tbuckley/cabot-search huggingface dataset:
NCCAM/NCI phase I study of mistletoe extract and gemcitabine in patients with advanced solid tumors.
Authors: P. J. Mansky, D. B. Wallerstedt, T. Sannes, J. Stagl, L. Johnson, M. R. Blackman, J. L. Grem, S. M. Swain, B. P. Monahan
Journal: Journal of Clinical Oncology (2010)

2559 Background: European mistletoe (viscum album L.) extracts (EMEX) are used for cancer treatment in Europe. Clinical efficacy remains controversial. Controlled safety and toxicity data are lacking. Objectives of this novel phase I dose-escalation study of an EMEX/gemcitabine (GEM) combination were 1) safety, toxicity, and MTD in patients with advanced solid cancers (ASC), 2) neutrophil count recovery, 3) formation of mistletoe lectin antibodies (ML ab), 4) plasma concentrations of IL-6, IL-12, IFNg, and TNF-a, 5) clinical response. Methods: ASC patients (n=44, breast 12, pancreas 10, colorectal 17, NSCLC 5, f:m=21:23, average age 55 years) received escalating doses of EMEX (HELIXOR A, Helixor GmbH, Rosenfeld, Germany) during stage 1 (20-250 mg s.c. daily) and increasing doses of GEM during stage 2 (750 - 1680 mg/m2 over 30 minutes i.v. on day 1 and 8, 3-week cycle) for 3 cycles. GEM plasma concentrations (Cp, baseline and week 8 (stable EMEX dose for 7 days) were determined during stage 1 by HPLC with UV detection. Plasma cytokine and MLab concentrations were measured by ELISA. Results: Five dose-limiting toxicities were observed: grade 4 neutropenia (2), grade 4 thrombocytopenia, grade 3 cellulitis, and grade 4 acute renal failure. GEM 1380 mg/m2 and EMEX 250 mg were the MTD. Of 44 patients 24 developed Non-neutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by EMEX. All patients developed ML3 IgG antibodies. Plasma cytokine concentrations were minimally affected. ANC values showed a trend to increase between baseline and C2 in stage I. Partial response and stable disease were found in 6% and 42% of patients, respectively. All partial responses occurred in patients with pancreatic cancer. Median survival was 190 days. Compliance with EMEX injections varied from 78.6-100%. Conclusions: The EMEX/GEM combination demonstrated limited toxicity, no alterations of GEM Cp during infusion of EMEX, clinical benefit in 48% of patients, good tolerability and excellent EMEX compliance. Addition of EMEX may allow for use of higher doses of GEM and increase the ANC nadir. No effects on the measured cytokines were observed. The long-term utility, safety, and tolerability of EMEX plus GEM warrant further study. No significant financial relationships to disclose.
Phase II feasibility study of adjuvant S-1 plus docetaxel for stage III gastric cancer patients after curative D2 gastrectomy (OGSG 0604)
Authors: K. Fujitani, S. Tamura, Y. Kimura, T. Tsuji, J. Matsuyama, S. Iijima, H. Imamura, Y. Kurokawa, T. Tsujinaka, H. Furukawa
Journal: Journal of Clinical Oncology (2009)

e15567 Background: Although an adjuvant chemotherapy with S-1 has become the standard treatment for stage II-III gastric cancer (GC) patients (pts) after curative D2 gastrectomy in Japan, the survival benefit for stage III pts obtained by S-1 is considered to be modest. S-1 plus docetaxel has shown a good response rate of 56% with prolonged median overall survival (OS) of 14.3 months in pts with advanced GC. This phase II study evaluated the feasibility and safety of adjuvant S-1 plus docetaxel for stage III GC pts after R0 resection. Methods: Patients with curatively resected pathological stage III GC receiving D2 dissection, age 20–80 years, performance status &lt; 1, no prior adjuvant treatment, adequate organ function, and informed consent were given S-1 (80 mg/m 2 /day) orally for consecutive 2 weeks plus docetaxel (40 mg/m 2 ) intravenously on day 1, repeated every 3 weeks. The treatment was started within 45 days after gastrectomy, and repeated for 4 cycles, followed by S-1 monotherapy until 1 year after surgery. Study endpoints included feasibility of the 4 cycles of S-1 plus docetaxel as primary, and safety, progression free survival (PFS), and OS as secondary. Sample size was set to be 50, which was determined to reject the feasibility of 50% under the expectation of 75% with power of 90% and two-sided α of 5%. Results: Fifty-three pts, 42 males and 11 females with a median age of 65 years, were enrolled between 5/2007 and 8/2008. Pathological stages included IIIA in 36 pts and IIIB in 17 pts. Planned 4 cycles of treatment were delivered to 41 out of 53 pts, with the feasibility of 77.4% (95% CI 63.8–87.7%, P&lt;0.001). Reasons for discontinuation were recurrent cancer in 1 pt, adverse events in 10, and miscellaneous in 1, respectively. Grade 4 neutropenia was observed in 28% of pts with grade 3 febrile neutropenia in 9%. Non-hematological toxicities of grade 3 or more involved fatigue in 6%, anorexia in 9%, and nausea in 6%. No treatment-related deaths occurred. Conclusions: Adjuvant S-1 plus docetaxel was well-tolerated and showed good compliance. Although follow-up is ongoing on survival, this regimen could be a candidate of future phase III trial seeking for the optimal adjuvant chemotherapy for stage III GC pts after curative D2 gastrectomy. No significant financial relationships to disclose.
BRCA1 mRNA expression and response in locally advanced esophageal cancer patients (p) treated with chemoradiotherapy.
Authors: A. Font, J. Maurel, M. Taron, V. Alonso, I. Chaib, M. Galan, J. Sanchez, P. Celiz, J. Giralt, R. Rosell
Journal: Journal of Clinical Oncology (2010)

e14573 Background: Chemoradiotherapy is an effective treatment in esophageal cancer p; however, there are no reliable pretreatment clinical parameters to predict the efficacy of this multimodal approach. BRCA1 plays a crucial role in DNA repair pathways, and decreased BRCA1 mRNA expression has been associated with sensitivity to cisplatin and to radiotherapy in several tumors. Methods: We analyzed BRCA1 mRNA expr ession by quantitative PCR in pretreatment endoscopic biopsies from 43 locally advanced esophageal cancer p treated with cisplatin plus fluorouracil and concurrent with radiotherapy, followed by esophagectomy when feasible. p were divided into groups according to tercil es of BRCA1 expression levels. Since the sample size was relatively small, outcomes for those in the lowest tercile were compared to those in the intermediate and high est tercil es together. Results: Eight of 43 p were classified as adenocarcinomas and 35 as squamous cell carcinomas. Nine p had stage II and 34 stage III disease. Of 23 p who underwent esophagectomy after chemoradiotherapy, 10 (43.5%) attained a significant pathological r esponse (pR) (pT0-2N0M0). Of 6 p in the lowest tercile of BRCA1 undergoing surgery, 4 (66%) had a significant pR, while of 17 p in the intermediate and highest tercil es, only 6 (36%) attained a significant pR (p = 0.3). 5-year survival was 18% for all 43 p, 21% for p in the low est tercile of BRCA1, and 17% for p in the intermediate and highest terciles (p = 0.8). Conclusions: Low BRCA1 expr ession is associated with a trend towards better pR in p treated with preoperative chemoradiotherapy. The fact that this association did not reach significance may be due to the small number of patients, and additional patients are currently being included in this analysis to further confirm these results. No significant financial relationships to disclose.
Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study.
Authors: G E Goodman, J J Crowley, J C Blasko, R B Livingston, T M Beck, M D Demattia, R M Bukowski
Journal: Journal of Clinical Oncology (1990)

The Goldie-Coldman model explaining the kinetics of tumor cell kill and drug resistance has a potential application in designing chemotherapy regimes. In this Southwest Oncology Group (SWOG) trial we tested the alternation of two potentially noncrossresistant drug combinations with a concurrent drug combination in patients with limited small-cell lung cancer. The concurrent drug combination consisted of etoposide (VP-16), 75 mg/m2/intravenously (IV), days 1, 2, and 3; vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), 40 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (EVAC). The alternating combination consisted of VP-16, 100 mg/m2/IV, days 1, 2, and 3; and cisplatin (CDDP), 100 mg/m2/IV, day 1, alternating with vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin, 50 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (VP-16/CDDP-VAC). Chemotherapy was administered at 3-week intervals for six cycles both before and after chest (5,000 rads/5 weeks) and whole brain radiotherapy (3,000 rads/2 weeks). One hundred ninety-nine patients received EVAC and 201 received the alternating combination. There was no significant difference in the response rate to the initial six cycles of treatment with EVAC (CR, 40%) versus the alternating combination (CR, 38%). There was no significant difference between the best response, EVAC (CR, 48%) and VP-16/CDDP-VAC (CR, 51%). Median survival for all randomized patients on EVAC is 15.1 months versus 16.5 months on the alternating combination (P = .58). Toxicities consisted primarily of bone marrow suppression, anorexia, nausea and vomiting, peripheral neuropathies, and alopecia. As in previous trials, the chest was the most common site of relapse (33%). There were no differences in the incidence and sites of relapse between the two treatment arms. These treatments appear equally effective at inducing remission and prolonging survival in patients with small-cell lung cancer.
Routine blood pressure lowering and kidney disease in type 2 diabetes
Authors: Bastiaan E. de Galan, Vlado Perkovic, T. Ninomiya, A. Pillai, Anushka Patel, Alan Cass, B Neal, N. Poulter, S. Harrap, C. E. Mogensen, M. Cooper, M. Marre, B. Williams, P. Hamet, G. Mancia, Mark Woodward, P. Glasziou, D. E. Grobbee, Stephen MacMahon, J. Chalmers
Journal: Journal of the American Society of Nephrology (2009)
Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection
Authors: Beatrice Ondondo, Hayato Murakoshi, Genevieve Clutton, Sultan Abdul-Jawad, Edmund G-T Wee, Hiroyuki Gatanaga, Shinichi Oka, Andrew J McMichael, Masafumi Takiguchi, Bette Korber, Tomáš Hanke
Journal: Molecular Therapy (2016)

An effective human immunodeficiency virus type 1 (HIV-1) vaccine is the best solution for halting the acquired immune deficiency syndrome epidemic. Here, we describe the design and preclinical immunogenicity of T-cell vaccine expressing novel immunogens tHIVconsvX, vectored by DNA, simian (chimpanzee) adenovirus, and poxvirus modified vaccinia virus Ankara (MVA), a combination highly immunogenic in humans. The tHIVconsvX immunogens combine the three leading strategies for elicitation of effective CD8(+) T cells: use of regions of HIV-1 proteins functionally conserved across all M group viruses (to make HIV-1 escape costly on viral fitness), inclusion of bivalent complementary mosaic immunogens (to maximize global epitope matching and breadth of responses, and block common escape paths), and inclusion of epitopes known to be associated with low viral load in infected untreated people (to induce field-proven protective responses). tHIVconsvX was highly immunogenic in two strains of mice. Furthermore, the magnitude and breadth of CD8(+) T-cell responses to tHIVconsvX-derived peptides in treatment-naive HIV-1(+) patients significantly correlated with high CD4(+) T-cell count and low viral load. Overall, the tHIVconsvX design, combining the mosaic and conserved-region approaches, provides an indisputably better coverage of global HIV-1 variants than previous T-cell vaccines. These immunogens delivered in a highly immunogenic framework of adenovirus prime and MVA boost are ready for clinical development.
Vistonuridine: An orally administered, life-saving antidote for 5-fluorouracil (5FU) overdose
Authors: R. von Borstel, J. O'Neil, M. Bamat
Journal: Journal of Clinical Oncology (2009)

9616 Background: 5FU is widely used to treat solid tumors and is often administered via infusion pump at or near its maximum tolerated dose (MTD). Toxicities and even death can occur in patients over-exposed to 5FU. Uridine is a direct biochemical antagonist of 5FU toxicity; uridine nucleotides dilute intracellular fluorouridine nucleotides derived from 5FU, reducing their lethal incorporation into RNA. However, uridine is poorly bioavailable (7%) and is therefore not a clinically viable antidote. Vistonuridine is an orally administered prodrug of uridine that delivers approximately 8-fold more uridine than administration of uridine itself. Methods: 17 patients overdosed with 5FU have been treated with vistonuridine as an antidote. Patients received vistonuridine (10g q6h for 20 doses) beginning 8 to 96 hours after overdose. Data from 13 patients with similar 5FU overdoses provide the time course and outcomes for patients receiving available supportive care without vistonuridine. A severity score, integrating dose and infusion rate, was calculated for all the patients, and this tool could be used by healthcare workers to determine the expected severity and outcome of a 5FU overdose. Results: All 17 overdose patients treated with vistonuridine recovered fully. Most, especially those for whom vistonuridine treatment was initiated sooner, had relatively modest toxicity. In marked contrast, all 11 of the literature-reported cases of 5FU overdose for which an outcome of death would have been predicted died from the overdose despite receiving available supportive care. Conclusions: These clinical data illustrate the serious, debilitating and life threatening nature of 5FU overdose and the current lack of effective treatments. Vistonuridine appears to be a safe and effective, life-saving antidote to 5FU overdose. [Table: see text]
Induction of cytochrome P450 by xenobiotics.
Authors: E Bresnick, R Foldes, R N Hines
Journal: Pharmacological Reviews (1984)

It is apparent that the exposure of animals to xenobiotics has a profound effect upon the expression of cytochrome P450. In this manuscript, phenobarbital and 3MC have been selected from the many xenobiotics capable of eliciting this affect to demonstrate the magnitude of changes occurring at the level of the nucleic acids. We have seen that effects include increased levels of particular RNA polymerase isozymes; stabilization of ribosomes and increased synthesis of ribosomal RNA; increase in the amount of mature messenger RNA for individual cytochrome P450 components; and an increase in the amount of nuclear RNA precursors. How these effects come about is a matter for speculation. However, it is clear that the mechanisms by which this is accomplished differ substantially for both phenobarbital and 3MC. 3MC may induce cytochrome P450c through its interaction with a cytosolic "receptor" and subsequent activation of chromatin. The details must await further study.
Trastuzumab-associated cardiac dysfunction
Authors: D. Singh, R. L. Burns, P. Silverman, B. W. Cooper, S. Krishnamurthi, P. Fu, B. A. Overmoyer
Journal: Journal of Clinical Oncology (2005)

800 Background: Cardiotoxicity first noted during the trastuzumab pivotal trials was most frequent in the elderly, and in patients receiving concomitant doxorubicin. However, the pathophysiologic basis, molecular mechanisms, and risk factors for trastuzumab-associated cardiac dysfunction (CD) are still poorly delineated. Methods: Our study sought to determine the effects of known cardiovascular risk factors on trastuzumab associated CD, to characterize the observed CD by severity, treatment, and clinical outcome; and to determine whether concurrent chemotherapy influences CD associated with trastuzumab. Results: We reviewed the medical records of 105 patients who received trastuzumab between October 1998 and October 2002. Cardiovascular risk factors assessed included; age, underlying cardiovascular disease, hyperlipidemia, diabetes, tobacco use, obesity, and radiation to the left chest or internal mammary lymph nodes. The New York Heart Association functional classification system was used to document clinical severity of CD. Asymptomatic decreases in left ventricular ejection fraction (LVEF) were classified using predefined criteria. Logistic regression was used to examine the effects of confounding factors on cardiac dysfunction. Conclusions: Our study suggests that trastuzumab-associated cardiotoxicity is greatest in obese patients, in patients with hyperlipidemia, and in those receiving concurrent vinorelbine. Most patients improve with standard treatment of CHF. The risk of CD can be justified given the improvement in overall survival reported in previous trials. No significant financial relationships to disclose.
Phase II study of E7820 in combination with cetuximab in subjects (pts) with metastatic and refractory colorectal cancer (CRC).
Authors: M. B. Sawyer, S. Iqbal, H. Lenz, C. S. Rocha Lima, D. P. Rossignol, I. Krivelevich, J. Fan, A. B. El-Khoueiry
Journal: Journal of Clinical Oncology (2010)

3537 Background: In vitro,E7820, inhibits α2-integrin expression, endothelial cell proliferation, and vascular tube formation. In colorectal cancer xenograft models, the combination of E7820 and cetuximab demonstrated additive antitumor activity. Methods: This phase II study evaluates the combination of E7820 and cetuximab in subjects with refractory mCRC. A phase Ib study established the maximum tolerated dose of E7820 (100 mg qd po) with cetuximab (400 mg/m2 iv Day 8/Cycle 1, followed by 250 mg/m2 weekly) to be administered in this study (JCO. 2008;26[May 20 suppl]; Abstr 3568). There were 28 evaluable subjects (ECOG 0-1) who relapsed following ≤ 3 prior regimens including 5 subjects from the phase Ib study. The primary endpoint was objective response rate. Results: A mean of 3 cycles (range, 1-13+) were administered. One case each of grade 4 pleuritic pain and pulmonary embolism were observed. E7820 related-grade 3 toxicities included increased AST (3/28, 11%), increased ALT (2/28, 7%), and diarrhea, hypomagnesemia, decreased glomerular filtration rate and elevated creatinine (1/28, 3% in each). E7820-related grade 2 toxicities (> 2 subjects) included anorexia, fatigue, dermatitis acneiform, diarrhea, increased ALT and headache. There were no treatment-related deaths. α2-Integrin levels (18 subjects) decreased over the first month to 81.5% of baseline levels (p = 0.0074) without significant changes in platelet function. Treatment outcomes: objective response rate (ORR = 3.6%), clinical benefit rate (CBR = 14.3%), median progression-free survival (PFS=1.9 mo) and median overall survival (OS = 9.6 mo). Kras mutations were detected in 7/15 (47%) tumor samples available for analysis; among this group, one PR was observed and continues for > 13 cycles. Conclusions: E7820 combined with cetuximab is well-tolerated in subjects with refractory mCRC. This study did not meet its primary endpoint. The single prolonged PR observed in a subject with mutated Kras may indicate possible activity of the E7820 and cetuximab combination in this subset of patients and will require additional confirmatory studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai
Activity and toxicity of docetaxel plus capecitabine in a pilot study in ovarian cancer
Authors: T. Safra, R. Bernstein-Molcho, M. J. Inbar, T. Levy
Journal: Journal of Clinical Oncology (2008)

16580 Background: Docetaxel and Capecitabine (Xeloda) have shown activity in epithelial ovarian cancer (EOC) as single agents, and their combination was synergistic in cell lines. In vivo, this combination was studied in metastatic breast cancer patients, showing improved progression free survival (PFS) and overall survival (OS). The objective of this trial was to evaluate the safety and efficacy of weekly docetaxel and capecitabine, in patients with recurrent ovarian cancers. Materials and Methods: Patients with recurrent or persistent EOC after one line of paclitaxel and carboplatin chemotherapy were enrolled. Docetaxel was administered at a dose of 35 mg/m2 on days 1 and 8 and oral Capecitabine was given at a dose of 1000 mg/m2 twice a day, on days 1–14 in a 21-day cycle. Therapy was discontinued due to progressive disease, intolerable side effects or patient request. Results: Eight patients were enrolled. The median age was 64 (range:37- 80) years. Disease stage was Ic-IV, mostly IIIc. Seven patients had platinum sensitive and one had platinum resistant disease. A median of 5 cycles (range:1.33–12.2) were administered. Response observed was: one complete response (CR) 3 partial responses (PR), 3 stable disease (SD) and one disease progression (DP). Time to progression (TTP) ranged from 1.67 to 11.27 months. Toxicity: No grade-3 or 4 bone marrow toxicity was observed. Nonhematological toxicity included: partial hair loss (n=3), fatigue (n=7), hand-foot syndrome (n=1), diarrhea (n=5) and fluid retention syndrome (n=1). Treatment was discontinued in three patients after 2 - 4 treatment cycles, two of them due to grade-3 diarrhea and grade-3 fatigue requiring dose reduction and repeat treatment delays and one due to severe fluid retention syndrome. Conclusion: The docetaxel/capecitabine combination showed antitumor activity as second-line therapy for recurrent EOC. However, it was frequently associated with moderate-to-severe nonhematological toxicities (mainly fatigue and diarrhea) resulting in treatment discontinuation and early study closure. Further studies are required in order to adjust dose schedule and to maximize therapeutic index. No significant financial relationships to disclose.