tbuckley/cabot-search huggingface dataset:
Effectiveness of the dual specific Src/Abl kinase inhibitor AZD0530 in combination with tamoxifen in preventing acquired anti-estrogen resistance in breast cancer cells
Authors: S. Hiscox, T. P. Green, C. Smith, N. Jordan, M. James, R. Nicholson
Journal: Journal of Clinical Oncology (2007)

14054 Background: AZD0530 is a novel, orally potent, once-daily, highly selective and dual-specific Src/Abl kinase inhibitor with potential for activity in a wide range of tumors. In the context of breast cancer, where tamoxifen resistance presents a major problem, Src inhibition may be a particularly valuable therapeutic strategy since we have previously observed that elevated Src kinase activity accompanies anti-estrogen resistance in vitro, promoting an aggressive cell phenotype. Here, we have explored the potential therapeutic effects of Src inhibition with AZD0530, alone and in combination with tamoxifen, on the acquisition of endocrine resistance in breast cancer cells. Methods: MCF7 and T47D breast cancer cells were exposed to tamoxifen (10–7 M), AZD0530 (1 μM), or both agents in combination for a minimum of 10 months with passaging as necessary, or until total cell death occurred. Cells were assayed at monthly intervals for intracellular signaling pathway activity (Western Blotting) and in vitro invasive capacity (Matrigel invasion assays). Apoptosis and proliferation were assessed by ELISA and Ki67 staining, respectively. Changes in c-Myc and cyclin-D1 were measured with RT-PCR. Results: Treatment of cells with tamoxifen alone ultimately resulted in acquired resistance, elevated Src kinase activity, and a Src- dependent increase in invasive capacity. Chronic exposure to AZD0530 alone resulted in outgrowth of AZD0530 resistant cells, in which Src kinase activity remained suppressed as did their in vitro invasiveness. Treatment of MCF7 and T47D cells with AZD0530 and tamoxifen combined resulted in a reduction of Src, FAK, and Akt activity, inhibition of c-Myc gene expression, and complete abrogation of their in vitro invasive behavior. Furthermore, combination treatment completely prevented cell proliferation and the subsequent emergence of a resistant phenotype, with a total loss of cells by 12 weeks. Conclusions: Inhibition of Src kinase with AZD0530, when used in conjunction with anti-estrogen therapies, effectively prevents acquired resistance in breast cancer cells in vitro suggesting a potential novel therapeutic benefit of Src kinase inhibitors clinically. No significant financial relationships to disclose.
Discontinuation of Primary Prophylaxis against<i>Pneumocystis carinii</i>Pneumonia in HIV-1–Infected Adults Treated with Combination Antiretroviral Therapy
Authors: Hansjakob Furrer, Matthias Egger, Milos Opravil, Enos Bernasconi, Bernard Hirschel, Manuel Battegay, Amalio Telenti, Pietro L. Vernazza, Martin Rickenbach, Markus Flepp, Raffaele Malinverni
Journal: New England Journal of Medicine (1999)

It is unclear whether primary prophylaxis against Pneumocystis carinii pneumonia can be discontinued in patients infected with the human immunodeficiency virus (HIV) who are successfully treated with combination antiretroviral therapy. We prospectively studied the safety of stopping prophylaxis among patients in the Swiss HIV Cohort Study.
Cardiovascular Disease After Aromatase Inhibitor Use
Authors: Reina Haque, Jiaxiao Shi, Joanne E. Schottinger, Joanie Chung, Chantal Avila, Britta Amundsen, Xiaoqing Xu, Ana Barac, Rowan T. Chlebowski
Journal: JAMA Oncology (2016)

Cardiovascular disease (CVD) is an important cause of death in older patients with breast cancer. However, limited information exists on the long-term effect of aromatase inhibitor (AI) use on CVD risk in breast cancer survivors. To this point, no other population-based studies have been able to adjust for CVD risk factors or cardiovascular medications.To determine the long-term influence of adjuvant endocrine therapies on CVD in a cohort of postmenopausal breast cancer survivors in analyses that accounted for major CVD risk factors, medication use, chemotherapy, and radiotherapy.A retrospective cohort of postmenopausal women with breast cancer diagnosed from January 1, 1991, to December 31, 2010, and followed up through December 31, 2011 (maximum, 21 years [72 886 person-years]), was evaluated using records from a managed care organization with nearly 20 community hospitals in California. A total of 13 273 postmenopausal women with hormone receptor-positive breast cancer without prior CVD were included. Cardiovascular disease incidence was compared across endocrine therapy categories. Information on demographics, comorbidity, medication, use, and CVD risk was captured from electronic health records. Multivariate Cox proportional hazards models using time-dependent endocrine drug use variables and propensity scores were conducted. Data analysis was conducted from September 15, 2014, to February 1, 2016.Women were grouped by endocrine therapy status (tamoxifen citrate only, AI only, both, or neither).Person-year rates of CVD for each therapy group.During 72 886 person-years in 13 273 women (mean [SD] age, 66.8 [8.1] years) with follow-up through 2011, we observed 3711 CVD events. In multivariable analyses (reported as hazard ratio [95% CI]), AI-only users had a similar risk of cardiac ischemia (myocardial infarction and angina) (adjusted, 0.97 [0.78-1.22]) and stroke (adjusted, 0.97 [0.70-1.33]) as tamoxifen-only users (reference). However, we found an increased risk of other CVD (dysrhythmia, valvular dysfunction, and pericarditis) (adjusted, 1.29 [1.11-1.50]) in women who used AIs only or sequentially after tamoxifen (1.26 [1.09-1.45]) vs tamoxifen (reference) as well nonhormone users (1.18 [1.02-1.35]).The risk of the most serious cardiovascular events (cardiac ischemia or stroke) was not elevated in AI-only users compared with tamoxifen users. The finding that other CVD events combined were greater in AI users requires further study.
Should lymphangioleiomyomatosis patients be permitted to donate blood?
Authors: Anne F. Eder, Jay H. Ryu, Joel Moss
Journal: European Respiratory Journal (2016)

Lymphangioleiomyomatosis (LAM) is a rare disease, seen primarily in women and characterised by cystic lung destruction, renal angiomyolipoma and lymphatic abnormalities ( e.g. lymphangioleiomyomas) [1]. LAM occurs sporadically in 3–7.8 women per million, and in tuberous sclerosis complex (TSC), an autosomal dominant disorder, that occurs in ∼1:5800 live births [1]. LAM behaves as a slowly progressive, chronic neoplasm [2, 3], which results from proliferation of phenotypically and genetically heterogeneous LAM cells [1]. Similar to cancer cells, LAM cells are capable of metastasis, invasion and destruction of surrounding matrix [3]. Circulating LAM cells, detected in ∼90% of patients, can be isolated from blood, urine and chyle, and presumably, represent a mechanism for metastasis [4]. The disease responds to treatment with sirolimus (rapamycin), an inhibitor of mechanistic target of rapamycin, which was recently approved by the US Food and Drug Administration (FDA) for LAM. Sirolimus stabilises lung function, shrinks angiomyolipomas and lymphangioleiomyomas, and reduces the ability to detect circulating LAM cells [1, 5]. LAM-related tumours, however, can still be identified by imaging studies. As a precaution to protect both donor and recipient, LAM patients should not donate blood <http://ow.ly/10CM0k>
Fatal Strongyloidiasis in Patients Receiving Corticosteroids
Authors: Thomas Cruz, Gilberto Reboucas, Heonir Rocha
Journal: New England Journal of Medicine (1966)

THE influence of corticosteroids in initiation or aggravation of infections has been described in detail.1 In addition to bacterial, viral, rickettsial or fungous infections,2 3 4 there is clinical and experimental evidence that some protozoan diseases such as trypanosomiasis, malaria and amebiasis may be aggravated by steroid therapy.5 6 7 Galliard and Berdonneau8 have reported that dogs previously refractory to Strongyloides stercoralis infection may become susceptible after treatment with cortisone. In spite of these observations the use of corticosteroids has been suggested in the treatment of selected cases of severe strongyloidiasis.9 This communication reports 5 cases of fatal strongyloidiasis in association with corticosteroid therapy . . .
Impatient Inpatient Care
Authors: Mridu Gulati, Sanjay Saint, Lawrence M. Tierney
Journal: New England Journal of Medicine (2000)

A 62-year-old, retired painter was hospitalized three weeks before transfer to a referral hospital. He reported a temperature of 38.8°C, chills, myalgias, headache, and dysuria of five days' duration. About three months earlier, he had also been hospitalized with fever and dysuria, which responded to treatment with ciprofloxacin; urine and blood cultures were negative at that time.In a retired painter, one thinks of lead intoxication or chronic alcoholism. Dysuria may indicate the presence of urethritis. The recurrence of symptoms after three months raises the question of a localized process in the genitourinary system, such as a prostatic . . .
Integrating early palliative care into cancer care: A qualitative analysis of implementation models, barriers, and strategies in community settings.
Authors: Lynne Slaughter Padgett, Mary Helen Davis, Colleen Tallen, Andrew Jdaydani, Angela Carrigan
Journal: Journal of Clinical Oncology (2014)

36 Background: There is a paucity of research providing evaluation of implementation strategies contributing to provision of high quality early palliative care. Data from the NCI Community Cancer Centers Program (NCCCP) offers insight into ways in which patients, providers, and systems negotiate the provision of early palliative care in the community setting. The purpose of this project was to test the implementation of early palliative care programs for patients diagnosed with a high lethality cancer in participating NCCCP centers. Methods: Thirteen of 21 NCCCP sites elected to participate. Data on project activities and progress was gathered quarterly between July 2012 and June 2014. Qualitative data were evaluated using inductive and deductive methods and models of care, barriers and strategies were identified. Results: Models of care described included group education visits for patients and caregivers, outpatient clinics, and electronic consultation referral triggers. Irrespective of the model of care, sites reported barriers at the patient, provider and system levels. Barriers included reluctance by both patients and providers to consider palliative care services due to the perception of "giving up," and inadequate staffing and clinic space were also cited as systemic barriers. Strategies for facilitating implementation included integrating palliative care staff into existing cancer center programs (e.g., multi-disciplinary clinics), electronic referrals, and utilizing navigation services, as well as a variety of programs targeted to increase oncologist "buy-in." Conclusions: These results provide guidance for both researchers and clinicians in designing future multi-level interventions to facilitate the delivery of early palliative care, and the importance of identifying and utilizing provider and system resources in program design, development and promotion. Provider buy-in is an essential factor, but patient and system resources are equally important components of a successful implementation strategy.
Wool as a Cause of Eczema in Children
Authors: Lewis Webb Hill
Journal: New England Journal of Medicine (1951)

THERE are many children affected with eczema who are nearly or entirely free from it in summer but in whom it recurs at the onset of cold weather and lasts through winter and spring. As soon as the weather becomes warm their condition begins to improve. It is obvious that something harms them in winter that is absent in summer.Wool deserves consideration as one possible cause. This has been noted by several observers.1 2 3 4 Young children are veritably smothered in wool in the winter. They wear mittens, coarse snow suits, wool hats, sweaters, scarfs and socks; they are continually in . . .
Hematopoietic Stem Cell–Based Gene Therapy for Acquired Immunodeficiency Syndrome: Efficient Transduction and Expression of RevM10 in Myeloid Cells In Vivo and In Vitro
Authors: Lishan Su, Robert Lee, Mark Bonyhadi, Hajime Matsuzaki, Sean Forestell, Sonia Escaich, Ernst Böhnlein, Hideto Kaneshima
Journal: Blood (1997)
Temozolomide for recurrent intracranial supratentorial platinum-refractory ependymoma
Authors: S. K. Johnston, M. C. Chamberlain
Journal: Journal of Clinical Oncology (2009)

2061 Background: There is no standard therapy for platinum-resistant ependymoma and hence a need exists for new therapies. Objective: A retrospective evaluation of temozolomide (TMZ) in adults with recurrent supratentorial platinum-refractory WHO grade 2 ependymoma with an objective of determining 6-month progression free survival (PFS). Methods: 25 patients, ages 28–63 years, with recurrent ependymoma were treated. All patients had previously been treated with surgery, radiotherapy, and platinum-based chemotherapy (cisplatin: 15; carboplatin 10). Nine patients underwent repeat surgery. Patients were treated at second recurrence with TMZ (5 consecutive days), once every 4 weeks, defined as a single cycle. Neurological evaluation was performed every 4 weeks and neuroradiographic assessment every 8 weeks. Results: A total of 68 cycles of TMZ (median 2 cycles; range 1–6) was administered. TMZ-related toxicity included leukopenia (7 patients; 1 grade 3), constipation (6 patients; 0 grade 3), fatigue (5 patients; 0 grade 3), anemia (2; 0 grade 3), thrombocytopenia (2; 0 grade 3), and deep vein thrombosis (2; 0 grade 3). One patient (4%) demonstrated a partial radiographic response, nine (36%) stable disease, and 15 (60%) progressive disease following two cycles of temozolomide. Time to tumor progression ranged from 1–7 months (median: 2 months). Survival ranged from 2–8 months (median: 3 months). 6-month and 12-month PFS were 2% and 0% respectively. Conclusions: Temozolomide in this dose schedule demonstrated little efficacy in a cohort of adults with recurrent intracranial platinum-refractory ependymoma. No significant financial relationships to disclose.
Experience with the Subcutaneous Cerebrospinal-Fluid Reservoir
Authors: Robert A. Ratcheson, Ayub K. Ommaya
Journal: New England Journal of Medicine (1968)

A subcutaneous cerebrospinal-fluid reservoir was used in 60 patients between 1962 and 1968. The total complication rate related to the reservoirs was 28 per cent. Major complications numbered six. Surgical revision, usually within the first three months after installation, was necessary in 25 per cent. After the first three months, complications were less frequent. The reservoirs were used for the chemotherapy of neoplasia, cystic tumor drainage, ventricular drainage, special diagnostic studies and the sampling of cerebrospinal fluid. The reservoirs were particularly useful for intrathecal chemotherapy of resistant meningeal leukemia with perfusion technics, and for drainage of intracranial cysts. In selected cases, the advantages of the subcutaneous reservoir outweigh the morbidity incurred.
Benign Postoperative Intrahepatic Cholestasis
Authors: Martin Schmid, Max L. Hefti, Ruth Gattiker, Hans J. Kistler, Åke Senning
Journal: New England Journal of Medicine (1965)

TRANSIENT jaundice occasionally appears after a surgical procedure, usually an operation for an abdominal problem. In such cases very little is known about the anatomic changes in the liver or their pathogenesis.1 A series of cases of benign postoperative jaundice occurring almost in epidemic proportions at the University of Zurich Hospital provided an opportunity for study of this phenomenon. Within an eight-month period (September, 1962, through May, 1963) 11 cases of postoperative jaundice were observed, and a twelfth case was added to the total thereafter. The clinical picture and course in all these cases were associated with histologic evidence of . . .
Myocardial Changes Associated with Cardiogenic Shock
Authors: David L. Page, James B. Caulfield, John A. Kastor, Roman W. DeSanctis, Charles A. Sanders
Journal: New England Journal of Medicine (1971)

The amount of left ventricular myocardium destroyed by recent and old infarcts in patients with acute myocardial infarction with and without cardiogenic shock was compared in hearts obtained at autopsy. All 20 patients with, and only one of 14 without, shock had lost 40 per cent or more of the left ventricle. The remainder lost 35 per cent or less. These results indicate that cardiogenic shock is associated with extensive loss of left ventricular myocardium due to new and frequently old infarcts as well. In five cases the new infarct was small as compared to the total amount of myocardial destruction. Patients with cardiogenic shock consistently showed marginal extension of the recent infarct (unlike those not in shock) and focal areas of necrosis throughout both left and right ventricles. Similar focal lesions were encountered in a third series of 20 patients with shock from other causes. A sharp reduction in coronary perfusion pressure could explain this combination of findings, which indicate that cardiogenic shock is a continuous, self-perpetuating, vicious circle leading to progressive, irreversible myocardial dysfunction.
Reducing Cardiac Risk in Noncardiac Surgery
Authors: Thomas H. Lee
Journal: New England Journal of Medicine (1999)

“Avoid hypotension.” That recommendation has appeared at the end of many preoperative consultation notes for patients undergoing major noncardiac surgery. This not-so-helpful advice has reflected the state of the science of perioperative cardiac risk reduction. A great deal of research provides insight into how to identify patients at moderate and high risk.14 Very little is known about strategies that might improve their outcomes.The era in which physicians can only guess at how to reduce a patient's risk of perioperative cardiac complications seems to be ending, however, as demonstrated by the study by Poldermans et al.5 in this issue . . .
Unstable Angina and Progression of Coronary Atherosclerosis
Authors: Alain Moise, Pierre Théroux, Yves Taeymans, Bénédicte Descoings, Jacques Lespérance, David D. Waters, Guy B. Pelletier, Martial G. Bourassa
Journal: New England Journal of Medicine (1983)

We studied the progression of atherosclerotic coronary lesions in 38 patients who had previously undergone angiography and were later hospitalized for an episode of unstable angina pectoris, and in 38 matched patients with stable angina who had also undergone prior catheterization. Patients with unstable angina and those with stable angina were similar in terms of age (mean, 49 and 50 years, respectively), number of risk factors (1.5 per patient in both groups), interval between studies (mean ±S.D., 44±31 and 35±31 months, respectively), number of diseased vessels on the first angiogram (1.52 in both groups), and initial ejection fraction (65 and 63 per cent, respectively). Progression of coronary lesions was demonstrated in 29 of the 38 patients with unstable angina, as compared with 12 of the 38 with stable angina (P<0.0005). Progression to 70 per cent or more stenosis was recorded in 21 of the patients with unstable angina but in only 5 of those with stable angina (P<0.0005). Also more frequent in the patients with unstable angina were multifocal progression (11 vs. 2, P<0.01) and progression of the left main or preseptal left anterior descending artery or both (9 vs. 1, P<0.01). Thus, we have demonstrated by angiography that unstable angina is associated with progression in the extent and severity of coronary atherosclerosis. (N Engl J Med 1983; 309:685–89.)
Sarcoidosis in Identical Twins
Authors: Joseph F. Sherer, Robert T. Kelley
Journal: New England Journal of Medicine (1949)

SINCE the original descriptions by Besnier, Boeck and Schaumann of the disease that now bears their names, many papers1 2 3 4 have adequately presented the characteristic clinical and pathological findings. However, relatively few authors have reported on the occurrence of sarcoidosis in siblings. No report has been made of sarcoidosis in twins.Leitner5 mentions several authors who have described sarcoidosis as it occurred among members of the same family. He states that Richter found sarcoidosis in sisters. The older one showed involvement of the skin, typical lung findings and splenomegaly; the younger sister had cystic changes in the bones and lesions of . . .
Abstract POSTER-BIOL-1327: Small cell carcinoma of the ovary, hypercalcemic type displays frequent inactivating germline and somatic mutations in SMARCA4
Authors: Pilar Ramos, Anthony N. Karnezis, David W. Craig, Aleksandar Sekulic, Megan L. Russell, William P.D. Hendricks, Jason J. Corneveaux, Michael T. Barrett, Karey Shumansky, Yidong Yang, Sohrab P. Shah, Leah M. Prentice, Marco A. Marra, Jeffrey Kiefer, Victoria L. Zismann, Troy A. McEachron, Bodour Salhia, Jaime Prat, Blaise A. Clarke, Joseph G. Pressey, John H. Farley, Stephen P. Anthony, Richard B.S. Roden, Heather E. Cunliffe, David G. Huntsman, Jeffrey M. Trent
Journal: Clinical Cancer Research (2015)

Abstract Introduction: Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is arguably the most aggressive ovarian cancer. Most patients are diagnosed at an advanced stage, do not respond to chemotherapy, and die of disease within 1-2 years. It affects children and young women and is reported to occur in families. The cause of the disease is poorly understood. Therefore, we used next generation sequencing technology to identify the genetic basis of the disease. Method: We performed whole genome, whole exome sequencing or targeted sequencing on tumours and germline samples from 17 SCCOHT patients and on the SCCOHT cell line BIN-67 and SCCOHT-1. Immunohistochemistry (IHC) was performed on formalin-fixed, paraffin-embedded tumors from 23 patients and on a tissue microarray of 485 primary ovarian tumours of other subtypes. BIN-67 cells harbouring biallelic inactivation of SMARCA4 were transduced with a lentivirus expressing wild type SMARCA4. Result: We identified inactivating germline and somatic mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 79% (11/14) of SCCOHT patients, 2 of whom bore germline mutations, and in both cell lines. SMARCA4 protein was lost in 87% (20/23) of SCCOHT tumours but in only 0.4% (2/485) of other primary ovarian tumours. Reintroduction of wild-type SMARCA4 into BIN-67 cells resulted in altered cell morphology and growth arrest. Conclusions: The mutation spectrum, IHC profile and cell culture phenotype implicate SMARCA4 as a critical tumour suppressor in SCCOHT pathogenesis. Citation Format: Pilar Ramos, Anthony N. Karnezis, David W. Craig, Aleksandar Sekulic, Megan L. Russell, William P.D. Hendricks, Jason J. Corneveaux, Michael T. Barrett, Karey Shumansky, Yidong Yang, Sohrab P. Shah, Leah M. Prentice, Marco A. Marra, Jeffrey Kiefer, Victoria L. Zismann, Troy A. McEachron, Bodour Salhia, Jaime Prat, Blaise A. Clarke, Joseph G. Pressey, John H. Farley, Stephen P. Anthony, Richard B.S. Roden, Heather E. Cunliffe, David G. Huntsman, Jeffrey M. Trent. Small cell carcinoma of the ovary, hypercalcemic type displays frequent inactivating germline and somatic mutations in SMARCA4 [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1327.