tbuckley/cabot-search huggingface dataset:
Dose escalation results of a phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in patients (Pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML).
Authors: Harry Paul Erba, Pamela S. Becker, Paul J. Shami, Michael Richard Grunwald, Donna L. Flesher, Yilong Zhang, Erik Rasmussen, Haby A. Henary, Eunice S. Wang
Journal: Journal of Clinical Oncology (2017)

7027 Background: The ubiquitin ligase MDM2 inhibits the tumor suppressor p53. In preclinical AML models, MDM2 inhibitors have antitumor activity as monotherapy that is synergistic when combined with MEK inhibitors. This open-label phase 1b study assessed the maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity of the investigational oral, selective MDM2 inhibitor AMG 232 as monotherapy or combined with the MEK kinase inhibitor trametinib in pts with r/r AML. Methods: Pts with r/r AML received AMG 232 for 7 days every 2 weeks (7 days on/7 days off) at 60, 120, 240, 480, and 960 mg PO QD as monotherapy (Arm 1) or combined with trametinib 2 mg PO QD (Arm 2). Primary endpoints were the incidence of adverse events (AEs), dose-limiting toxicities (DLTs), and PK. Additional endpoints included best response (revised IWG) and serum MIC-1 level (increased MIC-1 suggests p53 activation). p53 target gene ( P21, BAX, and PUMA) expression in bone marrow was assessed by microarray. Results: In total, 35 pts (Arm 1, n = 26; Arm 2, n = 9; median age, 68 y; range, 26–86) were treated. Arm 1 enrolled AMG 232 at 60 mg (n = 4), 90 mg (n = 4), 180 mg (n = 5), 240 mg (n = 3), and 360 (n = 10). Twenty-two (85%) pts in Arm 1 had treatment-related AEs; the most common were nausea (n = 14), diarrhea (n = 14), and vomiting (n = 6). No DLTs occurred; one pt is still on treatment. The MTD was determined as 360 mg based on tolerance of gastrointestinal toxicity. Arm 2 enrollment is ongoing at a fixed AMG 232 dose of 60 mg plus trametinib (n = 9). AMG 232 plasma exposure increased with dose escalation; PK was unaffected by trametinib. Trametinib PK was as expected. Increases from baseline (BL) to day 10 in serum MIC-1 were dose dependent. Evidence of increased P21, BAX, and PUMA expression (BL to day 7 or 8) was seen (n = 3). One pt (Arm 2) had complete remission (CR); three pts (Arm 1) achieved CRi/MLFS. Median response duration was 66 days [range, 21–377+]). Conclusions: AMG 232 monotherapy was tolerable in pts with r/r AML at doses up to 360 mg on a 7 days on/7 days off schedule with expected PK, on-target biological effects, and early evidence of antileukemia activity. Clinical trial information: NCT02016729.
Survival of elderly patients with advanced gastrointestinal stromal tumor in pre- and post- imatinib era: A population-based study.
Authors: Bibhusan Basnet, Amit Khanal, Dipesh Uprety, Amir Bista, Deepak Agarwal, Binay Kumar Shah
Journal: Journal of Clinical Oncology (2016)

10051 Background: Median age at the time of diagnosis of gastrointestinal stromal tumor (GIST) is 55-65 years. There is limited data on survival of older patients with GIST. This study was performed to evaluate survival trends in elderly (age ≥ 65 years) patients with advanced GIST in pre- (1992-2001) and post- (2002-2008) imatinib era in the United States. Methods: We selected newly diagnosed microscopically confirmed advanced GIST (regional and distant metastasis based on SEER’s LRD staging) in elderly (age ≥ 65 years) patients from the Surveillance, Epidemiology, and End Results (SEER) database. We used SEER 18 registry database to evaluate relative survival rate during 1992-2001 and 2002-2008. We excluded patients diagnosed at autopsy or from death certificate only, or those without survival data. The relative survival rates at 1- and 5- years were analyzed for various cohorts categorized by age ( ≥ 65-74 and ≥ 75 years), race (White, African-Americans (AA) & Other) and gender. The relative survival (RS) rates accompany standard error (SE). We used Z-test in SEER*Stat to compare RS rates. Results: There were total of 613 cases of advanced GIST during the study duration. Among them, 320 were men and 293 women. Median age at the time of diagnosis was 80.5(range: 65-95) years. There was an overall improvement in the 5- year RS for patients diagnosed in post-imatinib era compared to those in pre-imatinib era (71.4±3.7% to 78.9±2.1%; Z = 1.63 at 1 year and 40.8±4.4% to 49.5±3%; Z = 2.16 at 5 years). There was no significant increase in RS for younger (1 year: 74.6±4.8 to 83.2±2.6, Z = 1.62; 5 year: 44.6±5.8 to 52.7±3.8%, Z = 1.66) or older (1 year: 67.4±5.8% to 74.1±3.4%, Z = 0.71; 5 year: 36.0 ± 6.7% to 45.0 ± 4.6, Z = 1.32) patients. While no improvement in RS was seen in male patients, improvement in 5 yr RS was seen in females (5 year RS: 42.5±6.1% versus 55.7±4.2%; Z = 2.34). Subgroup analysis did not show any improvement in survival rates on the basis of ethnicity. Conclusions: Our study showed that 5 year relative survival rate of patients with advanced GIST has improved in the post- imatinib compared to pre- imatinib era. Improvement in survival was limited to female patients.
A randomized, placebo-controlled study of amatuximab in combination with pemetrexed and cisplatin (P/C) as front-line therapy for subjects with malignant pleural mesothelioma (MPM).
Authors: Raffit Hassan, Dean Fennell, Arnaud Scherpereel, Anna K. Nowak, Joachim Von Pawel, Silvia Novello, Megan McLaughlin, Kimberly Hoffman, Bruce A. Wallin
Journal: Journal of Clinical Oncology (2016)

TPS8577Background: Mesothelin is highly expressed in epithelioid mesothelioma. Amatuximab is a chimeric monoclonal antibody that binds to mesothelin. Amatuximab was studied in a Phase II trial in M...
Does access to cancer drugs relate to survival benefit? A European study in countries with different economic status.
Authors: Nils Erik Wilking, Bengt Jönsson, Peter Lindgren, Ulla Wilking
Journal: Journal of Clinical Oncology (2017)

6535 Background: As new cancer drugs come at a high cost, it is of interest to examine if drugs with high impact on survival has a relative higher uptake compared to drugs with limited impact on survival in countries with limited resources (low Gross National Product; GDP/capita) versus countries with better resources (medium or high GDP/capita). Methods: Based on published clinical trial data, including ESMO- and ASCO value scales, we selected three drugs with high impact on survival and their main indications; imatinib/Chronic Myeloid Leukemia (CML), rituximab (some use outside oncology)/lymphoma and trastuzumab/breast cancer compared to everolimus/ renal cancer, sorafenib/renal cancer and bevacizumab/colorectal cancer as drugs with limited impact on survival. Countries in Europe were divided into three economic groups: upper-tier GDP/ capita 36,000 – 73,400 €; (Austria, Belgium, Denmark, Finland, Ireland, The Netherlands, Norway, Sweden, Switzerland); mid-tier GDP 22,800 – 35,400 €; (France, Germany, Italy, Spain, UK) low-tier GDP 5,800 – 18,100 € (Bulgaria, Croatia, Czech Republic, Greece, Hungary, Poland, Portugal, Romania, Slovakia, Slovenia). Sales data from IMS Health and epidemiological data from IARC Cancer Mondial, (WHO) were used. Access to drugs was measured as use in g/case (defined as cancer mortality in 2012) and includes total usage from introduction until end of 2014. Access in the upper-tier country group was set as 100% usage. Results: As seen in the table, access in mid-tier countries was 64-76% and low-tier countries 34-55% respectively for drugs with higher survival impact and access in mid-tier countries was 73-105% and low-tier countries 34-59% respectively, for drugs with lower survival impact. More detailed data on access in individual countries within each GDP/capita group will also be presented. Conclusions: Proven survival benefit did not affect spending on costly cancer drugs in countries with lower GDP. [Table: see text]
Early-onset pancreatic ductal adenocarcinoma (PDAC) at Memorial Sloan Kettering Cancer Center (MSKCC).
Authors: Siddharth Kunte, Swathi Sangli, Alejandro Lemor, Maeve Aine Lowery, Kenneth H. Yu, Ghassan K. Abou-Alfa, Anna M. Varghese, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2017)

e15736 Background: PDAC is a leading and rising cause of cancer-related mortality. There is infrequent description of patients and outcomes with PDAC diagnosed aged &lt;=50 years old (Early onset PC: EOPC). We reviewed the epidemiology, risk factors, oncologic outcomes and genomic data of EOPC pts at MSKCC. Methods: Using an institutional dataline search, N=364 patients were identified with EOPC between 2008-2014 at MSKCC. N= 282 were included in final analysis based on data completeness. Results: Baseline characteristics are summarized in table 1. The average patient was male, aged between 40- 50 years, BMI 24 and had metastatic disease at diagnosis. Family history of malignancy was present in N= 216 patients. The median overall survival (OS) for stages IIA, IIB, III and IV was 19.2, 21.8, 18.8 and 9.7 months respectively. Age, gender, diabetes and smoking history did not have a significant impact on OS. No difference in OS was noted between the groups who received gemcitabine based first-line chemotherapy compared to those with 5-fluorouracil based regimen in metastatic disease (9.9 vs 12 months, p= 0.315). Conclusions: EOPC represents a small subset of patients with PDAC and very rarely arises &lt; 30 years of age. For this MSKCC cohort, outcomes appear similar to patients with average age onset PDAC. Further analyses on genomic characteristics may provide insight into outcomes and genetic underpinnings of EOPC. [Table: see text]
Safety of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection: A randomized, multicenter, prospective, phase III IOCCRC trial (IOCCRC).
Authors: Rong-xin Zhang, Jun-zhong Lin, Gong Chen, Li-ren LI, Zhen-hai LU, Pei-Rong Ding, Xiao Jun Wu, Desen Wan, Zhi-zhong Pan
Journal: Journal of Clinical Oncology (2017)

e15002 Background: The safety and efficacy of intraoperative chemotherapy in colorectal cancer have not yet been extensively investigated. This randomized control trial was designed to compare the safety and efficacy of intraoperative chemotherapy in combination with surgical resection to those of traditional surgical resection alone. Patients and Methods: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled in this study: 341 patients were randomly assigned to the intraoperative plus surgery group to receive intraoperative chemotherapy (portal vein, intraluminal, and intraperitoneal chemotherapy plus surgical resection), whereas 344 patients were randomized to the control group to undergo surgery alone. Eleven patients withdrew consent. Surgical complications and side effects of intraoperative chemotherapy were compared between the two groups. Results: Intraoperative chemotherapy did not increase the rate of surgical complications, and no severe chemotherapy-associated side effects were observed. There were no significant differences in the length of hospital stay (8.31 vs. 7.98 days, P = 0.138), length of surgery (170.4 vs. 167.0 min, P = 0.526), length of antibiotic use (2.28 vs. 2.15 days, P = 0.322), or length of drain usage (6.37 vs. 6.16 days, P = 0.387) between the intraoperative chemotherapy and control groups. Four patients in each of the intraoperative chemotherapy and the control groups experienced anastomotic leakage and underwent a second operation (1.2% vs. 1.2%, P = 0.99). There were no deaths within 90 days after surgery in the chemotherapy group, whereas one patient died in the control group (0% vs. 0.3%, P = 0.99). Intraoperative chemotherapy did not decrease the rate of patients who received postoperative adjuvant chemotherapy between the intraoperative group and control group (29.3% vs. 30.2%, P = 0.795). Conclusions: Intraoperative chemotherapy can be safely performed during colorectal surgery; however, follow-up is necessary for a better assessment of its efficacy. Register Number: NCT01465451. Clinical trial information: NCT01465451.
TCT-766 Coronary perforation complicating percutaneous coronary intervention in patients presenting with an acute coronary syndrome: an analysis of 1,013 perforation cases from the British Cardiovascular Intervention Society database
Authors: None Tim Kinnaird, Patrick Calvert, Richard Anderson, Alexander Sirker, Mark de Belder, Peter Ludman, Thomas Johnson, Mamas Mamas
Journal: Journal of the American College of Cardiology (2018)
Clinical relevance of primary tumor site and respective molecular characteristics in patients with early-stage colorectal cancer.
Authors: Elena Fountzilas, Vassiliki Kotoula, Ioannis Sotirios Tikas, Kyriaki Manousou, Kyriaki Papadopoulou, Christos Poulios, Vasilios Karavasilis, Ioannis Efstratiou, Dimitrios G. Pectasides, Kleo Papaparaskeva, Ioannis I. Varthalitis, Christos Christodoulou, George Papatsibas, Sofia Chrisafi, Georgios K. Glantzounis, Amanda Psyrri, Gerasimos Aravantinos, George K. Koukoulis, George E. Pentheroudakis, George Fountzilas
Journal: Journal of Clinical Oncology (2018)

e15606 Background: Right- and left-sided colorectal cancers (CRC) demonstrate a distinct clinical behavior. Whether this heterogeneity is associated with specific molecular profiles has yet to be determined. Our goal was to explore the clinical relevance of primary CRC location with respect to genotypic and phenotypic tumor characteristics in early-stage patients. Methods: We retrospectively examined primary paraffin tumors from 412 CRC patients who received standard adjuvant chemotherapy (258 [63%] stage III) for pathogenic mutations with a 59 gene panel; MMR immunophenotypes as proficient (MMRP) and deficient (MMRD); and, iCD8 (intratumoral) and sCD8 (stromal) lymphocytes as high – low, based on maximal density. All parameters were examined with respect to disease-free survival (DFS). Results: Tumors were located in the right colon (RsT 139 [34%]), left colon (LsT 171 [41%]) and rectum (102 [25%]). RsT were more likely to be high grade and MMRD (chi-square, p = 0.001 and p < 0.0001, respectively) compared to LsT and rectal tumors. The number of mutations or mutated genes per tumor did not differ between the three sites. RsT had a higher frequency of BRAF and PIK3CA mutations compared to LsT and rectum tumors (chi-square, p = 0.02 and p = 0.018, respectively). Rectal tumors were enriched for FBXW7 mutations compared to RsT and LsT (chi square, p = 0.002). RsT exhibited higher iCD8 and sCD8 density compared to the other sites (Kruskal-Wallis, p = 0.011 and p < 0.001, respectively). Among stage III patients with high i&sCD8+ infiltrates, patients with LsT/rectal cancer fared better compared to RsT patients (HR = 0.24, 95% CI 0.07-0.89, p = 0.032). In patients with TP53 mutated tumors, those with rectal cancer had better DFS compared to those with colon cancer (HR = 0.40, 95% CI 0.17-0.93, p = 0.034). Conclusions: Right-, left-sided and rectal tumors have distinct clinicopathological, mutational and immunophenotypic profiles associated with patient outcome. Particularly, the site-specific impact of cytotoxic lymphocytes and TP53 mutations, if validated, may aid in accurately stratifying patients for assessing treatment benefit.
Management of febrile neutropenia in the observation unit of a cancer hospital.
Authors: Adam Klotz, Susan Seo, Alberta Alickaj
Journal: Journal of Clinical Oncology (2016)

e18120 Background: The MASCC index is a well validated tool to identify low-risk patients who can be treated for febrile neutropenia (FN) in the outpatient setting. However, many physicians remain reluctant to use less resource-intensive treatment regimens and continue to admit low -risk patients. Observation units (OUs), which provide acute management and ongoing reassessment of ED patients who may be stable for discharge at a later time, have been shown to improve outcomes and cost-effectiveness for common complaints such as chest pain, AF, COPD exacerbations, and TIA. The role of observation medicine in the management of FN has not yet been defined. Methods: Between 7/13/13 and 1/5/16, patients seen in the Urgent Care Center (UCC), MSKCC’s emergency department, for FN, defined as a temperature equal ≥ 38.0, an ANC less than 1000, and a MASCC score ≥ 19 were placed in the OU for 24 hours of IV antibiotics and clinical reassessment. Patients who had signs of worsening infection or who developed other significant medical issues while in the OU were admitted . Patients discharged from the OU were monitored for development of positive blood cultures, and re-presentation to the UCC within one week. Results: During the study period, 41 patients with FN and MASCC scores ≥ 19 were treated in the OU. Of the 24 patients (58.5 %) discharged home, none developed a positive blood culture, and one required admission within 7 days of discharge. Of the 17 patients admitted to the hospital from the OU, the average length-of-stay was 3 days. One admitted patient with an initial MASCC score of 22 developed neutropenic sepsis and expired. Five patients with hematologic malignancies were discharged home from the OU. Conclusions: While the majority of low-risk cancer patients with FN were successfully discharged home, many required admission to the hospital. Some patients with hematologic malignancies and intermediate-risk MASCC scores were successfully discharged. Observation medicine may play a role as risk stratification schema and management paradigms for FN continue to evolve.
Correlation of obesity and metabolic syndrome with higher tumor percentage involvement in high and intermediate prostate cancer patients.
Authors: Arash Samiei, Ralph Miller, Jeffery Cohen, John Lyne, Shifeng Mao
Journal: Journal of Clinical Oncology (2018)

e17048 Background: Obesity and metabolic syndrome (MetS) have become prevalent in our society. We reported obesity and MetS associated with prostate cancer (PCa) of the higher risk category and increased risk of biochemical failure. Tumor percentage involvement (TPI) has been shown to be predictive of biochemical failure. A comparative study investigating a link between obesity or MetS and TPI after radical prostatectomy (RP) is still lacking. Objective: To investigate the association between Obesity and MetS with TPI in high and intermediate PCa patients following RP. Methods: This was a retrospective study of patients with high and intermediate-risk prostate cancer who underwent RP. The surgeries were performed by two trained surgeons in a single center from 2003 to 2013. Parameters, including fasting glucose, triglycerides, and HDL, blood pressure, PSA, Gleason score(GS), pathologic stage, surgical margin status, preoperative BMI, postoperative tumor and prostate volume were analyzed. MetS was defined according to the WHO classification. Patients were categorized into high and intermediate risk groups according to the National Comprehensive Cancer Network (NCCN) guideline. Results: A total of 956 patients with high and intermediate risk PCa who underwent RP were included in this study. The median follow-up was 44[6 -140] months. The median age at diagnosis was 61[44 -78] years old. More obese patients (BMI ≥30 kg/m2) were found in the high-risk PCa group compared to the intermediate group (41.2% vs 32.0%, p = 0.006). High TPI (≥ 25%) was more prevalent in MetS group as compared to non-Mets group (49% vs 29%, P < 0.001). Similarly, there was a strong association between high TPI and obesity (40.7% in obese vs 30.6% in non-obese patients, p = 0.001). Conclusions: Our findings demonstrated that obesity and MetS are associated with higher TPI value, which underlines the interplay between obesity, MetS and more aggressive tumor biology, leading to poor outcomes.
Measuring the effects of radiotherapy on DNA methylation in colorectal cancer.
Authors: Jedi Maher, Graeme P Young, Susanne Kartin Pedersen, Erin L. Symonds
Journal: Journal of Clinical Oncology (2017)

e15089 Background: BCAT1 and IKZF1are methylated with high frequency in colorectal cancer (CRC). This study aimed to investigate the level of methylation in these two genes in tissue samples from CRC patients who had undergone radiotherapy. Methods: Tumor and adjacent non-tumor tissue was collected from 50 CRC patients, including 14 subjected to radiotherapy prior to surgical resection. DNA was extracted, bisulfite converted and the levels of methylated BCAT1 and IKZF1 DNA were expressed as the percentage of 5ng tissue DNA (normalized to ACTB levels). Results: In the 36 CRC patients who did not receive radiotherapy prior to resection, tumor tissues had high levels of methylated BCAT1 and IKZF1 compared with adjacent non-tumor tissues (p &lt; 0.001, Table). The CRC tissues from the 14 patients who received radiotherapy pre-surgery had significantly lower levels of methylation compared to the levels in tumors from non-treated patients (p&lt;0.01, Table). Radiotherapy did not appear to affect the methylated BCAT1/IKZF1DNA levels in adjacent non-cancer tissues (p &gt; 0.05, Table). In this limited dataset, a correlation was observed with %methylation and response to radiotherapy measured based on tumor size relative to original size, with the lowest methylation in the tumors associated with the greatest downsizing. Conclusions: The high levels of methylated BCAT1 and IKZF1 in CRC tissue and the low levels in the surrounding non-cancer tissue suggest that the markers are tumor specific with no obvious field effect. In contrast, in the samples obtained from patients treated with radiotherapy prior to resection, the methylation levels in CRC tissues were similar to the levels measured in the adjacent non-tumor tissues. Further studies are necessary to determine the reason for this and whether it has implications for monitoring response to therapy based on blood levels of methylated BCAT1 and IKZF1. [Table: see text]