tbuckley/cabot-search huggingface dataset:
Association of microsatellite instability with distinct clinical and molecular characteristics in resected colon cancer: Analysis of a platform trial of the AIO colorectal study group—Colopredict Plus.
Authors: Anke C. Reinacher-Schick, Hendrik Juette, Stefanie Noepel-Duennebacke, Dirk Arnold, Nadezda Basara, Hinrich Boehner, Thorsten Dahm, Inke Sabine Feder, Olaf Hansen, Wolfgang Hiller, Alexander Leins, Lothar Müller, Torsten Ueberrueck, Christian Teschendorf, Guido Trenn, Berlinda Verdoodt, Nadine Zwingmann, Waldemar Uhl, Andrea Tannapfel
Journal: Journal of Clinical Oncology (2017)

e15086 Background: High microsatellite instability (MSI-H) is a prognostic marker in resected colon cancer (CC) identified in post-hoc analysis of multiple trials. However, validation in real-life cohorts and its association with clinical and molecular markers is lacking. Methods: In Sep 2013 we started a platform trial in 49 German cancer centers recruiting patients with UICC stage II and III CC diagnosed between 2008 to 2016. MSI was tested by immunohistochemistry (IHC) of mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. In case of any loss of protein expression (IHC neg), fragment length analysis (FLA) was performed, defining MSI high tumors (MSI-H) and MS stable tumors (MSS). Besides, mutations in known prognostic factors for CC such as RAS, BRAF, PI3K and others were determined by next generation sequencing (NGS). Results: By end of 2016, 1249 patients have been recruited into the trial: median age 73yrs., stage II/III: 686/563 pts. So far, tissue was analysed in 512 pts. Of these, 182 pts. were IHC neg with 116 pts. tested MSI-H upon FLA (22.7%). Median age was 73yrs., female/male: 260/252 pts., stageII/III: 292/220 pts. Association of MS status with clinical factors is shown in Table 1. Upon NGS analysis we found 16.3% BRAF mutations, 39% KRAS mutations, 2.8% NRAS mutations and 22.6% PI3K mutations. MSI-H status was significantly associated with BRAF mutation and wildtype status of RAS. Conclusions: We found a higher percentage of MSI-H cancers in our registry compared to reported data from randomised trials, possibly related to a higher median age in this real-life cohort. MSI-H was associated with female sex, primary tumor site, and distinct molecular markers and should therefore be considered a heterogeneous subgroup of CC. Updated analysis including NGS data and survival will be presented at the meeting. Clinical trial information: AIO- KRK-0413, DKRS:00004305. [Table: see text]
Gastric cancer detection using the serum pepsinogen test method in Croatian patients.
Authors: Dragan Trivanovic, Lorena Honovic, Marina Dembic, Katarina Matosevic, Mladenka Buic Grzeta
Journal: Journal of Clinical Oncology (2018)

e24055 Background: Gastric cancer (GC) is the eight most common cancer and fifth leading cause of cancer deaths in Croatia. The gold standard for the diagnosis of gastric cancer is the pathohistological study of biopsies obtained during an upper gastrointestinal (GI) endoscopy, an invasive method that is too complicated for use in population screening and patients with comorbidity. A reliable diagnostic tool for the early detection of the GC is essential. The potential usefulness of serum Pepsinogen (PG) tests has been evaluated in many countries but this evidence has not resulted in generalized use in GC screening and detection. We have conducted a prospective single center clinical study over a period of > 2 years to assess the sensitivity and specificity of a PG assay to detect gastric cancer in Croatian patiens with suspicious GC. Methods: A study was performed including patients scheduled for upper gastrointestinal endoscopy. Inclusion criteria for the study were: signed informed consent, life expectancy > 12 weeks, and exclusion criteria were: previous oncological treatments for any malignancy, current usage of IPP or NSAIDs medication, poor ECOG performance status ≥3, known history of H. pylori eradication treatment or gastric surgery. Results: Of the 102 patients, 14 patients had GC and 55 had non-malignant pathology on tissue biopsy (like atrophic gastritis). The best cut-off values for diagnosing GC using serum PG I and PG I / PG II ratios were found to be < 70 ng/ml for PG I and < 3.0 for PG I / PG II yielded an accuracy for the detection of GC of 83.1%, sensitivity of 60.8%, and specificity of 91.7%. The area under the ROC was 0.78 % (95% CI:0.62–0.94), the PPV was 73.7 % and the NPV was 85.9%. Conclusions: The single use of pepsinogen tests is not sufficient for stomach cancer detection; however, it provides a valuable test for selecting a population that needs further diagnosing with endoscopy.
Abstract 19113: Post-Traumatic Stress Disorder association to Obstructive Sleep Apnea Independent of Cardiovascular Risk
Authors: Rupa L Iyengar, Cynara L Maceda, Mary Ann McLaughlin
Journal: Circulation (2017)

Introduction: Obstructive sleep apnea (OSA) is a disorder with prevalence reported as high as 26% in adults between the ages of 30 and 70 years. Despite being a prevalent comorbidity, the clinical ...
Uridine triacetate for early onset, severe life-threatening toxicities of 5-fluorouracil and capecitabine.
Authors: Thomas H. Cartwright, Wen Wee Ma, Marwan Fakih, Bassel F. El-Rayes, James Posey, Thomas King, Julie Vanas, Reid von Borstel, Michael K. Bamat
Journal: Journal of Clinical Oncology (2016)

e21675 Background: Uridine triacetate was approved by FDA in late 2015 for adult and pediatric patients who receive an overdose of 5-fluorouracil or capecitabine or who exhibit early-onset, severe or life-threatening toxicities. Early-onset toxicities occur in patients due to genetic susceptibilities, including DPD deficiency that affect 5-FU exposure, anabolism and actions, and can be fatal. High-risk early-onset toxicities fall into several major categories–GI (mucositis, ulceration); hematologic (leukopenia, neutropenia, thrombocytopenia); CNS toxicities (such as altered mental status, encephalopathy/coma, ataxia); and severe cardiotoxicities (such as acute left ventricular dysfunction or serious vasospasm). Uridine triacetate is an oral prodrug of uridine, a direct antagonist that dilutes and competes with toxic 5-FU metabolites, particularly FUTP incorporation into RNA, and thereby reduces morbidity and mortality due to 5-FU and capecitabine. Methods: In 2 clinical studies, 173 patients have been treated with uridine triacetate to date, including 26 who presented with early-onset (within 96 hr post 5-FU or capecitabine dosing) severe toxicities. The Sponsor (Wellstat Therapeutics) was contacted by clinical sites upon recognition of early-onset toxicities and eligibility was evaluated. Treatment with uridine triacetate was to initiate as soon as possible within 96 hr post 5-FU/capecitabine dosing. The primary efficacy endpoint was survival at 30 days following uridine triacetate administration. Results: Of the 26 patients with early-onset, severe toxicities, all 18 initiating uridine triacetate within the 96-hr treatment window recovered and survived. Of 8 patients with comparable presenting symptoms treated outside of the 96-hr time window, 5 (63%) died during the 30 day monitoring period. Conclusions: Uridine triacetate was an effective life-saving antidote for patients following early-onset, severe GI, hematologic, cardiac and neurologic toxicities due to either 5-FU or capecitabine when administered within 96 hr after the end of fluoropyrimidine dosing.
P05.79 Semiautomatic image segmentation based volume approximation of intracranial meningiomas
Authors: M Timmer, M Kauke, A Safi, B Krischek, R Goldbrunner
Journal: Neuro-Oncology (2018)

Management of meningioma patients greatly depends on the extent of clinical disease manifestation as well as tumor shape and size. We introduce an easy usable and open access semi-automatic image segmentation for volumetric and morphometric brain tumor analysis. ITK-SNAP was utilized for semi-automatic image segmentation of 58 gadolinium-contrast enhanced T1-weighted thin-slice MRI datasets for volumetric and morphometric analysis. Furthermore, multimodal imaging datasets (including T2, FLAIR, T1) were evaluated for radiological biomarkers of aggressiveness and growth potential. Patient charts were retrospectively reviewed for accessory clinico-pathologic data including clinical disease manifestation, age, sex, weight, tumor grade and location. The statistical impact of various parameters was determined by Student’s t-test. Semiautomatic image segmentation at hand of a thin-slice gadolinium contrast-enhanced T1-weighted image series is feasible, freely accessible and enables quick volume approximation. Location (p=0.001), clinical disease manifestation (p=0.033), peritumoral edema (p= 0.038), tumor intrinsic cystic degeneration (p=0.007), multifocality (p=0.022) and meningioma mass effect (p=0.001) were statistically associated with higher volumes, irrespective of tumor grade. Conventional methods for size characterization of meningiomas neglect a large portion of an MRI-scans dataset. Hence, this study shows the usage of semi-automatic image segmentation for size characterization and morphometric analysis of meningiomas. Additionally, we highlight the importance of correct size indication by means of segmentation based volume approximation, particularly in the context of accurate neoplastic disease state quantification for patient observation and follow up.
Phase I study of talazoparib and irinotecan in children and young adults with recurrent/refractory solid tumors.
Authors: Sara Michele Federico, Elizabeth Stewart, Jamie L. Coleman, Michael William Bishop, Victor M. Santana, Catherine Lam, Dana Hawkins, Jianrong Wu, Shenghua Mao, David Ross Goshorn, Alberto S. Pappo, Michael A. Dyer
Journal: Journal of Clinical Oncology (2017)

10542 Background: Poly (ADP-ribose) Polymerase inhibitors (PARPi) target tumors with deficiencies in DNA repair mechanisms. Talazoparib (TAL), a potent PARP inhibitor, demonstrated significant efficacy in a Ewing sarcoma model when combined with DNA-damaging irinotecan (IRN). We performed a phase I trial to determine the maximum tolerated doses (MTDs) of TAL and IRN in pediatric patients with solid tumors. Methods: Cohorts of 3-6 eligible patients (pts) with recurrent/refractory solid tumors received escalating doses of oral (PO) TAL and intravenous (IV) IRN in a 3+3 design (Table 1). Each course was 21 days. Serum for TAL and IRN pharmacokinetics (PK) were obtained. Toxicities were assessed using CTCAE v.4 and responses were evaluated by RECIST v.1.1. Results: Twenty-four pts (9 male; median age, 11 years; 18 recurrent) received a median of 2 courses (range, 1-18). Fifteen pts had prior exposure to IRN. Table 1 summarizes the dose-limiting toxicities (DLTs) in course 1. The most common grade 3 or higher non-hematologic and hematologic toxicities in 82 evaluable courses were febrile neutropenia (5), elevated gamma-glutamyltransferase (GGT, 4), neutropenia (22) and lymphopenia (17). Two of 22 evaluable patients had a response (CR Ewing sarcoma, 18 courses; PR synovial sarcoma, 10 courses) and 9 had disease stabilization, median 4 courses (range, 4-10). Results of PK tests will be presented. Conclusions: The recommended phase II doses are TAL 600mcg/m 2 (max 1000mcg/dose) days 1-6 and IRN 40mg/m 2 /day days 2-6. This regimen is feasible with evidence of anti-tumor activity and warrants further investigation. Clinical trial information: NCT02392793. [Table: see text]
Outcomes of oxaliplatin-based (Ox) chemotherapy (CT) on R0 resection of colonic liver metastases (CLM).
Authors: Nicholas Adam Bosma, Maclean Thiesen, Winson Y. Cheung, Daniel John Renouf, Caroline Speers, Derek Tilley, Elijah Dixon, Chad Ball, Patricia A. Tang, Richard M. Lee-Ying
Journal: Journal of Clinical Oncology (2018)

3538 Background: In resected CLM, randomized studies of Ox CT have not demonstrated improvements in overall survival (OS) and Ox CT has not been compared to non-Ox CT. The aim of this study was to assess the impact of Ox CT regimens on OS in patients that have undergone resection of CLM in a real world setting. Methods: Patients who underwent resection of CLM in the provinces of Alberta and British Columbia, Canada were identified from 1996-2016. Perioperative (pre and/or post) CT regimens were reviewed and categorized as Ox CT, non-Ox CT or no CT. OS was measured from the time of metastatic diagnosis to death or last follow-up using the Kaplan-Meier method. CT regimens were compared using the log-rank test and a Cox regression model, adjusting for possible confounders including age, gender, primary tumor sidedness and the presence of synchronous metastatic disease. Results: 516 patients were identified who underwent R0 resection of CLM for mCRC, including 205 that received Ox CT, 129 non-Ox CT and 182 with no CT. Of these patients, 24% and 56% received pre-operative and post-operative CT, respectively. 70% of these patients received a fluoropyrimidine (5-FU or capecitabine), 40% oxaliplatin, 13% irinotecan, 7% received bevacizumab and 1% panitumumab. Median age of these patients was 64, with 60% male and 57% demonstrating synchronous metastatic disease and 38% right-sided primary. The median OS for patients receiving Ox CT was 98 months, for non-Ox CT 60 months and no CT 56 months, p = 0.01. After adjusting for potential confounders with a Cox-proportional hazard model, patients who received Ox CT had a lower risk of death HR of 0.65 (95% CI 0.48-0.87, p < 0.01), while the non-OX CT group did not, HR 0.84 (95% CI 0.62-1.13, p = 0.25) compared to no CT. Conclusions: Perioperative Ox CT appears to improve OS in conjunction with R0 resection of CLM in this multicenter population based study. This observation remained significant even after controlling for potential confounders. Ox CT should be considered in patients that undergo R0 resection of CLM, in favor of non-Ox CT. The addition of biologic agents to CT remains limited. Further studies should evaluate the optimal timing and duration of perioperative CT.
Safety and tolerability of the bolus 5-fluorouracil (5-FU) based FLOX and IFL regimens in patients who developed fluoropyrimidine-induced coronary vasospasm during therapy with infusional 5-FU or capecitabine.
Authors: Sakti Chakrabarti, Jaskanwal Deep S. Sara, Ronstan Lobo, Rachel Eiring, Heidi D. Finnes, Jessica L Mitchelll, Mindy L. Hartgers, Akiko Okano, Thorvardur Ragnar Halfdanarson, Axel Grothey
Journal: Journal of Clinical Oncology (2018)

e15513 Background: Coronary vasospasm associated with 5-FU based chemotherapy regimens is well described in the literature and has been reported to occur more often with infusional 5-FU or capecitabine than with bolus 5-FU. Patients suffering from fluoropyrimidine (FP) induced vasospasm have been successfully treated with bolus 5-FU based regimens. Given the additional benefit of oxaliplatin in the management of patients with early and advanced colorectal cancer, retaining oxaliplatin in the treatment regimens is desirable. We performed a retrospective review to explore the safety of substituting FLOX (bolus 5-FU, oxaliplatin, leucovorin) or IFL (irinotecan, bolus 5-FU and leucovorin) for FOLFOX (infusional 5-FU , oxaliplatin and leucovorin) and CAPOX (capecitabine and oxaliplatin) in patients with FP-induced coronary vasospasm. Methods: The pharmacy database at Mayo Clinic was queried to identify patients who developed coronary vasospasm associated with FOLFOX or CAPOX between January, 2011 and January, 2018. Information on adverse effects of FLOX and IFL regimens was obtained. Results: 11 patients (median age 54 years, range 36-77, 3 males and 8 females) developed 5-FU induced vasospasm, 10 with FOLFOX and 1 with CAPOX, 7 in adjuvant setting and 4 in metastatic setting. In 10 out of 11 patients, chest pain was the presenting complaint which started within 48 hours of beginning of 5-FU infusion. In 9 out of 11 patients, vasospastic event occurred after first cycle of chemotherapy. All patients made full recovery after discontinuation of infusional 5-FU or capecitabine. Of the11 patients, 10 subsequently received FLOX with median total bolus 5-FU doses of 7 (range 2-22), 7 days to 18 months after the event including 7 patients within 4 weeks of the event. FLOX did not cause any cardiovascular adverse events in any of the 10 patients. One patient received IFL about 51 months after initial exposure to FOLFOX and tolerated the regimen well. Conclusions: Bolus 5-FU based regimens such as FLOX are safe in patients who have experienced coronary vasospasm with infusional 5 FU or capecitabine.
Characterization and spatial localization of the tumor immune microenvironment in metastatic uveal melanoma.
Authors: Kimberly Mayumi Komatsubara, Robyn Denise Gartrell, Claire-Audrey Bayan, Jaya Sarin Pradhan, Syed Shabee Hasan, Thomas D Hart, Margaret Borgardus, Yan Lu, Douglas Kanter Marks, Jessica Yang, Adriana Lopez, Codruta Chiuzan, Basil Horst, Bret Taback, Larisa J. Geskin, Brian P. Marr, Gary K. Schwartz, Yvonne M. Saenger, Richard D. Carvajal
Journal: Journal of Clinical Oncology (2018)

9570 Background: Uveal melanoma (UM) is a rare subset of melanoma that is resistant to immune checkpoint blockade. High density of macrophages (Mϕ) and TILs is associated with poor prognosis in primary UM but little is known about the tumor microenvironment (TME) in metastatic UM (MUM). Here we performed quantitative spatial analysis using multiplex immunohistochemistry (mIHC) to characterize the TME in MUM, compare the TME of MUM to metastatic cutaneous melanoma (MCM), and identify potential mechanisms of MUM resistance to immunotherapy. Methods: We identified pts with untreated metastatic melanoma with clinical follow-up and available pre-treatment tissue who consented to an IRB-approved protocol. 5µm slides were stained using Opal mIHC for DAPI, CD3, CD8, CD68, HLA-DR, Ki67, and SOX10. Tumor areas were pre-selected by a dermatopathologist, visualized using Vectra and analyzed for density and spatial localization using inForm software. Results: 6 MUM and 8 MCM cases were evaluable at the time of this analysis. CD3+ and CD8+ T-cell density is similar between MUM and MCM, however, there is a trend towards a higher density of proliferating cytotoxic T lymphocytes (CTL) (CD8+Ki67+) in MCM (p = 0.05). Interestingly, CD68+ Mϕ density is lower in MUM compared to MCM (p = 0.03). Both CD68+HLA-DR+ Mϕ (activated) and CD68+HLA-DR- Mϕ (inactivated) density is lower in MUM. Using nearest neighbor spatial analysis, CD8+ CTLs are significantly farther from activated Mϕ (CD68+HLA-DR+) (p = 0.01), but not from inactivated Mϕ (CD68+HLA-DR-) in MUM compared to MCM. Conclusions: Unlike primary UM, our sample of untreated MUM is not characterized by a high Mϕ density. Fewer Mϕ are present in untreated MUM compared to MCM and activated Mϕ are located farther from CTLs in UM. Density of CTLs is similar in MUM and MCM, although proliferating CTL are more numerous in MCM. These preliminary results suggest that Mϕ may play a less prominent role in innate resistance to immunotherapy in MUM. Gene expression analysis and further classification of Mϕ type is ongoing. Additional cases are ongoing analysis and will be reported.
Outcome on 560 metastatic melanoma (MM) patients treated with pembrolizumab during the German Expanded Access Program (EAP).
Authors: Jessica Cecile Hassel, Andrea Forschner, Leonie Blum, Lucie Heinzerling, Lisa Zimmer, Jochen Utikal, Katharina C. Kähler, Max Schlaak, Carmen Loquai, Ralf Gutzmer, Felix Kiecker, Carola Berking, Armin Bender, Lars Schneider, Alexander Enk, Claus Garbe, Michael Weichenthal, Dirk Schadendorf, Axel Hauschild, Peter Mohr
Journal: Journal of Clinical Oncology (2016)

9558 Background: Treatment with immune checkpoint blockers has significantly improved overall survival of patients with MM. Data from phase III trials are available on the CTLA-4 antibody ipilimumab and antibodies against the PD-1/PD-L1 axis. However, EAPs demonstrate data in a patient population with “real world scenario.” Methods: Within the German EAP, pembrolizumab 2 mg/kg was given intravenously every 3 weeks to patients with unresectable mm on or following treatment with standard of care agents including ipilimumab, and when indicated a BRAF/MEK inhibitor. Excluded were patients with active brain metastases, a history of severe autoimmune disease or severe immune-related adverse events (irAEs) under pretreatment with another immunotherapy. Results: Of 605 patients from 79 participating centers, 560 patients definitely received pembrolizumab. 337 (60%) were males, 223 (40%) females with a median age of 64 years (range 18-91). ECOG was 0 in 363 (65%) and 1 in 194 (35%) patients. Response could be evaluated in 474 patients with 17 (4%) complete responses, 92 (19%) partial responses, and 95 (20%) stable diseases leading to a disease control rate (DCR) of 43%. A total of 430 AE occurred in 258 (46%) patients with 206 serious AE (SAE), a majority of which were related to the metastatic disease. Treatment-related AE (n = 99) occurred in 65 (12%) patients and contained a variety of likely or possibly irAE, including hypophysitis (n = 4), pneumonitis (n = 2), thyroid disease (n = 9), hepatitis (n = 4), skin reactions (n = 5), or other (n = 8). Among these 11 were CTC-AE grade 3 and 1 was CTC-AE grade 4. Despite of diarrhea in 6 cases, there was no proven case of autoimmune colitis. The remaining treatment-related AE contained constitutional (n = 17), laboratory (13), or other conditions (n = 24). Among these, 19 were CTC-AE grade 3 and 2 were grade 4. There was one possibly treatment-related death due to renal failure which was associated with multi-organ failure and pneumonia. Death was accompanied by disease progression. Conclusions: Pembrolizumab revealed a highly acceptable safety profile in real life situation within the German EAP and a confirmed remission rate as compared to the Keynote-002 trial and the US EAP.