tbuckley/cabot-search huggingface dataset:
Nasal Carcinomas in Beagles After Inhalation of Relatively Soluble Forms of Beta-Emitting Radionuclides&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: S A Benjamin, B B Boecker, R G Cuddihy, R O McClellan
Journal: JNCI Journal of the National Cancer Institute (1979)

Beagles were exposed by inhalation to relatively soluble forms of single beta-emitting radionuclides and are being held for life-span observation to evaluate biologic hazards associated with nuclear power production. The dogs were exposed to graded activity levels of 91YCl3, 144CeCl3, or 90SrCl2. With 91YCl3 and 144CeCl3, a significant radiation dose was delivered to the respiratory tract, liver, and skeleton. With 90SrCl2, the dose was almost totally to the skeleton. Squamous cell carcinomas associated with the nasal cavity have been the most frequently observed neoplasms in the 91YCl3 study and one of the most frequent in the 144CeCl3 study, whereas few squamous cell carcainomas have been seen in the 90SrCl2 study. One hemanglosarcoma in the nasal cavity was also seen in the 144Ce study. The incidence of nasal carcinomas may be related to higher relative concentrations of the radionuclides 91Y and 144Ce associated with the nasal turbinates. This relatively high risk of nasal cavity neoplasms suggests that standards for human exposure to these radionuclides should included a consideration of the nasal cavity epithelium as a major target tissue.
COPD and the asthma-COPD-overlap-syndrome
Authors: Timo Schiffer, Stephanie Korn, Luminita Cervis, Roland Buhl
Journal: European Respiratory Journal (2014)

In clinical practice separating asthma from COPD may be difficult due to overlapping clinical and functional features common to both diseases. To characterize the Asthma-COPD-Overlap-Syndrome (ACOS), 108 consecutive former or current smokers with physician-diagnosed COPD [mean age 65,5±8,5 yrs., 45,4% female, 21,3% smokers (55,3±25,8 py), 78,7% ex-smokers (53,0±32,5 py), FEV1 (postBD) 58,0±20,0%, diffusion capacity (DLCO) median 47,5% IQR 38,0%-64,0%] were prospectively recruited in 2012 and 2013 and evaluated for 11 pre-specified asthma features by history including standardized questionnaires, lung function and allergy tests, serum IgE levels, blood and induced sputum differential cell counts, and FeNO.

35 patients (32,4%) fulfilled at least one, 1 patient 8 asthma criteria. Based on typical asthma features 25,9% of patients were classified by three blinded experts (TS, SK,RB) as ACOS [mean age 64,3±11,2 y; 57,1% female; 21,4% smokers (32,5±17,8 py); FEV1 (postBD) 65,0±19,0%, DLCO median 65,3% IQR: 43,0%-75,8%]. Similarly, a score for ACOS diagnosis using asthma and COPD criteria was highly concordant with clinical judgment (AUC 0,944).

Compared with the 'pure' COPD population, ACOS patients (had) smoked less (p<0,001), were more often atopic (p<0,001), had more peripheral eosinophils (p=0,042), had similar lung function before bronchodilator (p=0,163), but with a higher reversibility (p=0,006) and a better diffusion capacity (p=0,003).

In conclusion, established diagnostic asthma and COPD criteria are able to characterize COPD and ACOS patients.
Efficacy of high-dose alkylating chemotherapy in the adjuvant treatment of HER2/neu-negative primary breast cancer: Update of the Dutch Randomized Trial
Authors: S. Rodenhuis, M. Bontenbal, L. V. A. M. Beex, D. J. Richel, M. A. Nooij, E. E. Voest, E. van der Wall, P. Hupperets, H. van Tinteren, M. van de Vijver, E. G. E. de Vries
Journal: Journal of Clinical Oncology (2005)

672 Background: Between August 1993 and July 1999, 885 patients with primary breast cancer were randomized in 10 Dutch centers in a study of high-dose chemotherapy. The results of this study at 57 months of follow-up (N Engl J Med 2003, 349:7–16) were updated at 83 months. Methods: Patients below 56 years of age who had undergone surgery for stage II or III breast cancer were eligible if they had at least 4 tumor-positive axillary lymph nodes. Patients in the conventional dose (CD) arm received 5 courses of FEC (fluorouracil 500 mg/m2, epirubicin 90 mg/m2 and cyclophosphamide 500 mg/m2; q 3 weeks) followed by radiation therapy and tamoxifen. The high-dose (HD) arm was identical, except that high-dose chemotherapy (CTC, cyclophosphamide 6 g/m2, thiotepa 480 mg/m2 and carboplatin 1600 mg/m2) with peripheral blood progenitor cell reinfusion was given instead of the fifth FEC course. Results: In a pathology review, 602 of the tumor samples were shown to be HER2/neu-negative. All cases were assessed by immunohistochemistry; HER2/neu status was negative if staining was 0; and for 1+ and 2+ cases if in situ hybridization showed no amplification. The transplant-related mortality was 1%. Patients with HER2/neu-negative disease had a 5-year RFS of 72% following HD and of 58% after CD (p=0.0008). Overall survival of the HD group was 79% at 5 years versus 71% for the CD group (p=0.01). Young age and low malignancy grade were associated with greater benefit for HD (tests for interactions: p=0.04 and p= 0.0057, respectively). There was no difference in second tumors between the treatment arms. Conclusions: Although the subgroup analysis of HER2/neu negative disease was not planned in the original protocol, these findings are consistent with findings from other studies. The marked efficacy of HD therapy in HER2/neu-negative breast cancer may have been masked in randomized studies by its lack of efficacy in the HER2/neu-positive group, which benefits from the often higher dose of anthracyclines in the control arm. No significant financial relationships to disclose.
Prescription of Benzodiazepines in a London Teaching Hospital
Authors: K Shan, J A Nolan, P Turner, S H D Jackson
Journal: Journal of the Royal Society of Medicine (1990)

A study of the extent of hospital inpatient prescribing of benzodiazepines and their continuation at discharge was carried out on all patients admitted to St Bartholomew's Hospital, London, during a 7-day period. A large majority (73.6%) were not prescribed benzodiazepines at any time. No discharge prescriptions for these drugs were initiated in hospital. The data do not suggest that hospital prescribing of benzodiazepines is contributing to community prescribing.
Protein expression (PE) and increased IGF1R gene copy number (GCN) in small cell lung cancer (SCLC).
Authors: A. Badzio, M. W. Wynes, R. Dziadziuszko, D. Merrick, M. Pardo, S. Singh, A. Kowalczyk, W. Rzyman, J. Jassem, F. R. Hirsch
Journal: Journal of Clinical Oncology (2010)

10584 Background: IGF1R plays an important role in pathogenesis and progression of many malignancies. We studied the occurrence and prognostic value of IGF1R PE, GCN and their combination in resected SCLC. Methods: PE and GCN were evaluated on a tissue microarray containing multiple cores from 90 SCLC patients (pts). Median age was 57 years; males 74%; stage IA 7%, IB 29%, IIA 6%, IIB 14%, IIIA 27%, IIIB 12%, IIIB/IV 1%, unknown 1%; median overall survival (OS) 17.8 months. PE was evaluated by immunohistochemistry (IHC) using the IGF1R specific G11 antibody (Ventana Medical Systems, Inc. (VMSI), Tucson, AZ) and GCN was evaluated using an experimental IGF1R silver in-situ hybridization (SISH) probe (VMSI). Two pathologists and one reader scored PE using an H-score from 0 to 400. Two pathologists scored GCN in 50 non-consecutive nuclei for each core and the mean number of IGF1R copies/nucleus/core was determined. Cores with the highest value for either PE or GCN were used for subsequent analyses. Results: At least one core with a valid score for PE, GCN and both was obtained in 84, 81 and 79 pts, respectively. There was excellent concordance between all the evaluators for PE and GCN. The median H-score was 90 (range 0-400). There was no significant correlation between scores above or below the median and pathoclinical characteristics or OS (p = 0.69 and 0.48 in univariate and multivariate analysis, respectively). Median GCN was 2.4 (range 1.3-18.4), 15 pts had 4 or more copies of IGF1R per nucleus, of those 5 pts had clusters (amplification). GCN above the median tended to associate with an increased age (p = 0.053) but not with other characteristics. There were no OS differences for those above or below the median (p = 0.36 and 0.40 for univariate and multivariate analysis). There was moderate not statistically significant correlation between PE and GCN (r = 0.49). No association with pathoclinical characteristics or OS was found. Conclusions: Increased IGF1R gene copy number and IGF1R protein overexpression was found in numerous SCLC patients, but did not affect prognosis. These findings support potential role of targeting IGF1 signaling pathway in SCLC and warrant further investigations in this field. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ventana Medical system, Ventana Medical Systems AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/ImClone, GlaxoSmithKline, Lilly, Merck Serono, OSI/Genenetech/Roche, Pfizer, Syndax Ventana Medical Systems AstraZeneca, Biogen Idec, Genentech, Genmab, Merck, OSI, Roche, Syndax, Ventana Medical Systems, Ventana-Roche Abbott Laboratories
Rapid surveying of DNA sequence variation in natural populations.
Authors: E P Lessa
Journal: Molecular Biology and Evolution (1992)

DNA sequencing can be costly and time consuming for population studies because of the relative rarity of variation along exons. These problems can be substantially reduced by the use of the polymerase chain reaction on introns using primers from the exon region. These problems can be further reduced by the use of denaturing gradient gel electrophoresis to identify those alleles in need of sequencing.
A phase II single-arm study of LDK378 in patients with ALK-activated (ALK+) non-small cell lung cancer (NSCLC) previously treated with chemotherapy and crizotinib (CRZ).
Authors: Alice Tsang Shaw, Tony Mok, David R. Spigel, Makoto Nishio, Enriqueta Felip, Daniel Shao-Weng Tan, M. Rosario Garcia-Campelo, Harry J.M. Groen, Shaker R. Dakhil, Eric Scott Schaefer, Nicholas John Farrell, Rick E. Blakesley, Alexander Weir, Mirta Ristic, Giovanni Selvaggi, Giorgio Scagliotti
Journal: Journal of Clinical Oncology (2013)

TPS8119 Background: NSCLC harboring anaplastic lymphoma kinase (ALK) gene rearrangements (2–8% of cases) are sensitive to CRZ, the only approved ALK inhibitor, but invariably develop resistance. There are currently no standard ALK-targeted treatments for CRZ-resistant ALK+ NSCLC. LDK378 is a novel, oral ALK inhibitor with 20-fold greater potency than CRZ in enzymatic assays. In an ongoing phase I trial, LDK378 has demonstrated substantial clinical activity in patients (pts) with ALK+ NSCLC whose disease has failed CRZ. At a dose ≥400 mg (45 pts), the overall response rate (ORR) was 80%, with 47% confirmed responses (data cutoff August 31, 2012). Nausea, vomiting, diarrhea and fatigue were the main toxicities. The recommended phase II dose is 750 mg daily. Methods: This phase II multicenter, open label, single-arm study (CLDK378A2201) is designed to evaluate the efficacy and safety of oral LDK378 750 mg once-daily in pts with ALK+ (by FDA-approved FISH test) advanced NSCLC. Pts must have received cytotoxic chemotherapy (1–3 lines, including 1 platinum doublet) and progressed on CRZ as the last therapy prior to study entry. Pts with ECOG PS 0–2 and stable CNS metastases are eligible. LDK378 may be continued beyond RECIST-defined PD if there is evidence of clinical benefit. The primary objective is to assess the antitumor activity of LDK378 in terms of ORR by investigator assessment (using RECIST v1.1). Secondary/exploratory objectives include evaluating response endpoints (duration of response, time to response and ORR by independent radiological review), PFS, OS, safety, PK, and impact on patient-reported outcomes. The primary analysis will occur when all pts have completed 6 cycles or discontinued treatment earlier. The study design (137 pts) provides 90% power to test a null hypothesis of ORR ≤25% vs. a target ORR of ≥38%: if ≥45 responses are observed (estimated ORR 33%), the null hypothesis will be rejected at a one-sided significance level of 0.025. The study is recruiting in 67 sites from 14 countries across Europe, Asia and North America. As of February 5, 2013, 7 pts have been enrolled. ClinicalTrials.gov identifier NCT01685060. Clinical trial information: NCT01685060.
Controversies in Management: Screening asymptomatic people at high risk for hepatitis C: The case against
Authors: M. C Allison, P. R Mills
Journal: BMJ (1996)

The hepatitis C virus is usually transmitted parenterally through blood products or shared needles. Most infected people develop mild chronic hepatitis, which tends to pursue an asymptomatic course over years or decades.1 It is not known how many of those affected will eventually develop clinical sequelae from liver disease.

Screening blood donations for antibodies to the hepatitis C virus has led to a considerable reduction in the incidence of transfusion associated hepatitis.2 The United Kingdom's National Blood Transfusion Service has introduced a hepatitis C “lookback” programme to identify and screen those known to have received infected blood before testing of donations began in 1991. Other individuals at risk include injecting drug users, people with haemophilia, and health care workers. According to one estimate there may be 200 000 people with chronic hepatitis C in the United Kingdom.3 Should asymptomatic individuals belonging to these groups be offered screening for hepatitis C? This question raises both medical and ethical issues which share an analogy with screening for infection with HIV.

A positive test result for hepatitis C comes as a devastating blow to a healthy person. Concerns are raised about the mode of viral acquisition, risk of transmission to close contacts, marriage, employment and life insurance prospects, and the future risk of cirrhosis and hepatoma. …
Counteractive effects of omentin-1 against atherogenesis
Authors: Kaho Watanabe, Rena Watanabe, Hanae Konii, Remina Shirai, Kengo Sato, Taka-aki Matsuyama, Hatsue Ishibashi-Ueda, Shinji Koba, Youichi Kobayashi, Tsutomu Hirano, Takuya Watanabe
Journal: Cardiovascular Research (2016)

Omentin-1, a novel adipocytokine expressed in visceral fat tissue, is negatively correlated with obesity, insulin resistance, and stable coronary artery disease (CAD). However, there have been no previous reports regarding the effects of omentin-1 on atherogenesis. This study was performed to evaluate the atheroprotective effects of omentin-1 on human monocyte-derived macrophages, human aortic smooth muscle cells (HASMCs) in vitro, and aortic lesions in Apoe−/− mice in vivo. The histological expression of omentin-1 in coronary artery lesions and epicardial adipose tissues and its plasma levels were compared between CAD and non-CAD patients. Omentin-1 was abundantly expressed in human umbilical vein endothelial cells, macrophages, HASMCs, and human coronary artery SMCs in vitro. Omentin-1 promoted anti-inflammatory M2 phenotype during differentiation of human monocytes into macrophages. Omentin-1 suppressed oxidized low-density lipoprotein-induced foam cell formation associated with down-regulation of CD36, scavenger receptor class A, and acyl-CoA:cholesterol acyltransferase-1 and up-regulation of neutral cholesterol ester hydrolase in human macrophages. Omentin-1 suppressed angiotensin II-induced migration and platelet-derived growth factor-BB-induced proliferation, and collagen-1 and -3 expression in HASMCs. Four-week infusion of omentin-1 into Apoe−/− mice retarded the development of aortic atherosclerotic lesions with reduced contents of monocytes/macrophages, SMCs, and collagen fibres along with peritoneal M2-activated macrophages with inflammasome down-regulation and lowered plasma total cholesterol levels. Omentin-1 levels were markedly reduced in coronary endothelium and epicardial fat but increased in plasma and atheromatous plaques (macrophages/SMCs) in CAD patients compared with non-CAD patients. This study provided the first evidence that omentin-1 may serve as a novel therapeutic target for atherosclerosis and CAD.
The Medical Reports of John Y. Bassett, M.D. The Alabama Student
Journal: JAMA (1941)

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Phase 1 trial of 17-AAG in patients with relapsed and refractory multiple myeloma (MM)
Authors: C. Mitsiades, A. Chanan-Khan, M. Alsina, D. Doss, B. Landrigan, D. Kettner, M. Albitar, G. F. Cropp, A. L. Hannah, P. Richardson
Journal: Journal of Clinical Oncology (2005)

3056 Background: 17AAG (denoted KOS-953 in a novel Cremophor-based formulation) inhibits the activity of HSP90, resulting in degradation of client proteins. In vitro, 17AAG induces apoptosis of drug-sensitive and resistant MM cell lines, and tumor cells from patients with refractory MM (including bortezomib- or IMiD-resistant). In vivo, 17AAG extends the survival of mice after MM cells are injected and home to the marrow. Study objectives: define the MTD, toxicity and PK. Methods: Pts receive 17AAG (150 & 220 mg/m2) IV twice weekly for 2 out of 3 weeks. PK is performed for 17AAG and 17AG (active metabolite). Bone marrow aspirates (BMA), collected prior to drug and 4 hours following the 1st and 4th infusion, are examined for apopotosis, proliferation, pAKT, and change in HSP, IL-6 and IGF-R1 expression. PBLs are collected for assessment of change in HSP70/90. Results: 13 pts (3 F/10 M; median age 62 yrs; KPS 90; prior regimens 4, range 2–19) were enrolled in 2 dose levels. Dose limiting toxicity was observed at 220 mg/m2: a pt with liver infiltration of plasma cells had a Grade 3 elevated ALT; the pt was retreated at a lower dose but continued with grade 1–2 elevations. Other drug-related toxicity (Grade 1–2): bone pain (back, leg, rib), fatigue, diarrhea, anemia and rash. BMAs at 220 mg/m2 showed increased apoptosis (as determined by mitochondrial potential) and decreased pAKT comparing screening and Day 11 (p=0.057, both parameters). Signs of antitumor activity include: 1 pt with 93% reduction in kappa light chain; 1 pt with a minor response in IgA. Progression of disease typically occurred in extramedullary plasmacytomas, with stabilization or improvement of M-protein and KPS. Conclusions: Preliminary signs of activity in patients with advanced, heavily pre-treated MM have been seen; evaluation of 220 mg/m2 is continuing. Manageable toxicity without neuropathy is observed. PK for 17AAG in this formulation at these doses are similar compared to 17AAG in an egg-phospholipid formulation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Kosan Biosciences Kosan Biosciences Kosan Biosciences
Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With Intermediate- or Poor-Risk Germ Cell Tumors
Authors: Darren R. Feldman, James Hu, Tanya B. Dorff, Kristina Lim, Sujata Patil, Kaitlin M. Woo, Maryann Carousso, Amanda Hughes, Joel Sheinfeld, Manjit Bains, Siamak Daneshmand, Charlene Ketchens, Dean F. Bajorin, George J. Bosl, David I. Quinn, Robert J. Motzer
Journal: Journal of Clinical Oncology (2016)

Paclitaxel, ifosfamide, and cisplatin (TIP) achieved complete responses (CRs) in two thirds of patients with advanced germ cell tumors (GCTs) who relapsed after first-line chemotherapy with cisplatin and etoposide with or without bleomycin. We tested the efficacy of first-line TIP in patients with intermediate- or poor-risk disease.In this prospective, multicenter, single-arm phase II trial, previously untreated patients with International Germ Cell Cancer Collaborative Group poor-risk or modified intermediate-risk GCTs received four cycles of TIP (paclitaxel 240 mg/m(2) over 2 days, ifosfamide 6 g/m(2) over 5 days with mesna support, and cisplatin 100 mg/m(2) over 5 days) once every 3 weeks with granulocyte colony-stimulating factor support. The primary end point was the CR rate.Of the first 41 evaluable patients, 28 (68%) achieved a CR, meeting the primary efficacy end point. After additional accrual on an extension phase, total enrollment was 60 patients, including 40 (67%) with poor risk and 20 (33%) with intermediate risk. Thirty-eight (68%) of 56 evaluable patients achieved a CR and seven (13%) achieved partial responses with negative markers (PR-negative) for a favorable response rate of 80%. Five of seven achieving PR-negative status had seminoma and therefore did not undergo postchemotherapy resection of residual masses. Estimated 3-year progression-free survival and overall survival rates were 72% (poor risk, 63%; intermediate risk, 90%) and 91% (poor risk, 87%; intermediate risk, 100%), respectively. Grade 3 to 4 toxicities consisted primarily of reversible hematologic or electrolyte abnormalities, including neutropenic fever in 18%.TIP demonstrated efficacy as first-line therapy for intermediate- and poor-risk GCTs with an acceptable safety profile. Given higher rates of favorable response, progression-free survival, and overall survival compared with prior first-line studies, TIP warrants further study in this population.
Restriction of Herpes Simplex Virus Type 1 Replication in Oncornavirus-Transformed Cells2
Authors: William F. Campbell, Byron K. Murray, Nilambar Biswal, Matilda Benyesh-Melnick
Journal: JNCI Journal of the National Cancer Institute (1974)

Replication of herpes simplex virus type 1 (HSV-1) was studied in various cell lines infected with and/or transformed by oncornaviruses. HSV-1 production was completely inhibited in calls transformed by sarcoma viruses of murine, feline, and avian origin. Replication of HSV-1 was only slightly restricted in cells infected with a murine leukemia virus. Associated with the HSV-1 restriction was a concomitant inhibition of viral DNA synthesis