tbuckley/cabot-search huggingface dataset:
Multicenter trial for assessing cytokine promoter gene polymorphism as a predictive parameter of PSK responder for curatively resected stage II or III colorectal cancer.
Authors: Shigefumi Yoshino, Furuya Takumi, Koichiro Sakata, Ryoichi Shimizu, Naoko Okayama, Shoichi Hazama, Masaaki Oka
Journal: Journal of Clinical Oncology (2015)

619 Background: Polysaccharide-K (PSK), a protein-bound polysaccharide extracted from the mycelia of Coriolus versicolor, is an immunomodulator widely used in colorectal cancer in Japan. PSK has immunological actions including enhancement or inhibition of cytokine production. It has been reported that levels of cytokine production are influenced by polymorphisms in the promoters of cytokine genes. We hypothesized that cytokine promoter gene polymorphisms may be responsible for genetic susceptibilities to immunological effect of PSK. Methods: This is a multicenter prospective trial. One hundred and ten patients with stage II or III colorectal cancer were enrolled. All patients received adjuvant immnochemotherapy after curative resection using UFT (stage II) or UFT/LV (stage III) combined with PSK (3.0 g/day, p.o.) for 1 year. Post-operative survey of recurrence was followed with CT scan at 6-month intervals during the first 2 years after surgery and at 1-year intervals thereafter until 5 year after surgery. DNA was extracted from peripheral blood cells in all patients. The following polymorphisms of the patients were genotyped: TNF-α-1031T/C, IL-1ß-511C/T, IL-6-634C/G, IL-10-819T/C. Results: Twenty (6 in stage II, 14 in stage III) out of 110 patients showed recurrence after more than 5 years survey. Fifteen out of 74 patients with TNF-α-1031 TT genotype and 5 out of 36 with TNF-α-1031 CC or CT showed disease recurrence. Five out of 39 patients with IL-1ß-511 CC and 15 out of 71 with IL-1ß-511 CT or TT showed disease recurrence. Eleven out of 61 patients with IL-6-634 CC and 9 out of 49 with IL-6-634 CG or GG showed disease recurrence. No association between genotype frequency and disease recurrence was observed for TNF-α, IL-1ß, IL-6. Fifteen out of 61 patients with IL-10-819 CC or CT genotype showed disease recurrence, whereas only 5 out of 49 with IL-10-819 TT showed tumor recurrence (p=0.052). Especially, significant association with disease recurrence was found in stage III patients (12/30 vs 2/17, p=0.042). Conclusions: It is suggested that colorectal cancer patients with IL-10-819 TT genotype could be PSK responder after curative resection.
Usefulness of modified PERCIST for defining response of neoadjuvant chemotherapy in esophageal cancer.
Authors: Daisuke Izumi, Naoya Yoshida, Masayuki Watanabe, Takatsugu Ishimoto, Keisuke Kosumi, Ryuma Tokunaga, Kazuto Harada, Satoshi Ida, Yukiharu Hiyoshi, Shiro Iwagami, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Hideo Baba
Journal: Journal of Clinical Oncology (2015)

209 Background: It is sometimes difficult to exactly measure maximum diameters of tumor after chemotherapy in esophageal cancer. Richard et al. proposed PET Response Criteria in Solid Tumor (PERCIST) for assessing response of tumor after chemotherapy by PET in 2009. The first purpose is to investigate the utility of PERCIST after neoadjvant chemotherapy in esophageal cancer. The second purpose is to clarify the utility of modified PERCIST of which we use the SUV of normal (non-cancerous) esophagus as a reference of comparison for diagnosing complete response (CR) instead of the right lobe liver SUV. Methods: The clinicopathological data of the 71 esophageal cancer patients who received neoadjuvant chemotherapy (DCF) and underwent curative resection from November 2008 to May 2012 were collected. Among them, we compared pathological grade with PERCIST of the 26 esophageal cancer patients who were examined by PET before and after chemotherapy. Furthermore we investigated which reference of comparison is appropriate for diagnosing complete response between the right lobe of liver (L group) and normal esophagus (E group). Results: We could measure the tumor size of all cases after chemotherapy by PERCIST although 6 cases could not be assessed by RECIST. All of the 6 cases which were diagnosed as stable disease or progressive disease by PERCIST were pathological grade1a. The cases of complete response are 7 cases in L group and 3 cases in esophageal cases. Among the complete response cases in L group, 1 case were pathological grade1 a and 2 cases were grade 2 although all the complete response cases in E group were pathological grade 3. One case of L group relapsed after curative resection although there was no recurrent case in E group. Conclusions: The esophageal cancer patients often have history of massive alcohol intake or liver damage caused by viral hepatitis or fatty liver. Although PERCIST is useful for evaluating the effect of neoadjuvant chemotherapy of esophageal cancer, it is better to use normal esophagus as a comparison standard for diagnosing complete response.
A phase II trial of alternating cycles of carboplatin/paclitaxel and carboplatin/gemcitabine for stage IIIB/IV non-small cell lung cancer
Authors: I. Ahmad, F. Arnold, S. Ahmed, A. Sami, T. Zhu, K. Haider, S. Yadav, K. Gesy, M. Brigden
Journal: Journal of Clinical Oncology (2008)

19113 Background: Combination chemotherapies have demonstrated response rate (RR) of 30–50% with median survival of only approx 10 months for patients with stage IIIB/ IV NSCLC. Therefore it is important to search for new agents or new combinations of existing regimens. Goldie and Codman model proposed that alternating non-cross resistant combinations would prevent the overgrowth of resistant cancer cells and improve the probability of tumor control. We conducted a phase II study at Saskatoon Cancer Ctr, (Canada) to determine clinical response of Carboplatin/Paclitaxel (C/P) alternating with Carboplatin/Gemcitabine (C/G) for advanced NSCLC. Methods: Patients with chemotherapy naïve Stage IIIB or IV NSCLC, ECOG PS ≤2, with measurable or evaluable disease and no known CNS metastases were eligible. Chemotherapy consisted of Paclitaxel (175 mg/m2) and Carboplatin (AUC=5) day 1 alternating with Carboplatin (AUC=5) day 1 and Gemcitabine 1000 mg/m2 days 1 and 8 every three weeks for a total of six cycles. Primary end point was PFS. Results: 15 out of 16 patients enrolled in this study were evaluable. Patient characteristics included: Median age 61 years; female 60%; stage IV (100%); PS 0–1 (53%), 2 (46%); adenocarcinoma (66%). 12 (80%) of patients completed the prescribed 6 cycles of chemotherapy. Among the 15 patients, none achieved CR, 3 (20%) had PR, 11 (73%) had stable disease, and 1 (6%) had disease progression. Median PFS was 26.7 weeks (95% CI. 22–33 weeks) and median OS was 47.8 weeks (95% CI: 37–80 weeks). The most common Grade 3 and 4 hematological toxicities were neutropenia (33%) and thrombocytopenia (26%). The most common Grade 3 and 4 nonhematological toxicities were dyspnea (26%) and vomiting (20%). There were no treatment related deaths. Conclusion: This regimen of alternating cycles of C/P and C/G has comparable response rates, PFS, OS and acceptable toxicity profile as compared with traditional 3rd generation chemo regimens. Alternating equally effective, non cross resistant chemo regimens can be considered for patients deemed intolerant to traditional chemo regimens. Studies with more patients accrual will be needed to confirm our observation. No significant financial relationships to disclose.
Cardiac risks of imatinib in chronic myelogenous leukemia (CML) patients who receive allogeneic hematopoietic cell transplantation (Allo-HCT)
Authors: M. J. Burke, A. Gursahaney, B. Trotz, X. Luo, K. S. Baker, D. J. Weisdorf, J. E. Wagner, V. R. Michael
Journal: Journal of Clinical Oncology (2008)

7039 Background: Since the introduction of imatinib, the role of an allo-HCT in patients with CML has been essentially reserved for patients with advanced disease or resistance to tyrosine kinase inhibitors. Although the side effect profile of imatinib appears tolerable, there have been recent concerns regarding long term use and cardiac toxicity. Whether cardiac related toxicities of imatinib are increased with the addition of myeloablative transplantation is currently unknown. Methods: We evaluated the outcome of sixty-two patients with CML who received an allo-HCT at the University of Minnesota between 1999 and 2006. The median age at HCT was 38.3 (range; 6.9–56.9) years. All patients were conditioned with cyclophosphamide (120 mg/kg) and total body irradiation (1320 cGy). GVHD prophylaxis included CSA-based regimens. Disease status at time of HCT included thirty-seven patients in first chronic phase, nineteen in either a second chronic phase or an accelerated phase and six patients in a second accelerated phase. Of the 62 patients, 27 received imatinib therapy pre-or-post-HCT and 35 patients, either never received imatinib (n=32) or received it at the time of relapse (n=3). The mean time to HCT was significantly shorter for the non-imatinib group (248 vs.587 days; Wilcoxon rank-sum test: p=0.01). Results: The median time to follow-up is 1.96 years (range 0.04–7.30). In multiple regression analysis, disease status at time of HCT had a significant impact on overall survival (OS) and relapse-free survival (RFS) providing 2-year OS and RFS rates of 66% (CI: 0.45, 0.81) and 53% (CI: 0.32, 0.71) for the imatinib group and 57% (95%CI: 0.39, 0.72) and 49% (95%CI: 0.31, 0.64) for the non-imatinib group (Log-rank: p=0.09, 0.09, respectively). Relapse rates (RR) at 2 years were 24% and 14% for the imatinib group and non-imatinib group respectively (Grey-test: p=0.26). Transplant related mortality at 2-years was similar between groups. The incidence of cardiac toxicity at 1-year was 26% and 31% for the imatinib and non-imatinib groups respectively (Grey-test: p=0.49). Conclusions: Patients that were treated with imatinib in the pre-or-post-HCT setting had no obvious increased risk of cardiac toxicity and a trend toward improved OS/RFS. No significant financial relationships to disclose.
Reply: “Could Noninvasive Ventilation Failure Rates Be Underestimated in the LUNG SAFE Study?” and “High-Flow Oxygen, Positive End-Expiratory Pressure, and the Berlin Definition of Acute Respiratory Distress Syndrome: Are They Mutually Exclusive?”
Authors: Giacomo Bellani, Fabiana Madotto, Tài Pham, Eddy Fan, John G. Laffey
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Impact of baseline prognostic factors on progression-free survival at 6 months (PFS6) and response in patients receiving second-line therapy for advanced urothelial carcinoma (UC).
Authors: Gregory Russell Pond, Neeraj Agarwal, Joaquim Bellmunt, Toni K. Choueiri, Angela Q. Qu, Ronan Fougeray, Guenter Niegisch, Matt D. Galsky, Yu-Ning Wong, Walter Michael Stadler, Srikala S. Sridhar, Cora N. Sternberg, Guru Sonpavde
Journal: Journal of Clinical Oncology (2013)

301 Background: PFS6 was identified to be a robust intermediate endpoint in the setting of second-line therapy for advanced UC (Sonpavde, ESMO Congress, 2012) We studied the impact of second-line prognostic factors (Sonpavde, ESMO Congress 2012) (liver metastasis [LM], anemia [Hb&lt;10 g/dl], ECOG-performance status [PS] ≥1, time from prior chemotherapy [TFPC]) on PFS6 and response rate (RR) to enable comparison of outcomes across phase II trials. Methods: Twelve phase II trials evaluating second-line chemotherapy and/or biologics (n=748) in patients with progressive disease were pooled. PFS was defined as tumor progression or death from any cause. PFS6 was defined from the date of registration and calculated using the Kaplan-Meier method. Results: Data regarding progression, Hb, LM, PS and TFPC were available in 570 patients, who were considered evaluable. The mean age was 65.1 years, 45.3% had ECOG-PS ≥1, 30.2% had LM, 14.6% had anemia and TFPC was &lt;6 months (mo) in 60.2%. The overall median PFS was 2.7 mo, PFS6 was 22.2% (95% CI: 18.8-25.9) and RR was 17.5% (95% CI: 14.5%-20.9%). PFS6 and RR varied significantly according to risk group (Table). For every unit increase in risk group, the hazard of progression in 6 mo increased by 41% and the odds of response decreased by 48%. Conclusions: PFS6 and RR vary as a function of prognostic factors in patients receiving second-line therapy for advanced UC. These data facilitate comparison of outcomes across phase II trials enrolling heterogeneous populations. [Table: see text]
The management of colorectal cancer (CRC) liver metastases with yttrium-90 microspheres (Y90): The south Australian (SA) experience.
Authors: Christos Stelios Karapetis, Sunita Jo-Anne Padman, Carol Beeke, Robert Padbury, Michael Kitchener, Ian Kirkwood, Frank Voyvodic, Oliver Ayres, Timothy Jay Price
Journal: Journal of Clinical Oncology (2014)

666 Background: Treatment of CRC liver metastases with Y90 may provide a survival benefit but remains under investigation. We report on the accumulated SA clinical experience of using Y90 in the treatment of patients with metastatic CRC. Methods: Data from the SA mCRC Database was used to analyse the baseline characteristics of patients treated with Y90 to determine patterns of care. Safety and adverse outcomes, tumour response, disease progression, and survival were also examined. Survival outcomes were analysed using Kaplan Meier estimates, and chi square testing used for comparisons. Results: 33 patients received Y90, with median age 67 (range 33-83), 25 male, 29 colon/4 rectal primary, 25 hepatic only metastatic disease. Systemic therapy pre Y90 was as follows; nil=4, 1 line=7, 2 lines=9, ≥3=11, unknown=2. There were no immediate Grade III/IV adverse events, though immediate toxicity occurred in 9 patients; liver capsule pain in 8, chest pain and vomiting in 1 patient. Following Y90 treatment, radiologist reported response showed: measurable reduction =3 (ORR 9%), SD=4, PD=20, and 1 patient unknown. Treatment beyond Y90; nil=16 patients, 1 line=7, 2 lines=7 and &gt;3=2 patients. Data on hepatic progression free survival (PFS) and overall PFS is currently being analysed. Median survival from the time of Y90 treatment was 10.3 months. Conclusions: Our data show Y90 use in SA occurs most often after 2 lines of chemotherapy. No immediate grade 3/4 toxicity was encountered. Survival for this select group appears longer than expected. Data on mOS from delivery of Y90, hepatic PFS and overall PFS for subgroups will be reported.
A phase I evaluation of vandetanib plus paclitaxel, carboplatin, 5-fluorouracil, and XRT induction therapy followed by surgery for previously untreated locally advanced cancer of the esophagus and GE junction.
Authors: Igor A. Astsaturov, Joshua E. Meyer, Jonathan D. Cheng, Anthony J. Olszanski, Holly Dushkin, Adam C. Berger, Monica Davey, Steven J. Cohen, Barbara Burtness, Walter Joseph Scott
Journal: Journal of Clinical Oncology (2012)

74 Background: Vandetanib (Vb) is an oral inhibitor that selectively targets VEGFR2, VEGFR3, RET and EGFR. Preclinical models indicate synergy with radiation and chemotherapy. We report the final results from an open-label phase I study of pre-operative Vb with carboplatin, paclitaxel, 5FU and radiation in pts with operable esophageal and GE junction (GEJ) carcinomas. Methods: Pts with operable PET/CT and EUS-staged carcinoma of the esophagus and GEJ received once daily Vb with concomitant RT (1.8 Gy/d, total 45 Gy) plus carboplatin AUC5 (d1 and 29), paclitaxel (50 mg/m 2 , d1,8,15,22,29), and 5-FU (CI 225 mg/m 2 , M-F, 5 wks). The primary objective was the safety, tolerability and the maximum tolerated dose of Vb in this combination. Planned dose escalations of Vb: 100, 200 and 300 mg daily with a “3+3” design. Results: Nine male pts (median age 58 (35-77), stage II, T 2-3 N 0 (2 pts), III, T 2-3 N + (7 pts)) were accrued between 03/2009 and 08/2010 at Fox Chase Cancer Center: 2/9 pts had esophageal squamous carcinoma (SCC) and 7/9 pts had adenocarcinoma including GEJ (2 pts). All patients completed the planned induction chemoradiation and underwent esophagectomy with curative intent. Of 3 initial pts at Vb 100 mg, one with SCC died on day 99 from GI hemorrhage which was considered treatment-related. Three more pts received Vb 100 mg and 3 pts received Vb 200 mg daily. Dose limiting toxicities (DLT) occurred in 2/3 pts receiving Vb 200 mg (esophago-gastric anastomotic leak, and diarrhea requiring Vb dose reduction). Grade 3 non-hematological toxicities included diarrhea (2), anorexia (1), abdominal pain (1), hyponatremia (1), AST/ALT (1), depression (1). Dose escalation to 300 mg Vb was not attempted. 5/9 pts had a pathologic complete response (no tumor seen, 56%), 5/9 remain disease free with median followup of 23 months (13-31). 3 pts had distant recurrences at 322, 334 and 561 days. Conclusions: Targeting VEGFR/RET/EGFR with Vb at 100 mg daily in combination with induction chemoradiotherapy for operable esophageal and GEJ cancer is well tolerated and with promising clinical activity warranting further phase II evaluation.
Antigen spread and survival with sipuleucel-T in patients with advanced prostate cancer.
Authors: Charles G. Drake, Li-Qun Fan, Debraj GuhaThakurta, Frances Stewart, Philip W. Kantoff, Eric Jay Small, Thomas A. Gardner, Nadeem A. Sheikh, James B. Trager, Celestia S. Higano
Journal: Journal of Clinical Oncology (2014)

88 Background: Tumor cell death in response to an immunotherapy may lead to the release of secondary (i.e. non-targeted) tumor antigens that prime subsequent immune responses (antigen spread). This may contribute to tumor control and reveal post-treatment biomarkers of clinical outcome. Sipuleucel-T, approved in the U.S. for treatment of patients with asymptomatic or minimally symptomatic, metastatic castration-resistant prostate cancer (mCRPC), is designed to elicit an immune response to prostatic acid phosphatase. Here we show that sipuleucel-T also elicits humoral antigen spread that may be associated with clinical benefit. Methods: We used protein microarrays and Luminex xMAP to identify and validate post-treatment serum immunoglobulin G (IgG) responses against secondary antigens. Association between IgG responder status (≥ 2-fold IgG elevation post-treatment) and overall survival (OS) was assessed using a Cox regression model adjusted for baseline prognostic factors (prostate-specific antigen [PSA], lactate dehydrogenase [LDH], bone lesions, Gleason score) and prior bisphosphonate use. Results: In IMPACT (NCT00065442, the pivotal trial of sipuleucel-T), IgG responses against secondary antigens were consistently observed three to four months post-treatment in the sipuleucel-T arm but not in the control arm. In evaluable sera from IMPACT (sipuleucel-T n=93; control n=40), IgG responses against an array of secondary antigens, including an oncogene (K-RAS) and a prostate-specific antigen (KLK2/hK2), were confirmed by Luminex xMAP in sipuleucel-T-treated patients (Wilcoxon test, p≤10 -6 ); responses were not observed in control patients (p&gt;0.1). Antigen spread was also observed post-sipuleucel-T treatment in ProACT (Wilcoxon test, p≤0.01), an independent study in patients with mCRPC (NCT00715078, evaluable n=26). In IMPACT, OS was longer in sipuleucel-T-treatment patients with IgG response to greater than or equal to two secondary antigens than in those without such response (Cox model, p≤0.01, HR≤0.4). Conclusions: Sipuleucel-T treatment resulted in humoral antigen spread that was associated with improved OS in IMPACT. These results contribute to an understanding of sipuleucel-T’s mechanism of action, and may enable identification of post-treatment biomarkers of clinical outcome. Clinical trial information: NCT00065442.
Molecular testing for BRAF V600 mutations in the BRIM-2 trial of the BRAF inhibitor vemurafenib in metastatic melanoma.
Authors: K. J. Bloom, S. M. Anderson, R. C. Schilling, J. R. Lee, H. Halait, S. Cheng, R. A. Langland, H. J. Lawrence
Journal: Journal of Clinical Oncology (2011)

10523 Background: The BRAF inhibitor vemurafenib (V) has shown dramatic activity in early clinical trials in patients with BRAFV600 mutation-positive melanoma. Preclinical and Phase 1 clinical data show the drug has minimal activity in tumors lacking BRAF mutations, creating a need for an accurate diagnostic test to identify appropriate patients for therapy. Methods: To assess eligibility for BRIM-2, a Phase 2 trial of V in patients with BRAFV600 mutation-positive metastatic melanoma, tumor samples were screened with an investigational PCR assay (cobas 4800 BRAF V600 Mutation Test) designed to detect the canonical V600E (1799T>A) mutation. 328 samples were tested of which 327 samples gave valid results. BRAF mutations were detected in 184 (56.3 %); 132 patients with BRAF-mutation positive melanoma were enrolled into the trial based on clinical eligibility criteria. Sanger sequencing was performed retrospectively on DNA samples from all enrolled patients. Results: Fifteen samples (11.4%) gave invalid Sanger results. Sanger detected a V600E mutation in 97 samples (73.5%), V600K mutation in 9 samples (6.8%) and a wild-type (WT) result in 11 cases (8.3%). Samples were also subjected to “deep” sequencing with a quantitative picotiter plate pyrosequencing method (454 GS-Titanium) to resolve differences between PCR and Sanger results. Using 454 sequencing of samples with invalid Sanger results revealed a V600E mutation in 14 cases and a V600K mutation in 1 case. Of 11 samples with a WT Sanger result, 454 sequencing detected a V600E mutation in all cases, with a median percentage of mutant alleles of 8%; ten of the 11 samples had a percentage < 25%. The presence of a V600K mutation was confirmed by 454 sequencing in all 9 samples identified as having V600K mutations by Sanger. Conclusions: 1) the investigational PCR test had a low failure rate; 2) the PCR test was more sensitive in the detection of V600E mutations than Sanger sequencing, which may miss mutations in cases with low % mutant alleles; 3) the PCR test detects V600K mutations, and 4) in all 132 cases, a codon 600 mutation was confirmed by Sanger and/or 454 sequencing. Robust, rapid and accurate molecular testing was achieved in this multi-center clinical trial.