tbuckley/cabot-search huggingface dataset:
Phase 3 study of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as front-line treatment for advanced classical Hodgkin lymphoma (HL): Echelon-1 study.
Authors: Stephen Maxted Ansell, Anas Younes, Joseph M. Connors, Andrea Gallamini, Won Seog Kim, Jonathan W. Friedberg, Tatyana A. Feldman, Graham Collins, Nancy Bartlett, Jingyuan Wang, Kelly Brady, Jessica Sachs, Dirk Huebner, Naomi N. H. Hunder, John Radford
Journal: Journal of Clinical Oncology (2014)

TPS8613 Background: Brentuximab vedotin (ADCETRIS), a CD30-targeted antibody-drug conjugate, has been approved for adults with relapsed or refractory CD30+ HL in 39 countries including the US and Europe. Front-line ABVD achieves complete response (CR) rates of 70–80% in patients (pts) with advanced HL. However, 10–20% of pts are refractory to front-line treatment and an additional ≤25% relapse. Further, bleomycin-induced pulmonary toxicity occurs in 10–25% of pts (Horning, J Clin Oncol 1994). In pts with relapsed HL post-autologous stem cell transplantation, objective response rate to single-agent brentuximab vedotin is 75% (CR, 33%; Chen, ASH 2012). In a ph 1 dose-escalation study (NCT01060904), 51 pts with treatment-naïve HL stage IIA bulky or stage IIB–IV disease were enrolled to evaluate safety, maximum tolerated dose and antitumor activity of brentuximab vedotin combined with ABVD (A+ABVD) or AVD (A+AVD) (Younes, Lancet Oncol 2013). 80% pts had stage III–IV, 25% had International Prognostic Score ≥4. Brentuximab vedotin was given on days 1 and 15 of 28-day cycles (≤6 cycles), 25 pts received ABVD plus brentuximab vedotin at 0.6, 0.9, or 1.2 mg/kg; 26 received AVD plus brentuximab vedotin 1.2 mg/kg. A+AVD was associated with a PET2 negative rate of 92%, CR rate of 96% and manageable toxicity. Although A+ABVD induced an unacceptably high rate of pulmonary toxicity compared to known rates with ABVD alone, pulmonary toxicity was not observed in the A+AVD cohort. We hypothesized that substituting bleomycin with brentuximab vedotin may improve progression-free survival (PFS) compared to ABVD and, eliminate bleomycin-related pulmonary toxicity. Methods: ECHELON-1 (NCT01712490), an ongoing, open-label, randomized, ph 3 study, will compare A+AVD vs ABVD in 1,040 pts with untreated stage III/IV classical HL. Pts will receive A+AVD (brentuximab vedotin 1.2 mg/kg with each dose of AVD) or ABVD on Days 1 and 15 of 28-day cycles (≤6 cycles). Primary endpoint: modified PFS (death, progression, receipt of chemotherapy or radiotherapy by pts not in CR after completing front-line therapy). Clinical trial information: NCT01712490.
Bullying in surgery isn’t just Australia’s problem
Authors: Nikki Stamp, Imogen Patterson
Journal: BMJ (2016)

We read with interest The BMJ ’s articles on bullying and sexism in surgery.1 2 3 We commend the journal for publishing on this issue, but we see some notable shortcomings in the articles.

It may seem logical to attribute bullying to a macho culture in Australia and in surgery, but this is a gross simplification of why bullying exists …
Aspirin and Acute Respiratory Distress Syndrome—Reply
Authors: Daryl J. Kor, Michelle Ng Gong, Bruce D. Levy
Journal: JAMA (2016)

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Retinal Vessel Calibers in Predicting Long-Term Cardiovascular Outcomes
Authors: Sara B. Seidelmann, Brian Claggett, Paco E. Bravo, Ankur Gupta, Hoshang Farhad, Barbara E. Klein, Ronald Klein, Marcelo Di Carli, Scott D. Solomon
Journal: Circulation (2016)

Narrower retinal arterioles and wider retinal venules have been associated with negative cardiovascular outcomes. We investigated whether retinal vessel calibers are associated with cardiovascular outcomes in long-term follow-up and provide incremental value over the 2013 American College of Cardiology/American Heart Association Pooled Cohort Equations in predicting atherosclerotic cardiovascular disease events. A total of 10 470 men and women without prior atherosclerotic cardiovascular disease events or heart failure in the ARIC Study (Atherosclerosis Risk in Communities) underwent retinal photography at visit 3 (1993-1995). During a mean follow-up of 16 years, there were 1779 incident coronary heart disease events, 548 ischemic strokes, 1395 heart failure events, and 2793 deaths. Rates of all outcomes were higher in those with wider retinal venules and narrower retinal arterioles. Subjects with wider retinal venules (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.08-1.18; HR, 1.18; 95% CI, 1.07-1.31; and HR, 1.10; 95% CI, 1.00-1.20 per 1-SD increase) and narrower retinal arterioles (HR, 1.06; 95% CI, 1.01-1.11; HR, 1.14; 95% CI, 1.03-1.26; and HR, 1.13; 95% CI, 1.03-1.24 per 1-SD decrease) had a higher risk of death and stroke in both sexes and incident coronary heart disease in women but not men (interaction P=0.02) after adjustment for the Pooled Cohort Equations risk score variables. The association between retinal vessel caliber and heart failure was nonsignificant after adjustment for systolic blood pressure. Among women with Pooled Cohort Equations-predicted 10-year atherosclerotic cardiovascular disease event risk <5% (overall risk, 3.9%), women in the narrowest arteriolar quartile had a 10-year event rate of 5.6% compared with 2.8% for women in the widest quartile (5.0% versus 3.4% for wider versus narrower venules). Retinal vessel caliber reclassified 21% of low-risk women (11% of all women) as intermediate risk (>5%). Narrower retinal arterioles and wider retinal venules conferred long-term risk of mortality and ischemic stroke in both sexes and coronary heart disease in women. These measures serve as an inexpensive, reproducible biomarker that added incremental value to current practice guidelines in atherosclerotic cardiovascular disease event risk prediction in low-risk women.
miRNA expression as a predictor of survival in patients with metastatic colorectal cancer treated with EGFR inhibitors.
Authors: Sandrine Imbeaud, Gilles Manceau, Jean-Baptiste Bachet, Jean-François Emile, Frédéric Bibeau, Marie Danielle Diebold, Charles Marcaillou, Thomas Rio Frio, Delphine Le Corre, Olivier Bouche, Francois Liebaert, Pierre Laurent-Puig
Journal: Journal of Clinical Oncology (2012)

e14059 Background: The epidermal growth factor receptor (EGFR) pathway is crucial in the development and progression of human epithelial cancers. EGFR inhibitors have been tested for treatment of a variety of cancers but they are generally plagued by low response rates, leading to ineffective or non-optimal chemotherapy, unnecessary drug toxicity and expense. In colorectal cancer, KRAS mutations are clearly associated with resistance to anti-EGFR antibodies. A major challenge is to identify, in non-mutated KRAS patients, markers that can predict response to this therapy. This study aimed to develop a miRNA expression-based model for evaluating the responsiveness of patients with KRAS wild-type metastatic colorectal cancer to one or more EGFR inhibitors prior to treatment. Methods: miRNA profiling of KRAS wild-type tumors was performed on a discovery set of 44 patients with metastatic colorectal cancer treated with anti-EGFR inhibitors. A miRNA expression-based predictor of survival risk group was calculated by combining a Cox proportional hazards model and a supervised principal component method. Results: miRNA profiling of the discovery set identified hsa-miRNA-31* whose expression in tumor samples was highly correlated with survival and displayed prediction prospective for disease-free and overall survivals. Parameters of the hsa-miRNA-31* expression-based prediction model were determined on a subgroup of 23 patients. Its discriminative ability was evaluated on the complementary 21 samples that included 19 events. In this validation set, 4 of the 6 patients classified as “low risk” by the model survived for more than 25 weeks as disease-free whereas 11 of the 13 patients classified as “high risk” displayed disease progression within 25 weeks, suggesting a specificity of 85% [95% CI: 54%-98%] and a sensitivity of 67% [95% CI: 22%-96%] for the prediction model. These values were associated with a PPV of 67%, [95% CI: 22%-95%] and a NPV of 85% [95% CI: 54%-98%]. Conclusions: Our findings demonstrated that a prediction model based on the level of expression of hsa-miRNA-31* could evaluate whether a patient with a KRAS wild-type metastatic colorectal cancer is likely to respond to an EGFR inhibitor.
Rates of Neonatal Abstinence Syndrome Amid Efforts to Combat the Opioid Abuse Epidemic
Authors: Joshua D. Brown, Pratik A. Doshi, Nathan J. Pauly, Jeffery C. Talbert
Journal: JAMA Pediatrics (2016)

This cross-sectional analysis aims to describe the current trend of neonatal abstinence syndrome in the United States and in Kentucky, a rural state that has a particularly high burden of opioid abuse.
TMEM16F Deficiency Causes a Strain-Dependent Lethality in Mice and Reduced Phosphatidylserine Exposure on Heterozygous As Well As Homozygous Deficient Mouse Platelets
Authors: Colin A Kretz, Valerie A Novakovic, Anna Kiseleva, Audrey C.A. Cleuren, Rami Khoriaty, Elizabeth Adams, David Ginsburg, Gary E. Gilbert
Journal: Blood (2014)
A retrospective study to determine the utility of measuring E6 and E7 antibody (Ab) levels in sera as a biomarker of recurrence in patients (pts) with locally advanced (LA), human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC).
Authors: Assuntina Gesualda Sacco, Emily Light Bellile, Laura S Rozek, Douglas Brian Chepeha, Matthew E Spector, Tamara Jones, Kan Sun, Carol Rossier Bradford, Gregory T. Wolf, Mark E Prince, Jeffrey Moyer, Kelly M Malloy, Avraham Eisbruch, Jonathan B. McHugh, Susan Urba, Francis P. Worden
Journal: Journal of Clinical Oncology (2014)

6096 Background: Approximately 20% of pts with LA, HPV+ OPSCC have poor survival outcomes. To date, there is a paucity of biomarkers to predict which pts will ultimately fail standard therapy. E6/E7 viral oncoproteins are constitutively expressed in HPV+ tumors and highly immunogenic, resulting in readily detected serum Ab. The relative absence of E6/E7 Ab in healthy controls and HPV negative tumors, coupled with cervical cancer data suggesting a correlation between E6/E7 Ab levels and prognosis, warrants evaluation in HPV+ OPSCC. Methods: Pts with previously untreated, LA (stage III, IV), HPV+ OPSCC receiving definitive chemoradiation from 2003-2010 were included. Baseline and longitudinal (post-treatment, at recurrence and >12 months post-treatment) serum samples were obtained from our archived repository. E6/E7 serum Ab was measured using a glutathione-S-transferase (GST) capture ELISA. Serial dilutions of each serum sample were performed, with area under the curve analysis calculated. E6/E7 change was quantified linearly and on a multiplicative scale using ratios of post and pre-treatment levels. Results: 30 of 171 (18%) pts recurred (16 distant, 6 regional, 2 local, 2 locoregional, 2 local/distant, 2 regional/distant). 22 of 30 had baseline serum; 15 had serum at recurrence. This group (R) was compared to 30 pts who remained disease-free (NR). R and NR were well-balanced except for a non-significant (NS) trend toward higher T and N stage in R. At baseline, higher T stage was associated with lower E7 levels (p=0.016), whereas higher N stage had higher E7 levels (NS). Current smokers had lower baseline E7 levels (NS). NR pts cleared more proportion E7 than R pts, p=0.0016. Current smokers had higher baseline E6 levels (NS) and cleared less E6, p=0.04. Age and gender did not affect Ab patterns. Conclusions: Pts who recur clear less E7 Ab after treatment. Smoking impacts E6/E7 Ab patterns. Impact of pack-year tobacco use, alcohol and marijuana use will be reported. These findings merit evaluation in a prospective clinical trial.
Re: Brian I. Rini, Tanya B. Dorff, Paul Elson, et al. Active Surveillance in Metastatic Renal-cell Carcinoma: A Prospective, Phase 2 Trial. Lancet Oncol Lancet 2016;17:1317–24
Authors: Umberto Capitanio, Alessandro Larcher, Paolo Dell’Oglio, Francesco Montorsi
Journal: European Urology (2016)
HIV-associated peripheral T-cell lymphoma
Authors: C. Milani, J. Castillo
Journal: Journal of Clinical Oncology (2009)

e19551 Background: T-cell lymphomas (TCL) constitute 3% of all AIDS-related lymphomas. Over the past 2 decades numerous case reports have documented the emergence of TCL among HIV-infected individuals. These lymphomas comprise a diverse group of disease entities, including peripheral T-cell lymphomas (PTCL), which represent the most common subtype. The aim of this study was to investigate the clinical and pathological features of HIV-associated PTCL. Methods: A MEDLINE search for cases of HIV-associated PTCL was conducted through December 2008. Data regarding patient age, gender, HIV status (CD4 count, viral load, opportunistic infections), use of HAART, lymphoma features (B symptoms, stage, sites of involvement, immunophenotype, molecular studies), EBV coinfection, therapy, and outcome (survival, cause of death) were analyzed and reported descriptively. Results: A total of 34 cases were included. Patients had a median age of 36 years with a male:female ratio of 4:1. Median CD4+ count was 126 cells/mm3. Seventeen patients (50%) had an opportunistic infection, but only 7 patients (26%) were on HAART treatment; 4 patients on HAART (57%) were alive at time of publication. PTCL was extranodal in 75% of cases, affecting predominantly the oral cavity, lung, and GI tract. B symptoms were present in 60% of cases. Stage III and IV disease was found in 17 and 5 cases, respectively, accounting for 76% of the total cases. T-cell receptor gene rearrangement was positive in 10 out of 10 (100%) analyzed cases. EBV was identified in 6 of 12 cases (50%). Median LDH level was 269 IU/L. Therapy for PTCL was administered in 23 cases (68%), while 10 cases (30%) did not receive therapy; 9 of the treated patients (39%) received CHOP with a 33% remission rate. Twenty-two patients (69%) died complicated by infections in 57% and lymphoma progression in 36% of cases. The reported median survival was 12 months. Conclusions: HIV-associated PTCL tends to affect young male individuals with low CD4 counts. Apart from marked immunosuppression, the poor prognosis of HIV-associated PTCL appears to be related to advanced stage at presentation, presence of B symptoms, elevated LDH levels, prominent extranodal disease, and poor response to CHOP chemotherapy. The role of HAART and EBV in the development of PTCL needs further clarification. No significant financial relationships to disclose.
Pulsed Cyclophoshamide, Thalidomide and Dexamethasone (CTD) Regimen for Previously Treated Patients with Multiple Myeloma: Long Term Follow up and Disease Control after Subsequent Treatments.
Authors: Maria Roussou, Athanasios Anagnostopoulos, Efstathios Kastrtis, Charis Matsouka, Despina Barmparoussi, Vasiliki Koutsoukou, Meletios A. Dimopoulos
Journal: Blood (2006)
Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML.
Authors: Jeffrey E. Lancet, Geoffrey L. Uy, Jorge E. Cortes, Laura F. Newell, Tara L. Lin, Ellen K. Ritchie, Robert K. Stuart, Stephen Anthony Strickland, Donna Hogge, Scott R. Solomon, Richard M. Stone, Dale L. Bixby, Jonathan E. Kolitz, Gary J. Schiller, Matthew Joseph Wieduwilt, Daniel H. Ryan, Antje Hoering, Michael Chiarella, Arthur Chin Louie, Bruno C. Medeiros
Journal: Journal of Clinical Oncology (2016)

7000 Background: Older patients with secondary AML have poor outcomes following first-line cytarabine and anthracycline-based treatment. CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio with enhanced efficacy among poor risk AML patients. We report final results from a randomized open-label study of first-line CPX-351 in patients with high-risk sAML (NCT01696084). Methods: Patients 60-75 years of age with untreated AML with a history of prior cytotoxic treatment, antecedent MDS or CMML (+/- prior hypomethylator treatment), or AML with WHO-defined MDS-related cytogenetic abnormalities were eligible. 300 patients were to be randomized 1:1 to CPX-351 (100 units/m2, days 1, 3, 5) or 7+3 (cytarabine 100 mg/m2/day x 7 days, daunorubicin 60 mg/m2 days 1, 2, 3) induction therapy. Endpoints included: overall (OS, 1o) and event free survival (EFS) assessed by stratified log rank analysis, independent blinded assessment of CR+CRi, and 60-day mortality. Patient enrollment was from Dec 2012 to Nov 2014 at 39 US and Canadian sites. Study assumptions included: exponential survival, control median OS=192d, accrual of 135 pt/yr, and analysis after 236 deaths, resulting in 93.7% power to detect a HR=0.635, p=0.05 (2-sided). Results: A total of 309 patients were randomized (153 to CPX-351 + 156 to 7+3) and were well balanced for sex, race, age, performance status, AML-subtype, MDS-related cytogenetics and prior HMA therapy. After minimum follow-up of 13.7 months final analysis began.CPX-351 treatment resulted in superior overall survival (HR=0.69; P=0.005; median OS 9.56 vs. 5.95 months), EFS (HR=0.74; P=0.021), and CR+CRi response (47.7% vs. 33.3%; P=0.016). 60-day mortality favored CPX-351 (13.7% vs. 21.2%). Grade 3-5 AEs were equal (92% vs. 91%) and were similar in frequency and severity in both arms. Similar numbers of patients were transplanted in both arms. Conclusion: CPX-351 treatment significantly improved overall survival, event free survival, and response without an increase in 60-day mortality or AE frequency or severity. CPX-351 should become the standard of care for older patients with secondary AML. Clinical trial information: NCT01696084.
Muscle Regeneration after Critical Illness: Are Satellite Cells the Answer?
Authors: Michael I. Polkey, Mark J. Griffiths, Paul R. Kemp
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

could be the use of prophylactic Pneumocystis-active agents in patients receiving long-term, high-dose inhaled or oral corticosteroid therapy.Unraveling these complex issues ought to be possible in larger longitudinal cohort-based studies.A possible weakness of the current study is that it employed crude extracts from murine P. murina infections, which may not be entirely consistent with human P. jirovecii antigen sensitization and are not suitable for skin hypersensitivity testing.To further develop the tools and approaches needed to further define the role on Pneumocystis in asthma, systematic definition of human Pneumocystis antigens could be very useful, opening a door to direct sensitization studies, assessment of individual cellar responses, and therapeutic vaccination.
Catheter Related Bloodstream Infection in Haematological Patients: A Prospective, Randomized Study Comparing Heparin-Coated with Chlorhexidine and Silver Sulfadiazine Impregnated Central Venous Catheters
Authors: Abderrahman Abdelkefi, Mouna Chelli, Wafa Achour, Neila Ben Romdhane, Lamia Torjman, Saloua Ladeb, Amel Lakhal, Mohamed Hsairi, Hajer Kallel, Fathi Ladeb, Assia Ben Hassen, Tarek Ben Othman
Journal: Blood (2008)
Phase I portion of the phase I-II study of the X-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: A. S. Lee, B. C. Zee, M. Lai, J. Jolivet, C. S. Wong, C. L. Chiang, M. Tong, S. Y. Tung
Journal: Journal of Clinical Oncology (2010)

e14519 Background: The X-linked Inhibitor of Apoptosis (XIAP) inhibits caspases 3, 7 and 9 which are proteases responsible for apoptotic cell death. XIAP has been shown to be highly expressed in HCC and is a potential therapeutic target. AEG35156 is a second generation antisense oligonucleotide targeting XIAP mRNA which lowers the apoptotic threshold of cancer cells and also accumulates in the liver. We report on the Phase I portion of a study which determined the recommended dose of AEG35156 administered in combination with sorafenib in patients with advanced HCC. Methods: Patients with histologically or clinically diagnosed HCC satisfying AASLD Criteria who had failed or were unsuitable for curative therapy were enrolled. The initial dose of AEG35156 was 100 mg administered by 2-hour infusion once weekly and escalated to 200 and 300 mg in the second and third cohorts. Three patients were initially entered at each dose level with additional patients added at the recommended dose. All patients received standard daily sorafenib at 400 mg BID. One cycle of therapy was 21 days. Dose-limiting toxicity was defined in cycle 1 as patients with any drug related grade 4 neutropenia or thrombocytopenia lasting > 7 days, febrile neutropenia or any grade 3 or 4 major organ toxicity except alopecia or nausea/vomiting. Results: A total of 13 patients were recruited with 3 patients treated in each of the first two cohorts and 7 patients treated with 300 mg of AEG35156. All patients were hepatitis B positive, 12/13 were male with an age range of 35 to 66, 10/13 patients had stage IVB disease and 12 were Child-Pugh A with one B. No DLT was observed. Common toxicities included hand foot skin reaction, fatigue, diarrhea, and anorexia. Encouraging signs of clinical efficacy were seen at AEG35156 doses ≥ 200 mg. Conclusions: AEG35156 is well tolerated in combination with sorafenib in patients with advanced HCC. The phase II portion of this study is ongoing with 48 patients being randomized (2:1) to receive either AEG35156 at 300 mg in combination with sorafenib or sorafenib alone. Efficacy will be evaluated based on progression-free survival. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aegera Therapeutics Aegera Therapeutics
Gallstone mimicry: a rare cause of abdominal pain
Authors: Abhinav Singh, Philip J Smith, Ian M Cropley, Katie L Planche, Mark I Hamilton, Charles D Murray
Journal: Gut (2016)

A previously fit and well 43-year-old male triathlete presented with severe central abdominal pain persisting for several hours. Three similar episodes in the past 18 months had spontaneously resolved. Prior investigations with abdominal ultrasound, upper and lower GI endoscopies had been unremarkable. On this presentation, the patient also had worsening malaise and fever at 40°C. He was fluid resuscitated and commenced on broad-spectrum antibiotics (intravenous piperacillin–tazobactam 4.5 g and 350 mg gentamicin).

Initial biochemistry revealed absolute eosinophil count 0.56×109/L, asparate aminotransferase serum 72 IU/L and alanine aminotransferase (ALT) 78 IU/L. The alkaline phosphatase 65 IU/L, bilirubin 10 μmol/L, white cell count 7.93×109/L and C-reactive protein 5 mg/L were all normal. CT abdomen (figure 1A) did not reveal gallstones nor any small bowel pathology. As the …