tbuckley/cabot-search huggingface dataset:
A randomized double-blind study of the biological effects of celecoxib as a chemopreventive agent in current and former smokers
Authors: E. S. Kim, W. K. Hong, J. J. Lee, L. Mao, R. C. Morice, D. D. Liu, C. A. Jimenez, G. A. Eapen, I. I. Wistuba, J. M. Kurie
Journal: Journal of Clinical Oncology (2008)

1501 Background: Cyclooxygenase-2 (COX-2) is overexpressed in bronchial premalignancy and promotes tumor cell proliferation and survival. Bronchial premalignant lesions have enhanced cellular proliferation as measured by nuclear Ki-67 expression. In histologically normal bronchial epithelium, Ki-67 is detectable in basal and parabasal layers. Celecoxib (COX-2 inhibitor) may have activity in the bronchial epithelium of current and former smokers and this was tested by measuring Ki-67 in bronchial biopsy samples. Methods: Patients (pts) with or without a prior cancer history were required to have at least a 20 pack-year smoking history and be disease-free for at least 6 months (mos). Pts were randomized into one of 4 treatments (3-mo intervals): celecoxib then placebo; celecoxib then celecoxib; placebo then celecoxib; placebo then placebo. Pts underwent bronchoscopy with biopsies at baseline, 3 and 6 mos. Celecoxib was administered at 200 mg bid (low dose, 81 pts), then changed to high-dose (400 mg bid, 123 pts). The study design had 80% power to detect a 1.2% difference in Ki-67 (celecoxib vs placebo) with 2 sided 5% level of significance. The primary endpoint was change in Ki-67 (baseline to 3 mos). Results: From 11/01 to 9/06, 204 of 212 registered pts were randomized (median age 53 years, 106 males, 175 Caucasian, 162 current smokers, and 182 with no prior cancer history). 127 pts completed 3 mos and 104 completed 6 mos of treatment. 3 pts experienced one grade 3 toxicity. No cardiac toxicities were observed. Baseline Ki-67 expression in basal and parabasal layers was higher in current smokers than in former smokers (p=.001 and p=.005, respectively). Multicovariable analyses revealed that basal layer Ki-67 expression decreased in current and former smokers treated with high-dose (p=0.003) but not low-dose (p=0.88) celecoxib (vs placebo). Conclusions: This study is the first reported randomized trial of celecoxib in lung chemoprevention and demonstrates the possible importance of COX-2 inhibition in the prevention of lung cancer. Celecoxib was safe and tolerable and may have an effect of downregulating proliferation in the bronchial epithelium of current smokers. Supported by grant 1P01 CA 091844, DOD W81XWH-04–0142, CA 16672 No significant financial relationships to disclose.
Fifty-two medical student suicides
Authors: F Pepitone-Arreola-Rockwell, D Rockwell, N Core
Journal: American Journal of Psychiatry (1981)

The authors surveyed all U.S. medical schools to ascertain the frequency with which medical students attempt suicide, complete suicide, and seek psychiatric treatment. In the classes of 1974-1981 the annual suicide rate for male students was 15.6 per 100,000, which is comparable to their agemates in the national population. The rate for female students equaled that of the male students but was three to four times that of their agemates. Seventy-six percent of the suicides were committed by sophomore and junior students, and 50% were committed in November, December, or January. The authors discuss four steps schools can take in suicidal prevention.
Results of a phase II trial of trastuzumab (H) and pertuzumab (P) in patients (pts) with HER2-positive metastatic breast cancer (MBC) who had progressed during trastuzumab therapy
Authors: K. A. Gelmon, P. Fumoleau, S. Verma, A. M. Wardley, P. F. Conte, D. Miles, L. Gianni, V. A. McNally, G. Ross, J. Baselga
Journal: Journal of Clinical Oncology (2008)

1026 Background: P is a humanized monoclonal antibody that binds to the specific dimerization epitope of HER2, blocking HER2 homo- and heterodimerization, thus preventing signal transduction. Xenograft studies indicate that the complementary mechanisms of action of P and H have a synergistic effect. Methods: This single-arm, Simon-type, two-stage phase II trial included pts with measurable, centrally tested HER2-positive MBC, ≥3 lines of prior therapy (including adjuvant therapy), disease progression during prior H therapy, and a baseline LVEF ≥55% that had not declined to <50% with H therapy. Consenting pts received H at 2 mg/kg qw (4 mg/kg loading dose [LD]) or 6 mg/kg q3w (8 mg/kg LD) plus P at 420 mg q3w (840 mg LD) starting within 9 weeks of the last dose of H. LVEF was assessed regularly in all pts. The primary endpoint was objective response and clinical benefit response rate (OR and SD ≥6 mths). Results: 66 pts have been enrolled and all have received ≥2 doses of study medication (41 are still on treatment). 63 pts have experienced ≥1 AE. Frequent AEs of all causes included diarrhea (63%), pain (35%), nausea/vomiting (30%), mucositis (32%), skin (27%), and rash (26%). Only 3 treatment-related AEs of severity G3, and none of G4, have been observed (diarrhea, pruritic rash due to contrast dye allergic reaction and a central line infection), all of which resolved and treatment continued. In addition 1 pt had a protocol-defined AE of special significance; an asymptomatic fall in LVEF of ≥10%-<50% based on a local reading which was not centrally confirmed. This pt was withdrawn due to progressive disease. No pts withdrew due to treatment-related or cardiac AEs. Preliminary RECIST response data (Baselga, ASCO 2007) are as follows: objective responses were seen in 6 of the 33 evaluable pts (1 CR, 5 PRs). Additionally, 7 pts achieved SD ≥6 mths and 10 pts SD <6 mths. Conclusions: The combination of H and P was well tolerated and active in pts with MBC whose disease had progressed during therapy with H. Biomarker data from this study are being analyzed. Further studies in pts with MBC and early breast cancer are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche, sanofi-aventis Roche F. Hoffmann-La Roche, Roche, sanofi-aventis F. Hoffmann-La Roche, Roche, Roche Canada Roche
Clinical/pathologic features and survival of patients with fibrolamellar-hepatocellular carcinoma (FLL-HCC): Data from the Fibrolamellar-Hepatocellular (FLL-HCC) Consortium.
Authors: C. Ang, A. P. Venook, M. A. Choti, R. P. DeMatteo, R. K. Kelley, D. Cosgrove, J. P. McGuire, M. S. Torbenson, T. M. Pawlik, W. R. Jarnagin, M. I. D'Angelica, Y. Fong, J. F. Chou, E. M. O'Reilly, D. S. Klimstra, A. C. Griffin, G. P. Vallarapu, M. Capanu, D. P. Kelsen, G. K. Abou-Alfa
Journal: Journal of Clinical Oncology (2011)

4089 Background: FLL-HCC is rare and develops in young individuals of either gender in the absence of underlying liver disease. There are limited data on the demographics and outcome of FLL-HCC. Methods: Institutional review board-approved medical record review was undertaken for all FLL-HCC patients seen since 1986 at Memorial Sloan-Kettering Cancer Center, the University of California at San Francisco and Johns Hopkins University. Demographic, clinical/pathologic, and treatment data were gathered. Kaplan-Meier survival outcomes were compared using the log-rank test. Results: Ninety-eight patients with pathologically confirmed FLL-HCC were identified. Median age at diagnosis was 23 years (range 11-65). Race: 87 (89%) White, 2 (2%) Hispanic, 3 (3%) Asian, 4 (4%) Black, and 2 (2%) unknown. TNM stage was 18 (18%), 17 (17%), 10 (10%) and 43 (44%) for stage I, II, III and IV disease, respectively. Stage was unknown for 10 (10%) patients. Seventy-six (78%) patients underwent surgery, and 19 received peri-operative therapy: neoadjuvant 8 (42%), adjuvant 9 (47%) and 2 (11%) both. Median overall survival was 6.3 years. Univariate analyses of survival outcome based on different variables are shown in the table. Conclusions: This is the largest reported series of patients with FLL-HCC. Patients with advanced, unresectable disease fare poorly, underscoring an urgent need for effective systemic therapies. The improved survival of males compared to females warrants further investigation. The FLL-HCC Consortium aims to promote awareness of this disease and to provide a platform for therapeutic development. This work was supported by the Fibrolamellar Foundation. Pathologically confirmed FLL-HCC (n = 98) Median survival (months) P value Gender Female Male 57 (58%) 41 (42%) 63.5 99.5 0.03 Age < 40 years > 40 years 84 (86%) 14 (14%) 90 68 0.09 Stage I/II III/IV 35 (36%) 53 (54%) 99.5 52 0.03 Surgery Yes No 76 (78%) 22 (22%) 99.5 18 < 0.001
Auricular Fibrillation
Authors: H. R. L. Fraser, R. W. D. Turner
Journal: BMJ (1955)

The auricles pipe and the ventricles perforce must dance . . .a dance that sometimes leads to death" (Hay and Jones, 1927). AetiologyThe most common causes of auricular fibrillation are rheumatic heart disease and degenerative heart disease due to coronary atheroma and hypertension.Less com- mon causes are thyrotoxicosis and constrictive pericarditis.Rare causes include pulmonary embolism, acute respiratory infections, carcinoma involving the medi- astinum, accidental electric shock, electric convulsion therapy, and the administration of digitalis.In addition it seems clear that auricular fibrillation may sometimes occur spontaneously, and recur or persist over many years without evidence of underlying organic heart disease.Fibrillation may follow thoracotomy in older patients without clinical evidence of underlying heart disease.
Vinblastine, bleomycin, and methotrexate: an effective adjuvant in favorable Hodgkin's disease.
Authors: S J Horning, R T Hoppe, S L Hancock, S A Rosenberg
Journal: Journal of Clinical Oncology (1988)

Sixty-seven patients with favorable pathologic stage (PS) I and IIA or B or IIIA Hodgkin's disease were randomized to receive subtotal or total lymphoid irradiation (STLI/TLI) alone or involved field irradiation (IF) plus six cycles of a novel adjuvant chemotherapy containing vinblastine, bleomycin, and methotrexate (VBM). With a follow-up from 6 to 72 months (median, 37 months), the actuarial freedom-from-progressive disease (FFP) at 5 years is 70% after STLI/TLI and 95% after IF plus VBM. One death has occurred in the irradiation-only treatment group. The data for IF plus VBM are significantly superior to previous actuarial results at 5 years using IF alone (FFP = 35%, P less than .00001) and compare favorably with prior results with IF plus nitrogen mustard, vincristine, procarbazine, +/- prednisone (MOP[P]) chemotherapy (FFP = 80% at 5 years, P = .10). VBM is well tolerated with greater than 90% of calculated doses delivered. As anticipated, VBM has had relatively little adverse effect on male or female fertility. Selected pulmonary functions are reduced early after IF plus VBM to a greater degree than with irradiation of the mediastinum alone, but the differences are modest. Based upon our current numbers and follow-up, we can be 90% confident that VBM as an adjuvant to irradiation in favorable Hodgkin's disease is as effective, or even superior, to MOP(P) chemotherapy. Because of its lesser toxicity, adjuvant VBM may have a broader role in the management of Hodgkin's disease.
Modulation of complement activation on hemodialysis membranes by immobilized heparin.
Authors: A K Cheung, C J Parker, J Janatova, E Brynda
Journal: Journal of the American Society of Nephrology (1992)

To determine the effects of surface-associated heparin on the capacity of hemodialysis membranes to activate complement, cellulose acetate (CA) membranes that were untreated and CA membranes that had been coated with heparin (HCA) were incubated with C3-depleted serum repleted with radio-labeled C3. Next, the proteins in the supernatant and those eluted from the membranes were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. C3 activation was quantified by determining the radioactivity of the C3a-containing band in the gel. Total C3a generation (fluid phase C3a plus membrane-associated C3a) was three times greater in the presence of HCA compared with CA. Most (88%) of the C3a generated in the presence of HCA, however, was adsorbed onto the membrane surface. Consequently, there was more C3a in the CA supernatant than in the HCA supernatant. To determine the mechanism by which heparin enhanced alternative pathway activity, binding studies with radiolabeled factor B and factor H were performed. HCA bound 3.4 times more factor B and 20 times more factor H than did CA. The binding of these proteins, however, was not dependent on complement activation. Studies designed to test the functional activity of isolated factor H and factor B that had been adsorbed to the membrane showed that factor H was active on both CA and HCA, whereas factor B was active only on HCA. These data demonstrate that heparin immobilized onto CA hemodialysis membrane enhances C3 activation but produces low levels of C3a in the fluid phase because of high surface adsorption of the anaphylatoxin. Heparin appears to augment alternative pathway activity by favoring the interactions of factor B with other constituents of the amplification C3 convertase of the alternative pathway of complement.
Suppression of cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.
Authors: J Cortes, M Talpaz, S O'Brien, M B Rios, A Majlis, M Keating, E J Freireich, H Kantarjian
Journal: Journal of Clinical Oncology (1998)

PURPOSE To investigate whether cytogenetic clonal evolution can be suppressed with interferon alfa (IFN-alpha) therapy in patients with chronic myelogenous leukemia (CML). PATIENTS AND METHODS Ninety patients with CML and cytogenetic clonal evolution who received IFN-alpha-based regimens were analyzed. Clonal evolution was defined as the presence of karyotypic abnormalities in addition to the Philadelphia (Ph) chromosome. Patients were evaluated for the suppression of cytogenetic clonal evolution after therapy, the cytogenetic response, and survival. RESULTS The median age of the population was 39 years (range, 15 to 70 years), median time from diagnosis to clonal evolution 14 months (range, 0 to 145 months), and median percentage of abnormal metaphases 18% (range, 4% to 100%). Fifty six patients (62%) achieved some suppression of cytogenetic clonal evolution; in 41 patients (46%), the suppression was complete. The overall median survival was 51 months, with 43% alive at 5 years. Patients who achieved a complete suppression of cytogenetic clonal evolution had a median survival of 66 months, with 51% alive at 5 years. Characteristics associated with a better response include a lower percentage of abnormal metaphases, time to cytogenetic clonal evolution of 24 months or less, and absence of other features of accelerated disease. A prognostic classification for cytogenetic clonal evolution defined three groups with complete response (CR) rates of 85%, 34%, and 0% (P &lt; .0001) and median survival times of 58, 31, and 30 months, respectively (P=.02). CONCLUSION Patients with cytogenetic clonal evolution can respond to IFN-alpha therapy, and this response is associated with longer survival. A previously described prognostic model separates patients into subsets with different probabilities of response to IFN-alpha and survival.
Genotype-phenotype correlations in patients with primary ciliary dyskinesia with central complex defects related to RSPH1, RSPH4A or RSPH9 mutations
Authors: Blandine Prévost, Nadia Nathan, Aline Tamalet, Sylvain Blanchon, Guy Montantin, Jean-François Papon, Esther Kott, Laurence Bassinet, Nicole Beydon, Nathalie Collot, Bruno Copin, Florence Dastot, Philippe Duquesnoy, Ralph Epaud, Isabelle Honoré, Véronique Houdouin, Sylvie Tissier, Guillaume Thouvenin, Ludovic Jeanson, Benoit Vallette, Jacques de Blic, Bruno Housset, André Coste, Annick Clément, Estelle Escudier, Serge Amselem, Marie Legendre
Journal: European Respiratory Journal (2014)

Background

The RSPH1 , RSPH4A and RSPH9 genes have been implicated in primary ciliary dyskinesia (PCD) with ultrastructural abnormalities of the central complex (CC). We studied phenotypic features of patients with RSPH1 , RSPH4A or RSPH9 mutations to guide the strategy for molecular analyses in patients with CC defects.

Methods

RSPH1 , RSPH4A and RSPH9 coding exons and their flanking intronic sequences were sequenced in 65 unrelated families (84 patients). We compared the following parameters: sex, origin, consanguinity, laterality defects, neonatal respiratory distress, airway infections, bronchiectasis, nasal polyposis, otitis media, hearing loss, infertility, nasal nitric oxide (NO), ciliary beat frequency and quantitative ultrastructural analyses of cilia.

Results

Biallelic RSPH1 , RSPH4A or RSPH9 mutations were identified in 21 (32%) unrelated families (30 patients): 10 (15%) with RSPH1 mutations, 7 (11%) with RSPH4A mutations and 4 (6%) with RSPH9 mutations. Patients with identified mutations shared a similar phenotype in terms of clinical features (sinopulmonary syndrome with no situs inversus), decreased nasal NO in most patients, presence of beating cilia normal frequency together with slow beating and immotile cilia, and CC defects in a minority of cilia.

Conclusion

Patients with RSPH1 , RSPH4A or RSPH9 mutations are phenotypically indistinguishable. Given the contribution of the 3 genes in this phenotype, the 1st one to be tested is RSPH1 , then RSPH4A before RSPH9 . The molecular analyses are decisive specialy when the diagnosis of PCD is difficult to establish. The molecular basis of PCD remains to be identified in 44 (68%) families.
Abstract P077: Sleep Disturbances and Risk of First Cardiovascular Events. Results from the MONICA Brianza and PAMELA Cohort Studies in Northern Italy
Authors: Lorenza Bertù, Marco M Ferrario, Francesco Gianfagna, Giovanni Veronesi, Guido Grassi, Giancarlo Cesana
Journal: Circulation (2015)

Background and aim: Poor sleep quality has been found associated with increasing risk of cardiovascular diseases. We aim to estimate the long-term risk of first cardiovascular (CVD) event (coronary or ischemic stroke) in subjects with sleep disturbances in North-Italian cohorts. Methods: Four independent population-based cohorts were enrolled between 1986 and 1994 from the Brianza population (Northern Italy). At baseline LDL-, HDL-cholesterol, systolic blood pressure, diabetes and cigarette smoking were ascertained through standardized MONICA procedures. The study sample comprises 3047 men and 3097 women, aged 25 to 75 years and CVD-free at baseline, who were followed-up for incidence of first coronary and ischemic stroke events (fatal and non-fatal; MONICA validated). Sleep disturbances were assessed with the Jenkins Sleep Questionnaire, investigating sleep disturbances (4 items) in the last month, and then categorized in three classes: none-some (reference), moderate, severe/extreme. Age and CVD risk factors adjusted HRs for first CVD, coronary or ischemic stroke event were estimated in the overall sample, in men and women, from separate Cox models. Results: In a median 15 years of follow-up 437 first CVD events occurred (305 coronary and ischemic stroke). When adjusting for LDL- and HDL-cholesterol, systolic blood pressure, diabetes and cigarette smoking, the risk of first CVD events was higher in subjects with severe sleep disorders compared with none-some (HR=1.84; 95%CI:1.19-2.84). Gender-stratification confirms the association both in men and women, but only in men resulted statistically significant (HR=2.34; 95%CI:1.34-4.08). The association was prominent for ischemic strokes (HR=2.10; 95%CI:1.11-3.97) and less clear for coronary events. These associations resulted higher when the follow-up was shortened to 10 years. Conclusions: In this population of middle-aged CVD-free subjects from Northern Italy, severe sleep disturbances were associated with first CVD events. The risk was higher in men and when ischemic strokes were considered only.
Coordinated modulation of sonic hedgehog (Shh) signaling and androgen receptor (AR) in the prostate tumor microenvironment by chemo-hormonal therapy
Authors: E. Efstathiou, P. Troncoso, S. Wen, K. Do, C. A. Pettaway, C. J. Logothetis
Journal: Journal of Clinical Oncology (2007)

5066 Background: Shh and androgen signaling are implicated experimentally in prostate development, regeneration and neoplastic progression. We assessed expression of components of these pathways in pretreated and control high risk prostate cancers (PCa) in a hypothesis generating search for an association with resistance to therapy. Methods: Sixty-four men with high risk PCa were randomized to receive either complete androgen ablation (AA) or AA and ketoconazole, adriamycin, vinblastine and estramustine (KAVE) for 16 weeks followed by radical prostatectomy (RP). We constructed 3 tissue microarrays from RP specimens of: a) (AA) 26 men pretreated with AA, b) (CH) 27 men pretreated with AA + KAVE and c) (Control) 26 untreated men matched for clinical stage, biopsy Gleason Score and PSA. A total of 3,178 cores were obtained [median cores: 36 (range 18–90), median blocks: 5 (range 3–9) per specimen]. Immunohistochemical expression of Shh pathway components (Shh, patched, smoothened, gli2) and AR were assessed in the tumor epithelium and stroma and recorded as percentage of cells exhibiting staining. A mixed model was used for fitting the correlated data (multiple observations from a subject). Pearson’s correlations between biomarkers were calculated based on mean expression. Results: Shh signaling, as indicated by mean expression (standard deviation) of nuclear gli2, was observed in the residual tumor epithelium [AA: 79.9 (17.4), CH: 85.7 (12.2)] and adjacent stroma [ AA: 43 (18.2),CH: 53 (16.4)] following treatment, in parallel (0.78 by Pearson’s correlation), and higher than in untreated control tumor epithelium [39.9 (20.6)] and stroma [22.9 (15.2)] (P&lt;.0001). Smoothened and Shh were expressed accordingly. AR expression was lower in the treated tumor epithelium [AA: 47.3 (20.8), CH: 46.8 (21.1)] (P&lt;.0001), with a trend toward increased stromal AR [AA: 8.6 (10.4), CH: 10.5 (8.2)] compared to control tumor epithelium [60.1 (24.1)] and stroma [6.4 (11.7)]. Conclusions: Shh and androgen pathways are modulated in a manner that suggests they behave in a compensatory fashion, and are determinants of response to therapy. These data support the hypothesis that the tumor microenvironment is implicated in PCa therapy resistance. No significant financial relationships to disclose.
All patients with HIV should get access to drug treatments regardless of CD4 count, says WHO
Authors: Anne Gulland
Journal: BMJ (2015)

All people with HIV, regardless of their blood cell count, should have immediate access to antiretroviral (ARV) therapies, a new guideline from the World Health Organization has stated.1

All populations and age groups are now recommended to have ARV drugs prescribed immediately after testing positive for the disease. In an early release guideline, WHO said that the expanded use of ARV …