tbuckley/cabot-search huggingface dataset:
The impact of positive margins on outcome among patients with gastric cancer treated with radiation.
Authors: Jonathan D. Schoenfeld, Jennifer Yon-Li Wo, Harvey J. Mamon, Eunice Lee Kwak, John Thomas Mullen, Peter C. Enzinger, Lawrence Scott Blaszkowsky, David P. Ryan, Theodore S. Hong
Journal: Journal of Clinical Oncology (2013)

81 Background: Positive surgical margins (PM) have been associated with worse outcomes in gastric cancer patients. We sought to evaluate the impact of PM among a modern cohort of gastric cancer patients treated with radiotherapy (RT), some of who also received epirubicin-based chemotherapy (CTX). Methods: We performed a retrospective analysis of patients with gastric adenocarcinoma treated at Massachusetts General Hospital from November 2005 and the Dana-Farber Cancer Institute from August 1998 through 2010. All underwent definitive surgery and RT and were followed through July 2012 for recurrence and survival. We assessed associations with PM using Chi-Squared tests and Cox proportional hazard models. Results: We followed 91 patients for a median of 42 months (interquartile range, IQR 15 – 61 months). Median age at surgery was 60 years (IQR 49 – 68 years). Seven patients were treated with neoadjuvant RT; 84 received adjuvant RT a median 88 days after surgery (IQR 73-108 days). Thirty-three patients received epirubicin-based CTX including 8 perioperatively and 25 postoperatively. PM were identified in 22 patients (24%), including two patients (25%) who received epirubicin-based CTX perioperatively (p = 0.95 versus no perioperative epirubicin-based CTX) and in no patients (0%) who received neoadjuvant RT (p = 0.19 versus adjuvant RT). There were 41 recurrences and 26 deaths. PM were associated with an increased crude risk of overall recurrence (36% versus 73%; p = 0.003). Adjusting for age, positive lymph nodes, pT stage and tumor differentiation, PM were associated with an increased hazard for time to recurrence (HR 2.3; 95% CI 1.2 – 4.3; p = 0.02) and marginally increased hazard for time to all-cause mortality (HR 2.2; 95% 0.9 – 5.2; p = 0.08). Conclusions: We confirm PM following surgical resection of gastric adenocarcinoma are associated with increased risk of recurrence and a trend towards reduced survival, despite aggressive multimodality therapy including RT and, in some cases, epirubicin-based CTX. These findings suggest that strategies that maximize the likelihood of achieving negative margins at the time of surgery, such as neoadjuvant chemoradiation, should continue to be evaluated.
A phase I study of MEK162 and FOLFOX in chemotherapy-resistant metastatic colorectal cancer.
Authors: May Thet Cho, Dean Lim, Timothy W. Synold, Paul Henry Frankel, Lucille A. Leong, Joseph Chao, Vincent M. Chung, Yuan Chen, Stephen Sentovich, Eloise Luevanos, Marwan Fakih
Journal: Journal of Clinical Oncology (2016)

679 Background: Pre-clinical studies have shown that the combination of MEK inhibitors and 5-FU improves antitumor activity and that MEK inhibition overcomes both 5FU and platinum resistance. This phase I study was conducted to determine the maximum tolerated dose (MTD) of the combination MEK162 and FOLFOX. Methods: Patients (pts) with metastatic colon or rectal cancer who progressed or failed prior 5FU, irinotecan, oxaliplatin and anti-EGFR therapy (in cases of RAS wild type tumors) received twice daily MEK162 in combination with every-2-week FOLFOX. Two dose levels of MEK162 (30mg and 45mg) were investigated in a standard 3 + 3 escalation design in combination with standard doses of FOLFOX without bolus 5-FU. Dose limiting toxicity (DLT) was defined as any treatment-related grade (G) 3 or 4 non-hematological toxicity (with the exception of G3 diarrhea or vomiting &lt; 48 hrs) or G 4 neutropenia or thrombocytopenia within the first 2 cycles (4 weeks) of the treatment. Limited pharmacokinetic (PK) analysis of 5FU, oxaliplatin and MEK162 was performed at the MTD level. Results: 16 pts were enrolled (median age (range) 53 yrs (49-78); 11 men; ECOG 0/1 in 9/7 patients). No DLT was noted on the study. The MTD of MEK162 was 45 mg PO BID. An additional 6 pts (for a total of 12) were enrolled at the MTD for PK analysis and none of them developed DLT defining toxicities. A median of 8 cycles (range 1-19) was administered. Treatment-related ≥ grade 3 toxicities included anaphylaxis due to oxaliplatin (n = 1), CPK elevation (n = 2), neutropenia (n = 1), peripheral neuropathy (n = 3), thrombocytopenia (n = 1), retinal vascular disorder (n = 1), and acneiform rash (n = 1). 10 pts had SD at 2 months (m) by radiographic assessment, 5 of whom with stabilizations of &gt; 5 months (5-10 months). There were no significant differences in the PKs of 5FU or oxaliplatin when administered with or without MEK162. Conclusions: The combination of MEK162 and FOLFOX has a manageable toxicity profile and promising antitumor activity in heavily pretreated metastatic colorectal cancer patients. Clinical trial information: NCT02041481.
Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions
Authors: A. Karam, J.A. Ledermann, J.-W. Kim, J. Sehouli, K. Lu, C. Gourley, N. Katsumata, R.A. Burger, B.-H. Nam, M. Bacon, C. Ng, J. Pfisterer, R.L.M. Bekkers, A. Casado Herráez, A. Redondo, H. Fujiwara, N. Gleeson, O. Rosengarten, G. Scambia, J. Zhu, A. Okamoto, G. Stuart, K. Ochiai
Journal: Annals of Oncology (2017)
Relation of methylenetetrahydrofolate reductase C677T polymorphism to chronic myeloid leukemia in Serbia.
Authors: R. N. Jankovic, K. Jakovljevic, M. Cavic, E. Malisic
Journal: Journal of Clinical Oncology (2011)

6581 Background: Chronic myeloid leukaemia (CML) is a clonal, myeloproliferative disease characterized by the Philadelphia chromosome. Since leukemias are derived from rapidly proliferating tissues, they are likely to be affected by the metabolic fate of folic acid. 5,10-methylenetetrahydrofolate reductase (MTHFR) is one of the important enzymes of the folate cycle and affects both nucleotide synthesis and methylation reactions. The C to T transition at nucleotide 677 in exon 4 (C677T) results into an Ala to Val substitution in the N-terminal domain which produces a thermolabile variant of the protein. The 677CT and the 677TT genotypes have approximately 60% and 30% of the MTHFR wild-type enzyme activity in vitro, respectively. The MTHFR enzyme has been considered as a leukemia susceptibility factor since the presence of the MTHFR polymorphisms changes folate distribution. The aim of this study was to analyze the association of MTHFR C677T polymorphism with CML in a Serbian study sample that included 43 CML patients and 26 apparently healthy controls. Methods: EDTA peripheral blood from patients and healthy individuals was used for leukocyte isolation. Genomic DNA was isolated using ABI PRISM™ 6100 Nucleic Acid PrepStation. Standard RFLP analysis was used for MTHFR genotyping. The association between the MTHFR C677T polymorphism and CML was assessed using the odds ratio (OR) and the 95% confidence interval (CI). The Hardy-Weinberg equilibrium was estimated with χ2 test. Results: The MTHFR polymorphism frequencies in patients vs. controls were 39.53% vs. 23.08% for CC, 48.84% vs. 61.54% for CT and 11.63% vs. 15.38% for TT. The C677T genotype distributions were in agreement with the Hardy-Weinberg equilibrium. No significant difference in CC vs. TT +CT (χ2 = 1.304, p>0.05), and CT+CC vs. TT (χ2 = 0.006, p>0.05) genotype frequencies was observed between CML patients and controls. The OR (and 95% CI) were 2.18 (0.73-6.54) for CC vs. TT+CT, and 1.38 (0.34-5.69) for CT+CC vs. TT. Conclusions: Although we found no statistically significant association between the MTHFR C677T polymorphism and CML, our results demonstrate that the MTHFR 677C allele is associated with an increased risk of CML in patients from Serbia.
Ponatinib in patients with acute myeloid leukemia (AML): Preliminary findings from a phase I study in hematologic malignancies.
Authors: M. Talpaz, N. P. Shah, M. W. Deininger, M. J. Mauro, I. W. Flinn, S. Lustgarten, W. Lindmark, J. M. Gozgit, T. Clackson, C. D. Turner, F. G. Haluska, H. Kantarjian, J. E. Cortes
Journal: Journal of Clinical Oncology (2011)

6518 Background: Ponatinib is an oral multiple tyrosine kinase inhibitor and potent pan-BCR-ABL inhibitor. Preliminary phase 1 results suggest substantial activity in BCR-ABL+ patients (pts). In preclinical models, ponatinib also inhibits the FLT3/ITD mutant prevalent in AML with potency similar to that of BCR-ABL (IC50 2 nM). A cohort of pts with AML was enrolled in a phase 1 trial of ponatinib to assess safety and preliminary efficacy in this population. Methods: Pts (≥18 years) with relapsed or refractory AML were enrolled after the recommended phase 2 dose of ponatinib was established in pts with chronic myeloid leukemia (CML). Pts received 45 mg ponatinib orally once daily: trough plasma concentrations are known to exceed the target for inhibition of FLT3/ITD activity (IC50) in cells at this dose. FLT3/ITD mutation status was determined at a central laboratory. Results: Of 81 total pts in this study, 12 were included in the AML cohort. The median age of AML pts was 49 (range 30-72) years. At the time of analysis (Dec 15, 2010), 4 (33%) AML pts remained on study (range 77-143 days) and 8 (67%) discontinued (range 10-97 days) (no discontinuations were treatment related). Seven AML pts had documented FLT3/ITD at baseline, 2 did not carry FLT3 alterations, and 3 pts had inadequate samples for testing; however, these 3 pts had a positive FLT3 status reported by investigative sites. Overall, 7 pts with the FLT3/ITD mutation were FLT3 inhibitor naïve. All pts had treatment emergent AEs consistent with those expected in refractory AML. Three pts had treatment related grade 2 pancreatitis: 1 pt subsequently discontinued due to investigator decision; 2 had the event resolve and continued therapy at a reduced dose. The overall response rate in the AML cohort was 25% (3/12): 2 pts (29%) had CRi and 1 (14%) had PR. All responses observed were in the subset of pts with the FLT3/ITD mutation who were naïve to FLT3 inhibitors: 3/7 (43%). Conclusions: Ponatinib was well‐tolerated in this small group of AML patients; the safety profile was similar to that observed in CML. Evidence of activity in pts with the FLT3/ITD mutation was observed, with a response rate of 43% (3/7) in FLT3 inhibitor naïve pts.
Reversal of glucocorticoid resistance by the g-secretase inhibitor PF-03084014 in T-cell acute lymphoblastic leukemia.
Authors: J. B. Samon, M. Castillo-Martin, J. L. Jakubczak, S. Randolph, C. Cordon-Cardo, A. A. Ferrando
Journal: Journal of Clinical Oncology (2011)

9553 Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer frequently characterized by activating mutations in NOTCH1. Early studies identified NOTCH1 as an attractive therapeutic target for the treatment of T-ALL through the use of g-secretase inhibitors (GSIs), but subsequent work found that inhibition of NOTCH signaling is characterized by a lack of cytotoxicity of human T-ALL cells and severe gastrointestinal toxicity. Our preliminary results show that combination therapy of generic GSIs plus glucocorticoids has improved antileukemic effects in vitro and in vivo and reduced gut toxicity. Here we characterized the interaction between PF-03084014, a clinically relevant GSI, and dexamethasone in preclinical models of glucocorticoid resistant T-ALL. Methods: Studies were performed using a panel of human T-ALL cell lines and primary patient samples. The effect of GSI treatment plus glucocorticoids was assessed using cell viability, cell cycle, and proliferation assays. Results: Combination treatment of the GSI PF-03084014 with glucocorticoids resulted in the impaired growth of glucocorticoid-resistant human T-ALL cell lines compared to GSI alone, characterized both by induction of apoptosis and G0/G1 cell cycle arrest. Further, the inhibition of cell growth was reproducible in several primary human T-ALL patient samples grown in vitro. Molecular characterization of the response to PF-03084014 plus glucocorticoids through gene expression profiling revealed upregulation of the glucocorticoid receptor and subsequent enhancement of the glucocorticoid response. Additionally, we found treatment of PF-03084014 with glucocorticoids to be highly efficacious in vivo, with enhanced reduction of tumor burden in a subcutaneous xenograft model of T-ALL. Finally, we found that glucocorticoid treatment was highly effective at reversing PF-03084014-induced gut toxicity via inhibition of goblet cell metaplasia. Conclusions: These results suggest that combination of PF-03084014 treatment with glucocorticoids may be well-tolerated and highly active for the treatment of glucorticoid-resistant T-ALL.
Malignant fibrous histiocytoma of the spermatic cord: A case report
Authors: A. Kumar, T. Bentley
Journal: Journal of Clinical Oncology (2005)

4804 Background: Malignant fibrous histiocytoma (MFH) is a common sarcoma of the soft tissue but it rarely occurs in the spermatic cord. Methods: We present a case of 54-year-old male who presented with a right painless scrotal mass for 1 year, which had progressively enlarged. Past medical history was not significant. Results: Ultrasound and a CT scan of the abdomen and pelvis showed a 7.4x7.1cm solid scrotal mass that appeared to involve the inguinal canal, possibly the spermatic cord on the right side. Metastatic work up was negative. He underwent right radical orchiectomy. Grossly, he was found to have an enormous right hemiscrotal mass, about the size of softball. The left testicle was pushed over from midline, but felt normal. The histologic diagnosis was myxoid malignant fibrous histiocytoma, high grade, focally involving the inked margin. Patient received adjuvent radiation therapy and so far there was no evidence of local recurrence. Conclusions: Malignant fibrous histiocytoma (MFH) is a common sarcoma of the soft tissue in late adult life and is usually found in the region of the extremities and retroperitoneum. It rarely occurs in the genitourinary organs and even rarely in the spermatic cord and so rarely been reported. The pre-operative clinical diagnosis of spermatic cord tumor is difficult and is usually confused with inguinal hernia, spermatocele, epididymo-orchitis and testicular tumor. The definitive diagnosis requires pathologic examination of the surgically resected specimen. It is known to spread rapidly and aggressively with a 2-year survival rates between 34 and 43%. The follow up in the reported cases have been relatively short and the characteristics of this tumor remain poorly understood. No significant financial relationships to disclose.
Clinical characteristics and comorbidity of veterans with pancreatic cancer.
Authors: K. Kim, F. Zhong, V. T. Chang, C. Quainoo, J. Cogswell, L. Duque, M. Sullivan
Journal: Journal of Clinical Oncology (2011)

e14549 Background: To describe pts with pancreatic cancer and determine whether comorbidity indices predict survival. Methods: In an IRB-approved protocol, we reviewed the records of patients (pts) diagnosed with pancreatic cancer at a VA Medical Center from January 1999 to October 2009. Records were reviewed for demographic, clinical, pathological data, ECOG performance status (PS), Veteran status, treatment and survival. Comorbidity was accessed with three comorbidity indices: the Charlson Comorbidity Index (CCI), the Kaplan-Feinstein Index (KFI), and Cumulative Illness Rating Scale (CIRS). Cox survival analyses were performed. Results: There were 52 pts with a median (M) age of 63yo (45-89). 27 pts were Caucasian, 22 pts were African American and 3 pts of Hispanic descent. Out of the 52 pts, 27 were Vietnam era veterans. The median (M) PS was 1 (0-4) . The M BMI was 23.4 kg/m2 (16.13-32). The M WBC was 9.75 (2.1-37.3), M hemoglobin (Hgb) 10.95 g/dl (7.1-15.4), M AST 59 U/L (20-498), M albumin (Alb) 3.1 g/dl (1.7-20), M alkaline phosphatase (ALP) 267.5 U/L (42-1234), M lactate dehydrogenase (LDH) 184.5 IU/L (53-2590), and M CEA 6.2 ng/ml (1.2-188.64). The M CCI was 3.35 (1.3-12.9), M KFI 2 (0-3), M CIRS15 3 (0-9), M CIRS16 6 (0-13), M CIRS17 2 (0-4) and M survival was 109 days (2-1968). In the univariate survival analysis, WBC (p<0.047), AST (p<0.032), Alb (p<0.043), LDH (p<0.057), and CEA (p<0.022) and treatment modalities were significant predictors of survival. In the multivariate analysis only PS (p<.033) and stage (p<0.004) were independent predictors. Vietnam and non-Vietnam patients differed by age of diagnosis (p<0.001), by stage distribution (p<0.04), and survival (p<0.001) and by predictors of survival. By univariate analysis, for Vietnam, vets, PS, LDH and albumin were significant and for Non Vietnam, WBC and AST were significant. Conclusions: Comorbidity indices were not predictors of survival. Interesting differences are seen between Vietnam and non-Vietnam veterans with pancreatic cancer that should be studied further. Partially supported by the New Jersey Commission for Cancer Research.
Predictive effects of serum VEGF, TGF-a and EGFR mutations in advanced non-small cell lung cancer treated by erlotinib
Authors: S. Zhou, C. Zhou, S. Ren, L. Yan, L. Zhang
Journal: Journal of Clinical Oncology (2008)

19133 Background: We had reported the initial safety and efficacy results of erlotinib in previously treated patients with advanced NSCLC in abstract N0 18183 in 2007 ASCO. Now we compared predictive effects of serum VEGF, TGF-a and EGFR mutations to efficacy of erlotinib in those pts. Methods: Pts with advanced NSCLC who had been previously treated with at least one regimen of platinum- based chemotherapy received 150 mg of erlotinib orally, once a day till disease progression.Serum levels of VEGF and TGF-a were detected with the method of ELISA before oral erlotinub and 4 weeks after the treatment. EGFR mutations of the serum were analysed using real-time PCR with TaqMan-MGB probes. Response rate, time to progression (TTP), overall survival were compared according to serum VEGF, TGF-a and EGFR mutations. Results: 50 NSCLC pts were enrolled into this study from Oct 2005 to Sep 2006, among them, serum VEGF, TGF-a data and EGFR mutation were available in 42 cases.The last follow-up date was on Dec 22, 2007 with median duration of 18 months. Median TTP and overall survival in the 50 pts were 7.0 and 13.7 months respectively. One year progression free survival rate and overall survival rate were 30% and 56%,respectively.After oral erlotinib, serum VEGF levels decreased in the pts with partial response (P<0.001), stable disease(P=0.001) and disease progression(P=0.020), while TGF-a levels increased in those with partial response (P=0.006), but not in those with stable disease(P=0.255) and disease progression (P=0.379). Serum levels of VEGF did not affact overall survival and response (p=0.357). Time to progression and median survival time were 5 months 9.9 months in those with serum level of TGF-a over 15.6pg/ml and 11 months and 17.6 months in those with serum level of TGF- below the 15.6pg/ml, respectively. Overall survival was significantly different between those with higher and lower serum TGF- a (p=0.007).Serum EGFR mutation rate was 13.3%. EGFR mutant patients had response rate (p<0.001), longer TTP (15.8 vs 6 months, p<0.001) and OS(25 months vs 12.4, p<0.001). Conclusions: Oral erlotinib was effective in the second or third line treatment of advanced NSCLC. Baseline serum levels of TGF- a and EGFR mutations may predict better efficacy of erlotinib in these group of pts. No significant financial relationships to disclose.
Is survival in advanced pancreas cancer (APC) correlated to treatment-related lymphopenia (TRL)?
Authors: Anuradha Jayaram, MinYuen Teo, Mohd Syahizul Nuhairy Mohd Sharial, Felicity McDonnell, Justin Geoghegan, Kevin C. Conlon, David Fennelly, Raymond S. McDermott
Journal: Journal of Clinical Oncology (2013)

313 Background: Relationship between TRL and survival has been described in patients (pts) who receive adjuvant chemoradiotherapy. Evidence on TLR in APC treated with chemotherapy (ctx) is limited. We investigate the effect of ctx on TRL and its association with survival. Methods: Pts with APC were identified from two institutional databases. Inclusion criteria were: locally advanced (LA) or metastatic disease (MPC) and receipt of ctx. Baseline clinicopathologic and biochemical details including lymphocyte count at baseline and between day 21 and 28 were collected. Degree of TRL was collected prior to initiation of ctx and graded according to CTCAE v4. Descriptive statistics and survival analyses were performed. Results: Between 2001 and 2012, 97 pts were included. Median age was 64 years (range: 42 – 79), 58% were males. MPC seen in 57% of pts and 46% received doublet ctx. Ca19-9 ≥10,000 was detected in 77% pts. Uni- and multivariate analyses for six variables are described in the table. Major reduction, as defined by a 33% change in TLC, was described as a major reduction, present in 14 pts (15%). A major reduction of TLC was associated with a median overall survival (OS) of 2.5 mths (95%CI=1.2-5.3) versus 7.1 mths in those with no TLC change (95%CI=5.6-9.3) (p=0.0149). When assessed by CTCAE, difference in OS was also noted for G0 (n=47), G1 (n=39), G&gt;=2(n=10) lymphopenia: 95 pts had grade 0-2 TLC 4 weeks post chemotherapy. OS was 9.7, 5.3 and 1.9 mths for grade 0, 1, and 2 lymphopenia. (p=&lt;0.0001) respectively. Conclusions: TRL is an independent prognostic factor for APC. In comparison to existing data where chemo-radiation increases the grade and rates of TRL, APC pts treated with ctx had lower rates of TRL. This raises the question whether TRL is determined by the underlying biology of APC versus radiotherapy related effect. [Table: see text]