bluuebunny/crossref_metadata_2025_split huggingface dataset:
An 11-gene expression signature related to tumorigenesis and immunosuppression in primary cutaneous melanoma predicts sentinel lymph node metastatic status.
Authors: Tarhini Ahmad A. , Hobbs Brian , Khunger Arjun , Yassine Ibrahim , Kobeissi Iyad , Hwu Patrick , Sondak Vernon K. , LaFramboise William , Kirkwood John M. 
Published: June 2022

e21579 Background: A biomarker derived from the primary melanoma tumor to predict regional sentinel lymph node (SLN) metastatic status can be valuable in guiding the decision making in planning the SLN surgical procedure for candidate patients. Methods: Gene expression profiling was performed on primary cutaneous melanoma tumor biopsies of 49 (24 known SLN+, 25 SLN-) patients (T3a/b, T4a/b) who underwent SLN for staging using transcriptome profiling analysis. U133A 2.0 Affymetrix gene chips were used. Significance Analysis of Microarrays (SAM) was used to test the association between gene expression level of the primary tumor and SLN status. Genes with fold change > 1.5 and q value < 0.05 were considered differentially expressed. Pathway analysis was performed using Ingenuity Pathway Analysis. Benjamini and Hochberg method was used to adjust for multiple testing in pathway analysis. All statistical analyses were implemented in R. Results: A total of 49 patients with primary cutaneous melanoma were studied, of which, 24 were diagnosed as SLN positive and 25 as SLN negative by routine H&E and immunohistochemistry. Using SLN metastatic status as the outcome, a univariate logistic regression model was fitted with individual probe sets. A total of 251 probe sets were filtered and 11 probe sets were considered as differentially expressed (DE) between SLN-ve and SLN+ve groups, with the selection criterion set at Benjamini- Hochberg method -adjusted p -value below 0.05 and the absolute log fold change above 0.5. As each of the 11 probe sets was matched to a unique known gene, an 11 gene signature was derived and among them, the expression level of 7 genes was significantly reduced in the SLN+ve group compared to the SLN-ve group, while 4 genes were overexpressed in the SLN+ve group. Integrative and interactive heatmaps were produced from hierarchical cluster analysis to show the 11 differentially expressed genes. Selected genes were found to be uniformly related to tumorigenesis, malignant progression, DNA repair, cell cycle regulation, chemoresistance, immunosuppression and/or involvement in multiple cancer-related pathways. Several of the selected genes were previously shown to be prognostic in various malignancies. Conclusions: We present a unique 11-gene expression signature derived from primary melanoma tumor biopsy samples and related to tumorigenesis and immunosuppression that may be useful for the prognostic stratification of melanoma patients. This may allow the optimal selection of patients for SLN biopsy.
Whole-slide multispectral imaging reveals the immune subtypes of melanoma associated with the tumor microenvironment: An automated 7-color mIF assay.
Authors: Patel Bhavika , Allen Stephanie , Boldt Brittney , Ramirez Noah , Mammadova Najiba , Haggerty Agnes , Mehra Navi 
Published: June 2022

e21591 Background: Immunotherapy and precision medicine are rapidly developing approaches to cancer therapy. Biomarkers that detect the tumor and tumor microenvironment allow for the development of strategies that accelerate the advancement of treatments to enhance a patient’s immune system. Akoya’s MOTiF PD-1/PD-L1 Auto Melanoma Kit is a validated, multiplex immunoassay enabling detection of the 6 most clinically relevant immuno-oncology and spatial biomarkers: FoxP3, PD-L1, Sox10/S100, PD-1, CD8 and CD68. Methods: In this study, the MOTiF PD-1/PD-L1 panel was used to analyze the tumor microenvironment and specifically assess immune phenotypes within melanoma samples from 3 patients. This study demonstrates a fully optimized and end-to-end workflow solution for biomarker discovery in melanoma. Results: We demonstrate the utility of Akoya’s MOTiF PD-1/PD-L1 Melanoma panel kit in studying the cellular diversity while retaining spatial context. Stained slides were analyzed using the InForm and Phenoptr Reports image analysis platforms to identify phenotypes and better understand spatial relationships between cell phenotypes. The MOTiF PD-1/PD-L1 panel kit provides reproducibility across different patient samples. Conclusions: This data provides insight into the innate and adaptive immune landscape for targeted design of new immunotherapies as well as improved efficacy and reduced toxicity in the treatment of melanoma.
NOTCH4 mutation as a potential predictive biomarker for immunotherapy in NRAS wildtype melanoma.
Authors: Li Hongxia , Zhang Qin , Duan Qianqian , Tan Yuan , Sun Tingting , Qi Chuang , Ren Yong 
Published: June 2022

e21594 Background: NRAS wildtype melanoma account for 80-85% melanoma patients and have been reported had a better response for immunotherapy. Although PD-L1 expression and tumor mutation burden (TMB) have been considered as important biomarkers for immunotherapy in many types of tumors, the predictive efficacy of them in melanoma is controversial. Since evidences showed NOTCH pathway mutation was a potential predictive biomarker for immune checkpoint inhibitors in some types of tumors. Here we explored the relationship between NOTCH family genes mutations and efficacy of NRAS wildtype melanoma immunotherapy. Methods: 265 NRAS wildtype ICI-pretreatment melanomas from cBioPortal (https://www.cbioportal.org), which is divided to discovery (N = 76) and validation (N = 189) cohort to analyze the association between NOTCH family genes (NOTCH1-4) mutation and efficacy of ICIs therapy. All nonsynonymous somatic mutations, including nonsense, missense, nonstop, frameshift deletion and insertion, in-frame deletion and insertion, and splice site mutations were considered for inclusion in our study. The potential mechanism was subsequently explored through RNA expression in immunotherapy treated population. Results: Patients with NOTCH4-Mut were identified to be associated with prolonged overall survival (OS) in discovery (HR: 0.30, 95%CI: 0.11-0.83, P = 0.01) and validation cohort (HR: 0.21, 95%CI: 0.07-0.68, P = 0.003). Further exploration found that NOTCH4-Mut tumors had higher tumor mutation burden (TMB) and tumor neoantigen burden (TNB) (P < 0.05). RNA data revealed that enhanced anti-tumor immunity was observed in NOTCH4-Mut tumors. Activated CD4 memory T cell, CD8 T cell, follicular helper T cell (Tfh) and Neutrophils were more abundant in NOTCH4-Mut tumors. In addition, the results of enrichment analysis showed that several immune-related pathways varied significantly between NOTCH4-Mut and NOTCH4-Wt tumors, including Interferon γ response, DNA repair, epithelial mesenchymal transition (EMT), angiogenesis. Conclusions: NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guiding immunotherapeutic responsiveness.
The GERMELATOX-A (Dermatologic Cooperative Oncology Group): Study attitude of German melanoma patients towards toxicity during adjuvant treatment.
Authors: Kähler Katharina C. , Hüning Svea , Nashan Dorothée , Meiss Frank , Rafei-Shamsabadi David A , Rißmann Hannes , Colapietro Chiara , Livingstone Elisabeth , Maul Lara Valeska , Heppt Markus V , Hassel Jessica Cecile , Gutzmer Ralf , Loquai Carmen , Heinzerling Lucie , Sachse Michael Max , Bohne Ann-Sophie , Moysig Laura , Peters Wienke , Rusch Judith , Blome Christine 
Published: June 2022

e21597 Background: Trials of adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in recurrence-free survival (RFS) with a very similar relative risk reduction. Both treatment modalities are characterized by specific side effects. Therefore the decision for or against a treatment modality is very often driven by the risk for toxicity. This study addressed for the first time the attitudes and preferences of German and Swiss patients and physicians for adjuvant treatment with ICI and TT. Methods: In this multicenter study („GERMELATOX-A“) patients with low-risk melanoma (pT1a, AJCC stage I, familiar with cancer diagnosis but no adjuvant treatment planned), and dermatooncologists from 11 German and 1 Swiss skin cancer centers were asked to fill out a questionnaire. Here, side effect scenarios typical for each ICI and TT with mild-to-moderate or severe toxicity and also melanoma recurrence leading to cancer death were described. We asked patients and physicians about the reduction in melanoma relapse (relapse-free survival, RFS) and the survival increase (overall survival, OS) at 5 yrs they would expect to tolerate defined side-effects. Results: Data were obtained from 136/107 patients/physicians, respectively (median age: 59 yrs/32 yrs, 56.2%/67.6% female).Overall, by visual analog scale, patients valued a melanoma relapse worse than all scenarios of side-effects during adjuvant treatment with ICI or TT. In general patients required higher risk reductions for DFS and OS for both ICI and TT and their drug related side effects compared to physicians to accept this treatment. In case of severe side effects, patients needed a 20% higher reduction of relapse rate at 5 yrs for ICI compared to TT (71.4%/50.0%). Physicians required identical relapse reduction rates for ICI and TT in case of severe side effects (42.9%). Conclusions: This study demonstrated a pronounced variation of German and Swiss patient preferences on adjuvant treatment related to drug class specific side effects and outcomes and a clear difference between patients' and physicians' attitudes. This difference might influence decision making for adjuvant treatment options and should therefore also be investigated in further trials for current adjuvant treatment modalities. As adjuvant melanoma treatment with ICI and TT will possibly be implemented in earlier stages soon, precise knowledge of the patient perspective can be helpful for the process of decision making.
MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients: A retrospective study.
Authors: Saint-Ghislain Mathilde , Geoffrois Lionnel , Gastaud Lauris , Lesimple Thierry , Negrier Sylvie , Penel Nicolas , Kurtz Jean Emmanuel , Le Corre Yannick , Dutriaux Caroline , Gardrat Sophie , Barnhill Raymond , Matet Alexandre , Cassoux Nathalie , Ramtohul Toulsie , Servois Vincent , Mariani Pascale , Piperno-Neumann Sophie , Rodrigues Manuel 
Published: June 2022

e21601 Background: MBD4 encodes a glycosylase implicated in repair of lesions induced by DNA deamination and its inactivation in tumors is associated with a hypermutated phenotype. Uveal melanoma (UM) is a rare but aggressive form of melanoma carrying an extremely low mutation burden. Although metastatic UM (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI. Since then, other MBD4-inactivated UMs, acute myeloid leukemias, colorectal adenocarcinomas, gliomas and spiradenocarcinoma cases have been reported. Methods: Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients. Results: Three hundred mUM patients were analyzed. Median follow-up was 17.3 months. Ten objective responses and 20 stable disease for > 12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (CB; i.e. responder patients and stable disease) rate of 10%. Median progression-free survivals (PFS) in patients without and with CB were 3.1 and 16.3 months, respectively (p < 0.0001). Of the 134 tumors sequenced for MBD4, five (3.7%) were mutated. MBD4 inactivation was associated with higher mutation burden (179 to 643 variants versus a median of 16 in MBD4 wild-type), better objective response rate as 60% of MBD4m versus 4% of MBD4-wild type patients responded (Fisher’s exact p-test = 0.0009). Median PFS was 4.0 months in MBD4-wild type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median overall survival was 16.6 months in MBD4-wild type and unreached in MBD4m patients (HR = 0.11; p = 0.004). Conclusions: In mUM patients, MBD4 mutation is highly predictive for response to ICI, PFS and overall survival benefit. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM and other tumor types where MBD4 mutations are reported.
Overall survival of children with brain tumors after radiation therapy in Kazakhstan.
Authors: Dushimova Zaure , Goncharova Alyona , Kaidarova Dilyara , Kopochkina Sabina 
Published: June 2022

e22011 Background: Tumors of the central nervous system in children occupy the 2nd place in frequency in the structure of malignant neoplasms of childhood and the 1st place among solid tumors. They make up about 20% of all malignant neoplasms of childhood and are mainly represented by brain tumors. The purpose of the study was to analyze the survival rate depending on various factors during radiation therapy (RT) of brain tumors in children. Methods: Retrospective study included 277 patients who received RT from 2016 to 2020 at the Pediatric Oncology Center of the Kazakh Research Institute of Oncology and Radiology. The average follow-up time was 34.3 months. The median age was 9.5 years. RT was performed on a linear accelerator “TrueBeam”, in a single dose of 1.8 Gy, total 50.4-54.0 Gy, 5 fractions per week. Survival distributions was estimated by Kaplan and Meier curves and survival differences were evaluated using the log-rank test. IBM SPSS Statistics V23 was used for statistical analyses. Results: The overall survival (OS) rate of 277 patients was 70.8%, with an average life time of 55.6 months, 95% confidence interval (CI) (51.9 - 59.2). Children under 10 years of age showed a 12.5 % worse OS compare to children after 10 years of age. In patients with unconfirmed morphological verification, OS is 31.5% worse than in children with confirmed morphological verification. In children with grade I-II tumor differentiation, OS was 30.6% higher than in children with grade III-IV tumors. The method of RT (conformal RT, IMLT), gender of patients did not have a statistically significant effect on OS. Conclusions: Our study showed that OS rate depends on various factors, such as age, presence of morphology verification, and the degree of tumor differentiation. RT allows to achieve better survival in patients older than 10 years who received RT with a morphologically confirmed diagnosis of GI-II. RT is one of the main treatments for brain tumors in children.[Table: see text]
Self-reported well-being of cancer survivor (CS)-caregivers: An analysis of the Behavioral Risk Factor Surveillance System (BRFSS).
Authors: Wang Qian , Jiang Changchuan , Xie Hui , Theodoropoulos Nicholas , Wen Chi , Li Yannan , Shapiro Charles L. 
Published: June 2022

e22022 Background: With the advancement in cancer therapies and supportive care, the 5-year survival rate for all cancers combined has surpassed 67%, indicating an increased proportion of CS are going back to their life roles, including providing care to others. Being a caregiver is associated with an increased risk of physical and mental distress, depression, and sleep disturbance. Nevertheless, the well-being of “dual role” CS-caregivers remains unknown. Methods: Data were extracted from the BRFSS survey from 2016, 2018, and 2020. Outcome variables included self-reported poor general health, physical health, mental health, depression, physical inactivity, and inadequate sleep. Weighted multivariable logistic regression models were used to calculate the odds of self-reported well-being comparing CS-caregivers to non-CS caregivers. Results: 20% of CSs were caregivers. Among a total of 18,590 caregivers, 18,124 (weighted N=12,311,109) were non-CSs and 466 (weighted N= 287,807) were CSs. CS-caregivers were significantly more likely to have poorer general and physical health and be physically inactive than non-CS caregivers (Table). Differential impacts on the well-being of CS-caregiver were also observed by the female sex and less than 5 years since cancer diagnosis. Conclusions: One in five CS is a caregiver, translating into 3.4 million CS in the US population. CS-caregivers experience diminished well-being across a variety of measures than non-CS caregivers. These data suggest CS-caregivers may need additional psychosocial support. Future prospective longitudinal studies are needed to investigate the outcomes in this growing and vulnerable population.[Table: see text]
Colorectal cancer mortality rates and socioeconomic factors in Brazil: Association with income inequality and availability of medical doctors.
Authors: Maselli-Schoueri Jean Henri , Werneck De Carvalho Luis Eduardo , Paiva Laercio da Silva , de Almeida Roediger Manuela , de Abreu Luiz Carlos , Fonseca Fernando Luiz Affonso , Adami Fernando 
Published: June 2022

e22516 Background: Colorectal cancer mortality is expected to rise in the upcoming years in Brazil, especially in less developed regions. It is also known that socioeconomic factors play a role not only in the development, but also in the outcome of this disease. Methods: Ecological study that analyzed secondary data from 2016-2018 to examine the relationship between both income-inequality and the amount of doctors per inhabitant on colorectal cancer mortality in Brazil and its Federative Units. All data were gathered from Brazil’s public health system. Mortality was standardized by the World Health Organization’s population and analyzed by sex and age. Income-Inequality was measured using the Gini index, obtained from the United Nations Development Programme. The number of doctors was obtained from the Unified Health System and also calculated as the rate per 100,000 inhabitants. For this study, linear regression was performed using stepwise selection/backward elimination. Results: In the present study, we found that female sex (β -0.616, IC95% -1.308;0.075), the number of gastroenterologists (β -2.506, IC95% -3.702;-1.309), clinicians (β -0.107, IC95% -0.155; -0.0600), and the number of general surgeons (β -0.845, IC95% -1.188; -0.501) were negatively associated with colorectal cancer mortality, whereas higher income (β 0.02, IC95% 0.001;0.003), the amount of doctors in the public health system as a whole (β 0.090, IC95% 0.064;0.116), generalists (β 1.760, IC95% 0.987; 2.533) and oncology surgeons (β 14.252, IC95% 3.937; 24.566), were positively associated with cancer mortality. Conclusions: Colorectal cancer presents different mortality rates depending on sex, socioeconomic status and availability of medical doctors and specialists, whether for diagnosis and higher notifications or treatment and lesser deaths form the disease.
Gender disparities in multiple myeloma publications.
Authors: Dweik Aala , Dweik Hadeel , Mian Hira , Mohan Meera , Schinke Carolina D. , Al Hadidi Samer 
Published: June 2022

e23000 Background: Gender disparities exist in academia and are disproportionately affecting females. We conducted a cross sectional study to analyze gender disparities in MM publications in high impact hematology/oncology journals between January 1st, 2016 and December 31st, 2020. Methods: Data was collected through Medline/PubMed database search. High impact journals (impact factor > 10) with at least ten MM related publications were included. Impact factor data was based on the 2016 InCites Journal Citation Report. We used Genderize, a validated database, to determine authors’ gender. Search engines were used if gender was undetermined or did not meet a cut-off of 0.9. Unclassified genders after search were excluded from analysis. Results: A total of 679 publications with 8898 authorships were analyzed. Mean number of authors for females vs. males, per publication was 4.4 and 8.7, respectively. Females constituted a third of total authors. Female first authors, corresponding authors and last/senior authors were 34%, 21% and 18%, respectively. 17% of authors of clinical trial publications were females. Publications by country had comparable percentages (30% females as first authors in the U.S. vs. 32% females as first authors in other countries). The proportion of female authorship in 2020 when compared to 2016 was similar (33%). Between 2016 and 2020, there was slight improvement in female first authors (32%-37%), last authors (16%-21%), and corresponding authors (17%-22%). Conclusions: Gender disparities in MM publications exist and are more obvious in the last/corresponding authorship in both the U.S. and other countries. Despite improvement in proportion of female authors, it remains suboptimal when compared to the growing proportion of female physicians. Efforts should be made to identify factors that contribute to these disparities and work to resolve them.
The effect of a series of online CME activities on the multidisciplinary management of patients with GEP-NETs.
Authors: Worst Michelle Arielle , Caracio Rich , Whitney Megan , Cohen Jacob , Yao James C. 
Published: June 2022

e23004 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare, heterogenous neoplasms characterized by a wide spectrum of clinical manifestations. Management strategies are varied and include surgery, radiological intervention, cytotoxic chemotherapies, somatostatin analogs, TKIs, and novel peptide receptor radionuclide therapy (PRRT). Due to their clinical complexity, the diagnosis and treatment of GEP-NETS should involve collaboration between specialists in multiple disciplines. The objective of this study was to assess the educational impact of a series of continuing medical education (CME) activities on the knowledge, competence, and confidence of oncologists, gastroenterologists, and pathologists with respect to the use of novel systemic therapies for the multidisciplinary management of patients with GEP-NETs. Methods: The educational series consisted of 3 online, CME-certified activities. Educational impact was assessed with repeated pre-/post-education including multiple choice knowledge/competence questions and 5-point Likert scale confidence questions. Data from all oncologists, gastroenterologists, and pathologists who completed pre- and/or post-education assessments were aggregated across activities and stratified by learning theme. Relative changes in percentage of correct responses and clinicians who were confident (value of 4 or 5) were used to measure improvement in knowledge, competence, and confidence. A McNemar’s test assessed significant levels of changes reported with P values < .05 considered statistically significant. The first activity in the series launched December 2020 and the last launched February 2021; data were collected until February 2022. Results: The educational series resulted in overall statistically significant improvements in oncologists’, gastroenterologists’, and pathologists’ knowledge, competence, and confidence after education (N = 125 to 455, P < .05). Conclusions: This analysis demonstrates that oncologists’, gastroenterologists’, and pathologists’ knowledge, competence, and confidence regarding the use of novel systemic therapies in the multidisciplinary management of patients with GEP-NETs improved after education. Despite these improvements, additional educational activities are needed to address residual gaps and further increase clinicians’ ability in this clinical setting.[Table: see text]