Cold Spring Harb Perspect Med
. 2020 Jun 29;a034892. doi: 10.1101/cshperspect.a034892. Online ahead of print.
MAP-Kinase-Driven Hematopoietic Neoplasms: A Decade of Progress in the Molecular Age
Rikhia Chakraborty 1 2, Omar Abdel-Wahab 3 3, Benjamin H Durham 3 3
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PMID: 32601132 DOI: 10.1101/cshperspect.a034892
Abstract
Mutations in members of the mitogen-activated protein kinase (MAPK) pathway are extensively studied in epithelial malignancies, with BRAF mutations being one of the most common alterations activating this pathway. However, BRAF mutations are overall quite rare in hematological malignancies. Studies over the past decade have identified high-frequency BRAF V600E, MAP2K1, and other kinase alterations in two groups of MAPK-driven hematopoietic neoplasms: hairy cell leukemia (HCL) and the systemic histiocytoses. Despite HCL and histiocytoses sharing common molecular alterations, these are phenotypically distinct malignancies that differ in respect to clinical presentation and suspected cell of origin. The purpose of this review is to highlight the molecular advancements over the last decade in the histiocytic neoplasms and HCL and discuss the impact these insights have had on our understanding of the molecular pathophysiology, cellular origins, and therapy of these enigmatic diseases as well as perspectives for future research directions.

Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.

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52
Cancer Chemother Pharmacol
. 2020 Jan;85(1):173-183. doi: 10.1007/s00280-019-03979-z. Epub 2019 Oct 30.
Population Pharmacokinetics of Vactosertib, a New TGF-β Receptor Type Ι Inhibitor, in Patients With Advanced Solid Tumors
Su Young Jung 1 2, Ji Seob Yug 3, Jeffery M Clarke 4, Todd M Bauer 5, Vicki L Keedy 6, Sunjin Hwang 7, Seong-Jin Kim 7, Eun Kyoung Chung 8, Jangik I Lee 9 10
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PMID: 31673825 DOI: 10.1007/s00280-019-03979-z
Abstract
Purpose: Vactosertib, a novel inhibitor of transforming growth factor-β type Ι receptor, is under development for the treatment of various cancers. The objective of this study was to characterize the population pharmacokinetics of vactosertib in patients with solid tumors.

Methods: Vactosertib population pharmacokinetics was assessed by nonlinear mixed-effects modelling of plasma concentration-time data obtained from a first-in-human phase 1 trial conducted in patients with advanced solid tumors. The final population pharmacokinetic model was constructed by assessing the effect of covariates on pharmacokinetic parameters including demographic characteristics, laboratory values, hepatic and renal function, and concomitant medications. The robustness of the final model was evaluated using a bootstrap method as well as visual predictive check based on Monte Carlo simulations and goodness-of-fit plots.

Results: A total of 559 concentrations from 29 patients were available for pharmacokinetic analysis. A two-compartment linear model with first-order absorption and absorption lag time adequately described the population pharmacokinetics of vactosertib. The estimates of apparent clearance (CL/F) and volume of central compartment (Vc/F) were 31.9 L/h (inter-individual variability, 0.481) and 82.9 L (inter-individual variability, 0.534), respectively. The mixture model accounts for both typical absorption profile in the majority of patients and distinct profile in some patients with uncommon gastrointestinal conditions. Body mass index was significantly associated with Vc/F.

Conclusions: The model developed in this study adequately describes the population pharmacokinetics of vactosertib in patients with advanced solid tumors. The pharmacokinetic characteristics assessed using the model would provide useful quantitative information to assist the future clinical development of vactosertib.

Keywords: Phase 1; Population pharmacokinetics; Solid tumors; TGF-β signaling inhibitor; Vactosertib.

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53
Biol Res Nurs
. 2020 Jun 30;1099800420938141. doi: 10.1177/1099800420938141. Online ahead of print.
Systematic Review of the Kynurenine Pathway and Psychoneurological Symptoms Among Adult Cancer Survivors
Hongjin Li 1 2, Tingting Liu 3, Lacey W Heinsberg 4, Mark B Lockwood 1, Derek A Wainwright 5, Min Kyeong Jang 1 2, Ardith Z Doorenbos 1 2
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PMID: 32602357 DOI: 10.1177/1099800420938141
Abstract
The co-occurrence of multiple psychoneurological symptoms, including pain, sleep disturbance, fatigue, depression, anxiety, and cognitive disturbance among adult cancer survivors led us to question which common biological mechanisms are shared among these conditions. Variances in tryptophan (Trp) levels and downstream metabolites of the kynurenine (Kyn) metabolic pathway are known to affect immune response and psychoneurological symptoms. The objective of this systematic review was to help us (a) better understand the role of the Kyn pathway in psychoneurological symptoms among adult cancer survivors and (b) identify common significant biomarkers across psychoneurological symptoms as a guide for future research. Some evidence has shown that decreased Trp levels and increased Kyn, Trp/Kyn ratio, and kynurenic acid/Trp ratio in parallel with immune activation are correlated with some psychoneurological symptoms among people undergoing cancer treatment, although discrepancies exist between studies. Kyn pathway activation could also be associated with psychoneurological symptoms among adult cancer survivors, but further research is needed to confirm its exact etiological role with respect to psychoneurological symptoms.

Keywords: cancer; kynurenine; metabolite; psychoneurological; survivor; symptom; tryptophan.

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54
Future Oncol
. 2020 Jun 29. doi: 10.2217/fon-2020-0248. Online ahead of print.
Real-world Effectiveness of Nivolumab in Patients With Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis
Yong-Jin Kim 1, Mark Oremus 1, Helen H Chen 1, Thomas McFarlane 2, Devanshi Shah 1, Susan Horton 1
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PMID: 32598192 DOI: 10.2217/fon-2020-0248
Abstract
Background: The effectiveness of immunotherapies for non-small-cell lung cancer under real-world clinical settings remains uncertain. Materials & methods: Systematic searches of PubMed, EMBASE and Web of Science were conducted. Random-effects models were used to estimate pooled median overall survival and progression-free survival estimates. Results: 36 studies of nivolumab were included for narrative synthesis and 11 of these studies were included for meta-analysis. Age, sex, histology and prior lines of treatment did not affect survival outcomes, while Eastern Cooperative Oncology Group Performance Status and brain metastasis were inversely associated with survival. In the meta-analysis, nivolumab was associated with 9.6 months (95% CI: 8.4-10.9) of overall survival and 2.6 months (95% CI: 1.6-3.6) of progression-free survival. Conclusion: Very-low-certainty evidence suggested the real-world effectiveness of nivolumab was consistent with those observed in the clinical trials.

Keywords: meta-analysis; nivolumab; non-small-cell lung cancer; real-world evidence; systematic review.

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55
Editorial Future Oncol
. 2020 Jun 27. doi: 10.2217/fon-2020-0533. Online ahead of print.
Implications of COVID-19 on Urological Laparoscopic Surgery
Benjamin Condon 1 2 3, Thomas Whish-Wilson 3 4 5, Niall F Davis 6 7, Nathan Lawrentschuk 1 2 8
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PMID: 32597203 DOI: 10.2217/fon-2020-0533
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56
J Pain Symptom Manage
. 2020 Jun 26;S0885-3924(20)30564-9. doi: 10.1016/j.jpainsymman.2020.06.023. Online ahead of print.
Measuring Goal-Concordant Care: Results and Reflections From Secondary Analysis of a Trial to Improve Serious Illness Communication
Justin J Sanders 1, Kate Miller 2, Meghna Desai 2, Olaf P Geerse 3, Joanna Paladino 4, Jane Kavanagh 5, Joshua R Lakin 6, Bridget A Neville 2, Susan D Block 7, Erik K Fromme 8, Rachelle Bernacki 8
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PMID: 32599148 DOI: 10.1016/j.jpainsymman.2020.06.023
Abstract
Context: Many consider goal-concordant care (GCC) to be the most important of advance care planning and palliative care. Researchers face significant challenges in attempting to measure this outcome. We conducted a randomized controlled trial to assess the effects of a system-level intervention to improve serious illness communication on goal-concordant care and other outcomes.

Objectives: To describe our measurement approach to GCC, present findings from a post-hoc analysis of trial data, and discuss lessons learned about measuring GCC.

Methods: Using trial data collected to measure GCC we analyzed ratings and rankings from a non-validated survey of patient priorities in the setting of advanced cancer, the Life Priorities Scale, and compared outcomes with correlative measures.

Results: Participants commonly rated several pre-determined and literature-derived priorities as important but did so in ways that were commonly incongruent with rankings. Ratings were frequently stable over time; rankings less so. Rankings are more likely to help assess the degree to which care is goal concordant but may be best augmented by corollary measures that signal achievement of a given priority.

Conclusion: Measuring GCC remains a fundamental challenge to palliative care researchers. Ratings attest to the fact that many things matter to patients, however rankings can better determine what matters most. Insights gained from our experience may guide future research aiming to utilize this outcome to assess the effect of intervention to improve serious illness care.

Keywords: Clinical Trial; Goal-concordant Care; Serious Illness Communication; Study Methods.

Copyright © 2020. Published by Elsevier Inc.

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57
J Assist Reprod Genet
. 2020 Jun 27. doi: 10.1007/s10815-020-01821-7. Online ahead of print.
Installing Oncofertility Programs for Common Cancers in Limited Resource Settings (Repro-Can-OPEN Study): An Extrapolation During the Global Crisis of Coronavirus (COVID-19) Pandemic
M Salama 1, L Ataman-Millhouse 2, M Braham 3, K Berjeb 3, M Khrouf 4, J K Rodrigues 5, F M Reis 5, T Cury- Silva 5, F Sánchez 6, S Romero 6, J Smitz 6, L Vásquez 7, M Vega 8, F Sobral 9, G Terrado 9, M G Lombardi 9, A Scarella 10, M T Bourlon 11, H Verduzco-Aguirre 11, A M Sánchez 12, S K Adiga 13, P Tholeti 13, K S Udupa 14, N Mahajan 15, M Patil 16, R Dalvi 17, C Venter 18, G Demetriou 19, J Geel 20, R Quintana 21, G Rodriguez 21, T Quintana 21, L Viale 21, M Fraguglia 21, M Coirini 22, Y A Remolina-Bonilla 23, J A R Noguera 23, J C Velásquez 23, A Suarez 23, G D Arango 24, J I D Pineda 25, M D C Aldecoa 25, M Javed 26, H Al Sufyan 26, N Daniels 27, B C Oranye 27, A A Ogunmokun 27, K I Onwuzurigbo 28, C J Okereke 28, T C Whesu 28, T K Woodruff 29
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PMID: 32594284 DOI: 10.1007/s10815-020-01821-7
Abstract
Purpose: The state of limited resource settings that Coronavirus (COVID-19) pandemic has created globally should be taken seriously into account especially in healthcare sector. In oncofertility, patients should receive their fertility preservation treatments urgently even in limited resource settings before initiation of anticancer therapy. Therefore, it is very crucial to learn more about oncofertility practice in limited resource settings such as in developing countries that suffer often from shortage of healthcare services provided to young patients with cancer.

Methods: As an extrapolation during the global crisis of COVID-19 pandemic, we surveyed oncofertility centers from 14 developing countries (Egypt, Tunisia, Brazil, Peru, Panama, Mexico, Colombia, Guatemala, Argentina, Chile, Nigeria, South Africa, Saudi Arabia, and India). Survey questionnaire included questions on the availability and degree of utilization of fertility preservation options in case of childhood cancer, breast cancer, and blood cancer.

Results: All surveyed centers responded to all questions. Responses and their calculated oncofertility scores showed different domestic standards for oncofertility practice in case of childhood cancer, breast cancer, and blood cancer in the developing countries under limited resource settings.

Conclusions: Medical practice in limited resource settings has become a critical topic especially after the global crisis of COVID-19 pandemic. Understanding the resources necessary to provide oncofertility treatments is important until the current COVID-19 pandemic resolves. Lessons learned will be valuable to future potential worldwide disruptions due to infectious diseases or other global crises.

Keywords: COVID-19; cancer; limited resource settings; oncofertility; pandemic.

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58
Antioxid Redox Signal
. 2020 Jun 29. doi: 10.1089/ars.2019.7968. Online ahead of print.
Common Signal Transduction Molecules Activated by Bacterial Entry Into a Host Cell and by Reactive Oxygen Species
Raffaella Bonavita 1, Mikko Olavi Laukkanen 2
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PMID: 32600071 DOI: 10.1089/ars.2019.7968
Abstract
Significance: An increasing number of pathogens are acquiring resistance to antibiotics. Efficient antimicrobial drug regimens are important even for the most advanced therapies, which range from cutting-edge invasive clinical protocols, such as robotic surgeries, to the treatment of harmless bacterial diseases and to minor scratches to the skin. Therefore, there is an urgent need to survey alternative antimicrobial drugs that can reinforce or replace existing antibiotics. Recent Advances: Bacterial proteins that are critical for energy metabolism, promising novel anticancer thiourea derivatives, and the use of synthetic molecules that increase the sensitivity of currently used antibiotics, are among the recently discovered antimicrobial drugs.

Critical issues: In the development of new drugs, serious consideration should be given to the previous bacterial evolutionary selection caused by antibiotics, by the high proliferation rate of bacteria, and by the simple prokaryotic structure of bacteria.

Future directions: The survey of drug targets has mainly focused on bacterial proteins, although host signaling molecules involved in the treatment of various pathologies may have unknown antimicrobial characteristics. Recent data have suggested that small molecule inhibitors might enhance the effect of antibiotics, e.g., by limiting bacterial entry into host cells. Phagocytosis, the mechanism by which host cells internalize pathogens through β-actin cytoskeletal rearrangement, induces calcium signaling, small GTPase activation, and phosphorylation of the PI3K-AKT pathway.

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59
Hum Reprod
. 2020 Jun 30;deaa128. doi: 10.1093/humrep/deaa128. Online ahead of print.
The PARP Inhibitor, Olaparib, Depletes the Ovarian Reserve in Mice: Implications for Fertility Preservation
Amy L Winship 1, Meaghan Griffiths 1, Carolina Lliberos Requesens 1, Urooza Sarma 1, Kelly-Anne Phillips 2 3 4, Karla J Hutt 1
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PMID: 32604417 DOI: 10.1093/humrep/deaa128
Abstract
Study question: What is the impact of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, alone or in combination with chemotherapy on the ovary in mice?

Summary answer: Olaparib treatment, when administered alone, depletes primordial follicle oocytes, but olaparib does not exacerbate chemotherapy-mediated ovarian follicle loss in mice.

What is known already: The ovary contains a finite number of oocytes stored within primordial follicles, which give rise to all mature ovulatory oocytes. Unfortunately, they are highly sensitive to exogenous DNA damaging insults, such as cytotoxic cancer treatments. Members of the PARP family of enzymes are central to the repair of single-strand DNA breaks. PARP inhibitors have shown promising clinical efficacy in reducing tumour burden, by blocking DNA repair capacity. Olaparib is a PARP1/2 inhibitor recently FDA-approved for treatment of BRCA1 and BRCA2 mutation carriers with metastatic breast cancer. It is currently being investigated as an adjunct to standard treatment at an earlier stage, potentially curable, BRCA1- and BRCA2-associated breast cancer which affects reproductive age women. Despite this, there is no preclinical or clinical information regarding the potential impacts of olaparib on the ovary or on female fertility. Unfortunately, it may be many years before clinical data on fertility outcomes for women treated with PARP inhibitors becomes available, highlighting the importance of rigorous preclinical research using animal models to establish the potential for new cancer therapies to affect the ovary in humans. We aimed to comprehensively determine the impact of olaparib alone, or following chemotherapy, on the ovary in mice.

Study design, size, duration: On Day 0, mice (n = 5/treatment group) were administered a single intraperitoneal dose of cyclophosphamide (75 mg/kg/body weight), doxorubicin (10 mg/kg), carboplatin (80 mg/kg), paclitaxel (7.5 mg/kg) or vehicle control. From Days 1 to 28, mice were administered subcutaneous olaparib (50 mg/kg) or vehicle control. This regimen is proven to reduce tumour burden in preclinical mouse studies and is also physiologically relevant for women.

Participants/materials, setting, methods: Adult female wild-type C57BL6/J mice at peak fertility (8 weeks) were administered a single intraperitoneal dose of chemotherapy, or vehicle, then either subcutaneous olaparib or vehicle for 28 days. Vaginal smears were performed on each animal for 14 consecutive days from Days 15 to 28 to monitor oestrous cycling. At 24 h after final treatment, ovaries were harvested for follicle enumeration and immunohistochemical analysis of primordial follicle remnants (FOXL2 expressing granulosa cells), DNA damage (γH2AX) and analysis of apoptosis by TUNEL assay. Serum was collected to measure circulating anti-Müllerian hormone (AMH) concentrations by ELISA.

Main results and the role of chance: Olaparib significantly depleted primordial follicles by 36% compared to the control (P < 0.05) but had no impact on other follicle classes, serum AMH, corpora lutea number (indicative of ovulation) or oestrous cycling. Primordial follicle remnants were rarely detected in control ovaries but were significantly elevated in ovaries from mice treated with olaparib alone (P < 0.05). Similarly, DNA damage denoted by γH2AX foci was completely undetectable in primordial follicles of control animals but was observed in ∼10% of surviving primordial follicle oocytes in mice treated with olaparib alone. These observations suggest that functional PARPs are essential for primordial follicle oocyte maintenance and survival. Olaparib did not exacerbate chemotherapy-mediated follicle depletion in the wild-type mouse ovary.

Large scale data: N/A.

Limitations, reasons for caution: This study was performed in mice, so the findings may not translate to women and further studies utilizing human ovarian tissue and sera samples should be performed in the future. Only one long-term time point was analysed, therefore olaparib-mediated follicle damage should be assessed at more immediate time points in the future to support our mechanistic findings.

Wider implications of the findings: Olaparib dramatically depleted primordial follicles and this could be attributed to loss of intrinsic PARP-mediated DNA repair mechanisms. Importantly, diminished ovarian reserve can result in premature ovarian insufficiency and infertility. Notably, the extent of follicle depletion might be enhanced in BRCA1 and BRCA2 mutation carriers, and this is the subject of current investigations. Together, our data suggest that fertility preservation options should be considered for young women prior to olaparib treatment, and that human studies of this issue should be prioritized.

Study funding/competing interest(s): This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. This work was supported by funding from the National Health and Medical Research Council (NHMRC); (K.J.H. #1050130) (A.L.W. #1120300). K.A.P. is a National Breast Cancer Foundation Fellow (Australia-PRAC-17-004). K.A.P. is the Breast Cancer Trials (Australia) Study Chair for the OlympiA clinical trial sponsored by AstraZeneca, the manufacturer of olaparib. All other authors declare no competing financial or other interests.

Keywords: BRCA1; BRCA2; DNA repair; PARP; fertility; olaparib; oocyte; primordial.

© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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60
Br J Radiol
. 2020 Jul;93(1111):20190464. doi: 10.1259/bjr.20190464. Epub 2020 May 21.
Analyzing Oropharyngeal Cancer Survival Outcomes: A Decision Tree Approach
Francesca De Felice 1 2, Laia Humbert-Vidan 3 4, Mary Lei 1, Andrew King 4, Teresa Guerrero Urbano 1
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PMID: 32391712 DOI: 10.1259/bjr.20190464
Abstract
Objectives: To analyze survival outcomes in patients with oropharygeal cancer treated with primary intensity modulated radiotherapy (IMRT) using decision tree algorithms.

Methods: A total of 273 patients with newly diagnosed oropharyngeal cancer were identified between March 2010 and December 2016. The data set contained nine predictor variables and a dependent variable (overall survival (OS) status). The open-source R software was used. Survival outcomes were estimated by Kaplan-Meier method. Important explanatory variables were selected using the random forest approach. A classification tree that optimally partitioned patients with different OS rates was then built.

Results: The 5 year OS for the entire population was 78.1%. The top three important variables identified were HPV status, N stage and early complete response to treatment. Patients were partitioned in five groups on the basis of these explanatory variables.

Conclusion: The proposed classification tree could help to guide future research in oropharyngeal cancer field.

Advances in knowledge: Decision tree method seems to be an appropriate tool to partition oropharyngeal cancer patients.

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61
Future Oncol
. 2020 Jun 29. doi: 10.2217/fon-2020-0020. Online ahead of print.
Clinico-radiological Monitoring Strategies in Patients With Metastatic Breast Cancer: A Real-World Study
Marta Bonotto 1, Debora Basile 1 2, Lorenzo Gerratana 1 2, Michele Bartoletti 1 2, Camilla Lisanti 1 2, Giacomo Pelizzari 1 2, Maria Grazia Vitale 1 2, Valentina Fanotto 1 2, Elena Poletto 1, Alessandro Marco Minisini 1, Stefania Russo 1, Claudia Andreetta 1, Mauro Mansutti 1, Gianpiero Fasola 1, Fabio Puglisi 2 3
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PMID: 32598185 DOI: 10.2217/fon-2020-0020
Abstract
Aim: A monitoring strategy for metastatic breast cancer patients (M-MBC) has been little studied. Materials & methods: This retrospective study analyzed a consecutive cohort of 382 MBC patients to analyze different M-MBC strategies to identify factors influencing intensive M-MBC. Results: Elevated baseline serum tumor markers (STM) was the strongest factor associated with increased use of STM tests. Having more frequent oncology office visits was associated with more intensive chemotherapy/magnetic resonance imaging (MRI) using. Increased use of imaging tests was associated with participation to clinical trial. Single and elderly patients were less likely to have frequent testing. Having clinically measurable disease was less likely to have more intensive M-MBC. Conclusion: STM testing and scans were frequently ordered in M-MBC. In the present study, strategies are little influenced by clinico-pathological characteristics.

Keywords: breast cancer, determinants of monitoring; metastatic breast cancer; monitoring breast cancer; monitoring strategies.

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62
Future Oncol
. 2020 Jun 29. doi: 10.2217/fon-2020-0131. Online ahead of print.
Rituximab Biosimilars in Hematologic Malignancies: The Need for a Real-World Approach
Pilar Nava-Parada 1 2, Ahmed Shelbaya 1 3, Chadi Nabhan 4 5
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PMID: 32598173 DOI: 10.2217/fon-2020-0131
Abstract
The introduction of rituximab biosimilars into healthcare systems can potentially help to control healthcare costs for the treatment of hematologic malignancies. However, there are currently several barriers to the uptake of biosimilars. This review discusses barriers to the adoption of rituximab biosimilars by stakeholders including patients and healthcare providers. We outline the importance of utilizing real-world evidence in providing additional clinical experience on rituximab biosimilars in hematologic malignancies to improve stakeholder confidence regarding their efficacy and safety. We conclude by offering recommendations for designing and conducting effective real-world studies. Such studies can provide evidence to help achieve lower-priced biologics and improved patient access to help sustain the treatment of hematologic malignancies with biologics, including rituximab biosimilars.

Keywords: biosimilars; hematologic malignancies; real-world evidence; rituximab.

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