tbuckley/cabot-search huggingface dataset:
Eight drugs in one day chemotherapy in children with brain tumors: a critical toxicity appraisal.
Authors: J R Geyer, T W Pendergrass, J M Milstein, W A Bleyer
Journal: Journal of Clinical Oncology (1988)

The toxicity of a new chemotherapeutic regimen for CNS tumors using eight anticancer agents administered in a 12-hour period was evaluated in 34 children with newly diagnosed and recurrent tumors treated at the Children's Hospital and Medical Center in Seattle. The chemotherapy included methylprednisolone, vincristine, lomustine (CCNU), procarbazine, hydroxyurea, cisplatin (CDDP), and either cyclophosphamide or imidazole carboximide (DTIC). The first five patients additionally received high-dose methotrexate (HDMTX), but because of excessive toxicity this was replaced by cytarabine. Of 125 courses administered without HDMTX, red cell transfusions were required in 15% of the courses and platelet transfusions were required in 8%. Hospitalization for empiric treatment of fever associated with neutropenia occurred in 6% of courses. Three episodes of documented sepsis occurred. Virtually all hematologic toxicity occurred in patients with recurrent disease. Renal toxicity occurred in 14% of patient courses. One patient died of renal failure and sepsis following therapy. Neurologic and hepatic complications were infrequent. High-frequency hearing loss above the voice range was common, but clinically significant hearing loss occurred in only three patients. Severe nausea and vomiting were infrequent. Overall, the toxicity of "eight in one" chemotherapy in newly diagnosed patients was minimal; toxicity was greater in patients with recurrent disease.
Aspergillus Cell Wall Melanin Blocks LC3-Associated Phagocytosis to Promote Pathogenicity
Authors: Tonia Akoumianaki, Irene Kyrmizi, Isabel Valsecchi, Mark S. Gresnigt, George Samonis, Elias Drakos, Dimitrios Boumpas, Laetitia Muszkieta, Marie-Christine Prevost, Dimitrios P. Kontoyiannis, Triantafyllos Chavakis, Mihai G. Netea, Frank L. van de Veerdonk, Axel A. Brakhage, Jamel El-Benna, Anne Beauvais, Jean-Paul Latge, Georgios Chamilos
Journal: Cell Host & Microbe (2015)
Charging £500 for work experience in hospital is “completely unfair,” says charity
Authors: Zosia Kmietowicz
Journal: BMJ (2015)

A charity that provides careers advice to children from disadvantaged backgrounds has condemned a private care provider for charging £500 (€690; $770) a week for work experience at its facilities.

Deborah Streatfield, from MyBigCareer, told The BMJ that some of the children she worked with could not afford their school uniform and that many came to school hungry. Yet for pupils in the private school sector the £500 placements offered by the Chartwell Trust “was nothing,” she said.

“It is not a level playing field,” said Streatfield.

Chartwell Trust runs a private hospital in …
Abstract 13400: 5-year Outcomes After Catheter Ablation in Patients With Atrial Fibrillation and Left Ventricular Systolic Dysfunction
Authors: Thomas J Bunch, Heidi T May, Tami L Bair, Victoria Jacobs, Brian G Crandall, Michael Cutler, J P Weiss, Charles Mallendar, Jeffrey S Osborn, Jeffrey L Anderson, John D Day
Journal: Circulation (2014)

Backgroud. Catheter ablation of atrial fibrillation (AF) is an established therapeutic rhythm approach in symptomatic patients. The efficacy and safety amongst patients with left ventricular systolic dysfunction has been demonstrated often over a 1 year follow-up with improved cardiac function, heart failure status, and quality of life. However, long-term data are needed to understand if progression of cardiomyopathy may result in recurrence of arrhythmia and if the 1-year favorable results after ablation are maintained.   Methods:  3 groups with systolic heart failure (SHF) and 5 years of follow-up were matched 1:4:4 by age (±5 years) and sex. AF ablation patients receiving their first ablation (n=267), AF patients that did not receive an ablation (n=1068), and SHF patient without AF (n=1068). A patient was deemed as having SHF if they had both a clinical diagnosis(ICD-9 code 428.8*) and an ejection fraction(EF)   Results:  The average age of the population was 67±13 years and 78% male. The AF was paroxysmal in 25%, persistent in 34.7%, and longstanding persistent in 41%. At 5 years, 60.7% of patients had clinical recurrence of AF. Diabetes and a prior heart attack were the only significant predictors of long-term risk of AF recurrence after ablation. Long-term mortality rates were 27%, 55%, 50%, in the AF ablation, AF, and no AF groups, respectively (p   Conclusion:  Recurrence rates of AF in patients with SHF are common after an initial procedure at 5 years with an anticipated ongoing increase. In general, early improvement in cardiac function is not maintained at 5 years, but heart failure hospitalization is less after ablation. Overall survival at 5 years is highest in the AF ablation group, largely attributed to less cardiovascular deaths.
Randomized biomarker trial of anastrozole and low-dose tamoxifen in breast intraepithelial neoplasia: Effects on bone turnover and drug concentrations
Authors: A. Decensi, D. Serrano, S. Gandini, G. Bollani, D. Macis, M. Lazzeroni, M. Cazzaniga, I. Feroce, A. Guerrieri-Gonzaga, B. Bonanni
Journal: Journal of Clinical Oncology (2005)

1000
Absence of Uniform Progressive Growth of Long-Term Transplants of Rat Liver Neoplastic Nodules&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: T Ohmori, K Watanabe, G M Williams
Journal: JNCI Journal of the National Cancer Institute (1980)

Fragments of normal rat liver and neoplastic nodules induced by feeding 0.02% N-2-fluorenylacetamide for 20 weeks were transplanted into the inguinal mammary fat pads of syngeneic rats. All animals were Charles River inbred male albino rats of the CDF strain derived from the F344 strain. Normal liver transplants and neoplastic nudule transplants were detected histologically in the transplant site up to 24 and 66 weeks of survival, respectively. Of 30 nodule transplants followed up to 121 weeks, only 1 neoplastic nodule developed progressive neoplastic growth. The tumor that arose in the transplant site from this nodule was a well-differentiated adenocarcinoma with mucin production. Thus rat liver neoplastic nodules lack the high frequency of progressive growth previously demonstrated for carcinomas.
Diversity of Clostridium difficile PCR ribotypes in Europe: results from the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID), 2012 and 2013
Authors: Kerrie A Davies, Helen Ashwin, Christopher M Longshaw, David A Burns, Georgina L Davis, Mark H Wilcox
Journal: Eurosurveillance (2016)

Clostridium difficile infection (CDI) is the major cause of infective diarrhoea in healthcare environments. As part of the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID), the largest C. difficile epidemiological study of its type, PCR ribotype distribution of C. difficile isolates in Europe was investigated. PCR ribotyping was performed on 1,196 C. difficile isolates from diarrhoeal samples sent to the European coordinating laboratory in 2012–13 and 2013 (from two sampling days) by 482 participating hospitals from 19 European countries. A total of 125 ribotypes were identified, of which ribotypes 027 (19%, n =222), 001/072 (11%, n = 134) and 014/020 (10%, n = 119) were the most prevalent. Distinct regional patterns of ribotype distribution were noted. Of 596 isolates from patients with toxin-positive stools (CDI cases), ribotype 027 accounted for 22% (32/144) of infections in cases aged from 18 to less than 65 years, but the prevalence decreased in those aged ≥ 65 years (14% (59/412)) and further decreased in those aged ≥ 81 years (9% (18/195)). The prevalence of ribotype 027 and 176, but not other epidemic strains, was inversely proportional to overall ribotype diversity (R 2 = 0.717). This study highlights an increased diversity of C. difficile ribotypes across Europe compared with previous studies, with considerable intercountry variation in ribotype distribution. Continuous surveillance programmes are necessary to monitor the changing epidemiology of C. difficile .
Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice
Authors: Ramesh Choudhari, Valerio Giacomo Minero, Matteo Menotti, Roberta Pulito, Cord Brakebusch, Mara Compagno, Claudia Voena, Chiara Ambrogio, Roberto Chiarle
Journal: Blood (2016)
Abstract P6-11-03: HACE1 loss results in hyperactive Rac signaling conferring resistance to HER2 targeted therapies
Authors: Erik T Goka, Dana S Senderoff, Gustavo Munguba, Marc E Lippman
Journal: Cancer Research (2015)

Abstract HER2-targeted therapies have been instrumental in improving the treatment of HER2+ breast cancer. However, drug resistance usually emerges and remains a big challenge in using anti-HER2 therapies. Previous studies have implicated activation of the Rho GTPase Rac1 by PTEN loss or IGF-1R overexpression as a mechanism of resistance to HER2-targeted therapies. We identified HACE1, an E3 ubiquitin ligase for Rac1, as a tumor suppressor capable of cooperating with HER2 to transform normal mammary epithelial cells. While HACE1 loss alone resulted in enhanced Rac activation, HER2 activation of Rac1 combined with HACE1 loss resulted in even higher levels of activated Rac resulting in the ability to form tumors in immunocompromised mice. In this study, we show that loss of HACE1 confers resistance to the HER2 tyrosine kinase inhibitor (TKI) Lapatinib due to sustained Rac signaling irrespective of EGFR/HER2 signaling. While Lapatinib inhibition alone is capable of attenuating proliferation of HER2 overexpressing mammary epithelial cells, HACE1 loss continues to drive proliferation of in vitro tumor formation (clonogenicity) as well in vivo tumor growth. We demonstrate that Lapatinib sensitivity can be restored using a Rac inhibitor in HACE1 knockdown cells. Moreover, while the Rac inhibitor alone was capable of attenuating the effects of HER2 overexpression and HACE1 loss, simultaneous inhibition of both HER2 and Rac signaling was superior to either monotherapy alone. These results support Rac activation as a mechanism of resistance to HER2-targeted therapies and highlight the use of a Rac inhibitor to treat HER2+ refractory breast cancers. Citation Format: Erik T Goka, Dana S Senderoff, Gustavo Munguba, Marc E Lippman. HACE1 loss results in hyperactive Rac signaling conferring resistance to HER2 targeted therapies [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-03.
Competitive CBFbeta/MYH11 reverse-transcriptase polymerase chain reaction for quantitative assessment of minimal residual disease during postremission therapy in acute myeloid leukemia with inversion(16): a pilot study.
Authors: K Laczika, M Novak, B Hilgarth, M Mitterbauer, G Mitterbauer, A Scheidel-Petrovic, C Scholten, R Thalhammer-Scherrer, S Brugger, F Keil, I Schwarzinger, O A Haas, K Lechner, U Jaeger
Journal: Journal of Clinical Oncology (1998)

PURPOSE (1) Quantification of minimal residual disease (MRD) by competitive CBFbeta/MYH11 reverse-transcriptase polymerase chain reaction (RT-PCR) in patients with acute myeloid leukemia (AML) and inversion(16) [inv(16)] during postremission therapy, (2) comparison of this method with conventional two-step RT-PCR, and (3) evaluation of a potential prognostic value. PATIENTS AND METHODS MRD of six consecutive adult patients with AML and inv(16)(p13;q22) or t(16;16)(p13;q22) who entered complete remission (CR) was monitored by competitive CBFbeta/MYH11 RT-PCR in their bone marrow (BM) during postremission therapy with high-dose cytarabine (HiDAC) or after BM transplantation with a matched unrelated-donor marrow (MUD-BMT) during an observation period of 4.5 to 27 months after initiation of treatment. RESULTS Competitive PCR showed a gradual decline by at least 4 orders of magnitude after 7 to 9 months in patients in continuous CR (CCR), while one patient who relapsed after 13.5 months only achieved a reduction by 2 orders of magnitude at the end of consolidation therapy. A rapid decrease below the detection limit was observed within 1 month in two patients after MUD-BMT. A temporary reappearance of molecular MRD was observed in these patients during immunosuppression for graft-versus-host disease (GvHD). After reduction of immunosuppression, the level of MRD dropped again below the PCR detection limit. Molecular monitoring by conventional two-step RT-PCR yielded comparable results only when multiple assays per time point were performed, while single-assay RT-PCR gave misleading results. CONCLUSION Competitive RT-PCR is a valuable tool for molecular monitoring during postremission chemotherapy, as well as after BMT.
Preliminary results of a clinical trial using chemo-immunotherapy in Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman’s disease (MCD)
Authors: D. O’Mahony, K. Aleman, W. B. Bernstein, K. Wyvill, D. Whitby, G. Tosato, E. S. Jaffe, S. Pittaluga, R. F. Little, R. Yarchoan
Journal: Journal of Clinical Oncology (2008)

19534 Background: Human herpes virus 8, also termed KSHV, is an oncogenic gamma-herpesvirus associated with Kaposi’s sarcoma (KS), primary effusion lymphoma and MCD. KSHV-associated MCD (KSHV-MCD) is a rare B-cell lymphoproliferative disease characterized by recurrent flares of a systemic syndrome including fatigue, fever, cytopenias, elevated serum C-reactive protein (CRP), and lytic KSHV replication. It is almost universally found in association with HIV infection. Prognosis is poor (median survival 14 months). Prospective study of MCD is limited, with no standard defined therapy or grading/staging system that accurately predicts prognosis. Our objectives were to study the natural history of KSHV-MCD and the effect of therapy on potential correlates of disease activity Methods: We investigated the efficacy of a chemo-immunotherapy approach in patients (pts) with biopsy proven KSHV-MCD. A combination of liposomal doxorubicin 20mg/m2 and rituximab 375mg/m2 [R-Dox] was administered every 21 days until substantial tumor reduction and symptom alleviation. Pts subsequently received thrice weekly subcutaneous alpha interferon (IFN-α) for a minimum of 9 months. Results: Six pts have been enrolled to date. Pt characteristics include median age 40 (range 33–56); median ECOG 2 (1–3); median CD4 190 (range 21–692 UL); median HIV viral load <50 copies/ml3 plasma (range <50 to 262). All pts were on HAART. Median MCD diagnosis duration was 6 months (range 0.5–50 months); five pts had received at least one prior therapy (range 1- 8). All had MCD-related constitutional symptoms, cytopenias and an elevated CRP (median 7.04, range 0.73–11.1 mg/dl) at enrollment. All but one achieved a PR or better, with a median of 3 cycles R-Dox (range 3–6). Four pts achieved a CR while on IFN-α. Off therapy only 1 pt has recurred (5 months) while the others remain in CR for 3–10 months. KS lesions present in 4 pts also showed an objective response to therapy. Grade 3 or 4 toxicities were limited to manageable IFN-α related hematological toxicity (4 pts) and transaminitis (1 pt). Conclusions: In summary, these preliminary data suggest that this regimen of chemo-immunotherapy has activity in the management of KSHV-MCD. Patient recruitment continues. No significant financial relationships to disclose.
A three-part, phase I, dose-escalation study of GSK1120212, a potent MEK inhibitor, administered orally to subjects with solid tumors or lymphoma
Authors: D. S. Thompson, K. Flaherty, W. Messersmith, K. Harlacker, S. Nallapareddy, C. Vincent, D. J. DeMarini, D. S. Cox, V. J. O'Neill, H. A. Burris
Journal: Journal of Clinical Oncology (2009)

e14584 Background: GSK1120212 is a potent and highly selective inhibitor of MEK1, a component of the MAP kinase pathway. GSK1120212 demonstrates efficient inhibition of p-ERK which correlates with inhibition of cell proliferation and induction of apoptosis. PO administration of GSK1120212 achieved tumor regression in multiple mouse xenograft models. The objectives of this study are to define the maximum tolerated dose (MTD) and to evaluate the pharmacokinetics (PK) and pharmacodynamic (PD) effects of GSK1120212. Methods: In Part 1, patients (pts) with solid tumors or lymphoma are enrolled in successive cohorts and receive a single PO dose of GSK1120212 followed by QD doses on days 1 - 21 of each 28-day cycle. Tumor response is assessed Q 8 weeks. PK blood samples are collected from all pts. Ophthalmic exams are administered at baseline and as clinically warranted. Dose escalation occurs via an accelerated titration followed by a standard 3+3 escalation. In Part 2, pts with pancreatic or K-Ras mutant CRC will be enrolled at the MTD. In Part 3, pts with biopsiable tumors will enroll at MTD and sub-MTD doses. Tumor biopsies will be taken pre- and post-dose to measure pERK and other markers of cell proliferation. Results: Six pts with advanced malignancies (neuroendocrine, thyroid, colorectal (n=2), melanoma (n=2) have been treated with tablets at four dose levels: 0.125 (n=2), 0.25 (n=1), 0.5 (n=2), and 1.0 mg (n=1). No DLTs or grade 2 toxicities have been reported. One patient was on study for over 17 weeks. Based on mean AUC and Cmax, GSK1120212 exposures following 15 days of repeat-dose administration were approximately dose proportional across the dose range (0.125–0.5 mg) with a median Tmax of approximately 1.5 hours. Conclusions: GSK1120212 has been well tolerated to date. Dose escalation is ongoing. [Table: see text]
Randomized trial of recombinant human interleukin-3 versus placebo in prevention of bone marrow depression during first-line chemotherapy for ovarian carcinoma.
Authors: L S Hofstra, G B Kristensen, P H Willemse, A Vindevoghel, H Meden, M Lahousen, F Oberling, B Sorbe, M Crump, I Sklenar, W J Sluiter, B Kiese, C G Trope, E G de Vries
Journal: Journal of Clinical Oncology (1998)

PURPOSE To determine whether recombinant human interleukin-3 (rhIL-3) reduces bone marrow depression and improves chemotherapeutic schedule adherence in ovarian cancer patients receiving first-line combination chemotherapy. PATIENTS AND METHODS In a randomized multicenter study, 185 patients received carboplatin (dose based on projected area under the concentration-time curve [AUC]=4) and cyclophosphamide (750 mg/m2) day 1, every 3 weeks for six cycles. Patients were randomized to receive rhIL-3 (5 microg/kg) or placebo once daily subcutaneously on days 3 to 12. RESULTS Adherence to chemotherapeutic regimen, mean chemotherapy cycle length, tumor response rate, and median survival at 24 months did not differ between groups. The number of side effects-primarily allergic reactions, flu-like symptoms and fever-were higher in the rhIL-3 group, which resulted in 21 discontinuations compared with one in the placebo group. Compared with placebo, the rhIL-3 group had higher platelet counts day 1 of cycles 2 to 6. The number of patients with World Health Organization (WHO) grade IV thrombocytopenia or number of platelet transfusions did not differ. Leukocyte counts differed only in cycles 1 and 2 between groups. The leukocyte nadir occurred earlier in the rhIL-3 (day 12) than in the placebo group (day 15, P=.006). Leukocytes and neutrophils were only higher in the rhIL-3 group day 1 of cycle 2. In cycles 4 and 5, more patients with WHO grade IV neutropenia received rhIL-3 (P &lt; .005). Eosinophil counts were higher day 1 of cycles 2 to 6 in the rhIL-3 group (P &lt; .0001). CONCLUSION rhIL-3 had stimulatory hematopoietic effects. This did not result either in reduction of platelet transfusions or in improvement of chemotherapeutic schedule adherence. There were more side effects in the rhIL-3 group than in the placebo group. rhIL-3 at 5 microg/kg/d is, therefore, not of clinical benefit in this chemotherapeutic regimen.
Telomere maintenance predicts progression and survival in pediatric intracranial ependymoma
Authors: U. Tabori, E. Bouffet, U. Bartels, D. Malkin, C. Hawkins
Journal: Journal of Clinical Oncology (2006)

10020 Background: Ependymoma is the third most common pediatric brain tumor. Despite the importance of surgical resection and pathology, its clinical course is highly unpredictable and the biological behavior is largely unknown. As part of ongoing studies to identify potential biological and therapeutic markers for the disease, we analyzed the role of telomere maintenance, which is required for cancers to sustain growth and evade senescence. Methods: We analyzed 111 primary and recurrent ependymomas that were resected at the Hospital for Sick Children in Toronto between 1986 and 2004. A tissue array was constructed. hTERT and γH2AX expression were evaluated. Thirty-one frozen samples were additionally analyzed for telomere length (TRF) and telomerase activity (TRAP assay). Results: Of the 111 samples, 40 tumors were hTERT(-) with progression-free survival (PFS) of 83±15% and 71 were hTERT(+) with PFS of 21±9% (p&lt;0.0001). Of the 65 patients with primary ependymomas, five-yr overall survival (OS) were 84±7% and 41±7% for hTERT(-) and hTERT(+) tumors, respectively (p=0.001). There was good correlation between telomerase activity and hTERT expression (κ=0.637). Multivariate analysis revealed hTERT expression to be the single most important predictor of survival of all known pathological, clinical and treatment factors (HR 60.4 (CI 6.4–561)). TRF measurement revealed lack of alternative lengthening of telomeres (ALT) and heterogenous telomere length in pediatric ependymomas. We observed a trend for better prognosis with telomere dysfunction manifested by shorter telomeres and positive γH2AX. Conclusions: This study suggest that telomere maintenance represents the first known biologic prognostic factor for intracranial ependymomas. Telomerase activity highlights the importance of senescence in carcinogenesis and a possible target for novel treatment approaches for the disease. No significant financial relationships to disclose.