tbuckley/cabot-search huggingface dataset:
Second-look laparotomy in the management of patients after radical surgery for ovarian cancer
Authors: M K Tuxen, B Lund, O P Hansen, M Hansen
Journal: Annals of Oncology (1993)

Radically excised ovarian cancers present an unsolved problem with regard to the value of routine second-look operation. This study presents the outcome of second-look operations in an effort to help elucidate this problem.Twenty-eight patients who underwent radical surgery for ovarian cancer stage IC-IIIA were given adjuvant chemotherapy with cyclophosphamide 500 mg/m2 i.v., adriamycin 40 mg/m2 i.v. and 5-fluorouracil 500 mg/m2 i.v., all administered on days 1 and 8 every 4 weeks until achievement of a cumulative adriamycin dose of 400 mg/m2. It was planned that second-look laparotomy would be performed 10-12 months after the primary operation.Four of 28 patients (14.3%) had positive findings at second-look laparotomy. Two of these 4 patients had only microscopic disease, and after second-line chemotherapy including cisplatin one of them is clinically free of tumor 50 months after the primary operation. Two of 28 patients had clinical recurrences before the planned second-look operation. Four of the 22 patients (18.2%) with negative second-look operations developed recurrent disease within a median time of 12 months later. The 5-year survival rate for all 28 patients was 67%.Although a small group of patients may benefit from a strategy that includes delayed second-look operation, we conclude that this should not be a routine procedure in the management of patients who undergo radical surgery for ovarian cancer.
Abstract 51: Aldosterone Induces Cardiac Deleterious Effects Through A Grk2 And Grk5 Dependent Pathway
Authors: Alessandro Cannavo, Daniela Liccardo, Sarah M Bass, Benjamin Woodall, Christopher J Traynham, Jessica Ibetti, Giuseppe Rengo, Walter J Koch
Journal: Circulation Research (2014)

High Aldosterone (Aldo) plasma levels are present in heart failure patients and are associated with increased cardiac fibrosis and hypertrophy. These effects have been shown to be, in part, related to the transactivation of the angiotensin II receptor (AT1R), a G-protein coupled receptor (GPCR). In this regard, the GPCR kinase 2 (GRK2) and 5 (GRK5) are both critical regulators of cardiac function through GPCR regulation. Since these GRKs have also been shown to play a role in cardiac hypertrophy and HF development we investigated whether these kinases may play a role in myocardial Aldo signaling. To test this, we first treated neonatal rat ventricular cardiomyocytes (NRVMs) with Aldo (1 μM) and looked for GRK regulation. Following 12 hrs of Aldo-stimulation we observed a significant increase in both GRK2 and GRK5 protein levels. We also found that Aldo induced the localization of GRK2 to mitochondria, which the lab has previously found to occur following ischemic injury leading to increased cell death and mitochondrial dysfuntion. Indeed, high Aldo on NRVMs led to a significant increase in ROS generation and cell death, as observed by Mitosox Red and TUNEL staining, respectively. Notably, all these effects were abolished respectively by Spironolactone (Spiro, an Aldo receptor blocker) or Losartan (Los, an AT1R antagonist) pre-treatment. Next, in nuclear fractions, purified from Aldo-treated NRVMs, we observed a consistent increase in GRK5 nuclear localization that consequently induced a significant activation of hypertrophic genes, which is consistent with previous studies showing GRK5 being a key regulator of maladaptive cardiac hypertrophy after pressure-overload. Importantly, Spiro pre-treatment efficiently abolished these effects of GRK5. Finally, we treated wild-type mice in vivo with Aldo for two and four weeks and not only found that this induced significant cardiac hypertrophy and fibrosis compared to saline-treated mice, we also found significant increases in levels of GRK2 and GRK5. Therefore, our study provide, for the first time, data demonstrating that GRK2 and GRK5 are potential regulators of Aldo-mediated cardiac pathology acting either down-stream of mineralocorticoid receptor or transactivated AT1Rs.
A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70
Authors: Alice Y. Chan, Divya Punwani, Theresa A. Kadlecek, Morton J. Cowan, Jean L. Olson, Erin F. Mathes, Uma Sunderam, Shu Man Fu, Rajgopal Srinivasan, John Kuriyan, Steven E. Brenner, Arthur Weiss, Jennifer M. Puck
Journal: The Journal of Experimental Medicine (2016)

A brother and sister developed a previously undescribed constellation of autoimmune manifestations within their first year of life, with uncontrollable bullous pemphigoid, colitis, and proteinuria. The boy had hemophilia due to a factor VIII autoantibody and nephrotic syndrome. Both children required allogeneic hematopoietic cell transplantation (HCT), which resolved their autoimmunity. The early onset, severity, and distinctive findings suggested a single gene disorder underlying the phenotype. Whole-exome sequencing performed on five family members revealed the affected siblings to be compound heterozygous for two unique missense mutations in the 70-kD T cell receptor ζ-chain associated protein (ZAP-70). Healthy relatives were heterozygous mutation carriers. Although pre-HCT patient T cells were not available, mutation effects were determined using transfected cell lines and peripheral blood from carriers and controls. Mutation R192W in the C-SH2 domain exhibited reduced binding to phosphorylated ζ-chain, whereas mutation R360P in the N lobe of the catalytic domain disrupted an autoinhibitory mechanism, producing a weakly hyperactive ZAP-70 protein. Although human ZAP-70 deficiency can have dysregulated T cells, and autoreactive mouse thymocytes with weak Zap-70 signaling can escape tolerance, our patients’ combination of hypomorphic and activating mutations suggested a new disease mechanism and produced previously undescribed human ZAP-70–associated autoimmune disease.
Comparison of Oncotype Dx (ODx) 21-gene recurrence score (RS) in African American (AA) and Caucasian (C) patients with hormone receptor-positive (HR+), HER2-negative (HER2-), lymph node-negative (LNN) breast cancer (BC).
Authors: K. B. Kabaker, J. Canar, R. D. Rao, M. A. Cobleigh
Journal: Journal of Clinical Oncology (2011)

620 Background: AA patients have a worse outcome from BC than their C counterparts, which is partly explained by their propensity to develop triple-negative breast cancers. Our hypothesis was that AA patients are more likely to develop BCs with a high RS. Methods: Patients with HR+, HER2-, LNN BC in whom ODx assay was evaluated at Rush University Medical Center were identified. Variables included race, age at diagnosis, tumor size, grade and histologic type, HR expression, and RS. Bivariate and multivariate analyses were performed using race as the independent variable. Results: We identified 323 patients, diagnosed with 332 tumors, who met the above criteria; 14.5% were AA and 77.7% were C with a mean age of 56 in both groups. See table for comparison of mean values for variables of interest. Multivariate analysis revealed no significant association between race and RS (p=0.997). RS was negatively associated with ER (p<0.001) and PR (p<0.001) expression and positively associated with Ki-67 category (p<0.001). AA race was associated with higher Ki-67 category (p=0.002). Race was not found to moderate the direct association of Ki-67 with RS. Further, race does not appear to moderate the significant association of Ki-67, ER and PR with RS. Conclusions: Our study, the largest analysis of RS and race to date, reveals no association between the two variables. AAs developed BCs with a higher proliferative index. A previous study found that all 5 genes in the ODx proliferation cluster were significantly more highly expressed in AAs vs. others (Albain, ASCO 2010). Since high proliferation correlates with benefit from chemotherapy, these data suggest that RS may be less predictive of benefit from chemotherapy in AA than C women. Further studies are necessary to explore this hypothesis. Ki-67 (p<.002) Mean Age Size (cm) ER (%) PR (%) RS <10% 10-20% >20% C 56 1.5 78 50 18 48% 27% 25% AA 56 1.6 80 50 18 19% 48% 33%
Association cannot be assumed to be causal
Authors: L. Whitaker, H. Ward
Journal: BMJ (1996)

injection of the suspect ampicillin.This batch of ampicillin was taken out of circulation immediately, and samples were sent for analysis in Europe.Chemical analysis confirmed the presence of ampicillin but also of high concentrations of N, N-dimethylanalin, a degradation product, and of another, unknown, substance.Culture showed Pseudomonas spp and an unknown organism in the first two phials and Bacillus spp and an unknown organism in the second two phials.The laboratory suggested
Mutagenic Mucus in the Cervix of Smokers&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: E A Holly, N L Petrakis, N F Friend, D L Sarles, R E Lee, L B Flander
Journal: JNCI Journal of the National Cancer Institute (1986)

A pilot study was conducted to determine whether any relationship exists between mutagenicity of a women's uterine cervical mucus and her current smoking status. Cervical fluids obtained from 78 premenopausal women seen between July 1983 and March 1984 at the University of California, San Francisco Dysplasia (and diethylstilbestrol) Clinic or in a private practice were tested for mutagenicity by means of the Ames-Salmonella microsomal test. Of 36 current smokers, 14 (39%) had positive tests as compared to 5 of 42 nonsmokers (12%). The odds ratio (OR) estimate was 4.7 with 95% confidence limits (CL) of 1.6-14.2. Secretions from 14 of 32 (44%) women who had smoked during the day of the sample collection--within the previous 7 hours--were positive on the laboratory test, whereas none of the 4 women was positive who had smoked 8 hours or more before the specimens were obtained. Fluids from women with dysplasia or carcinoma in situ were more likely to be mutagenic than were those from other women, although this finding may be due to chance (OR = 2.0 with 95% CL of .70-5.9). This relationship between smoking and mutagenic cervical fluids offers evidence that might help to explain the association between cervical cancer and cigarette smoking noted in previous epidemiologic studies.
Cancer care on a continuum: Maintaining fertility after diagnosis and treatment.
Authors: J. M. Knopman, J. A. Grifo, P. A. Labella, N. Noyes
Journal: Journal of Clinical Oncology (2010)

9067 Background: Early detection programs combined with improved treatment protocols have allowed cancer patients (CP) to live substantially longer lives. Therefore, quality-of-life issues, such as fertility preservation (FP), have become increasingly important. Previously, time constraints and poor success limited the effectiveness of such procedures. However, recent advancements in oocyte cryopreservation (OC) technology have made this a viable option. OC not only eliminates the need for donor gametes but also the ethical, personal and religious constraints associated with embryo freezing. The novelty of OC has limited its universality; only recently have oncologists begun to refer CP for OC with even fewer yet returning to use these oocytes. To ensure feasibility, we compared OC outcomes of CP to all women without cancer who have completed oocyte thaw (n=32). Methods: CP referred for FP underwent extensive counseling in compliance with the ASRM (2009); those electing OC were included. Ovarian stimulation was achieved with injectable gonadotropins. OC was performed using slow cooling and vitrification methods. Results: 50 CP completed an OC cycle (baseline ovarian reserve testing was normal for all CP); 6 had 1 child already. Malignant diagnoses included 22 gyn, 12 breast, 8 hematologic, 2 GI, 2 CNS and 4 other; 7/9 pts ≥age 38 had breast cancer. FP treatment was completed on average in 12 ±0.3 days. Outcome data are shown in the Table. Conclusions: OC is a novel and potentially successful FP option offering desired reproductive choice. With a dedicated team, OC can be performed expeditiously and successfully, minimizing interference with cancer treatment. As future parenthood greatly impacts quality-of-life, OC should be an integral component of FP counseling in young cancer patients. OC—Cancer (n = 50) OC with thaw—Noncancer (n = 32) P** Age (y) 31 ± 1 (19–43) 32 ± 1 (21–38) 0.9 No. oocytes retrieved 19 ± 2 (0*–55) 22 ± 2 (6–61) 0.2 No. mature oocytes frozen 15 ± 2 (0*–44) 14 ± 2 (5–55) 0.9 Pregnancy outcome 1 thaw: negative 20/32 (63%) pregnant16 delivered; 2 ongoing; 2 aborted Values are mean ± SEM (range). * One CP had 0 oocytes: 40 yo and 16-weeks pregnant at time of diagnosis. ** Mann-Whitney rank sum. No significant financial relationships to disclose.
Impact of timeliness of breast radiotherapy on health outcomes in early breast cancer
Authors: H. T. Gold, H. T. Do
Journal: Journal of Clinical Oncology (2007)

6591 Background: The objective of this study is to understand the impact of timely radiotherapy on disease-free survival (DFS) in early breast cancer patients ages 65 and above. Methods: The study population is women diagnosed from 1991–1999 in the linked SEER-Medicare database who underwent breast-conserving surgery and radiotherapy within 6 months of diagnosis. Median followup varies from 4 years for ductal carcinoma in situ (DCIS)(n=1,185) to 5 years for Stage 1 disease (n=7,481), and ranges from 0–11 years. Descriptive and proportional hazards analysis of this longitudinal cohort were conducted. Covariates include age, race, poverty, marital status, comorbidity, rurality, radiation completion and delay, elapsed time since diagnosis, comedo necrosis histology (DCIS only), and chemotherapy receipt (Stage 1 only). Subjects were censored at end of followup (including enrolling in Medicare managed care from Medicare fee-for-service) or death. Treatment delay is defined as radiotherapy beginning 8+ weeks post-surgery without chemotherapy or 4+ weeks after chemotherapy ends; other definitions also were explored. Radiotherapy is considered complete if the patient received greater than 16/22 of expected treatments, based on scientific literature. Results: DFS is negatively associated with radiation delay (OR=1.24, p=0.003 for Stage 1; OR=1.40, p=0.054 for DCIS) and Klabunde's inpatient comorbidity index (OR=1.32, p=0.004 for Stage 1; OR=1.66, p=0.065 for DCIS). Additional analyses suggest that a longer delay of 12+ weeks post-surgery (16+ weeks post-chemotherapy) further reduces DFS (OR=4.66, p&lt;0.0001 for Stage 1; OR=12.4, p&lt;0.0001 for DCIS). Non-white women with Stage 1 disease are more likely to delay radiotherapy (p&lt;0.0001), but are not more likely to have worse outcomes (p&gt;0.3). Conclusions: Delayed initiation of radiation therapy is associated with decreased DFS following radiotherapy for early breast cancer and DCIS. Non-white race is associated with delay, but not reduced DFS. Programs targeting referring physicians and patients should be developed to promote timely receipt of radiotherapy by early breast cancer patients, thereby reducing the risk of adverse health outcomes. No significant financial relationships to disclose.
Optimal Management of Small Renal Masses
Authors: Ralph Hauke
Journal: Journal of the National Comprehensive Cancer Network (2006)

The incidence of small renal masses is increasing. Limited data suggest that although most are malignant, they are also likely to show indolent behavior. The tendency of these tumors to occur in older patient populations with multiple comorbidities raises important issues. Retrospective and prospective studies suggest that a substantial proportion of these small renal masses can be observed without compromising the opportunity for cure or subjecting patients to invasive procedures that might impact negatively on quality of life. Less-invasive treatment modalities, including partial nephrectomy and energy ablation techniques, provide multiple options for some patients. This article reviews selected aspects of the management of small renal masses, including their natural history, imaging, diagnostic biopsies, and treatment options.
Factors associated with uncontrolled asthma in patients with aspirin-exacerbated respiratory disease (AERD)
Authors: Grazyna Bochenek, Joanna Kuschill-Dziurda, Krystyna Szafraniec, Ewa Nizankowska-Mogilnicka
Journal: European Respiratory Journal (2014)

Background: The control of asthma is the primary goal of its treatment. Despite the improved understanding of asthma pathogenesis and accessibility to novel therapies the rate of uncontrolled asthma is still high.

Aims: To assess the potential factors associated with uncontrolled asthma in a cohort of AERD patients.

Methods: Clinical data were collected using structured questionnaire. Demographics and a history on upper airway symptoms, course of asthma with special attention to exacerbations expressed as emergency department (ED) visits/hospitalizations and asthma treatment were taken. Spirometry, skin tests, total IgE, blood eosinophilia were evaluated. Asthma control was assessed by the Asthma Control Test (ACT).

Results: Among 201 AERD patients, 41 (20.4%) had controlled asthma, 69 (34.3%) and 91 (45.3%) had partially controlled and uncontrolled asthma, respectively. Females had the odds of having uncontrolled asthma by 1.57 (95%CI, 0.85-2.53) higher than males. Multivariate logistic regression analysis identified that 1) ED visits for asthma throughout the time of its duration (OR 1.05; 95%CI, 1.002-1.1), 2) hospitalizations for asthma in the previous 12 months (OR 3.4; 95%CI, 1.3-8.7), 3) total IgE (OR 1.27; 95%CI, 1.02-1.6), 4) FEV1 (OR 0.98; 95%CI, 0.96-0.996) and 5) medical care at referential specialty clinic (OR 0.49; 95%CI, 0.26-0.93) were the strongest independent factors associated with uncontrolled asthma.

Conclusions: Uncontrolled asthma was prevalent in a cohort of AERD patients with higher propensity in females. It seems that AERD patients should stay under regular medical care of the referential specialty clinic to secure a better control of their asthma.
Multicenter phase III trial of adjuvant chemoradiotherapy in stomach tumors 2 (ARTIST 2).
Authors: Se Hoon Park, Su Jin Lee, Seung Tae Kim, Jeeyun Lee, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang
Journal: Journal of Clinical Oncology (2015)

TPS228 Background: Treatment of gastric cancer (GC) has some notable differences between Asia and Western countries including the extent of surgery and the type of adjuvant therapy. In ARTIST trial comparing adjuvant chemotherapy involving capecitabine plus cisplatin with chemoradiotherapy, we reported comparable disease-free survival (DFS) in Korean patients with D2-resected GC. In subset analyses, patients with node-positive disease and intestinal type GC may have benefit with the addition of radiotherapy to adjuvant chemotherapy. Methods: ARTIST 2 (ClinicalTrials.gov, NCT0176146) is a 3-arm, multi-center, open-label phase III trial comparing adjuvant chemotherapy involving S-1 (40 mg/m2 bid 4-weeks-on/2-weeks-off) for one year (arm A) with S-1 plus oxaliplatin (SOX, S-1 40 mg/m2 bid 2-weeks-on/1-week-off plus oxaliplatin 130 mg/m2 iv on day 1) for 8 cycles (arm B) and chemoradiotherapy (arm C). Arm C patients receive SOX for 2 cycles, then concurrent chemoradiotherapy 45 Gy with S-1 40 mg bid daily, followed by additional SOX for 4 more cycles. Patients are randomized 1:1:1 with 3 strata: stage (II or III), type of surgery (subtotal or total gastrectomy) and Lauren classification (diffuse or intestinal type). Eligibility criteria include gastric or gastro-esophageal junction adenocarcinoma, D2 or higher surgery with no residual disease, pathologic stages 2 or 3, lymph node positive disease. Primary endpoint is DFS, and secondary endpoints include overall survival, safety, QOL and molecular biomarkers. To test if experimental arms (arm B or C) lower the hazard of recurrence by 50% (i.e., HR 1.5) compared to arm A, we need 900 patients (300 per arm) with 90% of overall statistical power. First patient entered onto the study in Feb 2013. As of Aug 2014, a total of 118 (13% of target) patients were recruited by 8 Korean tertiary centers. Clinical trial information: NCT0176146.
Preclinical in vitro characterization of anti-CTLA4 therapeutic antibody CP-675,206.
Authors: Douglas C. Hanson, Paul C. Canniff, Michael J. Primiano, Carol B. Donovan, Joseph P. Gardner, Edward J. Natoli, Rodney W. Morgan, Robert J. Mather, David H. Singleton, Paul A. Hermes, Mark J. Neveu, Glenn C. Andrews, Christopher D. Castro, Eileen A. Elliott, Vahe Bedian
Journal: Cancer Research (2004)

3801   Urokinase plasminogen activator (uPA) and its receptor (uPAR) are overexpressed in many cancer types compared to normal tissue. The presence of both uPA and uPAR in cancer tissue may potentially be exploited in cancer therapy for specific and targeted activation of prodrugs. We have constructed a modified form of anthrax protective antigen, PrAg-U2, in which a furin activation site is shifted with an uPA cleavage site. PrAg-U2 administered together with the fusion protein FP59, consisting of lethal factor residues 1–254 and the ADP ribosylation domain of  Pseudomonas  exotoxin A, constitutes a potent and uPA-activity dependent cytotoxic drug (OTP-001).  In vitro  binding of pro-uPA to uPAR is necessary for the cytotoxicity of OTP-001 (Liu et al., J. Biol. Chem, 276:17976–84, 2001) and local administration of OTP-001 in mice with transplanted tumors had a potent antitumor effect (Liu et al., PNAS, 100:657–62, 2003). The aim of the present studies was i) To examine the antitumor effect of OTP-001 after systemic administration, ii) To find the optimal ratio between the two components PrAg-U2 and FP59, iii) To define the “therapeutic window” of OTP-001. Five separate  in vivo  experiments were performed with three different transplanted tumors, Lewis lung carcinoma, T241 fibrosarcoma and B16 melanoma. In all studies, C57BI/6J mice where transplanted with 10 6  tumor cells. When the tumors had reached a volume of approximately 50 mm 3 , a dose range of OTP-001 was administered systemically to the mice at day 0, 3, and 6. Different ratios of PrAg-U2 and FP59 were tested. Tumor sizes were obtained by daily recording of two orthogonal diameters during the growth phase. All experiments unequivocally demonstrated that OTP-001 has significant antitumor effect after systemic administration in mice with transplanted B16, T241 or Lewis lung tumors. These studies showed that OTP-001 displays a clear dose-response relationship with regard to anti-tumor effect and systemic toxicity. The dose-limiting toxicity appears to be due to mucosal reactions in the gut. The anti-tumor effect was most pronounced with a ratio of the two components PrAg-U2 and FP59 of 25:1. Intraperitoneal administration of 30 μg PrAg-U2 and 1.2 μg FP59 day 0, day 3 and day 6 was found to have minimal toxic effects and still had a significant antitumor effect.
心力衰竭（二）—病理生理学
Authors: 卢朝晖, GJackson
Journal: BMJ (2001)

心力衰竭 (心衰 )是一种多系统的疾患 ,以心脏、骨骼肌及肾功能异常为特征 ,且伴有交感神经系统刺激及神经激素改变等一系列复杂的过程。 心肌收缩期功能障碍非瓣膜性心衰最初的异常改变为左心室功能下降 ,使心输出量降低。而心输出量降低又可激活某些神经激素代偿机制 ,这些代偿机制旨在改善心脏的动力学状况。例如 ,交感神经系统兴奋 ,通过加快心率、增加心肌收缩及外周血管收缩 (增加儿茶酚胺分泌 )而维持心输出量。肾素 血管紧张素 醛固酮系统兴奋也可使血管收缩 (血管紧张素 )、水钠潴留(醛固酮 )而增加血容量。此外还有血管加压素等促尿钠肽类增加。久之 ,可造成心腔扩张或心脏结构的改变 (改建 )