tbuckley/cabot-search huggingface dataset:
Pembroliuzmab in gastrointestinal (GI) malignancies with defective DNA mismatch repair (dMMR): A single institution experience.
Authors: Courtney C Cavalieri, Eric Swanson, Jonathan R. Whisenant, John R. Weis, Glynn Weldon Gilcrease, David D. Stenehjem, Sunil Sharma, Ignacio Garrido-Laguna
Journal: Journal of Clinical Oncology (2017)

792 Background: Defective DNA mismatch repair is associated with increased mutation load and expression of neoantigens. Increased activity of PD-1 inhibitor is reported in patients with GI cancers with dMMR. Here, we describe our experience at Huntsman Cancer Institute with PD-1 inhibition in subjects with GI malignancies with dMMR. Methods: Retrospective chart review of patients with metastatic GI malignancies with dMMR, treated with pembrolizumab at Huntsman Cancer Institute between July 15, 2015 and September 26, 2016. Results: A total of 9 patients were identified that received at least 1 dose of pembrolizumab (colorectal n=5; cholangiocarcinoma n=2; pancreatic n=2). Of the 9 patients, 5 received concurrent cytoxic chemotherapy. Median number of doses given was 3 (range 1 to 17). Three patients received pembrolizumab on clinical trial with concomitant mFOLFOX6. Five patients have restaging scans at the time of abstract submission. The first patient has cholangiocarcinoma and experienced a -73% response per RECIST criteria from baseline (time to progression +8 months). The second patient has pancreatic adenocarcinoma and showed a total -56.7% response per RECIST criteria from baseline (time to progression +5 months). The third patient has colorectal carcinoma and had stable disease by RECIST at restaging after 2 months (biochemical response with a 50% decrease in CEA). The fourth patient has cholangiocarcinoma and had a biochemical response with a 50% decrease in CA 19-9 and a mixed response on first restaging scan (time to progression +3.5 months). All 4 of these patients continue to have response to therapy at the time of abstract submission. The fifth patient who had colorectal cancer and died from upper GI bleeding. Restaging CT scans showed response to therapy after 6 weeks of treatment. Four additional patients initiated treatment recently and have yet to undergo restaging scans. Conclusions: Single-institution data seem to confirm activity of PD-1 inhibitor in GI malignancies that harbor dMMR. All 5 restaged patients demonstrated response to PD-1 inhibition by RECIST criteria or decreased tumor marker. Updated responses for all patients will be presented during the meeting.
Phase I dose-escalating study to evaluate the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of Foxy-5 in patients with metastatic breast, colorectal, or prostate cancer.
Authors: Peter Grundtvig Soerensen, Tommy Andersson, Ulla Buhl, Tine Moelvadgaard, Peter Buhl Jensen, Nils Brunner, Dorte Nielsen
Journal: Journal of Clinical Oncology (2014)

TPS1140 Background: The primary tumor is rarely the cause of death of cancer patients. Instead cancer-associated mortality is generally the result of tumor metastasis. However, most current therapeutic approaches fail to specifically target the dissemination process. A low-level or lack of Wnt-5a protein expression in primary invasive breast carcinomas has been shown to correlate with shortened recurrence-free survival. A similar role for Wnt-5a as a tumor suppressor has been described in thyroid, hematopoietic, prostate and colon cancer tissues. Based on these findings we developed a formulated hexapeptide (Foxy-5) that mimicked the ability of the Wnt-5a molecule to impair cancer cell migration in vitro. Foxy-5 also reduced the metastatic burden in the lungs by 70-90% in vivo in a mouse model (Safholm et al., Clin Cancer Res, 2008). Methods: The primary objective of the phase 1 study is to evaluate the safety and tolerability of treatment with Foxy-5. The secondary objectives are to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of Foxy-5 in patients with metastatic breast, colorectal or prostate cancer, to characterize the single and multiple dose pharmacokinetic (PK) profile of Foxy-5, and to characterize the pharmacodynamic (PD) profile of Foxy-5 by assessing evidence of anti-tumor activity of Foxy-5, e.g. by analysing the amount of circulating tumor cells before and after treatment with Foxy-5. All eligible patients are screened for Wnt5a immunoreactivity in their cancer cells and only Wnt5a negative or low patients are enrolled in the study. Clinical trial information: NCT02020291.
ERCC1 Codon 118 polymorphism is a useful prognostic marker in patients with pancreatic cancer treated with platinum-based chemotherapy
Authors: H. Kamikozuru, H. Kuramochi, K. Hayashi, K. Uchida, M. Yamamoto
Journal: Journal of Clinical Oncology (2007)

15012 Background: Excision repair cross-complementation 1 (ERCC1) has been reported to play a major role in the response to platinum-based therapies. A synonymous polymorphism at codon 118 converting a common codon usage (AAC) to an infrequent one (AAT) has recently been proposed to impair ERCC1 translation and to affect the response to cisplatin chemotherapy. This polymorphism has been reported in lung, colorectal and ovarian cancer, but not in pancreatic cancer. The aim of our study was to assess whether this polymorphism had an effect on tumor response and survival time in patients with relapsed pancreatic cancer treated with cisplatin and S-1. Methods: Fifty-eight patients with relapsed pancreatic cancer were analyzed in our study. Twenty-eight patients out of 58 were treated with cisplatin and S- 1, and 30 patients were treated with S-1 alone. Genomic DNA was extracted from a formalin-fixed paraffin-embedded tumor specimen and the ERCC1 codon 118 polymorphism was analyzed by PCR-RFLP method. Results: Thirty-one (53%) were homozygous for AAC codon, 6 (10%) were homozygous for AAT codon, and 21 (36%) were heterozygous. Among the patients treated with cisplatin and S-1, no significant difference in objective response rate was observed between each genotype. However, the patients with one or two AAT codon had a significantly longer progression free survival (PFS) and overall survival (OS) than those with homozygous for AAC allele (PFS: 12.7 months vs 2.4 months, p=0.0022, OS: 25.4 months vs 13.8 months, p=0.029). In contrast, no significant difference in PFS or OS was observed between each genotype among the patients treated with S-1 alone. No differences in the frequency of toxicity were found between each genotype in both treatment groups. Conclusions: ERCC1 polymorphism is a useful prognostic marker in patients with pancreatic cancer treated with platinum-based chemotherapy. No significant financial relationships to disclose.
Effect of alvimopan (ALV) on gastrointestinal (GI) recovery, length of hospital stay (LOS), and postoperative ileus (POI)-related morbidity in patients (PTS) undergoing bowel resection (BR) for colon or rectal cancer (CRC)
Authors: J. L. Weese, W. Du, L. Techner
Journal: Journal of Clinical Oncology (2007)

4014 Background: POI, an interruption of bowel motility, occurs universally after BR and is exacerbated by exogenous opioid analgesia. ALV, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, accelerated GI recovery after BR in multicenter, randomized phase III efficacy trials. CRC is the most common reason for BR in the US, and in the ALV trials CRC was the primary reason for BR for 723 of 1,409 (51%) PTS. This abstract examines GI recovery, LOS, POI-related morbidity, and safety in only this subset of PTS. Methods: This pooled ad hoc analysis assessed the subset of PTS in phase III ALV trials who underwent BR via laparotomy because of CRC and received ALV 12 mg or placebo (PLA) (N = 723). All PTS were scheduled for postoperative intravenous patient-controlled opioid analgesia and received oral ALV or PLA preoperatively and BID postoperatively until hospital discharge or for = 7 postoperative days. Efficacy endpoints included GI-2 recovery (first bowel movement and tolerance of solid food) and postoperative LOS (calendar day after surgery to hospital discharge order written). Treatment effect on GI-2 recovery was analyzed using Cox proportional hazards models, and magnitude of effect was expressed with Kaplan-Meier means. POI-related morbidity included nasogastric tube insertion or complications of POI resulting in prolonged hospital stay or readmission. Safety was monitored by adverse event reports. Conclusions: ALV significantly accelerated GI recovery, reduced postoperative LOS, and reduced the proportion of PTS with POI-related morbidity compared with PLA in PTS undergoing BR for CRC. ALV was well tolerated with a lower incidence of nausea and vomiting in the ALV group than in the PLA group. [Table: see text] No significant financial relationships to disclose.
Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab
Authors: N. Chaput, P. Lepage, C. Coutzac, E. Soularue, K. Le Roux, C. Monot, L. Boselli, E. Routier, L. Cassard, M. Collins, T. Vaysse, L. Marthey, A. Eggermont, V. Asvatourian, E. Lanoy, C. Mateus, C. Robert, F. Carbonnel
Journal: Annals of Oncology (2017)
Improved Outcome of Unrelated Bone Marrow Transplantation for Severe Aplastic Anemia.
Authors: Hiroshi Yagasaki, Seiji Kojima, Hiromasa Yabe, Koji Kato, Hisato Kigasawa, Hisashi Sakamaki, Masahiro Tsuchida, Shunichi Kato, Takakazu Kawase, Yasuo Morishima, Yoshihisa Kodera
Journal: Blood (2007)
Cetuximab (C), fluorouracil (F), and cisplatin (P) alone or with docetaxel (D) for recurrent/metastatic (RM) head and neck cancer (HNSCC): First analysis of AIO trial # 1108.
Authors: Ulrich Keilholz, Thomas Christoph Gauler, Andreas Dietz, Viktor Gruenwald, Jan Stoehlmacher-Williams, Stephan Knipping, Michael Schroeder, Orlando Guntinas-Lichius, Norbert Frickhofen, Hans Walter Lindemann, Rainer Fietkau, Boris Haxel, Christian Junghanss, Georg Maschmeyer, Matthias Zipfel, Peter Martus, Maren Kristina Knoedler
Journal: Journal of Clinical Oncology (2014)

6018 Background: This trial was based on the findings that D in addition to PF in induction treatment and C in addition to PF in RM disease both improved outcome in HNSCC. The question was, whether TPFC would be feasible and superior to PFC in patients with RM-HNSCC without limiting comorbidities. Methods: In an open-label randomized multicenter trial, 180 patients were assigned 1:1 to receive either (arm A) P 40 mg/sqm, D 40 mg/sqm, F 2000 mg/sqm days 1+8, C 400/250 mg/sqm days 1, 8, 15 q3w or (arm B) standard PFC (P 100 mg/sqm day 1, F 1000 mg/sqm days 1-4, C 400/250 mg/sqm days 1, 8, 15) q3w. Chemotherapy was continued for a maximum of 6 cycles in absence of disease progression or limiting toxicity, followed by C maintenance (500 mg/sqm q2w). Primary endpoint was PFS. Results: Accrual was completed in Nov 2013. A planned safety analysis had revealed excessive toxicity (gastrointestinal and infections) in arm A, necessitating an amendment with reduction of P to 30 and F to 1000 mg/sqm after 20 patients/arm. After the amendment, toxicity was similar in both arms, with a rate of grade 4 toxicities of 21.3% vs. 30.8% of patients in arms A vs. B. 11.2% vs. 6.6% potentially treatment related deaths were observed in arms A vs. B. Median PFS A vs. B was 5.5 vs. 5.0 mo (HR 0.78, p=0.375), and response rates 38.2% vs. 31.9%, respectively. Further follow-up is required to describe OS. Conclusions: Despite of the previously described advantage of both components D and C in treatment of HNSCC, the four-drug regimen was not associated with improved median PFS, the primary endpoint of the trial. There is a tail of the curve effect, which will require further follow up. Clinical trial information: 1108.
Anti-inflammatory therapy combined with angiostatic scheduling of chemotherapy in advanced biliary tract cancer, hepatocellular carcinoma and gastric cancer
Authors: A. Reichle, F. Klebl, K. Bross, A. Berand, H. Wagner, S. W. Krause, F. Kullmann, F. Bataille, R. Andreesen
Journal: Journal of Clinical Oncology (2004)

4175 Background:Chronic inflammatory processes are involved in carcinogenesis and promotion of liver (HCC), cholangiocellular (CCC) and gastric cancer (GC). Methods: A pilot trial was started to analyze the activity of angiostatic scheduled chemotherapy, capecitabine 2 x 1 g/m2 from day 14 to 28 every 3 weeks, combined with an anti-inflammatory therapy (daily 45 mg pioglitazone po and 25 mg rofecoxib po) in advanced CCC, HCC and GC. Results: Fifteen patients (pts) with CCC, 5 pts with HCC and 13 pts with GC were evaluable (preceding chemotherapies in CCCs and HCCs/ GCs: mean 0.35/1.3, range 0 to 3/ 1 to 3). Major side effects (WHO grade 3 to 4) were due to capecitabine treatment. Therapy was stopped in 2 cases due to hand-foot syndrome. Objective responses were observed in CCC 20%, HCC 20%, and GC 15% including CR in 3 pts (CCC, n=1, one marker-negative CR in HCC, GC, n=1), PR in 2 pts with CCC and 1 pt with GC. Additional 8 pts (24%) achieved disease stabilization (SD) lasting >6 months (CCC, n=6, HCC, n=1, GC n=1). Overall clinical benefit occurred in 42% (CR/PR/SD). Median progression-free survival has not been reached in CCC at a median observation time of 12.1 months, was 3.2 months in HCC, and 3 months in GC. Conclusions: The new combined all-oral anti-inflammatory and metronomic chemotherapy is remarkably well tolerated in advanced HCC, CCC and GC and may induce CR as well as prolonged disease stabilization even in pre-treated pts. Therefore, the present combination therapy reveals further evaluation. No significant financial relationships to disclose.
Nausea and vomiting during high-dose interleukin-2 (HD IL-2) therapy.
Authors: Mark Fesler, Melinda Bernabe Chu, Eric Armbrecht, Scott Fosko, Eddy C. Hsueh, John M. Richart
Journal: Journal of Clinical Oncology (2013)

e20661 Background: Nausea and vomiting (N/V) are two common side effects during HD IL-2 therapy. They may be severe enough to cause electrolyte imbalances or lead to missed doses, which may compromise response. Our aim was to describe the incidence of N/V during HD IL-2 therapy at our institution. Methods: A retrospective chart review of patients treated with HD IL-2 therapy (720,000 IU/kg per dose intravenously; 14 doses, 2 cycles per course, maximum 2 courses) from January 1999 to June 2011 at Saint Louis University was performed. Patients received scheduled PO ondansetron 24 mg daily and prochlorperazine 10 mg IV or PO every 4 hours as needed per standard protocol. Additional antiemetics were ordered at the clinician’s discretion. Data regarding incidence of N/V and use and type of rescue medication for N/V were recorded. Results: 104 patients were identified (68 melanoma and 36 renal cell carcinoma). Median age was 53.7 years (17.7-77.7 years) and there were 66 men and 38 women. Only 3.8% of patients (4 out of 104) were able to complete HD IL-2 therapy without rescue medication. All patients (n = 100) who needed rescue therapy received prochlorperazine on day 1 of treatment (acute phase) and at least 1 additional day during days 2-6 of each admission (delayed phase). Metoclopramide (n = 23) was the most common supplemental antiemetic ordered followed by promethazine (n = 16), meclizine (n = 5), and palonsetron (n = 3). Conclusions: Almost all patients who underwent HD IL-2 therapy had N/V that necessitated rescue therapy during both the acute phase and the delayed phase. Decreasing the incidence and severity of N/V may increase patients’ quality of life during this demanding regimen. Current protocols are single-institution based, but generally include daily 5HT-3 antagonists and prochlorperazine as needed. Our data suggests that this regimen is inadequate. One challenge to management is that steroids, which are commonly used as adjuncts, are contraindicated during immunotherapy. Additional therapeutic options are still needed. Recently new drug targets, including neurokinin-1 receptor (NK1R) inhibitors, have been approved to treat N/V during chemotherapy. NK1R inhibitors may be of assistance during immunotherapy with HD IL-2 in the future.
Early Adoption of Sacubitril/Valsartan for Patients With Heart Failure With Reduced Ejection Fraction
Authors: Nancy Luo, Gregg C. Fonarow, Steven J. Lippmann, Xiaojuan Mi, Paul A. Heidenreich, Clyde W. Yancy, Melissa A. Greiner, Bradley G. Hammill, N. Chantelle Hardy, Stuart J. Turner, Warren K. Laskey, Lesley H. Curtis, Adrian F. Hernandez, Robert J. Mentz, Emily C. O’Brien
Journal: JACC Heart Failure (2017)
Participation of metastasis-associated in colon cancer-1 gene on lipogenesis and chemoresistance of gastric cancer.
Authors: Jiangman Duan, Li Sun, Liang Zhao, Wenjun Liao, Jing Liu, Yulin Liao, Wangjun Liao
Journal: Journal of Clinical Oncology (2014)

e15026 Background: The effectiveness of chemotherapy are limited as a result of drug resistance which is a problem to be solved in the clinical field. However, little is known about resistance mechanisms about Herceptin in gastric cancer. Metastasis-associated in colon cancer-1(MACC1), a newly oncogene associated with proliferation, invasion, metastasis and prognosis in different cancers, was also identified in gastric cancer. Our studies aim to investigate whether MACC1 is invovled in drug resistance and to explore the potential mechanisms concerned. Methods: We successfully established two gastric cancer cell lines(BGC-823 and MKN-28) with MACC1 overexpression and downregulation. And then, MACC1 expression levels were significantly correlated with the major enzymes of lipogenesis containing fatty acid synthase (FASN)/ATP citrate lyase (ACLY) and acetyl-CoA carboxylase (ACC) by QRT-PCR and Western blot. We used C75, a FASN inhibitor and siFASN(that is, small interfering RNA targeted at FASN) to mediate the endogenous fatty acid metabolism in GC cells. Meanwhile, we confirmed this conclusion in athymic mice. Results: MACC1 overexpression were more likely resistant to herceptin. High MACC1 expression promoted FASN/ACC/ACLY expression and FASN activity(P<0.05).A clinical pathological analysis of 172 GC patients (Stage I-IV) revealed that high FASN expression predicted more advanced disease, more frequent postoperative recurrence, more metastases, a higher mortality rate and correlated with MACC1 expression. The proliferation effect of MACC1 acted on GC was attenuated by FASN blockade with different schedules. Conclusions: These outcomes highlight MACC1, as a novel prognostic factor, is linked to Herceptin resistance by mediating the activiation of the lipogenic enzymes to promote cancer cell lipogenesis.
Health resource utilization and patient burden associated with SREs in a randomized controlled trial setting.
Authors: Jean-Jacques Body, Roger Von Moos, Fred Saad, Gary Edward Richardson, Janet Elizabeth Brown, Allan Lipton, Karim Fizazi, Wendy Ying, Carsten Dietrich Goessl, Akshara Richhariya
Journal: Journal of Clinical Oncology (2012)

e19514 Background: Bone metastases (BM) are common in patients (pts) with solid tumors and may result in skeletal related events (SREs) such as spinal cord compression (SCC), pathologic fracture (PF), surgery to bone (SB), and radiation to bone (RT). SREs result in significant morbidity, debilitating pain, decreased health-related quality of life and increased health resource utilization (HRU). Data from 3 registrational phase 3 trials that showed superiority of denosumab over zoledronic acid in patients with solid tumors and BM were combined to assess HRU associated with different SRE types. Methods: Data through 41 weeks for pts with solid tumors and ≥ 1 BM enrolled in these randomized, active-controlled trials were included in this posthoc analysis. HRU were evaluated by SRE type and data were compared between pts with ≥ 1 on-study SRE and those not experiencing an on-study SRE. The index date for pts with on-study SREs was defined as the date that the first SRE was reported. The median time from randomization to incidence of first SRE for each SRE type was used to establish an index date for the control (no SRE) group. The HRU window encompassed a 3-month period (i.e.1 month before and 2 months after the index date) and was assessed by mean number of various types of medical visits during this window. Results: Data from 5,543 pts were included. PF was the most common type of first SRE (n=1,017), followed by RT (n=940), SCC (n=156), and SB (n=74). 3,618 pts did not have an on-study SRE. For all types of medical visits, HRU was higher for pts with an on-study SRE than those without (Table). Conclusions: SREs are associated with increased health resource utilization, reflecting an increased burden for patients with solid tumors and bone metastases. [Table: see text]
Deep tissue hyperthermia (DTH) for recurrent/progressive malignancies.
Authors: Giuseppe Del Priore, Michael Payne, David Simon, Tyler Gutschenritter, James P Flynn, Douglas Kelly
Journal: Journal of Clinical Oncology (2014)

e22241 Background: Hyperthermia has been used an adjuvant to traditional cancer therapies. We report a cohort of patients retreated with radiotherapy (RT) and DTH after failing traditional therapies. Methods: IRB approved, tertiary care referral center prospective cohort of all patients treated with DTH and RT March 2011 to Jan 2013. All patients referred to RT with progressive disease refractory to chemotherapy and/or in a prior radiated field were considered for DTH. DTH temperatures were monitored via bladder, rectum, intragluteal fold, and vagina (women) catheters. Results: DTH (2/wk) and radiation (5/wk) was administered according to previously reported protocols from randomized clinical trials to 26 subjects: median age: 52(25-71); 23% African-Americans; 73% female; 15 also receive chemosensitization (taxane, platinum or anti-metabolite). All had pelvic primaries: cervix(31%) colorectal(23%) other GYN (15%). Median DTH treatments were 9(1-10). Mean therapeutic temperature(TT) was 39.9C, maximum TT 41.3C and time at TT 39.6 minutes. Median RT dose was 45Gy(range 23-68). DTH was generally well tolerated rated 1–6, with 1 being “good”. Self reported tolerance was 2(median); 23% rating it as “good”; 83% reporting some pain; 4 withdrew before completing DTH due to vital signs and discomfort. Baseline KPS compared to 30 days post DTH was better in 4/19, unchanged in 7/19, and worse in 8/19 evaluable patients; at 3 months post DTH KPS was better in 7/13, unchanged in 5/13, and worsened in 1/13 evaluable patients. Only 9 patients were evaluable for disease response at 3 months including 4 CR, 1 PR, 2 unchanged, and 2 progression. Conclusions: DTH is tolerable and associated with stable or improved short term outcomes including performance status. In evaluable subjects KPS was unchanged or better in 92% and 44% were free of disease at 3 months. Some heavily pretreated patients are able to achieve a complete response in previously radiated fields.