tbuckley/cabot-search huggingface dataset:
Abstract P209: Effects of Blood Pressure Lowering on Vascular Outcomes in Different Cardiovascular Risk Groups Among Patients With Type 2 Diabetes: New Results From Advance
Authors: Susan van Dieren, Andre Pascal Kengne, John Chalmers, Joline Beulens, Yvonne van der Schouw, Sophia Zoungas
Journal: Circulation (2012)

Background/Aim: Although patients with type 2 diabetes constitute a high risk group there is a gradation in cardiovascular risk which may lead to differences in outcomes and effects of treatment. The objective of this study was to assess for differences in treatment effects of the fixed combination of perindopril-indapamide across subgroups of cardiovascular risk. Methods: 11,140 patients with type 2 diabetes, participating in the ADVANCE trial, were randomized to perindopril-indapamide or matching placebo. The UKPDS risk engine was used to calculate baseline 5-year coronary heart disease risk and to stratify patients into three risk groups (0-10%; 10–15%; &gt;15%). Endpoints were composites of major macrovascular and microvascular events. Homogeneity of treatment effects across risk subgroups were tested by adding interaction terms to the Cox models. Results: The median estimated 5-year coronary heart disease risk at baseline was 10% (IQR 7%−16%). 1000 macrovascular and 916 microvascular events were recorded during a median follow-up of 4.3 years. The relative treatment effects were similar across all risk groups for all endpoints, with no heterogeneity (all P -values for heterogeneity ≥ 0.38). The hazard ratios for combined macro- and microvascular events were 0.89 (95% confidence interval: 0.77–1.03) for the moderate-high risk group and 0.92 (0.81–1.03) for the very high risk group. The absolute risk reductions were greater in the highest risk groups, with numbers needed to treat ranging from 38 to 244. Conclusions: Reductions in relative risk achieved with the fixed combination of perindopril-indapamide among patients with type 2 diabetes were consistent across subgroups defined by baseline cardiovascular risk, but reductions in absolute risk were greatest in those with the highest initial risk. Acknowledgements: This research was supported by a program grant from the National Health and Medical Research Council of Australia, the Center for Translational Molecular Medicine (CTMM) and the Netherlands Heart Foundation, Dutch Diabetes Research Foundation and Dutch Kidney Foundation (PREDICCt).
Comparative study of survival off CML patients under treatment with busulphan, hydroxyurea, interferon A, imatinib
Authors: B. V. Ausekar
Journal: Journal of Clinical Oncology (2004)

6738 Background: During the period of 1992-September 2003, 97 cases of CML were studied, of those 60 were male patients and 37 female patients. Age varied from 12 to 72 years. 8 patients refused treatment after diagnosis and 43 patients discontinued after few months < 12 months. Method: MEDIAN SURVIVAL. NAME OF DRUGS NO. OF PATIENTS SURVIVAL IN MONTHS. Busulphan 2 26.5 Hydroxyurea 27 32.2 Busulphan -> Hydroxyurea 3 36 Busulphan -> Hydroxyurea -> Interferon A 3 41 Hydroxyurea -> Interferon A 8 42.7 Imatinib 6 - Result: Of those who received regular treatment 7 survived 5 years (16.3%) with Median Survival 77.4 months. 5 patients were treated with Hydroxyurea and survived 75.4 months. 2 patients were treated with Hydroxyurea + Interferon A survived 82.5 months. All 7 patients had complete hematological response —WBC < 10000,Spleen not palpable and Cytogenetic investigations were not done due to lack of required facility.6 patients started receiving capsule Imatinib 400mg daily since March 2003. All patients are alive and continuing the treatment. It is too early to make any conclusions regarding survival duration of these patients. Conclusion: Our study suggests 1) Hydroxyurea + Interferon A give better survival for CML patients. 2) More time is necesarry to observe the results of Imatinib. No significant financial relationships to disclose.
Hodgkin's disease in childhood and adolescence: results of chemotherapy-radiotherapy in clinical stages IA-IIB.
Authors: P Cramer, J M Andrieu
Journal: Journal of Clinical Oncology (1985)

From April 1972 to May 1980, 72 children and adolescents (aged 5 to 19 years old, median 16) with Hodgkin's disease, clinical stages IA-IIB (IA, 18; II2A, two areas involved on the same side of the diaphragm, 23; II3+A, three areas or more, 16; IIB, 15) were prospectively treated in two successive clinical trials (H 72 and H 77). Clinical stages IA and II2A received three courses of mechlorethamine, Oncovin, procarbazine, and prednisone (MOPP) and supradiaphragmatic radiotherapy (40 Gy), and no laparotomy was performed. Clinical stages II3+A and IIB received either six cycles of MOPP (H 72), three cycles of MOPP, or three cycles of CCNU, vinblastine, procarbazine, and prednisone (CVPP) (H 77) and subsequently had a laparotomy followed by supradiaphragmatic radiotherapy and a lumboaortic field if results of laparotomy were positive. Patients without evidence of mediastinal involvement did not have mediastinal radiotherapy. At the completion of therapy, the disease in 70 of 72 patients was in complete remission (one failure, one death during treatment). Eight patients relapsed (in situ, 1; marginal, 1; nonirradiated subdiaphragmatic area, 6) after three to 57 months of complete remission (median 20 months); one patient died after relapse. There were three deaths after complete remission of the disease (infection, two; acute nonlymphocytic leukemia [ANLL], one). As of June 1984 the median follow-up was 82 months (range, 49 to 145 months), the actuarial probabilities for survival and freedom from relapse for all patients being 91.6% and 87.6%, respectively. There was no statistical difference according to clinical stage, age (greater than 15 or less than 15 years), sex, or number of cycles of chemotherapy (six or three). Bone growth defects related to radiotherapy were reduced particularly in the 29 patients who did not receive mediastinal radiotherapy. None of these patients had a mediastinal relapse. Azoospermia was the rule for the male patients studied, but young girls and young women retained reproductive integrity.
Correlation of <i>PIK3CA</i> mutation with pathological complete response in primary HER2-positive breast cancer: Combined analysis of 967 patients from three prospective clinical trials.
Authors: Sibylle Loibl, Ian Majewski, Valentina Guarneri, Valentina Nekljudova, Eileen McCormick Holmes, Emilio Bria, Carsten Denkert, Holger Eidtmann, Christos Sotiriou, Sherene Loi, Fabrice Andre, Michael Untch, Pier Franco Conte, Martine J. Piccart-Gebhart, Gunter Von Minckwitz, Jose Baselga
Journal: Journal of Clinical Oncology (2015)

511 Background: The predictive value of PIK3CA mutations in HER2+ BC has been shown conclusively. Data on subgroup analyses are lacking. Methods: We combined data from three studies evaluating PIK3CA mutations as predictor for pCR: the neoadjuvant GEPAR studies (n = 504) (Loibl et al. JCO 2014), the Neo-ALTTO study (n = 355) (Majewski et al. JCO 2015) and the CHERLOB study (n = 108) (ESMO 2014). Patients received either trastuzumab (T), lapatinib (L) or the combination T/L in addition to taxane-based chemotherapy. PIK3CA was genotyped in tumor biopsies prior to therapy. Results: 967 patients were included. Median age was 48 (range 21-80); most tumors were cT1-2 (69.5%); cN+ (61.7%); ductal invasive (93.4%), grade 3 (56.2%); HR+ (56.2%). Overall, 21.7% had at least one mutation, 7.2% in exon 9 and 14.5% in exon 20. PIK3CA mutations were equally frequent in the HR+ compared to the HR- group: 21.7% in both groups. Overall, pCR rate was significantly lower in the PIK3CA mutant (mut) compared to the wild type (wt) group (16.2% vs 29.6%; p < 0.001). There was no difference in pCR rate whether the mutation was in exon 9 (15.7%) or exon 20 (16.4%). Within the HR+ subgroup the PIK3CA mut pts had a pCR rate of only 7.6% compared to 24.2% in the wt group (p < 0.001). In contrast, the difference in pCR (27.2% vs 36.4%) according to PIK3CAmutation status was not significant in the HER2+/HR- group (p = 0.125; interaction p = 0.036). The pCR rate for mut vs wt was 20.3% vs 27.1% for T (p = 0.343); 11.3% vs 16.9% for L (0.369) and 16.7% vs 39.1% for T/ L (p < 0.001). In the HR+ T/L group the pCR rate was 5.5% vs 33.9% (interaction p = 0.008). Conclusions: This metaanalysis confirms a significantly lower pCR rate in HER+, PIK3CA mutant tumors after anti-HER2 treatment. Patients with a HER2+/HR+/PIK3CA mutant tumor had a pCR rate of 5.5% only when treated with double-blockade and might be considered for alternative treatment. The project was funded within the EU-FP7 project RESPONSIFY No 278659. % pCR All cases HR-ve HR+ve Mut wt Mut wt Mut wt All Treatments 16.2 29.6 27.2 36.4 7.6 24.4 T 20.3 27.1 25.0 34.8 14.3 20.9 L 11.3 16.9 18.5 22.9 5.7 12.3 T/L 16.7 39.1 37.9 46.0 5.5 33.9
A retrospective study of surgical treatment for gastric cancer in our institute as a clinical hospital in Japan
Authors: T. Kishimoto, H. Imamura, K. Yamamoto, Y. Miyazaki, H. Furukawa
Journal: Journal of Clinical Oncology (2007)

15125 Background: Two European randomized controlled trials comparing D1 and D2 gastrectomy revealed a high operative mortality in the D2 group. Based on these reports, D1 gastrectomy is a standard treatment for western patients. In contrast, D2 gastrectomy is considered a standard and safe procedure in Japan. Moreover, the operative morbidity/mortality and the incidence of the major surgical complications were not different between D2and extended para-aortic lymphadenectomy in a prospective randomized controlled trial in Japan. We report a retrospective study of surgical treatment for gastric cancer in our institute as a clinical hospital in Japan. Methods: Patients who underwent gastrectomy between January 1998 and November 2006 in our institute were analyzed. Survival according to the staging by Japanese Classification of Gastric Cancer, the level of the dissection of lymph nodes, and all complications were studied. Results: A total 1342 patients underwent gastrectomy between January 1998 and November 2006 in our institute. The male/female ratio was 2.2 and the mean age was 64.7±11.4 years(range,27–94 years). The 5-year survival according to the staging by Japanese Classification of Gastric Cancer was 98.4%, 84.7%, 77.2%, 46.1%, 40.2% and 33.4% in the stage IA, IB, II, IIIA, IIIB, and IV, respectively. D0, D1, D2, and D3 or D4 gastrectomy was performed in 48, 200, 610, and 27 patients, respectively. Complications were identified in 295 patients(22%) involving 2 patients with treatment death(0.01%) and anastomotic leak, surgical site infection, pancreatic fistula, ileus, anastomotic stenosis, abdominal abcess, liver dysfunction, postoperative bleeding, pneumonia , DIC , peritonitis, and others were identified in 66, 51, 42, 28, 26, 23, 21, 14, 13, 4, 3, and 4 patients, respectively. We analyzed the D0/D1 and D2/D3/D4 dissection subgroups about complications. There was no significant difference in the incidence of complications between the two groups (p=0.093). Conclusions: Our data suggested that gastrectomy with D2 dissection has been a safe treatment with a good prognosis in our institute. D2 gastrectomy is considered a safe treatmemt without increasing surgical complications. No significant financial relationships to disclose.
Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis
Authors: Alexander S. Pym, Andreas H. Diacon, Shen-Jie Tang, Francesca Conradie, Manfred Danilovits, Charoen Chuchottaworn, Irina Vasilyeva, Koen Andries, Nyasha Bakare, Tine De Marez, Myriam Haxaire-Theeuwes, Nacer Lounis, Paul Meyvisch, Ben Van Baelen, Rolf P.G. van Heeswijk, Brian Dannemann
Journal: European Respiratory Journal (2015)

Bedaquiline, a diarylquinoline, improved cure rates when added to a multidrug-resistant tuberculosis (MDR-TB) treatment regimen in a previous placebo-controlled, phase 2 trial (TMC207-C208; NCT00449644 ). The current phase 2, multicenter, open-label, single-arm trial (TMC207-C209; NCT00910871 ) reported here was conducted to confirm the safety and efficacy of bedaquiline. Newly diagnosed or previously treated patients with MDR-TB (including pre-extensively drug-resistant (pre-XDR)-TB or extensively drug-resistant (XDR)-TB) received bedaquiline for 24 weeks with a background regimen of anti-TB drugs continued according to National TB Programme treatment guidelines. Patients were assessed during and up to 120 weeks after starting bedaquiline. Of 233 enrolled patients, 63.5% had MDR-TB, 18.9% had pre-XDR-TB and 16.3% had XDR-TB, with 87.1% having taken second-line drugs prior to enrolment. 16 patients (6.9%) died. 20 patients (8.6%) discontinued before week 24, most commonly due to adverse events or MDR-TB-related events. Adverse events were generally those commonly associated with MDR-TB treatment. In the efficacy population (n=205), culture conversion (missing outcome classified as failure) was 72.2% at 120 weeks, and 73.1%, 70.5% and 62.2% in MDR-TB, pre-XDR-TB and XDR-TB patients, respectively. Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB.
Sex-Related Resistance in Hamsters to Adenovirus-12 Oncogenesis. Influence of Thymectomy at Three Weeks of Age&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: David S. Yohn, Clare A. Funk, Vitauts I. Kalnins, James T. Grace, Jr.
Journal: JNCI Journal of the National Cancer Institute (1965)

Newborn randombred Syrian hamsters were given injections at birth of 106.0 ± 0.2 TCID50 of prototype adenovirus 12. At 3 weeks of age the animals were weaned, segregated according to sex, and 50 to 60 percent of each sex thymectomized. Development of tumors was followed until the animals were 4 months old. Male hamsters were more resistant to viral oncogenesis than females; final tumor incidence in males was one half that of females and the rate of tumor appearance was slower in males. Susceptibility of males could be partially enhanced by thymectomy as shown by an increase in rate of tumor appearance and tumor incidence. Antibody responses to adenovirus-12 tumor antigen were depressed by thymectomy in both sexes, though more markedly in males. The implications of the sex-related resistance and the effect of thymectomy thereon are discussed, as well as the nature of the antigen responsible for induction of resistance and possible mechanisms responsible for a difference in susceptibility between hamsters of different sex to adenovirus-12 oncogenicity.
A phase 1b study of trebananib plus paclitaxel (P) and trastuzumab (T) in patients (pts) with HER2+ locally recurrent or metastatic breast cancer (MBC).
Authors: Peter Andrew Kaufman, Gilles Freyer, Margaret Kemeny, Anthony Goncalves, Guy Heinrich Maria Jerusalem, Alison Stopeck, Nandagopal Vrindavanam, Florence Dalenc, Nuwan Nanayakkara, Benjamin Wu, Cheryl Ann Pickett-Gies, Hans Wildiers
Journal: Journal of Clinical Oncology (2014)

502 Background: Trebananib (AMG 386) suppresses tumor angiogenesis by neutralizing the interaction between the Tie2 receptor and its ligands, angiopoietin-1 and -2. This study evaluated the tolerability and efficacy of trebananib plus P and T as first-line treatment in HER2+ MBC. Methods: Pts in cohorts A1 and A3 received open-label trebananib (A1, 10 mg/kg; A3, 30 mg/kg) IV QW plus P 80 mg/m2IV QW and T (loading dose of 8 mg/kg, then 6 mg/kg Q3W). If dose-limiting toxicity (DLT) criteria were not met, each cohort was expanded to 20 pts. A3 enrollment was initiated if DLT criteria were not met for A1. Results describing trebananib plus capecitabine and lapatinib will be reported elsewhere. Endpoints were the incidence of DLTs and treatment-emergent adverse events (AEs; primary); and efficacy and pharmacokinetics (PK). Results: Of 40 enrolled pts in A1 (n = 20) and A3 (n = 20), two DLTs occurred across A1 (grade 3 transient ischemic attack, n = 1) and A3 (grade 3 increased gamma-glutamyltransferase, n = 1). The most common (> 50%) AEs in A1/A3 were peripheral edema (n = 13/15), diarrhea (n = 13/14), alopecia (n = 13/13), fatigue (n = 15/9), nausea (n = 11/13), nail disorder (n = 12/7), and rash (n = 12/6). Grade ≥ 3 AEs occurring in > 10% of pts were peripheral neuropathy (n = 4/4), peripheral sensory neuropathy (n = 4/0), and dyspnea (n = 3/1). In evaluable pts (A1/A3, n = 20/17), confirmed objective response rates (ORRs) were 80% (complete responses [CRs], n = 0; partial responses [PRs], n = 16) in A1 and 88.2% (CRs, n = 3; PRs, n = 12) in A3. The median duration of response (DOR; 95% CI) was 12.6 (4.3 – 20.2) months in A1 and 16.8 (8.2 – not evaluable) months in A3. Median (95% CI) progression-free survival (PFS) was 14.5 (6.9 – 20.6) months and 18.7 (10.4 – not evaluable) months in A1 and A3, respectively. No apparent PK drug-drug interaction was observed. Trebananib exposure appeared dose proportional with intersubject variability of 40.5% and 28.6% in A1 and A3, respectively. Conclusions: In this phase 1b study, trebananib at 10 mg/kg and 30 mg/kg plus P and T appeared tolerable. The ORR, DOR, and PFS observed in this study suggest that further investigation of trebananib in this setting is warranted. Clinical trial information: NCT00807859.
Interleukin-35 Limits Anti-Tumor Immunity
Authors: Meghan E. Turnis, Deepali V. Sawant, Andrea L. Szymczak-Workman, Lawrence P. Andrews, Greg M. Delgoffe, Hiroshi Yano, Amy J. Beres, Peter Vogel, Creg J. Workman, Dario A.A. Vignali
Journal: Immunity (2016)

Regulatory T (Treg) cells pose a major barrier to effective anti-tumor immunity. Although Treg cell depletion enhances tumor rejection, the ensuing autoimmune sequelae limits its utility in the clinic and highlights the need for limiting Treg cell activity within the tumor microenvironment. Interleukin-35 (IL-35) is a Treg cell-secreted cytokine that inhibits T cell proliferation and function. Using an IL-35 reporter mouse, we observed substantial enrichment of IL-35(+) Treg cells in tumors. Neutralization with an IL-35-specific antibody or Treg cell-restricted deletion of IL-35 production limited tumor growth in multiple murine models of human cancer. Limiting intratumoral IL-35 enhanced T cell proliferation, effector function, antigen-specific responses, and long-term T cell memory. Treg cell-derived IL-35 promoted the expression of multiple inhibitory receptors (PD1, TIM3, LAG3), thereby facilitating intratumoral T cell exhaustion. These findings reveal previously unappreciated roles for IL-35 in limiting anti-tumor immunity and contributing to T cell dysfunction in the tumor microenvironment.
Use of amolecular mimicry approach to identify effective agents in pancreatic cancer
Authors: A. Tan, A. Jimeno, I. Garrido-Laguna, M. Uson, E. De Oliveira, A. Wilson, B. Rubio-Viqueira, N. V. Rajeshkumar, M. Hidalgo
Journal: Journal of Clinical Oncology (2009)

4603 Background: We proposed a molecular mimicry approach (prêt-à-porter), based on pathway-expression signatures that systematically connect a query case with the most similar profile from a reference profile database and extrapolates the most effective drug for personalized medicine. Here we report the pre-clinical and clinical validation of this concept in pancreatic cancer treatment. Methods: Baseline gene expression profiles of 24 patients that received gemcitabine as adjuvant chemotherapy were collected. A patient is defined as sensitive and resistant to gemcitabine if the disease free survival (DFS) is more and less than 300 days, respectively. We also performed a small scale pre-clinical study on comparing patient-derived xenografts refractory to gemcitabine in a second-line treatment of prêt-à-porter choice of drugs vs. one-size-fits-all choice of drug (erlotinib). Four gemcitabine resistant xenografts were randomly assigned into control, erlotinib and the prêt-à-porter choice of drug groups. Tumor growth inhibition values (TGI) were calculated at the end of the experiment. Results: Using the molecular mimcry concept, where a patient is connected to a sensitive cell line, s/he will be predicted as sensitive to gemcitabine and vice versa. The prêt-à-porter achieved an overall prediction accuracy of 71% on these retrospective patient samples. Our approach correctly classified 67% and 75% of the patients that were sensitive and resistant to gemcitabine as adjuvant chemotherapy, respectively. The median DFS for the sensitive and resistant groups are 491 and 162 days, respectively. This difference was statistically significant (log-rank test, p = 0.04). Furthermore, the mean TGI% for the prêt-à-porter is about 10-fold lower than the erlotinib arm (3% vs. 30%, Chi-square test, p = 0.02) in the pre-clinical study. This demonstrates that prêt-à-porter approach can be used to tailor personalized medicine and achieved better clinical response as compared to the current treatment approach. Conclusions: We comprehensively validated the prêt-à-porter approach in pre-clinical and clinical data and demonstrated that this approach can be used as a powerful translation research tool in enriching patient selection of novel drugs in clinical trials and realizing personalized medicine. [Table: see text]
Brief Communication: Estrogen Receptor Interaction With the Antitumor Agent Estradiol Mustard23
Authors: Roger E. Shepherd, Karen Huff, William L. McGuire
Journal: JNCI Journal of the National Cancer Institute (1974)

The interaction of the steroid alkylating agent estradiol mustard (EM) with estrogen receptor was investigated under cell-free conditions. EM failed to bind to cytoplasmic estrogen receptor obtained from either rat uterus or human breast-cancer tissue. Nevertheless, in vivo studies in the rat uterus demonstrated that intraperitoneal injections of EM translocated estrogen receptor into the nucleus within 10 hours. Estradiol injections caused a similar depletion of cytosol receptor and transfer to the nucleus, but this translocation was completed within 2 hours. These studies suggest that, in vivo, EM is slowly converted to a metabolite, possibly free estradiol, which binds to estrogen receptor and transfers it to the nucleus.