tbuckley/cabot-search huggingface dataset:
Association of Caribbean HTLV-1 T-cell leukemia/lymphoma (HTLVL) and clinical evidence of central nervous system (CNS) involvement at presentation or relapse.
Authors: K. A. Killoran, A. S. Braverman, G. S. Sidhu
Journal: Journal of Clinical Oncology (2010)

e18508 Background: HTLVL is endemic in the Caribbean and Japan. It is aggressive, incurable and responses to chemotherapy are usually brief. In Japan 20% of these patients present with or develop central nervous system (CNS) involvement. The Kings County and Downstate Medical Centers are located in the East Flatbush section of Brooklyn, NY, where many Caribbean immigrants reside. Methods: The charts of HTLVL patients who presented to these Centers since 2005 were reviewed for sites of disease and of relapse. Results: Data was available for 52 patients, 26 female and 26 male, ranging from 27-81 (median 54) years of age. Diagnosis was established by circulating flower cells, hypercalcemia, and pathology. Serum lactic dehydrogenase was elevated in 49. HTLV serology was available in 21 (40%) patients and positive in all. Only one patient presented with signs of CNS involvement. Chemotherapy was administered to 39 patients, including cyclophosphamide, doxorubicin, vincristine, prednisone and etoposide; 7 also received prophylactic intrathecal methotrexate (ITM). Follow-up was ≤6 months in 37 (71%) patients; 33 died despite therapy, 2 were alive and 2 lost to follow-up. In patients with >6 month follow up, 5 are alive, 7 died of recurrent lymphoma and the rest were lost to follow up. Systemic relapse was responsible for 6 of the 7 deaths, while one had CNS relapse. CNS involvement was observed in only 1 patient who had received ITM. The patient who presented with CNS signs succumbed to systemic disease. No other relapsing patients had evidence of CNS involvement. Conclusions: CNS involvement seems much less common in Caribbean than in Japanese patients with HTLVL. As a means of eliminating the CNS sanctuary ITM is unlikely to have much impact on this lethal disorder. Since CNS involvement rarely develops in our patients, ITM to avert it may not be indicated. No significant financial relationships to disclose.
Five-year results of a randomized phase III trial of pre-operative vs post-operative radiotherapy in extremity soft tissue sarcoma
Authors: B. O'Sullivan, A. Davis, R. Turcotte, R. Bell, J. Wunder, C. Catton, R. Kandel, A. Sadura, D. Tu, J. Pater
Journal: Journal of Clinical Oncology (2004)

9007 Background: In the limb preservation approach to soft tissue sarcoma (STS), controversy exists about whether pre-operative (pre-op) or post-operative (post-op) radiotherapy is the preferred external beam radiotherapy (EBRT) strategy. Preliminary analysis of a randomized phase III trial undertaken from 1994–97 that compared pre-op (50 Gy / 25 fractions) vs post-op (66 Gy / 33 fractions) showed greater wound complications confined to the lower limb with pre-op, greater late fibrosis and limb edema with post-op, and potentially different disease-specific outcomes. The purpose here is to report 5-year disease-specific outcomes in this trial. Methods: The trial was originally powered to address the incidence of wound complication four months following protocol treatment. Secondary end-points included disease control, late toxicity and function. The randomization process included stratification by tumor size dichotomized at 10 cm. Actuarial methods were used to assess disease-specific outcomes and followed the 'intention to treat' principle. Cox proportional hazards models were used to adjust for potential predictive factors. Results: One hundred and ninety patient were randomized (94 to pre-op and 96 to post-op) with median follow-up of 6.9 years. Demographics were equally balanced between both arms. The 5-year results for pre-op vs post-op respectively were, local control: 93% vs 92%; metastatic-relapse free: 67% vs 69%; recurrence-free survival: 58% vs 59%; overall survival: 73% vs 67% (P=0.48); cause specific survival: 78% vs. 73% (P=0.64). Cox modeling showed only resection margins as significant for local control. Tumor size and grade were the only significant factors for metastatic-relapse, overall survival and cause specific survival. Grade was the only consistent predictor of recurrence-free survival. Conclusions: Pre-op and post-op EBRT are equally effective in achieving control and survival in extremity STS. Because the normal tissue complication profile differs for both approaches, anatomic site should be considered in the choice of EBRT approach. No significant financial relationships to disclose.
Chromosome enumeration probe 17 (CEP) ratio to predict chemosensitivity in HER-2 overexpressing breast cancer
Authors: D. Miura, Y. Saitoh, T. Iwatani, H. Kawabata, N. Inoshita
Journal: Journal of Clinical Oncology (2009)

e11600 Background: Precise assessment of HER-2 is critical in breast cancers and predicts benefit of trastuzumab (T). Although subset analysis of CALGB 9840 suggests benefit in FISH-negative patients with chromosome 17 polysomy (C17), clinical significance of C17 in FISH-positive patients is still less known. To analyze the epidemiologic feature of C17 in Japanese patients, consecutive operable breast cancer patients during 05–07 treated in single institution were studied. Methods: HER-2 status of consecutive 307 patients excluding DCIS and whose specimens were poor quality for study, were analyzed with Pathvysion (FISH). We defined HER- 2 (+) and C17 as HER-2/chromosome 17 ratio ≥ 2.2 and CEP ratio ≥ 2.2, respectively. Pathological response following neoadjuvant chemotherapy (NACT) was assigned according to the Japanese Breast Cancer Society (G3; no invasive or in situ residual tumor in the breast, G2; up to two thirds of primary cancer cells having pathologically severe changes or disappearance, G1; up to one third to two thirds of primary cancer cells having pathologically severe changes or disappearance). Results: HER-2 (+) was found in 22% (67/307) and C17 in 25% (77/307). Twenty-four of 67(36%) in HER-2 (+) had C17 and 53 of 240 (22%) in HER-2 (-) did C17. Among HER-2 (+), 23 cases received T-contained regimens as NACT (FEC/EC followed by PAC+T in 18 and DOC+CPA+T in 5). Six of 9 (67%) with C17 had G3 and 2 of 14 (14%) with non-C17 did G3. CEP ratio significantly predicts to have G3 (p=0.02) but HER-2/chromosome 17 ratio by logistic regression analysis. Conclusions: C17 was found in 25% of Japanese operable breast cancer patients of which was similar to that of CALGB. CEP ratio is a good predictive marker for chemo- sensitivity in HER-2 (+) subset. No significant financial relationships to disclose.
bcl-2 automated and quantitative immunocytochemical assays in breast carcinomas: correlation with 10-year follow-up.
Authors: C Charpin, S Garcia, P Bonnier, F Martini, L Andrac, N Horschowski, M N Lavaut, C Allasia
Journal: Journal of Clinical Oncology (1998)

bcl-2 protein is detectable in human cancers and may be involved in the response to antineoplastic drugs or endocrine therapy in breast carcinomas. In a previous study, we had developed optimal technical conditions for bcl-2 immunodetection. The aim of the present report was to determine the prognostic significance of bcl-2 expression in breast carinomas by the use of a similar immunocytochemical procedure.bcl-2 immunocytochemical assays were performed on frozen sections by automated immunoperoxidase technique (Ventana) and computer-assisted analysis of digitized colored microscopic images (SAMBA) in a series of 170 breast carcinomas. The results of automated quantitative immunocytochemical assays were correlated with patient follow-up (120 months).Intense bcl-2 immunocytochemical expression in tumors (cutpoint, 15%) significantly correlated with longer disease-free survival and longer recurrence-free survival in the entire cohort of patients (P = .028 and P = .035, respectively) and also in node-negative subgroups of patients (P = .028 and P = .01; Kaplan-Meier long-rank test; NCSS 6.0.1 software). But bcl-2 immunostained surfaces (cutpoint, 15%) did not correlate with overall survival. In multivariate analysis (proportional hazards regression, Cox model), bcl-2 prognostic significance in terms of disease-free survival was only independent of the tumor size and grade and histoprognostic index (Nottingham prognostic index [NPI]).bcl-2 immunohistochemical expression is a significant indicator of favorable outcome only in terms of disease-free and local recurrence-free survival. However, bcl-2 expression in tumors is an independent weakly prognostic indicator in breast carcinomas. bcl-2 immunodetection assessed in optimal technical conditions (frozen samples, automation, quantitative analysis, scatter diagram cutoffs) may have some limited practical clinical relevance for the management of patients with breast carcinomas.
THE METABOLISM OF CATECHOLAMINES IN VIVO AND IN VITRO
Authors: Julius Axelrod
Journal: Pharmacological Reviews (1959)

The principal pathway for the metabolism of epinephrine in rat and man is O-methylation to metanephrine, a physiologically inactive metabolite, which is then conjugated or deaminated and oxidized to 3-methoxy-4-hydroxymandelic acid. Norepinephrine undergoes the same transformation in the rat and presumably in man.

An enzyme, catechol O-methyl transferase, that catalyzes the O-methylation of epinephrine, norepinephrine and other normally occurring and synthetic catechols, is described. Catechol-O-methyl transferase is widely distributed in all organ tissues including the autonomic and central nervous system, and appears to be the enzyme mainly responsible for the metabolism of epinephrine and norepinephrine.

Evidence is presented which indicates that amine oxidase is concerned chiefly with the deamination of the O-methylated metabolites of the catecholamines.

Enzymes involved in the conjugation of metanephrine and normetanephrine with glucuronic acid and the conversion of metanephrine to epinephrine are briefly described.

Metanephrine and normetanephrine were found to be normal constituents in rat urine and certain tissues of the rat.
Don’t forget to smile
Authors: Naaheed Mukadam
Journal: BMJ (2015)

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A pilot study of sorafenib examining biomarkers in refractory or relapsed T-cell lymphoma patients.
Authors: F. Lansigan, M. Komarovskaya, S. Seropian, D. Cooper, F. M. Foss
Journal: Journal of Clinical Oncology (2010)

TPS300 Background: Aggressive T-cell lymphomas represent 10-15% of non-Hodgkin lymphomas and have a worse prognosis than aggressive B-cell lymphomas. The multikinase inhibitor sorafenib inhibits the Raf/Mek/Erk pathway, as well as the tyrosine kinases vascular endothelial growth factor receptors and platelet-derived growth factor receptor. Preclinical studies with sorafenib in B-cell lymphoma cell lines have demonstrated activity; however, the effect of sorafenib on T-cell lymphoma and leukemia cell lines has not been well established. We evaluated the inhibitory concentration (IC50) of sorafenib on Jurkat, HH and HUT78 cell lines. IC50 ranged from 1μ M to 15μ M while normal CD3+ cells remained insensitive to sorafenib at doses up to 15μ M. Based on these data a clinical trial of sorafenib for relapsed and refractory T-cell lymphoma patients has been initiated. Methods: This is a pilot study of sorafenib 400 mg orally twice daily in relapsed or refractory T- cell lymphomas including peripheral T-cell (PTCL), angioimmunoblastic T-cell (AITL), cutaneous T-cell (CTCL), anaplastic large cell (ALCL), and other transformed T-cell lymphomas. The primary objective is to study the biological effects of sorafenib on the MAPK pathway, specifically the inhibition of Erk phosphorylation, and to correlate with clinical activity in patients with T-cell lymphoma. We will examine changes in Erk phosphorylation of peripheral blood lymphocytes comparing day 29 levels to the baseline values. This will be done by a whole blood activation assay using phorbol myristate acetate (PMA). Erk phosphorylation will be assayed by flow cytometry (Chow et al, Cytometry 46:72–78, 2001). The secondary objective is to demonstrate the clinical activity by determining the response rate and progression-free survival. Exploratory objectives are to determine if there is an increased immunostimulatory TH1 response, and a decrease in the number of regulatory T-cells. Serial biopsies of cutaneous lesions will be analyzed for microvessel density. This trial is open with an accrual goal of 14 patients. If 3 or more patients respond out of 14 evaluable patients, this provides evidence of activity and the trial will be considered for further phase II study. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx
A phase II randomized study to compare the neoadjuvant dose dense administration of docetaxel (D) and vinorelbine (V) or D followed by doxorubicin (A) and cyclophosphamide (C) administered to women with stage II or III breast cancer. Toxicity data
Authors: P. Rubin, A. Brufsky, R. Lambert-Falls, M. Carroll, S. Limentani
Journal: Journal of Clinical Oncology (2005)

776 Background: Previously we demonstrated that a combination of docetaxel (D) (60 mg/m2) and vinorelbine (V) (45 mg/m2) (TN) administered neoadjuvantly every two weeks for 6 cycles to women with breast cancer resulted in a pathologic complete response rate (pCR) of 27%. However, the incidence of fever and neutropenia (F/N) was unacceptably high (22%) in spite of the use of prophylactic growth factors. Methods: We reasoned that a decrease in the dose of V (30 mg/m2) would result in a lower incidence of F/N. Furthermore, the incorporation of A (60 mg/m2) and C (600 mg/m2) administered every two weeks for 4 cycles following the completion of TN would result in an increased pCR rate (arm 1). Based on the Norton-Simon hypothesis we also evaluated the administration of D (75 mg/m2) for 6 cycles followed by AC for four cycles with all chemotherapy administered every two weeks (arm 2). All patients received neulasta on day 2 of each treatment cycle. Results: 65 patients (pts) (arm 1 = 32, arm 2 = 33) have been enrolled with a planned accrual of 70 pts per arm. Arm 1, 21 pts stage II, 11 pts stage III, arm 2, 26 pts stage II, 7 pts stage III. 181 cycles have been administered on arm 1 and 176 cycles on arm 2. Grade 3/4 toxicities include mucositis: arm 1 = 2, arm 2 = 0, fatigue: arm 1 = 2, arm 2 = 1, epiphora: arm 1 = 0, arm 2 = 1, hand foot syndrome: arm 1 = 1, arm 2 = 1, diarrhea: arm 1 = 0, arm 2 = 1, pulmonary: arm 1 = 0, arm 2 = 2, fever and neutropenia: arm 1 = 3, arm 2 = 0. Dose modifications have been performed in 8 (2 were AC) pts on arm 1 and 9 (1 AC) pts on arm 2. 4 pts (2 each arm) have had chemotherapy stopped prematurely because of toxicity. Conclusions: In summary, chemotherapy has been well tolerated by most patients irrespective of the treatment arm. This provides a basis for further evaluation of dose dense D. Data on pathologic response rate will be available in May, 2005. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis GlaxoSmithKline, sanofi-aventis GlaxoSmithKline, sanofi-aventis Amgen, GlaxoSmithKline, sanofi-aventis
Dose and duration of dexamethasone in patients with high grade gliomas (HGG): Relationship to steroid myopathy (SM)
Authors: J. O. Blakeley, T. Peng, X. Ye, S. A. Grossman
Journal: Journal of Clinical Oncology (2006)

18517 Background: Steroids are critical in the management of HGG due to their ability to control peri-tumoral edema. Myopathy is a disabling complication of steroids leading to loss of ambulation and respiratory compromise. We sought to describe the use of steroids in the first 8 months after the diagnosis of HGG and its relationship to SM. Methods: Charts of all adults with HGG diagnosed and treated at Johns Hopkins Hospital from June 2004 to May 2005 were reviewed. Patients who died in less than 8 months were excluded. Starting steroid dose, subsequent documented doses, initial date and dates of change were recorded. Only charts with the phrase “steroid myopathy” were defined as SM positive. Results: Twenty-eight patients met all inclusion criteria. The mean age was 57.2 ± 8.7 years and 19 (67.8%) were males. All patients (100%) received steroids. Dexamethasone was used exclusively. Ninety-three percent of patients received &gt;16mg/day and 36% were on &gt;16mg/day for at least a month. The average daily dose was 15.3 ± 7.1 mg. Mean cumulative dose was 2.8 ± 1.8 grams. The median peak dose was 40mg/day (range 16–120mg/day). Median days on steroids was 224 days (range 5–224 days) from diagnosis and 67.8% of patients were on continuous steroids for 8 months. Eleven (39% [95% CI: 22%-59%]) of the 28 patients were defined as SM. Seven of the 11 (63.6%) SM patients required wheelchairs versus two (11.8%) without SM (p = 0.004). Days on steroid was significantly longer (p = 0.012) in the SM group (214 ± 32 days) versus the non-SM group (155 ± 81days). No strong evidence supported differences between groups in total dose, average daily dose, peak dose or days on high dose steroids. Conclusions: Patients with HGG are exposed to high doses of steroids for long periods. SM was noted in 39% of our patients and most required wheelchairs within 8 months of diagnosis. These figures are likely significant underestimates given the amount of steroids administered and the retrospective nature of this study. Our data confirm prior reports of an association between duration of steroid use and SM. The findings highlight the need to prevent SM using alternate dosing schedules and agents and to develop effective treatment interventions for SM. No significant financial relationships to disclose.
Abstract #LB-297: BRCA2 interaction with DSS1 is critical for homologous recombination
Authors: Akinori Egashira, Nicolas Siaud, Nicole Christ, Maria Jasin
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

The BRCA2 tumor suppressor plays an important role in the repair of DNA damage by homologous recombination (HR). Human BRCA2 is 3,418 amino acids and is composed of several domains. The central part of the protein contains multiple copies of a motif that binds the Rad51 recombinase (the BRC repeat), and the C terminus contains domain which binds DNA and small protein DSS1. DSS1 has been implicated in HR in various organisms but the precise function of DSS1 through the interaction with BRCA2 is still unclear in mammalian cells. To gain insight into the role of the DSS1-BRCA2 interaction in the repair of DNA damage, we put mutations into BRCA2 peptides which restore HR in Brca2 mutant hamster cells. BRCA2 with mutations which reduced DSS1 binding impaired the ability of these peptides to promote HR when compared to wild type peptides. Excessive DSS1 expression partially restored HR activity of BRCA2 mutants which weakly bind DSS1. We currently performing experiments to determine the role of DSS1 in BRCA2-mediated HR.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-297.
Effect of the Fluoride/Calcium Regimen on Vertebral Fracture Occurrence in Postmenopausal Osteoporosis
Authors: B. Lawrence Riggs, Ego Seeman, Stephen F. Hodgson, Donald R. Taves, W. Michael O'Fallon
Journal: New England Journal of Medicine (1982)

We assessed the rates of vertebral fracture in patients with postmenopausal osteoporosis. Forty-five patients were not treated (91 person-years of observation); 59 were treated conventionally, with calcium (alone or combined with estrogen) or vitamin D or both (218 years); and 61 were treated with sodium fluoride combined with conventional therapy (251 years). The fracture rate (per thousand person-years) was 834 in untreated patients, 419 in those given calcium with or without vitamin D, 304 in those given fluoride and calcium with or without vitamin D, 181 in those given estrogen and calcium with or without vitamin D, and 53 in those given fluoride, estrogen, and calcium with or without vitamin D. It was reduced in all treatment groups (P<0.001 for calcium and P<1×10-6 for other combinations); fluoride (one year of treatment) and estrogen (but not vitamin D) independently reduced the rate from that observed with calcium alone (P<0.001). The combination of calcium, fluoride, and estrogen was more effective than any other combination (P<0.001). These results provide grounds for optimism about the efficacy of combinations of available agents with sodium fluoride for fracture in postmenopausal osteoporosis. (N Engl J Med. 1982; 306:446–50.)
Serum concentration of laminin, and course of the disease in patients with various malignancies.
Authors: C Rochlitz, C Hasslacher, D G Brocks, R Herrmann
Journal: Journal of Clinical Oncology (1987)

Serum concentration of laminin was measured radioimmunologically in 96 patients suffering from various malignancies. Laminin levels were significantly elevated in patients with carcinomas and leukemias, but not in patients with sarcomas or lymphomas when compared with healthy controls. A good correlation could be found between serum laminin concentration and response to therapy in patients with carcinoma and leukemia. Elevated laminin levels were associated with a progressive course of the tumor condition. Furthermore, a close correlation has been detected between serum concentrations of laminin and carcinoembryonic antigen (CEA) in patients with carcinoma of the colon. The serum laminin level seems to be a valuable parameter for observation of the course of certain malignancies.