tbuckley/cabot-search huggingface dataset:
Tolerability of docetaxel and carboplatin followed by tumor directed radiation for advanced stage uterine cancer
Authors: D. R. Scribner, L. Puls, M. A. Gold, N. S. Gould
Journal: Journal of Clinical Oncology (2008)

16592 Background: To evaluate the safety and tolerability of this treatment in patients (pts) diagnosed with stage III, IV uterine cancer. Methods: All pts with Stage III or IV (confined to the pelvis) and endometrial adenocarcinoma were enrolled in this phase II trial. Pts with sarcomas, prior radiation or chemotherapy, or a baseline > gr 1 neuropathy were excluded. Surgical staging was performed in all pts. The treatment consisted of 6 cycles of IV docetaxel, 75 mg/m2 and carboplatin, AUC 6, every 21 days × 6 followed by radiation within 4–6 weeks after chemotherapy. Radiation doses were tumor and volume directed. External pelvic radiation total dose was 5040 cGy with 4350 cGy given to the paraaortic region for positive aortic nodes. Brachytherapy was given at the discretion of the radiation oncologist. Pts were allowed to have G- CSF and erythropoietin per the research institution’s standard operating procedures. All toxicities were graded according to the NCI CTC version 3.0. Results: Pts were enrolled from 4/04 through 12/07 at 3 institutions. 35 were evaluable for treatment toxicity analysis. 27 stage IIIC and 8 stage IIIA pts. Mean age was 65 (45–87). 26/35 (74.3%) completed all 6 cycles of chemotherapy. Most common tx related reasons for stopping chemo were 3/9 (33.3%) fatigue and 2/9 (22.2%) allergic rxn to docetaxel. A dose reduction, per protocol, occurred in 5/35 (14.3%). Most common reason for dose reduction was gr 3 neutropenia 3/5 (60.0%). Most common grade 3,4 adverse events were neutropenia 4/35 (11.4%), fatigue 3/35 (8.6%), and diarrhea 3/35 (8.6%). SAE’s related to treatment included 2 pts with gr 4 neutropenia (1 febrile), 3 gr 4 fatigue and 2 gr 4 allergic reactions to docetaxel. There were 2 deaths due to pulmonary emboli. 8/35 (22.9%) were given GCSF and 13/35 (37.1%) were given erythropoietin. 22/25 (88.0%) received XRT with 1 SAE for gr 4 dehydration. Median external beam XRT dose was 5040 cGy. 3 pts received paraortic boost and 3 pts brachytherapy. Conclusions: Docetaxel 75 mg/m2 and Carboplatin AUC 6 q 21 days × 6 followed by radiation is well tolerated in advanced endometrial cancer pts. Most common adverse effects are neutropenia, fatigue and diarrhea. Future analysis will determine if this combined therapy extends disease free interval and overall survival. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis
Population PKPD of paclitaxel and carboplatin in ovarian cancer patients: A study by the EORTC-PAMM-NDDG
Authors: M. Joerger
Journal: Journal of Clinical Oncology (2007)

2529 Background: Paclitaxel (P) and carboplatin (C) are considered standard first-line treatment in advanced ovarian cancer following cytoreductive surgery. Threshold-models have been used to predict P PKPD, whereas the time above P plasma concentration of 0.05- 0.2 μmol/L (P t C&gt;0.05–0.2 ) predicts neutropenia. The objectives of this study was to build a population PKPD-model of PC in ovarian cancer patients. Methods: 139 ovarian cancer patients received P 175 mg/m 2 over three hours followed by C AUC 5 over 30 min. Plasma concentration-time data of PC were measured, and data processed using nonlinear mixed-effect modelling. Semiphysiological models with linear or sigmoidal maximum response, and threshold models were adapted to the data. Results: 105 patients had complete PK and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Mean P t C&gt;0.05 was 61.4 hrs. P t C&gt;0.05 was significantly higher in patients with a complete (91.8 hrs) or partial response (76.3 hrs) compared to patients with progressive disease (31.5 hrs) (p=0.02 and 0.05, respectively). Patients with P t C&gt;0.05 &gt; 61.4 hrs had a longer time to disease- progression compared to patients with P t C&gt;0.05 &lt; 61.4 hours (89.0 vs 61.9 weeks, p=0.05). P t C&gt;0.05 was a good predictor for severe neutropenia (p=0.01), while carboplatin exposure (C max and AUC) was the best predictor for thrombocytopenia (p&lt;10 -4 ). Conclusions: In this group of patients, P t C&gt;0.05 is a good predictive marker for severe neutropenia and clinical outcome, while C exposure is a good predictive marker for thrombocytopenia. (Biomed grant PL96–2333, JHM Schellens coordinator) No significant financial relationships to disclose.
A Two-Disease Model of Female Breast Cancer: Mortality in 1969 Among White Females in the United States&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;
Authors: K G Manton, E Stallard
Journal: JNCI Journal of the National Cancer Institute (1980)

A mathematical model of the age distribution of breast cancer mortality was developed on the basis of the two-disease theory of breast cancer incidence. The model included representations of the time from tumor initiation to death, the competing risk effects of other disease, and differential susceptibility to each of the disease components. This model successfully predicted the single year of age frequency of breast canceomponents of this model was consistent with several epidemiologic findings. Most significantly, the age distribution of breast cancer deaths from premenopausal disease was consistent with incidence patterns in non-Western countries, where the incidence of the postmenopausal disease component was hypothesized to be lower because of nutritional differences.
Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study
Authors: Kerryn A Moore, Julie A Simpson, Moo Kho Paw, MuPawJay Pimanpanarak, Jacher Wiladphaingern, Marcus J Rijken, Podjanee Jittamala, Nicholas J White, Freya J I Fowkes, François Nosten, Rose McGready
Journal: The Lancet Infectious Diseases (2016)

BackgroundArtemisinins, the most effective antimalarials available, are not recommended for falciparum malaria during the first trimester of pregnancy because of safety concerns. Therefore, quinine is used despite its poor effectiveness. Assessing artemisinin safety requires weighing the risks of malaria and its treatment. We aimed to assess the effect of first-trimester malaria and artemisinin treatment on miscarriage and major congenital malformations.MethodsIn this observational study, we assessed data from antenatal clinics on the Thai–Myanmar border between Jan 1, 1994, and Dec 31, 2013. We included women who presented to antenatal clinics during their first trimester with a viable fetus. Women were screened for malaria, and data on malaria, antimalarial treatment, and birth outcomes were collected. The relationship between artemisinin treatments (artesunate, dihydroartemisinin, or artemether) and miscarriage or malformation was assessed using Cox regression with left-truncation and time-varying exposures.FindingsOf 55 636 pregnancies registered between 1994 and 2013, 25 485 pregnancies were analysed for first-trimester malaria and miscarriage, in which 2558 (10%) had first-trimester malaria. The hazard of miscarriage increased 1·61-fold after an initial first-trimester falciparum episode (95% CI 1·32–1·97; p<0·0001), 3·24-fold following falciparum recurrence (2·24–4·68; p<0·0001), and 2·44-fold (1·01–5·88; p=0·0473) following recurrent symptomatic vivax malaria. No difference was noted in miscarriage in first-line falciparum treatments with artemisinin (n=183) versus quinine (n=842; HR 0·78 [95% CI 0·45–1·34]; p=0·3645) or in risk of major congenital malformations (two [2%] of 109 [95% CI 0·22–6·47] versus eight (1%) of 641 [0·54–2·44], respectively).InterpretationFirst-trimester falciparum and vivax malaria both increase the risk of miscarriage. We noted no evidence of an increased risk of miscarriage or of major congenital malformations associated with first-line treatment with an artemisinin derivative compared with quinine. In view of the low efficacy of quinine and wide availability of highly effective artemisinin-based combination therapies, it is time to reconsider first-trimester antimalarial treatment recommendations.FundingThe Wellcome Trust and The Bill & Melinda Gates Foundation.
Cell-Surface Expression of the Channel Activating Protease xCAP-1 Is Required for Activation of ENaC in the Xenopus Oocyte
Authors: Véronique Vallet, Corinne Pfister, Johannes Loffing, Bernard C. Rossier
Journal: Journal of the American Society of Nephrology (2002)

Sodium balance, extracellular fluid volume, and ultimately BP are maintained by precise regulation of the activity of the epithelial sodium channel (ENaC). Using a functional complementation assay in the Xenopus laevis oocyte expression system, a channel-activating protease (CAP-1) that increases ENaC activity two to threefold in the Xenopus oocyte expression system is here identified. External application of trypsin mimics the effect of Xenopus CAP-1 (xCAP-1) on ENaC activity, which can be blocked by aprotinin, a serine protease inhibitor, suggesting the existence of a novel extracellular pathway for controlling ENaC activity. Sequence analysis predicts that CAP-1 is a secreted and/or glycosyl-phosphatidyl-inositol (GPI)-anchored protein. The aim of the present study was to determine whether cell-surface expression of xCAP-1 is required for ENaC activation. By site-directed mutagenesis of xCAP-1, the importance of the catalytic site, N-glycosylation, and the GPI anchor of xCAP-1 on ENaC activity were analyzed. Glycosylation or catalytic activity is not required for cell-surface expression of xCAP-1, whereas the deletion of the GPI anchor consensus motif at the C-terminus of xCAP-1 (G305Stop) abolishes cell-surface expression and ENaC activation. G305Stop-mutated xCAP-1 is recovered as a secreted protein in the external medium. A catalytic mutant of xCAP-1 significantly decreased ENaC activation but did not fully abolish the effect of xCAP-1. The data indicate the critical role of the GPI anchor in ENaC activation and suggest that catalytic and noncatalytic mechanisms are involved.
Epidemiology of breast cancer in Lebanon between 1997 and 2007: A retrospective and descriptive study.
Authors: E. El Helou, P. G. Aftimos, G. Y. Chahine
Journal: Journal of Clinical Oncology (2010)

e12055 Background: The Lebanese breast cancer screening campaign's impact has never been evaluated. This study is the first to describe the epidemiologic characteristics of breast cancer patients, the tumor characteristics, the evolution of breast cancer epidemiology, the impact of the Lebanese breast cancer screening campaign, and the prognostic value of some epidemiologic criteria. Methods: This descriptive, retrospective study includes 220 breast cancer patients diagnosed between 1997 and 2007. It describes the epidemiologic characteristics of these patients, as well as those of their tumors. The correlational part evaluates the impact of the Lebanese breast cancer screening campaign, launched in October of 2002, and investigates the prognostic value of HER2/neu overexpression, of the histological grade, of the tumor size and of lymphatic ganglia invasion. Results: 24% of patients have had their first period before the age of 12 and 61% have entered menopause after the age of 55. 30% are nulliparous. 31% have never breastfed. 29% have used oral contraceptives. 12% of menopausal women have been on hormonal substitution for at least 5 years. 33% have a relative affected by breast cancer. 64% have asked for medical care after palpating a lump. Only 15% of tumors were detected on routine mammograms. 69% of the tumors measure more than 2 cm. Infiltrating ductal carcinomas are by far the most frequent (86%). Estrogen receptors are positive in 68% of cases. HER2/neu is over-expressed in 41% of cases. When it comes to epidemiologic criteria evolution, significantly less women have discovered the tumor because of symptoms between the years 2005 and 2007 (7%). No relation has been demonstrated between HER2/neu over- expression, the histological grade, the tumor's size and the lymph nodes' invasion on the one hand, and the 5-year prognosis (in terms of DFS) on the other hand. Conclusions: Patients in this study exhibit epidemiologic features in the field of reproductive life habits that are close to those of the occidental world. Nevertheless, they might still be victims of an oriental mentality fueled by fatalism, which keeps them from abiding by the requirements of the breast cancer screening campaign. No significant financial relationships to disclose.
Phase I study of repeated cycles of high-dose cyclophosphamide, etoposide, and cisplatin administered without bone marrow transplantation.
Authors: J A Neidhart, W Kohler, C Stidley, A Mangalik, A Plauche, T Anderson, R W Quenzer, J J Rinehart
Journal: Journal of Clinical Oncology (1990)

Forty-two patients with advanced malignancy judged unlikely to respond to standard treatment received high-dose combination chemotherapy with cyclophosphamide, etoposide, and cisplatin in a phase I trial. Twenty-two of these patients who had at least a partial response (PR) to the first cycle of therapy received a second cycle, and eight patients received three or more cycles of therapy. Bone marrow replacement was not used. The maximum-tolerated doses (MTDs) were cyclophosphamide 2.5 g/m2 on days 1 and 2; etoposide 500 mg/m2 on days 1, 2, and 3; and cisplatin 50 mg/m2 on days 1, 2, and 3. Hematologic toxicity was not dose-limiting by study design. Recovery to an absolute granulocyte count above 100/microL occurred at a median of 9 days from onset (range, 3 to 23 days) at the MTD. Recovery was delayed after the third cycle. Only one patient on his third cycle failed to recover peripheral blood counts and died of sepsis an day 43. Hematologic toxicity was not dose-dependent. Nonhematologic toxicities included emesis, fatigue, alopecia, diarrhea, and anorexia and were generally well tolerated. The dose-limiting toxicities were fatal pulmonary or cardiac toxicities in five of nine patients treated at the highest dose level. Patients likely to do well can be selected by tumor type, response to prior therapy, and performance status. Nine of 36 assessable patients had a complete response (CR) and 13 a PR for a response rate of 61%. Five patients (12%) remain alive and free of disease at 15 to 32 months. Repeated cycles of dose-intensive combination therapy can produce long-term disease-free remissions in patients with refractory tumor types. The toxicity of the regimen is acceptable if patients are carefully selected.
Candidate Antimetastasis Drugs Suppress the Metastatic Capacity of Breast Cancer Cells by Reducing Membrane Fluidity
Authors: Weina Zhao, Sara Prijic, Bettina C. Urban, Michael J. Tisza, Yan Zuo, Lin Li, Zhi Tan, Xiaoling Chen, Sendurai A. Mani, Jeffrey T. Chang
Journal: Cancer Research (2016)

Abstract Despite the high mortality from metastatic cancer, therapeutic targets to prevent metastasis are limited. Efforts to identify genetic aberrations that predispose tumors to metastasis have been mostly unsuccessful. To understand the nature of candidate targets for metastatic disease, we performed an in silico screen to identify drugs that can inhibit a gene expression signature associated with epithelial–mesenchymal transition (EMT). Compounds discovered through this method, including those previously identified, appeared to restrict metastatic capacity through a common mechanism, the ability to modulate the fluidity of cell membranes. Treatment of breast cancer cell lines with the putative antimetastasis agents reduced membrane fluidity, resulting in decreased cell motility, stem cell–like properties, and EMT in vitro, and the drugs also inhibited spontaneous metastasis in vivo. When fluidity was unchanged, the antimetastasis compounds could no longer restrict metastasis, indicating a causal association between fluidity and metastasis. We further demonstrate that fluidity can be regulated by cellular cholesterol flux, as the cholesterol efflux channel ABCA1 potentiated metastatic behaviors in vitro and in vivo. The requirement for fluidity was further supported by the finding in breast cancer patients that ABCA1 was overexpressed in 41% of metastatic tumors, reducing time to metastasis by 9 years. Collectively, our findings reveal increased membrane fluidity as a necessary cellular feature of metastatic potential that can be controlled by many currently available drugs, offering a viable therapeutic opportunity to prevent cancer metastasis. Cancer Res; 76(7); 2037–49. ©2016 AACR.
Abstract 35: 2-deoxy Adenosine Triphosphate Improves Contraction In Human End-stage Heart Failure
Authors: Farid Moussavi-Harami, Maria V Razumova, Yuanhua Cheng, Alice W Racca, April Stempien-Otero, Michael Regnier
Journal: Circulation Research (2014)

We are developing a novel approach to treat heart failure that involves adeno-associated virus vectors to elevate intracellular 2 deoxy-ATP (dATP) via increased expression of the enzyme Ribonucleotide Reductase. Our studies in rodents have shown that substitution of dATP for ATP as the energy substrate increases contraction in striated muscle. Here we report for the first time the effect of dATP on human cardiac muscle contraction. We measured the contractile properties of demembranated multicellular ventricular wall preparations and isolated myofibrils from adult human heart tissue obtained from twelve patients undergoing surgery for cardiac transplantation or placement of left ventricular-assist device for end-stage heart failure. Isometric force at saturating calcium concentration was increased by about ten percent from 38.6±3.8 mN/mm2 to 42.8±4.2 mN/mm2 when dATP was substituted for ATP (P&lt;0.001). The effect was even greater at physiologic calcium concentrations with an approximate increase of thirty percent. Isometric force increased from 21.2 ± 6.1 mN/mm2 to 26.4± 6.4 mN/mm2 (p&lt;0.001) at pCa=5.6 and from 22.6 ± 5.9 mN/mm2 to 27.5± 6.3 mN/mm2 (p&lt;0.001) at pCa=5.8 with dATP for ATP substitution. The result was an increase in the Ca2+ sensitivity of force as the [Ca2+] required to elicit half maximum force (pCa50) increased by 0.08 units from 5.68±0.03 to 5.79±0.03 (N=24, P&lt; 0.001). The maximum rate of force redevelopment (ktr) in demembranated wall muscle increased (0.82±0.01 s-1 vs. 0.62±0.01 s-1, P&lt; 0.05), as was the rate of contractile activation in isolated myofibrils (0.80±0.06 s-1 vs. 0.57±0.06 s-1, P&lt;0.01) suggesting dATP may increase dP/dT in failing human myocardium. Importantly, there was no slowing of relaxation, as the time to 50% and 90% myofibril relaxation were unchanged. Purified myosin from failing human myocardium showed enhanced NTPase activity with dATP (0.89±0.17 s-1/head) vs. ATP (0.55±0.20 s-1/head, P&lt;0.05). In conclusion, the data strongly suggest dATP increases cross-bridge cycling, compared with ATP in failing human myocardium and shows promise in restoring cardiac pump function. These data support a novel myofilament approach for treating heart failure that warrants further pre-clinical evaluation.
Effects of angiotensin-converting enzyme inhibition on glomerular capillary wall ultrastructure in MWF/Ztm rats.
Authors: B E Iordache, O Imberti, C Foglieni, G Remuzzi, T Bertani, A Remuzzi
Journal: Journal of the American Society of Nephrology (1994)

Previous studies have documented that treatment with angiotensin-converting enzyme (ACE) inhibitors prevents spontaneous proteinuria and enhances the glomerular ultrafiltration coefficient in male MWF/Ztm rats. The aim of this study was to study whether these beneficial effects of ACE inhibitors on glomerular capillary wall function are derived from the preservation of its ultrastructure. Conventional morphometrical analysis of kidney tissue, by light and electron microscopy, was used to quantify glomerular structural changes in the male MWF/Ztm rats treated with the ACE inhibitor cilazapril for 2 and 6 months and in age-matched untreated controls. At the end of the observation periods, both systolic blood pressure and urinary protein excretion were significantly reduced in treated animals as compared with controls. Glomerular volume increased significantly with time but was comparable in control and in treated rats. Surface area available for filtration (measured as peripheral capillary wall) was comparable in control and in treated animals at the same time and increased significantly with time only in treated rats. Mesangial volume was significantly higher in cilazapril-treated animals than in controls after 2 months of treatment and was comparable after 6 months. ACE inhibitor treatment did not induce significant ultrastructural changes such as basement membrane thickness, configuration of epithelial podocytes, and the width and the frequency of the epithelial slit diaphragms. These results indicate that the previously observed increase in the glomerular ultrafiltration coefficient by an ACE inhibitor in these animals is not the consequence of changes in filtering surface area but likely reflects an increase in membrane hydraulic permeability.(ABSTRACT TRUNCATED AT 250 WORDS)
Assessment of the hematopoietic cell transplantation comorbidity index in non-Hodgkin lymphoma patients receiving reduced intensity allogeneic hematopoietic cell transplantation
Authors: S. Pollack, S. Steinberg, J. Odom, R. Dean, D. Fowler, M. R. Bishop
Journal: Journal of Clinical Oncology (2007)

7096 Background: Several patient-related factors influence outcomes after allogeneic hematopoietic cell transplantation (HCT). The Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), a weighted index of 17 pre-transplant comorbidities, has been validated in non- myeloablative HCT studies, but it has not been tested in non-Hodgkin's lymphoma (NHL) patients receiving reduced-intensity conditioning (RIC) HCT nor has it been compared with a number of other pre-transplant factors. Methods: We performed an analysis of 63 NHL patients treated with RIC HCT to assess the HCT-CI's impact on overall survival (OS), treatment-related mortality (TRM) and disease-related mortality (DRM). Individual factors, including performance status, single comorbidities, CD34 dose, prior chemotherapy number, pre-transplant induction chemotherapy response, and NHL histology, were also analyzed relative to their impact on OS. Prior to transplant, all patients received an identical induction regimen (EPOCH-fludarabine). All patients received identical RIC (Cy/Flu) and were transplanted from HLA-matched siblings. Results: In univariate analysis, each of the above factors, except for histology and CD34 dose, exhibited a trend toward an association with OS (adjusted p&lt;0.10). The HCT-CI (0–2 comorbidities vs. 3+ comorbidities) demonstrated an association with TRM at 100 days (4.5% vs. 26.3%) and 1 year (13.6% vs. 36.8%) post-transplant, but not DRM. The factor most strongly associated with OS was response to induction chemotherapy (CR/PR/SD vs. PD; p=0.0025). In a Cox model for OS, induction chemotherapy response remained the sole important factor, while the HCT-CI and other pre-transplant factors added little predictive value to the induction chemotherapy response. The HCT-CI was more strongly associated with OS and TRM in a subset analysis restricted to patients in CR/PR following induction chemotherapy. Conclusions: These findings suggest that the HCT-CI may be useful for estimating probabilities of TRM and OS in NHL patients being considered for RIC HCT. The data further suggest that chemotherapy response at transplant may have significant impact on transplant outcomes. No significant financial relationships to disclose.