tbuckley/cabot-search huggingface dataset:
Von Hippel-Lindau gene mutation status is associated with a dichotomous response in primary and metastatic tumors in patients receiving bevacizumab and erlotinib for metastatic renal cell carcinoma
Authors: D. Tsavachidou, N. M. Tannir, C. G. Wood, P. Corn, K. Do, P. Tamboli, L. A. Smith, S. Matin, E. Jonasch
Journal: Journal of Clinical Oncology (2007)

15522 Background: A single arm phase II study is underway evaluating the safety and clinical benefit of presurgical bevacizumab and erlotinib in the management of patients with untreated conventional renal cell carcinoma (RCC). It is not known how the presence or absence of von Hippel Lindau (VHL) mutations affect the response to therapy in the primary or metastatic site, and whether VHL mutational status is predictive for either. Methods: Patients enrolled had conventional RCC, measurable metastatic disease, a primary tumor in place, no prior systemic therapy, a PS of 0 or 1 and no brain metastases. A total of 35 patients were enrolled as of January 8, 2007. Patients were treated with bevacizumab for 4 cycles and erlotinib for 8 weeks, and underwent cytoreductive nephrectomy at week 10 (4 weeks after the last dose of bevacizumab). A VHL gene mutation and methylation analysis was completed on nephrectomy specimens from the first 18 evaluable patients. Patients were grouped according to the presence or absence of functional VHL gene inactivation (mutation and/or methylation). Two-sample T-test and Fisher’s exact test were performed. Results: Ten patients (55%) demonstrated either VHL mutation or methylation ( table 1 ). Patients with no VHL gene inactivation demonstrated more robust primary tumor shrinkage, but did not demonstrate partial responses (PRs). Table 1 . Conclusions: These findings, although preliminary, suggest a dichotomous response in the primary and metastatic disease sites according to VHL functional status. Ongoing evaluation of new treatment strategies using antivascular/targeted agents in RCC may benefit from molecular stratification. [Table: see text] No significant financial relationships to disclose.
Phase II study of neoadjuvant chemotherapy with paclitaxel and cisplatin in Stage IIIA N2 non-small cell lung cancer
Authors: I. S. Choi, D. Y. Oh, D. W. Kim, Y. T. Kim, T. Y. Kim, C. K. Yoo, Y. W. Kim, D. S. Heo, Y. J. Bang, N. K. Kim
Journal: Journal of Clinical Oncology (2004)

7305 Background: The objective of the current study was to define the activity and tolerability, as well as the influence on resectability, of the combination of paclitaxel and cisplatin as induction chemotherapy for patients with stage IIIA N2 non-small cell lung cancer (NSCLC). Methods: Thirty-four chemotherapy-naïve patients with NSCLC, median age of 61 years, stage IIIA N2 disease, and the ability to tolerate pneumonectomy received a combination of paclitaxel 175mg/m2over 3 hours and cisplatin 60mg/m2every 3 weeks for two cycles preoperatively. Three postoperative cycles, each consisting of an attenuated dose of paclitaxel 135mg/m2 over 3 hours and carboplatin AUC 5, were planned every 3 weeks for patients undergoing surgical resection. Results: Of the 34 eligible patients, there were no patients who showed a complete response (CR) and 22 who showed a partial response (PR), resulting in a response rate of 65%. Overall, 29 patients (85%) underwent thoracotomy and 25 (74%) underwent complete resection. The mediastinal nodes were tumor free in 21%. Grade 3–4 hematologic toxicity was uncommon. Grade 3 leukopenia occurred in three cycles (4%) and there was one case of neutropenic fever. Grade 3–4 non-hematologic toxicity was also uncommon, apart from alopecia. Grade 1–2 peripheral neuropathy occurred in 21% of the patients. At a median follow-up of 19.5 months, the median time to progression for the 34 patients was 12.1 months (95% CI, 9.2–14.9 months) and the median overall survival was 23.6 months (95% CI, 19.9–29.3 months). Conclusions: In patients with stage IIIA N2 NSCLC, paclitaxel and cisplatin is an active and very well-tolerated induction regimen. No significant financial relationships to disclose.
The British Society of Gastroenterology spring meeting
Authors: T C Northfield, A F Hofmann
Journal: Gut (1973)

The spring meeting this year was held at the University Hospital of Wales, Cardiff, where the programme was arranged in two simultaneous sessions of free communications on 6 April and a final session of such papers on the afternoon of 7 April.The morning of 7 April was occupied by a symposium on 'Secretion of bile' in which invited speakers introduced each topic and finally formed a panel to answer questions from the audience.The speakers were G. Erlinger ('Secretion of bile'), K. Heaton ('Bile in the intestine-physiology'), R. Hermon Dowling ('Bile in the intestine-pathol- ogy'), N. Javitt ('Bile salts and cholestasis'), and Ian Bouchier ('Gallstones').Abstracts of papers read at the meeting are printed below.
Effect of the farnesyl transferase inhibitor lonafarnib on sensitivity of melanoma cells to the multikinase inhibitor sorafenib and on Rheb farnesylation and mTOR signaling
Authors: F. E. Meier, H. Niessner, K. Flaherty, D. Schadendorf, T. Sinnberg, B. Schittek, C. Garbe
Journal: Journal of Clinical Oncology (2009)

9077 Background: Farnesyl transferase inhibitors (FTIs) inhibit the post-translational farnesylation of a number of target proteins, including Ras and Rheb, preventing their signaling function. Ras signals to the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways which are constitutively activated in melanoma and appear to play a major role in tumor progression and drug resistance. Rheb positively regulates mTOR signaling. Methods: Using a panel of melanoma cell lines we evaluated the effects of the FTI lonafarnib alone and in combination with chemotherapeutic agents (temozolomide, cisplatin) or pharmacological MAPK pathway inhibitors (sorafenib, U0126, PD98059) or AKT pathway inhibitors (LY294002, wortmannin, rapamycin) on proliferation, survival and invasive tumor growth of melanoma cells in monolayer and organotypic culture. Results: Lonafarnib did not significantly inhibit growth of metastatic melanoma cells. Also, lonafarnib did not sensitize melanoma cells to the chemotherapeutic agents tested. Most combinations of the FTI lonafarnib with MAPK or AKT pathway inhibitors lacked significant enhancement of growth inhibition compared to monotherapy. In contrast, lonafarnib significantly augmented the growth inhibitory effects of the multikinase inhibitor sorafenib in eight metastatic melanoma cell lines tested. These effects did not appear to depend on BRAF or NRAS mutation status. Moreover, lonafarnib combined with sorafenib induced marked apoptosis and abrogated invasive melanoma growth. Interestingly, the FTI lonafarnib did not inhibit phosphorylation of ERK or AKT but of p70S6K, a downstream target of Rheb and mTOR signaling. Conclusions: These data suggest that lonafarnib sensitizes melanoma cells to sorafenib by inhibiting mTOR signaling via inhibition of Rheb farnesylation. No significant financial relationships to disclose.
A phase II multicenter study of cetuximab monotherapy in patients with EGFR-undetectable refractory metastatic colorectal carcinoma (mCRC)
Authors: R. Wierzbicki, D. J. Jonker, M. J. Moore, S. R. Berry, P. J. Loehrer, F. Fox, T. Katz, E. K. Rowinsky, H. Youssoufian
Journal: Journal of Clinical Oncology (2008)

4065 Background: Cetuximab is a chimeric IgG1 Mab that targets the human epidermal growth factor receptor (EGFR). Most clinical trials using cetuximab in mCRC treated patients (pts) with EGFR positive tumors determined by immunohistochemistry (IHC). The intensity of EGFR immunostaining (IS) has not been related to the activity of cetuximab, and objective responses have been reported in pts with EGFR negative tumors. Potential reasons will be presented. Methods: This phase II multicenter study enrolled pts with refractory EGFR-undetectable mCRC who have received at least 1 standard fluoropyrimidine-containing chemotherapy regimen and an ECOG PS<2. Local results of EGFR by IHC were confirmed centrally. EGFR-undetectable disease is defined as no membrane staining above background for all tumor cells examined in a well preserved tissue section. Pts received weekly cetuximab infusions (400/250mg/m2 initial/weekly dose) and were evaluated for tumor response every 6 weeks. The primary outcome was overall response rate (ORR), and secondary outcomes included disease control rate, time to progression, survival, and safety. Results: 85 of the 88 patients enrolled received at least 1 dose of cetuximab and are evaluable for response. 86% of patients failed both oxaliplatin- and irinotecan-containing regimens, whereas 7%, 6%, and 1% failed only irinotecan-, oxaliplatin-, or fluoropyrimidine-containing regimens, respectively. To date, 6 pts had confirmed partial responses (PR): ORR=7% (95% CI=3–15%) as assessed by investigator. One pt has an unconfirmed PR and 7 pts are ongoing. There have been 4 cetuximab-related adverse events (Aes)>grade 3: infusion related reaction, hypomagnesaemia, dyspnea and skin rash. Two pts discontinued treatment due to Aes: 1 each with an infusion related reaction (above) and a small bowel obstruction. Efficacy endpoints will also be determined by an independent review. Conclusions: These preliminary results indicate that cetuximab monotherapy is active in refractory mCRC pts with EGFR undetectable disease. This activity is comparable to cetuximab monotherapy in EGFR-detectable, refractory mCRC, confirming that EGFR IHC is an unreliable indicator of cetuximab activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ImClone ImClone ImClone
Correlation of global expresssion of ERCC1 in head and neck squamous cell carcinoma with prognosis
Authors: E. Saada, J. Thariat, F. Ettore, A. Sudaka, E. Chamorey, A. Italiano, G. Poissonet, R. Bensadoun, O. Dassonville, F. Peyrade
Journal: Journal of Clinical Oncology (2009)

e17016 Background: The overexpression of excision repair cross-complementation group 1 (ERCC1), element of the Nucleotid Excision Repair (NER) pathway has been associated with resistance to platinum-based chemotherapy. We studied the correlation of ERCC1 immunohistochemical expression with overall survival and cancer-specific survival in patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) treated with cisplatin-based chemotherapy. Methods: Using a monoclonal antibody against ERCC1 (clone 8F1, Neomarker), we analyzed its immunohistochemical expression in pretherapeutic samples of 142 HNSCC patients treated in our center from 2000 to 2006. Forty-three patients were treated with surgery followed by adjuvant radiochemotherapy, 86 with concomitant radiochemotherapy with or without neoadjuvant chemotherapy and 13 with cisplatin-based chemotherapy for metastatic disease. Two independent observers blinded to clinical data evaluated ERCC1 expression using the H-score protocol (ranging from 0 to 3). Survival rates were estimated using the Kaplan-Meier method. Survival univariate analysis was performed using log-Rank test. Results: ERCC1was expressed intensively and diffusely in the nuclei 89% of the tumor samples had an H-score at least equal to 2. Treatment type and metastatic status were predictive of overall survival (respectively, p = 0.003 and p = 0.005). Higher expression of ERCC1 tended to be correlated with longer overall survival (p = 0.08). Conclusions: Our observations are at variance with recently published data about the predictive role of ERCC1 (Handra Luca CCR 2008). Overexpression of ERCC1 has also been associated with better outcome of operated NSCLC. Such differences may be due to inherent biological differences between study populations and certainly attributable to different roles of ERCC1 through oncogenesis.These controversial correlative results among studies and the intense and diffuse patterns of ERCC1 expression might also indicate a central role of ERCC1 in HNSCC oncogenesis and then provide a potential target. Further investigations about the role and predictive value of ERCC1 protein in anticancer treatments including cisplatin are warranted. No significant financial relationships to disclose.
Immune response to Gastrin-17 is an independent covariate in determination of survival in colorectal, gastric and pancreatic cancers
Authors: P. Broome, R. D. Buck, D. Michaeli
Journal: Journal of Clinical Oncology (2004)

4073 Background: Many gastrointestinal (GI) cancers express the gastrin CCK2 receptor and are sensitive to the mitogenic effects of autocrine/endocrine Gastrin-17 (G17). The immunogen G17DT elicits antibodies that neutralize G17, thereby blocking its proliferative activity. We analyzed the data from three clinical trials in three different GI cancers to determine the extent of dependence of the effect of the G17DT antibody response on survival from general health status. Methods: A G17 immune responder was defined as a subject with an anti-G17 titer > 1 ELISA unit. The relationships of demographics, tumor stage at onset, number and location of metastases, baseline Karnofsky performance status (KPS) and laboratory values to immune response were examined in each study; their joint relationships with immune response on survival was analyzed using Cox regression analysis. Results: In 158 metastatic colorectal cancer patients who had previously failed chemotherapy, median survival (MS) was 227 days; MS of G17 responders was 249 days vs. 119 days for non-responders (p<0.001, log-rank). For 102 advanced gastric cancer patients on chemo-immunotherapy, MS was 265 days; for G17 responders, 303 days vs. 70 days for non-responders (p<0.001, log-rank). In a placebo-controlled trial in 152 stage II-IV pancreatic cancer patients, MS was 111 days; MS of G17 responders was 176 days, of non-responders 63 days and of the placebo group 83 days (p=0.028, log-rank). With the exception of race (for colorectal cancer) and KPS, no parameter significantly affected the antibody response to G17. After adjustment for KPS (from 70–100%) the anti-G17 response remained a significant determining factor for survival in a Cox proportional hazards model (p<0.001) in all 3 trials. Conclusions: Subjects with advanced colorectal, gastric or pancreatic cancers, who generated antibodies to G17 following immunization with G17DT, had a significantly prolonged survival compared to those who did not. This effect was independent of other covariates analyzed. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aphton Corp. Aphton Corporation
A Validated Scoring System to Predict Proximal Neoplasia for Colorectal Cancer Screening
Authors: Martin C.S. Wong, Jessica Y.L. Ching, Jeffrey P. Shum, Victor C.W. Chan, Thomas Y.T. Lam, Arthur K.C. Luk, Sunny H. Wong, Siew C. Ng, Simon S.M. Ng, Justin C.Y. Wu, Francis K.L. Chan, Joseph J.Y. Sung
Journal: Clinical Gastroenterology and Hepatology (2015)
Effect of alternating combination chemotherapy on survival of ambulatory patients with metastatic large-cell and adenocarcinoma of the lung. A Southwest Oncology Group Study.
Authors: T P Miller, T T Chen, C A Coltman, R M O'Bryan, R B Vance, G B Weiss, W S Fletcher, R L Stephens, R B Livingston
Journal: Journal of Clinical Oncology (1986)

Using a randomized prospective trial design, chemotherapy with 5-fluorouracil, vincristine, and mitomycin C (FOMi) was compared with cyclophosphamide, doxorubicin, and cisplatin (CAP) and with FOMi alternating with CAP (FOMi/CAP) in 452 eligible patients with metastatic large-cell undifferentiated and adenocarcinoma of the lung. Objective responses were obtained in 26%, 17%, and 22% of patients treated with FOMi, CAP, and FOMi/CAP, respectively. The median survival was similar for FOMi, CAP, and FOMi/CAP therapies (20, 24, and 23 weeks, respectively), but the overall survival (log rank test), 1-year survival, and remission duration were longer for FOMi/CAP-treated patients. Survival was significantly longer for fully ambulatory FOMi/CAP-treated patients compared with either FOMi (P = .01) or CAP (P = .04). Younger patients treated with full doses of therapy responded more often than older patients receiving reduced drug doses (26% and 11%, respectively; P = .003). A prognostic factor regression analysis of all eligible patients indicates that sex, performance status, stage, and treatment assigned were important independent variables determining survival (P less than .05). Toxicity was comparable in each treatment group.
Abstract 13830: Impact of Atrial Fibrillation on Clinical Outcome of Femoropopliteal Artery Intervention in Critical Limb Ischemia
Authors: Hiroyuki Jinnouchi, Yoshimitsu Soga, Yohei Kobayashi, Yusuke Tomoi
Journal: Circulation (2014)

Introduction: Clinical outcome of patients with atrial fibrillation (AF) after endovascular therapy for critical limb ischemia (CLI) is unclear. The aim of this study was to investigate if atrial fibrillation (AF) influences clinical outcomes after femoropopliteal artery intervention in patients with CLI. Methods: A retrospective review of all patients undergoing femoropopliteal artery intervention for CLI was performed. We compared clinical outcome between patients with and without AF. The primary endpoint was amputation free survival (AFS). The secondary endpoints were overall survival, limb salvage, freedom from repeat revascularization, and freedom from surgical conversion were compared between two groups. Kaplan-Meier analyses were performed to assess time-dependent outcomes. Factor analyses were performed using a Cox proportional hazard model for time-dependent variables. Results: A total of 398 limbs with 342 patients were performed with femoropopliteal artery intervention in patients with CLI. (male 58.4%, 73.9±10.8 years old, mean follow up 17 months; interquartile range 5-32 months). We identified 58 limbs with AF, 340 without AF. At median follow-up period, AFS and overall survival was significantly lower in patients with AF (51.0 % vs 70.5 % P=0.0004 by log-rank, 53.9 % vs 77.1 % P&lt;0.0001; relatively). Other outcomes were not significantly different between the groups. Risk-adjusted Cox proportional hazards regression showed that AF predicts poor AFS and overall survival (hazard ratio [HR], 1.59; 95% confidential interval [CI] 1.01-2.43; adjusted P=0.044, HR, 1.89; 95%CI, 1.19-2.98; adjusted P=0.008). Conclusion: AF may worse AFS and overall survival rate in patients who underwent femoropopliteal intervention in CLI.
High-dose chemotherapy with autologous stem cell transplantation for relapsed Ewing's sarcoma
Authors: E. Palmerini, A. Brach Del Prever, F. Fagioli, R. Luksch, A. Prete, A. Tamburini, M. E. Abate, P. Picci, S. Ferrari, A. Tienghi
Journal: Journal of Clinical Oncology (2009)

10545 Background: Nearly 30–40% of patients with newly diagnosed, non-metastatic Ewing's Sarcoma (EWS) relapse. Post-relapse survival (PRS) in EWS is very poor, with less than 15–20% alive 5-years after recurrence. The role of high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is under investigation in metastatic and high risk localized EWS patients. In order to improve PRS, we employed HDCT with ASCT in EWS patients at 1 st relapse. Methods: All non-metastatic EWS patients treated in Italian Sarcoma Group centers who relapsed between 1999 and June 2008 were offered HDCT (busulfan 4 mg/kg × 4 days orally and melphalan 140 mg/m 2 ) with ASCT whenever possible (no previous HDCT; stable or responding disease after standard dose chemotherapy; adequate peripheral blood stem cells harvest). Results: 72 EWS patients experienced disease recurrence. Fifty (62%) were male. Twenty-eight (39%) of patients had previously received HDCT. Median relapse free interval (RFI) was 16 months (2.8–64). Pattern of relapse was: lung metastases in 20 (28%) patients, bone metastases in 12 (16%), local recurrence in 11 (15%) and multiple sites in 29 (40%). Treatment at 1 st relapse was: standard dose chemotherapy in 31 (43%) patients; HDCT followed by ASCT in 24 (33%); palliative treatment in 12 (17%) and surgery only in 5 (7%). Three patients died of treatment-related toxicity. With a median follow-up of 24 months (1–64), the 3-year post-relapse survival (PRS) was 21% (95%CI 7–35). 3-year PRS was better for patients with a lung only relapse [48%, (95%CI 21–74)] and a RFI &gt; 2 years [51%, (95%CI 27–76)]. 3-year PRS was 33% (95%CI 13–54) for patients treated with HDCT and 22% (95%CI 6–39) for those receiving standard dose chemotherapy. A significant (P 0.02) advantage was observed in the subgroup of patients with a shorter RFI treated with HDCT [3-year PRS 29% (95%CI 5–52)] compared to those treated with standard dose chemotherapy [3-years PRS 13%, (95%CI 2–29)]. Conclusions: Pattern of recurrence and RFI are the main factors influencing PRS in EWS. The use of HDCT with ASCT in recurrent EWS is investigational. Patients with shorter RFI could more likely benefit from HDCT. No significant financial relationships to disclose.
Prediction of residual retroperitoneal mass histology following postchemotherapy retroperitoneal surgery for metastatic nonseminomatous germ cell tumors: Role of MDR-1 and mismatch repair genes
Authors: A. N. Heidenreich, D. Pfister, D. Thüer, U. H. Engelmann, C. H. Ohlmann
Journal: Journal of Clinical Oncology (2007)

5088 Background: Following inductive chemotherapy for metastatic nonseminomatous germ cell tumours (NSGCT) about 35% and 15% of patients undergoing residual tumor resection (RTR) demonstrate mature teratoma and vital cancer, respectively. It was the aim of our study to evaluate the expression of mdr-1, hMLH1 and hMLH2 in primary NSGCT and their resected residual tumors. Methods: 185 patients with NSGCT underwent RTR of retroperitoneal masses. Immunohistochemical investigations of mdr-1, hMLH1/2 were performed on paraffin-embedded tissue section of the primary tumour and the resected lymph nodes using monoclonal, commercially available antibodies. Staining was analysed according to a semiquantitative scoring system; furthermore, detailed morphometry was performed. Preoperative serum and clinical parameters were assessed to predict necrosis/fibrosis or teratoma in residual tumors. Statistical analysis was performed by uni- and multivariate analysis to correlate data with histology of the RTR specimens. Parameters were statistically significant if p&lt;0.05. Results: A total of 122 patients (65.9%) had necrosis, 23 patients (12.4%) and 40 patients (21.6%) had viable cancer and mature teratoma, resp. After multivariate analysis pre-chemotherapeutic AFP-levels, tumor size before RTR, mature teratoma in the primary and mdr-1 expression in the primary were independent predictors of final necrosis. Positive predictive values were 74%, 76%, 78% and 88% resp., sensitivity was 81%, 52.8%, 65% and 86%, resp.; specificity was 59%, 79.3%, 81% and 90% resp.. Nonseminomatous elements demonstrated a significantly higher staining intensity for hMLH1 than seminomas, whereas staining intensity for hMLH2 was lower (p=0.03). IHC for hMLH1/2 of GCT with necrosis was higher as compared to GCT exhibiting mature teratoma or vital cancer approaching statistical significance (p=0.07). Conclusions: Pre-chemotherapy AFP levels &lt; 15 ng/ml and a residual mass &lt; 2 cm are associated with a favourable histology in the RTR specimen. The addition of mdr-1 expression in the primary NSGCT improves sensitivity to 88% and represents a clinically useful prediction marker. No significant financial relationships to disclose.