tbuckley/cabot-search huggingface dataset:
A multicenter phase II study of sorafenib in combination with erlotinib in patients with advanced non-small cell lung cancer (NSCLC).
Authors: B. Cho, S. Kim, D. S. Heo, S. Kang, H. Kim, D. Lee, D. Kim, M. Jung, J. Choi, J. Kim
Journal: Journal of Clinical Oncology (2010)

7547 Background: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, we conducted a phase II study to determine the clinical activity of sorafenib in combination with erlotinib in patients with advanced NSCLC. Methods: Pts with advanced NSCLC with measurable disease who have received one or two prior chemotherapy regimens for metastatic disease, ECOG 0-2, and adequate organ function were eligible. Pts received 400 mg twice daily sorafenib and 150 mg daily erlotinib in 28-day cycles. Epidermal growth factor receptor mutation and its downstream pathways were analyzed from available tumor samples. Changes in plasma cytokine and angiogenic factors at day 29 and disease progression from baseline were correlated with clinical outcomes. Results: 46 pts enrolled; median age 56 years; number of prior chemotherapy regimens (two; n = 24); male sex (n = 27); non-adenocarcinoma (n = 11); and ever-smoker status (n = 24). The median number of cycles administered was 3.5 (range, 1-16+). The response rate (primary endpoint) and disease control rate (complete/partial response or stable disease ≥ 90 days) were 30.4% and 63%, respectively. The median duration of response was 97 days. The progression-free survival and overall survival were 183 days and not-reached, respectively. The most frequent adverse events (AEs) of all grades were dermatologic toxicities (63%) followed by gastrointestinal and constitutional in nature. These AEs were predominantly mild to moderate and responded to supportive care. G3/4 hematologic AEs: anemia (1), neutropenia (2). G3/4 non- hematological AEs: diarrhea (2), vomiting (1), rash (4), hypokalemia (1), hypocalcemia (1), elevated LFTs (5) and venous thrombosis (1). No serious bleeding event occurred, with minor mucocutaneous bleeding in 16 (35%) pts. Results from biomarker analyses will be presented at the conference. Conclusions: Sorafenib combined with erlotinib appears to be effective against advanced NSCLC. Further randomized trials are needed to confirm this finding. No significant financial relationships to disclose.
HCVerso2: a phase III study of faldaprevir plus deleobuvir and ribavirin for chronic HCV genotype 1b infection in treatment naïve patients including those ineligible for pegylated interferon
Authors: D Nelson, P Andreone, M Colombo, F Calinas, A Olveira, Jean Delwaide, D Haussinger, D Ouzan, S Strasser, T Asselah, C Cooper, J Stern, W Boecher, G Kukolj, S Aslanyan, Q Deng, E Wang, F Mensa
Journal: Hepatology (2014)
JNK Activation and Fas Up-Regulation Precede Proteasomal Degradation of Topoisomerase I in SN38-Mediated Cytotoxicity Against Multiple Myeloma.
Authors: Laurence Catley, Yu-Tzu Tai, Reshma Shringarpure, Renate Burger, Moni Son, Klaus Podar, Dharminder Chauhan, Teru Hideshima, Louis Denis, Paul G. Richardson, Nikhil C. Munshi, Kenneth C. Anderson
Journal: Blood (2004)
HIF-2α-mediated induction of pulmonary thrombospondin-1 contributes to hypoxia-driven vascular remodelling and vasoconstriction
Authors: David Labrousse-Arias, Raquel Castillo-González, Natasha M. Rogers, Mar Torres-Capelli, Bianca Barreira, Julián Aragonés, Ángel Cogolludo, Jeffrey S. Isenberg, María J. Calzada
Journal: Cardiovascular Research (2015)

Hypoxic conditions stimulate pulmonary vasoconstriction and vascular remodelling, both pathognomonic changes in pulmonary arterial hypertension (PAH). The secreted protein thrombospondin-1 (TSP1) is involved in the maintenance of lung homeostasis. New work identified a role for TSP1 in promoting PAH. Nonetheless, it is largely unknown how hypoxia regulates TSP1 in the lung and whether this contributes to pathological events during PAH.In cell and animal experiments, we found that hypoxia induces TSP1 in lungs, pulmonary artery smooth muscle cells and endothelial cells, and pulmonary fibroblasts. Using a murine model of constitutive hypoxia, gene silencing, and luciferase reporter experiments, we found that hypoxia-mediated induction of pulmonary TSP1 is a hypoxia-inducible factor (HIF)-2α-dependent process. Additionally, hypoxic tsp1(-/-) pulmonary fibroblasts and pulmonary artery smooth muscle cell displayed decreased migration compared with wild-type (WT) cells. Furthermore, hypoxia-mediated induction of TSP1 destabilized endothelial cell-cell interactions. This provides genetic evidence that TSP1 contributes to vascular remodelling during PAH. Expanding cell data to whole tissues, we found that, under hypoxia, pulmonary arteries (PAs) from WT mice had significantly decreased sensitivity to acetylcholine (Ach)-stimulated endothelial-dependent vasodilation. In contrast, hypoxic tsp1(-/-) PAs retained sensitivity to Ach, mediated in part by TSP1 regulation of pulmonary Kv channels. Translating these preclinical studies, we find in the lungs from individuals with end-stage PAH, both TSP1 and HIF-2α protein expression increased in the pulmonary vasculature compared with non-PAH controls.These findings demonstrate that HIF-2α is clearly implicated in the TSP1 pulmonary regulation and provide new insights on its contribution to PAH-driven vascular remodelling and vasoconstriction.
Diagnosis of invasive fungal infections by RQ-PCR assay in pediatric acute leukemia induction.
Authors: S. Mandhaniya, S. Iqbal, S. K. Sharawat, I. Xess, S. Bakhshi
Journal: Journal of Clinical Oncology (2010)

9579 Background: Sensitive and specific diagnostic tools for invasive fungal infections (IFI) in acute leukemia (AL) patients are lacking. Blood cultures are often negative and performing invasive procedure is difficult in critically ill patients. Studies on fungal DNA detection by RQ- PCR in childhood leukemia induction are lacking. Pan-AC PCR assay used in present study targets 28S subunit of fungal rDNA and detects 10 Candida and 6 Aspergillus species Methods: Out of 100 randomized pediatric AL patients receiving antifungal prophylaxis with voriconazole/ amphotericin B, single peripheral whole blood sample in EDTA was used for RQ-PCR assay in patients who failed prophylaxis due to proven, probable, possible or suspected fungal infections (FI). PCR results were retrospectively correlated with clinical profile Results: Single reaction RQ-PCR test was positive in 18/29 (62%) patients who failed prophylaxis. In the only patient with proven FI (mucormycosis), RQ-PCR assay was negative. No patient had probable FI. RQ-PCR was positive in 2/4 (50%) patients with possible and 16/24 (66.6%) suspected FI and 4/10 (40%) patients with pneumonia. By applying method A/B (Maertens et al, Blood 2001), sensitivity and positive predictive value (PPV) could not be commented due to no proven Aspergillus or Candida infections; specificity and negative predictive values (NPV) were 41% and 100% respectively; by method C (included episodes of possible IFI as true positive), sensitivity, specificity, PPV and NPV were 50%, 36%, 11% and 81% respectively. Two patients died on PCR positive arm as compared to none in PCR negative arm (p=0.218). Total number therapeutic antifungal days were similar in PCR-positive and PCR-negative group (p=0.475). In suspected FI patients, 8/24 (33.3%) were PCR negative and unnecessarily received empirical antifungal therapy (EAFT). Conclusions: RQ-PCR is a practical, rapid, non-invasive screening test for excluding IFI in pediatric AL. The high NPV makes RQ-PCR a promising tool to use this prior to initiating EAFT in antibiotic resistant febrile neutropenic pediatric AL patients; this would avoid toxicity, cost and hospitalization for EAFT (ClinicalTrials.gov identifier:NCT00624143). No significant financial relationships to disclose.
Changes in epidermal growth factor receptor signaling in serum and tumor biopsies obtained from patients with progressive metastatic colorectal cancer (MCRC) treated with gefitinib (ZD1839): an Eastern Cooperative Oncology Group study
Authors: M. L. Rothenberg, B. Lafleur, M. K. Washington, D. E. Levy, S. L. Morgan-Meadows, R. K. Ramanathan, J. D. Berlin, A. I. B. Benson, R. J. Coffey
Journal: Journal of Clinical Oncology (2004)

3000 Background: EGFR is overexpressed in 25–50% of colorectal cancers. This trial was undertaken to determine the clinical and biological effects of gefitinib, a tyrosine kinase inhibitor of EGFR, in patients (pts) with progressive MCRC. Methods: This Phase II trial randomized pts between 250 and 500 mg po qd of gefitinib. When possible, tumor biopsies were obtained pre- and 1-week post-treatment initiation and analyzed using immunohistochemical methods for markers of EGFR activation. Serum was collected and analyzed for major ligands of EGFR: TGFa and amphiregulin by RIA. Results: 115 pts were enrolled and 80 (70%) agreed to undergo tumor biopsies. At least 1 biopsy was obtained in 50 pts (43%) and paired tumor biopsies were obtained per protocol and yielded biological data in approximately 25 patients (21%). The average difference from baseline (post-pre) in biological markers in this last subset of patients is: Although there were no statistically significant differences between pre- and post-treatment serum or tumor markers, some trends were identified when stratified by clinical variables. For example, f-MAPK levels were unexpectedly higher at both baseline and 1 week post-treatment in the group that was progression-free at 2 months.Conclusion: No significant changes were detected in biological indicators of EGFR pathway activation from serum or tumor biopsies obtained before and 1-week after treatment with gefitinib. The data, however, do show trends that might be useful in future studies with larger sample size. This work was supported by the Vanderbilt SPORE in GI Cancer (P50 CA95103), the Eastern Cooperative Oncology Group (U10 CA021115), and K24 CA82301 (to MLR). Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca
Association between skin toxicities and treatment outcomes in patients with pancreatic cancer (PC) receiving erlotinib (E): Memorial Sloan-Kettering Cancer Center (MSKCC) experience.
Authors: Linh My Alejandro, Nelly G. Adel, Eileen Mary O'Reilly, Elyn Riedel, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2012)

294 Background: Rash is a common adverse event of E, an epidermal growth factor receptor (EGFR) inhibitor approved for advanced PC. Clinical trial results have shown that E-related rash grade 2 or higher is associated with a survival benefit in PC. We examined the correlation between all grades of rash and overall survival (OS) in PC patients receiving E at MSKCC. Methods: This was a retrospective single-institution study that included a review of all PC patients treated with E between March 1 st 2005 and December 15 th 2009 at MSKCC. The association of development of rash on OS was examined using a Cox proportional hazards model using development of rash as a time dependent covariate. The associations were examined univariately and after adjusting for gender, race, smoking history, prior lines of treatment for metastatic disease, and chemotherapy. An intervention was defined as a dose change, interruption, discontinuation or medical intervention for rash. Results: N=193 constituted the cohort of analysis. The median age was 64; 116 (60%) were male and 162 (84%) were Caucasian. Most patients (N=111, 58%) did not receive any prior medical treatment for pancreatic cancer. Skin rash occurred in 113 (59%) of patients. The median OS was 6.7 months (95% confidence interval, 5.7-7.9 months). In a univariate analysis, rash was protective compared to no skin rash (Grade 1 HR 0.71; 95% CI 0.50-1.00, Grade 2+ HR 0.57; 95% CI 0.40-0.82; P=0.007). In the multivariate model, rash appeared to have a protective effect on survival, but this was not statistically significant (Grade 1 HR 0.69; 95% CI 0.49-0.97, Grade 2+ HR 0.78; 95% CI 0.48-1.27). Non-medical interventions for rash included dose adjustment (5%), dose interruption (6%) and dose discontinuation (9%). 33 (29%) patients received medical intervention for rash. Conclusions: Our findings suggest that grade 1 or higher E-related rash may be a surrogate for survival. Appropriate symptom interventions are recommended to enhance patient comfort and avoid discontinuation of treatment.
The international Prognostic Index for patients with CLL (CLL-IPI): An international meta-analysis.
Authors: Nadine Kutsch, Jasmin Bahlo, John C. Byrd, Hartmut Dohner, Barbara Eichhorst, Monica Else, Christian Geisler, Michael R. Grever, Stephane Leprêtre, Manuela Bergman, Donna S. Neuberg, David Oscier, Richard Rosenquist, Tadeusz Robak, Tait D. Shanafelt, Stephan Stilgenbauer, Michael J. Hallek
Journal: Journal of Clinical Oncology (2015)

7002 Background: In the era of more effective treatments for CLL, the established clinical staging systems [Rai/Binet] do not accurately discriminate between prognostic groups. There are several new prognostic markers, but no system integrates the major clinical, biological and genetic variables into one widely accepted score. Therefore we performed a comprehensive analysis of 26 prognostic factors to develop an internationally applicable prognostic index for CLL patients (pts) [CLL-IPI]. Methods: Our full analysis set (FAS) was collected from 8 phase 3 trials from France, Germany, UK, USA and Poland [3472 pts at early & advanced stage; median age 61 years (yr) (range 27 - 86); median observation time (OT) 80 months (ms)]. The FAS was randomly divided into training and internal validation datasets [TD, 2308 (67%); IVD, 1164 (33%)]. Methods of multivariable statistics were applied and the main end point was overall survival (OS). Handling of missing data was performed by complete case analysis. The model was externally validated in a third dataset comprised of 845 newly diagnosed CLL pts from Mayo Clinic [median age 62 yr (range 25 - 89); median OT 63 ms]. Results: Based on 1192 (52%) pts from the TD, 5 independent predictors for OS were identified: age, clinical stage, del(17p) and/or TP53 mutation, IGHV mutation status and β2-microglobulin (B2M) level. Using weighted grading, a prognostic index was derived separating 4 different pt groups: low (score 0-1), intermediate (score 2-3), high (score 4-6) and very high risk (score 7-10) with significantly different OS [93%, 79%, 64% and 23% OS at 5 yr for the low to very high risk group respectively, p < 0.001; C-statistic c = 0.72 (95% CI, 0.69-0.76)]. This multivariable model was confirmed on the IVD [575 (49%) pts; c = 0.777 (0.73-0.82)] and the 4 risk groups were reproduced with 97%, 91%, 68% and 21% 5-yr OS [(p < 0.001), c = 0.79 (0.74-0.85)] on the Mayo set. Conclusions: The resulting CLL-IPI combines the most important genetic risk factors (IGHV, del(17p)/TP53 mutation) with clinical stage, age, and B2M into an easily applicable prognostic score for CLL pts. Moreover, it both discriminates between prognostic groups and is informative regarding current treatment recommendations.
Circadian variations in plasma 5-fluorouracil (5-FU) levels during 24-hour infusions
Authors: G. Friberg, P. Schumm, M. J. Ratain, R. L. Schilsky, G. F. Fleming
Journal: Journal of Clinical Oncology (2004)

2055 Background: Plasma 5-FU levels display marked intrapatient variability over 24-hours when the drug is given as a continuous constant-rate infusion. Investigators have attributed such variability to circadian alterations in 5-FU metabolism, though confirmatory studies have been inconsistent. Methods: Solid-tumor patients with hepatic or mild renal dysfunction received weekly 24-hour 5-FU infusions (1000, 1800, or 2600 mg/m2). LV was given simultaneously over 24 hours at 500 mg/m2. The first infusion was randomized to start at 6AM or 6PM, with the second crossed over to the alternate time. Plasma 5-FU and serum cortisol samples were collected at 3-hour intervals (7 samples/treatment) during these first two weekly treatments. Results: Data from 61 patients (111 cycles) were analyzed by regressing log 5-FU level on dose, cycle (first or second), time since start of infusion, and time of day using a marginal model fit via generalized estimating equations. Mean 5-FU levels rose steadily during each infusion by 35% in the 1800 mg/m2 group (p < 0.001) and by 54% in the 2600 mg/m2 group (p < 0.001) but not in the 1000 mg/m2 group. After controlling for this effect, a circadian pattern was observed (p < 0.001) with the peak mean level at 6am and trough level at 3 pm. A 21% difference was measured between the means at these two times. A similar circadian pattern (in both shape and magnitude) was observed in each of the individual organ dysfunction cohorts. Despite these consistent circadian patterns, few of the individual 5-FU profiles conformed to the circadian pattern observed in the mean levels. A preliminary analysis of individual cortisol profiles revealed a large proportion of abnormally elevated 24-hour mean levels and/or diminished amplitudes. Conclusions: Mean plasma 5-FU levels from 61 patients displayed statistically significant variability based solely upon time of day, but this accounts for only a small portion of the intrapatient variability in 5-FU levels, and individual patients rarely exhibited the circadian pattern observed in the mean levels of the group. No significant financial relationships to disclose.
Phase III trial of sunitinib (Su) versus sorafenib (So) in advanced hepatocellular carcinoma (HCC).
Authors: A. Cheng, Y. Kang, D. Lin, J. Park, M. Kudo, S. Qin, M. Omata, S. W. Pitman Lowenthal, S. Lanzalone, L. Yang, M. Lechuga, E. Raymond
Journal: Journal of Clinical Oncology (2011)

4000 Background: The oral multitargeted tyrosine kinase inhibitor Su had antitumor activity in phase II HCC trials, leading to a phase III open-label trial comparing the efficacy and safety of Su with So. Methods: Patients (pts) with advanced HCC, Child-Pugh A, ECOG PS 0/1 and no prior systemic chemotherapy were stratified by geographic region, prior TACE and tumor invasion. Pts were randomized 1:1 to Su 37.5 mg/day or So 400 mg BID. The primary endpoint was overall survival (OS; 1-sided log-rank test; α=0.025, 90% power) with 600 pts/arm required in this superiority/non-inferiority trial design. Secondary endpoints were progression-free survival (PFS), time to progression (TTP) and safety. Efficacy and futility boundaries were set using the Lan-DeMets and O'Brien–Fleming methods for interim analyses. Results: 1,073 pts were randomized (Su 529/So 544) from July 2008 to May 2010. An Independent Data Monitoring Committee stopped the trial early for futility and safety concerns. Pts were notified. Su discontinuation was recommended with the option for investigator discretion in cases of clinical benefit. For Su/So: median follow-up 7.4/7.8 mo; median age 59/59 yr; Asian 76/75%; male 82/84%; ECOG PS 0 53/53%; >3 prior TACE 16/17%; tumor invasion 79/76%; ≥1 dose interruption 69/55% and ≥1 dose reduction 47/69%. Median OS was 8.1/10.0 mo (HR 1.31 [95% CI: 1.13–1.52], P=0.0019); PFS was 3.6/2.9 mo (HR 1.12 [95% CI: 0.98–1.29], P=0.1386) and TTP was 4.1/4.0 mo (HR 1.13 [95% CI: 0.97–1.31], P=0.1785). OS for pts with hepatitis B (Hep B; Su 290/So 288; post hoc analysis) was 7.8/7.9 mo (HR 1.09 [95%CI: 0.9–1.32], P=0.236). In 526/541 pts evaluable for safety, all-causality, grade 3/4 adverse events (AEs) occurred in 82/73% of pts; the most common were thrombocytopenia (19%) and neutropenia (16%) for Su, and skin disorders (21%) for So. Discontinuations due to AEs occurred in 26/23% of pts. Serious AEs were noted in 44/36% of pts, with grade 5 AEs in 18/16%. Conclusions: In advanced HCC, Su failed its primary OS endpoint. However, PFS and TTP results were similar between Su and So. In a Hep-B pt subgroup, no significant difference in OS was detected between Su and So. Su was associated with more frequent toxicities vs So. 65 pts (Su 17/So 48) remain on study.
Cisplatin versus carboplatin-based chemotherapy in inoperable or recurrent urothelial carcinoma: A retrospective analysis
Authors: A. Bamias, E. Kastritis, G. Bozas, V. Koutsoukou, N. Antoniou, H. Katsifotis, K. Konstantinidis, A. Skolarikos, C. Deliveliotis, M. A. Dimopoulos
Journal: Journal of Clinical Oncology (2006)

14558 Background: Cisplatin-based chemotherapy represents the standard for patients with inoperable or recurrent urothelial carcinoma. Carboplatin-based chemotherapy is reserved for not-fit-for-cisplatin patients. Recent data suggest that carboplatin-based chemotherapy may be effective in fit-for-cisplatin patients. We examined the differences in the outcome according to the compound used as first-line treatment. Methods: We selected patients who received first-line combination chemotherapy based on cisplatin or carboplatin. The major end point was survival. Survival curves were estimated with the Kaplan-Meier method, while cox regression analysis was used for multivariate models. Results: 445 patients, treated with cisplatin (330) or carboplatin (115)-based chemotherapy were included in this analysis. After a median follow-up of 52 months, there was no significant difference in survival between the two treatment groups (Table). Subgroup analyses according to PS, distant metastases, Hb, weight loss, showed that the use of cisplatin was independently associated with improved survival only in the PS 2,3 subgroup (see Table). When patients were stratified according to the Bajorin prognostic criteria (PS 0,1 vs. 2,3 and/or distant metastases yes vs. no; J Clin Oncol 1999, 17: 3173), again cisplatin-based chemotherapy was associated with a trend towards improved outcome only in the worst prognostic group (Table). Conclusions: Carboplatin-based chemotherapy may be equally effective to cisplatin-based treatment in patients with inoperable or recurrent urothelial cancer and no or one adverse factors. Cisplatin-based treatment may be beneficial in patients with poor prognosis. Nevertheless, the clinical relevance of this superiority is limited due to the poor outcome and the poor tolerance of cisplatin-based combination chemotherapy in this group of patients. (see Table) Median survival (95% CI) after first-line chemotherapy for advanced urothelial carcinoma. [Table: see text] No significant financial relationships to disclose.