tbuckley/cabot-search huggingface dataset:
Signet ring cell colorectal cancer: Genomic insights into a rare subpopulation of colorectal adenocarcinoma.
Authors: Krittiya Korphaisarn, Van Karlyle Morris, Michael J. Overman, David R. Fogelman, Imad Shureiqui, Bryan K. Kee, Robert A. Wolff, Cathy Eng, David Menter, Stanley R. Hamilton, A. Dasari, Kanwal Pratap Singh Raghav, Trupti R. Mehta, Shanequa Manuel, Scott Kopetz
Journal: Journal of Clinical Oncology (2017)

606 Background: Colorectal signet ring cell carcinoma (SRCC) has been shown to be associated with advanced tumor stage at presentation and worse outcomes. Due to the rarity of this subtype, 1% of all colorectal adenocarcinoma (CRC), little is known about its molecular characteristics. We aimed to characterize the molecular alterations of this subgroup. Methods: Metastatic CRC (mCRC) patients (pts) with signet ring cell (SC) histology who had tumors evaluated with next generation sequencing between February 2009 and November 2015 were reviewed. SC mCRC were classified into 2 groups; SRCC (&gt;50% of signet cells) and adenocarcinoma (AC) with SC component. Genomic alterations, microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) status noted in SC mCRC were compared to non-SC mCRC pts from the Assessment of Targeted Therapies Against Colorectal Cancer program at MD Anderson Cancer Center using Pearson’s χ 2 test. Results: A total of 665 mCRC pts were included in this study. 93 pts (14%) had SC histology of which 30 (32.3%) pts were SRCC. The Table below shows key cancer genes mutation frequencies. Conclusions: Colorectal SRCC has distinct molecular features compared with non-SC and AC with SC component CRC. The frequencies of KRAS, PIK3CA and APC mutations were lower than the frequencies reported in non-SC CRC. SRCC was not associated with MSI-H or CIMP-H tumor in this study. Further studies on identification of activated pathways underlying this worse prognosis and potential therapeutic targets are required. [Table: see text]
A comparison of ascertainment of Lynch syndrome in colorectal cancer patients via reflex testing vs. hereditary guideline-based testing.
Authors: Setareh Samimi, Richard M. Lee-Ying, David Schaeffer, Robert Wolber, Daniel John Renouf, Winson Y. Cheung, Kasmintan A Schrader, Gillian Mitchell, Howard John Lim
Journal: Journal of Clinical Oncology (2015)

1517 Background: In accordance with The American College of Medical Genetics and Genomics (ACMG), many institutions including The Hereditary Cancer Program (HCP) of the B.C. Cancer Agency recommend initiating testing for Lynch Syndrome (LS) based on the Bethesda criteria and/or on an age threshold of less than 50 years. Reflex immunohistochemical (IHC) testing independent of family history to infer deficient Mismatch Repair (dMMR) status combined with mutant BRAF 600E (mBRAF) IHC assessment provides an alternative means of screening for LS. Although many centers have adapted a reflex approach to screening for LS, this approach is still not standard. This study compares the efficacy of the two methods. Methods: From January 2012 to July 2013, reflex IHC testing to detect dMMR and mBRAF was performed in all cases of resected CRC across different jurisdictions in the greater Vancouver catchment area. Additional characteristics such as age at diagnosis, personal history of cancer, family history of cancer, and status of referral to HCP were reviewed. Results: In total, 1458 CRC patients were analysed, of which 194 (13%) were dMMR. The dMMR subset comprised abnormal staining of hMLH1 (n = 162), hMSH2 (n = 18), hPMS2 (n = 7) and hMSH6 (n = 7). Of these 194 patients, 103 (53%) were mBRAF, 60 (31%) were BRAF Wt and in 31 (16%), results are unknown. Using dMMR and BRAF Wt combined testing results to initiate referral to the HCP, only 60 patients would require further genetic evaluation, obviating the need for assessment of 103 potentially unnecessary referrals if only dMMR IHC was considered. Of the 60 dMMR and BRAF Wt patients, 54 (90%) were older than 50 years of age and 35 (65%) did not meet Bethesda criteria on chart review. Conclusions: A significant number of potential cases of LS would not be identified using established guidelines. Conversely, using only MMR testing would lead to unnecessary referrals. The combination of MMR and BRAF IHC testing may serve as a simple cost efficient and time saving tool to identify patients at highest risk for LS, supporting the role of reflex IHC testing of MMR and BRAF in CRC.
A phase I trial of pazopanib and vorinostat: The role of <i>TP53</i> mutations.
Authors: Ming-Mou Hou, Jorge Bellido, Aung Naing, Gerald Steven Falchook, Kenneth R. Hess, Ralph Zinner, Jennifer J. Wheler, Vivek Subbiah, David S. Hong, Sarina Anne Piha-Paul, Apostolia Maria Tsimberidou, Daniel D. Karp, Razelle Kurzrock, Funda Meric-Bernstam, Siqing Fu
Journal: Journal of Clinical Oncology (2014)

2576 Background: VEGF inhibition-mediated tumor hypoxia promotes invasive growth by transcriptional activation of hypoxia-induced factors mediated by tumor hypoxia. Accordingly, we conducted this phase 1 study of pazopanib plus vorinostat to overcome resistance to antiangiogenesis (NCT01339871). Methods: Primary objective of this phase I trial was to define the maximum tolerated dosage (MTD) and the safety profile following a zone-based, modified 3 + 3 dose escalation design (12 dose levels). Toxicity and efficacy were evaluated according to CTCAE 4.0 and RECIST 1.1. Results: A total of 78 evaluable patients enrolled. Six patients (7.7%) experienced dose-limiting toxicity (DLT): 2 hypertension, 2 diarrhea, 1 thrombocytopenia, and 1 skin rash. The most frequent drug-related grade 2 or higher adverse events were thrombocytopenia, neutropenia, fatigue, hypertension, diarrhea, and vomiting in 39 patients (50%). Pazopanib plus vorinostat (800 mg/200 mg [4A], 600 mg/300 mg [4B], 400 mg/400 mg [4C] PO daily) in zone 4 were defined as the MTDs, with dose reduction in 67%, 33% and 57% of patients, respectively. The dose level 4B was chosen for further evaluation. Four patients (5.1%) achieved partial response (PR) and 9 patients (11.5%) experienced stable disease for at least 6 months (SD≥6months). This cohort of patients showed a median progression-free survival (PFS) of 2.2 months (95% CI, 1.8-2.6) and a median overall survival (OS) of 8.3 months (95% CI, 6.2-10.4). Further evaluation revealed that patients with TP53 mutations (n=10) showed a median PFS of 3.5 months and a median OS of 12.7 months (95% CI, 2.2-23.2), compared favorably with 2.0 months (95%CI, 1.9-2.1; p=0.08), and 7.5 months (95%CI, 5.0-9.4; p=0.12) in those with TP53 mutation undetected (n=21), respectively. In 13 patients who achieved PR/SD≥6months, 4 patients had TP53 mutations, 2 undetected, and 7 unknown. Conclusions: Dose level 4B (pazopanib 600 mg PO daily plus vorinostat 300 mg PO daily) was considered as the recommended phase II dosage. Antitumor activity in patients with advanced solid tumors was demonstrated. Early clinical evidence indicated that further evaluation of the efficacy and safety of this regimen, and role of TP53 mutations in treatment sensitivity is warranted. Clinical trial information: NCT01339871.
Correlation between the international consensus definition of the cancer anorexia cachexia syndrome (CACS) and patient outcomes in advanced non-small cell lung cancer (NSCLC).
Authors: Ryan David Nipp, Christel Rushing, Greg Samsa, Susan C. Locke, Arif Kamal, Amy Pickar Abernethy, Thomas William LeBlanc
Journal: Journal of Clinical Oncology (2014)

e19042 Background: CACS is a problematic clinical syndrome, difficult to objectively define. A consensus-derived, weight-based definition has been proposed. An observational study was analyzed to explore this definition’s utility in a cohort of patients with advanced NSCLC. Methods: Patients with stage IIIB or IV NSCLC completed up to four study visits over a 6 month period. Using the weight-based CACS definition (weight loss >5%, or weight loss >2% in individuals already showing depletion according to body-mass index <20 kg/m²), patients were categorized as either CACS or control. Longitudinal assessments from each visit included measures of physical function, quality of life (QOL), albumin, weight, survival, and patient-reported outcome measures. Survival was analyzed by standard methods. This updated analysis used linear mixed effect models to explore longitudinal trends. Results: CACS patients had a median survival of 239.5 days [95% CI 142, 437], compared to 446 [95% CI 339, 779] days in the control group (HR 2.06 [95% CI 1.24-3.42], p <0.05). The baseline mean Karnofsky score was 68 in the CACS group, vs. 77 in the controls, and ECOG was 1.8 vs. 1.3, respectively. QOL was worse in the CACS group, with a mean FACT-G of 69.7 vs. 78.1, Lung Cancer Subscale of 17.2 vs. 19.9, Anorexia/Cachexia Subscale of 31.4 vs 37.9, and Fatigue Subscale of 30.6 vs. 35.4. Longitudinally, all measures of physical function and QOL worsened regardless of CACS status, but the rate of decline was more rapid in the CACS group. The rate of decline in both measures of physical function (Karnofsky and ECOG) was significantly different across groups, with slopes of -0.34 and 0.01, vs. -0.09 and 0.004 respectively (p=0.01 and 0.02). Conclusions: The weight-based component of the recently-proposed international consensus definition of CACS is useful in identifying advanced NSCLC patients who are likely to have significantly inferior survival and to develop more precipitous declines in physical function and QOL. This definition may be useful for clinical screening of CACS and for clinical trial enrollment purposes.
Gastrointestinal stromal tumors (GISTs) of the esophagus and gastroesophageal junction (GEJ).
Authors: Andrew M. Briggler, Rondell P Graham, Gustavo Figueiredo Marcondes Westin, Andrew Folpe, Dawn E. Jaroszewski, Scott H. Okuno, Thorvardur Ragnar Halfdanarson
Journal: Journal of Clinical Oncology (2017)

179 Background: GISTs arise from interstitial cells of Cajal anywhere within the gastrointestinal tract, but those of the esophagus and GEJ are exceedingly rare ( &lt; 1% of cases). Our aim was to characterize clinicopathological features and outcomes of esophageal and GEJ GISTs and compare survival with a population-based registry (SEER). Methods: 28 cases were identified using the Mayo Clinic Cancer Registry from 1997 to 2016, and 378 cases from the SEER 18 registry from 2000 to 2013. Mayo cases were re-reviewed by Mayo pathologists. We analyzed patient characteristics, tumor location, TNM staging, mitotic index, molecular diagnostics, IHC staining, and histomorphology. JMP software was used to calculate time to recurrence (TTR) and overall survival (OS) utilizing Kaplan-Meier and log-rank. Results: At Mayo, 60% of tumors arose in the distal esophagus. Mean tumor size was 5.73 cm. 42% of cases were low grade. None had nodal involvement. Five cases were metastatic at diagnosis, all to the liver. 86.7% had spindle cell morphology. IHC staining was positive for KIT in 92%, followed by CD34 (52%), DOG-1 (24%), and actin (16%). Mutational analysis was done on 10 cases and KIT mutation was found in 8 cases; 2 were wild-type. Two-thirds of patients underwent surgery, mostly esophagectomy. 14 patients received adjuvant imatinib. Median time to diagnosis from symptom onset was 2 months; median time to surgery from diagnosis was 1 month. Of 10 patients with complete follow-up, 2 had recurrences: 1at the anastomotic site and 1 in the liver. Median TTR from surgery was 36.5 months. Median follow-up time was 31.5 months. Median OS from diagnosis for the Mayo cohort was 129.5 months (95% CI 55.7-x). SEER cohort median OS was 81 months (95% CI 63-101), and females had superior OS compared to males (HR 0.67; 95% CI 0.48-0.93, p = 0.016). Conclusions: Patients undergoing surgical resection for esophageal and GEJ GISTs had a favorable prognosis, but recurrences occurred. The superior OS seen in the Mayo cohort suggests early resection and adjuvant imatinib may improve outcomes.
FDG PET/MR for therapy response assessment in sarcoma.
Authors: Stephan Richter, Bettina Beuthien-Baumann, Joerg Kotzerke, Michael Laniado, Joerg van den Hoff, Gerhard Ehninger, Markus Kajo Schuler, Ivan Platzek
Journal: Journal of Clinical Oncology (2013)

e21518 Background: Magnetic resonance imaging is the preferred modality for local staging of sarcoma. Positron emission tomography (PET) allows for the evaluation of tissue metabolism. Recently, PET and MR can be performed as a combined examination on a single scanner. The aim of this pilot study was to evaluate the agreement of PET and MR regarding therapy response in patients who received PET/MR for sarcoma staging and assess the diagnostic value of PET/MR in contrast to standalone MR. Methods: Thirteen patients with soft tissue sarcoma (7 m, 6 f, mean age 50 y, age range 18-80 y) received FDG PET MR on to occasions to assess therapy response. Average time between the two scans was 47 d (21-98 d). Average time between tracer injection and the beginning of the PET scan was 70 min (58-106 min). 4.5 MBq 18 F-FDG /kg body weight were applied before the examination (252-331 MBq 18 F-FDG /patient, 289 MBq on average). Image evaluation was performed separately by a radiologist and a nuclear medicine physician, respectively, who were blinded for other imaging procedures or clinical data. On MR images therapy response was determined according to the RECIST criteria. PET data evaluation included the calculation of mean an maximum SUV (=standardized uptake value) and metabolic volume. In this case, an increase or decrease of 30% or more of the base value was considered a progressive disease or positive response, respectively. Agreement of PET and MR regarding response was evaluated using Cohen's kappa. Results: The primary tumor showed increased FDG uptake in all patients. Response assessment based on RECIST and SUVmean differed in six of 13 cases (k=0,25). Assessment based on RECIST and metabolic volume showed slightly better agreement (k=0,35). Assessment based on RECIST and SUVmax differed in x cases (k=0,34). Conclusions: Sarcoma therapy response based on morphologic MR imaging and PET parameters yield differing results in many cases. FDG positive sarcoma may show a decrease of metabolic parameters on PET scans, while they appear largely unchanged on MR scans. Due to additional information about tumor metabolism provided by PET, PET/MR is a promising modality for sarcoma imaging. Further studies are necessary to evaluate the prognostic significance of PET findings in sarcoma patients.
Temozolomide plus bevacizumab in elderly patients with newly diagnosed glioblastoma and poor performance status: An Anocef phase II trial.
Authors: German Reyes-Botero, Jerôme Honnorat, Oliver L. Chinot, Luc Taillandier, Isabelle Catry-Thomas, Jerome Barriere, Jean Sebastien Guillamo, Michel Fabbro, Didier Frappaz, Alexandra Benouaich Amiel, Emilie Le Rhun, Chantal Campello, Isabelle Tennevet, François Ghiringhelli, Marie-Laure Tanguy, Karima Mokhtari, Jean-Yves Delattre
Journal: Journal of Clinical Oncology (2013)

2020 Background: The optimal treatment of glioblastoma multiforme (GBM) in elderly patients (age ≥70 years) with impaired functional status (Karnofsky performance status, KPS&lt;70) remains to be established. A previous study using temozolomide (TMZ) alone suggested an increase in median overall survival (OS) compared to supportive care (25 weeks vs. 12-16 weeks, respectively). Median progression-free survival (PFS) was 16 weeks and 26% of patients became transiently capable of self-care (IK&gt;70) (J Clin Oncol. 2011; 29: 3050-5). The present clinical trial evaluated the efficacy and safety of the combination of TMZ with bevacizumab (BV) as an initial treatment for elderly patients with GBM and KPS&lt;70. Methods: Patients aged ≥ 70 years with KPS &lt; 70 and a newly supratentorial GBM diagnosed by biopsy were eligible for this multicentric, prospective and non-randomised phase II trial. The primary endpoint was the OS and secondary endpoints included median PFS, quality of life, safety and cognition. Treatment consisted of TMZ 130-150 mgs/m 2 /d for 5 days every 4 weeks plus BV 10mgs/kg every 2 weeks, until 12 cycles or tumoral progression. Neither surgical resection nor radiotherapy was performed. Follow-up included clinical assessment every 2 weeks and brain MRI every 8 weeks. Results: Between October 2010 and March 2012, 66 patients (median age, 77 years; median KPS, 60) were enrolled. Median OS was 24 weeks (95% CI, 19-27.6) and median PFS was 16 weeks (95% CI, 13.1–19.3). Twenty-five patients (38%) became transiently capable of self-care (IK&gt;70). Grade 3 and 4 haematological toxicity occurred in 13(19.6%) cases, whereas non-haematological toxicities were reported in 21(32%), including high blood pressure in 7(10%), thromboembolic events in 3(4.5%), intracerebral haemorrhage in 2(3%) and intestinal perforation in 2(3%) cases. Conclusions: This study confirms that TMZ-based treatment is of help in elderly GBM patients with poor KPS. However, the addition of bevacizumab does not appear to be of benefit in term of PFS and OS.
A study of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb-004) in metastatic soft tissue sarcoma.
Authors: Sant P. Chawla, Patrick Schoffski, Jean-Yves Blay, Robin Lewis Jones, Hans Gelderblom, Steven Attia, Bartosz Chmielowski, Brian Andrew Van Tine, Jonathan C. Trent, Shreyaskumar Patel, Andrew J. Wagner, James Kert Viele, Rashmi Chugh, Axel Le Cesne, Gabriel Tinoco, Kamalesh Kumar Sankhala, Julianne Falcone, Charles Schweizer, Susan Weil, Robert G. Maki
Journal: Journal of Clinical Oncology (2015)

TPS10577 Background: Ontuxizumab is a humanized immunoglobulin G-1-kappa monoclonal antibody (mAb) that is the first clinical stage agent to target endosialin. Endosialin (TEM-1/CD248) is a cell surface glycoprotein expressed on cells involved in the development of tumor vasculature, but has generally limited expression in normal tissue. In some tumors, such as sarcomas, endosialin is expressed directly by the tumor cells and therefore soft tissue sarcomas (STS) may be a suitable treatment target. Methods: This Phase 2 multicenter study in subjects with metastatic STS (0-2 prior regimens) is being conducted in two sequential parts. Part 1 was an open label, dose-escalation, safety lead in: 4, 6 and 8 mg/kg ontuxizumab (administered on days 1 and 8 of a 21 day cycle) combined with gemcitabine and docetaxel (G/D) (900 mg/m2 on days 1/8 and 75 mg/m2 on day 8, respectively)). Based on the observed safety profile in Part 1, 8 mg/kg was utilized in Part 2 efficacy design. In Part 2 subjects are randomized in a double-blind 2:1 ratio to G/D plus ontuxizumab (8 mg/kg) or G/D plus placebo. Using an adaptive population finder design, randomization is stratified by four histological cohorts (liposarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma, and other STS). An independent unblinded statistical committee (ISC) monitors the trial adaptations for futility, success, or maximal cohort sizes (60). Primary objective is progression-free survival (PFS) by RECIST1.1. Secondary objectives include overall survival (OS), overall response rate (ORR), and predictive/ response biomarkers. Enrollment ended in August 2014 with 209 subjects randomized. Primary result analysis is anticipated in December, 2015. Clinical trial information: NCT01574716.
Correlations between tumor-infiltrating and circulating lymphocyte subpopulations in mRCC patients treated with immune-checkpoint inhibitors.
Authors: Melissa Bersanelli, Letizia Gnetti, Augusto Vaglio, Nicola Sverzellati, Nicoletta Campanini, Maricla Galetti, Monia Incerti, Elena Varotti, Raffaele Parziale, Michele Corrado, Lorena Bottarelli, Cinzia Azzoni, Elena Rapacchi, Giuseppe Caruso, Agnese Cosenza, Leonarda Ferri, Enrico Maria Silini, Francesco Leonardi, Sebastiano Buti
Journal: Journal of Clinical Oncology (2017)

494 Background: In clinical trials with immune-checkpoint inhibitors (CKI), histological features such as tumor-infiltrating lymphocites (TILs) are investigated as potential predictive biomarkers, with the possible limit of an outdated parameter for a typically dynamic element. Methods: This explorative study compared, in metastatic renal cell carcinoma (mRCC) patients, basal pathological data about TILs on diagnostic histological specimens with circulating lymphocyte subpopulations measured before and during therapy with nivolumab, with the primary aim to assess their concordance. Secondarily, with the limit of a small sample size, a possible relation with treatment outcome was explored. Results: Of 11 mRCC patients, 5 had low presence of TILs (L-TILs), 3 moderate amount (M-TILs), and 3 high number (H-TILs). Overall, 8 patients had low intratumoral pathological CD4+/CD8+ ratio (LIPR) ≤ 1 and 3 cases high intratumoral pathological ratio (HIPR) ≥ 2. Of 8 patients with LIPR, only 2 cases matched with low circulating CD4+/CD8+ ratio (LCR) ≤1, whilst 5 cases had high circulating ratio (HCR) ≥ 2 (1 undetermined). All 3 cases with HIPR (≥ 2) conversely had LCR (≤ 1). Unexpectedly, independently from the clinical outcome, circulating CD4+/CD8+ ratio remained unchanged during therapy with CKI in each patient, maintaining the same value after 8 weeks (mean -0.12). The respective percentage values of CD4+ and CD8+ circulating T cells also remained stable during treatment (mean variation 0%); the absolute value of CD4+ was more likely to increase (mean +46.3/mm 3 ); the level of CD8+ tended to slightly decrease (mean -6.5/mm 3 ). No correlation of lymphocyte subpopulations with treatment outcome was found. Conclusions: Of note, this study did not evidence any correspondence between histopathological and circulating findings in terms of T-lymphocyte subpopulations in mRCC patients undergoing treatment with CKI, also suggesting the inconsistency of circulating data in terms of relative variations. Considering the likely high dynamism of TILs, rebiopsy before CKI therapy might be the most reliable way to assess the utility of TILs characterization for predictive purpose.