Possible association of CAG repeat polymorphism in KCNN3 encoding the potassium channel SK3 with oxaliplatin-induced neurotoxicity

Abstract

Introduction

Data suggest a role of the potassium channel SK3 (KCNN3 gene) in oxaliplatin-induced neurotoxicity (OIN). Length variations in the polymorphic CAG repeat of the KCNN3 gene may be associated with the risk of OIN.

Materials and methods

We performed patch-clamp experiments on HEK293 cell lines, expressing SK3 channel isoforms with short (11) or long (24) CAG repetitions, to measure intracellular calcium concentrations to test the effects of oxaliplatin on current density. A retrospective study was carried out on patients with colorectal cancer who had received oxaliplatin-based chemotherapy. DNA for KCNN3 genotyping was extracted from leukocytes. The region containing the CAG repeats was amplified by PCR and the products separated by capillary electrophoresis for length analysis. The patients were divided into three groups depending on whether they carried two short alleles, one short allele and one long allele, or two long alleles. The primary endpoint was the onset of grade 2 or 3 neuropathy to oxaliplatin.

Results

There was no difference in current density, but oxaliplatin induced a differential effect on apamin-sensitive current density between the two isoforms expressed in the HEK cell lines. There was a significant reduction of store-operated calcium entry into cells expressing the short and more active isoform only after high concentration of oxaliplatin exposition. Eighty-six patients were included in the clinical study. There was no significant association between OIN and KCNN3 polymorphism for the three groups.

Conclusion

We observed a slight association between OIN and CAG repeat polymorphisms of the KCNN3 gene in a preclinical model, but not a clinical study.

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Out of my league: Appraisals of anxiety and confidence in others by individuals with and without social anxiety disorder

Publication date: Available online 16 May 2018
Source:Journal of Anxiety Disorders
Author(s): Tatiana Bielak, David A. Moscovitch, Stephanie Waechter
Forty participants with social anxiety disorder (SAD) and 42 healthy controls (HCs) were randomized to watch a confederate deliver a speech in either a visibly anxious or confident manner. Participants rated their perception of the presenter's desirability across five attributes and compared themselves to the presenter along these same dimensions. Participants then delivered their own speeches, and were rated in a similar manner by trained research assistants who were naïve to participants' group status and study objectives. Results demonstrated that all participants, irrespective of group status, judged the visibly anxious presenter as being less desirable and the confident presenter as more desirable. Socially anxious participants tended to view themselves as inferior to confident others. Coders also rated participants with SAD, based on their speeches, as being less interpersonally desirable than HCs. These results suggest that individuals who appear visibly anxious may be objectively disadvantaged in their ability to make a positive first impression on others. We discuss these findings in relation to theoretical models of social anxiety and explore how to address such interpersonal factors in psychological interventions for SAD.



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Global Acceptance of Biosimilars: Importance of Regulatory Consistency, Education, and Trust

AbstractGlobally, biosimilars are expected to have a key role in improving patient access to biological therapies and addressing concerns regarding the escalating cost of health care. Indeed, in Europe, increased use of biologics and reduced drug prices have been observed after the introduction of biosimilars. Recently, several monoclonal antibody biosimilars of anticancer therapies have been approved, and numerous others are in various stages of clinical development. Biosimilars are authorized via a regulatory pathway separate from that used for generic drugs; they are also regulated separately from novel biologics. Biosimilar approval pathways in many major regulatory regions worldwide are, to a broad degree, scientifically aligned. However, owing to regional differences in health care priorities, policies, and resources, some important regulatory inconsistencies are evident. Acceptance of biosimilars by health care systems, health care professionals, and patients will be a key factor in the uptake of these therapies, and such regulatory variations could contribute to confusion and diminished confidence regarding the quality, efficacy, and reliability of these agents. Furthermore, the need for manufacturers to account for regulatory inconsistencies introduces inefficiencies and delays into biosimilar development programs. These issues should be addressed if biosimilars are to attain their maximal global potential. This review summarizes the evolution of the global biosimilar landscape and provides examples of inconsistencies between regulatory requirements in different regions. In addition, we review ongoing efforts to improve regulatory alignment and highlight the importance of education as a crucial factor in generating trust in, and acceptance of, biosimilars on a worldwide scale.Implications for Practice.Biosimilars of monoclonal antibody anticancer therapies are beginning to emerge, and more are likely to become available for clinical use in the near future. The extent to which biosimilars can contribute to cancer care will depend on their level of acceptance by health care systems, health care professionals, and patients. A better understanding of the regulatory basis for the approval of biosimilars may enhance confidence and trust in these agents. In order to have informed discussions about treatment choices with their patients, oncologists should familiarize themselves with the biosimilar paradigm.

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Phase II Study of Irinotecan Plus Panitumumab as Second‐Line Therapy for Patients with Advanced Esophageal Adenocarcinoma

AbstractLesson Learned. Panitumumab plus irinotecan is not active for the treatment of esophageal adenocarcinoma.Background.Esophageal adenocarcinoma (EAC) is a lethal cancer with increasing incidence. Panitumumab (Pa) is a fully humanized IgG2 monoclonal antibody against human EGFR. Cetuximab (Cx) combined with irinotecan (Ir) is active for second‐line treatment of colorectal cancer. This phase II study was designed to evaluate Pa plus Ir as second‐line therapy for advanced EAC.Methods.The primary endpoint was response rate (RR). Patients with one prior treatment were given Pa 9 mg/m2 on day 1 and Ir 125 mg/m2 on days 1 and 8 of each 21‐day cycle. Inclusion criteria were confirmed EAC, measurable disease, no prior Ir or Pa, performance status <2, and normal organ function.Results.Twenty‐four patients were enrolled; 18 were eligible and evaluable. These patients were all white, with a median age of 62.5 years (range, 33–79 years), and included 15 men and 3 women. The median number of cycles was 3.5. The most common grade 1–2 adverse events were fatigue, diarrhea, anemia, leukopenia, and hypoalbuminemia. Grade 3–4 adverse events included hematologic, gastrointestinal, electrolyte, rash, fatigue, and weight loss. The median follow‐up was 7.2 months (range, 2.3–14 months). There were no complete remissions. The partial response rate was 6% (1/18; 95% confidence interval [CI], 0.01–0.26). The clinical benefit (partial response [PR] plus stable disease [SD]) rate was 50%. The median overall survival was 7.2 months (95% CI, 4.1–8.9) with an 11.1% 1‐year survival rate. The median progression‐free survival was 2.9 months (95% CI, 1.6–5.3).Conclusion.Irinotecan and panitumumab as second‐line treatment for advanced EAC are not active.

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Meta‐Research on Oncology Trials: A Toolkit for Researchers with Limited Resources

Abstract"Meta‐research" is a discipline that investigates research practices. Meta‐research on clinical trials is an attempt to summarize descriptive and methodological features of published or ongoing clinical trials, including aspects of their implementation, design, analysis, reporting, and interpretation. In this type of investigation, the unit of analysis is a primary source of information about a clinical trial (e.g., published reports, study protocols, or abstracts), with meta‐research being a second layer of information that summarizes what is known from various primary sources. After the formulation of the primary research question, the methodology of meta‐research resembles that of other research projects, with predefined eligibility criteria, exposure variables, primary and secondary outcomes of interest, and an analysis plan. This type of study usually provides a high‐level picture of the literature on a specific topic, always accompanied by a critical evaluation of the methodology and/or the quality of reporting of the studies included. Because relatively few resources are consumed to produce meta‐research, these studies offer a great opportunity for clinical scientists working in settings with limited resources. In this article, we present the principles of designing and conducting meta‐research and use our experience to suggest recommendations on how to perform and how to report this type of potentially very creative study.Implications for Practice.The term meta‐research pertains to a type of study in which the unit of analysis is, in most cases, the publication of a clinical trial. This type of study usually provides a high‐level picture of the literature on a specific topic, always accompanied by a critical evaluation of the methodology, design, and/or the quality of reporting of the studies included. Because relatively few resources are consumed to produce meta‐research, these studies offer a great opportunity for clinical scientists who work in low‐income countries. This article presents the principles of designing and conducting meta‐research and proposes practical recommendations on how to perform and report this type of potentially very creative study.

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Incidence of Thyroid Function Test Abnormalities in Patients Receiving Immune‐Checkpoint Inhibitors for Cancer Treatment

AbstractBackground.With the advent of immune‐checkpoint inhibitor (ICI) therapy (anti‐CTLA‐4, anti‐PD‐1), immune‐related adverse events such as thyroid function test abnormalities (TFTAs) are common, with a reported incidence range of 2%–15% depending upon the ICI used. The aim of this study is to describe the incidence of TFTAs retrospectively in patients who received ICI therapy.Methods.A total of 285 patients were reviewed (178 male, 107 female; 16–94 years of age), of whom 218 had no baseline TFTAs, 61 had baseline TFTAs, and 6 had a history of thyroidectomy (excluded). At least one dose of ipilimumab and/or nivolumab or pembrolizumab was administered. Post‐ICI therapy TFTAs were classified according to standard definitions of thyroid conditions when possible.Results.A total of 35% (76/218) patients had new‐onset TFTAs on ICI therapy. Of note, 70.5% (43/61) had baseline TFTAs that were exacerbated by ICI therapy. The median times to new‐onset or exacerbated baseline TFTA were 46 and 33 days, respectively. Of note, 64.5% (20/31) of patients on both ipilimumab and nivolumab had new‐onset TFTAs, compared with 31.3% (15/48) on ipilimumab, 31.5% (28/89) on nivolumab, and 26% (13/50) on pembrolizumab.Conclusion.The incidence of TFTAs with ICI therapy was higher than previously reported. Patients with baseline TFTAs and/or who were receiving ipilimumab and nivolumab combination therapy had a higher incidence of TFTAs than patients receiving single‐agent ICI therapy. We recommend more frequent evaluation of thyroid function in the first 8 weeks, especially in patients with baseline TFTAs.Implications for Practice.Increased use of immune‐checkpoint inhibitors in cancer treatment has highlighted the importance of monitoring for and treating immune‐related adverse events. This study was conducted to assess the incidence of thyroid function test abnormalities retrospectively in patients with cancer on immune‐checkpoint inhibitors, which is not known exactly. This study is unique in that it included patients with a variety of histologic subtypes of cancer and also followed the clinical course of patients with baseline thyroid function test abnormalities. This study can help make oncologists aware that the incidence of thyroid function test abnormalities is higher than anticipated. Early identification and timely treatment can help ameliorate symptoms for patients and improve their overall quality of life.

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Personalized Symptom Goals and Patient Global Impression on Clinical Changes in Advanced Cancer Patients

AbstractBackground.The aim of this study was to assess the patients' global impression (PGI) after symptom management, as well as the achievement of personalized symptom goals (PSG). The secondary outcome was to assess related factors.Subjects, Materials, and Methods. Advanced cancer patients admitted to palliative care units rated symptom intensity by using the Edmonton Symptom Assessment Score (ESAS) at admission and then after 1 week. For each symptom, patient‐reported PGI and PSG, as well as the rate of PSG response, were evaluated.Results.Eight hundred seventy‐six patients were taken into consideration for this study. A mean of 1.71–2.16 points was necessary to perceive a bit better improvement of symptom intensity. Most patients had a PSG of ≤3. A statistically significant number of patients achieved their PSG after starting palliative care. Patients with high intensity of ESAS items at admission achieved a more favorable PGI response. In the multivariate analysis, symptom intensity and PSG were the most frequent factors independently associated to a best PGI, whereas high levels of Karnofsky had a lower odd ratio.Conclusion.PSG and PGI seem to be relevant for patients' assessment and decision‐making process, translating in terms of therapeutic intervention. Some factors may be implicated in determining the individual target and clinical response.Implications for Practice.Personalized symptom goals and global impression of change are relevant for patients' assessment and decision‐making process, translating in terms of therapeutic intervention. Some factors may be implicated in determining the individual target and clinical response.

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Contamination of Scots pine forests with polycyclic aromatic hydrocarbons on the territory of industrial city of Siberia, Russia

Abstract

Anthropogenic contamination with polycyclic aromatic hydrocarbons (PAH) coming from a powerful aluminum smelter has been estimated by the accumulation of these substances (17 substances: phenanthrene, fluoranthene, pyrene, chrysene, acenaphthylene, acenaphthene, anthracene, fluorene, benz[а]anthracene, benz[b]fluoranthene, benz[k]fluoranthene, benz[а]pyrene, benz[е]pyrene, perylene, indeno[1,2,3-c,d]pyrene, benz[g,h,i]perylene, dibenz[a,h]anthracene) in needles of Scots pine (Pinus sylvestris L.) in the residential areas of Bratsk, East Siberia, Russia. It has been found that the total PAH amount reaches the maximum values (982 ng/g) in the needles of trees growing in a residential zone, remote from the smelter up to 10 km (Central Urban District), where more than half of the city's population lives. On the territory remote up to 25 km (Padunsky District), PAH needle levels decline, but are still 14.5–17.5 times higher than the background ones and at a distance of 45 km (Pravoberezhny District), they still exceed background levels (30 ng/g) by 4.7–8.1 times. Qualitative analysis of PAH showed the prevalence (up to 90% of the total amount) of 3–4 ring PAHs in pine needles on the entire studied territory. PAH concentrations increase when approaching the smelter with the highest values in the Central City District. Within the urban area, the content of PAHs with 5–6 rings (benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene (B[a]P), benz[a]anthracene, dibenz[a,h]anthracene, indeno[1,2,3-c,d]pyrene, benzo[g,h,i]perylene) is also significantly increased. In the Central District, needle concentration of B[a]P, which is a class 1 carcinogen, exceeds the background one by 22 times, the Padunsky District—by 7 times, and the Pravoberezhny District—by 3 times. In the territories of the Central Districts, needle level of perylene, which is a marker of territory pollution by aluminum smelter emissions, is 18 times, the Padunsky District—by 10 times, Pravoberezhny District—by 2.5–3 times higher than in the background, where the perylene level is below the detection limit (< 0.2 ng/g).

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The clinical significance of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) in gastric cancer: A systematic review and meta-analysis

Publication date: July 2018
Source:Critical Reviews in Oncology/Hematology, Volume 127
Author(s): Hai Qian, Kwaku Appiah-Kubi, Ying Wang, Min Wu, Yan Tao, Yan Wu, Yongchang Chen
BackgroundThe overexpression and mutation of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are widespread in cancers and have been recognized as attractive oncologic targets with diverse therapeutic targets. Reports of the overexpression of genes, proteins and mutations of PDGFs/PDGFRs in gastric cancer and their associations with clinicopathological features, Western and Asian patients, as well as prognostic role have shown variable outcomes. This study sought to employ meta-analysis to evaluate PDGFs/PDGFRs status prognostic significance and their association with clinicopathological features of gastric cancer.MethodA comprehensive search of PubMed database for studies that investigated the overexpression of mRNA/Protein and mutation of PDGFs/PDGFRs in gastric cancer of Western and Asian patients, their prognostic significance and association with clinicopathological characteristics in May, 2017 or earlier was carried out by two reviewers independently. Pooled odd ratios and hazard ratios at 95% confidence intervals were estimated and summarized using fixed-effect and random-effect Mantel-Haenszel models and Inverse Variance models in Review Manager software version 5.3.ResultsFourteen studies with 16 datasets of 1178 patients were included in meta-analysis. Fourteen studies of 1178 patients with 1446 cases and 7 studies of 1076 patients with 1280 cases were included in meta-analysis of clinicopathological and prognostic significance of high or positive PDGF/PDGFR status respectively. Odd ratio at 95% confidence intervals for different groups of analysis are as follows: males versus females(OR = 1.38, 95% CI: 1.04–1.83, POR = 0.03); ≥T2 stage versus T1 stage(OR = 2.06, 95% CI: 1.22–3.49, POR = 0.007); nodal metastasis versus no nodal metastasis(OR = 2.78, 95% CI: 1.48–5.22, POR = 0.002); TNM stage ≥II versus TNM stage I(OR = 3.55, 95% CI: 1.89–6.69, POR<0.0001). Subgroup analysis of the association of PDGF/PDGFR among Western patients(OR = 0.24 95% CI: 0.10–0.58, POR = 0.002) and association of PDGFs/PDGFRs gene mutation among gastric cancer patients(OR = 0.15, 95% CI: 0.05–0.45, POR = 0.0008) were significant. The association of PDGFs/PDGFRs in young and middle age versus elderly aged, undifferentiated versus well differentiated tumors, large tumor size group(>6 cm) versus small tumor size group(≤6 cm) were insignificant. Subgroup analysis of the association of PDGFs/PDGFRs among Western Asian patients; PDGF/PDGFR mRNA expression and protein expression among gastric cancer patients were insignificant. In addition, PDGF/PDGFR status among gastric cancer patients was insignificant in overall effect analysis PDGF/PDGFR status has shown to predict reduced overall survival(HR = 1.25, 95% CI: 0.49–3.22, PHR = 0.64) and relapse free survival(HR = 0.93, 95% CI: 0.36–2.41, PHR = 0.88) insignificantly. Also, overall prognostic effect analysis(HR = 1.07, 95% CI: 0.58–1.96, PHR = 0.84) was insignificant.ConclusionPDGFs/PDGFRs status amongst gastric cancer patients plays a key role in clinical variables and nodal metastasis. These insights might be helpful in providing guidelines for diagnosis, molecular target therapy, and prognosis of gastric cancer.



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Estrogen receptor-negative progesterone receptor-positive breast cancer – “Nobody's land“ or just an artifact?

Publication date: June 2018
Source:Cancer Treatment Reviews, Volume 67
Author(s): Michał Kunc, Wojciech Biernat, Elżbieta Senkus-Konefka
The estrogen receptor α (ER) and the progesterone receptor (PgR) are one of the most important prognostic and predictive immunohistochemical markers in breast cancer. Breast cancers may express various profiles of hormone receptors: ER(+)/PgR(+), ER(−)/PgR(−), ER(+)/PgR(−) and ER(−)/PgR(+). The existence of the latter profile is a matter of controversy since PgR expressions is induced by ER-dependent pathways in breast cancer cells. One of the most extensively propagated hypotheses trying to explain the origin of ER(−)/PgR(+) breast cancers claims that they are technical artifacts dependent on the immunohistochemical procedure. On the other hand, in recent years there is a growing body of evidence, suggesting that such cancers create a unique group with distinct molecular and clinical features. In the following review, we present background theories on the ER(−)/PgR(+) breast cancer origin and their epidemiological and clinicopathological characteristics, including the predictive and prognostic significance of these rare tumors.



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Burnout in Oncologists is a serious issue: What can we do about it?

Publication date: Available online 16 May 2018
Source:Cancer Treatment Reviews
Author(s): Krithika Murali, Susana Banerjee
The cancer burden is rising globally with an increasing need for oncologists. The significant demands associated with caring for cancer patients within a rapidly evolving scientific field, poses manifold challenges, including the risk of work-related burnout. Surveys have already shown that the prevalence of burnout in oncologists worldwide is significant. There is growing concern that burnout has a detrimental impact on the wellbeing of oncologists and their patients. In this review article, we provide an oncologist's perspective on this important and topical issue. We have summarised the literature with regard to the consequences of physician burnout, its associated risk factors and previously evaluated solutions. We conclude by suggesting further strategies for addressing this problem.



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33. SNP microarray autozygosity-directed mutation assessment of children and families with heritable retinal dystrophies in Costa Rica; identification of autosomal recessive mutations and one copy number variant

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Daynna J. Wolff, Iya Znoyko, W. Bailey Glen, Joaquin Martinez Arguedas, Rames Badilla Porras, Mae Millicent Peterseim




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21. Clinical utility of comprehensive genomic profiling in pediatric acute leukemias

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Gordana Raca, Jianling Ji, Matthew Oberley, Deepa Bhojwani, Jaclyn Biegel, Matthew Hiemenz




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29. Development and validation of 15-min FISH hybridization technology for interphase and metaphase cytogenetic samples

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Ramesh Babu, Daniel L. Van Dyke, Stephen L. Papa, Ernesto Fuentes, Sarah Fuentes, Srikanthi Kopuri, Cynthia Williamson, Mingya Liu, Vaithilingam G. Dev, Jim Tepperberg, Stuart Schwartz, Peter Papenhausen, Prasad Koduru




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Editorial Board

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225





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1. Detection of mosaicism and chimerism using SNP arrays in pediatric clinical testing: 10 year experience

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Laura K. Conlin, Brooke Weckselblatt, Jinbo Fan, Elaine Zackai, Matthew C. Dulik, Nancy B. Spinner, Minjie Luo




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23. Prevalence of KANK1-NTRK3 fusion in renal metanephric adenomas that lack BRAF mutations

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Aida Catic, Amina Kurtovic-Kozaric, Ardis Sophian, Lech Mazur, Faruk Skenderi, Ondrej Hes, Stephen Rohan, Dinesh Rakheja, Jillene Kogan, Michael R Pins




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3. Unusual case of mosaic Robertsonian Down syndrome with three cell lines and review of history of Robertsonian translocations at Greenwood Genetic Center

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Barbara DuPont, Frank Bartel, Alka Chaubey




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31. Assessing telomere length and chromosome aberrations in twin and unrelated astronauts

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Susan M. Bailey, Miles J. McKenna, Lynn Taylor, Kerry A. George




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4. Non-invasive prenatal screening: Understanding the underlying mechanisms for discordance

Publication date: August 2018
Source:Cancer Genetics, Volumes 224–225
Author(s): Rupa Udani, Kim Oxendine, Jennifer Laffin, Vanessa Horner




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