tbuckley/cabot-search huggingface dataset:
Is cytoreductive surgery and hyperthermic intraperitonealchemotherapy reasonable treatment for gastric signet-ring cell adenocarcinoma and linitis plastica with peritoneal metastasis? CYTO<i>-CHIP</i> study—Ancillary results.
Authors: Pierre Emmanuel Bonnot, Guillaume Piessen, Frederic Mercier, Marc Pocard, Bernard Meunier, Jean Marc Bereder, Karine Abboud, Frederic Marchal, Francois Quenet, Diane Goere, Catherine Arvieux, Simon Msika, Denis Pezet, Nicolas Pirro, Romuald Wernert, Patrick RAT, Jérémie Lefevre, Thomas Courvoisier, Michel Rivoire, Olivier Glehen
Journal: Journal of Clinical Oncology (2018)

4073 Background: Incidence of gastric signet-ring cell adenocarcinoma (SRCa) is increasing. Linitis plastica (LP) is its typical presentation. SRCa are associated with less chemosensitivity and more peritoneal metastasis (PM). Most consider PM from a gastric SRCa as an end-stage disease. Cytoreductive surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) are highly debated in those indications. Methods: 277 patients treated for gastric cancer with PM by CRS with or without HIPEC in 19 French centers from 1989 to 2014 were included. Diagnosis of an SRCa was based on the presence of isolated carcinoma cells containing mucin. Purpose: to evaluate the impact of CRS and HIPEC in patients with PM from SRCa compared with those with PM from non-SRCa. Results: 188 patients had an SRCa with 55.1 % of LP. One tumor was a LP in the 89 patients with a non-SRCa. Patients with SRCa were more frequently female and younger, with more diffuse PM, undifferentiated and pN3 tumors. There was no difference in perioperative treatments. 124 (66%) patients in the SRCa group and 56 (62.9%) in the non-SRCa group underwent an HIPEC. Median Peritoneal Cancer Index (PCI) was higher in HIPEC sub-groups (SRCa: 7 v 2; non-SRCa: 5 v 1). PM from SRCa was associated with worse survival from surgery. After CRS, with or without HIPEC, 3-year OS was 14% in the SRCa v 38.4% in the non-SRCa (P = < .001). In the SRCa group, HIPEC was associated with better survival on multivariate analysis than CRS alone (median OS: 16.3 v 11 months, HR, 0.526; 95% CI, 0.34- 0.81; P = .003). LP, tumor grade, PCI and adjuvant treatment were independent prognostic factors. In the non-SRCa group, effect of HIPEC was more significant with 3 and 5-year OS of 50.1% and 45.4 v 17 % and 17 % (P = .004). ASA score, PCI and nodal status were independent prognostic factors. Conclusions: PM from gastric SRCa or non-SRCa have distinct prognosis. HIPEC seems a valuable option therapy for resectable PM from SRCa. Concerning PM from non-SRCa, this study is currently the best evidence that HIPEC can offer similar survival rates to non-metastatic tumors on selected patients. NCT:03253939.
The role of YAP/TAZ activity in cancer metabolic reprogramming
Authors: Xiaodong Zhang, Haiying Zhao, Yan Li, Di Xia, Liang Yang, Yingbo Ma, Hangyu Li
Journal: Molecular Cancer (2018)

In contrast to normal cells, which use the aerobic oxidation of glucose as their main energy production method, cancer cells prefer to use anaerobic glycolysis to maintain their growth and survival, even under normoxic conditions. Such tumor cell metabolic reprogramming is regulated by factors such as hypoxia and the tumor microenvironment. In addition, dysregulation of certain signaling pathways also contributes to cancer metabolic reprogramming. Among them, the Hippo signaling pathway is a highly conserved tumor suppressor pathway. The core oncosuppressive kinase cascade of Hippo pathway inhibits the nuclear transcriptional co-activators YAP and TAZ, which are the downstream effectors of Hippo pathway and oncogenic factors in many solid cancers. YAP/TAZ function as key nodes of multiple signaling pathways and play multiple regulatory roles in cancer cells. However, their roles in cancer metabolic reprograming are less clear. In the present review, we examine progress in research into the regulatory mechanisms of YAP/TAZ on glucose metabolism, fatty acid metabolism, mevalonate metabolism, and glutamine metabolism in cancer cells. Determining the roles of YAP/TAZ in tumor energy metabolism, particularly in relation to the tumor microenvironment, will provide new strategies and targets for the selective therapy of metabolism-related cancers.
Neurological death in patients with EGFR-mutant non-small cell lung cancer.
Authors: Matthew Ramotar, Sierra Barnes, Mark Doherty, David Benjamin Shultz
Journal: Journal of Clinical Oncology (2018)

2062 Background: Patients with EGFR mutant non-small cell lung cancer (EGFRmNSCLC) have a high incidence of brain metastases (BM). We sought to determine the rate of neurologic death in EGFRmNSCLC patients diagnosed with brain metastases. Methods: A single-institution prospectively managed database identified 204 patients with EGFRmNSCLC treated for brain metastases between 2000 and 2016. We estimated actuarial survival rates using the Kaplan-Meier method. The incidence of neurologic death (ND) was determined using a competing risks analysis. ND was correlated to clinical and treatment variables using Fisher’s exact test. Survival was calculated from the date of BM diagnosis. We defined neurologic death as death due to brain metastases or leptomeningeal disease Results: Fifty-six percent of patients had BM at the time of initial diagnosis. The initial BM treatment was up front stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), or tyrosine-kinase inhibitor (TKI) alone in 22, 60, and 18 percent of patients, respectively. Two-year rates of OS in these subgroups were 64%, 38%, and 50%, respectively (p = 0.016). The 5-year rate of neurologic death was 38%. Thirty-four percent died of non-neurologic causes, 8% died of unknown causes, and the remaining patients were alive at last follow-up. Median survival (MS) was 19 months; MS in patients who died of non-neurologic causes and neurologic causes was 23, and 15 months, respectively. Of age, staging, BM at diagnosis, history of TKI therapy, initial treatment of BM, staging at diagnosis, and leptomeningeal disease at diagnosis (LMD), only LMD was significantly associated with ND (p = 0.047). Conclusions: Neurologic death due to EGFRmNSCLC BM was more common in our cohort than has been previously reported, highlighting the need for dedicated studies focused on the best management of BM in this population.
National Comprehensive Cancer Network (NCCN) infusion efficiency workgroup study: Optimizing patient flow in infusion centers.
Authors: Jessica Sugalski, Daniel Mulkerin, Rebecca Caires, Penny J. Moore, Rosanna Fiorarancio Fahy, Jeanine N. Gordon, Connie Z. Augustyniak, Gina M. Szymanski, MiKaela M. Olsen, Diedra K. Frantz, Marisa A. Quinn, Sharol K. Kidd, Diana M. Cartwright, Lisa G. Kimbro, Robert W. Carlson, F. Marc Stewart
Journal: Journal of Clinical Oncology (2018)

e18502 Background: The National Comprehensive Cancer Network (NCCN) formed an Infusion Efficiency Workgroup to determine best practices for operating efficient and effective infusion centers. Methods: The Workgroup conducted three surveys that were distributed to NCCN Member Institutions regarding average patient wait time, chemotherapy premixing practices, infusion chair utilization, and premedication protocols. To assess chair utilization, the Workgroup identified and defined five components of chair time. Results: The average patient wait time in infusion centers ranged from 25 minutes to 102 minutes (n = 23; mean = 58 minutes). Five of 26 cancer centers (19%) routinely mix chemotherapy drugs before patient arrival for patients meeting specified criteria. Total planned chair time for subsequent doses of the same drug regimens for the same diseases varied greatly among centers as follows: AC ranged from 85 to 240 minutes (n = 22), FOLFIRINOX ranged from 270 to 420 minutes (n = 22), rituximab ranged from 120 minutes to 350 minutes (n = 21); Paclitaxel/carboplatin ranged from 255 to 380 minutes (n = 21), and zoledronic acid ranged from 30 to 150 minutes (n = 22) for planned total chair time. It was also found that cancer centers utilize different premedication regimens with varying administration routes that ranged in administration times from zero to 60 minutes. Conclusions: There is a high degree of variation among cancer centers in regards to planned chair time for the same chemotherapy regimens, which provides opportunities for improved efficiency and increased standardization across centers. For example, the average infusion time reported by NCCN Member Institutions for a subsequent dose of the AC regimen for breast cancer was 56% longer than the recommended infusion time on the NCCN Chemotherapy Template for this regimen. The Workgroup provides recommendations for cancer centers to move towards more efficient and more standard practices. NCCN Chemotherapy Order Templates (recommended infusion time, in minutes) Survey Results (infusion time range, in minutes) AC: Breast Cancer 30 40 – 100 FOLFIRINOX: Pancreatic Cancer 210 210 - 245 Rituximab: Follicular Lymphoma 90 90 - 270
Expression of androgen receptor, somatostatin receptor subtypes, aurora kinase A, and interleukin-6 in prostate cancer before androgen ablation.
Authors: Angela Gernone, Senia Trabucco, Eliano Cascardi, Leonardo Resta, Franco Silvestris, Anna Napoli
Journal: Journal of Clinical Oncology (2017)

e16508 Background: Neuroendocrine differentiation (NED) in prostate cancer (PC) can be detected by immunohistochemistry as single cells in conventional adenocarcinoma. NEPC is a poor-recognized late presentation of hormone refractory subtype of PC AR-negative. NEPC correlates with poor prognosis, tumor progression during androgen-deprivation therapy and frequent visceral metastases. Aurora kinase A (AURKA) and Interleukin-6 (IL-6) cooperate to induce NED. The aim of this study was to correlate the expression of somatostatin receptor (SSTR) 1- 2- 3- 4- 5 subtypes, AURKA and IL-6 in primary PC with NED pattern before androgen ablation and OS. Methods: PC tissues were reviewed from 60 pts who had undergone biopsy or radical prostatectomy for previously untreated advanced or metastatic PC from 2010 to 2016. 10 samples expressed histologically chromogranin A (CgA), a marker of NED expression. Median age was 67 years (47-80), Gleason score ≥ 7, median PSA was 60 ng/ml (1.3-1000), ECOG 0/1 and bone-visceral sites measurable in 90% of cases. For comparison purposes, 8 pathology specimens from pts with primary PC negative for CgA expression were used. Results: SSTR1-2-4-5 were detected only in the nucleus of PC cells in 10/10 samples. AR was expressed in all 10 samples CgA positive. SSTR3 and AURKA were not expressed in all 10 samples. IL-6 was detected in 9/10 samples. All 10 pts developed early onset of CRPC, more aggressive clinical course with rapid occurrence of visceral metastases and OS was &lt; 12 mos. Conclusions: In metastatic prostate cancer, pretreatment NED pattern can be a predictor for progression and survival after hormonal and during standard chemotherapy. Most likely NEPC become AR negative during disease progression and in response to androgen deprivation therapy. We supposed, according to other data, that the novel potent AR-targeted drugs should be not used in this subset of patients. SSTRs and somatostatin analogs are not potential targets for prostate cancer.
Radiographic features of metastatic brain tumors from non-small cell lung cancer with ALK rearrangement.
Authors: Li Chu, Ruimin Li, Xi Yang, Fan Xia, Zhengfei Zhu
Journal: Journal of Clinical Oncology (2017)

e20533 Background: Approximately 5% of Non-Small Cell Lung Cancer (NSCLCs) have ALK rearrangement, in which brain metastases are common. The radiographic features of metastatic brain tumors have not been previously studied. Finding the features of brain metastasis could help establishing the treatment pattern for the ALK-rearranged NSCLC patients. Methods: All NSCLC patients with ALK rearrangement (132 patients) were detected from March 2008 through December 2016. The metastatic brain tumors (34 patients) detected from July 2014 through December 2016 were divided into metachronous brain metastasis (MBM) and synchronous brain metastasis (SBM) groups according to the diagnosis time. All patients were followed up using brain magnetic resonance imaging (MRI). The number of brain tumors, size of the largest brain tumors, and size of peritumoral brain edema were compared between the two groups. Results: Thirty-four patients were observed.The number of brain tumors in ALK-rearranged NSCLC patients is 4.6 with 41.07mm Peritumoral Brain Edema Size (PBES). Only one patient has the military brain metastases. All patients were divided into two groups: metachronous (15 patients) and synchronous (19 patients). The two groups had rare active and former smoker. The SBM group had more female patients. The SBM group had larger number of brain tumors (6.1 VS 2.8), but there was no significant difference ( P= 0.0672). The MBM group had smaller brain tumors (14.2mm vs 20.9mm, P= 0.0798) with smaller PBES (25.7mm vs 53.2mm, P= 0.0018) and Peritumoral Brain Edema Index (PBEI) (0.9 vs 1.9, P= 0.0201) than the SBM group. Conclusions: Only one patient in SBM group has the military brain metastases. The SBM group has larger brain tumors with larger peritumoral brain edema and PBEI. The MBM patients have smaller ones. Our studies show that ALK-rearranged NSCLC patients have a small number brain tumors and relatively large PBES.
Immune-related tumor response dynamics as a marker for survival and treatment benefit during PD-1 inhibitor therapy.
Authors: Mizuki Nishino, Anita Giobbie-Hurder, Nancy Bailey, Elizabeth Iannotti Buchbinder, Patrick Alexander Ott, Nikhil H. Ramaiya, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2016)

9521 Background: PD-1 inhibitors are promising anti-cancer agents and are associated with unique immune-related response patterns. We characterized patterns of tumor response dynamics on CT scans during PD-1 inhibitor therapy and investigated the association with overall survival (OS) in advanced melanoma patients (pts). Methods: Forty-nine advanced melanoma pts (22 males; median age: 55) treated with single-agent pembrolizumab at DFCI were retrospectively studied. Baseline and all follow-up CT during therapy were reviewed to quantify tumor burden using irRECIST, which uses unidimensional measurements and includes new lesions in tumor burden [Clin Cancer Res. 2013;19:3936-43]. Association between OS and tumor burden dynamics was studied. Results: Tumor burden change at best overall response ranged from -100% to 357% (median:-11%). Response rate was 41% (20/49; irCR in 4, irPR in 16). Spiderplot showed 3 distinct patterns of tumor response dynamics: A) tumor burden < 20% increase from baseline throughout therapy (n = 27, 55%); B) tumor burden ≥ 20% increase from baseline without subsequent response (n = 19, 39%); and C) pseudoprogression with initial tumor burden increase ( ≥ 20%) and subsequent response (n = 3, 6%). Pseudoprogressors were younger than others (median age: 40 vs. 56; p = 0.05), and achieved response after irPD was confirmed on 2 consecutive scans. Using a 3-month landmark analysis, pts with < 20% tumor burden increase from baseline at 3 months had longer OS than pts with ≥ 20% increase (12-month OS rate: 78 vs 51%). In extended Cox models, pts with < 20% tumor burden increase during therapy had significantly reduced hazards of death (HR = 0.16, 95% CI (0.05 - 0.54), p = 0.003 univariate; HR = 0.14, 95% CI (0.04 - 0.48), p = 0.002 multivariable). Conclusions: Three distinct patterns of tumor response dynamics were noted during pembrolizumab therapy. Pseudoprogressors achieved response after experiencing confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluation. Tumor burden < 20% increase from baseline on follow-up CT scans was associated with longer OS, proposing a practical marker for survival and treatment benefit of PD-1 inhibitor therapy.
A novel in vitro approach for the identification of exceptional responders in acute myeloid leukemia.
Authors: Eric Justin O'Brien, Brett VanCauwenbergh, Alexander Merk, Luke Byerly, Mark Wunderlich, Mayur Sarangdhar, Mitali Basu, William Seibel, Benjamin Mizukawa, Lynn Hua Lee, Erin Haag Breese, John Peter Perentesis
Journal: Journal of Clinical Oncology (2018)

e19011 Background: Each case of acute myeloid leukemia (AML) represents a unique ecosystem. Despite recent advances in our understanding of the genetic landscape of AML, this information remains insufficient to accurately predict an individual patient’s response to therapy. Real-time ex-vivo functional screening can identify mechanisms underpinning drug response and diversity between tumors, aiding in stratification. In this work, we established a screening platform to explore patient specific drug sensitivity and resistance, which we believe provides novel insight into prioritization of agents for an individual patient with refractory leukemia as well as clinical trial development. Methods: Samples were acquired from 14 pediatric AML patients after informed consent was obtained. Samples were cultured in the presence of SCF, TPO, FLT3-L, IL-3, and IL-6. A panel of 38 drugs was identified which included standard chemotherapy agents used in AML and drugs currently under clinical development. Cells were exposed to drugs for 72hrs. An MTS assay was performed and reported as % viability normalized to vehicle control wells. Targeted DNA NGS sequencing of 406 genes, 31 introns, and RNA sequencing of 265 genes was performed for genetic characterization. In vitro samples underwent serial passage until either cell exhaustion or immortalization, which was defined as exceeding 60 doublings, the upper boundary of the Hayflick Limit. Results: Of the relapsed samples, 5/11 samples became immortalized following serial passage, in contrast to 0/3 of the de novo samples. Engraftment of long term cultures into immunodeficient mice was able to produce aggressive disease in all cases. All immortalized samples’ driver genetic architecture was well preserved, with only minor differences noted. In vitro drug screening revealed variations in drug sensitivity between samples. When possible, clinical responses to therapy were compared with in vitro responses to the same drugs. Conclusions: This screening approach highlighted well established agents that showed significant activity in highly refractory disease providing rationale for further clinical trial development.
Adjuvant chemotherapy and survival outcomes in diabetic patients with colon cancer: A population-based analysis.
Authors: Shiru Lucy Liu, Sharlene Gill, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2018)

3589 Background: Diabetes can pose challenges when using adjuvant chemotherapy (AC), as specific cytotoxic drugs, including oxaliplatin, may potentiate certain diabetic complications, such as neuropathy. We performed a provincial analysis of resected colon cancer patients to evaluate the prevalence of diabetes, type of chemotherapy used, and survival outcomes. Methods: We examined 5,440 patients with resected stage 2 or 3 colon cancer who were diagnosed from 2004 to 2015 in Alberta. Baseline patient, tumor, and treatment characteristics were compared between those with and without diabetes. Survival analysis was conducted based on Kaplan-Meier methods. Results: 608 patients (11%) had uncomplicated diabetes (UDM) and 436 (8%) patients had diabetes with complications (CDM), defined as neuropathy or other micro/macrovascular end-organ damage. CDM patients were older and had worse Charlson comorbidity index (p < 0.001). While 34% of UDM patients and 35% of non-diabetic patients received AC, only 15% of CDM patients received AC (p < 0.001). Among those who received AC (N = 1574), an oxaliplatin-based regimen was given to 45% and 52% of UDM and non-diabetic patients, respectively, but only 35% of CDM patients (p < 0.001). Kaplan-Meier analysis revealed significantly worse overall survival (OS) in the CDM group when compared to the UDM or non-diabetic groups (p < 0.001). Of those treated with AC however, there were no statistical differences in OS (p = 0.188) or cancer-specific survival (CSS) (p = 0.461) across all groups regardless of diabetes or complication status (see Table). Receipt of oxaliplatin was associated with improved OS among patients with stage 3 disease compared to monotherapy (p = 0.006). Conclusions: Patients with CDM are less likely to receive AC; however, patients treated with oxaliplatin-AC appear to have similar survival outcomes as their UDM and non-diabetic counterparts. N = 1574 5-year OS 5-year CSS Non-Diabetic (N = 1345) Monotherapy 75% 80% Oxaliplatin 80% 82% UDM (N = 175) Monotherapy 72% 78% Oxaliplatin 75% 79% CDM (N = 54) Monotherapy 60% 72% Oxaliplatin 64% 79%
TCT-70 Incidence, Trends, and Risk Factors for Early Stroke after Transcatheter Aortic Valve Replacement in the First 5 years of US Clinical Practice: Report of the STS/ACC TVT Registry.
Authors: Chetan Huded, E. Murat Tuzcu, Amar Krishnaswamy, Stephanie Mick, Neal Kleiman, Lars Svensson, Vinod Thourani, Ajay Jayant Kirtane, Pratik Manandhar, Sreekanth Vemulapalli, Samir Kapadia
Journal: Journal of the American College of Cardiology (2018)
Impact of early tumor response on prognostic of patients with unresectable liver metastases from wt-KRAS colorectal cancer (LM-CRC) treated with hepatic artery infusion of irinotecan, 5-fluorouracil and oxaliplatin plus intravenous cetuximab after failure of systemic chemotherapy (European Phase II OPTILIV).
Authors: Mohamed Bouchahda, Valerie Boige, Denis Michel Smith, Abdoulaye KarabouÃ©, Mohamed Hebbar, Céline Lepère, C. N. J. Focan, Rosine Guimbaud, Pasquale F. Innominato, Sameh Awad, Carlos Carvalho, Salvatore Tumolo, Stephanie Truant, Thierry De Baere, Denis Castaing, Philippe Rougier, Julien Taïeb, Jean F. Morere, Michel Ducreux, Francis Levi
Journal: Journal of Clinical Oncology (2016)

e15036 Background: Early tumor shrinkage has been associated with improved long-term outcome in patients (pts) with chemotherapy (chemo)-refractory LM-CRC. We examined the prognostic relevance of early tumor response after hepatic artery infusion of triplet chemotherapy combined with intravenous (IV) Cetuximab (Cet) in pts with unresectable LM-CRC. Methods: Pts received IV-Cet (500 mg/m2) and HAI of Irinotecan (180mg/m2), 5–Fluorouracil (2800 mg/m2), and Oxaliplatin (85mg/m2) every two weeks. Tumor response (RECIST) was based on CT scans ± MRI q3 courses. Pts were categorized as early-responders (CR or PR after 3 courses – at » 6 weeks), late responders (CR or PR > 3 courses) and non-responders (SD or PD). The rate of conversion to liver surgery (R0-R1), progression free survival (PFS) and overall survival (OS) were compared. Results: 57/64 registered pts (89%) received ³ 3 courses. They were assessed for response, which occurred early for 16/57 pts (28%), late for 10 pts (17.5%) or not at all for 31 pts (54.4%). The early-responders had similarly extensive disease as the other pts (median of 12 LM, median largest diameter = 37 mm, bilateral LM for 81% pts). Grade 3-4 diarrhea and asthenia were least in the early responders (6.3% vs 22.0%, and 0% vs 26.8%, p = 0.024, respectively).R0-R1 resection rate was twice as high in the early response group as compared to the other group (7/16; 48,8% vs 10/41; 24,4%, p = 0.10). PFS curves did not differ. In contrast. median OS was significantly longer in the 16 early-responders - 34.5 months [32.1 -36.9] - as compared to both the 41 non-early responders - 20.2 [13.6 – 26.8]; p = 0.010); and the 10 late responders - 12.0 [6.9 -17.2]; p = 0.001. Conclusions: Best clinical tolerability, LM conversion-to-resection, and survival outcomes were obtained in pts achieving an early tumor response on combined triplet hepatic artery infusion and IV Cet. The rapid disease-modifying effect of HAI is an important asset for curative intent medico-surgical strategies, and awaits prospective confirmation. Clinical trial information: NCT00852228.