reproducible preparation technique and a broadened application to novel modalities, including nucleic acid therapies, CRISPR/Cas9 therapies and immunotherapies. This review focuses on the recent liposome' preparation techniques, the excipients of liposomal formulations used in various novel studies and the routes of administration used to deliver liposomes to targeted areas of disease. It aims to update the research in liposomal delivery and highlights future nanotechnological approaches.

Keywords: Cancer immunotherapy; Liposomes; Microfluidics; Nucleic acid therapies; Recent advancement; Routes of administration.

Copyright © 2020. Published by Elsevier B.V.

Conflict of interest statement
Declaration of Competing Interest The authors declare no conflict of interest.

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15
Lab Invest
. 2019 Oct;99(10):1484-1500. doi: 10.1038/s41374-019-0270-5. Epub 2019 Jun 14.
miR-26a Promotes Hepatocellular Carcinoma Invasion and Metastasis by Inhibiting PTEN and Inhibits Cell Growth by Repressing EZH2
Wen-Tao Zhao 1 2 3, Xiao-Lin Lin 1, Yu Liu 4, Liu-Xin Han 5, Jing Li 1, Tao-Yan Lin 1, Jun-Wen Shi 1, Sheng-Chun Wang 1, Mei Lian 4, Heng-Wei Chen 4, Yan Sun 6, Kang Xu 7 8, Jun-Shuang Jia 9, Rong-Cheng Luo 10 11, Dong Xiao 12 13
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PMID: 31201367 DOI: 10.1038/s41374-019-0270-5
Abstract
A previous study revealed that therapeutic miR-26a delivery suppresses tumorigenesis in a murine liver cancer model, whereas we found that forced miR-26a expression increased hepatocellular carcinoma (HCC) cell migration and invasion, which prompted us to characterize the causes and mechanisms underlying enhanced invasion due to ectopic miR-26a expression. Gain-of-function and loss-of-function experiments demonstrated that miR-26a promoted migration and invasion of BEL-7402 and HepG2 cells in vitro and positively modulated matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, and MMP-10 expression. In addition, exogenous miR-26a expression significantly enhanced the metastatic ability of HepG2 cells in vivo. miR-26a negatively regulated in vitro proliferation of HCC cells, and miR-26a overexpression suppressed HepG2 cell tumor growth in nude mice. Further studies revealed that miR-26a inhibited cell growth by repressing the methyltransferase EZH2 and promoted cell migration and invasion by inhibiting the phosphatase PTEN. Furthermore, PTEN expression negatively correlated with miR-26a expression in HCC specimens from patients with and without metastasis. Thus, our findings suggest for the first time that miR-26a promotes invasion/metastasis by inhibiting PTEN and inhibits cell proliferation by repressing EZH2 in HCC. More importantly, our data also suggest caution if miR-26a is used as a target for cancer therapy in the future.

Cited by 4 articles
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16
Clin Oncol (R Coll Radiol)
. 2020 Jun 26;S0936-6555(20)30237-5. doi: 10.1016/j.clon.2020.06.003. Online ahead of print.
Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in the Treatment of Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer With Central Nervous System Metastases for Patients Currently or Previously Treated With Trastuzumab (LANTERN): A Phase II Randomised Trial
J F Seligmann 1, A Wright-Hughes 1, A Pottinger 1, G Velikova 2, J B Oughton 1, G Murden 1, M Rizwanullah 3, C Price 4, H Passant 5, P Heudtlass 1, H Marshall 1, S Johnston 6, D Dodwell 7
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PMID: 32600919 DOI: 10.1016/j.clon.2020.06.003
Abstract
Aims: Brain (central nervous system; CNS) metastases occur in 30-50% of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). A substantive evidence base for treatment is lacking, but activity with lapatinib plus capecitabine (lap-cap) has been reported. We compared lap-cap with trastuzumab plus capecitabine (tras-cap) in patients with HER2-positive MBC with CNS metastases previously treated with trastuzumab.

Materials and methods: This open-label randomised phase II screening trial aimed to randomise 130 participants over 2 years to receive lap-cap or tras-cap. Eligible patients had HER2-positive MBC with newly diagnosed or recently progressed CNS metastases; previous, or current, treatment included: trastuzumab, a taxane or anthracycline and recent completion of local cranial therapy. The primary end point was time to progression of CNS metastases within the 24-week trial period. Secondary objectives included CNS response rate, progression-free survival, steroid use for CNS symptoms and feasibility of recruitment to a large phase III trial.

Results: Between September 2011 and October 2013, 30 participants were randomised, 16 to lap-cap and 14 to tras-cap. Recruitment to a large phase III trial was determined not to be feasible. At 24 weeks, CNS disease progression was 41.8% (95% confidence interval 16.1-67.5%) in lap-cap and 41.2% (95% confidence interval 12.8-69.6%) in tras-cap arms; progression-free survival was 44.4% (95% confidence interval 18.1-70.8%) in lap-cap and 50.0% (95% confidence interval 20.9-79.1%) in tras-cap arms.

Conclusion: Poor recruitment confirmed that a larger phase III trial would not be feasible and prohibited a preliminary evaluation of the superiority of lap-cap over tras-cap. Descriptive statistics are presented to inform the limited evidence base and future study design.

Keywords: Brain metastases; HER2; breast cancer; lapatinib; radiotherapy; trastuzumab.

Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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17
Review Pharmacol Res
. 2020 Jul;157:104859. doi: 10.1016/j.phrs.2020.104859. Epub 2020 Apr 29.
Candidate Drugs Against SARS-CoV-2 and COVID-19
Dwight L McKee 1, Ariane Sternberg 2, Ulrike Stange 2, Stefan Laufer 3, Cord Naujokat 4
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PMID: 32360480 PMCID: PMC7189851 DOI: 10.1016/j.phrs.2020.104859
Free PMC article
Abstract
Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may limit spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.

Keywords: Arbidol; COVID-19; Camostat; Chloroquine; Drugs; Favipiravir; Lopinavir; Phytochemicals; Remdesivir; Ritonavir; SARS-CoV-2.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Conflict of interest statement
Declaration of Competing Interest None.

Cited by 4 articles144 references2 figures
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18
Cancer Immunol Immunother
. 2020 Jul;69(7):1253-1263. doi: 10.1007/s00262-019-02465-y. Epub 2020 Mar 13.
Differential Expression of Tim-3, PD-1, and CCR5 on Peripheral T and B Lymphocytes in Hepatitis C Virus-Related Hepatocellular Carcinoma and Their Impact on Treatment Outcomes
Asmaa M Zahran 1, Helal F Hetta 2 3, Amal Rayan 4, Abeer Sharaf Eldin 5, Elham Ahmed Hassan 5, Hussein Fakhry 6, Ahmed Soliman 7, Omnia El-Badawy 8
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PMID: 32170378 DOI: 10.1007/s00262-019-02465-y
Abstract
Background and objective: Activation of the immune checkpoints and expression of chemokines and chemokine receptors have been reported to promote HCC progression. This study aimed to assess the differential expression of Tim-3, PD-1, and CCR5 on peripheral blood lymphocytes from patients with HCV-related HCC and correlate their expression with the treatment outcomes.

Patients and methods: The study incorporated 40 patients with chronic HCV-related HCC and 40 healthy controls. Patients were radiologically assessed for hepatic focal lesions and portal vein thrombosis. Response to HCC treatment and overall survival (OS) outcomes were determined. The expression of Tim-3, PD-1, and CCR5 among CD19+, CD4+, and CD8+ lymphocytes was assessed by flow cytometry.

Results: Higher frequencies of CD4+ and CD8+ cells expressing each of Tim-3 and PD-1 and PD-1+CD19+ cells were observed in the HCV-related HCC patients in comparison with controls. The highest expression of Tim-3 and PD-1 was by the CD8+ cells. Strong relations were detected among PD-1+CD19+, PD-1+CD4+ and PD-1+CD8+ cells. Elevated levels of PD-1+ lymphocytes were significantly associated with poor treatment response and shorter OS.

Conclusion: Modulation of the expression of immune checkpoints as Tim-3 and PD-1, and of CCR5 on T cells is somehow related to HCC. CD8+ T cells expressing PD-1 were the most relevant to HCC prognosis (OS and treatment response) and could represent a promising target for immune therapy against HCC. Future studies need to focus on exploring PD-1+ B cells and Tim-3+CD4+ cells, which seem to play a significant role in the pathogenesis of HCC.

Keywords: CCR5; HCC; HCV; PD-1; Survival; Tim-3.

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19
Observational Study Cancer Med
. 2019 May;8(5):2196-2204. doi: 10.1002/cam4.2126. Epub 2019 Apr 1.
Survival After Radiotherapy Versus Radical Cystectomy for Primary Muscle-Invasive Bladder Cancer: A Swedish Nationwide Population-Based Cohort Study
Christel Häggström 1 2, Hans Garmo 3 4, Xavier de Luna 5, Mieke Van Hemelrijck 3 6, Karin Söderkvist 7, Firas Aljabery 8, Viveka Ströck 9, Abolfazl Hosseini 10, Truls Gårdmark 11, Per-Uno Malmström 1, Staffan Jahnson 8, Fredrik Liedberg 12 13, Lars Holmberg 1 3
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PMID: 30938068 PMCID: PMC6536982 DOI: 10.1002/cam4.2126
Free PMC article
Abstract
Background: Studies of survival comparing radical cystectomy (RC) and radiotherapy for muscle-invasive bladder cancer have provided inconsistent results and have methodological limitations. The aim of the study was to investigate risk of death after radiotherapy as compared to RC.

Methods: We selected patients with muscle-invasive urothelial carcinoma without distant metastases, treated with radiotherapy or RC from 1997 to 2014 in the Bladder Cancer Data Base Sweden (BladderBaSe) and estimated absolute and relative risk of bladder cancer death and all-cause death. In a group of patients, theoretically eligible for a trial comparing radiotherapy and RC, we calculated risk difference in an instrumental variable analysis. We have not investigated chemoradiotherapy as this treatment was not used in the study time period.

Results: The study included 3 309 patients, of those 17% were treated with radiotherapy and 83% with RC. Patients treated with radiotherapy were older, had more advanced comorbidity, and had a higher risk of death as compared to patients treated with RC (relative risks of 1.5-1.6). In the "trial population," all-cause death risk difference was 6 per 100 patients lower after radiotherapy at 5 years of follow-up, 95% confidence interval -41 to 29.

Conclusion(s): Patient selection between the treatments make it difficult to evaluate results from conventionally adjusted and propensity-score matched survival analysis. When taking into account unmeasured confounding by instrumental variable analysis, no differences in survival was found between the treatments for a selected group of patients. Further clinical studies are needed to characterize this group of patients, which can serve as a basis for future comparison studies for treatment recommendations.

Keywords: bladder cancer; muscle-invasive; radical cystectomy; radiotherapy; urothelial carcinoma.

© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Conflict of interest statement
None declared.

33 references2 figures
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20
Randomized Controlled Trial J Thorac Oncol
. 2019 May;14(5):933-939. doi: 10.1016/j.jtho.2019.02.001. Epub 2019 Feb 11.
Osimertinib Plus Durvalumab Versus Osimertinib Monotherapy in EGFR T790M-Positive NSCLC Following Previous EGFR TKI Therapy: CAURAL Brief Report
James Chih-Hsin Yang 1, Frances A Shepherd 2, Dong-Wan Kim 3, Gyeong-Won Lee 4, Jong Seok Lee 5, Gee-Chen Chang 6, Sung Sook Lee 7, Yu-Feng Wei 8, Yun Gyoo Lee 9, Gianluca Laus 10, Barbara Collins 10, Francesca Pisetzky 11, Leora Horn 12
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PMID: 30763730 DOI: 10.1016/j.jtho.2019.02.001
Abstract
Introduction: Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti-programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) investigated osimertinib plus durvalumab versus osimertinib monotherapy in patients with EGFR-TKI sensitizing and EGFR T790M mutation-positive advanced NSCLC and disease progression after EGFR-TKI therapy.

Methods: Patients were randomly assigned 1:1 to receive orally administered osimertinib (80 mg once daily) with or without durvalumab (10 mg/kg administered intravenously every 2 weeks) until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by the investigator). The amended primary objective was to assess the safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective.

Results: CAURAL recruitment was terminated early because of increased incidence of interstitial lung disease-like events in the osimertinib plus durvalumab arm from the separate phase Ib TATTON trial (NCT02143466). At termination of CAURAL recruitment, 15 patients had been randomly assigned to treatment with osimertinib and 14 to treatment with osimertinib plus durvalumab. The most common AEs were diarrhea (53% [grade ≥3 in 6% of patients]) in the osimertinib arm and rash (67% [grade ≥3 in 0 patients]) in the combination arm. One patient who had been randomized to the combination arm reported grade 2 interstitial lung disease while receiving osimertinib monotherapy (after discontinuing durvalumab therapy after one dose). The objective response rates were 80% in the osimertinib arm and 64% in the combination arm.

Conclusion: Limited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of programmed cell death 1/programmed death ligand 1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but it requires a careful approach if considered in the future.

Keywords: Combination; Durvalumab; EGFR; Non–small cell lung cancer; Osimertinib.

Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Comment in
Combination of Osimertinib with Durvalumab in Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer: Is There Room for Reinvestigation?
Ahn MJ.
J Thorac Oncol. 2019 May;14(5):766-767. doi: 10.1016/j.jtho.2019.03.005.
PMID: 31027741 No abstract available.
Cited by 13 articles
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21
Review Crit Rev Oncol Hematol
. 2020 Jul;151:102977. doi: 10.1016/j.critrevonc.2020.102977. Epub 2020 May 12.
Current Concepts and Future Directions for Hemato-Oncologic Diagnostics
Johanna Flach 1, Evgenii Shumilov 2, Raphael Joncourt 3, Naomi Porret 3, Urban Novak 4, Thomas Pabst 4, Ulrike Bacher 5
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PMID: 32446181 DOI: 10.1016/j.critrevonc.2020.102977
Abstract
At present, hemato-oncologic diagnostics is facing dynamic changes. This applies to the exploration and introduction of novel technologies such as next-generation sequencing or digital droplet PCR for myeloid and lymphatic malignancies in laboratory routine, or liquid biopsy for patients with lymphoid malignancies. Targeted therapies such as FLT3 or IDH1/IDH2 inhibitors for acute myeloid leukemia are entering clinical practice. Thus, the demand for hematologic precision diagnostics both at initial diagnosis and during the course of the disease are equally increasing, and a short turn-around time becomes crucial. NGS expands the armamentarium for minimal residual disease diagnostics, but novel questions arise relating to sensitivity, the appropriate time points of this analysis, or the thresholds triggering therapeutic interventions. In this review article, we summarize some of the most relevant current changes and subsequent challenges for diagnostics in various myeloid and lymphatic malignancies. Future directions of hemato-oncologic diagnostics in the next 5-10 years are highlighted.

Keywords: Acute lymphatic leukemia (ALL); Acute myeloid leukemia (AML); Hemato-oncologic diagnostics; Liquid biopsy; Lymphomas; Multiple myeloma; Next-generation sequencing (NGS); Novel technologies.

Copyright © 2020 Elsevier B.V. All rights reserved.

Conflict of interest statement
Declaration of Competing Interest The authors declare no potential conflicts of interest.

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22
Review Cancer Lett
. 2020 Jan 28;469:142-150. doi: 10.1016/j.canlet.2019.10.036. Epub 2019 Oct 25.
PD-1 and PD-L1 Inhibitors in Oesophago-Gastric Cancers
Tugba Akin Telli 1, Giacomo Bregni 1, Silvia Camera 1, Amelie Deleporte 1, Alain Hendlisz 1, Francesco Sclafani 2
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PMID: 31669518 DOI: 10.1016/j.canlet.2019.10.036
Abstract
Oesophago-gastric cancers (OGCs) are aggressive tumours. While better peri-operative strategies, increased number of cytotoxic agents and availability of targeted therapies have improved survival, there remains an unmet need for novel treatment approaches. Immune checkpoint inhibitors (ICIs) have marked a new era in cancer management with unprecedented results in several malignancies. Although OGC lagged behind other solid tumours, evidence has increasingly accumulated supporting the contention that modulation of the anti-cancer host immune response may be beneficial for at least some patients. Many trials have been completed in Eastern and Western countries, some of these leading to the approval of ICIs in the refractory setting, and favorable opinion from regulatory agencies is expected also in treatment-naïve, advanced OGC. Furthermore, studies are evaluating ICIs in the early stage setting and exploring the potential of combination treatments. In this article we discuss the biological bases underlying the successful development of ICIs in OGC and review the available data on PD-1 and PD-L1 monoclonal antibodies in this disease. Also, we present ongoing clinical trials of these ICIs that could shape the future treatment landscape of OGC.

Keywords: Immune checkpoint inhibitors; Immunotherapy; Oesophageal-gastric cancer; PD-1; PD-L1.

Copyright © 2019 Elsevier B.V. All rights reserved.

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23
J Cancer Educ
. 2019 Oct;34(5):1010-1013. doi: 10.1007/s13187-018-1404-y.
Twenty-five-Year Follow-up of Short-term Cancer Research Trainees at the University of Alabama at Birmingham: A Brief Report
Renee A Desmond 1, Raam Venkatesh 2, Luz A Padilla 3, Casey L Daniel 4, Allison G Litton 3, Douglas C Heimburger 5, C Michael Brooks 6, John W Waterbor 7
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PMID: 30043388 DOI: 10.1007/s13187-018-1404-y
Abstract
Long-term follow-up is needed to evaluate the impact of short-term cancer research programs on the career trajectories of medical and graduate students. Participation in these programs may be crucial in fostering the next generation of cancer research scientists. This report presents the career outcomes and research productivity of 77 medical and public health students with 25 years of tracking data following their participation in a summer cancer research training program at the University of Alabama at Birmingham (UAB) in 1990-1998. Of 64 summer trainees with contact information, complete survey responses were received from 55 (86.0%) individuals. Over half reported clinical care of cancer patients and 18.2% stated that they were engaged in cancer research. Literature searches confirmed that 23.4% (18/77) of trainees have published cancer research papers. Future studies should explore the optimal timing of short-term post-baccalaureate academic cancer training experiences to identify participant characteristics and institutional factors that influence career choices and determine research productivity.

Keywords: Cancer training; Longitudinal tracking; Summer research programs.

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24
J Med Imaging Radiat Sci
. 2019 Mar;50(1):119-128. doi: 10.1016/j.jmir.2018.09.003. Epub 2018 Nov 13.
The Feasibility of Integrating Resting-State fMRI Networks Into Radiotherapy Treatment Planning
Chandler Sours Rhodes 1, Hao Zhang 2, Kruti Patel 3, Nilesh Mistry 4, Young Kwok 2, Warren D D'Souza 2, William F Regine 2, Rao P Gullapalli 5
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PMID: 30777232 DOI: 10.1016/j.jmir.2018.09.003
Abstract
Background: Functional magnetic resonance imaging (fMRI) presents the ability to selectively protect functionally significant regions of the brain when primary brain tumors are treated with radiation therapy. Previous research has focused on task-based fMRI of language and sensory networks; however, there has been limited investigation on the inclusion of resting-state fMRI into the design of radiation treatment plans.

Methods and materials: In this pilot study of 9 patients with primary brain tumors, functional data from the default mode network (DMN), a network supporting cognitive functioning, was obtained from resting-state fMRI and retrospectively incorporated into the design of radiation treatment plans. We compared the dosimetry of these fMRI DMN avoidance treatment plans with standard of care treatment plans to demonstrate feasibility. In addition, we used normal tissue complication probability models to estimate the relative benefit of fMRI DMN avoidance treatment plans over standard of care treatment plans in potentially reducing memory loss, a surrogate for cognitive function.

Results: On average, we achieved 20% (P = 0.002) and 12% (P = 0.002) reductions in the mean and maximum doses, respectively, to the DMN without compromising the dose coverage to the planning tumor volume or the dose-volume constraints to organs at risk. Normal tissue complication probability models revealed that when the fMRI DMN was considered during radiation treatment planning, the probability of developing memory loss was lowered by more than 20%.

Conclusion: In this pilot study, we demonstrated the feasibility of including rs-MRI data into the design of radiation treatment plans to spare cognitively relevant brain regions during radiation therapy. These results lay the groundwork for future clinical trials that incorporate such treatment planning methods to investigate the long-term behavioral impact of this reduction in dose to the cognitive areas and their neural networks that support cognitive performance.

Keywords: Radiation therapy treatment plan; default mode network; resting-state fMRI.

Copyright © 2018. Published by Elsevier Inc.

Cited by 1 article
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25
Review Front Oncol
. 2020 Jun 12;10:930. doi: 10.3389/fonc.2020.00930. eCollection 2020.
Quality of Life, Toxicity and Unmet Needs in Nasopharyngeal Cancer Survivors
Lachlan McDowell 1 2, June Corry 3 4, Jolie Ringash 5, Danny Rischin 2 6
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PMID: 32596155 PMCID: PMC7303258 DOI: 10.3389/fonc.2020.00930
Free PMC article
Abstract
Concerted research efforts over the last three decades have resulted in improved survival and outcomes for patients diagnosed with nasopharyngeal carcinoma (NPC). The evolution of radiotherapy techniques has facilitated improved dose delivery to target volumes while reducing dose to the surrounding normal tissue, improving both disease control and quality of life (QoL). In parallel, clinical trials focusing on determining the optimal systemic therapy to use in conjunction with radiotherapy have been largely successful, resulting in improved locoregional, and distant control. As a consequence, neoadjuvant chemotherapy (NACT) prior to definitive chemoradiotherapy has recently emerged as the preferred standard for patients with locally advanced NPC. Two of the major challenges in interpreting toxicity and QoL data from the published literature have been the reliance on: (1) clinician rather than patient reported outcomes; and (2) reporting statistical rather than clinical meaningful differences in measures. Despite the lower rates of toxicity that have been achieved with highly conformal radiotherapy techniques, survivors remain at moderate risk of persistent and long-lasting treatment effects, and the development of late radiation toxicities such as hearing loss, cranial neuropathies and cognitive impairment many years after successful treatment can herald a significant decline in QoL. Future approaches to reduce long-term toxicity will rely on: (1) identifying individual patients most likely to benefit from NACT; (2) development of response-adapted radiation strategies following NACT; and (3) anticipated further dose reductions to organs at risk with proton and particle therapy. With increasing numbers of survivors, many in the prime of their adult life, research to identify, and strategies to address the unmet needs of NPC survivors are required. This contemporary review will summarize our current knowledge of long-term toxicity, QoL and unmet needs of this survivorship group.

Keywords: chemotherapy; nasopharyngeal carcinoma; quality of life; radiotherapy; survivorship; toxicity; unmet needs.

Copyright © 2020 McDowell, Corry, Ringash and Rischin.

128 references
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26
Review Oncology
. 2020 Jun 30;1-10. doi: 10.1159/000507959. Online ahead of print.
A Fragile Balance: The Important Role of the Intestinal Microbiota in the Prevention and Management of Colorectal Cancer
Daniela Toumazi 1, Constantina Constantinou 2
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PMID: 32604093 DOI: 10.1159/000507959
Abstract
Background: Colorectal cancer is the second leading cause of cancer-related death worldwide. In recent years, researchers have focussed on the role of the intestinal microbiota in both the prevention and the treatment of colorectal cancer.

Summary: The evidence in the literature supports that there is a fragile balance between different species of bacteria in the human gut. A disturbance of this balance towards increased levels of the bacteria Fusobacterium nucleatum and Bacteroides fragilis is associated with an increased risk of colorectal cancer. The mechanisms involved include the release of toxins which activate inflammation and the regulation of specific miRNAs (with an increase in the expression of oncogenic miRNAs and a decrease in the expression of tumour suppressor miRNAs), thereby increasing cell proliferation and leading to tumorigenesis. On the other hand, Lactobacillus and Bifidobacterium have a protective effect against the development of colorectal cancer through mechanisms that involve an increase in the levels of anticarcinogenic metabolites such as butyrate and a decrease in the activity of proinflammatory pathways. Even though preliminary studies support that the use of probiotics in the prevention and management of colorectal cancer is promising, more research is needed in this field. Key Message: The association between the intestinal microbiota, diet and colorectal cancer remains an active area of research with expected future applications in the use of probiotics for the prevention and management of this significant disease.

Keywords: Colorectal cancer; Intestinal microbiota; Prevention; Probiotics; Treatment.

© 2020 S. Karger AG, Basel.

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27
Review Neuro Oncol
. 2019 Nov 4;21(11):1376-1388. doi: 10.1093/neuonc/noz108.
Germline Genetic Landscape of Pediatric Central Nervous System Tumors
Ivo S Muskens 1, Chenan Zhang 2, Adam J de Smith 1, Jaclyn A Biegel 3 4, Kyle M Walsh 2 5, Joseph L Wiemels 1 2
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PMID: 31247102 PMCID: PMC6827836 (available on 2020-11-04) DOI: 10.1093/neuonc/noz108
Free PMC article
Abstract
Central nervous system (CNS) tumors are the second most common type of cancer among children. Depending on histopathology, anatomic location, and genomic factors, specific subgroups of brain tumors have some of the highest cancer-related mortality rates or result in considerable lifelong morbidity. Pediatric CNS tumors often occur in patients with genetic predisposition, at times revealing underlying cancer predisposition syndromes. Advances in next-generation sequencing (NGS) have resulted in the identification of an increasing number of cancer predisposition genes. In this review, the literature on genetic predisposition to pediatric CNS tumors is evaluated with a discussion of potential future targets for NGS and clinical implications. Furthermore, we explore potential strategies for enhancing the understanding of genetic predisposition of pediatric CNS tumors, including evaluation of non-European populations, pan-genomic approaches, and large collaborative studies.

Keywords: genetics; pediatric brain tumor; predisposition; syndromes.

© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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28
Review J Med Virol
. 2020 Jun;92(6):568-576. doi: 10.1002/jmv.25748. Epub 2020 Mar 29.
Unique Epidemiological and Clinical Features of the Emerging 2019 Novel Coronavirus Pneumonia (COVID-19) Implicate Special Control Measures
Yixuan Wang 1, Yuyi Wang 1, Yan Chen 2, Qingsong Qin 1
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PMID: 32134116 PMCID: PMC7228347 DOI: 10.1002/jmv.25748
Free PMC article
Abstract
By 27 February 2020, the outbreak of coronavirus disease 2019 (COVID-19) caused 82 623 confirmed cases and 2858 deaths globally, more than severe acute respiratory syndrome (SARS) (8273 cases, 775 deaths) and Middle East respiratory syndrome (MERS) (1139 cases, 431 deaths) caused in 2003 and 2013, respectively. COVID-19 has spread to 46 countries internationally. Total fatality rate of COVID-19 is estimated at 3.46% by far based on published data from the Chinese Center for Disease Control and Prevention (China CDC). Average incubation period of COVID-19 is around 6.4 days, ranges from 0 to 24 days. The basic reproductive number (R0 ) of COVID-19 ranges from 2 to 3.5 at the early phase regardless of different prediction models, which is higher than SARS and MERS. A study from China CDC showed majority of patients (80.9%) were considered asymptomatic or mild pneumonia but released large amounts of viruses at the early phase of infection, which posed enormous challenges for containing the spread of COVID-19. Nosocomial transmission was another severe problem. A total of 3019 health workers were infected by 12 February 2020, which accounted for 3.83% of total number of infections, and extremely burdened the health system, especially in Wuhan. Limited epidemiological and clinical data suggest that the disease spectrum of COVID-19 may differ from SARS or MERS. We summarize latest literatures on genetic, epidemiological, and clinical features of COVID-19 in comparison to SARS and MERS and emphasize special measures on diagnosis and potential interventions. This review will improve our understanding of the unique features of COVID-19 and enhance our control measures in the future.

Keywords: COVID-19; diagnosis and interventions; features.

© 2020 Wiley Periodicals, Inc.

Conflict of interest statement
The authors declare that there are no conflict of interests.

Cited by 59 articles92 references1 figure
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29
Review Biochim Biophys Acta Mol Cell Res
. 2020 Apr;1867(4):118626. doi: 10.1016/j.bbamcr.2019.118626. Epub 2020 Jan 25.
GSK-3: An Important Kinase in Colon and Pancreatic Cancers
Roberto J Vidri 1, Timothy L Fitzgerald 2
Affiliations expand
PMID: 31987793 DOI: 10.1016/j.bbamcr.2019.118626
Abstract
In this review, the role of glycogen synthase kinase 3 (GSK-3) in pancreatic and colon cancers will be explored. GSK-3 plays a fundamental role in many metabolic processes, primarily as the final enzyme in glycogen synthesis. Active β-catenin represents the final step for the transcription of Wnt target genes. Both GSK-3 and β-catenin are key in the neoplastic transformation and tumorigenesis of human cells. Despite the advances in diagnosis and treatment of pancreatic malignancies, survival remains dismal. Continued poor outcomes are attributable to tumor cell resistance and high frequency of metastatic disease. Survival for patients diagnosed with colon cancer is often excellent, and many patients achieve long term remission. However, the incidence of colon cancers continues to increase, especially among the young. The future use of targeted therapy in pancreatic and colo-rectal cancer utilizing GSK-3 may be promising, pending a more thorough understanding of potential downstream effects. This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.

Keywords: Cancer; Colon; GSK-3; Pancreas; β-Catenin.

Copyright © 2020 Elsevier B.V. All rights reserved.

Conflict of interest statement
Declaration of competing interest None.

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30
Review Cytokine Growth Factor Rev
. 2020 Jun;53:43-52. doi: 10.1016/j.cytogfr.2020.05.001. Epub 2020 May 6.
Understanding Novel COVID-19: Its Impact on Organ Failure and Risk Assessment for Diabetic and Cancer Patients
Begum Dariya 1, Ganji Purnachandra Nagaraju 2
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PMID: 32409230 PMCID: PMC7202812 DOI: 10.1016/j.cytogfr.2020.05.001
Free PMC article
Abstract
The current pandemic outbreak of COVID-19 originated from Wuhan, China. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with significant mortality and morbidity rate. The severe risk factors are commonly detected in patients of older age and with medical comorbidities like cancer and diabetes. Scientists and doctors have scrambled to gain knowledge about the novel virus and its pathophysiology in order to discover possible therapeutic regimens and vaccines for COVID-19. The therapeutic strategies like targeting the viral genome emphasize the promising approach to target COVID-19. Additionally, blocking the receptor, ACE2 via the neutralizing antibodies for viral escape that prevents it from entering into the cells provides another therapeutic regimen. In this review article, we have presented the effect of SARS-CoV-2 infection in comorbid patients and discussed organ failure caused by this virus. Based on the data available from the scientific literature and ongoing clinical trials, we have focused on therapeutic strategies. We hope that we would fill the gaps that puzzled the researchers and clinicians with the best of our knowledge collected for the betterment of the patients for the coming future.

Keywords: COVID-19; Clinical trials; Pandemic; SARS; SARS-CoV-2.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Conflict of interest statement
Declaration of Competing Interest None to declared.

Cited by 1 article96 references3 figures
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31
J Voice
. 2020 Jun 4;S0892-1997(20)30183-1. doi: 10.1016/j.jvoice.2020.05.012. Online ahead of print.
Features of Mild-to-Moderate COVID-19 Patients With Dysphonia
Jerome R Lechien 1, Carlos M Chiesa-Estomba 2, Pierre Cabaraux 3, Quentin Mat 4, Kathy Huet 5, Bernard Harmegnies 5, Mihaela Horoi 6, Serge D Le Bon 6, Alexandra Rodriguez 6, Didier Dequanter 6, Stéphane Hans 7, Lise Crevier-Buchman 7, Baptiste Hochet 7, Lea Distinguin 7, Younes Chekkoury-Idrissi 7, Marta Circiu 7, Fahd El Afia 7, Maria Rosaria Barillari 8, Giovanni Cammaroto 9, Nicolas Fakhry 10, Justin Michel 10, Thomas Radulesco 10, Delphine Martiny 11, Philippe Lavigne 12, Lionel Jouffe 13, Géraldine Descamps 14, Fabrice Journe 14, Eleonora M C Trecca 15, Julien Hsieh 16, Irene Lopez Delgado 17, Christian Calvo-Henriquez 18, Sebastien Vergez 19, Mohamad Khalife 20, Gabriele Molteni 21, Giuditta Mannelli 22, Giovanna Cantarella 23, Manuel Tucciarone 24, Christel Souchay 25, Pierre Leich 25, Tareck Ayad 12, Sven Saussez 26
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PMID: 32600873 DOI: 10.1016/j.jvoice.2020.05.012
Abstract
Introduction: To explore the prevalence of dysphonia in European patients with mild-to-moderate COVID-19 and the clinical features of dysphonic patients.

Methods: The clinical and epidemiological data of 702 patients with mild-to-moderate COVID-19 were collected from 19 European Hospitals. The following data were extracted: age, sex, ethnicity, tobacco consumption, comorbidities, general, and otolaryngological symptoms. Dysphonia and otolaryngological symptoms were self-assessed through a 4-point scale. The prevalence of dysphonia, as part of the COVID-19 symptoms, was assessed. The outcomes were compared between dysphonic and nondysphonic patients. The association between dysphonia severity and outcomes was studied through Bayesian analysis.

Results: A total of 188 patients were dysphonic, accounting for 26.8% of cases. Females developed more frequently dysphonia than males (P = 0.022). The proportion of smokers was significantly higher in the dysphonic group (P = 0.042). The prevalence of the following symptoms was higher in dysphonic patients compared with nondysphonic patients: cough, chest pain, sticky sputum, arthralgia, diarrhea, headache, fatigue, nausea, and vomiting. The severity of dyspnea, dysphagia, ear pain, face pain, throat pain, and nasal obstruction was higher in dysphonic group compared with nondysphonic group. There were significant associations between the severity of dysphonia, dysphagia, and cough.

Conclusion: Dysphonia may be encountered in a quarter of patients with mild-to-moderate COVID-19 and should be considered as a symptom list of the infection. Dysphonic COVID-19 patients are more symptomatic than nondysphonic individuals. Future studies are needed to investigate the relevance of dysphonia in the COVID-19 clinical presentation.

Keywords: Clinical; Coronavirus; Covid-19; Dysphonia; ENT; Findings; Symptoms; Voice.

Copyright © 2020 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

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32
Review Crit Rev Oncol Hematol
. 2020 Jul;151:102981. doi: 10.1016/j.critrevonc.2020.102981. Epub 2020 May 15.
Novel Aspects on Gonadotoxicity and Fertility Preservation in Lymphoproliferative Neoplasms
Erica Silvestris 1, Gennaro Cormio 2, Tetiana Skrypets 3, Miriam Dellino 4, Angelo Virgilio Paradiso 5, Attilio Guarini 6, Carla Minoia 7
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PMID: 32485429 DOI: 10.1016/j.critrevonc.2020.102981
Abstract
The topic of fertility preservation in patients with a lymphoproliferative disease offers new aspects of debate, due to the introduction of novel chemotherapeutic regimens and small molecules in the clinical landscape. Cancer related infertility is mostly dependent on gonadotoxic treatments and fertile female patients are today addressed to the oocyte cryopreservation or to ovarian cortex fragment cryopreservation. These methods present advantages and disadvantages, which will be discussed in the present review, together with the options for male patients. The recent discovery of functional ovarian stem cells (OCSs) in woman ovarian cortex, opens new avenues offering a innovative procedure for fertility preservation through as model of regenerative medicine. Here, we review the gonadotoxic potential of "classical" chemotherapeutic treatments as well as of "novel" targeted therapies actually employed for lymphoproliferative neoplasms in young patients and revisit both the today available and future chances to preserve and restore fertility after the cancer healing.

Keywords: Chemotherapy; Fertility preservation; Lymphoma; Lymphoproliferative neoplasms; Ovarian function; Targeted therapies.

Copyright © 2020 Elsevier B.V. All rights reserved.

Conflict of interest statement
Declaration of Competing Interest Authors declare no conflict of interest.

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33
J Geriatr Oncol
. 2020 Jun 26;S1879-4068(20)30098-9. doi: 10.1016/j.jgo.2020.06.002. Online ahead of print.
Management of Older and Frail Patients With Multiple Myeloma in the Portuguese Routine Clinical Practice: Deliberations and Recommendations From an Expert Panel of Hematologists
Cristina João 1, Catarina Geraldes 2, Manuel Neves 3, Mário Mariz 4, Fernanda Trigo 5
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PMID: 32601004 DOI: 10.1016/j.jgo.2020.06.002
Abstract
The management of older patients with Multiple Myeloma (MM) is particularly challenging due to the highly heterogeneous nature of this population, both in terms of physical and cognitive functioning. Older patients may be divided into fit, intermediate and frail, with variable abilities to tolerate treatments. A careful and correct assessment of the frailty status is thus paramount for the success of therapy and for improving outcomes. With the aging of the European population, the number of older patients with MM is rapidly growing. We hereby present the deliberations and recommendations from an expert panel of Portuguese hematologists conducted to discuss the management of this population, including how to stratify and treat older patients with MM according to their frailty status. The use of frailty tools is critical for the development of individualized risk-adapted treatment strategies and to minimize the risk of under or overtreatment. Aggressive therapies should be used in fitter patients to improve survival outcomes, while frail patients should generally be treated with less toxic approaches to control symptoms while minimizing toxicity. In intermediate-fit patients, low-dose triplets are recommended to achieve a balance between improving survival and maintaining quality of life. The management of older patients with MM should be performed by a multidisciplinary team in view of their advanced age and high prevalence of comorbidities. The inclusion of older and frail patients in future clinical trials investigating treatment regimens for MM is crucial to evaluate treatment feasibility and to improve clinical decision making in this population.

Keywords: Frailty; Management; Multiple Myeloma; Older patients.

Copyright © 2020. Published by Elsevier Ltd.. All rights reserved.

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34
Br J Radiol
. 2020 Jul;93(1111):20190958. doi: 10.1259/bjr.20190958. Epub 2020 May 11.
Hemostatic Radiotherapy for Inoperable Gastric Cancer: A Pilot Study
Osamu Tanaka 1, Akihiko Sugiyama 2, Tatsushi Omatsu 3, Masahiro Tawada 4, Chiyoko Makita 5, Masayuki Matsuo 5
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PMID: 32356453 DOI: 10.1259/bjr.20190958
Abstract
Objective: Standard treatment for progressive gastric cancer with bleeding includes hemostatic radiotherapy (RT); however, the only prospective study using a fixed dose with fractions during hemostatic RT did not introduce re-irradiation. Therefore, we determined the utility of RT including re-irradiation for gastric cancer.

Methods: In this study, 31 patients with gastric cancer and bleeding were treated with an initial dose of 20 Gy/5 fractions for the whole stomach and a salvage dose of 15 Gy/5 fractions for the partial stomach. Patients achieving hemostasis, defined as a stable hemoglobin level within 30 days following irradiation, were considered responders, whereas those with no cessation of bleeding and those with re-bleeding within 30 days of irradiation were considered non-responders. We evaluated response rate, disease-free survival, overall survival (OS), re-irradiation, and adverse events (AEs).

Results: The response rate of initial RT was 80% (25/31). 6 of the 25 patients underwent re-irradiation, and all 6 were responders (100%). The median OS was significantly different among the entire cohort and one-time irradiation and re-irradiation groups (91, 76, and 112 days, respectively). No AEs of grade ≥3 were observed. Initial low-dose RT followed by reirradiation was effective in reducing AEs and did not cause any further AEs.

Conclusion: Hemostatic RT was an effective approach with low toxicity, and re-irradiation was effective and tolerable, with no patients developing severe AEs. Further, randomized controlled studies are warranted to determine the ideal dose and number of fractions for initial RT in patients with gastric cancer and bleeding.

Advances in knowledge: In this prospective study on hemostatic radiotherapy for gastric cancer, the response rate was 80% using a fixed dose of 20 Gy/5 fractions and the salvage dose of 15 Gy for re-bleeding was effective. Future comparative studies should include other doses with 20 Gy as a control.

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35
Review Crit Rev Oncol Hematol
. 2020 Jul;151:102963. doi: 10.1016/j.critrevonc.2020.102963. Epub 2020 May 7.
Early Ageing After Cytotoxic Treatment for Testicular Cancer and Cellular Senescence: Time to Act
Sjoukje Lubberts 1, Coby Meijer 1, Marco Demaria 2, Jourik A Gietema 3
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PMID: 32446180 DOI: 10.1016/j.critrevonc.2020.102963
Abstract
Treatment of testicular cancer (TC) has an exceptionally high success rate compared to other cancer types; even in case of metastasized disease, 80-90 % of TC patients can be cured. Consequently, attention has been drawn to a potential downside of this treatment success: late adverse treatment effects such as the accelerated development of otherwise age-associated features like cardiovascular disease and second malignancies. Underlying mechanisms are poorly understood. Emerging data suggest that cytotoxic treatment induces cellular senescence, resulting in secretion of inflammatory factors contributing to this early ageing phenotype. Molecular and cellular characterization of this early ageing will enhance understanding the pathogenesis of TC treatment-induced morbidity and contribute to better recognition and prevention of late effects. In this review, we describe clinical manifestations of the early ageing phenotype among TC survivors, and subsequently focus on potential underlying mechanisms. We discuss the clinical implications and describe perspectives for future research and intervention strategies.

Keywords: Cisplatin; Late effects; Senescence; Testicular cancer.

Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Conflict of interest statement
Declaration of Competing Interest Sjoukje Lubberts and Coby Meijer have nothing to disclose Marco Demaria is a co-founder of Cleara Biotech, a company devoted to develop agents against senescent cells. Jourik Gietema reports grants from Abbvie, Roche and Siemens, paid to the institution; outside the submitted work.

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36
Eur Urol
. 2020 Jun 24;S0302-2838(20)30419-X. doi: 10.1016/j.eururo.2020.05.041. Online ahead of print.
Modified Apical Dissection and Lateral Prostatic Fascia Preservation Improves Early Postoperative Functional Recovery in Robotic-assisted Laparoscopic Radical Prostatectomy: Results From a Propensity Score-matched Analysis
Marcio Covas Moschovas 1, Seetharam Bhat 1, Fikret Fatih Onol 2, Travis Rogers 1, Shannon Roof 1, Elio Mazzone 3, Alexandre Mottrie 4, Vipul Patel 1
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PMID: 32593529 DOI: 10.1016/j.eururo.2020.05.041
Abstract
Background: Early recovery of continence and potency after robotic-assisted laparoscopic prostatectomy (RALP) still remains a challenge.

Objective: To assess the effect of our modified apical dissection and lateral prostatic fascia preservation (mod-RALP) technique on early functional outcomes.

Design, setting, and participants: Among 2168 patients who underwent RALP between 2017 and 2019, 104 received a mod-RALP, and for the purposes of this study they were propensity score (PS) matched with a control group of conventional RALP cases based on preoperative and histological characteristics.

Surgical procedure: In the mod-RALP technique, significant dissection of the apical complex was avoided with maximized preservation of periurethral tissue around the urethral stump. Nerve sparing was also modified with intrafascial dissection inside of the lateral fascia, leaving the lateral tissue including the neurovascular bundle (NVB) untouched and covered.

Measurements: The mod-RALP and conventional RALP groups were compared for continence and potency recovery at 1 and 6 wk postoperatively, as well as at 3, 6, and 12 mo. Kaplan-Meier curves and multivariate Cox regression models were used to identify survival estimations and their predictors.

Results and limitations: The mod-RALP technique resulted in faster continence (mean 46 vs 70 d) and potency (mean 74 vs 118 d, p < 0.05 for both) recovery. Functional recovery rates at postoperative follow-up were significantly higher in the mod-RALP group at all time points within the first 6 mo following surgery. Multivariate analyses revealed age, baseline functional status, surgical technique, and lymph node dissection as independent predictors of early functional recovery. This study is limited by its retrospective design and small size of the study groups.

Conclusions: Our results with a modified technique intended to better preserve the apical complex and NVBs suggest earlier recovery of urinary continence and sexual function. These results should be tested with future randomized studies.

Patient summary: We report a modified approach to apical dissection and lateral prostatic fascia preservation in robotic-assisted laparoscopic prostatectomy that resulted in earlier continence and potency recovery as compared with our conventional technique.

Keywords: Continence; Potency; Prostate cancer; Recovery; Robotic surgery.

Copyright © 2020. Published by Elsevier B.V.

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37
Review Curr Oncol Rep
. 2020 Jun 30;22(8):82. doi: 10.1007/s11912-020-00942-7.
An Update on Surgical Margins in the Head Neck Squamous Cell Carcinoma: Assessment, Clinical Outcome, and Future Directions
Arjun Singh 1, Burhanuddin Qayyumi 1, Pankaj Chaturvedi 2
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PMID: 32601821 DOI: 10.1007/s11912-020-00942-7
Abstract
Purpose of review: Failure to achieve tumor-free margins is the single largest cause of death for head neck cancer patients. At the same time, it is the only factor that is in complete control of the surgeon. This review summarizes evidence for the definition, clinical implications, and methods to achieve optimal margins.

Recent findings: The previous universally followed definition of adequate margin (5 mm in final histopathology) has been disputed. Various biological, optical, and imaging adjuncts can aid in achieving optimal margins. Extent of resection and margins in human papilloma virus (HPV)-positive oropharyngeal cancers and following induction chemotherapy remain controversial. Though practiced widely, frozen section-guided margin revision has not conclusively shown improved local control rates. The role of molecular assessment of margins is promising but not established. The definition of adequate margin differs according to the site in the head neck region. Currently, the 5-mm margin at final histopathology is the most commonly accepted definition of an "adequate" margin.

Keywords: Adequate margins; Frozen section; Head neck cancer; Margins; Squamous cell carcinoma.

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38
Adv Wound Care (New Rochelle)
. 2020 Jun 30. doi: 10.1089/wound.2019.1085. Online ahead of print.
Emerging Role of Elastin-Like Polypeptides (ELPs) in Regenerative Medicine
Vijaya Sarangthem 1, Thoudam Debraj Singh 2, Amit K Dinda 3
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PMID: 32602815 DOI: 10.1089/wound.2019.1085
Abstract
Significance: Wound dressing based on naturally derived polymer provides a useful platform for the treatment of skin injuries. Owing to the high mechanical strength, tunable structural and physicochemical properties of human elastin-like polypeptides (ELPs), they may be used as excellent material for fabricating biocompatible scaffold and other products for wound management. Recent Advances: Designing recombinant ELPs mimicking the natural elastin to fabricate synthetic polymers suitable for human health care has generated significant interest. ELP-based cell adhesive biopolymers have been used as an alternative for successful suture less wound closure, due to its physicochemical characteristic of the extracellular matrix.

Critical issues: Different system of ELPs are being made in the form of scaffolds, films, hydrogels, photo-linkable sheets and composites linked with various types of growth factors for wound healing application. However, optimizing the quality and safety attributes for specific application need designing of recombinant ELPs with structural and functional modifications as needed for the intervention. Future Direction: Chronic wounds are difficult to treat as the wound repair process is interrupted by conditions such as excessive inflammation, impaired ECM formation and persistent infections. Conventional therapies like skin substitutes or autologous skin grafts in many cases unable to reestablish tissue homeostasis and proper healing. The development of innovative materials could induce a better regenerative healing response. Here we are reviewing the different types of elastin-based materials for wound care application and their future prospect in regenerative medicine.

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39
Clin Transl Radiat Oncol
. 2020 May 6;24:11-15. doi: 10.1016/j.ctro.2020.05.001. eCollection 2020 Sep.
Age, Pathology and CA-125 Are Prognostic Factors for Survival in Patients With Brain Metastases From Gynaecological Tumours
S H J Nagtegaal 1, A F C Hulsbergen 2 3, E B L van Dorst 4, V K Kavouridis 2, C A C Jessurun 2, M L D Broekman 3 5, T R Smith 2, J J C Verhoeff 1
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PMID: 32596517 PMCID: PMC7306503 DOI: 10.1016/j.ctro.2020.05.001
Free PMC article
Abstract
Background and purpose: Brain metastases originating from gynaecological tumours are a rare phenomenon, but have an increasing incidence due to better targeted therapies. This study aimed to identify factors that predict survival in these patients, which can be used in creating a robust prognostic tool for shared decision making.

Materials and methods: We identified a consecutive cohort of 73 patients treated for gynaecological brain metastases in two tertiary institutions. Baseline demographics, pathology and serum CA-125 were included in a multivariable Cox proportional hazards model.

Results: Median overall survival in our cohort was 14.4 months, with a one-year survival of 56.4% and a two-year survival of 39.1%. Thirty-eight patients (52.1%) had ovarian carcinoma as the primary malignancy. The following factors were significantly associated with survival: age (HR 1.05 per year), CA-125 (HR 1.02 par 50 U/ml), and uterine and vulvar primary tumours (when compared to ovarian carcinoma, with HRs 3.07 and 8.70). A post-hoc analysis with primary tumour site reclassified into ovary versus non-ovary showed a HR of 0.50 for ovarian primary tumour type.

Conclusion: We have found that age, pathology and CA-125 are prognostic factors for survival in patients with brain metastases from gynaecological tumours. Our findings may provide a foundation for future development of prediction models, for the benefit of both patients and physicians.

Keywords: Brain metastasis; Gynaecological malignancies; Prognosis; Survival.

© 2020 The Authors.

Conflict of interest statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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40
Review Urol Clin North Am
. 2020 Aug;47(3):399-411. doi: 10.1016/j.ucl.2020.04.011. Epub 2020 Jun 8.
Radiation Therapy for Patients With Advanced Renal Cell Carcinoma
Joseph A Miccio 1, Oluwadamilola T Oladeru 2, Sung Jun Ma 3, Kimberly L Johung 4
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PMID: 32600541 DOI: 10.1016/j.ucl.2020.04.011
Abstract
Stereotactic radiosurgery and stereotactic body radiation therapy (SBRT) have led to a resurgence of the use of radiotherapy in the management of advanced renal cell carcinoma (RCC). These techniques provide excellent local control and palliation of metastatic sites of disease with minimal toxicity. Additionally, SBRT to the primary tumor may be efficacious and well tolerated in select patients that are not surgical candidates. Emerging data suggest that SBRT may potentiate the immune response, and current and future study will evaluate if SBRT can improve survival outcomes in patients with metastatic RCC.

Keywords: Radiotherapy; Renal cell carcinoma; Stereotactic body radiation therapy; Stereotactic radiosurgery.

Copyright © 2020 Elsevier Inc. All rights reserved.

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41
Clin Oncol (R Coll Radiol)
. 2020 Jun 25;S0936-6555(20)30198-9. doi: 10.1016/j.clon.2020.05.004. Online ahead of print.
Obesity and Cancer Treatment Outcomes: Interpreting the Complex Evidence
C G V Slawinski 1, J Barriuso 2, H Guo 3, A G Renehan 4
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PMID: 32595101 DOI: 10.1016/j.clon.2020.05.004
Abstract
A wealth of epidemiological evidence, combined with plausible biological mechanisms, present a convincing argument for a causal relationship between excess adiposity, commonly approximated as body mass index (BMI, kg/m2), and incident cancer risk. Beyond this relationship, there are a number of challenges posed in the context of interpreting whether being overweight (BMI 25.0-29.9 kg/m2) or obese (BMI ≥ 30.0 kg/m2) adversely influences disease progression, cancer mortality and survival. Elevated BMI (≥ 25.0 kg/m2) may influence treatment selection of, for example, the approach to surgery; the choice of chemotherapy dosing; the inclusion of patients into randomised clinical trials. Furthermore, the technical challenges posed by an elevated BMI may adversely affect surgical outcomes, for example, morbidity (increasing the risk of surgical site infections), reduced lymph node harvest (and subsequent risk of under-staging and under-treatment) and increased risk of margin positivity. Suboptimal chemotherapy dosing, associated with capping chemotherapy in obese patients as an attempt to avoid excess toxicity, might be a driver of poor prognostic outcomes. By contrast, the efficacy of immune checkpoint inhibition may be enhanced in patients who are obese, although in turn, this observation might be due to reverse causality. So, a central research question is whether being overweight or obese adversely affects outcomes either directly through effects of cancer biology or whether adverse outcomes are mediated through indirect pathways. A further dimension to this complex relationship is the obesity paradox, a phenomenon where being overweight or obese is associated with improved survival where the reverse is expected. In this overview, we describe a framework for evaluating methodological problems such as selection bias, confounding and reverse causality, which may contribute to spurious interpretations. Future studies will need to focus on prospective studies with well-considered methodology in order to improve the interpretation of causality.

Keywords: Cancer; chemotherapy; immunotherapy; obesity; radiotherapy; surgery.

Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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42
J Emerg Med
. 2020 Jun 24;S0736-4679(20)30404-2. doi: 10.1016/j.jemermed.2020.05.006. Online ahead of print.
Management of Nonpregnant Women Presenting to the Emergency Department With Iron Deficiency Anemia Caused by Uterine Blood Loss: A Retrospective Cohort Study
Stephen Boone 1, W Frank Peacock 2, Edgardo Ordonez 2, Jacquelyn M Powers 3
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PMID: 32593579 DOI: 10.1016/j.jemermed.2020.05.006
Abstract
Background: Women with abnormal uterine bleeding are commonly encountered in the emergency department (ED). Contemporary management of severe iron deficiency anemia (IDA) in this setting may be inadequate and expose patients to unnecessary blood transfusions.

Objective: We sought to describe the characteristics and management of women presenting to the ED with moderate to severe anemia caused by uterine bleeding. We hypothesized that blood transfusions were frequently administered to stable patients without severe symptoms or active bleeding.

Methods: This is a retrospective cohort study of women presenting to the ED from October 31, 2018 to March 31, 2019 with IDA from uterine bleeding. Eligible subjects were adult females with IDA caused by uterine blood loss, hemoglobin ≤10 g/dL, and who were discharged from the ED.

Results: One hundred twenty-seven encounters (117 unique patients, mean 40 years of age) met the eligibility criteria. No patients were hemodynamically unstable and clinically significant active bleeding was rare (6%). Blood transfusion was administered during 70 (55%) encounters, with ≥2 units given to more than half (53%) of those transfused. Subsequent ED visits (14%) and transfusions (16%) during the follow-up period were common.

Conclusion: In this cohort of adult females with moderate to severe IDA caused by uterine bleeding, blood transfusion was often administered in the absence of hemodynamic instability or active hemorrhage, iron deficiency was inadequately treated, and a high rate of subsequent transfusions occurred. Future studies should investigate optimal indications for transfusion and emphasize adequate iron supplementation.

Keywords: abnormal uterine bleeding; anemia; anemia iron deficiency; patient blood management; transfusion.

Copyright © 2020 Elsevier Inc. All rights reserved.

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43
J Neuropathol Exp Neurol
. 2020 Jun 28;nlaa051. doi: 10.1093/jnen/nlaa051. Online ahead of print.
Exploring DNA Methylation for Prognosis and Analyzing the Tumor Microenvironment in Pleomorphic Xanthoastrocytoma
Karen Tang 1 2, David Kurland 3, Varshini Vasudevaraja 4, Jonathan Serrano 4, Michael Delorenzo 5, Alireza Radmanesh 6, Cheddhi Thomas 1 5 7 8, Marissa Spino 1 5, Sharon Gardner 1, Jeffrey C Allen 1, Theodore Nicolaides 1, Diana S Osorio 1 9, Jonathan L Finlay 1 9, Daniel R Boué 10, Matija Snuderl 1 5
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PMID: 32594172 DOI: 10.1093/jnen/nlaa051
Abstract
Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that affects children and young adults. Molecular prognostic markers of PXAs remain poorly established. Similar to gangliogliomas, PXAs show prominent immune cell infiltrate, but its composition also remains unknown. In this study, we correlated DNA methylation and BRAF status with clinical outcome and explored the tumor microenvironment. We performed DNA methylation in 21 tumor samples from 18 subjects with a histological diagnosis of PXA. MethylCIBERSORT was used to deconvolute the PXA microenvironment by analyzing the associated immune cell-types. Median age at diagnosis was 16 years (range 7-32). At median follow-up of 30 months, 3-year and 5-year overall survival was 73% and 71%, respectively. Overall survival ranged from 1 to 139 months. Eleven out of 18 subjects (61%) showed disease progression. Progression-free survival ranged from 1 to 89 months. Trisomy 7 and CDKN2A/B (p16) homozygous deletion did not show any association with overall survival (p = 0.67 and p = 0.74, respectively). Decreased overall survival was observed for subjects with tumors lacking the BRAF V600E mutation (p = 0.02). PXAs had significantly increased CD8 T-cell epigenetic signatures compared with previously profiled gangliogliomas (p = 0.0019). The characterization of immune cell-types in PXAs may have implications for future development of immunotherapy.

Keywords: BRAF V600E; CDKN2A/B; Brain tumor; DNA methylation; Pleomorphic xanthoastrocytoma; Tumor immune microenvironment.

© 2020 American Association of Neuropathologists, Inc. All rights reserved.

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44
Ther Adv Med Oncol
. 2020 Jun 17;12:1758835920929583. doi: 10.1177/1758835920929583. eCollection 2020.
Surrogate Endpoints for Overall Survival in Anti-Programmed death-1 and Anti-Programmed Death Ligand 1 Trials of Advanced Melanoma
Run-Cong Nie 1, Shu-Qiang Yuan 1, Yun Wang 2, Xue-Bin Zou 3, Shi Chen 4, Shu-Man Li 5, Jin-Ling Duan 5, Jie Zhou 5, Guo-Ming Chen 1, Tian-Qi Luo 1, Zhi-Wei Zhou 6, Yuan-Fang Li 6
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PMID: 32595775 PMCID: PMC7301660 DOI: 10.1177/1758835920929583
Free PMC article
Abstract
Background: We assessed the surrogacy of objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) for overall survival (OS) in anti-PD-1/PD-L1 trials of metastatic melanoma through a meta-analysis of randomized controlled trials (RCTs).

Methods: PubMed and EMBASE were searched for phase II/III RCTs till June 2019 investigating anti-PD-1/PD-L1 agents. Treatment effect (hazard ratio or odds ratio) on potential surrogates (ORR/DCR/PFS) and OS were collected. At trial level, we assessed the correlation between treatment effect on potential surrogates and OS, weighted by sample size, fixed and random effect models, and calculated the surrogate threshold effect (STE). Sensitivity analyses and leave-one-out cross-validation approach were performed to evaluate the robustness of our findings.

Results: We included 8 RCTs (4110 patients; 11 comparisons). We did not identify strong correlations between ORR [coefficient of determination (R 2): 0.09-0.25], DCR (0.41-0.57) and OS. However, we noted a strong correlation between PFS and OS, with R 2 of 0.82 in sample size, 0.75 in fixed effect and 0.72 in random effect model weighting, the robustness of which was further verified by leave-one-out cross-validation approach. Sensitivity analyses with restriction to trials with less than 50% crossover, phase III trials, large trials and first-line trials strengthened the correlation (0.78-0.94). The STE for PFS was 0.78.

Conclusions: PFS may be the appropriate surrogate for OS in anti-PD-1/PD-L1 trials of metastatic melanoma. A future anti-PD-1/PD-L1 trial would need less than 0.78 for PFS of the upper limit of confidence interval to predict an OS benefit.

Keywords: PD-1; PD-L1; immune checkpoint; overall survival; surrogate endpoint.

© The Author(s), 2020.

Conflict of interest statement
Conflict of interest: The authors declare that there is no conflict of interest.

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45
Helicobacter
. 2020 Jun 29;e12719. doi: 10.1111/hel.12719. Online ahead of print.
Efficacy and Safety of a New Rifabutin-Based Triple Therapy With Vonoprazan for Refractory Helicobacter Pylori Infection: A Prospective Single-Arm Study
Yoshihiro Hirata 1 2, Atsuo Yamada 1, Ryota Niikura 1, Satoki Shichijo 1 3, Yoku Hayakawa 1, Kazuhiko Koike 1
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PMID: 32602161 DOI: 10.1111/hel.12719
Abstract
Background: A small proportion of Helicobacter pylori-infected individuals in Japan suffer failure of eradication therapy with third-line regimens containing the potent acid suppressor, vonoprazan, and a quinolone.

Objectives: This prospective study evaluated the efficacy and safety of rifabutin-based triple therapy with vonoprazan for refractory H pylori infection.

Methods: Patients who failed H pylori eradication by clarithromycin-based first-line, metronidazole-based second-line, and sitafloxacin-based third-line therapies were recruited. After obtaining informed consent, patients received eradication therapy with vonoprazan (20 mg), amoxicillin (750 mg), and rifabutin (150 mg) twice daily for 10 days. Eradication was confirmed by a negative H pylori stool antigen or urea breath test at least 8 weeks after the end of therapy.

Results: Nineteen patients were included in the study. All of the patients completed the course of medication. Eradication of H pylori was confirmed in all of the patients (19/19; 100%, 95% confidence interval; 83-100%). The most common adverse event was soft stool/diarrhea (4/19, 21%). No severe adverse event was observed.

Conclusions: Ten-day rifabutin with amoxicillin and vonoprazan triple therapy appears to be effective and safe for refractory H pylori infections. However, considering the recent publications showing high eradication rates with vonoprazan amoxicillin dual therapy, confirmation will require future studies comparing our new therapy with vonoprazan-amoxicillin dual with similar doses and duration and with vonoprazan-rifabutin dual therapy.

Keywords: Refractory H. pylori infection; rescue therapy; rifabutin; vonoprazan.

© 2020 John Wiley & Sons Ltd.

40 references
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46
Lab Invest
. 2019 Sep;99(9):1275-1286. doi: 10.1038/s41374-019-0247-4. Epub 2019 Apr 17.
Therapeutic Potential of PLK1 Inhibition in Triple-Negative Breast Cancer
Ai Ueda 1, Keiki Oikawa 2, Koji Fujita 2, Akio Ishikawa 2, Eiichi Sato 3, Takashi Ishikawa 1, Masahiko Kuroda 4, Kohsuke Kanekura 5
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PMID: 30996295 DOI: 10.1038/s41374-019-0247-4
Abstract
Triple negative breast cancer (TNBC) is responsible for significant number of breast cancer-associated deaths because of lacking of successful molecular-targeted therapy. To explore a therapeutic target for TNBC, we performed a siRNA-mediated knockdown screening and identified Polo-like kinase 1 (PLK1) as a potential therapeutic target for TNBC. Knockdown of PLK1 as well as a small compound inhibitor for PLK1, BI-2536, induced G2/M arrest and created polyploid cell population, shown by increased DNA content and nuclear size. Inhibition of PLK1 eventually triggered apoptosis in multiple TNBC cell lines. In addition, we confirmed that PLK1 was significantly overexpressed in the tissues from TNBC patients compared with the tissues of normal mammary glands and benign breast tumors. Our data indicated that PLK1 plays a pivotal role in the regulation of mitosis of TNBC cells. Although future in vivo studies are warranted, targeting PLK1 by a selective inhibitor such as BI-2536 can be an attractive molecular-targeted therapy for TNBC.

Cited by 2 articles
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47
Review Future Med Chem
. 2019 Sep;11(17):2241-2245. doi: 10.4155/fmc-2019-0153.
Management of Diabetic Nephropathy: The Role of sirtuin-1
Wanning Wang 1 2, Weixia Sun 1, Yanli Cheng 1, Zhonggao Xu 1, Lu Cai 2 3
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PMID: 31581918 DOI: 10.4155/fmc-2019-0153
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48
Semin Thromb Hemost
. 2020 Jul;46(5):521-523. doi: 10.1055/s-0040-1713680. Epub 2020 Jun 30.
Nanomedicine in Thrombosis and Hemostasis: The Future of Nanotechnology in Thrombosis and Hemostasis Research and Clinical Applications
Christoph E Hagemeyer 1, Ton Lisman 2, Hau C Kwaan 3
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PMID: 32604418 DOI: 10.1055/s-0040-1713680
Conflict of interest statement
None.

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49
Mater Sci Eng C Mater Biol Appl
. 2020 Oct;115:111139. doi: 10.1016/j.msec.2020.111139. Epub 2020 May 31.
Development of Pharmaceutically Scalable Inhaled Anti-Cancer Nanotherapy - Repurposing Amodiaquine for Non-Small Cell Lung Cancer (NSCLC)
Vineela Parvathaneni 1, Nishant S Kulkarni 1, Gautam Chauhan 1, Snehal K Shukla 1, Rasha Elbatanony 2, BrijeshKumar Patel 3, Nitesh K Kunda 1, Aaron Muth 1, Vivek Gupta 4
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PMID: 32600728 DOI: 10.1016/j.msec.2020.111139
Abstract
New drug and dosage form development faces significant challenges, especially in oncology, due to longer development cycle and associated scale-up complexities. Repurposing of existing drugs with potential anti-cancer activity into new therapeutic regimens provides a feasible alternative. In this project, amodiaquine (AQ), an anti-malarial drug, has been explored for its anti-cancer efficacy through formulating inhalable nanoparticulate systems using high-pressure homogenization (HPH) with scale-up feasibility and high reproducibility. A 32 multifactorial design was employed to better understand critical processes (probe homogenization speed while formulating coarse emulsion) and formulation parameters (concentration of cationic polymer in external aqueous phase) so as to ensure product quality with improved anticancer efficacy in non-small cell lung cancer (NSCLC). Optimized AQ loaded nanoparticles (AQ NP) were evaluated for physicochemical properties, stability profile, in-vitro aerosol deposition behavior, cytotoxic potential against NSCLC cells in-vitro and in 3D simulated tumor spheroid model. The highest probe homogenization speed (25,000 rpm) resulted in lower particle size. Incorporation of cationic polymer, polyethylenimine (0.5% w/v) resulted in high drug loading efficiencies at optimal drug quantity of 5 mg. Formulated nanoparticles (liquid state) exhibited an aerodynamic diameter of 4.7 ± 0.1 μm and fine particle fraction of 81.0 ± 9.1%, indicating drug deposition in the respirable airways. Cytotoxicity studies in different NSCLC cell lines revealed significant reduction in IC50 values with AQ-loaded nanoparticles compared to plain drug, along with significant cell migration inhibition (scratch assay) and reduced % colony growth (clonogenic assay) in A549 cells with AQ NP. Moreover, 3D simulated spheroid studies revealed efficacy of nanoparticles in penetration to tumor core, and growth inhibition. AQ's autophagy inhibition ability significantly increased (increased LC3B-II levels) with nanoparticle encapsulation, along with moderate improvement in apoptosis induction (Caspase-3 levels). No impact was observed on HUVEC angiogenesis suggesting alternative anticancer mechanisms. To conclude, amodiaquine can be a promising candidate for repurposing to treat NSCLC while delivering inhalable nanoparticles developed using a scalable HPH process. Despite the involvement of complex parameters, application of DoE has simplified the process of product and process optimization.

Keywords: 3D spheroid; Amodiaquine; Autophagy; Design of experiments; Drug repurposing; High pressure homogenization; Non-small cell lung cancer; Scale-up.

Copyright © 2020 Elsevier B.V. All rights reserved.

Conflict of interest statement
Declaration of competing interest The authors declare no conflict of interest.

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50
Future Oncol
. 2020 Jun 27. doi: 10.2217/fon-2020-0086. Online ahead of print.
Association Between Single Nucleotide Polymorphisms of DNA Damage Response Pathway Genes and Increased Risk in Breast Cancer
Azhar Mehmood 1, Mahmood Akhtar Kayani 1, Malik Waqar Ahmed 1, Asif Nisar 1, Ishrat Mahjabeen 1
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PMID: 32597209 DOI: 10.2217/fon-2020-0086
Abstract
Aim: We aimed to evaluate the role of selected single nucleotide polymorphisms of DNA damage response pathway genes in breast cancer (BC). Materials & methods: In present study, 500 BC patients and 500 controls was used to estimate the frequency of single nucleotide polymorphisms of DNA damage response pathway genes. Tetra-amplification refractory mutation system-PCR technique was used for screening of the six selected polymorphisms. Results: Logistic regression analysis showed that heterozygous mutant genotype of rs1800057 (p < 0.0001) and homozygous mutant genotype of rs1801516 (p < 0.0001) was associated with significant increased risk of BC. In the ATR gene, heterozygous mutant genotype of rs2227931 (p < 0.0001) was associated with significant increased risk of BC. However, significant decreased risk of BC was found associated with heterozygous mutant genotype of rs2227928 (p < 0.0002) and homozygous mutant genotype of rs2229032 (p < 0.0001) in patients compared with controls. Conclusion: The present results showed that alteration in DNA damage response pathway gene (ATM & ATR) results in increased BC risk.

Keywords: ATM gene; ATR gene; DDR pathway; breast cancer; treatment modalities.

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