tbuckley/cabot-search huggingface dataset:
The impact of less than 8% weight loss on overall survival in subjects with non-small cell lung cancer (NSCLC) treated in a phase IIb trial of GTx-024.
Authors: S. Dodson, A. Dobs, M. L. Hancock, M. A. Johnston, M. S. Steiner
Journal: Journal of Clinical Oncology (2011)

9117 Background: Cancer cachexia causes muscle wasting and decline in physical function. Studies show that NSCLC patients with weight loss at diagnosis have worse treatment outcomes and shorter overall survival. This muscle wasting and decline in function may have detrimental consequences early in the course of a patient’s malignancy, underscoring the importance of diagnosing and treating this condition at an early stage. We conducted a Phase IIb, randomized, double blind, placebo controlled, multi center study to evaluate the effect of GTx-024 on muscle wasting and physical function in patients with cancer cachexia. Methods: Subjects (n=159) were randomized to oral GTx-024 (1 or 3 mg) or placebo (pbo) daily for 16 weeks. Subjects were males >45 y and postmenopausal females, had experienced ≥2% weight loss in the 6 mths prior to randomization, had a BMI <35 and either NSCLC, colorectal cancer, non-Hodgkin lymphoma, chronic lymphocytic leukemia or breast cancer. The primary endpoint was change in total lean body mass (muscle). We report on overall survival in the entire study population and NSCLC cohort based on weight loss of > or ≤8% in the previous 6 months. Results: In pbo subjects in the ITT population, overall survival was significantly (P=0.003, log rank) reduced in subjects with >8% weight loss compared to subjects with ≤8% weight loss. Among NSCLC subjects (n=61) pbo subjects with >8% weight loss demonstrated a similar survival disadvantage (P=0.04); 4 month Kaplan-Meier estimates 100% vs 49% ±14.8%. In GTx-024 treated subjects in both the ITT and NSCLC groups, increased weight loss did not negatively affect survival. Conclusions: Preceding weight loss among NSCLC patients not treated with GTx-024 is predictive of decreased overall survival. In this 16 week Phase IIb trial, NSCLC subjects randomized to placebo with >8% weight loss at baseline were 2 times more likely to die than subjects with ≤8% weight loss. In the GTx-024 group, weight loss was not predictive of overall survival. These data suggest that GTx-024 treatment may overcome the negative prognostic effect of >8% weight loss. Further research is needed to assess the effect of GTx-024 on overall survival.
Discrepancies between immunohistochemistry and fluorescence in situ hybridization for HER-2 testing in breast cancer: The role of a quality assurance program on a cohort of 3564 patients
Authors: H. Yaziji, T. S. Barry, L. C. Goldstein, H. H. Hwang, A. W. Hing, A. M. Gown
Journal: Journal of Clinical Oncology (2004)

679 Background: While determination of HER-2 status in breast cancer by fluorescence in situ hybridization (FISH) is now widely employed, its utility as part of a QC/QA program for IHC has not been established. The aim of this study was to (a) determine whether the use of FISH could improve the utility of immunohistochemistry (IHC), (b) attempt to identify sources of discrepancy between HER-2 protein, tested by IHC and HER-2 gene status, tested by FISH, and (c) design a reasonable and cost-effective testing algorithm. Methods: We commenced a QA/QC program for HER-2 testing in 1999, accruing 3564 tumors to date. As part of the program, parallel IHC testing was performed for each clinical FISH test. Routine components of this program also include random monthly review of HER-2 IHC and FISH results, targeted review of tumors with discrepant results, and intra- and inter-pathologist review of IHC and FISH scores. FISH and IHC tests were performed using FDA-approved testing kits (Vysis/Abbott and DakoCytomation, respectively). Results: With FISH to be the presumed gold standard, the sensitivity of IHC was 92.6%. The specificity of positive (3+) overexpression was 98%. The positive and negative predictive values of IHC were 94.8% and 97.4% respectively. Using some of the components of this QA/QC program, we were able to identify tumors with potential IHC-FISH discrepancy. These include tumors with (a) heterogeneity of gene status, and (b) polysomy of chromosome 17 (with/without true gene amplification). Significant discordance was only observed in the 2+ IHC group. Conclusions: Establishing a strict QC/QA program allowed us to significantly improve the sensitivity and specificity of IHC testing. According to these results, IHC can be used for screening. FISH testing should be mandatory only on tumors with 2+ IHC scores. Such program also helped identify sources of discrepant IHC and FISH results. Tumors containing either instable HER-2/neu gene or polysomy of chromosome 17 are largely the source of discrepant IHC and FISH results, and should be further investigated. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NexCura NexCura Genentech, Inc.
Liposome‐Loaded Cell Backpacks
Authors: Roberta Polak, Rosanna M. Lim, Marisa M. Beppu, Ronaldo N. M. Pitombo, Robert E. Cohen, Michael F. Rubner
Journal: Advanced Healthcare Materials (2015)

Cell backpacks, or micron-scale patches of a few hundred nanometers in thickness fabricated by layer-by-layer (LbL) assembly, are potentially useful vehicles for targeted drug delivery on the cellular level. In this work, echogenic liposomes (ELIPs) containing the anticancer drug doxorubicin (DOX) are embedded into backpacks through electrostatic interactions and LbL assembly. Poly(allylamine hydrochloride)/poly(acrylic acid) (PAH/PAA)n , and poly(diallyldimethylammonium chloride)/poly(styrene sulfonate) (PDAC/SPS)n film systems show the greatest ELIP incorporation of the films studied while maintaining the structural integrity of the vesicles. The use of ELIPs for drug encapsulation into backpacks facilitates up to three times greater DOX loading compared to backpacks without ELIPs. Cytotoxicity studies reveal that monocyte backpack conjugates remain viable even after 72 h, demonstrating promise as drug delivery vehicles. Because artificial vesicles can load many different types of drugs, ELIP containing backpacks offer a unique versatility for broadening the range of possible applications for cell backpacks.
Abstract P312: San Diego County Medical Leaders Collaborate to Achieve Leading-Edge Heart Attack and Stroke Prevention Goals
Authors: Robert J Dudl, Susan L Ivey, James Dunford, Carol M Mangione, Allen M Fremont, Anthony DeMaria
Journal: Circulation (2012)

The Right Care Initiative (RCI) is a California-wide, public-private coalition formed in 2007 to improve healthcare quality and outcomes. One RCI focus is cardiovascular disease (CVD) due to its high prevalence and evidence of specific healthcare improvement strategies. San Diego County, with its small set of large medical groups, was selected as a pilot project site. RCI leaders in San Diego hypothesized that outcome-focused meetings promoting the sharing of CVD prevention efforts among medical group leaders could lead to community-wide collaboration behind measurable action steps to achieve target goals. The high impact potential of the project attracted participation from the majority of San Diego medical groups. Two promising strategies were identified: (1) the delivery of bundled medication therapy consisting of aspirin, an angiotensin-converting enzyme (ACE) inhibitor, and a lipid-lowering medication for all CVD patients and patients &gt; age 55 with diabetes, and (2) the use of pharmacists on care teams to assist with medication management. In addition, collaboration with the American Heart Association, Centers for Disease Control and Prevention, San Diego County Health and Human Services Agency and private citizens leverages existing heart-healthy lifestyle and screening programs. The participants also developed and plan to launch a local media outreach campaign to activate heart-healthy behavior adoption among San Diegans. To build team unity in the pilot project, San Diego medical group and community health leaders conducted monthly “University of Best Practices” conferences. At these non-competitive medical and academic meetings, presenters shared the successful quality improvement strategies of “high-performing” groups and participants experienced the benefits of working together. After several meetings, participants set a goal of reducing heart attacks and strokes in San Diego County by 50% within five years. Their “stretch goal” is to make the San Diego region the first “heart attack and stroke free zone.” The next step will be to track progress by routinely sharing group-specific data and action plans. Conclusions: Medical groups who normally compete in the clinical care arena found they could collaborate toward a common goal, as shown by agreement on action steps. The opportunity to regularly convene medical group leaders in San Diego proved critical to establishing necessary trust. This community-based approach is intended to catalyze the uptake of promising, evidence-based practices and improve care for San Diego’s high risk cardiovascular and diabetes patients. The recently announced national “Million Hearts” campaign synergizes closely with this pilot project’s focus on community-wide heart attack and stroke prevention.
The IVS4 + 4 A to T mutation of the Fanconi anemia geneFANCC is not associated with a severe phenotype in Japanese patients
Authors: Makoto Futaki, Takayuki Yamashita, Hiroshi Yagasaki, Tatsushi Toda, Miharu Yabe, Shunichi Kato, Shigetaka Asano, Tatsutoshi Nakahata
Journal: Blood (2000)
A Prospective, Multicenter Phase II Study Of Continuous Infusion Of FLAG For Patients Older Than 60 Years With Resistant Acute Myeloid Leukemia: A Comparison With Intensive Younger patients’ Trial
Authors: Hawk Kim, Je-Hwan Lee, Young-Don Joo, Sung-Hwa Bae, Jung-Hee Lee, Dae-Young Kim, Jae-Cheol Jo, Jae Hoo Park, Won Sik Lee, Hun-Mo Ryoo, Sang-Kyu Park, Kyoo-Hyung Lee
Journal: Blood (2013)
간의 낭성 병변과 염증성 병변
Authors: 윤정희
Journal: Clinical and Molecular Hepatology (2012)

Fibrocystic liver disease에는 발생과정에서 bile duct의 근원이 되는 ductal plate의 비정상적 발생에 의한 intrahepatic 또는 extrahepatic bile duct의 발달이상에 의한 질환들로 1977년 Jorgensen에 의해 처음 기술되었다. 다양한 정도의 duct dilatation, cyst formation, fibrosis와 같은 ductal pathology를 보인다.
Everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET): Impact of somatostatin analog use on progression-free survival in the RADIANT-3 trial.
Authors: M. H. Shah, C. Lombard-Bohas, T. Ito, E. M. Wolin, E. Van Cutsem, C. Sachs, R. E. Winkler, J. Lincy, T. J. Hobday, J. C. Yao
Journal: Journal of Clinical Oncology (2011)

4010 Background: In the phase III RADIANT-3 trial, everolimus, an oral mTOR inhibitor, demonstrated superiority in progression-free survival (PFS) with a median of 11.0 versus 4.6 mo for placebo (HR=0.35; 95% CI, 0.27-0.45; P<0.0001) in patients with advanced pNET (ESMO 2010, Abstract LBA9). Here we present an exploratory analysis of the impact of long-acting somatostatin analog (SSA) therapy in this trial. Methods: Patients with progressive advanced low- or intermediate-grade pNET were randomized to everolimus 10 mg/d orally (n=207) or placebo (n=203); both arms received best supportive care. Long-acting SSAs were permitted before entry and as best supportive care during the study. The primary endpoint was PFS (RECIST v1.0). Patients who received SSA therapy before and during the study in each treatment arm were identified. Results: Overall, 203 (50%) patients received SSA therapy before study entry, and 163 (40%) received SSA therapy during the study. Of those patients with prior SSA therapy, 145 (71%) also received SSA therapy during the trial. Treatment arms were well balanced with respect to prior SSA treatment (50%, everolimus arm; 50%, placebo arm) and on-study SSA treatment (39%, everolimus arm; 40%, placebo arm). An improvement in median PFS was observed with everolimus compared with placebo in patients who had any SSA (11.4 mo vs 3.9 mo; HR=0.40; 95% CI, 0.29-0.56) and in those without any SSA (10.8 vs 4.6; HR=0.35; 95% CI, 0.24-0.50). The PFS benefit with everolimus was observed across all patients subgroups regardless of SSA use (Table). Conclusions: Everolimus significantly prolonged PFS compared with placebo in patients with advanced pNET in this large phase III clinical trial. This benefit was seen across all patient subgroups, including patients receiving prior and on-study SSA treatment. Hazard ratio (95% CI) Everolimus vs. placebo All patients 0.35 (0.27-0.45) Without concomitant SSA 0.34 (0.25-0.46) With concomitant SSA 0.43 (0.29-0.64) Without prior SSA 0.36 (0.25-0.51) With prior SSA 0.40 (0.28-0.56) Without prior and concomitant SSA 0.34 (0.25-0.47) With prior and concomitant SSA 0.43 (0.28-0.66)
A phase II study of axitinib (AG-013736 [AG]) in patients (pts) with advanced thyroid cancers
Authors: E. E. Cohen, E. E. Vokes, L. S. Rosen, M. S. Kies, A. A. Forastiere, F. P. Worden, M. A. Kane, K. F. Liau, D. R. Shalinsky, R. B. Cohen
Journal: Journal of Clinical Oncology (2007)

6008 Background: Elevated VEGF-A and VEGF-C have been reported in thyroid tumor tissue compared with normal thyroid. AG is a potent, small molecule inhibitor of VEGF receptors 1, 2 and 3. The efficacy and safety of AG therapy in pts with advanced thyroid cancers was examined in this single-arm, multi-center study. Methods: 60 pts with metastatic or unresectable locally-advanced thyroid cancer refractory to, or not suitable candidates for, 131 iodine ( 131 I) treatment, with measurable disease received AG at a starting dose of 5 mg orally BID. The primary endpoint was response rate (RR) by RECIST criteria. A Simon 2-stage minimax design was used (a=0.1; β=0.1; null RR=5%; alternative RR=20%). Samples were collected pretreatment and q8wks to explore relationships between clinical response and plasma soluble proteins. Results: Median age was 59 yrs (26–84), 35 (58%) were male. Histological subtypes included papillary: 29 pts (48%); follicular: 15 pts (25%)-11 (18%) with Hurthle cell variant; medullary: 12 pts (20%); anaplastic: 2 pts (3%), and other/unknown: 2 pts (3%). 53 pts (88%) had prior surgery, 42 (70%) had prior 131 I treatment, 27 (45%) had prior external beam radiation, and 9 (15%) had prior chemotherapy. Partial response (PR) by investigator report was achieved in 13 pts (22% CI: 12.1, 34.2), with 31- 68% maximum tumor regression and duration of response (DOR) of 1–16 months. 30 pts (50%) have stable disease with a duration range of 4–13 months and 13–67% maximum tumor regression in 28 pts. Response assessments are ongoing. The treatment duration range is 6–670 days with 38 pts currently on study. Median PFS has not been reached with a median follow up of 273 days. The most common treatment-related adverse events were fatigue (37%), proteinuria (27%), stomatitis/mucositis (25%), diarrhea (22%), hypertension (20%) and nausea (18%). AG therapy consistently decreased soluble VEGFR2 and VEGFR3, and increased VEGF in the blood, demonstrating pharmacodynamic activity against targeted VEGF receptors. Conclusions: AG has substantial anti-tumor activity in advanced thyroid cancer with demonstrated pharmacodynamic activity. A global pivotal trial testing AG in doxorubicin refractory thyroid cancer is ongoing. [Table: see text]
Deadlock persists over junior doctor contract
Authors: Gareth Iacobucci
Journal: BMJ (2016)

The ongoing dispute between the government and the BMA over the junior doctors’ contract showed no sign of abating this week, as both sides traded blows in the media.

The prospect of a last minute agreement between junior doctors in England and the government before the planned strike on Wednesday 10 February looked unlikely as The BMJ went to press, with Hunt launching a broadside against the BMA during an appearance on the BBC’s Andrew Marr Show on Sunday 7 February.1

In the interview Hunt accused the BMA of “spreading misinformation” about the terms being offered by the government and behaving in a “totally irresponsible way” by encouraging grievance among its members.

The chair of the BMA’s Junior …
FOLFOX4 as adjuvant treatment for stage II colon cancer (CC): Subpopulation data from the MOSAIC trial
Authors: T. Hickish, C. Boni, M. Navarro, J. Tabernero, C. Topham, A. Bonetti, P. Clingan, A. Figer, T. Andre, A. De Gramont
Journal: Journal of Clinical Oncology (2004)

3619 Background: Currently, stage II (Dukes B2) CC patients (pts) are included in clinical trials testing adjuvant chemotherapy as benefit of such treatment remains to be confirmed for these pts. Methods: FOLFOX4 [oxaliplatin/5-Fluorouracil (5FU)/leucovorin (LV)] is the first combination which improves 3-year disease free survival (DFS) (78.2%) when compared with 5-FU/LV (LV5FU2) alone (72.9%) in stage II/III CC as demonstrated in a large phase III randomized study (MOSAIC). The decrease in the risk of recurrence (RRR) is 23% in the overall population (p=0.002) (de Gramont, ASCO 2003). Stage II sub population data are presented here. Results: 40% of the 2246 patients were stage II: 451 in FOLFOX4, and 448 in LV5FU2; main characteristics were well balanced between the 2 groups with respectively for FOLFOX4/LV5FU2 (%): Male 57/52, median age (years) 61/60, colon 57/56, sigmoid 32/34, recto-sigmoid 11/9, KPS ≥ 80%: 88/ 90, Bowel obstruction: 16/19, Tumor perforation: 8/10, T4 (%)19/19, venous invasion: 8/10. The observed reduced risk of recurrence with FOLFOX4 was consistent in both stage II and stage III as shown by a non-significant treatment-by-stage interaction (p=0.77). Overall per patient major safety events on study [incidence of SAE, treatment discontinuation and/or death] were less frequent in stage II (19.8%) than in stage III (25.6%). Conclusion: In the FOLFOX4 arm of MOSAIC, stage II patients benefited from a 20% relative reduction in the risk of recurrence versus those of the LV5FU2 arm with a limited incidence of major safety events. This reflects the favorable benefit-risk of FOLFOX4 in this population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi-Synthelabo Sanofi-Synthelabo
Inflammatory markers predicts future cardiovascular and neurological events in patient undergoing carotid stent implantation
Authors: F Versaci, C Del Giudice, A Gaspardone, G Condorelli, A Pellegrino, A Mauriello, L Liberatoscioli, I Proietti, Gme Simonetti, C Cortese, L Chiariello
Journal: Journal of the American College of Cardiology (2008)
Laparoscopic Lavage for Perforated Diverticulitis With Purulent Peritonitis
Authors: Anders Thornell, Eva Angenete, Thue Bisgaard, David Bock, Jakob Burcharth, Jane Heath, Hans-Christian Pommergaard, Jacob Rosenberg, Nikolaj Stilling, Stefan Skullman, Eva Haglind
Journal: Annals of Internal Medicine (2016)

Background: Perforated diverticulitis with purulent peritonitis has traditionally been treated with open colon resection and stoma formation with risk for reoperations, morbidity, and mortality. Laparoscopic lavage alone has been suggested as definitive treatment. Objective: To compare laparoscopic lavage with open colon resection and colostomy (Hartmann procedure) for perforated diverticulitis with purulent peritonitis. Design: Randomized, controlled, multicenter, open-label trial. (ISRCTN registry number: ISRCTN82208287) Setting: 9 hospitals in Sweden and Denmark. Patients: Patients who have confirmed Hinchey grade III perforated diverticulitis with purulent peritonitis at diagnostic laparoscopy. Intervention: Randomization between laparoscopic lavage and the Hartmann procedure. Measurements: Primary outcome was the percentage of patients having 1 or more reoperations within 12 months. Key secondary outcomes were number of reoperations, hospital readmissions, total length of hospital stay during 12 months, and adverse events. Results: A total of 43 and 40 patients were randomly assigned to laparoscopic lavage and the Hartmann procedure with a median (first, third quartiles) follow-up of 372 days (336, 394) and 378 days (226, 396), respectively. Fewer patients in the laparoscopic group (12 of 43; 27.9%) than in the Hartmann group (25 of 40; 62.5%) had at least 1 reoperation within 12 months (relative risk reduction, 59%; relative risk, 0.41 [95% CI, 0.23 to 0.72]; P = 0.004). Mortality and severe adverse events did not differ between groups. Total length of hospital stay (days) within 12 months was shorter for the laparoscopic group than the Hartmann group, with a reduction of 35% (relative risk, 0.65 [CI, 0.45 to 0.94]; P = 0.047). After 12 months, 3 patients in the laparoscopic group and 11 in the Hartmann group had a stoma. Limitation: Not all patients presenting with suspected diverticulitis were enrolled. Conclusion: Laparoscopic lavage reduced the need for reoperations, had a similar safety profile to the Hartmann procedure, and may be an appropriate treatment of choice for acute perforated diverticulitis with purulent peritonitis. Primary Funding Source: ALF; Sahlgrenska University Hospital, Gothenburg.
FGF10 identifies early lipofibroblast progenitors and controls their fate during embryonic lung development
Authors: Denise Al Alam, Elie El Agha, Soula Danopoulos, Virender Rehan, Saverio Bellusci
Journal: European Respiratory Journal (2013)

Introduction: Lipofibroblasts (LIFs) are lipid-containing fibroblasts found in the late fetal and postnatal lung parenchyma. LIFs assimilate lipids and transfer triglycerides to adjacent alveolar epithelial type II cells to elaborate surfactant.  Aims: Although LIFs have been studied in postnatal lungs, their cellular origin and mechanism of differentiation are unknown. We aim to determine the origin of LIFs and the molecular pathway that control their fate.  Methods: Using Fgf10-LacZ and Fgf10iCre mouse lines, we analyzed the expression of LIFs markers in the Fgf10-positive cells in situ and after sorting. In addition, we used in vivo knockdown of FGFR2b ligand activity from E14.5 to E18.5 and Fgf10 hypomorphs as well as in vitro models (WI-38, NIH3T3-L1 cell lines and primary cultures of fibroblasts) to test whether FGF10 is capable on acting directly on the mesenchyme to promote LIFs differentiation.  Results: We demonstrated that LIFs express Fgf10 and that Fgf10-positive cells permanently labeled at embryonic days E11.5 or E15.5 give rise to LIFs. In addition, in vivo knockdown of FGFR2b ligand activity as well as reduction of Fgf10 expression led to decreased expression of LIF markers at E18.5. Using primary culture of lung mesenchyme as well as WI-38 human LIF progenitor cells and NIH3T3-L1 adipocyte progenitor cells, we demonstrate that recombinant FGF10 is capable of directly acting on the mesenchyme to trigger the commitment of these cells to the adipogenic lineage. Moreover, FGF10 also antagonizes TGFβ1-induced myofibroblast transdifferentiation of Fgf10-positive cells.  Conclusion: Our results demonstrate the essential role of FGF10 signaling in LIF formation.
Lower Cea and Ca19-9 Levels May Predict Longer Pfs in Patients with Her2 Positive Gc Treated by T-Mab Based Chemotherapy
Authors: Takeru Wakatsuki, Keisyo Chin, Mariko Ogura, Masato Osaka, Mitsukuni Suenaga, Eiji Shinozaki, Satoshi Matsusaka, Yousuke Kumekawa, Izuma Nakayama, Nobuyuki Mizunuma
Journal: Annals of Oncology (2014)