tbuckley/cabot-search huggingface dataset:
Dietary fat in relation to overall and progression-free survival among patients (pts) with advanced or metastatic colorectal cancer (CRC): Data from CALGB 80405 (Alliance).
Authors: Erin Van Blarigan, Chao Ma, Fang-Shu Ou, Alan P. Venook, Kimmie Ng, Donna Niedzwiecki, Edward L. Giovannucci, Heinz-Josef Lenz, Federico Innocenti, James Edward Shaw, Blase N. Polite, Howard S. Hochster, Richard M. Goldberg, Robert J. Mayer, Eileen Mary O'Reilly, Charles S. Fuchs, Jeffrey A. Meyerhardt
Journal: Journal of Clinical Oncology (2021)

3588 Background: Growing data suggest dietary factors are associated with survival among pts with non-metastatic CRC. However, data on diet and survival among pts with advanced or metastatic disease are very limited. Methods: We prospectively examined dietary fat intake assessed at initiation of treatment for advanced or metastatic CRC in relation to OS and PFS. This analysis was conducted among 1,149 pts in the CALGB 80405 randomized controlled trial who completed a validated food frequency questionnaire. We examined intakes of saturated, monounsaturated, and polyunsaturated (total n-3, long-chain n-3, and total n-6) fats as well as animal and vegetable fats. Based on data from non-metastatic CRC and other cancers, we hypothesized that higher intakes of long-chain n-3 fatty acids and vegetable fats would be associated with longer OS and PFS and higher intakes of saturated fat and animal fat would be associated with shorter OS and PFS. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: Over a median follow-up of 6.1 years [y; interquartile range (IQR): 5.3, 7.2 y], we observed 974 deaths and 103 events of progression without death during follow-up. Participants in this analysis had a median age of 59 y (IQR: 51 to 67 y); 41% were female and 86% identified as white. We observed no statistically significant associations between any type of dietary fat and OS. However, vegetable fat was non-linearly associated with longer PFS (HR comparing 4 th to 1 st quartile: 0.78; 95% CI: 0.64, 0.96; p-trend: 0.10). We also observed a linear association between continuous saturated fat and PFS (HR per 5% kcal/d: 1.21; 95% CI: 1.03, 1.42; p-value: 0.02), perhaps driven by pts with high saturated fat intake. Conclusions: We observed no statistically significant associations between types of dietary fat and OS among pts with advanced or metastatic CRC. However, a healthy diet that includes vegetable fat and is modest in saturated fat may be associated with longer PFS. Future studies to replicate these findings and examine diet in relation to cancer survival in racially/ethnically diverse populations are needed. Support: K07CA197077, U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org . Clinical trial information: NCT00265850.
Phase I study of ruxolitinib with radiation and temozolomide in patients with newly diagnosed grade III gliomas and glioblastoma.
Authors: Yasmeen Rauf, Rachel Hufsey, Kathy Robinson, John H. Suh, Samuel T. Chao, Erin Sennett Murphy, Jennifer S. Yu, David M. Peereboom, Manmeet Singh Ahluwalia, Wei Wei
Journal: Journal of Clinical Oncology (2021)

2060 Background: Ruxolitinib is a novel, potent, and selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3, respectively. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells. Methods: Newly diagnosed patients with unmethylated MGMT Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks over 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3+3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily and level -1 was 5 mg twice daily. Arm 2 was started once safe dose was established for Arm 1 for each dose level. Patients with methylated MGMT glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks. Overall survival (OS) and progression-free survival (PFS) were estimate by Kaplan-Meier method and compared using log rank test. Results: 45 patients had survival data, 25 patients were Arm I and 20 arm II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p = 0.01 and p = 0.002), respectively. Conclusions: Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone. Clinical trial information: NCT03514069.
Prior DCIS and overall mortality in women with stage I breast cancer.
Authors: Rebecca A. Nelson, Lily L. Lai, Joanne E. Mortimer, Enrique Soto Perez De Celis, Rowan T. Chlebowski, Laura Kruper
Journal: Journal of Clinical Oncology (2021)

e12593 Background: Whether a prior diagnosis of ductal carcinoma in situ (DCIS) impacts women later diagnosed with invasive breast cancer is unclear. If localized breast cancer following DCIS is more aggressive than localized breast cancer alone, this could inform therapy decisions. To our knowledge, no study has examined the impact of prior DCIS on overall mortality in women with stage I invasive breast cancer. The study objective was to determine if overall mortality for women with stage I breast cancer with prior DCIS is different from those with stage I disease without prior DCIS. Our hypothesis was that women with prior DCIS would have higher mortality compared to those without prior DCIS. Methods: 302,484 patients with stage I cancer diagnosed from 1998 to 2016 were ascertained from SEER. Of these, 5,011 (1.7%) had prior DCIS. Patients with DCIS were matched 1:2 to women with no prior DCIS based on age, year of diagnosis, race/ethnicity, marital status, and invasive breast cancer characteristics including histology, tumor grade, tumor size, T stage, N stage, ER/PR status, surgery type, radiation, and chemotherapy status. The primary study outcome was overall mortality. Cox proportional hazards models were used to compute hazard ratios (HR) and 95% confidence intervals (CI). Results: Cases and controls had similar demographics. Compared to women with stage I breast cancer without prior DCIS, overall mortality was statistically significantly lower in women with stage I breast cancer with prior DCIS (hazard ratio [HR] 0.89 95% confidence interval [CI]0.80-0.98). Other factors associated with overall mortality were bilateral mastectomy (adjusted HR: 0.62; 95% CI: 0.49-0.78), radiation therapy (adjusted HR: 0.64; 95% CI: 0.56-0.75) and chemotherapy (adjusted HR: 0.85; 95% CI: 0.72-0.99). Factors associated with higher overall mortality included age (trend p &lt; 0.001), tumor grade (trend p = 0.003), and negative PR receptor status (adjusted HR: 1.29; 95% CI: 1.13-1.45). Breast cancer specific mortality, however, was statistically significantly higher in women with prior DCIS to their breast cancer diagnosis compared to women without prior DCIS to their breast cancer diagnosis (HR 1.24 95% CI 1.01-1.52). Conclusions: Contrary to our hypothesis, women with prior DCIS and subsequent stage I breast cancer have lower overall mortality compared to matched controls with stage I breast cancer without prior DCIS. In contrast, those with prior DCIS have higher breast cancer specific mortality than those without prior DCIS. Reasons for this discrepancy are unknown, but since DCIS is most commonly diagnosed on mammogram, differences may be related to sociodemographic characteristics that are associated with both higher screening adherence and higher overall survival, such as higher income, higher education achievement , and higher access to health care.
Three FDA advisory panel members resign over approval of Alzheimer’s drug
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Three members of a US Food and Drug Administration (FDA) advisory committee, which advised against authorising the Alzheimer’s disease drug aducanumab because of a lack of efficacy, have resigned after the agency went ahead and approved it.1

One of those who resigned, Harvard professor of medicine Aaron Kesselheim, wrote in a letter to acting FDA commissioner Janet Woodcock that the approval of Biogen’s drug was “probably the worst drug approval decision in recent US history.”

Kesselheim was joined in resignation by Mayo Clinic neurologist David Knopman and Washington University neurologist Joel Perlmutter. They were all members of the independent Peripheral and Central Nervous …
Improving cancer patient care with a digital telemonitoring platform: The ConnectPatienToDoctor study.
Authors: Carole Helissey, Claire Duverger, Hélène Vanquaethem, Yasmine Meghiref, Charles Parnot
Journal: Journal of Clinical Oncology (2021)

1581 Background: During COVID19 pandemic, clinicians have had to face two challenges in an unprecedented context: ensuring continuity of patient care for a disease that involves a life-threatening prognosis while reducing patients' vulnerability to this virus. The ConnectPatientToDoctor study aimed to evaluate a connected telemonitoring platform, Cureety, in cancer patient care. Patients and Methods: This prospective study was conducted at the Military Hospital Bégin. Each cancer patient was allowed to respond to a personalized symptomatology questionnaire based on CTCAE v.5.0, and personalized to their pathology and treatment. An algorithm evaluated the health status of the patient based on the reported adverse events and provided adapted recommendations. The calculated score allows to classify the patient into four different levels: (1) Correct State (green) (2) Compromised State (yellow) (3) State to be monitored (orange) (4) Critical State (red) In the case of orange or red classification, the patient was invited to call the hospital. In case of green or yellow classification, the patient received therapeutic advice set by the doctor, for each of the adverse events reported. The primary endpoint was to assess the feasibility of monitoring cancer patient with the connected platform. The secondary endpoint was to assess patient and caregivers’ satisfaction. Results: There were 108 patients included in the program between July 1st, 2020 and January 31 st , 2021. The median age was 70 and 77% presented a metastatic stage. The most represented cancer was prostate (50%), followed by lung (24%) and breast (15%). Overall, 1864 questionnaires were completed by the patients, resulting in 543 yellow alerts and 133 orange or red alerts. More than 60% of the alerts was managed through outpatient care or with a rapid intervention to resolve the adverse events. On a satisfaction scale from 1 to 10, where 10 was the highest, 72% of the patients responded with a 9 or 10. And all caregivers were satisfied because they could offer a better care, prioritize care, and save time. Conclusions: Participants in ConnectPatientToDoctor study reported that they had a clear benefit from using a connected platform to monitor their treatment. Patients felt less isolated and felt that they benefited from personalized care. This solution makes it possible to streamline the patient care process.[Table: see text]
Convergence of cytokine dysregulation and antibody deficiency in common variable immunodeficiency with inflammatory complications
Authors: Miranda L. Abyazi, Kayla A. Bell, Gavin Gyimesi, Turner S. Baker, Minji Byun, Huaibin M. Ko, Charlotte Cunningham-Rundles, Feng Feng, Paul J. Maglione
Journal: Journal of Allergy and Clinical Immunology (2021)
Application of a colorectal cancer ctDNA methylation test in endocrine cancers.
Authors: Jean M. Winter, Lorraine Sheehan-Hennessy, Susanne Kartin Pedersen, Molla M. Wassie, Graeme P. Young, Erin L. Symonds
Journal: Journal of Clinical Oncology (2021)

e15533 Background: Assays for circulating tumor DNA (ctDNA) have shown utility for cancer detection and management. It is important to demonstrate cancer specificity of targeted ctDNA biomarkers. Detection of methylated BCAT1 and IKZF1 ctDNA has shown high sensitivity for colorectal cancer (CRC). The aim of this study was to investigate whether hypermethylation of these two biomarkers is also present in prostate or breast adenocarcinoma (PCa or BCa) tissues, and if they are detectable as ctDNA from such cancer patients. Methods: A subset of TCGA data comprising matched tumor and normal samples from PRAD (n = 50), BRCA (n = 90) and COADREAD (n = 44) cohorts were accessed to interrogate DNA methylation (450K) at CpG probes covered by the BCAT1/ IKZF1 ctDNA assay (cg10764357 and cg07589773/cg18607529, respectively). Linear regression of BCAT1/ IKZF1 methylation and tumor staging was performed for cases with AJCC staging data (PRAD n = 503; BRCA n = 788; COADREAD n = 284). Blood was collected from BCa (n = 32) or PCa (n = 101) patients prior to starting treatment at Flinders Medical Centre (South Australia). DNA isolated from plasma was bisulphite-converted and assayed for BCAT1/ IKZF1 methylation. Age-adjusted comparisons of ctDNA positivity were made with blood results from N = 310 pre-treatment CRC patients (60% male), as well as male (N = 344) and female (N = 383) controls with a clear colonoscopy and no history of cancer. Results: BCAT1 and IKZF1 were significantly hypermethylated in PCa and CRC tumors compared to matched normal tissues (Table). Conversely, BCAT1/ IKZF1 CpG probes were hypomethylated in breast tumors compared to matched normal samples. There was no correlation between hypermethylation in IKZF1/ BCAT1 and stage of PCa or CRC. In contrast to PCa in silico findings of hypermethylation, BCAT1/IKZF1 ctDNA methylation was only positive in 7/101 PCa blood samples (6.9%; 95%CI 3.2-13.9%). Three of 32 BCa blood samples (9.4%; 95%CI 2.5-25%) were positive for BCAT1/IKZF1 methylation. These positivity rates were not significantly different to controls at 8.5% for females (p = 0.80 vs BCa) and 8.2% for males (p = 0.73 vs PCa), but all were significantly lower than that observed in CRC cases (59.0%, 183/310; p &lt; 0.001). Conclusions: While interrogation of TCGA datasets revealed IKZF1 and BCAT1 hypermethylation in prostate tumors, detection rate of these biomarkers in blood from PCa patients was not higher than that of non-cancer controls. Likewise, the BCAT1/IKZF1 ctDNA assay positivity rate in BCa patients was also no different to non-cancer controls. These findings highlight the specificity of methylated BCAT1 and IKZF1 ctDNA for detection of CRC.[Table: see text]
New genetic biomarkers to differentiate non-pathogenic from clinically relevant Bacillus cereus strains
Authors: Devon W. Kavanaugh, Benjamin Glasset, Rozenn Dervyn, Cyprien Guérin, Sandra Plancade, Sabine Herbin, Anne Brisabois, Pierre Nicolas, Nalini Ramarao
Journal: Clinical Microbiology and Infection (2021)
Dual role for CXCR3 and CCR5 in asthmatic type 1 inflammation
Authors: Marc Gauthier, Sagar Laxman Kale, Timothy B. Oriss, Kathryn Scholl, Sudipta Das, Huijuan Yuan, Sanmei Hu, Jie Chen, Matthew Camiolo, Prabir Ray, Sally Wenzel, Anuradha Ray
Journal: Journal of Allergy and Clinical Immunology (2021)
Pre-operative exercise therapy triggers anti-inflammatory trained immunity of Kupffer cells through metabolic reprogramming
Authors: Hongji Zhang, Tianmeng Chen, Jinghua Ren, Yujia Xia, Amblessed Onuma, Yu Wang, Jiayi He, Junru Wu, Han Wang, Ahmad Hamad, Chengli Shen, Jinxiang Zhang, John M. Asara, Gregory K. Behbehani, Haitao Wen, Meihong Deng, Allan Tsung, Hai Huang
Journal: Nature Metabolism (2021)
Burden of chemotherapy-induced peripheral neuropathy and associations with long-term sexual impairment in testicular germ cell tumor survivors.
Authors: Michal Chovanec, Dominika Galikova, Lucia Vasilkova, Valentina De Angelis, Katarina Rejlekova, Jana Obertova, Zuzana Sycova-Mila, Patrik Palacka, Katarina Kalavska, Daniela Svetlovska, Beata Mladosievicova, Jozef Mardiak, Michal Mego
Journal: Journal of Clinical Oncology (2021)

e17014 Background: Chemotherapy-induced peripheral neuropathy (CIPN20) after curative treatment for testicular germ cell tumors (GCTs) has been previously reported. The association of CIPN with long-term sexual function in GCT survivors remains unclear. Methods: European Organization for Research and Treatment of Cancer (EORTC) CIPN20 and PROMIS modified sexual function (SexF) questionnaires were prospectively completed by GCT survivors (N = 128) at National Cancer Institute in Slovakia during their annual follow-up visit. The median follow-up after completion of treatment was 10 years (range 4-25). Upon obtaining the scores from each questionnaire per recommended guidelines, each score from SexF was correlated with CIPN defined as high or low (above and below median) as obtained from CIPN20. Survivors were treated with cisplatin-based chemotherapy, radiotherapy to the retroperitoneum or both. Results: GCT survivors with CIPN reported a self-perceived sexual impairment. The overall perceived sexual impairment was higher in survivors with high vs low CIPN (mean score ± SEM: 7.44 ± 0.24 vs. 6.76 ± 0.21, P = 0.05). However, the overall perceived sexual abilities were not significantly different in CIPN high vs low (16.9 ± 0.68 vs. 16.8 ± 0.59, P = 0.97). The trend towards higher difficulty in maintaining erection was seen in CIPN high vs low survivors (3.94 ± 0.21 vs. 4.12 ± 0.18, P = 0.07). Furthermore, survivors with CIPN high were more disappointed with the quality of their sex life compared to those with CIPN low (1.96 ± 0.12 vs. 1.47 ± 0.11, P = 0.01). Patients with CIPN high had trend towards more anxiety from sexual relationships compared to CIPN low survivors (1.66 ± 0.11 vs. 1.33 ± 0.10, P = 0.06). The level of sexual desire, number of attempts to initiate sexual intercourse, ability to achieve erection, achieve orgasm were not different ( P all &gt; 0.05). Conclusions: GCT survivors with higher burden of CIPN have certain impairment in sexual functioning. We hypothesize there may be a common pathogenetic mechanism of induction in these long-term toxicities of curative treatments.
Analysis of circulating tumor DNA identifies homologous recombination repair molecular features of Chinese breast cancer.
Authors: Mingwei Li, Tongtong Yang, Huina Wang, Feng Lou, Shanbo Cao
Journal: Journal of Clinical Oncology (2021)

e13006 Background: Breast cancer (BC) is the most common cancer in women world-wide. Assessments of genomic variants in circulating tumor DNA (ctDNA) have generated great enthusiasm for their potential application as clinically actionable biomarkers in the management of BC. Alterations in homologous recombination repair (HRR), are a determinant of sensitivity to platinum chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARPi) in BC. However, as far as we known, most of HRR genes, except BRCA1/2, have not yet been fully understood to date. In this study, we aimed to elucidate the comprehensive HRR genetic alteration profile of breast tumors among Chinese patients by ctDNA analysis. Methods: Plasma ctDNA from 259 patients with BC were deeply sequenced via next-generation sequencing (NGS) techniques using AcornMed Biotechnology for 808 genes panel. Molecular profiles were reviewed to identify somatic and germline pathogenic mutations in the 14 HRR genes ( ATM, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, CDK12, and BARD1) . Results: At our institution, 259 patients underwent NGS analysis of BC specimens. The median age was 46 (range from 31 to 79). Based on the analysis of the genetic alteration profile from our cohort, at least one of the HRR genes was observed from 29.34% of the tumor samples, with BRCA1 (8.11%), BRCA2 (5.79%), RAD51C (5.02%), CDK12 (4.63%), CHEK2 (1.93%), ATM (1.16%), and BARD1 (1.16%) as the most commonly altered genes. As compared with MSKCC dataset (Table), genetic alterations detected from our cohort affected genes involved in HRR (29.34% vs. 14.03%, P＜0.0001) pathways, with statistically different genetic alteration rates. Moreover, BRCA1/2, RAD51C, CDK12 and CHEK2 mutations exhibited higher mutation rates, whereas ATM, BRIP1 and PALB2 mutations presented a lower mutation rate in Chinese patients with breast cancer (P＜0.05). Conclusions: CtDNA can characterize the mutational feature of HRR in BC. our study contributes to the understanding of the HRR pathways and specific genetic alterations harbored by Chinese patients with BC that could potentially be developed as markers of treatment response to targeted therapeutics. Ref: Razavi P, Chang MT, Xu GT, et al. The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer Cell. 2018 Sep 10;34(3):427-438.e6. doi: 10.1016/j.ccell.2018.08.008.[Table: see text]
Comorbidity affects Вcl-2 levels in mitochondria in C57BL/6 mice with transplantable B16/F10 melanoma.
Authors: Irina V. Neskubina, Elena M. Frantsiyants, Valeria A. Bandovkina, Natalia D. Cheryarina, Alla I. Shikhlyarova, Ekaterina I. Surikova, Irina V. Kaplieva, Ludmila A. Nemashkalova, Viktoria V. Pozdnyakova, Yuriy V. Przhedetskiy, Viktoria Yu. Przhedetskaya, Maria G. Ilchenko, Elena I. Agarkova, Natalia A. Maksimova, Olga Khokhlova, Natalia A. Zakharova, Oleg I. Kit
Journal: Journal of Clinical Oncology (2021)

e21581 Background: Overexpression of the Bcl-2 protein inhibits apoptosis and promotes carcinogenesis. Stress causes signaling leading to cell buffering with Bcl-2 protein above acceptable levels. The purpose of the study was to analyze the influence of comorbidity – chronic neurogenic pain (CNP) – on the Bcl-2 levels in mitochondria of cells of melanoma, the heart, skin and brain in female mice with growing tumors. Methods: Female С57ВL/6 mice were divided into groups: intact group (n = 21); control group with a CNP model – bilateral sciatic nerve ligation (n = 21); group M – B16/F10 melanoma (n = 63); CNP+M group – B16/F10 melanoma was transplanted 3 weeks after the CNP model creation (n = 63). The concentration of Bcl-2 (ng/mg of protein) was determined in mitochondrial samples by ELISA (Thermo Fisher Scientific, Austria). Statictical analysis of results: Statistica 10.0. Results: CNP decreased the Bcl-2 level in heart mitochondria by 1.3 times (p &lt; 0.05), but increased it in skin and brain mitochondria by 5.8 and 1.3 times, respectively. Similar changes were observed in melanoma growth 1 week after its transplantation: Bcl-2 levels decreased in heart mitochondria by 1.3 times, and increased in the skin and brain by 8.9 and 1.3 times, respectively. After 2 weeks of the tumor growth, Bcl-2 in brain mitochondria decreased by 1.7 times, and it started declining in the skin by the 3rd week – by 4 times, compared to intact females. Bcl-2 in tumor mitochondria exceeded the values in the skin by more than 4 times throughout the experiment. Tumor growth in presence of CNP caused a decrease in Bcl-2 in brain mitochondria by 2.4 times after 3 weeks, and in the heart and skin – by 2 and 1.7 times, respectively, after 2 weeks. Bcl-2 in tumor mitochondria in presence of CNP was lower than in the intact skin on average by 1.8 times throughout the experiment. Conclusions: CNP as a comorbidity caused a modulating effect on the mechanisms of survival and apoptosis of cells both in the tumor and in the main organs providing the vital functions of the body - the brain and heart, and also affects the target organ of melanoma - the skin. The results demonstrated the ability of comorbidity to change levels of Bcl-2 in mitochondria depending on the stage of tumor development.