tbuckley/cabot-search huggingface dataset:
Long-term outcomes of ruxolitinib (RUX) therapy in patients (pts) with myelofibrosis (MF): 5-year update from COMFORT-I.
Authors: Vikas Gupta, Srdan Verstovsek, Ruben A. Mesa, Jason R. Gotlib, John F. DiPersio, John V. Catalano, Michael W.N. Deininger, Carole Brennan Miller, Richard T. Silver, Moshe Talpaz, Elliott F. Winton, Jimmie Huling Harvey, Murat O. Arcasoy, Elizabeth O. Hexner, Roger M. Lyons, Ronald Paquette, Azra Raza, Deanna Kornacki, Kang Sun, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2016)

7012 Background: The JAK1/JAK2 inhibitor RUX has demonstrated rapid and durable improvements in splenomegaly and symptoms and improved survival in the phase 3 COMFORT studies in pts with MF. Here we report final long-term safety and efficacy results after 5 years (y) of RUX treatment in COMFORT-I. Methods: In COMFORT-I, 309 pts were randomized (1:1) to RUX or placebo (PBO). RUX starting dose was based on baseline platelet count (100–200×109/L: 15 mg BID; > 200×109/L: 20 mg BID). Pts receiving PBO could crossover to RUX after the primary analysis (when all pts completed week [wk] 24 and half completed wk 36) or at any time if they had prespecified worsening of splenomegaly. The primary endpoint was the proportion of pts achieving ≥ 35% reduction in spleen volume (SV) at wk 24. Overall survival (OS) was estimated by Kaplan-Meier analysis according to randomized treatment. Results: Median follow-up was 268 wk at the time of this analysis. Of 154 pts randomized to PBO, 111 crossed over to RUX; median time to crossover was 41.1 wk. At wk 24, pts originally randomized to RUX had a mean SV reduction of 31.6%; this was durable for pts who continued on RUX (mean SV reduction at wk 264, 37.6%). Median duration of ≥ 35% SV reduction was 168.3 wk (range, 107.7–NE). OS favored RUX (HR 0.69; 95% CI: 0.50, 0.96; P= 0.025), with 69 and 82 deaths among pts originally randomized to RUX and PBO, respectively. Median OS has not been reached for RUX. Mean platelet count and Hgb initially decreased through 3 mo. Mean Hgb gradually increased toward baseline. After wk 24, mean Hgb and platelet count generally remain stable through 5 y. New onset grade 3 or 4 anemia was 25.2% for the RUX arm and 26.1% for PBO crossover; grade 3 or 4 thrombocytopenia occurred in 12.3% and 13.5% of pts, respectively. Notable AEs included herpes zoster (10.3% and 13.5% of RUX and PBO crossover pts, respectively); basal cell carcinoma (7.7% and 9.0%, respectively); acute myeloid leukemia (5 pts in each arm). Conclusions: After a median follow-up of 268 wk, the hazard ratio for OS favored pts randomized to RUX over those randomized to PBO, and SV reductions were sustained with long-term therapy. Collectively, these data support the durable efficacy and long-term safety of RUX in pts with MF. Clinical trial information: NCT00952289.
The persistence of symptom burden after radiation treatment for head and neck cancer (HNC).
Authors: D. I. Rosenthal, T. R. Mendoza, G. B. Gunn, X. S. Wang, A. C. Hessel, A. S. Garden, W. H. Morrison, C. S. Cleeland
Journal: Journal of Clinical Oncology (2010)

5573 Background: Radiation therapy (RT) for HNC causes significant toxicity. Most patients do not return for medical follow up for about 6 weeks after completing RT. There is no symptom data reported about this interval, and most patients do not receive ongoing symptom assessment or intervention. We performed a longitudinal study including this interval using the M.D. Anderson Symptom Inventory - Head and Neck module (MDASI-HN). Methods: 161 HNC patients participated. Patients completed the MDASI-HN using paper and pencil before RT/chemo-RT and weekly during the 6-7 weeks of treatment, and for another 8 weeks using an interactive voice response (IVR) system. We report the prevalence of symptom burden over time using descriptive statistics. Results: Fewer than 10% HNC patients had moderate or severe (M/S) symptoms before treatment. Symptom burden peaks for most patients by the end of treatment, but some patients reach their M/S symptom peak after treatment. For the selected potentially serious symptoms for which interventions exist, the proportions of patients experiencing M/S symptoms at any time versus those experiencing the M/S peak after treatment, respectively, are: pain (67%, 20%), mouth/throat sores (73%, 18%), problems with mucus (71%, 34%), appetite (67%, 25%), choking (aspiration) (50%, 31%), skin problems (59%, 35%), and fatigue (71%, 24%). Only 4 of the top 10 symptoms returned to within 10-percentage points of baseline by 2 months after treatment. At 2 month follow up, ≥15% of the patients reported M/S problems with tasting food (37%), mucous (29%), mouth/throat sores (16%), chewing (26%), voice (17%), appetite (33%), drowsiness (15%), dry mouth (49%), pain (15%), and fatigue (27%). Conclusions: While most HNC patients have modest symptom burden pre-treatment, the majority experience moderate to severe symptoms from treatment that do not return to baseline by 2 months. For a significant proportion of patients, moderate to severe symptom severity peaks after treatment, during an interval with no routine medical surveillance or intervention. Monitoring patient symptoms after therapy, including by use of an IVR system, may allow for a reduction in symptom burden with simple validated interventions. No significant financial relationships to disclose.
Comparative efficacy and safety of first-line antiretroviral therapy for the treatment of HIV infection: a systematic review and network meta-analysis
Authors: Steve Kanters, Marco Vitoria, Meg Doherty, Maria Eugenia Socias, Nathan Ford, Jamie I Forrest, Evan Popoff, Nick Bansback, Sabin Nsanzimana, Kristian Thorlund, Edward J Mills
Journal: The Lancet HIV (2016)
Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression
Authors: R. Obermannová, E. Van Cutsem, T. Yoshino, G. Bodoky, J. Prausová, R. Garcia-Carbonero, T. Ciuleanu, P. Garcia Alfonso, D. Portnoy, A. Cohn, K. Yamazaki, P. Clingan, S. Lonardi, T.W. Kim, L. Yang, F. Nasroulah, J. Tabernero
Journal: Annals of Oncology (2016)

The RAISE phase III clinical trial demonstrated that ramucirumab + FOLFIRI improved overall survival (OS) [hazard ratio (HR) = 0.844, P = 0.0219] and progression-free survival (PFS) (HR = 0.793, P < 0.0005) compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Since some patient or disease characteristics could be associated with differential efficacy or safety, prespecified subgroup analyses were undertaken. This report focuses on three of the most relevant ones: KRAS status (wild-type versus mutant), age (<65 versus ≥65 years), and time to progression (TTP) on first-line therapy (<6 versus ≥6 months).OS and PFS were evaluated by the Kaplan-Meier analysis, with HR determined by the Cox proportional hazards model. Treatment-by-subgroup interaction was tested to determine whether treatment effect was consistent between subgroup pairs.Patients with both wild-type and mutant KRAS benefited from ramucirumab + FOLFIRI treatment over placebo + FOLFIRI (interaction P = 0.526); although numerically, wild-type KRAS patients benefited more (wild-type KRAS: median OS = 14.4 versus 11.9 months, HR = 0.82, P = 0.049; mutant KRAS: median OS = 12.7 versus 11.3 months, HR = 0.89, P = 0.263). Patients with both longer and shorter first-line TTP benefited from ramucirumab (interaction P = 0.9434), although TTP <6 months was associated with poorer OS (TTP ≥6 months: median OS = 14.3 versus 12.5 months, HR = 0.86, P = 0.061; TTP <6 months: median OS = 10.4 versus 8.0 months, HR = 0.86, P = 0.276). The subgroups of patients ≥65 versus <65 years also derived a similar ramucirumab survival benefit (interaction P = 0.9521) (≥65 years: median OS = 13.8 versus 11.7 months, HR = 0.85, P = 0.156; <65 years: median OS = 13.1 versus 11.9 months, HR = 0.86, P = 0.098). The safety profile of ramucirumab + FOLFIRI was similar across subgroups.These analyses revealed similar efficacy and safety among patient subgroups with differing KRAS mutation status, longer or shorter first-line TTP, and age. Ramucirumab is a beneficial addition to second-line FOLFIRI treatment for a wide range of patients with mCRC.ClinicalTrials.gov, NCT01183780.
To detect Lynch syndrome patients, which colorectal cancers should be tested for microsatellite instability?
Authors: B. M. Boman, K. Orio, N. J. Petrelli, M. Parker, C. Somerman, Z. Ali-Khan Catts
Journal: Journal of Clinical Oncology (2010)

3630 Background: Currently there is no consensus on when to use microsatellite instability (MSI) and/or immunohistochemistry (IHC) testing of colorectal cancers (CRC) to detect carriers of the Lynch syndrome (LS) trait. Lynch syndrome (also called hereditary nonpolyposis colorectal cancer [HNPCC]) is usually detected using family-history-based clinical criteria. However, these criteria have weak sensitivity and many cases with LS will be missed. This is problematic because identifying probands of LS families can effectively prevent CRC, through colonoscopic screening, in those family members who carry the trait and are at high risk (80%) for CRC. Although MSI and IHC testing done on CRCs can identify potential LS patients, the clinical feasibility and cost-effectiveness of this diagnostic approach has not been determined. Methods: A retrospective review was done on the age-at-diagnosis of all CRC cases in 19 families having germline DNA mismatch repair mutations. The age distribution of cases was then compared to that for CRC patients with germline MMR mutations (Hampel et al) to determine the test performance characteristics for various age cutoffs for LS detection and cost-effectiveness of MSI and/or IHC testing on CRCs. Results: Among families, 8 had MLH1, 8 had MSH2, and 3 had MSH6 germline mutations. CRC cases in families with MLH1 and MSH2 mutations were predominantly younger (43 ± 20 and 34 ± 32 years, respectively), while CRC cases in families with MSH6 mutations were older (68 ± 15 years). Age 60 at CRC diagnosis was found to be the optimal age cutoff for identifying LS bases on test performance characteristics and cost-effectiveness of testing using MSI and/or IHC. Overall, the sensitivity at age 60 was 86% for detecting CRC cases with LS. Sensitivity was 93% for families with MHL1, 92% for MSH2, and 40% for MSH6 mutations. Conclusions: As a population screening tool, MSI and IHC is not cost-effective when done on all CRCs. When CRC is stratified by age, MSI and IHC can be used in a cost-effective manner, making population-based screening feasible. No significant financial relationships to disclose.
JAK2V617F Mutation In Hematologic Malignancies In Childhood and Myeloproliferative Disorders In Adulthood
Authors: Akin Yigin, Bulent Ali Antmen, Hatice Korkmaz Guvenmez, Mustafa Yilmaz, Ilgen Sasmaz, Yurdanur Kilinc
Journal: Blood (2013)
IgMκ and IgMλ Measurements for the Assessment of Patients with Waldenström's Macroglobulinaemia
Authors: Eileen Boyle, Salomon Manier, Julie Lejeune, Guillemette Fouquet, Stephanie Guidez, Sarah Bonnet, Houria Debarri, Helene Demarquette, Remy Dulery, Julie Gay, Bernadette Hennache, Brigitte Onraed, Jean-Luc Faucompré, Suzanna Schraen, Thierry Facon, Hervé Avet-Loiseau, Sylvie Chevret, Veronique Leblond, Stephen Harding, Xavier Leleu
Journal: Clinical Cancer Research (2016)

Accurate quantification of monoclonal IgM immunoglobulins is essential for response assessment in patients with Waldenström's macroglobulinaemia (WM). The propensity of IgM to form multimers in serum makes sample evaluation by current laboratory methods particularly challenging.We assessed the precision and linearity of IgMκ and IgMλ heavy/light chain (HLC, Hevylite) assays, and established reference intervals using 120 normal donor sera. We compared the quantitative performance of HLC assays with serum protein electrophoresis (SPE) and total IgM nephelometry for 78 diagnostic samples and follow-up samples from 25 patients with WM. Comparisons were made between the three methods for diagnostic sensitivity and response assessment.IgMκ and IgMλ HLC assays showed low imprecision and good linearity. There was good agreement between summated HLC (IgMκ + IgMλ) and total IgM (measured nephelometrically; R2 = 0.90), but only moderate agreement between involved IgM HLC and SPE densitometry (R2 = 0.49). Analysis of 120 normal donor sera produced the following normal ranges: IgMκ: 0.29-1.82 g/L; IgMλ: 0.17-0.94 g/L; IgMκ/IgMλ ratio: 0.96-2.30. Using these ranges, IgM HLC ratios were abnormal in all WM presentation sera tested, including 15 with non-quantifiable SPE. Despite discordance in quantitation, responses assigned with HLC assays showed excellent agreement to those based on international guidelines using SPE or total IgM; although abnormal HLC ratios indicated residual disease in some patients with negative electrophoresis results.Nephelometric assessment of IgMκ and IgMλ HLC pairs offers a quantitative alternative to traditional laboratory techniques for the measurement of monoclonal IgM and may aid in the management of WM. Clin Cancer Res; 22(20); 5152-8. ©2016 AACR.
Metabolic preconditioning protects BSEP/ABCB11−/− mice against cholestatic liver injury
Authors: Claudia D. Fuchs, Gustav Paumgartner, Annika Wahlström, Philipp Schwabl, Thomas Reiberger, Nadja Leditznig, Tatjana Stojakovic, Nataliya Rohr-Udilova, Peter Chiba, Hanns-Ulrich Marschall, Michael Trauner
Journal: Journal of Hepatology (2016)

Cholestasis is characterized by intrahepatic accumulation of potentially cytotoxic bile acids (BAs) subsequently leading to liver injury with disruption of hepatocellular integrity, inflammation, fibrosis and ultimately liver cirrhosis. Bile salt export pump (BSEP/ABCB11) is the main canalicular BA transporter and therefore the rate limiting step for hepatobiliary BA excretion. In this study we aimed to investigate the role of BSEP/ABCB11 in the development of acquired cholestatic liver and bile duct injury.Wild-type (WT) and BSEP knockout (BSEP-/-) mice were subjected to common bile duct ligation (CBDL) or 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) feeding as models for cholestasis with biliary obstruction and bile duct injury. mRNA expression profile, serum biochemistry, liver histology, immunohistochemistry, hepatic hydroxyproline levels and BA composition as well as biliary pressure were assessed.BSEP-/- mice were protected against acquired cholestatic liver injury induced by 7days of CBDL or 4weeks of DDC feeding, as reflected by unchanged serum levels of liver transaminases, alkaline phosphatase and BAs. Notably, BSEP-/- mice were also protected from cholestasis-induced hepatic inflammation and biliary fibrosis. In line with induced BA detoxification/hydroxylation pathways in BSEP-/- mice, polyhydroxylated BAs were increased 4-fold after CBDL and 6-fold after DDC feeding in comparison with cholestatic WT mice. Finally, following CBDL, biliary pressure in WT mice increased up to 47mmH2O but remained below 11mmH2O in BSEP-/- mice.Metabolic preconditioning with subsequent changes in BA metabolism favors detoxification of potentially toxic BAs and thereby protects BSEP-/- mice from cholestatic liver and bile duct injury.Reduced hepatobiliary bile acid transport due to loss of BSEP function leads to increased hydroxylation of bile acids in the liver. Metabolic preconditioning with a hydrophilic bile pool protects the BSEP-/- mice from acquired cholestatic liver disease.
Evaluating the Impact of National Public Health Department Accreditation ― United States, 2016
Authors: Jessica Kronstadt, Michael Meit, Alexa Siegfried, Teddi Nicolaus, Kaye Bender, Liza Corso
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

In 2011, the nonprofit Public Health Accreditation Board (PHAB) launched the national, voluntary public health accreditation program for state, tribal, local, and territorial public health departments. As of May 2016, 134 health departments have achieved 5-year accreditation through PHAB and 176 more have begun the formal process of pursuing accreditation. In addition, Florida, a centralized state in which the employees of all 67 local health departments are employees of the state, achieved accreditation for the entire integrated local public health department system in the state. PHAB-accredited health departments range in size from a small Indiana health department that serves approximately 17,000 persons to the much larger California Department of Public Health, which serves approximately 38 million persons. Collectively, approximately half the U.S. population, or nearly 167 million persons, is covered by an accredited health department. Forty-two states and the District of Columbia now have at least one nationally accredited health department. In a survey conducted through a contract with a social science research organization during 2013-2016, >90% of health departments that had been accredited for 1 year reported that accreditation has stimulated quality improvement and performance improvement opportunities, increased accountability and transparency, and improved management processes.
Cessation of Trivalent Oral Poliovirus Vaccine and Introduction of Inactivated Poliovirus Vaccine — Worldwide, 2016
Authors: Lee M. Hampton, Margaret Farrell, Alejandro Ramirez-Gonzalez, Lisa Menning, Stephanie Shendale, Ian Lewis, Jennifer Rubin, Julie Garon, Jennifer Harris, Terri Hyde, Steven Wassilak, Manish Patel, Robin Nandy, Diana Chang-Blanc
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Since the 1988 World Health Assembly resolution to eradicate poliomyelitis, transmission of the three types of wild poliovirus (WPV) has been sharply reduced (1). WPV type 2 (WPV2) has not been detected since 1999 and was declared eradicated in September 2015. Because WPV type 3 has not been detected since November 2012, WPV type 1 (WPV1) is likely the only WPV that remains in circulation (1). This marked progress has been achieved through widespread use of oral poliovirus vaccines (OPVs), most commonly trivalent OPV (tOPV), which contains types 1, 2, and 3 live, attenuated polioviruses and has been a mainstay of efforts to prevent polio since the early 1960s. However, attenuated polioviruses in OPV can undergo genetic changes during replication, and in communities with low vaccination coverage, can result in vaccine-derived polioviruses (VDPVs) that can cause paralytic polio indistinguishable from the disease caused by WPVs (2). Among the 721 polio cases caused by circulating VDPVs (cVDPVs*) detected during January 2006-May 2016, type 2 cVDPVs (cVDPV2s) accounted for >94% (2). Eliminating the risk for polio caused by VDPVs will require stopping all OPV use. The first stage of OPV withdrawal involved a global, synchronized replacement of tOPV with bivalent OPV (bOPV) containing only types 1 and 3 attenuated polioviruses, planned for April 18-May 1, 2016, thereby withdrawing OPV type 2 from all immunization activities (3). Complementing the switch from tOPV to bOPV, introduction of at least 1 dose of injectable, trivalent inactivated poliovirus vaccine (IPV) into childhood immunization schedules reduces risks from and facilitates responses to cVDPV2 outbreaks. All 155 countries and territories that were still using OPV in immunization schedules in 2015 have reported that they had ceased use of tOPV by mid-May 2016.(†) As of August 31, 2016, 173 (89%) of 194 World Health Organization (WHO) countries included IPV in their immunization schedules.(§) The cessation of tOPV use is a major milestone toward the global goal of eradicating polio; however, careful surveillance for polioviruses and prompt, aggressive responses to polio outbreaks are still needed to realize a polio-free world.
Vitamin D supplements poison dozens of Danish children
Authors: Ned Stafford
Journal: BMJ (2016)

Dozens of infants in Denmark were poisoned after being given a liquid vitamin D supplement that contained 75 times the level indicated, according to Danish health authorities.

The supplement—produced in 10 ml bottles by the family owned, Danish firm Inno Pharma and marketed as an organic supplement for infants and pregnant women—was recalled from the market on 21 July after the incorrect vitamin D content level was discovered. The recall was followed by public warnings from the Danish Health Authority urging parents to stop using the supplement and to have their children tested to determine their vitamin D and calcium levels.

Danish health officials recommend vitamin D supplements for infants up …
Changing Continuing Medical Education
Authors: Alexander M. Djuricich, Mary G. Turco, Ajit K. Sachdeva
Journal: JAMA (2015)

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