tbuckley/cabot-search huggingface dataset:
CCR5 Δ32 mutation and gene expression to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and MAVERICC phase III trials.
Authors: Annika Lenz, Wu Zhang, Yi Xiao, Joshua Millstein, Shivani Soni, Hiroyuki Arai, Jingyuan Wang, Aparna Raj Parikh, Christoph Mancao, Sebastian Stintzing, Volker Heinemann, Francesca Battaglin
Journal: Journal of Clinical Oncology (2020)

170 Background: Germline polymorphisms in CCR5 have been associated with treatment outcome in pts with mCRC receiving regorafenib and cetuximab-based treatment. CCR5 Δ32, a loss of function deletion, plays a key role in infectious diseases but data in CRC are scarce. We tested whether CCR Δ32 and CCR5 gene expression may be associated with outcome in mCRC pts receiving first-line treatment. Methods: The impact of CCR5 Δ32 was evaluated in 614 pts enrolled in the randomized FIRE-3 trial (FOLFIRI/cetuximab, cet, n = 313; FOLFIRI/bevacizumab, bev, n = 301). Gene expression was evaluated in 102 pts in the FOLFIRI/cet arm from FIRE-3 and 155 pts treated in the MAVERICC trial (FOLFIRI/bev, n = 76; FOLFOX6/bev, n = 79) from tumor tissue by HTG EdgeSeq Oncology Biomarker Panel and NanoString expression panel, respectively. The association between CCR5 Δ32 and clinical outcomes was evaluated using Cox regression and log-rank tests. Gene expression was dichotomized using an optimal cutoff and P-values computed using a permutation-based approach. Results: In FIRE-3, CCR5 Δ32 was significantly associated with worse PFS in patients with right-sided tumors (RT) receiving FOLFIRI/cet (n = 32; median PFS 3.41 vs 7.84 mo; HR 4.39, 95%CI 1.12-17.24; P= .022;). These associations were not observed in left-sided tumors or pts treated with bev. Lower levels of CCR5 expression trended to be associated with shorter PFS and OS in the same subgroup of RT treated in the cet arm ( P= .096 and P= .063 for PFS and OS, respectively). Lower CCR5 expression was associated with longer PFS in pts treated with FOLFIRI/bev in the MAVERICC trial, regardless of tumor side (mPFS 17.91 vs 11.04 mo; P= .03). A significant interaction between the impact of CCR5 expression levels on PFS and chemotherapy backbone was observed ( P= .019). Low CCR5 expression was associated with worse PFS in pts with RT treated with oxaliplatin (11.10 vs 13.80 mo; P= 0.023). Conclusions: Our results provide the first evidence that CCR5 Δ32 and CCR5 gene expression levels may predict outcomes in mCRC pts receiving first-line treatment with a differential effect depending on tumor location, biologic agent and chemotherapy backbone.
Final Results of a Randomized, Double-Blind Phase II Study to Compare Nitroglycerin (N) Plus Oral Vinorelbine (NVBO) Plus Cisplatin (C) with Placebo (P) Plus NVBO Plus C in Patients (Pts) with Stage IIIB/IV Non-Small Cell Lung Cancer (NSCLC)
Authors: M. Reck, A. Meyer, D. Hartwigsen, C. Schaeper, R. Skock-Lober, A. Bier, G. Huebner, U. Gereke, C. Rose, C.P. Held
Journal: Annals of Oncology (2012)
Use of glycosylated hemoglobin and C-peptide levels in the diagnosis and prevention of type 1 diabetes mellitus as an immune-related adverse event secondary to treatment with immunotherapy in solid tumors.
Authors: Alejandro J. Olivares Hernández, Roberto Andrés Escala Cornejo, Luis Figuero Pérez, Rosario Vidal, Elena Escalera Martín, Juncal Claros Ampuero, Diego Casado Elía, María García Muñoz, Arantzazu Amores Martin, Cesar Augusto Rodriguez, Rogelio González Sarmiento, José Pablo Miramontes González, Juan J. Cruz-Hernández
Journal: Journal of Clinical Oncology (2020)

97 Background: Type 1 diabetes mellitus (T1D) as an immune-related adverse event (irAE) is found in 0.5-5% of all patients treated with immunotherapy (IT) and it is associated with life-threatening complications. However, there are no official guidelines that suggest methods for the prevention and monitoring of T1D during treatment with IT. The algorithms described in the literature only assess the fasting blood sugar levels for prevention and monitoring. The objective of this review is to find factors that establish a relationship with the appearance of T1D as an irAE and to put forward a new algorithm for prevention and monitoring based on those findings. Methods: We carried out a clinical review of the cases published in the literature on T1D secondary to IT between 2012 and 2019. Through a statistical analysis, the relevant clinical characteristics will be determined, together with the factors related to the appearance of T1D, which will make it possible to put forward a new algorithm for the prevention and monitoring of T1D during treatment with IT for solid tumors. Results: Eighty one cases were reported. Of the reported cases, 90% were associated with Nivolumab or Pembrolizumab. The median age was 67 years (23-84 years), and the patients were predominantly men. The average number of administered doses was 5.3 with a lapse of 14.6 weeks from the administration of the first dose until diagnosis. In 48 cases (59%) the levels of C-peptide were low or undetectable, and the glycosylated hemoglobin (HbA1c) levels were elevated by an average of 8.8% (73 mmol/mol). Anti-β-cell antibodies were found in less than half of the patients (44). Diabetic ketoacidosis was observed at diagnosis in 61 patients (75%). Conclusions: Based on the results of our review, we propose including the levels of C-peptide and HbA1C in the usual protocol for the management of adverse events related to IT. Our algorithm suggests that the levels must be determined prior to the IT, after the first 2 cycles, and then every 2 months. This algorithm will enable the prevention, early diagnosis and monitoring of T1D during treatment with IT.
Glucocorticoid prescribing habits of sports medicine physicians working in high-performance sport: a 30-nation survey
Authors: David Hughes, Nicole Vlahovich, Marijke Welvaert, Nicolin Tee, Peter Harcourt, Susan White, Alan Vernec, Ken Fitch, Gordon Waddington
Journal: British Journal of Sports Medicine (2020)

Glucocorticoids are commonly prescribed in medicine. When administered via certain routes, glucocorticoids are prohibited for incompetition use by WADA. The glucocorticoid prescribing habits of sports medicine doctors have not been reported.An online survey was distributed internationally to physicians working in high-performance sports. The survey queried the doctors about their use of glucocorticoids with athletes and their understanding of WADA's regulations regarding glucocorticoid use in competition.603 sports medicine doctors from 30 different countries participated. The majority (>85%) routinely injected glucocorticoids and/or prescribed glucocorticoids by other routes. There were substantial differences in the common routes of injection as well as types of glucocorticoid used among the physicians from various countries. A relatively small percentage of sports doctors (<25%) accurately identified which routes of glucocorticoid administration are prohibited in competition by WADA. There was a great variation in how long before competition the use of glucocorticoids would cause the doctor to consider applying for a therapeutic use exemption (TUE). A better understanding of the clearance rates of glucocorticoids from athletes' bodies would greatly aid sports medicine doctors' decisions on how and when to apply for a TUE. A small number of doctors had observed side effects of glucocorticoid administration, with the majority of side effects being minor in nature.Glucocorticoids are widely prescribed by sports physicians. There is a need to better educate sports physicians on the current WADA regulations in relation to glucocorticoid administration.
One small step for man, one giant leap for men’s health: a meta-analysis of behaviour change interventions to increase men’s physical activity
Authors: Paul Sharp, John C Spence, Joan L Bottorff, John L Oliffe, Kate Hunt, Mathew Vis-Dunbar, Cristina M Caperchione
Journal: British Journal of Sports Medicine (2020)

To determine the effects of behaviour change interventions on men's physical activity (postintervention), sustained change in physical activity behaviour (≥12 months postintervention) and to identify variations in effects due to potential moderating variables (eg, theoretical underpinning, gender-tailored, contact frequency).Systematic review with meta-analysis. Pooled effect size (Cohen's d) was calculated assuming a random-effects model. Homogeneity and subsequent exploratory moderator analyses were assessed using Q, T2 and I2.Medline, EMBASE, CINAHL, SportDiscus and Web of Science to April 2019.Randomised control trials of behaviour change interventions in men (≥18 years) where physical activity was an outcome and data were from men-only studies or disaggregated by sex.Twenty-six articles described 24 eligible studies. The overall mean intervention effect on men's physical activity was 0.35 (SE=0.05; 95% CI 0.26 to 0.45; p<0.001). This effect size is consistent with an increase of approximately 97 min of total physical activity per week or 980 steps per day. Intervention moderators associated with greater increases in physical activity included objective physical activity outcome measures, a gender-tailored design, use of a theoretical framework, shorter length programmes (≤12 weeks), using four or more types of behaviour change techniques and frequent contact with participants (≥1 contact per week). 12 studies included additional follow-up assessments (≥12 months postintervention) and the overall mean effect was 0.32 (SE=0.09; 95% CI 0.15 to 0.48; p<0.001) for that sustained increase in physical activity.Behaviour change interventions targeting men's physical activity can be effective. Moderator analyses are preliminary and suggest research directions.
Outcomes after high-dose radiation in management of neuroendocrine neoplasms.
Authors: Katherine Chen, Julia Whitman, Alan Paciorek, Eric K. Nakakura, Nicholas Fidelman, Mary Uan-Sian Feng, Emily K. Bergsland, Mekhail Anwar
Journal: Journal of Clinical Oncology (2020)

616 Background: In this study, we analyze outcomes after the use of high-dose radiation therapy (RT) in management of neuroendocrine neoplasms (NENs) at a high-volume center. Methods: We performed a retrospective review of patients who received high-dose RT (defined as biologically effective dose (BED) &gt;40, α/β = 10) for their NEN. Patients with small cell lung cancer and Merkel cell carcinoma were excluded, given their unique treatment paradigms. Results: 61 patients completed a radiation course with BED &gt;40 for their NEN (median BED 70, range 44-180). Most tumors were gastroenteropancreatic in origin (n = 20); additional primary sites included lung (n = 11), head and neck (n = 10), cervix (n = 6), other (n = 9) and unknown (n = 5). 56% (n = 34) had well-differentiated (WD) neuroendocrine tumors, and 44% (n = 27) had poorly-differentiated (PD) neuroendocrine carcinomas. Disease stage at the time of RT was localized/locally advanced (LLA, n = 27), or metastatic/recurrent (MR, n = 34). The intent of RT was definitive (n = 18), post-operative (n = 10), for oligoprogression (n = 18), or purely palliative (n = 15). 48 patients had follow-up imaging at a median follow-up of 20 months after radiation. Outcomes were grouped by differentiation and stage, with median time to progression (mTTP) in months (Table). 8% of patients had local progression, while 44% developed new metastases, including 38% of WD-LLA, 47% of PD-LLA, 37% of WD-MR, and 67% of PD-MR disease with progressively shorter median time to progression (26, 10, 8, and 3 months, respectively). Conclusions: These data suggest that focal, high-dose radiation has a role in the management of NENs. Local failure is rare in patients with both WD-LLA and PD-LLA disease. The predominant pattern of failure is development of new metastases, which appear to occur sooner and more frequently in patients with PD and MR disease. [Table: see text]
Role of precision medicine for patients with advanced biliary tract cancers.
Authors: Antoine Hollebecque, Oumrou Nabi, Michel Ducreux, Valerie Boige, Jean-Yves Scoazec, Etienne Rouleau, Alice Boileve, Cristina Smolenschi, Loic Verlingue, Margarida Matias, Pascal Burtin, Caroline Prieux-Klotz, Christophe Massard, David Malka
Journal: Journal of Clinical Oncology (2020)

552 Background: Biliary tract cancers (BTC) are rare and heterogeneous cancers with poor prognosis. Several actionable genomic targets have been described in BTC but data on the efficacy of targeted therapies remain limited. The main objectives of this retrospective study was to evaluate the frequency of actionable genomic alterations among BTC and the impact of targeted therapy. Methods: We performed a retrospective analysis on BTC patients seen at Gustave Roussy (IGR) from Dec 2011 to Jul 2019. All clinical and genomic reports were reviewed. Results: The study population included 212 patients with the main following characteristics: median age 61 years, female 51%, intrahepatic cholangiocarcinoma 57%, median of 2 previous lines. Of 212 BTC patients, 170 patients had a genomic profile based on archival tissue or a new tumor biopsy (IGR panel n = 120; Foundation One panel n = 92 ). 124 patients (73%) had at least one genomic alteration and 68 (40%) patients had genomic alteration considered as actionable. The most common actionable targets were FGFR2 rearrangement/mutation (n = 24, 35.3%), HER2/3 mutations (n = 9, 13.2%) and IDH1/2 mutations (n = 7, 10.3%). Of those 68 patients, 58 received the matched targeted therapy: FGFR inhibitor n = 24, HER2/3 inhibitors n = 9, Akt/PIK3CA/mTOR inhibitors n = 7, IDH1 inhibitor n = 6. In the treated population, the objective response rate was 36.2% and the disease control rate 85.1%. Progression-free survival (PFS) was 6.2 months compared to 2.8 months (p = 0.02) for patients who did not received targeted treatment. Overall survival (OS) was 17.7 months compared to 11.0 months (p = 0.03) for patients who did not received targeted treatment. Conclusions: Actionable genomic targets are frequent among BTC. Profiling-directed therapies resulted in a 36% response rate, a 85% tumor control rate and a 6.2 months PFS which compare favorably to second-line chemotherapy. A randomized trial is required to confirm the benefit of precision medicine in BTC.
Stent-Related Adverse Events &gt;1 Year After Percutaneous Coronary Intervention
Authors: Mahesh V. Madhavan, Ajay J. Kirtane, Björn Redfors, Philippe Généreux, Ori Ben-Yehuda, Tullio Palmerini, Umberto Benedetto, Giuseppe Biondi-Zoccai, Pieter C. Smits, Clemens von Birgelen, Roxana Mehran, Thomas McAndrew, Patrick W. Serruys, Martin B. Leon, Stuart J. Pocock, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2020)
Exploratory longitudinal analysis of cfDNA to reveal potential biomarkers of CRC progression and treatment response.
Authors: Francesco Vallania, Karen Assayag, Hayley Warsinske, Peter Ulz, John St John, Carrie Brachmann, Scott D. Patterson, Dung Thai, Pankaj Bhargava, Manish A. Shah, Heinz-Josef Lenz, Johanna C. Bendell, Claudia Rubio
Journal: Journal of Clinical Oncology (2020)

207 Background: Blood-based tests can predict drug response and disease progression. Many tests rely on detecting tumor DNA, which represents only a fraction of all cell-free DNA (cfDNA). Here, we used a novel methodology to infer gene activation from cfDNA. This unique platform offers the ability to identify potential non-tumor derived biomarkers that may be associated with clinical outcomes in colorectal cancer (CRC). Methods: Longitudinal plasma samples from metastatic CRC patients enrolled in NCT01803282 (andecaliximab/chemotherapy/bevacizumab; 92 samples from 12 patients) were evaluated. Patients were classified as progressors (SD+PD) or responders (CR+PR) based on best objective response. Gene activation was inferred from cfDNA fragment length and counts around transcription start sites using whole-genome sequencing. Transcription factor activity was estimated by measuring binding site accessibility across the genome. Tumor fraction (TF) was estimated using ichorCNA. Results: Gene activation profiles inferred from cfDNA across the entire genome identified several genes differentially expressed in progressors or responders. Specifically, all patients with elevated KIR2DL1, an inhibitory NK cell receptor, progressed (p = 6.35e-14). Additionally, BMPR1A activation decreased in responders (p = 0.002) while the DNA- binding activity of SMAD1, which functions directly downstream of BMPR1A in the BMP2 pathway, increased in responders post-therapy (p = 0.03). These 3 genes (i.e., KIR2DL1, BMPR1A and SMAD1) are related to NK cell maturation, suggesting an immunological mechanism. Notably, pre-therapy TF did not predict response. Conclusions: In this pilot study, we demonstrated the ability of a unique cfDNA platform to interrogate multiple features to reveal genes associated with drug response and their underlying mechanism. We identified that KIR2DL1 is associated with progression, and BMPR1A and SMAD1 are associated with response. This work highlights the potential of cfDNA to provide biological insights beyond TF and that identification of non-tumor-derived signals may benefit biomarker discovery and drug target identification.
A phase I/IIa clinical trial investigating the therapeutic cancer vaccine UV1 in combination with ipilimumab in patients with malignant melanoma: Four-year survival update.
Authors: Espen Basmo Ellingsen, Elin Aamdal, Else Marit Inderberg, Wenche Rasch, Paal Brunsvig, Steinar Aamdal, Eivind Hovig, Marta Nyakas, Tormod Kyrre Guren, Gustav Gaudernack
Journal: Journal of Clinical Oncology (2020)

62 Background: Combining checkpoint blockade with a cancer vaccine may induce broader immune responses, leading to better clinical outcomes. UV1 targets the enzyme telomerase (hTERT) which is expressed in almost all cancer types and is essential for the immortality of cancer cells and a hallmark of cancer. UV1 consists of three synthetic long peptides and vaccination induces Th1 responses in most patients irrespective of HLA type. This trial explores the synergistic effect of CTLA-4 blockade and hTERT vaccination, allowing unchecked expansion of hTERT-specific T cell clones. Increased number of tumor-specific T cells is associated with a favorable clinical outcome in patients with metastatic melanoma. We investigated the safety, immunological and clinical responses of UV1 vaccine and ipilimumab in this group of patients. Methods: In a phase I/IIa, single-center trial (NCT02275416) patients with metastatic melanoma received treatment with UV1 (300 µg) + GM-CSF (75 µg) as an adjuvant, combined with ipilimumab (3 mg/kg). Safety was assessed according to CTCAE v. 4.0, and tumor responses according to RECIST v.1.1. Immune responses against UV1 peptides were monitored in peripheral mononuclear blood cells by using 3 H-thymidine proliferation and IFN-γ ELISPOT assays. Tumor mutational burden (TMB) estimations were based on whole-exome sequencing. Results: 12 patients were treated from Feb to Nov 2015. Treatment was generally well tolerated. Adverse events mainly included injection site reactions and diarrhea. Immune responses occurred very early and 10/11 evaluable patients showed an immune response. Three patients obtained a partial response, and one patient a complete response. 3-year overall survival (OS) was 67%. 4-year survival outcome will be presented along with baseline characteristics and TMB estimations. Conclusions: Combining UV1 and ipilimumab is safe and induces clinical responses in melanoma. The high proportion of immunological responders and early induction of detectable immune responses suggest synergism. OS compares favorably to historical controls. Clinical trial information: NCT02275416.
A conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer target
Authors: Zachary T. Freeman, Thomas R. Nirschl, Daniel H. Hovelson, Robert J. Johnston, John J. Engelhardt, Mark J. Selby, Christina M. Kochel, Ruth Y. Lan, Jingyi Zhai, Ali Ghasemzadeh, Anuj Gupta, Alyza M. Skaist, Sarah J. Wheelan, Hui Jiang, Alexander T. Pearson, Linda A. Snyder, Alan J. Korman, Scott A. Tomlins, Srinivasan Yegnasubramanian, Charles G. Drake
Journal: Journal of Clinical Investigation (2020)

Despite advancements in targeting the immune checkpoints program cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte–associated protein 4 (CTLA-4) for cancer immunotherapy, a large number of patients and cancer types remain unresponsive. Current immunotherapies focus on modulating an antitumor immune response by directly or indirectly expanding antitumor CD8 T cells. A complementary strategy might involve inhibition of Tregs that otherwise suppress antitumor immune responses. Here, we sought to identify functional immune molecules preferentially expressed on tumor-infiltrating Tregs. Using genome-wide RNA-Seq analysis of purified Tregs sorted from multiple human cancer types, we identified a conserved Treg immune checkpoint signature. Using immunocompetent murine tumor models, we found that antibody-mediated depletion of 4-1BB–expressing cells (4-1BB is also known as TNFRSF9 or CD137) decreased tumor growth without negatively affecting CD8 T cell function. Furthermore, we found that the immune checkpoint 4-1BB had a high selectivity for human tumor Tregs and was associated with worse survival outcomes in patients with multiple tumor types. Thus, antibody-mediated depletion of 4-1BB–expressing Tregs represents a strategy with potential activity across cancer types.
Efficacy and safety of the combination of aflibercept with fluorouracil, leucovorin, and irinotecan in patients aged 70 years and older with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen in Spain: A retrospective multicenter cohort study.
Authors: Laura Gutiérrez Sainz, Sergio Martínez-Recio, Oliver Higuera, Ismael Ghanem, Ana López-Alfonso, Mar Pérez, Ana M. Jimenez-Gordo, Miriam Lopez-Gomez, Raquel Molina, Patricia Ibeas, Jaime Feliu, Nuria Rodriguez-Salas
Journal: Journal of Clinical Oncology (2020)

124 Background: Colorectal cancer is currently the third most common cancer worldwide. The results of the VELOUR study showed that the addition of aflibercept to Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) produced an advantage in both progression-free and overall survival (PFS and OS) in patients with metastatic colorectal cancer (mCRC) previously treated with an oxaliplatin-based regimen. The purpose of this study was to evaluate the efficacy and safety of the combination of aflibercept with FOLFIRI in patients aged 70 years and older with mCRC. Methods: We conducted a retrospective multicenter study, which included all patients aged 70 years and older with mCRC treated with Aflibercept plus FOLFIRI between May 2013 and March 2019 in 5 centers in Spain. Data regarding clinical and pathological characteristics, treatment response and survival were collected. Results: We selected 69 patients, of whom the majority (n = 48, 69.6%) were males with a median age of 75 years (range 70 to 84 years). Patients received an average of nine courses of aflibercept with FOLFIRI overall. Regarding response rates, 17 patients (24.6%) achieved a partial response, 37 (53.6%) had stable disease and 15 (21.7%) experienced disease progression. The median PFS was 6.1 months (CI 95%: 4.4–7.8), and the median OS was 13.9 months (CI 95%: 11.1–16.7). Treatment adverse events grade 3 and 4 were reported in 42 patients (60.9%). The most frequently reported treatment adverse events grade 3 and 4 were asthenia (24.6%), diarrhea (18.8%), stomatitis and ulceration (18.8%) and neutropenia (14.5%). Adverse events grade 3 and 4 typically associated with anti-VEGF therapy were infrequent. Adverse events led to permanent discontinuation of treatment in 26.1% of patients. Conclusions: In our sample the combination of aflibercept with FOLFIRI in patients aged 70 years and older with mCRC was effective and safe. Aflibercept plus FOLFIRI is a good therapeutic option for the treatment of mCRC in patients aged 70 years and older previously treated with oxaliplatin.