tbuckley/cabot-search huggingface dataset:
Risk of severe radiation pneumonitis in gemcitabine (GEM) based consolidation chemotherapy after concurrent chemo-radiation (C-RT) in stage III non-small-cell lung cancer (NSCLC)
Authors: T. Mok, L. Zhang, M. Liao, M. Boyer, J. Yang, Y. Wu, C. Zhou, B. Zee, J. Lee
Journal: Journal of Clinical Oncology (2006)

17079 Background: Recent phase II study (S9504) showed that 3 cycles of consolidation docetaxel after C-RT is associated with prolonged survival but 6 pts (7%) had severe (≥gr 3) radiation pneumonitis and 2 (2.4%) died.(None at S9019) LCRG, a multinational Asian study group, designed a randomized phase II study aiming to assess the treatment outcomes of consolidation GEM or GEM/Carboplatin (CAR) after C-RT. GEM is a potent radiation sensitizer with known recall phenomena, thus we evaluated the risk of severe radiation pneumonitis with GEM-based consolidation chemotherapy after C-RT in this interim report. Methods: Enrollment criteria: Histologic proven NSCLC; attained CR/PR/SD after C-RT (Cisplatin-based chemotherapy between 25 mg/m 2 and 40 mg/m 2 per week or 60 mg/m 2 to 100mg/m 2 every 3 to 4 weeks; fraction dose not more than 2.0 Gy; total dose not less than 54 Gy and not higher than 64 Gy); ECOG PS 0–1; adequate hematologic/renal/liver function. Patients were screened for eligibility within 6 weeks after C-RT. Eligible patients are randomized to receive GEM 1250mg/m 2 day 1,8 q21days with or without CAR 5XAUC day 1. Results: Between 3/04 and 9/05 we screened 51 patients and excluded 19. Six (31.5%) were excluded due to radiation pneumonitis.(gr 1=5 and gr 3 = 1). C-RT induced toxicity was the main reason for difficulty with accrual to this trial. We enrolled 32 patients (m:f 29:3; mean age 58 (40–78); adeno:scc:other 14:16:2; IIIa:IIIb 4:28) Median RT fraction and dose was 30 (27–32) and 60 Gy (54–64), respectively. 19 pts received GEM and 13 received GEM/CAR. Severe (≥gr 3) radiation pneumonitis was reported in 3 pts (9.3%) and 1 (3.1%) died from the complication. Another 10 and 6 pts had grade 1 and 2 radiation pneumonitis, respectively, but without significant clinical compromise. Conclusions: Radiation pneumonitis is common after C-RT with or without consolidation chemotherapy. However, severe radiation pneumonitis is relatively uncommon in pts who received GEM based consolidation chemotherapy after C-RT. A possible explanation is that we have screened out the high risk pts prior to enrollment. [Table: see text]
Voices unite to demand free healthcare for refugees in Germany
Authors: Ned Stafford
Journal: BMJ (2016)

Germany’s healthcare system needs urgent realignment to improve medical care for refugees, say a growing number of politicians, healthcare experts, and medical groups.

A key element of the “realignment,” the term used in a recent report on healthcare for refugees issued by the Berlin based Robert Bosch Foundation,1 would be placing all refugees under the umbrella of Germany’s massive public health insurance system, which now covers more than 90% of the population. Germany accepted 1.1 million refugees in 2015, and the flow is expected to remain strong in 2016.

Frank Ulrich Montgomery, president of the German Medical Association, said in a recent video message to association members that one of several major challenges facing doctors in Germany …
Delphinidin, a major anthocyanin in pigmented fruits and vegetables is a potent inhibitor of epidermal growth factor receptor and its downstream signaling pathway
Authors: Najia Zaman, Farrukh Afaq, Naghma Khan, Deeba N. Syed, Hasan Mukhtar
Journal: Cancer Research (2006)

2266   Abnormalities in the expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) contribute to progression, invasion, and maintenance of the malignant phenotype in breast cancer. EGFR is expressed at high levels in at least 30% of breast cancers and is associated with poor prognosis. Many synthetic inhibitors of EGFR are known, but their use is limited because of their unacceptable cytotoxic effects on normal cells. Therefore, identification of a natural, nontoxic agent(s) as an inhibitor of EGFR is of utmost importance. Delphinidin, a major anthocyanin known to be present in pigmented fruits and vegetables (such as pomegranate, berries, dark grapes, egg plant, tomato, carrot and red onion) possesses potent antioxidant and antiproliferative properties. In this study, employing EGFR positive breast cancer cell lines, we evaluated the effect of delphinidin on EGFR and its downstream signaling pathways. Delphinidin (5-40 μM; 3h) treatment to EGFR positive breast cancer cells AU-565 and MCF-10A was found to result in a dose-dependent decrease in the phosphorylation of specific tyrosine residues of EGFR at 1068, 1045 and 845 sites. Delphinidin was also found to inhibit phosphorylation of EGFR in other EGFR positive cancer cells such as A431 and A549. The signaling pathways induced by activated EGFR include the PI3K/AKT and MAPK, both of which play a significant role in the mitogenic and cell survival responses mediated by EGFR. Therefore, we analyzed the expression of these proteins and found that delphinidin treatment of AU-565 and MCF-10A cells inhibited the (i) activation of PI3K, (ii) phosphorylation of AKT, and (iii) phosphorylation of MAPK in a dose-dependent manner. In additional experiments, serum starved AU-565 cells were treated with delphinidin (5-40 μM; 3 h) and then incubated without or with EGF (50 ng/ml) for 15 minutes. We found that delphinidin treatment of AU-565 cells inhibited EGF-induced phosphorylation of EGFR, AKT and MAPK, and activation of PI3K in a dose-dependent manner. We next investigated whether blockage of EGFR signaling pathways by delphinidin would inhibit cell growth and induce apoptosis. Treatment of AU-565 and MCF-10A cells with delphindin (5-40 μM; 48 h) inhibited cell growth and induced apoptosis in both these cell lines as determined by MTT assay, confocal microscopy and TUNEL assay. Delphinidin treatment of AU-565 and MCF-10A cells also resulted in cleavage of PARP protein, activation of caspase-3, downregulation of Bcl-2 and increased expression of Bax protein. In summary this study identifies an abundant fruits and vegetables based anthocyanin delphinidin as an effective blocker of EGFR signaling at least in breast cancer cells. Delphinidin could be developed as an agent for the management of EGFR positive human cancers.
Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm).
Authors: Jonathan A. Ledermann, Philipp Harter, Charlie Gourley, Michael Friedlander, Ignace Vergote, Gordon J. S. Rustin, Clare L. Scott, Werner Meier, Ronnie Shapira-Frommer, Tamar Safra, Daniela Matei, Anitra Fielding, Euan Macpherson, Brian Dougherty, Juliane M. Jürgensmeier, Maria Orr, Ursula Matulonis
Journal: Journal of Clinical Oncology (2013)

5505 Background: Previously, we reported that maintenance treatment with the oral PARP inhibitor olaparib (400 mg bid) led to a significant PFS improvement vs placebo in patients (pts) with platinum-sensitive relapsed SOC (Ledermann et al NEJM2012). A preplanned subgroup analysis from this randomized, double-blind Phase II trial (NCT00753545) suggested that olaparib may lead to a greater PFS, and an OS, benefit in pts with a known germline BRCAm (gBRCAm). Since gBRCA wild-type (gBRCAwt) pts may develop somatic tumor (t)BRCAm, efficacy analyses were performed for all pts with BRCAm. Methods: gBRCAm status was determined retrospectively for all consenting pts (n = 166) using blood samples taken before randomization. tBRCAm status was determined from archival tumor samples of 196 pts. We analyzed PFS/OS by gBRCAm and total BRCAm status. Preliminary data are reported. Results: gBRCA status was known for 218/265 pts (gBRCAm, 96; gBRCAwt, 122). Including tBRCAm, 136 pts had a BRCAm (BRCAwt, 116). gBRCAm pts had the greatest PFS benefit with olaparib maintenance vs placebo (median: 11.2 vs 4.1 months [m]; HR, 0.17; 95% CI 0.09-0.32; P&lt;0.001) and a significant QoL improvement, as measured with Trial Outcome Index (OR, 4.08; 95% CI 1.11-19.85; p = 0.03). The PFS benefit was consistent when tBRCAm pts were included (median: 11.2 vs 4.3 m; HR, 0.19; 95% CI 0.11-0.32; p &lt;0.0001). In an interim analysis of OS (58% maturity), a comparison of olaparib vs placebo in the overall population led to a HR of 0.88 (95% CI 0.64-1.21) with medians of 29.8 vs 27.8 m, respectively. Although HRs from the gBRCAm and gBRCAwt subgroups were similar (0.85 and 0.84, respectively), 13/37 gBRCAm placebo pts received a subsequent PARP inhibitor, confounding the OS data in this subgroup. The analysis of all BRCAm pts was less confounded and resulted in an OS HR of 0.74 (95% CI 0.46-1.19; median: 34.9 vs 31.9 m). 19 pts have received olaparib for &gt;3 years. Olaparib tolerability was similar in BRCAm pts and the overall population. Conclusions: Olaparib maintenance treatment led to the greatest clinical benefit in pts with a BRCAm. These compelling data warrant confirmation in phase III trials. Clinical trial information: NCT00753545.
Serum IL-6 as a prognostic biomarker in patients with stage IIB-III melanoma.
Authors: Lise Hoejberg, Lars Bastholt, Julia S. Johansen, Ib Jarle Christensen, Merete Krogh, Kirsten Fode, Henrik Schmidt
Journal: Journal of Clinical Oncology (2012)

8545 Background: Interleukin (IL)-6 is an immunomodulatory cytokine produced by cancer cells and different immune cells. The specific function of IL-6 in cancer is unknown. Serum IL-6 is elevated in patients with different types of cancer. Elevated serum concentration of IL-6 is related to short survival in patients with stage IV melanoma. Methods: IL-6 was measured by ELISA (R&amp;D) in pretreatment serum samples from 435 patients with stage IIB-III melanoma (151 women and 284 men, median age 51 years, range 18-77). After surgery patients were treated in a randomized study (The Nordic IFN trial) with either adjuvant interferon for 1 or 2 years, or observation. Results: Median serum concentration of IL-6 after surgery and before treatment was 1.8 ng/l, range 0.23-24 ng/l. Patients with serum IL-6 above the median had shorter overall survival (OS) compared to patients with serum IL-6 below the median (p=0.004). Median OS was 4.5 years in patients with serum IL-6 above the median (95% confidence interval (CI): 3.05-7.60). In patients with serum IL-6 below the median, median OS was not reached at the last survival-update. Multivariate Cox analysis including serum IL-6, ulceration in primary melanoma, LDH, white blood cells, lymph node metastases and Breslow thickness of primary melanoma showed that only serum IL-6 (hazard ratio (HR) = 1.48, 95% confidence interval (CI) : 1.13-1.94, p=0.004) was an independent prognostic factor for OS. In subgroup analysis of the control group and the two treatment groups, serum IL-6 demonstrated a negative prognostic impact in the control group (HR = 1.62, 95% CI: 1.02-2.57, p=0.04) and in the group treated with 2 years interferon HR = 1.69, 95% CI: 1.06-2.7, p=0.03). In the group treated with 1 year interferon this negative impact was not significant (HR = 1.15, 95% CI: 0.71-1.85, p=0.58). An interaction between IL-6 and treatment arm was not significant (p=0.45), suggesting that the negative prognostic effect of elevated pretreatment serum IL-6 is independent of treatment. Conclusions: Serum IL-6 above the median is an independent prognostic biomarker of short OS in patients operated for stage IIB-III melanoma.
The role of complement in the pathogenesis of tubulointerstitial lesions in rat mesangial proliferative glomerulonephritis.
Authors: Y Morita, A Nomura, Y Yuzawa, K Nishikawa, N Hotta, F Shimizu, S Matsuo
Journal: Journal of the American Society of Nephrology (1997)

Persistent proteinuria and tubulointerstitial lesions are important signs of progressive renal disease. The purpose of this study was to assess the role of complement in the development of tubulointerstitial lesions in rats with proteinuria due to primary glomerulonephritis. Mesangial proliferative glomerulonephritis was induced in mononephrectomized rats by intravenous injection of monoclonal antibody (mAb) 1-22-3 (Clin Exp Immunol 102: 181-185, 1995). As early as 24 h after the injection, proteinuria became evident, persisted throughout the observation period, and was associated with mesangial cell proliferation and tubulointerstitial lesions when examined at 7 and 14 d after mAb administration. Deposition of rat C3 and C5b-9 was observed at the luminal surface of proximal tubules and in cellular debris present in the tubular lumen (group I). Rats injected with mAb 1-22-3 and depleted of complement by injections of cobra venom factor starting at day 3 developed glomerulonephritis and proteinuria comparable to rats of group I, but complement deposition in the tubules and the tubulointerstitial lesions were markedly reduced (group II). Rats in group III were injected with mAb and, from day 3, with soluble complement receptor type 1, which became detectable at the luminal surface of proximal tubules and in the urine. Deposition of C5b-9 in tubular cells was not detectable, and the severity of tubulointerstitial lesions was reduced compared with rats in group I. These results indicate that, in this model of primary mesangial proliferative glomerulonephritis with proteinuria, the development of tubulointerstitial lesions is associated with activation of serum complement at the level of tubular brush border, and tubulointerstitial lesions can be reduced by inhibition of complement activity.
OLEATE UPREGULATES LECTIN GALACTOSIDE-BINDING SOLUBLE, 2 (LGALS2) IN IN VITRO MODEL OF CELLULAR STEATOSIS
Authors: K. A. Lockman, N. Plevris, A. Pryde, P. Lee, P. Cowan, A. J. Jaap, P. C. Hayes, C. Filippi, J. N. Plevris
Journal: Journal of Hepatology (2011)
Trastuzumab-based adjuvant chemotherapy for breast cancer: Early myocardial dysfunction detected by “speckle tracking” echocardiography (STE).
Authors: Giovanni Mantovani, Mariele Dessi, Laura Orgiano, Alessandra Piras, Christian Cadeddu, Martino Deidda, Massimo Ghiani, Giorgia Antoni, Roberto Serpe, Giuseppe Mercuro
Journal: Journal of Clinical Oncology (2013)

603 Background: While anthracycline-induced type 1 cardiotoxicity is well established, type 2 trastuzumab (TZM)-induced cardiotoxicity, although less relevant and reversible, is nonetheless significant in combination with other drugs, such as taxanes (TAX). A paradigmatic clinical example of this regimen is the adjuvant setting of breast cancer patients overexpressing HER-2. In the present study we chose STE with longitudinal and circumferential Strain (S) and Strain Rate (SR), as a very sensitive tool to timely identifying left ventricular dysfunction. The biological markers of chronic inflammation/oxidative stress were also studied. Methods: A phase IV prospective non-randomized study was carried out to assess cardio-toxicity induced by the combination of epirubicin (EPI) + TAX followed by TZM administered with the conventional schedule in adjuvant setting of breast cancer patients (pts) overexpressing HER-2. Inclusion criteria: 18–70 y, histologically confirmed HER-2+ve breast cancer candidates for TZM-based 3 weekly regimen; LVEF ≥55%; ECOG PS score 0-1, no history of cardiac disease. STE parameters (longitudinal and circumferential S and SR) and chronic inflammation (IL-6 and TNF-a)/oxidative stress (reactive oxygen species) markers were assessed at baseline before TZM and after each of the subsequent 18 TZM administrations. Results: Forty pts (mean±SD age 53±10 y) were assessed up to the 8 th TZM administration. A progressive reduction of longitudinal SR was observed, becoming significant from the 4 th TZM dose (0.65±0.18 s-1 vs 0.81±0.16 s-1, p&lt;0.005); a significant reduction of circumferential SR (0.60±0.15 s-1 vs 0.51 ±0.14 s-1, p&lt; 0.01) and rotation index was also observed from the 2 nd TZM dose. These changes are all indicative of myocardial systolic dysfunction. No changes of biological parameters were observed. Conclusions: The sequential administration of TZM after EPI/TAX induced an early left ventricular dysfunction detected by STE which persisted at least up to the 8 th TZM administration. This study is in progress with close monitoring of pts and its ultimate goal is to select pts candidates for an effective cardio protective treatment.
A classification system for tableting behaviors of binary powder mixtures
Authors: Changquan Calvin Sun
Journal: Asian Journal of Pharmaceutical Sciences (2016)

The ability to predict tableting properties of a powder mixture from individual components is of both fundamental and practical importance to the efficient formulation development of tablet products. A common tableting classification system (TCS) of binary powder mixtures facilitates the systematic development of new knowledge in this direction. Based on the dependence of tablet tensile strength on weight fraction in a binary mixture, three main types of tableting behavior are identified. Each type is further divided to arrive at a total of 15 sub-classes. The proposed classification system lays a framework for a better understanding of powder interactions during compaction. Potential applications and limitations of this classification system are discussed.
Disseminating Justified, Well-Designed, and Well-Executed Studies Despite Nonsignificant Tests
Authors: Gunther Meinlschmidt, Jan K. Woike, Marion Tegethoff
Journal: JAMA Psychiatry (2015)

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An intraspecific gene duplication polymorphism of the urate oxidase gene of Drosophila virilis: a genetic and molecular analysis.
Authors: S Lootens, J Burnett, T B Friedman
Journal: Molecular Biology and Evolution (1993)

Nineteen strains of Drosophila virilis from diverse geographic locations were examined by genetic and molecular analyses, revealing (a) 12 strains with a single copy of the urate oxidase (UO) gene per haploid genome and (b) 7 strains with a tandem duplication of the UO locus. The D. virilis strains with the UO duplication appear to have identical restriction maps of this region, implying either a single origin for the duplication or several similar events occurring at a hot spot. On the basis of the location of the duplication breakpoints and the restriction sites flanking these breakpoints, this duplication probably arose through nonhomologous recombination involving either a breakage and rejoining event or replication slippage. because documented cases of intraspecific gene duplication polymorphism are rare, the D. virilis UO duplication will be useful in identifying the molecular event giving rise to a gene duplication.
Sarcopenia and Acute Severe Toxicity in Sarcoma Patients Treated with Doxorubicin-Based Chemotherapy
Authors: A. Comte, O. Huillard, D. Biau, A. Babinet, J. Durand, V. Dumaine, F. Larousserie, V. Audard, J. Alexandre, P. Anract, F. Goldwasser, P. Boudou Rouquette
Journal: Annals of Oncology (2014)
Comparative clinical efficacy of adjuvant chemotherapy regimens in randomized controlled trials (RCTs) of early-stage colon cancer: Systematic review and meta-analysis.
Authors: J. Cassidy, H. Schmoll, E. Chu, N. Hawkins, I. Tatt, J. P. Saini, A. Urspruch
Journal: Journal of Clinical Oncology (2011)

498 Background: A systematic review was conducted to identify RCTs of adjuvant chemotherapy regimens for early-stage colon cancer and a network meta-analysis performed to compare efficacy of oxaliplatin/fluoropyrimidine regimens. Methods: A systematic review identified RCTs recruiting adult patients with early-stage (adjuvant) stage II/III colon cancer. Outcome measures included hazard ratios for DFS and OS. Only publications in English were considered. Study quality was assessed using the Cochrane Collaboration “risk of bias” assessment tool. A single reviewer screened abstracts/titles using predefined selection criteria, with critical appraisal and data extraction conducted independently by two reviewers. A Bayesian network meta-analysis was used to estimate comparative efficacy of adjuvant chemotherapy across RCTs. Results: 56 articles describing 40 trials were selected, of which six reported data on regimens accepted as current standard of care (capecitabine/X-ACT, XELOX/NO16968, FOLFOX/MOSAIC, FLOX/C-07) or common comparators: bolus 5FU/LV and LV5FU2 (C-96-1, PETACC-2). Statistical assessment of heterogeneity was not possible due to the limited study network. Baseline characteristics were similar across trials with the exception of three trials recruiting only stage III patients; sub-group analysis on these trials was not possible due to lack of common comparators. There was no significant difference in DFS at a median follow-up of 3-years (or closest reported analysis) for XELOX vs. FLOX (HR=0.99, 95% CI 0.80–1.22) or FOLFOX (HR=1.00, 95% CI 0.72–1.41). There was also no significant difference in OS at a median follow-up of at least 5 years. Taken as a class, oxaliplatin-containing regimens (XELOX, FOLFOX, FLOX) improved DFS vs. non-oxaliplatin-containing regimens (HR=0.80, 95% CI 0.73–0.87). This result was confirmed for OS. Conclusions: Despite the limited number of available trials, the results of these analyses demonstrate a clear benefit of incorporating oxaliplatin into combination regimens for early-stage colon cancer. XELOX, FOLFOX and FLOX appear to be equivalent in terms of efficacy in this setting. [Table: see text]