tbuckley/cabot-search huggingface dataset:
Efficacy and safety of first-line bevacizumab (BEV) plus interferon-α2a (IFN) in patients (pts) ≥65 years with metastatic renal cell carcinoma (mRCC)
Authors: E. Bajetta, A. Ravaud, S. Bracarda, S. Négrier, C. Szczylik, J. Bellmunt Molins, N. Moore, P. Pisa, B. J. Escudier
Journal: Journal of Clinical Oncology (2008)

5095 Background: BEV is an antibody which directly inhibits VEGF, a key mediator of angiogenesis. A double-blind phase III trial evaluated BEV in combination with IFN as first-line treatment for mRCC (AVOREN). Efficacy and safety data for pts ≥65 years are reported. Methods: Pts with clear-cell mRCC, prior nephrectomy, no prior systemic therapy for metastatic disease, KPS ≥70%, no CNS metastases and adequate organ function received IFN three times per week (at an aimed starting dose of 9 MIU for ≤1 year) plus BEV (10mg/kg every 2 weeks) or placebo (PL) until disease progression. In a prespecified subgroup analysis, efficacy and safety outcomes were assessed according to age. Results: Between June 2004 and October 2005, 649 pts were randomised; 327 pts received BEV/IFN, and 322 received IFN/PL. The progression-free survival (PFS) benefit due to BEV was similar in the 239 pts aged ≥65 (HR=0.77; 95% CI: 0.58–1.03) and the 410 pts aged <65 (HR=0.54; 95% CI: 0.43–0.68). The incidence of grade 1–5 adverse events (AEs) was similar between age groups. The incidence of grade ≥3 AEs was higher in pts aged ≥65 years than in pts aged <65 years in both BEV and PL arms (BEV: 66% vs 58%; PL: 48% vs 45%) with a higher incidence of fatigue in pts aged ≥65 years in both arms, and a higher incidence of asthenia in the BEV arm. Conclusions: Despite an increase of fatigue and asthenia, pts aged ≥65 years benefit to a similar extent from BEV/IFN therapy compared with pts <65 years of age. Grade ≥3 AE (>4% incidence in BEV arm) Grade ≥3 AE n (%) <65 years IFN+PL(n=204) <65 years BEV+IFN(n=206) ≥65 years IFN+PL(n=118) ≥65 years BEV+IFN(n=121) Fatigue 15 (7) 18 (9) 11 (9) 22 (18) Asthenia 16 (8) 15 (7) 6 (5) 17 (14) Proteinuria 0 14 (7) 0 8 (7) Anaemia 10 (5) 4 (2) 7 (6) 5 (4) Hypertension 1 (<1) 8 (4) 1 (<1) 4 (3) Neutropenia 7 (3) 6 (3) 2 (2) 7 (6) Influenza-like illness 5 (2) 3 (1) 1 (<1) 7 (6) Anorexia 5 (2) 4 (2) 3 (3) 6 (5) Depression 3 (1) 4 (2) 1 (<1) 6 (5) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Bayer, Inate Pharma, Pfizer, Roche, Schering-Plough, Wyeth Roche Antigenics, Bayer, Genentech, Novartis, Pfizer, Roche, Wyeth GlaxoSmithKline, Roche Bayer, Novartis, Pfizer
Final hematologic results: Epoetin alfa (EPO) 40,000 U QW vs darbepoetin alfa (DARB) 200 μg Q2W in anemic cancer patients (pts) receiving chemotherapy (CT)
Authors: R. J. Waltzman, C. Croot, D. Williams
Journal: Journal of Clinical Oncology (2005)

8030 Background: We report final results of a trial comparing hematologic outcomes, QOL, & safety for EPO & DARB using dosing regimens commonly prescribed in anemic pts with cancer receiving CT. Methods: Randomized, open-label trial enrolled pts ≥18 y with solid tumors, baseline (BL) hemoglobin (Hb) ≤11 g/dL, scheduled for ≥12 weeks (wks) of CT. Pts were stratified by +/− platinum CT, then randomized to EPO 40,000 U SC QW or DARB 200 μg SC Q2W for 12–16 wks; dose adjustments per NCCN guidelines. 150 pts per arm ensured 90% power to detect ≥20% difference in primary endpoint, Hb response rate (HRR; proportion of pts with Hb increase ≥1 g/dL within first 4 wks). Interim analysis of primary endpoint was planned after first 300 pts completed 4 wks. If HRR was statistically greater (P<.0125, 1-sided) for EPO compared with DARB, the null hypothesis would be refuted & enrollment would be terminated. Results: 358 pts were randomized to EPO (178) or DARB (180). Primary endpoint achieved based on interim analysis of first 305 pts (EPO 151, DARB 154) demonstrating HRR was significantly higher for EPO (47%) vs DARB (33%) (P=.0078, 1-sided). Analyses of secondary endpoints were performed on 352 (EPO 175, DARB 177) pts with ≥1 post-BL Hb or transfusion (TFN). Mean BL Hb was 10.2 g/dL (EPO) & 10.1 g/dL (DARB). Mean Hb change, median time to 1-g/dL rise, & % of pts with ≥2-g/dL rise are reported below using last value carried forward. Incidence of RBC TFN from wk 5 to end of study was 11% (EPO) & 16% (DARB) (P=.2078). Preliminary (exploratory) analysis of QOL suggested change scores were similar between groups. Clinically relevant thrombovascular events occurred in 11% of EPO & 9% of DARB pts. 13% of EPO & 16% of DARB pts died on study. Conclusions: This comparative trial in pts with CT-induced anemia demonstrated that Hb response rates were higher & time to 1-g/dL Hb rise was shorter in pts treated with EPO 40,000 U QW compared with DARB 200 μg Q2W. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ortho-Biotech/ Johnson & Johnson Johnson & Johnson Pharmaceutical Services Amgen, Johnson & Johnson Pharmaceutical Services, Ortho-Biotech/ Johnson & Johnson Johnson & Johnson Pharmaceutical Services, Ortho-Biotech Johnson & Johnson Pharmaceutical Services Ortho-Biotech/ Johnson & Johnson
Single agent vs combination chemotherapy (CT) as second-line treatment of advanced non-small-cell lung cancer (NSCLC): A meta-analysis of individual data of five randomized trials
Authors: M. Di Maio, P. Chiodini, V. Georgoulias, D. Hatzidaki, K. Takeda, F. M. Wachters, V. Gebbia, A. Morabito, F. Perrone, C. Gridelli
Journal: Journal of Clinical Oncology (2008)

8052 Background: Doublet CT is more effective than single-agent as first-line treatment of advanced NSCLC. As second-line treatment, despite several randomized trials have been performed comparing single agent with combination CT, each single trial had an insufficient power to detect potentially relevant differences in survival. Methods: We performed a meta-analysis based on individual patient data from randomized trials, both published and unpublished, comparing single agent with combination CT as second-line treatment of advanced NSCLC. Baseline characteristics, treatment assigned and outcome data were collected for each patient. Primary endpoint was overall survival (OS). All statistical analyses were stratified by trial. OS curves were compared using the log-rank test. Response rate and toxicities were compared using the Mantel-Haenszel Chi-square test. Chi-square tests for heterogeneity were used to detect differences in treatment effect among the trials. Results: Six eligible trials were identified, for a total of 738 pts. Data of one trial (130 pts) were not available. Data of the other 5 trials (608 pts) were collected. 307 pts had been assigned to single agent, and 301 to combination CT. Median age was 61 years (34–78). Performance Status (PS) was 0 in 30%, 1 in 59% and 2 in 11%; 72% of pts had received previous platin-based CT. With 465 deaths recorded (76%), median OS was 35.0 weeks with single agent, and 37.9 weeks with combination CT (p = 0.70). There was no significant heterogeneity among the five trials. No relevant differential effect was detected in subgroup analyses. Response rate was 8% and 14%, with single agent and combination CT, respectively (p = 0.01). Median progression-free survival was 10.9 and 12.4 weeks, for single agent and combination CT, respectively (p = 0.06). Pts treated with combination CT had significantly more grade 3–4 hematological (45% vs 31%, p<0.0001) and grade 3–4 non-hematological toxicity (33% vs 24%, p = 0.01). Conclusion: Combination CT as second-line treatment of advanced NSCLC slightly increases response rate, but is more toxic and does not improve survival compared to single agent. No significant financial relationships to disclose.
Existence of blood brain barrier in brain metastases with breast cancer
Authors: M. Ono, K. Tsuta, K. Yonemori, C. Shimizu, S. Shibui, T. Kouno, M. Ando, K. Tamura, N. Katsumata, Y. Fujiwara
Journal: Journal of Clinical Oncology (2008)

13513 Background: Increasing of the incidence of brain metastases in breast cancer patients is an important clinical problem. Brain metastases are refractory to chemotherapy due to existence of blood brain barrier (BBB). However, the structure and mechanism of BBB is not fully understood. We examine expression and localization of BBB with representative immunohistochemical markers of glucose transporter 1 (Glut-1) and breast cancer resistance protein (BCRP) in brain metastases with breast cancer patients. Methods: Between 1999 and 2006 at National Cancer Center Hospital in Japan, 29 patients who had metastatic breast cancer underwent metastatic brain tumor excision. Glut-1 and BCRP expression of brain metastases in 29 patients were examined by immunohistochemistry. We also performed the immunohistochemical analyses for estrogen receptor (ER), progesterone receptor (PgR), HER2 and phosphohistone-H3 (PHH3). If intratumoral microvessels in brain metastases were negative for both Glut-1 and BCRP, we regarded as absence of BBB. Results: Nine (31%) and eleven (38%) out of total 29 in tumor microvessels were negative for Glut-1 and BCRP, respectively. Eight (28%) were negative for both Glut-1 and BCRP. There was significant association between Glut-1 and BCRP (p=0.0001). Glut-1 was significantly associated with HER2 (p=0.004). BBB had no correlation with ER and PgR. PHH3 was not associated with BBB. Conclusions: BBB was absent in 8 (28%) out of total 29 in brain metastases with breast cancer. Although further studies are warranted, drug bioavailability to tumors may be also different in brain metastases of breast cancer. No significant financial relationships to disclose.
Macula Densa Nitric Oxide Synthase 1β Protects against Salt-Sensitive Hypertension
Authors: Yan Lu, Jin Wei, David E. Stec, Richard J. Roman, Ying Ge, Liang Cheng, Eddie Y. Liu, Jie Zhang, Pernille B. Laerkegaard Hansen, Fan Fan, Luis A. Juncos, Lei Wang, Jennifer Pollock, Paul L. Huang, Yiling Fu, Shaohui Wang, Ruisheng Liu
Journal: Journal of the American Society of Nephrology (2015)

Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses α -, β -, and γ -splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1 β expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1 β expression in the macula densa affects sodium excretion and salt-sensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1 β mRNA and protein were 30- and five-fold higher, respectively, than those of NOS1 α in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1 α -knockout (NOS1 α KO) mice. Compared with control mice, mice with macula densa–specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice ( P &lt;0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice ( P &lt;0.01) fed a high-salt diet. These results indicate that NOS1 β is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.
Outcome-impact of a cervical cancer (CC) screening program (SP) in a developing country
Authors: J. J. Zarba, S. Holgado, M. Sanchez Segura, A. Gonzalez, C. Lorente, C. Monroy, V. Cano Busnelli, A. Elias
Journal: Journal of Clinical Oncology (2006)

1032 Background: CC is the 2 nd cause of cancer death in women in Argentine. Early detection following screening programs has demonstrated to reduce mortality in CC. The evaluation of the efficacy and efficiency of CC SP is associated with the proportion of positive cases in the smears and with the relation between pre-invasive lesion (CIN III) and invasive carcinoma (IC) in the biopsies done in positive cases. In 1997 a population based CC screening program was started in our province. The objective of this trial was to determinate the relationship between CIN III and IC in the program population and compare this results with this proportion in pre-program years an as an indicator of the quality of the program. Methods: We analyzed 2446 cervix biopsies performed in public Hospitals of Tucuman between 1985 and 2004 (archives of biopsies of the Serv. de Patología del Hosp. Centro de Salud Z. Santillán, Regional M. Belascuain and Hospital Angel C. Padilla), Since 1997 biopsies were done in patients within the SP We analyzed the proportions of pre-invasive lesions (CIN III) and invasive lesions in periods of 4 years. Results: The proportion of CIN III by periods of 4 years was: 85–88: 13%, 90–92: 20%; 93–96: 20%; 97–00 32% and 01–04 37%. The proportion of CIN III in pre-screening years was 21% and during the SP: 54%. Conclusion: These results shows an increase of CIN III over IC which could translate into a better survival. The quality control analysis of the public programs must be central in the public health policy. [Table: see text] No significant financial relationships to disclose.
Predictive value of using beagle dog in assessing relative bioavailability between solid dosage formulations of AMG 706 in patients
Authors: S. Wong, L. Yan, L. Wathen, N. Cauchon, M. Ingram, D. Chang, L. Rosen
Journal: Journal of Clinical Oncology (2005)

3204 Introduction: AMG 706 is a potent, oral, multikinase inhibitor with antiangiogenic and antitumor activity, with high permeability and low solubility. During clinical development, it is not uncommon to change the formulation of orally delivered drugs such as AMG 706. However, clinical studies of anticancer agents, including assessment of relative bioavailability or bioequivalence between formulations, are usually only performed in patients (pts), which greatly complicates study execution. Thus, it is often desirable to assess new formulations in animals before performing such studies in pts. Methods: Before performing relative bioavailability assessment in humans, the pharmacokinetic (PK) profiles of new tablet formulations were assessed in beagle dogs and compared to that from the original capsule formulation. Sufficient PK samples were collected to fully characterize the plasma concentration-time profile for each formulation after gavage administration in dogs in a crossover design under fasting conditions. When the optimized tablet formulation was identified, tablet and capsule formulations (at a dose of 100 mg each) were then compared in a cohort of 12 pts with advanced solid tumors in a crossover manner with a 2–3 day wash-out period. Results: In dogs, after a single 100 mg dose, the mean plasma AUC ratios for tablet regimens B (100 mg tablet) and C (4x25 mg tablets) to capsule regimen A (100 mg capsule) were 1.11 and 1.12, respectively, suggesting comparable PK behavior between tablet and capsule formulations. In the human PK study, the 100 mg tablet and 100 mg capsule were compared; the point estimate of the geometric mean ratio (tablet/capsule) was 1.02 and 1.23 for AUC and Cmax, respectively. These estimates were limited by the number of samples that could be obtained from the cancer pts around Tmax. Conclusions: Oral dosing in cancer pts with a new tablet formulation of AMG 706 resulted in similar circulating concentrations of drug compared to the original capsule formulation. Beagle dogs appear to be a good predictor for the evaluation of the relative bioavailability of new formulations of AMG 706 and could be used for screening before conducting a clinical study in cancer pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen
Gastrectomy in combination with S-1, intravenous, and intraperitoneal paclitaxel: A novel multidisciplinary treatment strategy for gastric cancer with peritoneal metastasis.
Authors: H. Ishigami, J. Kitayama, S. Kaisaki, M. Kato, H. Yamaguchi, K. Otani, T. Kamei, H. Nagawa
Journal: Journal of Clinical Oncology (2010)

e14527 Background: The prognosis of gastric cancer patients with peritoneal metastasis is extremely poor. Neither systemic chemotherapy nor surgery alone prolongs survival of patients significantly. Methods: Patients diagnosed with advanced gastric cancer underwent staging laparoscopy and received chemotherapy when peritoneal dissemination and/or cancer cells on peritoneal cytology were confirmed. The chemotherapy regimen consisted of S-1, weekly intravenous and intraperitoneal paclitaxel, which was verified in our phase II trial (Ann Oncol 2010). S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8. Clinical response of chemotherapy was assessed by computed tomography, gastroendoscopy, peritoneal cytology and second-look laparoscopy. Radical gastrectomy was performed when macroscopic curative resection was made achievable after the chemotherapy. Chemotherapy was restarted after operation as soon as possible. Overall survival, relapse free survival, morbidity and mortality of gastrectomy were evaluated. Results: Out of 62 patients with peritoneal metastasis, 32 patients, including 26 with macroscopic metastasis and 6 with positive peritoneal cytology only, underwent gastrectomy after response to chemotherapy. A median of 3 courses were administered preoperatively (range 1-16). Total or distal gastrectomy with lymph node dissection was performed in 28 or 4 patients, respectively. The median survival time was 34.5 months (95% CI, 23.6 months-not reached), and the 2-year overall survival rate was 64% (95% CI, 45-82%). The median relapse free survival was 22.9 months (95% CI, 13.8-29.8 months). Postoperative complications included anastomotic leakage and pancreatic fistula in 2 patients each, which could be treated conservatively. There were no treatment-related deaths. Conclusions: Gastrectomy combined with S-1, intravenous and intraperitoneal paclitaxel is a safe and effective strategy for gastric cancer with peritoneal metastasis. No significant financial relationships to disclose.
Epirubicin (E) cardiac toxicity: A retrospective analysis of 1,097 patients (pts) treated for metastatic breast cancer (MBC)
Authors: M. Ryberg, D. L. Nielsen, G. Cortese, G. Nielsen, P. K. Andersen, T. Skovsgaard
Journal: Journal of Clinical Oncology (2007)

1029 Background: The object of the study was to conduct an analysis and assess a recommended cumulative dose of E corresponding to a 5 % risk for cardiotoxicity taking into account: dose administrations, concurrent risk of dying of MBC and possible predictors of cardiotoxicity. Methods: Data from 1097 consecutive anthracycline naïve pts was retrieved. Pts developing cardiac heart failure according to New York Heart Association (NYHA) Class =II were recorded as having E cardiotoxicity. Statistics: two extended Cox multivariate analysis (events: cardiotoxicity and mortality of MBC) followed by competing risk analysis. Results: 125 pts (11.4%) developed cardiotoxicity. Predictors for increasing the cardiotoxicity hazard ratio (HR) were: 1. cumulative dose of E: as the rate increased with 37% per every 100 mg/m 2 E, when given as first line treatment for advanced disease, 2. increasing age as the rate increased with 28.7 % per additional 10 year, 3. x-ray including the heart (HR=2.08), 4. tamoxifen for relapse (HR=1.87), 5. pre-disposition to cardiac disease (HR=3.01). Mortality rate for MBC: the survival was significant lower in pts with increasing tumour burden, poorer performance status, previous adjuvant CMF, and with increasing age. The HR for mortality was significantly increased by increased duration of treatment with E and was highest in the first three months than later on. The risk of cardiotoxicity increased mostly during the first 8 months after cessation of E nearly becoming constant later on. The cumulative dose of E corresponding to a 5 % cardiotoxicity risk was found to be both significantly lower than previously assumed (900 mg/m 2 ) and depend on predictors for mortality and cardiotoxicity. Thus, a pts with no predictors at age 40 the level of 5% risk was 806 mg/m 2 , at age 50 = 739 mg/m 2 , at age 60 = 673 mg/m 2 and at age 70 = 609 mg/m 2 . Conclusion: The risk of cardiotoxicity of E was more pronounced than expected and occurred on a much lower cumulative dose of E. Increasing age, x-ray, tamoxifen and pre-disposition to cardiac disease contributed significantly to this. No significant financial relationships to disclose.
Targeting the PI3K/AKT/mTOR pathway with MLN0128 (mTORC1/2 inh) and MLN1117 (PI3K alpha inh) in bladder cancer: Rational for its testing in clinical trials.
Authors: Alejandro Martinez, Anna Hernandez, Oriol Arpi, Silvia Menendez, Natalia Iarchouk, Elena Gavilan, Beatriz Bellosillo, Montserrat Arumí, Federico Rojo, Stephanie A. Mullane, Toni K. Choueiri, Ana Rovira, Joan Albanell, Rachael Brake, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2015)

369 Background: PI3K/AKT/mTOR pathway is a promising target for cancer treatment being commonly deregulated in human bladder tumors and resulting in the promotion of tumor cell growth, survival, and resistance to chemotherapy. The aim of this study is to characterize the effects of MLN0128, a novel mammalian target of rapamycin (mTOR) complex 1 and 2 (mTORC1/2) dual inhibitor, and MLN1117, an orally bioavailable inhibitor of the class I phosphoinositide 3-kinase (PI3K) alpha isoform that may be more efficacious and less toxic than pan-PI3K inhibitors as bladder cancer therapies. Methods: We evaluated the effects of MLN0128 and MLN1117 both as single agents and in combination with each other or with a SOC chemotherapy agent (paclitaxel). The effects of the agents alone or in combination were analysed in a panel of six bladder cancer cell lines and in tumor xenografts. These models were selected based on specific genomic alterations that could be considered as potential therapeutic targets (PIK3CA and TSC mutations). Molecular effects of both agents and the combinations on cell-cycle, apoptosis, autophagy and on cell viability were tested in the bladder cancer cell lines. The in vivo effects on tumor growth inhibition were also assessed. Results: Both MLN0128 and MLN1117 inhibit the PI3K/AKT/mTOR pathway and reduce cell proliferation in bladder cancer cell lines with diverse genetic backgrounds. Combination of MLN0128 + MLN1117 produced synergistic antiproliferative effects in cell lines and improved the effect of each drug alone in vitro and in vivo, with no signs of toxicity in these models. Similar effects were observed with the combination of paclitaxel + MLN0128. Conclusions: Our results show that MLN0128 and MLN1117 are promising investigational agents that might be of value for bladder cancer patients. Further investigation as novel anti-cancer agents alone or in combination with chemotherapy in clinical trials in humans is warranted.