tbuckley/cabot-search huggingface dataset:
Phase II study of induction chemotherapy with fixed dose rate (FDR) gemcitabine and cisplatin followed by concurrent chemoradiation with capecitabine for locally advanced pancreatic cancer (LAPC)
Authors: J. Kim, S. Im, H. Park, E. Chie, J. Hwang, J. Kim, T. Kim, Y. Bang, S. Ha, Y. Yoon
Journal: Journal of Clinical Oncology (2007)

15122 Background: Despite the use of 5-FU based chemoradiotherapy (CRT) over the past decades, prognosis of patients with LAPC remains dismal. To deliver more efficient systemic treatment earlier and reduce toxicity of CRT, we designed a treatment protocol consisting of induction (IND) chemotherapy with FDR gemcitabine (GEM) and cisplatin (CDDP), followed by CRT with capecitabine (CAP) in LAPC. Methods: Eligible patients had unresectable, histologically confirmed adenocarcinoma of pancreas, ECOG PS of 0–2, and no prior chemo- or radiotherapy for this phase II study. Patients received FDR GEM 1000 mg/m2 (D1,8) and CDDP 60 mg/m 2 (D1) every 3 weeks for 3 cycles. Patients without disease progression subsequently received CRT of 55.8 Gy in 31 fractions concurrently with CAP, 650 mg/m 2 given twice daily without drug holidays. Four weeks after CRT, FDR GEM 1000 mg/m 2 was given on day 1, 8 every 3 weeks for 3 cycles. Time to progression was the primary endpoint. Results: Between Jan 2005 and Nov 2006, 21 patients were enrolled (median age 59, M/F: 13/8, ECOG PS 0/1: 3/18). Two patients withdrew consent after 1 st and 2 nd cycle and remaining 19 patients completed all three cycles of IND chemotherapy, with three (15.8%) out of 19 evaluable patients achieving partial response (0 CR, 3 PR, 14 SD, 2 PD). All 17 patients completed CRT with mean radiation dose of 55.4 Gy. Further four patients progressed during CRT, while one additional patient achieved partial response. As of Jan 2007, 5 patients died and 12 patients showed tumor progression. Median TTP was 12.5 mo (95% CI: 4.2–20.8) and median survival was not reached with median follow up duration of 9.7 months. Grade III/IV toxicities included neutropenia (38.1%/9.5%), thrombocytopenia (4.8%/0%), and anemia (14.3%/0%) during IND phase. Toxicites were generally mild during CRT phase with grade III neutropenia and diarrhea occurring in one and two patients, respectively. One patient died of neutropenic sepsis after 3 rd cycle of IND chemotherapy. Conclusions: FDR GEM-CDDP induction chemotherapy followed by CAP-RT and maintenance FDR GEM is feasible and active with promising TTP of 12.5 months. Enrollment continues till reaching target accrual of 37 patients. No significant financial relationships to disclose.
Clinical evaluation of nitric oxide responses to anti-VEGF therapy with bevacizumab
Authors: A. Nixon, J. Allen, E. Miller, S. Savage, N. Kaplan, M. Starr, J. Bendell, H. Uronis, N. Fernando, H. Hurwitz
Journal: Journal of Clinical Oncology (2007)

14039 Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy has been linked to hypertension (HTN) and arterial thrombo-embolic events that may involve changes in nitric oxide (NO) bioavailability. Methods: 25 patients (pts) with advanced cancer, normal renal function and blood pressure (BP), no increased risks for anti-VEGF toxicities, and not on medications known to confound biomarker studies (including anti-hypertensives) were treated with bevacizumab (BV) 15mg/kg d1, then 10mg/kg q2 week. Prior to biomarker assessment, all patients were placed on a calorie-, nitrate-, and salt-restricted diet for 72 hr. All measures were taken pre-treatment (preRx) and on day 28 of treatment (onRx). Dependant variables included; a) Brachial artery reactivity (BAR) following hyperemic flow stimulus (endothelium-dependent) and sub-lingual nitroglycerine (NTG; endothelium-independent); b) exhaled and plasma/urine total NO 2 /NO 3 using chemiluminescence (Sievers 280NOA) with either KI or VCl 3 in HCl as the reductants; c) blood pressure. Additionally, we measured multiple regulators of vascular tone and injury. Comparisons were analyzed using Spearman signed rank tests. Results: Of 25 pts (16 F, 9 M) treated, 21 patients were fully evaluable. Significant changes or strong trends were observed upon comparing preRx vs. onRx for BP (SBP +12.4, DBP +5.6, MAP +7.9 mm Hg), and flow-mediated BAR (-2.0%) with no changes in hyperemic flow/shear stimulus or smooth muscle function (BAR NTG), indicating a decrease in brachial artery endothelial responsiveness. Exhaled NO decreased (-0.8% d1vs d28 and -0.6% pre/post infusion day1). Measurement and data analysis of urinary/plasma NO 2 /NO 3 , as well as angiogenic markers, are almost complete and will be reported. Conclusions: After one month of treatment, BV increased BP and decreased endothelium- dependent BAR and exhaled NO, suggesting potentially broad, mechanism-based effects on NO bioavailability in patients. [Table: see text]
Prospective cohort study of the alternate healthy eating index-2010 and risk of chronic obstructive pulmonary disease in US women and men
Authors: Raphaëlle Varraso, Stephanie Chiuve, Teresa Fung, Graham Barr, Frank Hu, Walter Willett, Carlos Camargo
Journal: European Respiratory Journal (2013)

The Alternate Healthy Eating Index 2010 (AHEI-2010), a new measure of diet quality based on current scientific knowledge, has been associated with decreased risk for major chronic diseases. The relation of AHEI-2010 with chronic obstructive pulmonary disease (COPD) is not known.  We investigated the relation between AHEI-2010 and the risk of newly-diagnosed COPD between 1984 and 2000 in 73,239 women from the Nurses’ Health Study (723 self-reported cases), and between 1986 and 1998 in 46,967 men from the Health Professional Follow-up Study (167 self-reported cases). The cumulative average of the AHEI-2010 score was categorized into quintiles and the risk of COPD compared between quintiles using Cox proportional hazard models.  After adjustment for potential confounders, we reported a statistically significant, inverse association between the AHEI-2010 and risk of COPD in women (multivariable RR [95% CI] for Q1 vs. Q5 of AHEI-2010: 0.67 [0.52-0.88], p for trend  The AHEI-2010 diet score (reflecting high intakes of whole grains, PUFA, nuts, and fish and low intakes of red and processed meats, refined grains, and sugar-sweetened beverages) was associated with a lower risk of COPD, and supports the importance of diet in COPD pathogenesis.
Phase II study of gemcitabine and carboplatin plus bevacizumab for stage III/IV non-small cell lung cancer: Preliminary safety data
Authors: M. J. Kraut
Journal: Journal of Clinical Oncology (2006)

17091 Background: The current standard of care for stage III/IV non-small cell lung cancer (NSCLC) is platinum-based chemotherapy. Bevacizumab (BV) is a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody that improves survival when used in combination with chemotherapy. In a randomized, phase II study of patients (pts) with advanced NSCLC, the addition of bevacizumab 15 mg/kg to paclitaxel/carboplatin (PC) resulted in prolonged survival and progression-free survival compared with PC alone (Sandler AB et al, ASCO 2005). In the present study, we are using BV 15 mg/kg in combination with gemcitabine/carboplatin (GC) for the treatment of NSCLC. Preliminary safety findings are summarized. Methods: Eligible pts with stage IV NSCLC, PS 0–1, and adequate hematologic, renal and hepatic function, were enrolled; pts with squamous cell carcinoma, tumor in the central airways, baseline hemoptysis, or brain metastases were excluded. GC/BV treatment was given in q 3-weekly cycles for 6 cycles, with BV continued in stable and responding patients. G 1250 mg/m 2 was given on days 1 and 8 and C AUC 5 was given on day 1. BV 15 mg/kg was given on day 1. After 7 pts were enrolled, the study was amended to reduce the dose of G to 1000 mg/m 2 on days 1 and 8 due to unacceptable neutropenia. Primary endpoint of the study is time to progression. Results: To date, 9 pts have received treatment; we report here the hematologic toxicity of the first 8, and non-hematologic toxicity of the first 7. There are 6 men and 2 women, median age 61.5 years. There was one episode of grade 4 thrombocytopenia, and Grade 3 events have been reported a number of patients: leukopenia (5 pts); neutropenia (4 pts); thrombocytopenia (4 pts); infection (1 pt); hemoglobin toxicity (1 pt); fatigue (1 pt); diarrhea (1 pt); dyspnea (1 pt); and dehydration (1 pt). Adverse events possible related to BV include Grade 3 hypertension (1 pt) and Grade 1 epistaxis (2 pts). No thrombosis or proteinuria has been reported. There have been no fatal toxicities. Conclusions: To date, the addition of BV to GC in pts with NSCLC is generally well tolerated and no unexpected adverse events possibly related to BV were observed. Enrollment is ongoing. [Table: see text]
춘계학술대회 : 총회구연 ; 제한효소질량다형성 분석을 통한 한국인 환자에서의 C형 간염 바이러스 유전형 6형 동정
Authors: 김강모, 오흥범, 임영석, 이한주, 정영화, 이영상, 김수옥, 정현재, 김은옥, 홍선표, 유왕돈, 서동진
Journal: Clinical and Molecular Hepatology (2005)

배경/목적: C형 간염 바이러스(HCV) 게놈 상의 5`-UTR 부위는 염기 서열이 잘 보존되어 있고, 유전형 특이 염기 서열들이 존재하므로 이 부위의 염기 서열을 분석함으로써 1형부터 6형까지 주요 유전형을 분류할 수 있다. HCV 유전형 분포는 지리적인 차이를 보이며, 우리나라의 경우 1형과 2형이 90% 이상을 차지하는 것으로 알려져 있으나 그 외에 다른 유전형에 대한 분포는 잘 알려져 있지 않다. 반면 홍콩, 마카오, 베트남 등 동남아시아 지역은
The clinical utility of a tumour microenvironment-based histopathological score in patients with primary operable colorectal cancer.
Authors: James Hugh Park, Donald C. Mcmillan, Paul G. Horgan, Campbell S.D. Roxburgh
Journal: Journal of Clinical Oncology (2015)

664 Background: The tumor microenvironment is increasingly recognized as an important determinant of disease progression and outcome in colorectal cancer (CRC). The aim of the present study was to examine the clinical utility of a novel histopathological prognostic score based on both the tumor inflammatory cell infiltrate and the tumor stroma percentage, termed the Glasgow Microenvironment Score (GMS), in patients with primary operable CRC. Methods: Using routine H&amp;E pathological sections, Klintrup-Mäkinen (KM) grade was graded as strong or weak, and tumor stroma percentage (TSP) was assessed as high (&gt;50%) or low (≤50%) retrospectively in 319 patients undergoing resection of stage II-III CRC. The relationship between a cumulative score based on these factors and cancer-specific survival (CSS) was examined. Results: Median survival of survivors was 122 months with 106 cancer deaths. 63% of patients had stage II CRC. 5-year CSS of patients with stage II and stage III CRC was 82% and 58% respectively (p&lt;0.001). 33% of patients were GMS=0 (strong KM/high or low TSP), 47% were GMS=1 (weak KM/low TSP), and 20% GMS=2 (weak KM/high TSP), with 5-year CSS of 86%, 74%, and 48% (p&lt;0.001) respectively. On multivariate analysis, GMS was associated with CSS (HR 1.77, p&lt;0.001), independent of age, emergency presentation, TNM stage and venous invasion (all p&lt;0.01), and peritoneal involvement (p&lt;0.05). The combination of TNM and GMS stratified 5-year CSS from 92% (stage II, GMS=0) to 35% (stage III, GMS=2) (Table). Conclusions: The present study shows the clinical utility of a novel, routinely available assessment of the tumor microenvironment in patients undergoing curative resection of CRC. [Table: see text]
Placebolotherapy
Authors: Nick J Woodhead
Journal: BMJ (2008)

I am thinking of setting myself up as a placebolotherapist.1 Placebolotherapy—the standard by which all other treatments are measured. At least as effective as all types of psychotherapy and all “alternative” healthcare treatments. Treats physical health conditions and mental health problems (especially mood disorders). Evidence based. No spurious claims or pseudoscientific explanations. No reliance on ill defined terms such as “energy,” “auras,” “crystal power,” or “spirituality.”

Placebolotherapy is not a replacement for any proven treatment, it is an enormously helpful adjunct.

Placebolotherapists spend an hour with the “patient” in a pleasant room, giving them their full and undivided attention. They explain that what they are doing is backed up by rigorous scientific evidence, is extremely effective, and that the patient will feel better afterwards.

That’s it. Cost £50 a session. Research into placebo shows that the more value the patient puts on it, the more effective it is (a placebo injection is more effective than a placebo pill), so an expensive session will be more effective than a cheap one.

Or should I set myself up as a homoeopath?
Preclinical modeling of a phase 0 clinical trial protocol
Authors: R. J. Kinders, M. Hollingshead, R. E. Parchment, S. Khin, G. Kaur, L. Phillips, J. Tomaszewski, J. Doroshow
Journal: Journal of Clinical Oncology (2007)

14058 Background: The Exploratory IND program initiated at NCI (“Phase 0”) is designed to evaluate the pharmacodynamic effects (PD) of candidate drugs at the molecular level in the clinic. Trials employ patient biopsies and surrogate tissues (e.g. PBMCs) to determine the quantitative effect of the agent on its putative target, after a minimum number of doses. The approach requires repeated biopsy of the tumor, an understanding of the time-effect window, and some knowledge of the dose level likely to cause a measurable drug effect. Methods: Prior to initiating a Phase 0 study of the PARP (PolyAdenosyl-Ribose Polymerase) inhibitor, ABT-888, we developed a pre-clinical model to mirror the clinical protocol. Colo 829 and A375 xenografts in athymic nude [nu/nu (NCr)] mice were examined for time and dose effect on PARP using a validated, quantitative PAR assay. Extracts of entire xenografts, quartered xenografts and 18 gauge needle biopsies were examined for variability of baseline and post-treatment PAR levels. Results were cross-checked with Western analysis for polyADP-Ribose (PAR)-labeled proteins in treated mice. Pharmacokinetics (PK) were modeled using plasma drug levels. Additional studies examined the influence of previous biopsy, contralateral biopsy, vehicle treatment, and general anesthesia on PAR in xenografts. Results: A single dose of ABT-888 produced a significant decrease in intracellular PAR levels that could be measured 2 to 6 hours post-dose. PAR levels and drug effect on PAR levels were not influenced by repeated needle biopsies. Variation across xenografts was random for single and bilateral xenograft animal models in the ABT-888 treated, vehicle- and topotecan-treated control groups. Animal handling and socialization appeared to elevate baseline PAR levels, which could confound analysis of study results. Conclusions: Pre-clinical modeling of a specific Phase 0 clinical protocol for drug effects and biological variability provided valuable insights into the development, refinement, and analysis of the currently-active NCI Phase 0 clinical trial of ABT-888. Animal studies were conducted in an AAALAC approved facility under an approved IACUC protocol. Funded by NCI Contract N01-CO-12400. No significant financial relationships to disclose.
Clinical Pharmacokinetics of High-Dose Metoclopramide in Cancer Patients Receiving Cisplatin Therapy
Authors: Jonathan E. McDermed, Jordan L. Cohen, Corrine Joseph, Stephen B. Strum
Journal: Journal of Clinical Oncology (1985)

Using a sensitive and specific high-pressure liquid chromatographic (HPLC) assay, we measured serum levels of metoclopramide in 18 cancer patients receiving high-dose intravenous (IV) therapy to prevent cisplatin-induced emesis. Ten patients were treated with one or more courses with metoclopramide alone (1.0 to 3.0 mg/kg) in an open-label study, and eight patients were treated with a fixed 2.0 mg/kg dose of metoclopramide with or without adjunct dexamethasone (20 mg) using a randomized, crossover design. The pharmacokinetics of metoclopramide were determined, and the relationship between serum levels and clinical response was evaluated. The pharmacokinetic parameters of high-dose metoclopramide were found to be similar to those reported for standard promotility doses, and no dose dependency was demonstrated over the range of doses studied. No clear correlation between serum metoclopramide levels and prevention of cisplatin-induced emesis was observed. The addition of dexamethasone resulted in clinical improvement in two of eight patients, but had no effect on serum metoclopramide levels or kinetic parameters. Results in this study population do not show metoclopramide levels to be related to antiemetic effect following IV cisplatin therapy.
Frances Cress Welsing
Authors: Ned Stafford
Journal: BMJ (2016)

African American psychiatrist who developed theories on racism and white supremacy



Elvert Barnes

In 1974 Frances Cress Welsing agreed to a debate with William Shockley on the topic of racial superiority—or, conversely, racial inferiority. The debate would be seen across the US on Tony Brown’s Journal , a programme focusing on African American issues that was broadcast by the public TV network PBS.1

At the time Welsing was a virtually unknown assistant professor of paediatrics at Howard University in Washington, DC. Shockley was a world famous physicist who in 1956 had won the Nobel prize for helping discover the “transistor effect” of semiconductors. During the 1960s and early 1970s, however, Shockley had become controversial for his theory that black people as a group were genetically inferior to white people, and therefore generally not as intelligent. The speeches he gave to promote his theories at universities across the US were often disrupted by students opposed to his views.

But Welsing had also developed a controversial theory, which she had explained in a 15 page essay entitled: “The Cress Theory of Color-Confrontation and Racism (White Supremacy).” In 1970 she had read the essay at a meeting of the psychiatry and neurology section of the National Medical Association that represented African American physicians.

In simple terms, Welsing’s theory states that the skin of white people is a result of a genetic recessive and deficiency condition that causes an inability to produce …
Phytoestrogen Suppresses Efflux of the Diagnostic Marker Protoporphyrin IX in Lung Carcinoma
Authors: Hirofumi Fujita, Keisuke Nagakawa, Hirotsugu Kobuchi, Tetsuya Ogino, Yoichi Kondo, Keiji Inoue, Taro Shuin, Toshihiko Utsumi, Kozo Utsumi, Junzo Sasaki, Hideyo Ohuchi
Journal: Cancer Research (2016)

One promising method to visualize cancer cells is based on the detection of the fluorescent photosensitizer protoporphyrin IX (PpIX) synthesized from 5-aminolevulinic acid (ALA), but this method cannot be used in cancers that exhibit poor PpIX accumulation. PpIX appears to be pumped out of cancer cells by the ABC transporter G2 (ABCG2), which is associated with multidrug resistance. Genistein is a phytoestrogen that appears to competitively inhibit ABCG2 activity. Therefore, we investigated whether genistein can promote PpIX accumulation in human lung carcinoma cells. Here we report that treatment of A549 lung carcinoma cells with genistein or a specific ABCG2 inhibitor promoted ALA-mediated accumulation of PpIX by approximately 2-fold. ABCG2 depletion and overexpression studies further revealed that genistein promoted PpIX accumulation via functional repression of ABCG2. After an extended period of genistein treatment, a significant increase in PpIX accumulation was observed in A549 cells (3.7-fold) and in other cell lines. Systemic preconditioning with genistein in a mouse xenograft model of lung carcinoma resulted in a 1.8-fold increase in accumulated PpIX. Long-term genistein treatment stimulated the expression of genes encoding enzymes involved in PpIX synthesis, such as porphobilinogen deaminase, uroporphyrinogen decarboxylase, and protoporphyrinogen oxidase. Accordingly, the rate of PpIX synthesis was also accelerated by genistein pretreatment. Thus, our results suggest that genistein treatment effectively enhances ALA-induced PpIX accumulation by preventing the ABCG2-mediated efflux of PpIX from lung cancer cells and may represent a promising strategy to improve ALA-based diagnostic approaches in a broader set of malignancies. Cancer Res; 76(7); 1837-46. ©2016 AACR.
Differential effects of budesonide and fluticasone propionate on expression of lactotransferrin in airway epithelium
Authors: Irene Heijink, Marnix Jonker, Dirkje Postma, Maarten Van den Berge
Journal: European Respiratory Journal (2014)

Rationale:  Although inhaled corticosteroids reduce the number of exacerbations and improve quality of life, COPD patients treated with fluticasone propionate(FP) have an increased risk of pneumonia, a finding not reported or in lower frequency with budesonide (BUD). The mechanisms underlying this difference are not yet understood. Based on preliminary findings, we hypothesized that FP is more potent than BUD in the suppression of immune defense gene lactotransferrin, anantimicrobial peptide abundantly expressed in airway epithelium.   Methods:  We assessed lactotransferrin mRNA (qPCR) and protein (immunodetection) expression upon 24- and 48-hour treatment of human bronchial 16HBE cells with equivalent concentrations of FP and BUD, i.e. 10 nM FP and 16 nM BUD, which were equally effective in suppressing pro-inflammatory cytokine production.   Results:  FP significantly reduced lactotransferrin mRNA expression in 16HBE cells at 24 hours. This effect was not observed for BUD, resulting in a statistically significant difference between BUD and FP treatments. Western blotting performed at 48 hours confirmed a significantly higher expression of lactotransferrin protein upon treatment with BUD compared with FP, although FP had no effect on lactotransferrin protein expression, while there was a trend for increased expression by BUD.   Conclusions:  Treatment of human bronchial epithelium with BUD results in a significantly higher expression of lactotransferrin than treatment with FP. The differential regulation of this antimicrobial peptide may help to explain the putative differential clinical adverse effects of FP as compared to BUD with respect to the risk to develop pneumonia.