tbuckley/cabot-search huggingface dataset:
Biomarker analysis for UPCI 14-118: Phase II study of pembrolizumab in combination with azacitidine in patients with refractory metastatic colorectal cancer.
Authors: Chaoyuan Kuang, Yongseok Park, Nathan Bahary, Weijing Sun, James Ohr, John C. Rhee, Stanley M. Marks, H. Scott Beasley, Yongli Shuai, Yan Lin, Reetesh K. Pai, Anuradha Krishnamurthy, Hassane M. Zarour, James Herman, Edward Chu, James J. Lee
Journal: Journal of Clinical Oncology (2020)

173 Background: DNA mismatch repair (MMR) proficient colorectal cancer (CRC) is resistant to immune checkpoint therapy compared to MMR deficient CRC. DNA hypomethylating agents may promote anti-tumor immune response by re-expression of cancer-testis antigen and reactivating immune genes suppressed by DNA methylation. This trial tested whether epigenetic modulation by concurrent treatment with azacitidine could enhance the anti-tumor activity of pembrolizumab in mCRC. Methods: Phase II trial was conducted to evaluate activity, safety, and tolerability of pembrolizumab in combination with azacitidine in patients with previously treated pMMR metastatic CRC. Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg daily SQ injection on days 1-5 every 3 weeks. The primary endpoint of the study was ORR. Tumors were biopsied pre-treatment and on-treatment for biomarker studies. Results: 30 patients received at least one dose of therapy. One patient experienced a confirmed partial response, one experienced stable disease. ORR was 3% (1/30; 95% CI, 0.1-17%). Median PFS was 1.9 months, median OS was 6.3 months. Treatment was well tolerated with only one patient (3%) experiencing grade 3 adverse event. The patient with a PR had positive pre-treatment TILs, but no evaluable tumor from on-treatment biopsy. 2 of 6 patients who continued therapy despite PD on first restaging experienced temporary stabilization of disease later. 5 of 16 evaluable biopsy pairs demonstrated increased TILs on treatment compared to baseline; however, all of these patients experienced PD. 10 of 15 paired samples demonstrated decreased methylation of hypermethylated loci on-treatment. Clustering analysis demonstrated a correlation between pre-treatment methylation of immune activation genes with overall survival of the patients. Conclusions: Combining azacitidine and pembrolizumab is safe and tolerable for pMMR mCRC with only limited activity. DNA methylation and TIL changes are detectable after 3 cycles of therapy. DNA methylation of immune activation genes correlate with overall survival. RNA sequencing and peripheral immune cell flow cytometry are ongoing. Clinical trial information: NCT02260440.
Helicobacter pylori‐negative gastric cancer in Guatemala: Incidence, clinical characteristics, treatment modalities, and outcomes.
Authors: Rixci Ramirez, Daniel Estuardo Rosales Lopez, Francisco Javier Godinez, Carolina Camey, Marisol Gramajo
Journal: Journal of Clinical Oncology (2020)

318 Background: Gastric cancer (GC) in Guatemala is the second most common cancer diagnosis and the second leading cause of cancer death in both sexes. It is difficult to determine the exact incidence rate of H. pylori infection‐negative gastric cancer (HPIN‐GC) because H. pylori detection rates decrease with the progression of gastric atrophy and intestinal metaplasia. The aim of this study was to evaluate the incidence, clinicopathologic characteristics, treatment modalities and outcomes. Methods: A retrospective review of the medical records of 210 pts with histological diagnosis of gastric cancer evaluated at the General Hospital of Diseases from the Guatemalan Social Security Institute (IGSS) from January 2010 to December 2018. Helicobacter pylori infection status was evaluated by histology, a rapid urease test Current H. pylori infection was defined as positive results from histology. Overall survival was estimated by Kaplan Meier method and compared by Log-rank test. P value &lt; 0.05 was considered significant. Results: The rate of HPIN‐GC occurrence was 36% (n = 76). Sex, age, location of the tumor, Lauren’s classification and treatment modalities were not different according to H. pylori infection status. However, HPIN‐GC had a more advanced pT classification (T3/T4; 58 vs 28%, p=.019) and a more advanced stage (more than stage I; 64 vs 44%, p=.033) than H. pylori‐positive gastric cancer. Treatment modalities: 22% gastrectomy, 24% palliative care, 54% systemic chemotherapy at any time of disease course, 33% initial palliative surgery (derivative o gastrectomy), gastrectomy at any time in 16% (n 7). For those patients who received systemic chemotherapy (n 113) objective response rate was 38% and disease control rate 66%.Median OS was 26 months: 47 m for localized, 18 for locally advanced, and 8 m for advanced disease ( P=.0001). Only 17% of patients received second line chemotherapy and 4% a third line. Conclusions: At least 36% cases of gastric cancer were H. pylori negative. HPIN‐GC looks like to have a poorer prognosis than H. pylori‐positive cases. Chemotherapy can be offered to less than a half of patients. the earliest stages are associated with better survival.
Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial
Authors: Hartmut Goldschmidt, Elias K. Mai, Jan Dürig, Christof Scheid, Katja C. Weisel, Christina Kunz, Uta Bertsch, Thomas Hielscher, Maximilian Merz, Markus Munder, Hans-Walter Lindemann, Barbara Hügle-Dörr, Diana Tichy, Nicola Giesen, Dirk Hose, Anja Seckinger, Stefanie Huhn, Steffen Luntz, Anna Jauch, Ahmet Elmaagacli, Bernhard Rabold, Stephan Fuhrmann, Peter Brossart, Martin Goerner, Helga Bernhard, Martin Hoffmann, Jens Hillengass, Marc S. Raab, Igor W. Blau, Mathias Hänel, Hans J. Salwender
Journal: Leukemia (2020)
IDH1-dependent α-KG regulates brown fat differentiation and function by modulating histone methylation
Authors: Hyun Sup Kang, Jae Ho Lee, Kyoung-Jin Oh, Eun Woo Lee, Baek Soo Han, Kun-Young Park, Jae Myoung Suh, Jeong-Ki Min, Seung-Wook Chi, Sang Chul Lee, Kwang-Hee Bae, Won Kon Kim
Journal: Metabolism (2020)
Prediction of lymph node metastasis in early gastric cancer using artificial intelligence technology.
Authors: Tomoyuki Irino, Hirofumi Kawakubo, Satoru Matsuda, Shuhei Mayanagi, Rieko Nakamura, Norihito Wada, Satoshi Kamiya, Yutaka Tanizawa, Etsuro Bando, Masanori Terashima, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2020)

289 Background: Early gastric cancer shows lymph node involvement in about 10-15% of patients. Despite the fact, we perform radical lymphadenectomy for all patients because predicting lymph node metastasis has yet to be successful. In this study, we hypothesize that image analysis using artificial intelligence (AI) technology may help solve the problem. Methods: We retrospectively collected 82 patients with clinical T1N0 and pathological node negative and 82 patients with clinical T1N0 and pathological node positives and then divided the 164 patients into a training:validation set in ratio of 9:1. Endoscopic images of the early tumors were analyzed by transfer learning using AlexNet, a deep neural network containing 5 convolutional layers and 3 fully-connected layers. The model was validated with newly-collected 40 images from 20 clinical T1N0 and pathological node negative and 20 patients with clinical T1N0 and pathological node positives as a test set. For comparison, three methods of prediction were implemented: prediction at random, by logistic regression, and by skilled endoscopists. Results: The AI predicted LNM with accuracy of 80.9% in the validation set and 66.9% in the test set. (48.3% for node negative cancers and 85.4% for node positive cancers) On the other hand, prediction at random, by logistic regression, and by 2 endoscopists resulted in 50.3%, 50.0%, and 47.5%, respectively. Conclusions: Although the accuracy still needs to be improved, image analysis using the AI technology resulted in the best prediction of lymph node metastasis, indicating that AI is a promising technology for the diagnosis of lymph node metastasis in early gastric cancer.
Prognostic and predictive value of circulating tumour DNA (ctDNA) by amplicon-based next generation sequencing (NGS) of advanced pancreatic cancer (APC) in a phase I trial of oxaliplatin capecitabine and irinotecan (OXIRI) triplet chemotherapy.
Authors: Amanda Oon Lim Seet, Su Pin Choo, David Wai-Meng Tai, Justina Yick Ching Lam, Tira Jing Ying Tan, Daniel Shao-Weng Tan, Aaron C. Tan, Yvonne Chang, Balram Chowbay, Matthew C.H. Ng
Journal: Journal of Clinical Oncology (2020)

730 Background: Tumoral KRAS mutations (KRAS mt ) are detected in ~80% of APC and associated with a negative prognosis. Digital droplet PCR (ddPCR) has high sensitivity for circulating KRAS mt but narrower gene coverage. NGS using hybrid-capture methods has reported ctDNA KRAS mt in ~30% of patients (pt). We previously presented clinical results of the Phase I trial of OXIRI (GI ASCO 18 #411). We now present the first prospective evaluation of ctDNA in APC by an amplicon-based NGS approach in this Phase I trial. Methods: Paired ctDNA and CA19-9 samples were taken at baseline, C2D1, C3D1 and end of trial. A targeted panel with error-correction (Lucence Diagnostics) was used to detect for mtin KRAS, TP53, SMAD4, CDKN2A, CTNNB1, GNAS, APC and MYC. CT scans were performed every 2 cycles. Survival curves by Kaplan Meier were compared by mutational status, ctDNA and CA19-9 response using the log-rank test. Spearman correlation of ctDNA and CA19-9 changes was performed. Results: ctDNA mt was detected at baseline in 19/23 (83%) samples, comprising KRAS 17/23 (73%), TP53 (61%), SMAD4 (48%) and CDKN2A (30%). KRAS mt and SMAD4 mt conferred a negative prognosis for overall survival with a hazard ratio of 4.2 (CI: 1.6-10.4; p = 0.01) and 2.8 (CI: 0.9-8.65; p = 0.01) respectively. Drop in ctDNA and CA19-9 was associated with a trend for longer progression free survival at C2D1 (both) and C3D1 (ctDNA only). Radiological partial response (PR) was associated with lower ctDNA in 5/5 pt and CA 19-9 in 4/5 pt. Decrease in ctDNA and CA19-9 was associated with disease control (PR/SD) at C2D1 in 11/14 pt and 10/10 pt; at C3D1 in 11/12 pt and 6/7 respectively. No significant correlation between the amplitude of CA19-9 and ctDNA changes was found. Conclusions: ctDNA could be detected in 83% of pts of whom KRAS mt rates were similar to reports using tissue NGS. Determination of RAS mt and SMAD4 mt in ctDNA may aid in the prognostication of pts and decrease in ctDNA levels may predict for treatment benefit, similar in extent to CA 19-9. This may be particularly useful in non-CA19-9 secreting APC as an adjunct to imaging. Clinical trial information: NCT02368860.
Conformational Landscapes of HER2 Exon 20 Insertions Explain Their Sensitivity to Kinase Inhibitors in Lung Adenocarcinoma
Authors: Shen Zhao, Wenfeng Fang, Hui Pan, Yunpeng Yang, Ying Liang, Lin Yang, Xiaorong Dong, Jianhua Zhan, Kai Wang, Li Zhang
Journal: Journal of Thoracic Oncology (2020)
Comprehensive molecular profiling of <i>IDH1/2</i> mutant biliary cancers (BC).
Authors: Francesca Battaglin, Joanne Xiu, Yasmine Baca, Anthony Frank Shields, Richard M. Goldberg, Andreas Seeber, Diane Habib, Shivani Soni, Alberto Puccini, Ryuma Tokunaga, Hiroyuki Arai, Jingyuan Wang, Martin D. Berger, Igor A. Astsaturov, Albert Craig Lockhart, Wu Zhang, John Marshall, W. Michael Korn, Heinz-Josef Lenz, Anthony B. El-Khoueiry
Journal: Journal of Clinical Oncology (2020)

479 Background: Isocitrate dehydrogenases (IDH) play a key role in energetic metabolism and IDH mutations (mut) promote oncogenesis via epigenetic and genetic changes. Data addressing the molecular contexture of IDH1/2 mut in BC are lacking. We aimed to characterize the molecular profile of IDH1/2 mutant (mIDH) GI cancers with a focus on BC. Methods: 27954 GI cancer samples collected between August 2000 and July 2019 were included: 2057 BC (1159 ICC, 277 extrahepatic CC, 573 gallbladder, 48 unspecified CC), 13807 colorectal, 4183 gastric/esophageal, 3060 other. Samples were analyzed using NextGen DNA sequencing, in situ hybridization, RNA sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mut. MMR/MSI status was evaluated by a combination of IHC, Fragment Analysis and NGS. Results: mIDH frequency in BC was 10.3% (211/2057), with higher prevalence of IDH1 mut (8.2%). ICC showed the highest mut prevalence: IDH1 13.5%, IDH2 4%. Mut rates in other GI cancers types were &lt; 1%, except for HCC (1.9%, 11/582) and small bowel (1.1%, 8/736). When compared to IDH wild type (WT), mIDH BC showed lower mut rates in TP53 (13 vs 43%), KRAS (8 vs 19%), CDKN2A (1 vs 9%), and SMAD4 (0 vs 9%), whereas PBRM1 mut were higher (14 vs 5%) ( P &lt; .001 for all comparisons). There was a trend towards higher frequency of ARID1A and BAP1 in mIDH BC. HER2 expression and amplification rates were lower in mIDH vs WT BC (0.5 vs 3%, P = .048 and 0 vs 6%, P = .002). FGFR2 fusion was detected in 7% of WT vs 2% of mIDH BC. mIDH BC showed a lower TMB (0.7 vs 3.7%, P = .048) and a trend for lower MSI rates (0.6 vs 3%, P = .06) vs WT BC. Conversely, IDH mut were associated with higher TMB and MSI ( P &lt; .001) and higher PD-L1 expression in other GI cancers. Conclusions: This is the largest and most extensive profiling study to investigate the molecular makeup of mIDH BC and GI tumors. Our data show distinct gene alteration patterns characterizing mIDH BC, involving genes related to chromatin remodeling and DNA repair, and a differential expression of immune related markers compared to other mIDH GI tumors. These findings can contribute to the development of rational combination therapies and to improved patient selection in the future.
Eligibility for second-line therapy in patients with advanced hepatocellular carcinoma (aHCC): A BC Cancer population-based study.
Authors: Erica S. Tsang, Janine Marie Davies, Jonathan M. Loree, Howard John Lim, Daniel John Renouf, Sharlene Gill
Journal: Journal of Clinical Oncology (2020)

491 Background: Evidence supporting second-line therapies has become available for aHCC, including regorafenib, cabozantinib, ramucirumab, and nivolumab. The optimal second-line treatment regimen is unknown, and there remains limited real-world data about the eligibility of patients for second-line therapies in aHCC. We aimed to characterize the real-world eligibility and use of second-line therapies post sorafenib. Methods: We identified all patients with aHCC who received ≥1 cycle of first-line sorafenib between January 1, 2014 and December 31, 2017 across 6 centers in British Columbia (BC), Canada. All patients were required to be Child-Pugh class A for initiation of sorafenib in BC. Baseline characteristics and clinical outcomes were reviewed. Eligibility for second-line therapy was determined using the RESORCE and CELESTIAL study entry criteria. Results: Of 144 patients with advanced HCC who received ≥1 cycle of first-line sorafenib, median age was 65.3 years (range 32.2-83.4) and 85% were male. Median duration of sorafenib was 2.6 months. 12 patients (8%) went on to receive second-line treatment. 37 patients (26%) were deemed eligible for second-line systemic therapy. Primary reasons for ineligibility included ECOG ≥2 (58%), and deterioration to Child-Pugh status B (28%). On Cox regression, improved survival was associated with better ECOG and recurrent disease. (Table). Kaplan-Meier analysis demonstrated that eligibility for second-line treatment was associated with improved median overall survival from end of first-line treatment (8.5 vs. 5.1 months; p&lt;0.01). Conclusions: Only a minority of real-world patients with aHCC were eligible for second-line therapies based on second-line trial criteria. Given the high-rate of attrition, improved first-line treatment options are urgently needed. [Table: see text]
Association of antibiotic exposure with overall survival and colitis in patients with stage III and IV melanoma receiving immune checkpoint inhibitors.
Authors: Brian Chu, Jahan J. Mohiuddin, Andrea Facciabene, Xingmei Wang, Abigail Doucette, Cathy Zheng, Wei Xu, Ravi K. Amaravadi, Giorgos C. Karakousis, Tara C. Mitchell, Amit Maity, Lynn Mara Schuchter, John Nicholas Lukens
Journal: Journal of Clinical Oncology (2020)

56 Background: Recent studies suggest that changes in the gut microbiome modulate response to cancer treatment, including immune checkpoint inhibitors (ICI). Broad-spectrum antibiotics (Abx) are known to cause significant dysbiosis. We hypothesize that recent Abx exposure worsens outcomes in patients (pts) with stage III/IV melanoma (MM) receiving ICI. Methods: We identified MM pts treated with ICI from our institutional database. All received their first ICI between 2004-2019. Antibiotic exposure was defined as receipt of Abx within 3 months prior to the first infusion of ICI. The primary outcome was overall survival (OS) and the secondary outcome was immune-mediated colitis requiring intravenous (IV) steroids. Stage III and IV pts were analyzed separately for the primary analysis. Results: Of 568 pts in our database, 20% received Abx within the 3 months prior to ICI. 36% of pts had stage III disease and 26% of pts were treated with either adjuvant or neoadjuvant ICI. 1.6% of pts died of causes other than MM. The Abx+ and Abx- groups were balanced in terms of stage, race, age, sex, BRAF status, LDH, prior systemic therapies, and class of ICI received. Only 4 pts were hospitalized due to the infection prompting the Abx, and no pts died due to the infection. In the Stage IV group, Abx+ pts had worse OS on MV analysis (HR 1.6, 95% CI 1.1-2.2). Stage III Abx+ also had worse OS (HR 2.8, 95% CI 1.3-5.9). In a sensitivity analysis excluding pts who received IV Abx or were admitted due to infection, survival was still worse for Abx+ pts (HR 1.7, 95% CI 1.2-2.4). In a Fine-Grey competing risk MV model, Abx+ had a higher rate of immune-mediated colitis requiring IV steroids (HR 2.1, 95% CI 1.02-4.5). Conclusions: In MM pts treated with ICI, receipt of Abx within 3 months prior to ICI initiation was associated with decreased OS and increased colitis. Future research should include prospective studies to better define the risk/benefit profile of antibiotics in close proximity to ICI. [Table: see text]
Multicenter retrospective observational study of pancreatic cancer with positive peritoneal lavage cytology intended for surgical resection.
Authors: Akiko Todaka, Satoshi Nara, Fuyuhiko Motoi, Soichiro Morinaga, Naoki Hama, Ryota Higuchi, Masaru Konishi, Hirofumi Shirakawa, Hidetaka Tsumura, Hiroyuki Okuyama, Hiroto Matsui, Kazuhiko Shioji, Keishi Sugimachi, Akinori Asagi, Nobumasa Mizuno, Akira Fukutomi, Junji Furuse
Journal: Journal of Clinical Oncology (2020)

695 Background: Although macroscopically curative resection has been performed for pancreatic cancer with positive peritoneal lavage cytology (CY1), the prognosis is poor in most reports. In 2013, the JASPAC01 trial showed that S-1 was superior to Gemcitabine (GEM) as adjuvant chemotherapy for resected pancreatic cancer, and S-1 was also administered to the patients with CY1 who had undergone macroscopically curative resection. Methods: This is a multicenter retrospective observational study that collected data of the patients with pancreatic adenocarcinoma who were diagnosed with CY1 between 2007 and 2015 and had no other noncurable factors. Results: One hundred twenty-seven patients were enrolled from 14 institutions, and 3 were excluded due to liver metastasis or non-adenocarcinoma. The median age was 67 years old and almost patients had PS 0 or 1. Of the 124 patients, 114 underwent macroscopically curative resection and the median overall survival (OS) and recurrence free survival (RFS) were 16.7 and 7.2 months. Of the resected patients, 80 (70%) had no early recurrence and started postoperative adjuvant chemotherapy. Adjuvant chemotherapy regimens were S-1 in 43 patients (54%), GEM in 31 (39%) and others in 6 (7%). The median OS was 21.0 months with S-1 and 19.2 months with GEM (HR: 0.73, 95%CI: 0.44-1.22, P = 0.23), whereas the median RFS was 10.2 and 7.1 months (HR: 0.58, 95%CI: 0.36-0.95, P = 0.03), respectively. Conclusions: After the report of JASPAC01, most patients with pancreatic cancer with CY1 received macroscopically curative resection and treated with S-1 as adjuvant therapy, however the efficacy was insufficient. We should consider appropriate treatment strategies for patients with pancreatic cancer with CY1 intended for surgical resection.
When non-coding is not enough
Authors: Simone Anfossi, George A. Calin
Journal: The Journal of Experimental Medicine (2020)

A new concept is emerging in the non-coding RNA (ncRNA) field: an increasing number of ncRNAs in fact codify for short peptides that have biological activities. In this issue of JEM, Wang et al. (https://doi.org/10.1084/jem.20190950) report the identification of a long ncRNA (lncRNA)–encoded 60–amino acid polypeptide that they name ASRPS, as well as its ability to inhibit angiogenesis in the deadly triple-negative breast cancer (TNBC).
Palliative Care and the Management of Common Distressing Symptoms in Advanced Cancer: Pain, Breathlessness, Nausea and Vomiting, and Fatigue
Authors: Lesley A. Henson, Matthew Maddocks, Catherine Evans, Martin Davidson, Stephanie Hicks, Irene J. Higginson
Journal: Journal of Clinical Oncology (2020)

Good symptom management in oncology is associated with improved patient and family quality of life, greater treatment compliance, and may even offer survival advantages. With population growth and aging, the proportion of patients with multiple symptoms-both related and unrelated to their cancer-is anticipated to increase, supporting calls for a more routine and integrated approach to symptom management. This article presents a summary of the literature for the use of symptom assessment tools and reviews the management of four common and distressing symptoms commonly experienced by people with advanced cancer: pain, breathlessness, nausea and vomiting, and fatigue. We also discuss the role of palliative care in supporting a holistic approach to symptom management throughout the cancer trajectory.