tbuckley/cabot-search huggingface dataset:
Pilot study of neoadjuvant FOLFIRINOX in unresectable locally advanced (LA) pancreatic carcinoma (PC).
Authors: P. J. Hosein, C. Kawamura, J. Macintyre, A. Loaiza-Bonilla, J. R. Merchan, J. U. Levi, C. S. Rocha Lima
Journal: Journal of Clinical Oncology (2011)

324 Background: 5-flourouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) is superior to gemcitabine in patients (pts) with advanced PC who have a good performance status (Conroy et al, ACCORD 11 trial, ASCO 2010). After the initial data on FOLFIRINOX were presented at ASCO 2007, we began using it off-protocol as neoadjuvant therapy for LAPC. We report our experience herein. Methods: In this retrospective series, we included pts with unresectable LAPC who received neoadjuvant FOLFIRINOX. The doses were identical to the ACCORD 11 trial, with G-CSF prophylaxis from cycle 1. The primary endpoint was R0 resection rate. Secondary endpoints were overall survival (OS), safety and tolerability. Results: Between 5/2008 and 9/2010, we treated 12 pts with LAPC with neoadjuvant FOLFIRINOX. All pts met consensus criteria for unresectability after multidisciplinary review. The median age was 57.5 years and 9/12 were men. All had ECOG PS of 0 or 1. Two pts received gemcitabine prior to FOLFIRINOX and 10 were treatment-naive. Two pts are still on therapy and 10 completed a median of 6 cycles (range 3-17) and were evaluable; 6 were felt to have converted to resectability by imaging and were taken for surgery. Four had R0 resections (40% of evaluable, 33% of all patients), 1 had R1 resection, and 1 had unresectable disease at laparotomy. To date, 2 pts have died and 10 remain alive with a Kaplan-Meier estimated median OS of 20.7 months (95% CI 18.8-22.6). All 4 pts with R0 resections are alive and disease- free. Grade 3/4 chemotherapy-related toxicities were neutropenia (17%), neutropenic fever (8%) and fatigue (17%). Common grade 1/2 toxicities were neutropenia (42%), anemia (92%), thrombocytopenia (50%), fatigue (92%), nausea (58%), diarrhea (42%) and neuropathy (33%). Two of the 6 surgical pts had significant postoperative complications - 1 with C. Difficile colitis, gastroparesis and a subhepatic collection and another with an infected pancreatic bed collection requiring percutaneous drainage 3 times. Conclusions: FOLFIRINOX is feasible as neoadjuvant therapy in patients with unresectable LAPC, with manageable toxicities. In this small series, the R0 resection rate was at least 33%. A prospective trial is warranted. No significant financial relationships to disclose.
Final results of phase I/II study of decitabine (DAC) combined with temozolomide (TMZ) in metastatic melanoma (MM).
Authors: J. H. Beumer, H. A. Tawbi, A. A. Tarhini, S. J. Moschos, M. J. Egorin, S. C. Buch, Y. Lin, J. M. Kirkwood
Journal: Journal of Clinical Oncology (2011)

8530 Background: TMZ is widely used in MM despite low response rates (7-13%) and no improvement in median overall survival (OS) 7.7 months (m) when compared to dacarbazine in Phase III trials. The DNA repair protein, O6-methylguanine-DNA-methyltransferase (MGMT), is implicated in melanoma resistance to TMZ and can be depleted with extended schedule TMZ. DNA mismatch repair (MMR) deficiency is another mechanism of resistance that can be reversed with DNA hypomethylators such as DAC. We sought to determine the recommended phase II Dose (RP2D), safety, and efficacy of DAC in combination with extended schedule TMZ in MM. Methods: In the Phase I portion, pts were treated with 2 dose levels (DL) of DAC: 0.075 mg/kg IV QD and 0.15 mg/kg IV QD. DAC was administered qd x 5 d/wk for 2 wks, and TMZ was administered PO at 75 mg/m2 qd for 4 wks, starting on wk 2 of each 6-wk cycle. A Simon 2-stage Phase II design with success defined as ≥5 Objective Responses (OR) in 34 evaluable patients gave µ=0.10 and 85% power. PK sampling was performed on Days 1 and 8; PBMC and tumor tissues were studied on Days 1, 8, 15 and 29 of cycle 1. Results: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m2. 35 patients were accrued to the Phase II portion of the study, the majority with M1c disease (88%); brain metastases were present in 42%. 2/35 were not evaluable (NE) for efficacy. For the remaining 33 patients, the best RECIST responses were 1CR, 4 PR, 13 SD, and 15 PD, for an OR rate of 15% and a clinical benefit rate (CR+PR+SD) of 54%. The median PFS was 2.8 m, median OS was 15.2 m (compared to 7.7 m), and 1-year OS rate was 62% (compared to 25%). Grade 3/4 neutropenia was observed in 68% of pts but reversible, lasting >7 d in only 5 pts (DLT rate 15%). Only 2 patients discontinued therapy for hematologic toxicity. PK studies revealed no effect of DAC on the PK profile of TMZ. Conclusions: The combination of DAC and TMZ is safe and results in improved median OS from historic reference of 7.7 m to 15.2 m, and 1-year OS rate from 25% to 62%. The addition of DAC appears to improve the clinical activity of TMZ, possibly through dual modulation of DNA repair (depletion of MGMT and re-expression of MMR), and warrants further evaluation in a randomized setting.
Adverse event (AE) reporting of oral clodronate with emphasis on osteonecrosis of the jaw
Authors: G. R. Jones, T. Lehtinen, F. E. Riphagen, R. von Roemeling
Journal: Journal of Clinical Oncology (2005)

799 Background: Clodronate (CD) is a non-aminobisphosphonate with 18 years of use, representing over 260,000 patient-years. Recent reports describe osteonecrosis or osteomyelitis of the jaw associated with aminobisphosphonates, mainly pamidronate and zoledronic acid. This analysis reviewed spontaneous AE reporting of CD, emphasizing symptoms associated with the jaw. Methods: Schering AG clodronate worldwide database on spontaneous AE reporting and distribution was assessed for serious AE data reported during the marketing history of CD until 30 September 2004. All AE reports were coded using MedDRA (Medical Dictionary for Regulatory Activities). AE reporting rates were estimated using numbers of MedDRA preferred terms against estimated patient exposure for oral formulations. For certain AEs related to bone necrosis or infection, data from clinical trials were analyzed. Results: Overall spontaneous AE reporting rate was 6/10,000 patient-years for oral CD. There were no reports of osteonecrosis, osteomyelitis, or avascular necrosis of the jaw from spontaneous sources or serious AE reports from clinical trials. Two cases of osteomyelitis were reported from clinical trials, one involving the distal fibula associated with placebo of a trial for osteoporosis, the other involving the heel in an adjuvant breast cancer trial that remains blinded as to CD vs placebo arm. In both, osteomyelitis was preceded by local cellulitis and was considered unrelated to study drug. Conclusions: The spontaneous AE reporting rate for oral clodronate use is low. No cases of osteonecrosis of the mandible or maxilla were reported. Reports of osteomyelitis involving other sites appear to be related to factors other than clodronate. Continued safety monitoring and evaluation is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Berlex Laboratories, Schering AG, Schering Oy Schering Oy, Schering AG
S-1 and intraperitoneal and intravenous paclitaxel as neoadjuvant chemotherapy for gastric cancer with positive peritoneal cytology.
Authors: Y. Peng, M. Imano, H. Imamoto, K. Nishiki, Y. Nakamori, O. Shiraishi, A. Yasuda, M. Shinkai, T. Yasuda, H. Shiozaki
Journal: Journal of Clinical Oncology (2011)

142 Background: The prognosis of gastric cancer with positive peritoneal cytology is dismal. Standard treatments for these patients have not been established. The purpose of this study was to evaluate the safety and response of the regimen. Methods: Patients who were diagnosed with advanced gastric cancer between 2007 and 2010 underwent staging laparoscopy and received intraperitoneal paclitaxel when peritoneal cytology were positive and sequential systemic chemotherapy, S-1 combined with intravenous paclitaxel within 14 days after staging laparoscopy. Paclitaxel was administered intraperitoneally at 80 mg/m 2 . S-1 was administered at 80 mg/m 2 /day for 14 consecutive days, followed by 7 days rest. Paclitaxel was administered intravenously at 50 mg/m 2 on day 1 and day 8. After 2 courses of S-1 combined with paclitaxel were administered, clinical response was assessed by gastroendoscopy and computed tomography. Additional 2 or 3 courses were administered unless progression of disease was proved. Patients who achieved complete response (CR) or partial response (PR) and patients with stable disease (SD) underwent second-look laparoscopy following gastrectomy when peritoneal cytology turned negative. Results: 8 (7 male, 1 female) patients were enrolled: median age was 64 years (range 40-75). Of 8 patients, 1 patient achieved CR, and 5 PR. 2 patients showed progressive disease (PD). Grade 3 neutropenia occurred in 1 patient. 6 patients underwent second-look laparoscopy and peritoneal cytology turned negative in all 6 patients. Total or distal gastrectomy with lymphnode dissection was performed consecutively in 3 or 3 patients, respectively. Median follow-up duration was 775 days (range 187-1,028). No recurrence has not been observed, while the 1-year and 2-year survival rates of 14 patients with peritoneal cytology positive gastric cancer who have not received neoadjuvant chemotherapy were 58.3% and 33.3%, respectively. Conclusions: S-1, intraperitoneal and intravenous paclitaxel as neoadjuvant chemotherapy seems to be a effective strategy against gastric cancer with positive peritoneal cytology. No significant financial relationships to disclose.
Association of 2-O, 3-O desulfated heparin (ODSH) plus combination gemcitabine (G)/nab-paclitaxel (A) with preliminary benefit in untreated metastatic pancreatic cancer.
Authors: Darren Sigal, Stephen G Marcus, Peter J. Rosen, Steven J. Cohen, Peter Lee, Timmy Nguyen, Thomas Edward Gribbin, Pedro Quintana Diez, Mitesh J. Borad
Journal: Journal of Clinical Oncology (2013)

284 Background: ODSH, a low anticoagulant heparin derivative, interferes with several important pancreatic cancer cell survival pathways. A randomized phase II trial was initiated to determine if ODSH improves the activity of G/A, a promising pancreatic cancer investigational therapy. Preliminary data are presented here for the first 10 patients administered ODSH as part of an initial run-in phase prior to patient randomization. Methods: Patients with previously untreated, metastatic pancreatic cancer were treated with G (1,000 mg/m 2 ) and A (125 mg/m 2 ) plus ODSH (4 mg/kg bolus followed by a 48 hr. continuous IV infusion at a dose of 0.375 mg/kg/hr) on days 1, 8, and 15 every 28 days until disease progression or unacceptable toxicity. Patients were required to have ECOG ≤ 1 and appropriate blood and liver function levels. The primary endpoint was progression-free survival (PFS). Results: 10 patients (median age, 66 years) were administered up to 5 cycles of G/A plus ODSH. Per RECIST criteria, a partial response (PR) was achieved in 5 patients (50%) and the median PFS will exceed 6 months. Disease control (PR or stable disease for &gt; 16 weeks) occurred in all 10 patients. Of 9 patients with baseline elevated CA 19-9 levels, 8 had &gt; 60% reduction. ODSH was well tolerated and unexpectedly appeared to preserve marrow function as no patients had grade 3/4 thrombocytopenia or grade 4 neutropenia during any of the cycles. Conclusions: Although G/A and FOLFIRINOX are important advances, additional progress is necessary for metastatic pancreatic cancer patients. ODSH may interfere with pancreatic cancer invasion, metastasis, and chemo-resistance by inhibiting P- and L-selectins, heparanase, and the HMGB1-RAGE axis, respectively, suggesting that ODSH may enhance chemotherapy activity. This preliminary analysis in a small number of patients is encouraging and consistent with a previous report for this regimen (Von Hoff, J Clin Oncol, 2011). ODSH has also been very well tolerated and early data suggests that it may preserve platelet and neutrophil levels. Further follow-up of the ongoing randomized phase II trial is warranted. Clinical trial information: NCT01461915.
Investigating the association of cytoplasmic and nuclear HIF-2 expression with cancer specific survival (CSS) in clear cell renal cell carcinoma.
Authors: Nils Kroeger, David B. Seligson, Sabina Signoretti, Hong Yu, Frederic D. Birkhaeuser, Clara Magyar, Jiaoti Huang, Joseph Riss, Fairooz F. Kabbinavar, Arie S. Belldegrun, Allan J. Pantuck
Journal: Journal of Clinical Oncology (2013)

387 Background: Studies support the prognostic importance of HIF-2α for ccRCC. Interestingly, a recent study has implicated HIF-2α as part of a protein translational initiation complex, a cytoplasmic function that goes far beyond its role as a nuclear transcription factor. We hypothesized that both the absolute expression as well as the subcellular localization of HIF-2α would predict clinicopathological features and CSS in ccRCC. Methods: A tissue microarray (TMA) study was conducted on 308 ccRCC patients. Survival differences were investigated with the log rank test and associations with CSS with uni- and multivariate Cox regression analyses. Recursive partition tree analysis was used to identify relevant cutoff values. Results: The median follow-up was 2.29 years (IQR 11.82). The mean percentage of positive cells was 22.45±18.00 and 0.12 ± 0.29 for HIF-2α nuclear (N) and cytoplasmic (C), respectively. High HIF-2α N (cutoff&gt;32%) expression was associated with smaller tumor sizes (p = 0.002) and less advanced Fuhrman grades (p = 0.044). To the contrary, tumors with high HIF-2α C (&gt;0%) more often had lymph node (p = 0.004), distant metastases (p = 0.021), and higher Fuhrman grades (p&lt;0.0001). Univariate analyses showed an association of high HIF-2α N (p = 0.035) with better CSS. This was not found when HIF-2α N was used as a continuous variable (p = 0.067). In contrast, HIF-2α C demonstrated an association with CSS when examined as both a continuous (p &lt; 0.0001) and as a dichotomized variable (p &lt; 0.0001). After adjustment for TNM stage, ECOG PS, and Fuhrman grade, both continuous (p &lt; 0.0001) and dichotomized (p &lt; 0.0001) HIF-2α C variables remained significant predictors of CSS, while neither HIF-2α N variable was retained. The ratio of HIF-2α C/N was the strongest predictor of CSS in multivariate analysis (p = 0.001; HR 4.83 [95% CI: 1.99 – 11.76]). Conclusions: Our investigation suggests an important role for HIF-2α as a cytoplasmic protein translational initiation complex in ccRCC. This novel observation warrants further molecular and genetic studies examining biological pathways that are involved in the tumor promotive properties of HIF-2α in the cytoplasm.
Frequent truncating mutations of the cohesin complex gene STAG2 in urothelial carcinoma of the bladder.
Authors: David A. Solomon, Jung-Sik Kim, Jolanta Bondaruk, Shahrokh F. Shariat, Zeng-Feng Wang, Abdel Elkahloun, Julia Gerard, DaZhong Zhuang, Shizhen Zhang, Brian D. Robinson, Mark A. Rubin, Bjoern Volkmer, Richard Hautmann, Rainer Kuefer, George J. Netto, Dan Theodorescu, Bogdan Czerniak, Markku Miettinen, Todd Waldman
Journal: Journal of Clinical Oncology (2014)

290 Background: We have recently identified the cohesin complex subunit STAG2 as a gene that is somatically mutated in human cancer and whose inactivation leads directly to chromosomal instability and aneuploidy (Solomon et al, Science, 2011 Aug 19). However, the complete tumor spectrum harboring STAG2 mutations and the clinical significance of STAG2 inactivation in cancer remain undefined. Methods: Immunohistochemistry was used to screen 2,214 tumors from each of the major tumor types for somatic loss of STAG2 expression. Sequencing of the STAG2 gene was performed on 111 urothelial carcinomas, and Affymetrix CytoscanHD Arrays were performed on STAG2 mutant tumors. Clinical data from 34 patients with non-muscle invasive urothelial carcinoma treated with transurethral resection and 349 patients with invasive urothelial carcinoma treated with radical cystectomy was correlated with tumor STAG2 status. Results: Complete loss of STAG2 expression was discovered in 52/295 urothelial carcinomas (18%), ranging from low grade papillary to high grade muscle invasive tumors. DNA sequencing revealed somatic truncating mutations of STAG2 in 23/111 urothelial carcinomas of the bladder, including 9/25 papillary non-invasive carcinomas (36%), 6/22 superficially invasive carcinomas (27%), and 8/64 muscle invasive carcinomas (16%). STAG2 mutation was found to be an early event in bladder tumorigenesis, frequently associated with alterations in p53 signaling, and often correlated with numerous chromosomal copy number aberrations per tumor. STAG2 loss in non-muscle invasive urothelial carcinomas treated with transurethral resection was found to be associated with increased disease-free survival (p=0.05), while STAG2 loss in invasive urothelial carcinomas treated with radical cystectomy was found to be associated with increased lymph node metastasis (p=0.03), earlier disease recurrence (p=0.04), and reduced cancer-specific survival (p=0.04). Conclusions: These results identify STAG2 as one of the most commonly mutated genes in bladder cancer, and demonstrate that STAG2 loss defines molecular subgroups of urothelial carcinomas with distinct clinical outcomes.
HER2 expression in patients with advanced pancreatic cancer: Preliminary results from a multifactorial biologic analysis.
Authors: Luca Faloppi, Alessandra Mandolesi, Elena Maccaroni, Riccardo Giampieri, Maristella Bianconi, Alessandro Bittoni, Michela Del Prete, Stefania Antognoli, Mario Scartozzi, Italo Bearzi, Stefano Cascinu
Journal: Journal of Clinical Oncology (2012)

250 Background: Pancreatic cancer is the deadliest solid cancer and currently the fourth most frequent cause of cancer-related deaths. Many studies have demonstrated that pancreatic cancer is a group of heterougeneous disease with different therapeutical implications and prognosis. Aim of our analysis was to analyze the HER-family status in pancreatic cancer. Methods: We immunohistochemically assessed surgical specimens and macrobiopses for several biological targets. K-ras, HER-1, HER-2 and HER-3 were analyzed. Results: 62 specimens were analyzed in our centre. 30 samples were K-ras wild-type, 70% of these were EGFR positive. While 32 samples have a mutant form of K-ras, 87.5% were EGFR positive. HER-2 resulted negative in all specimens. In the K-ras wild-type group, 17% have high expression of HER-3, 20% a low one; in mutant K-ras group 16% are high expressing while 34% have a low HER-3. Conclusions: Over the past decades, there has hardly been any substantial therapeutic progress regarding clinical endpoints in pancreatic cancer, thus in the era of target therapies the molecular biological classification of these neoplasms have an ever more important role for developing tailored therapies. Our analysis show a low rate of k-ras mutations (52%) and seems to suggest that anti-EGFR strategies may represent an interesting treatment option in pancreatic cancer as long as a preliminary molecular selection is applied. Numerous international trials are evaluating the role of new drugs targeting HER-2 in association with chemotherapy in metastatic pancreatic cancer. On the contrary, our data suggest that HER-2 directed therapies are not likely to represent a relevant choice in this setting.
Implementing Lynch syndrome screening utilizing a community partnership.
Authors: Jennifer N. Eichmeyer, Matthew Burtelow, Michael Carey, Paul Montgomery, Cynthia Graham, Dan Sayam Zuckerman, Thomas M. Beck
Journal: Journal of Clinical Oncology (2013)

203 Background: Lynch syndrome (LS) is an autosomal dominant condition associated with an 80% risk of colorectal cancer, a 60% risk of endometrial cancer, and additional risks for extra-colonic cancers. Amsterdam and Bethesda criteria can be used to identify patients who may be at risk. However, 25% of colon cancer and 65% of endometrial cancer patients with LS will be missed by using family history criteria alone. LS is caused by mutations in mismatch repair genes (MMR): MLH1, MSH2, MSH6, PMS2, and EPCAM. Tumor screening by immunohistochemistry (IHC) is available, and abnormal results can be flagged for more definitive genetic counseling and testing. Recommendations from the 2009 EGAPP (Evaluation of Genomic Applications in Practice and Prevention) Working Group concluded there is sufficient evidence to use this tumor testing for LS, and the screening would provide moderate population benefits. Cost effectiveness studies have shown universal screening detects nearly twice as many cases of LS and is &lt; $25,000 per life year saved. Methods: St. Luke’s Mountain States Tumor Institute (MSTI) implemented these recommendations in 2012 using a unique strategy: collaborating with a community organization. The Brian Olson Foundation (BOF) strives to “prevent(ing) colon cancer through community outreach and education and saving lives by detecting colon cancer as early as possible.”These objectives were aligned with the MSTI screening program for LS in Idaho by using BOF funding to eliminate a financial burden to the patient for 12 months. Results: 204 specimens were screened for LS using IHC with the following results: 73% normal, 21% abnormal staining for MLH1/PMS2, and 6% abnormal staining for a single protein. Three families were confirmed to have LS after molecular genetic testing, and 6 families have genetic test results pending. Conclusions: Our system had IHC numbers consistent with national data, if not slightly higher. MSTI has elected to continue the program long-term. This kind of collaboration eased the change in practice such that LS screening could become a standard of care in Idaho.
Radioembolization for unresectable hepatocellular carcinoma (HCC) in the elderly.
Authors: B. Sangro, G. M. Ettorre, R. Cianni, D. Gasparini, R. Golfieri, S. Ezzidin, F. T. Kolligs, F. Izzo
Journal: Journal of Clinical Oncology (2011)

e14618 Background: The effects of advancing age on the tolerance and clinical outcomes following radioembolization in elderly patients with HCC are largely unknown. Methods: A retrospective analysis was conducted by the European Network on Radioembolization with yttrium-90 resin microspheres (ENRY) study group to evaluate the clinical outcomes among 128 elderly (70 years and older) patients and 197 younger patients (less than 70 years) with unresectable HCC who had received radioembolization (RE) consecutively between 09/2003 and 12/2009. Results: The mean age of the elderly cohort was 74 (range: 70-87) years and 58 (range: 22-69) years in the younger cohort. Regardless of age, the patients considered suitable for RE were very similar in the elderly and young in terms of: liver function tests (bilirubin >1.5 mg/dL: 13.3% vs. 19.5%), Child-Pugh class (A: 85.2% vs. 80.7%), underlying cirrhosis (81.3% vs. 76.6%) and performance status (ECOG 0-1: 89.8% vs. 86.2%), respectively. Many elderly and younger patients alike had multinodular (73.4% vs. 77.6%), advanced BCLC ‘C’ disease (56.3% vs. 56.3%) invading both lobes (51.2% vs. 54.3%); although elderly patients had a lower tumor burden in the liver (target tumor volume: 180.0 vs. 268.5 mL; p=0.006), a smaller median liver volume (1372 vs. 1476 mL; p= 0.024) and were more likely to receive segmental treatment (10.9% vs. 5.1%; p=0.054). Median overall survival [95%CI] following RE did not deteriorate with advancing age (14.5 [10.6-16.8] months in elderly vs. 12.8 [10.8-17.9] months; p=0.942). Radioembolization was equally well tolerated in both cohorts. Common procedure-related adverse events (fatigue, nausea and/or vomiting, abdominal pain, fever and raised bilirubin) were predominately Grade 1-2 and of short duration. Severe increases in bilirubin (to grade ≥3) were observed in 4.3% and 6.9% of older and younger populations, respectively. Conclusions: RE is a well-tolerated and effective treatment option for elderly patients with unresectable HCC.