tbuckley/cabot-search huggingface dataset:
Creation of a library of harmonized standard research variables and case report forms (CRFs) for oncology research
Authors: D. M. Reeves, E. Helton, J. Speakman, E. Ness, G. Komatsoulis
Journal: Journal of Clinical Oncology (2009)

e17512 Background: Oncology clinical research can be facilitated through use of a set of core variables to collect, aggregate, analyze and report data across a number of diverse research settings. These elements can be captured in Case Report Form (CRF) templates, and cloned to expedite the activation of a clinical trial and the collection of data. Through the efforts of the Cancer Biomedical Informatics Grid or caBIG community, the creation of a set of CRFs to support NCI-sponsored trials has been underway since the summer of 2007. Methods: A schematic to represent commonly-used CRFs in oncology trials was created as a roadmap for the project. Priorities were established, and community broadcasts used to recruit workgroup members with clinical, biostatistical, and regulatory expertise. CRFs were contributed by the community-at-large, including the pharmaceutical industry and NCI cooperative groups. Variables from a set of CRFs were partitioned into one of four groups: mandatory, conditional, optional, or not to be included in a CRF. After all the variables for a CRF were finalized by consensus, data elements were created and registered into an NCI ISO/IEC 11179 metadata repository that facilitates the reuse of data elements and CRFs. Results: Eight workgroups have completed their work by the end of 2008, with additional groups underway. The results of the first eight groups were harmonized with the Clinical Data Acquisitions Standards Harmonization or CDASH version 1.0, a standard for CDISC. After approval, the variables are assembled into CRFs with instructions that are available through NCI's data standards repository in a variety of electronic formats. The variables will undergo a rigorous change management process with regular review and versioning as required. Conclusions: The identification and reuse of standards to support the conduct of oncology research depends upon our ability to manage data sets that can be aggregated and analyzed in a timely manner. The caBIG CRF harmonization and standardization variables are being implemented now through a series of early adoption activities and a phased deployment plan that will result in the reuse of a single set of variables to support the conduct of oncology clinical trials. No significant financial relationships to disclose.
Chronic physical effects and health care utilization in long-term ovarian germ cell tumor survivors
Authors: S. Williams, P. Monahan, A. Miller, D. M. Gershenson, Q. Zhao, D. Cella, V. Champion, D. Matei
Journal: Journal of Clinical Oncology (2008)

9551 Background: Ovarian germ cell tumors (OGCT) are rare tumors curable with modern surgery and chemotherapy. Late effects of therapy in survivors have not been described. This multi-site study compares the late effects of treatment on physical well being and utilization of health care resources between OGCT survivors and an age/race/education-matched control group. Methods: Eligible patients had a history of OGCT treated with surgery plus platinum-based chemotherapy on GOG protocols and were free of disease for at least 2 years at time of enrollment. The matched control group was selected from acquaintances recommended by survivors. Data were collected through mailed background questionnaires and computer-assisted telephone interviews. Physical functioning was measured using validated scales (SF36 and FACT/GOG-NTX). Health care utilization was assessed by questions regarding health insurance coverage, health services utilization and employment. Wilcoxon Rank Sum and Fisher’s exact tests were used for statistical analyses. Results: 132 survivors and 137 controls completed the study. Mean age for both survivors and controls was 36 years; survivors were on average 10 years post-treatment. Survivors were more likely to report a diagnosis of hypertension (17% vs. 8%, p-value = 0.02), hypercholesterolemia (9.8% vs. 4.4%, p-value = 0.09) and hearing loss (5.3% vs. 1.5%, p-value = 0.09) compared to controls. There were no significant differences in the rates of self-reported arthritis, heart, pulmonary or kidney disease, diabetes, non-OGCT malignancies, anxiety, hearing loss, or eating disorders between the two groups. Among chronic functional problems, numbness and tingling, tinnitus, nausea elicited by reminders of chemotherapy (vs. general nausea for controls), and Raynaud’s symptoms were reported more frequently by survivors (p-value < 0.05). Health care utilization was similar between the groups, but 15.9% of survivors reported being denied health insurance, compared to 4.4 % of controls (p-value < 0.001). Conclusions: The results describe late toxicity from treatment in adult OGCT survivors. Although some late sequelae of treatment persist, in general, OGCT survivors enjoy a healthy life comparable to that of matched controls. No significant financial relationships to disclose.
Abstract 12149: Impact of Concomitant Administration Hypertonic Saline Solution and Daily Use Furosemide in Treatment of Acute Decompensated Heart Failure
Authors: Yoshitaka Okuhara, Shinichi Hirotani, Yoshirou Naito, Toshihiro Iwasaku, Akiyo Eguchi, Hisashi Sawada, Eri Manabe, Tohru Masuyama
Journal: Circulation (2012)

Background While sodium infusion supplemented with furosemide is theoretically anticipated to promote diuresis in patients with acute decompensated heart failure (ADHF), there is little evidence to...
President Mbeki might have a case on rethinking AIDS [letter]
Authors: Dwyer Sw
Journal: BMJ (2002)

The writer of this letter to the editor is a South African prison medical officer who finds some validity in South African President Thabo Mbekis skeptical view of the link between HIV and AIDS.  He notes that research data tend to be formulated from actuarial models and short trials in pregnant women attending antenatal clinics.  However he claims that pregnancy is known to cause a raised rate of false positive results on testing for HIV infection with enzyme linked immunosorbent assay. Moreover he also claims that the HIV prevalence rate in the South African prison population which should be higher than that in the general population are far below the numbers generated by the actuarial models and antenatal data.  He concludes that the widespread mystical attitude towards HIV/AIDS gives this disease recognition out of all proportion to its incidence compared to a number of other diseases.
Dominant negative Hes1 blocks osteosarcoma invasion driven by Notch pathway signaling
Authors: D. P. Hughes, P. Zhang, Y. Yang, K. E. Lee, P. A. Zweidler-McKay
Journal: Journal of Clinical Oncology (2007)

9549 Background: Osteosarcoma (OS) is the most common bone cancer, with a peak incidence in mid-adolescence. OS outcome is poor for metastatic or recurrent disease (&lt;30% and 10–20% survival respectively at 5 years). We investigated mechanisms regulating invasion and metastasis to identify new therapeutic targets for OS. One potential target is γ-secretase, required for activating Notch, Her-4 and β-catenin pathways. We have shown previously that Notch pathways genes are expressed in OS cells, and recently identified an association between Notch-mediated Hes1 expression and OS invasiveness. Here we sought to determine if OS invasiveness could be eliminated by direct blockade of Hes1 function. Methods: OS cell lines OS 187, COL, Saos-2 and Saos2-LM7 (a metastatic subline of Saos-2) were used for all studies. Functional analyses included proliferation, anchorage-independent growth, cell-cycle/apoptosis and matrigel invasion. Notch pathway signaling was genetically manipulated by transduction with constitutively active Notch 1 (ICN1), a dominant negative inhibitor of Notch signaling (dnMAM), normal Hes1, and dominant negative Hes1 (dnHes1). The efficacy of dnHes1 in blocking Hes1 was confirmed in Shep neuroblastoma cells by demonstrating upregulation of Hash1, a gene suppressed by Hes1. Comparisons were made to cells transduced with empty vector (negative control) and cells treated with γ-secretase inhibitor (positive control). Results: Notch pathway manipulation did not affect proliferation, cell cycle or in vitro tumorigenesis. Retroviral transduction with ICN1 or Hes1 increased invasion in all cell lines, and dnMAM reduced invasiveness in OS 187, Saos-2 and LM7, similar to γ-secretase inhibition. Hes1 expression in COL was constitutively active, did not suppress with dnMAM, but invasiveness was proportional to the Hes1 expression. dnHes1 suppressed invasiveness of all lines, indicating the importance of Hes1 expression in regulating invasion, an essential feature of metastasis in OS. Conclusions: Hes1 expression may be useful as a marker of increased metastatic risk. Therapies blocking Hes1 expression, including γ-secretase inhibitors, may have therapeutic potential for OS. Further preclinical and clinical trials are warranted. No significant financial relationships to disclose.
Clinical benefits and risks of phase I oncology trials: experience from a single institution
Authors: R. Gollamudi, B. M. Wong, M. H. Ghalib, M. Kumar, K. Desai, I. Chaudhary, S. Goel, S. Mani
Journal: Journal of Clinical Oncology (2008)

6572 Background: The majority of published series of phase I oncology trials has reported response rates between 4 to 6 percent. A recent meta-analysis of phase I studies showed a higher response rate of 10.6%. Few reports on single-institution phase I experience have been published. Methods: Results from phase I trials conducted at our institution from 1999 to 2007 were reviewed. Data including clinical responses to treatment, toxic events, and treatment-related deaths were recorded. Results: Data from 33 phase I studies [cytotoxic agents (50%), biologic agents (40%), and both (10%)] involving 491 patients (pts) were analyzed. Primary diagnoses included colorectal (25%), ovarian (20%), breast (8.5%), and lung (7%) cancer. 391 pts were assessable for response and the overall response rate (RR) was 8.2% (complete response rate of 1.5%). Patients with documented response had a lower baseline LDH (234 vs 342 U/l, p=0.04), platelet count (167,000 vs 209,000/μl, p=0.03) and serum protein (6.97 vs 7.23 gm/dl, p=0.06) than patients with stable or progressive disease. Notably, patients with a response had a lower mean CTC pain grade while on study (1.1 vs 1.45, p=0.08) than patients with lack of response. Seven of the 32 responses (22%) were observed below the maximum tolerated dose. The rate of stable disease was 39.4%. The mean and median duration on study were 79 days and 53 days, respectively. The treatment-related mortality rate was 1.2%. The rates of hematologic and non-hematologic grade 4 toxic events were 16.7% and 4.3%, respectively. Conclusions: This is one of the largest single-institution series of phase I oncology trials. Our response rate of 8.2% is comparable to that reported in a recently published multi- institution series. This RR falls within the 95% confidence interval of the RR of a majority of third line (and greater) chemotherapy for solid malignancy, and the concept of phase I studies as being ‘non-therapeutic‘ is called into question. No significant financial relationships to disclose.
Phase I dose escalation study of fludarabine, bortezomib, and rituximab for relapsed/refractory indolent and mantle cell non- Hodgkin lymphoma
Authors: P. M. Barr, P. Fu, H. M. Lazarus, N. J. Bahlis, O. N. Koc, N. J. Horvath, B. W. Cooper
Journal: Journal of Clinical Oncology (2008)

8553 Background: Fludarabine (F) and bortezomib (B) have each demonstrated tolerability and efficacy in patients with non- Hodgkin lymphoma (NHL). Despite potential synergy between these agents, the combination remains untested. This phase I study was designed to obtain preliminary toxicity data and to determine the maximum tolerated dose (MTD) of the regimen. Methods: Relapsed or refractory indolent and mantle cell NHL and patients with chronic lymphocytic leukemia (CLL) were eligible. Dose levels of F and B were escalated as per the schema below with rituximab (R) being added to the 5th cohort. Due to unanticipated hematologic toxicity at dose level 5, cohorts 5a and 5b were subsequently added. Cycles were repeated every 21 days for a maximum of 8 cycles. Dose escalation occurred in cohorts of 3 patients. Cohorts were expanded to 6 patients if a dose limiting toxicity (DLT) was observed. The MTD was defined as one dose level below the cohort at which 1/3 of the patients experienced a DLT. Results: 23 patients have been enrolled to date. Patient histologies include 11 with grade 1/2 follicular, 4 with marginal zone, 3 with lymphoplasmacytic, 2 with CLL/small lymphocytic, 2 with mantle cell and 1 with grade 3 follicular NHL. No dose limiting toxicities were observed in cohorts 1 through 4. The addition of R in cohort 5 resulted in dose limiting hematologic toxicity. An additional DLT, grade 3 neuropathy, occurred in 1 patient. At dose levels 5a and 5b, no further grade 3 or 4 hematologic toxicity has been observed with cycle 1. Of the 17 patients currently evaluable for a response, 3 have achieved a complete response, 4 have achieved a partial response, 8 had stable disease, and 2 patients progressed on therapy. The median time of stable disease for the 8 patients was 9 months (range 3–30+). Conclusions: FBR is a well-tolerated and active regimen for patients with relapsed or refractory NHL. R may worsen the hematologic toxicity of a nucleoside analog and proteasome inhibitor containing regimen. Dose escalation of fludarabine, bortezomib, and rituximab Dose Level Fludarabine (25 mg/m2) Bortezomib (mg/m2 on days 1,4,8,11) Rituximab (mg/m2 on day 1) 1 days 1-3 0.7 - 2 days 1-3 1.0 - 3 days 1- 3 1.3 - 4 days 1-5 1.3 - 5 days 1-5 1.3 375 5a days 1-3 1.0 375 5b days 1- 3 1.3 375 No significant financial relationships to disclose.
Reply
Authors: Qilin Gu, Zongbin Cui
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Dr. Closs has raised some interesting questions that are associated with the production and distribution of nitric oxide in the body. Several plasma membrane proteins including cationic amino acid transporter‐1 (CAT‐1), CAT‐2A, CAT‐2B, and CAT‐3 have been identified to function as selective transporters of arginine.1 Expression of CAT1 is ubiquitous,2 and CAT‐2 has two transcripts, CAT2A and CAT2B, which are expressed in hepatocytes and macrophages, respectively4; CAT‐3 is mainly expressed in the brain of adult mice.5 Their corresponding homologs in zebrafish are Slc7a1, Slc7a2, and Slc7a3a.6 It appears that Slc7a3a plays a key role in intracellular transport of arginine because the defective function of Slc7a3a cannot be compensated by Slc7a1 and Slc7a2 in fasted slc7a3a‐null mutants. In addition, Slc7a3a is not expressed in zebrafish liver, so the liver is not the major organ for the production of nitric oxide; however, nitric oxide produced in other organs is soluble in body fluid and blood and thus can be delivered from the blood vessel to all tissues including the liver in zebrafish.6 Thus, the decreased production of nitric oxide in other tissues of the whole body due to the failure of arginine transport can also impair the adenosine monophosphate–activated protein kinase signaling that controls the lipid oxidation and synthesis in hepatocytes. Indeed, cyclic guanosine monophosphate levels in Slc7a3‐knockdown mice under starvation are significantly lower than those in the siCtrl‐group (see fig. 7F).6 Western blotting assays were performed to detect the expression of Slc7a3 in several tissues including brain, lung, heart, liver, stomach, intestine, and muscle after adenovirus‐based small interfering RNA knockdown in mice. After knockdown of Slc7a3 with two small interfering RNAs in mice, representative western blotting assays for the brain were conducted (results shown in fig. 7D of our article).6 We do not think the western blotting results of CAT‐3 knockdown in mice are off‐target effects. However, further experiments are needed to address whether CAT‐2A plays a role in the mouse liver under starvation.
A phase I/II study of photodynamic therapy (PDT) using HPPH for the treatment of Barrett's and precancerous lesions of the esophagus.
Authors: H. R. Nava, S. S. Allamaneni, M. T. Cooper, T. Dougherty, G. E. Wilding, B. W. Henderson
Journal: Journal of Clinical Oncology (2010)

4161 Background: FDA approved PDT with porfimer sodium has been explored to treat lesions associated with Barrett's esophagus. Porfimer sodium PDT has the drawback of skin photosensitivity for 6-8 weeks. The photosensitizer HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) showed minimal photosensitization of short duration and promising efficacy in preclinical studies. Here we explore toxicity and optimal drug and light dose with endoscopic HPPH-PDT. Methods: Two phase I/II nonrandomized dose escalation studies involving 36 patients with biopsy-proven High grade dysplasia, carcinoma in situ or early intramucosal adenocarcinoma of esophagus were performed between 2000 and 2004. The studies were approved by IRB. HPPH doses ranged from 3 to 6 mg/m2. At 24 to 48 hours after HPPH administration the lesion was exposed to 665 nm light for a light dose of 150, 175 or 200 J/cm from a cylindrical diffuser fiber. Endoscopy and 4-quadrant biopsies every 2 cm were done during the procedure and on follow-up at 2, 4 and 6 months, and every 6 months thereafter up to 5 years. Results: A total of 32 men and 4 women, age range 50-86 yrs, were treated. Most patients experienced mild to moderate chest pain requiring symptomatic treatment only. Ten expected serious adverse events, mainly related to respiratory and cardiac system, were treated uneventfully. Three esophageal strictures were treated with dilatation. No clear pattern of dose dependence of toxicities emerged. In the first dose ranging study with 18 patients 3 and 4 mg/m2 of HPPH showed initial complete responses, while HPPH doses of 5 and 6 mg/m2 achieved no complete responses. In the second dose ranging study of 18 patients with HPPH doses of 3 and 4 mg/m2 and light doses of 150, 175 and 200 J/cm achieved an initial complete response rate (best response) of 72.22%, with 100% initial complete responses with the combinations of 3 mg/m2-175 J/cm and 4 mg/m2-150 J/cm. Conclusions: We established that 3 or 4 mg/m2 HPPH with 150 or 175 J/cm appears to be effective. The best initial response results are comparable to published results of porfimer sodium-PDT. No significant financial relationships to disclose.
Procalcitonin (PCT) as an adjunct to the Multinational Association of Supportive Care in Cancer (MASCC) risk-index score in cancer patients with febrile neutropenia
Authors: A. Uys, H. Fickl, P. W. A. Meyer, R. Anderson, B. L. Rapoport
Journal: Journal of Clinical Oncology (2005)

8120 Background: The majority of cancer patients who present with febrile neutropenia experience uncomplicated and speedy recovery. Nevertheless, the frequency of complications remains unacceptably high, with a reported mortality rate by all major cooperative groups of approximately 10%. Infections are the major cause of morbidity/mortality in cancer patients undergoing chemotherapy. In this setting, there is a critical requirement for the development of strategies, such as the MASCC risk- index, which enables early identification of patients at high risk for serious infective complications, who would benefit from hospitalization and prompt, aggressive antimicrobial therapy. Methods: The objective was to determine the value of combining PCT, a selective, systemic marker of severe bacterial infection, measured in cancer patients on presentation with chemotherapy-induced febrile neutropenia, with the MASCC score, as a strategy to distinguish between patients with serious infection and those with less serious infection, or non-infective causes of pyrexia. Patients, who experienced 78 febrile neutropenic episodes were classified, into groups with low (<0.5 ng/ml) or high (≥0.5 ng/ml) initial circulating levels of PCT and these groups were compared with MASCC scores, neutrophil and monocyte counts Results: Sixty four % of patients (all survived), presented with low-risk MASCC scores and low PCT values. 19.2%, presenting with high-risk MASCC scores and high PCT values, (46.7% of whom died, p <0.0001), was considered to be at extremely high risk. The remaining patients (16.8%) were classified either as low-risk MASCC score/high PCT (all survived) or high-risk MASCC/low PCT (1 died). By using the MASCC score in conjunction with measurement of PCT, it was possible to categorize around 83% of patients into those at low risk and those at extremely high risk for severe infection and death. Conclusions: PCT values measured on presentation with febrile neutropenia, combined with the MASCC score, distinguish patients with severe infection, who are at high risk of death, from those with less severe infection and non-infective causes of pyrexia. No significant financial relationships to disclose.
European verdict on minimum alcohol pricing puts ball in Scottish courts
Authors: Bryan Christie
Journal: BMJ (2015)

Scotland’s plan to introduce a minimum price for a unit of alcohol may be contrary to European law but can still be introduced if it is considered the most effective way to reduce the harm caused by cheap drinks.

Scotland’s Court of Session will now decide whether minimum pricing, which was approved by the Scottish parliament more than three years ago, can go ahead. It follows a ruling by the European Court of Justice that the measure would restrict trade and would breach European Union law if less restrictive tax measures, such as an increase in …