tbuckley/cabot-search huggingface dataset:
Role of lung volumes in sleep apnoea-related oxygen desaturation
Authors: F Series, Y Cormier, J La Forge
Journal: European Respiratory Journal (1989)

We studied the influence of lung volumes on apnoea-induced desaturation in ten subjects with sleep apnoea syndrome. Lung volumes were measured by helium dilution in the sitting and supine position and closing volume with the single-breath nitrogen washout test. To characterize the severity of apnoea-induced desaturations, we determined a desaturation curve for each patient. This curve was obtained by plotting the fall in arterial oxygen saturation (SaO2) reached at the end of each apnoea against the apnoea duration. From this curve we selected two indices: 1) the SaO2 fall following 30 s of obstructive apnoea (delta SaO2 30); and 2) the desaturation surface between 10-30 s of obstructive apnoea (DS 10-30). Both the delta SaO2 30 and the DS 10-30 were significantly correlated with the expiratory reserve volume (ERV), measured in the sitting (r = 0.77 and 0.65, respectively; p less than 0.05) and the supine positions (r = 0.96 and 0.87; p less than 0.005). A strong correlation was also observed with the difference between the supine ERV and the seated closing volume CV) (r = 0.99 with delta SaO2 30 and 0.89 with DS 10-30; p less than 0.005). Obesity influenced sitting and supine ERV values. We conclude that, among lung volumes, supine ERV and supine ERV-seated CV are the best indicators of the severity of apnoea-induced desaturation.
Metabolism of Volatile Amines: IV. Role of Drugs in Pathogenesis of Hepatic Encephalopathy
Authors: B A TOBE, B S GOLDMAN
Journal: JAMA (1963)

The effects of certain drugs on metabolism of ammonia by the liver and kidneys in dogs were investigated by a technique in which both hepatic inflow and outflow bloods could be repeatedly sampled in unanesthetized healthy animals. Specific representatives of the classes of the drugs studied included thiopental (barbiturates), morphine (opiates and analgesics), promazine (tranquillizers), and chlorothiazide (oral diuretics).The three drugs commonly used as sedatives were all found to impair the ability of the liver to metabolize ammonia. The diuretic, by contrast, increased the amount of ammonia put into the systemic system by the kidneys. Ethanol appeared to have little or no direct effect on ammonia metabolism.The possibility exists that the occurrence of acute hepatic encephalopathy in patients with severe liver disease may be avoided in many cases if these drugs are administered with proper care. Results also indicated that current concepts of the pharmacological action of sedatives, opiates and tranquillizers may require revision.
Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL).
Authors: Antoni Ribas, F. Stephen Hodi, Richard Kefford, Omid Hamid, Adil Daud, Jedd D. Wolchok, Wen-Jen Hwu, Tara C. Gangadhar, Amita Patnaik, Anthony M. Joshua, Peter Hersey, Jeffrey S. Weber, Roxana Stefania Dronca, Hassane M. Zarour, Kevin Gergich, Xiaoyun (Nicole) Li, Robert Iannone, Soonmo Peter Kang, Scot Ebbinghaus, Caroline Robert
Journal: Journal of Clinical Oncology (2014)

LBA9000^ Background: The humanized monoclonal IgG4 anti-PD-1 antibody MK-3475 has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated MK-3475 efficacy and safety in a pooled analysis of 411 MEL pts. Methods: A nonrandomized cohort of ipilimumab-naive (IPI-N) and IPI-treated (IPI-T) pts treated with MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W and randomized cohorts of IPI-N and IPI-T pts treated with 2 Q3W or 10 Q3W were included. Response was assessed every 12 wk by RECIST 1.1 by independent central review and by immune-related response criteria (irRC) by investigator. Results: 162 pts were treated at 2 Q3W, 192 at 10 Q3W, and 57 at 10 Q2W. 190 pts were IPI-N and 221 were IPI-T. As of the 10/18/2013 cutoff, all pts had ≥6 mo follow-up and &gt;75% had ≥9 mo follow-up. Among the 365 pts with measurable disease at baseline, ORR by RECIST was 40% (95% CI 32%-48%) in IPI-N and 28% (95% CI 22%-35%) in IPI-T pts. Responses were durable (88% ongoing at analysis). Median PFS by RECIST was 24 wk in IPI-N and 23 wk in IPI-T pts. Median OS was not reached, with 1-y OS of 71% in all pts. Benefit was observed by both RECIST and irRC at all doses and schedules in IPI-N and IPI-T pts (Table). MK-3475 demonstrated activity in all major subgroups irrespective of ECOG PS, LDH levels, BRAFmutation, M stage, and number and type of prior therapy. Overall, 12% of pts experienced drug-related grade 3/4 AEs and 4% discontinued due to a drug-related AE. There were no drug-related deaths. Conclusions: MK-3475 showed durable responses and a manageable safety profile across dose and schedules in IPI-N and IPI-T MEL pts. The observed efficacy and safety suggest MK-3475 may be an appropriate treatment for all pts with MEL. Clinical trial information: NCT01295827. [Table: see text]
Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population
Authors: Neil E. Bhola, Valerie M. Jansen, James P. Koch, Hua Li, Luigi Formisano, Janice A. Williams, Jennifer R. Grandis, Carlos L. Arteaga
Journal: Cancer Research (2015)

Abstract Approximately 30% of triple-negative breast cancers (TNBC) harbor molecular alterations in PI3K/mTOR signaling, but therapeutic inhibition of this pathway has not been effective. We hypothesized that intrinsic resistance to TORC1/2 inhibition is driven by cancer stem cell (CSC)-like populations that could be targeted to enhance the antitumor action of these drugs. Therefore, we investigated the molecular mechanisms by which PI3K/mTOR inhibitors affect the stem-like properties of TNBC cells. Treatment of established TNBC cell lines with a PI3K/mTOR inhibitor or a TORC1/2 inhibitor increased the expression of CSC markers and mammosphere formation. A CSC-specific PCR array revealed that inhibition of TORC1/2 increased FGF1 and Notch1 expression. Notch1 activity was also induced in TNBC cells treated with TORC1/2 inhibitors and associated with increased mitochondrial metabolism and FGFR1 signaling. Notably, genetic and pharmacologic blockade of Notch1 abrogated the increase in CSC markers, mammosphere formation, and in vivo tumor-initiating capacity induced by TORC1/2 inhibition. These results suggest that targeting the FGFR–mitochondrial metabolism–Notch1 axis prevents resistance to TORC1/2 inhibitors by eradicating drug-resistant CSCs in TNBC, and may thus represent an attractive therapeutic strategy to improve drug responsiveness and efficacy. Cancer Res; 76(2); 440–52. ©2015 AACR.
Intratumoral lactate dehydrogenase 5 (LDH5) protein expression is associated with expression of angiogenesis markers and hypoxia in patients with colorectal cancer (CRC)
Authors: M. I. Koukourakis, A. Giatromanolaki, E. Sivridis, K. C. Gatter, A. L. Harris, T. Trarbach, G. Folprecht, M. M. Shi, G. Meinhardt
Journal: Journal of Clinical Oncology (2007)

4107 Background: Recent clinical trials (CONFIRM 1 and CONFIRM 2) have shown that metastatic CRC patients (pts) with high serum lactate dehydrogenase (LDH) derive the greatest therapeutic benefit from PTK787/ZK 222584 (PTK/ZK). PTK/ZK is a novel, oral tyrosine kinase inhibitor (TKI), which blocks all known VEGF receptors (VEGFR). From previous studies, total LDH and isoenzyme LDH5 have been associated with tumor aggressiveness and hypoxia. In the present study, we tested whether CRC pts with high levels of tumor LDH5 have increased expression of proteins involved with hypoxia (hypoxia inducible factors [HIF1a and 2a], pyruvate dehydrokinase [PDHK]), increased vessel density (VD), angiogenesis (VEGFA; phosphorylated VEGFR2 [pKDR]), acidity (carbonic anhydrase 9 [CA9]), and others. Methods: Baseline sections from either primary or metastatic tumor sites from 42 pts of the CONFIRM 1 and 2 trials were analysed with immunohistochemistry utilizing an established nominal scoring system. The degree of association between the scores of protein expressed was estimated by the phi-coefficient (correlation coefficient) and assessed by means of p-values from pairwise Fisher’s exact test (two- sided). Results: Associations were observed between LDH5 and the following: pKDR (Phi=.53; p&lt;.001), VEGF (Phi=.41; p=.006), HIF-1a (Phi=.56; p&lt;.001), VD (Phi=.34; p=.052), and PDHK (Phi=.58; p=.014), respectively. HIF-1a associated with pKDR (Phi=.38; p=.027), VD (Phi=.34; p=.045), and VEGFA (Phi=.33; p=.067). VEGFA associated with PDHK (Phi=.52; p=.035). Conclusions: Our results demonstrate that mCRC patients with high level of intratumoral protein expression of LDH5 have elevated HIF-1a, pKDR, VEGFA, PDHK expression and VD. These results support the concept that tumor hypoxia and angiogenesis are associated and that elevated LDH protein expression may serve as a surrogate marker for activated HIF-1a pathway. No significant financial relationships to disclose.
Costly hospital mergers have not delivered solutions to failing trusts, says report
Authors: Gareth Iacobucci
Journal: BMJ (2015)

The NHS in England has spent £2bn (€2.74bn; $3.06bn) on 12 hospital mergers over the past five years that have largely failed to resolve the problems they were intended to deal with, a report from the King’s Fund has found.

The report from the healthcare think tank1 found that most of the £2bn committed by the Department of Health to initiate the mergers had been spent on tackling historical debts and covering deficits and capital investment rather than on delivering the service changes required to make the merged organisations sustainable.

The report analysed 20 mergers of NHS trusts and foundation trusts undertaken from 2010 to 2015 and found that …
Prospective Study of <sup>68</sup>Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites
Authors: Samira M. Sadowski, Vladimir Neychev, Corina Millo, Joanna Shih, Naris Nilubol, Peter Herscovitch, Karel Pacak, Stephen J. Marx, Electron Kebebew
Journal: Journal of Clinical Oncology (2015)

Purpose Gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) are increasing in incidence, and accurate staging is important for selecting the appropriate treatment. 68 Ga-DOTATATE imaging is a promising approach for detecting GEPNETs and could help in selecting optimal therapeutic strategies. The aim of this study was to prospectively determine the clinical utility of 68 Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) in detecting unknown primary and metastatic GEPNETs. Patients and Methods One hundred thirty-one patients were enrolled in a prospective study of patients undergoing 68 Ga-DOTATATE PET/CT, 111 In-pentetreotide single-photon emission computed tomography (SPECT)/CT and multiphasic CT scan, and/or magnetic resonance imaging in a blinded fashion with comprehensive biochemical testing. The primary outcome measure was the detection of lesions by each imaging study. Results 68 Ga-DOTATATE PET/CT imaging detected 95.1% of lesions (95% CI, 92.4% to 96.8%) with an average maximum standardized uptake value of 65.4 ± 47 (range, 6.9 to 244), anatomic imaging detected 45.3% of lesions (95% CI, 37.9% to 52.9%), and 111 In-pentetreotide SPECT/CT detected 30.9% of lesions (95% CI, 25.0% to 37.5%), with a significant difference between imaging modalities (P &lt; .001). In four of 14 patients (28.6%), 68 Ga-DOTATATE PET/CT found a previously unknown primary tumor, and detected primary GEPNET, lymph node, and distant metastases correctly in 72 of 113 lesions (63.7%) when compared with histopathology, with 22.1% and 38.9% detected by using 111 In-pentetreotide SPECT/CT and anatomic imaging, respectively. On the basis of findings with 68 Ga-DOTATATE PET/CT, 43 of 131 patients (32.8%) had a change in management recommendation. In patients with carcinoid symptoms but negative biochemical testing, 68 Ga-DOTATATE PET/CT detected lesions in 65.2% of patients, 40% of which were detected neither by anatomic imaging nor by 111 In-pentetreotide SPECT/CT. Conclusion 68 Ga-DOTATATE PET/CT imaging provides important information for accurate staging of GEPNETs and selection of appropriate treatment interventions even in the absence of biochemical evidence of disease in symptomatic patients.
New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 1 Diabetes: A Randomized, Phase 3a, Open-Label Clinical Trial (EDITION 4)
Authors: Philip D. Home, Richard M. Bergenstal, Geremia B. Bolli, Monika Ziemen, Maria Rojeski, Melanie Espinasse, Matthew C. Riddle
Journal: Diabetes Care (2015)

OBJECTIVE Insulin therapy in type 1 diabetes still provides suboptimal outcomes. Insulin glargine 300 units/mL (Gla-300), with a flatter pharmacodynamic profile compared with insulin glargine 100 units/mL (Gla-100), is an approach to this problem. RESEARCH DESIGN AND METHODS People with type 1 diabetes, using a mealtime and basal insulin regimen, were randomized open-label to Gla-300 or Gla-100 and to morning or evening injection, continuing the mealtime analog, and followed for 6 months. RESULTS Participants (n = 549) were a mean age of 47 years and had a mean duration of diabetes of 21 years and BMI of 27.6 kg/m2. The change in HbA1c (primary end point; baseline 8.1%) was equivalent in the two treatment groups (difference, 0.04% [95% CI −0.10 to 0.19]) (0.4 mmol/mol [−1.1 to 2.1]), and Gla-300 was thus noninferior. Similar results with wider 95% CIs were found for morning and evening injection times and for prebreakfast self-measured plasma glucose (SMPG) overall. Results were also similar for Gla-300 when morning and evening injection time was compared, including overlapping 8-point SMPG profiles. Hypoglycemia did not differ, except for the first 8 weeks of the study, when nocturnal confirmed or severe hypoglycemia was lower with Gla-300 (rate ratio 0.69 [95% CI 0.53–0.91]). Hypoglycemia with Gla-300 did not differ by time of injection. The basal insulin dose was somewhat higher at 6 months for Gla-300. The adverse event profile did not differ and was independent of the Gla-300 time of injection. Weight gain was lower with Gla-300. CONCLUSIONS In long-duration type 1 diabetes, Gla-300 provides similar glucose control to Gla-100, with a lower risk of hypoglycemia after transfer from other insulins, independent of time of injection, and less weight gain.
Association Between Younger Age and Targetable Genomic Alterations and Prognosis in Non–Small-Cell Lung Cancer
Authors: Adrian G. Sacher, Suzanne E. Dahlberg, Jennifer Heng, Stacy Mach, Pasi A. Jänne, Geoffrey R. Oxnard
Journal: JAMA Oncology (2015)

Non-small-cell lung cancer (NSCLC) diagnosed in young patients is rare, and the genomics and clinical characteristics of this disease are poorly understood. In contrast, the diagnosis of other cancers at a young age has been demonstrated to define unique disease biology. Herein, we report on the association of young age with targetable genomic alterations and prognosis in a cohort of 2237 patients with NSCLC.To determine the relationship between young age at diagnosis and the presence of a potentially targetable genomic alteration, disease prognosis, and natural history.A cohort of all 2237 patients with NSCLC who were genotyped at the Dana-Farber Cancer Institute between January 2002 and December 2014 were identified. Tumor genotype, patient characteristics, and clinical outcomes were collected and studied at a National Cancer Institute-designated comprehensive cancer center. Multivariate logistic regression was used to analyze the relationship between age and mutation status, and multivariate Cox proportional hazard models were fitted for survival analysis.The frequency of targetable genomic alterations by defined age categories as well as the association of these age groups with survival. Age categories used in this analysis were younger than 40, 40 to 49, 50 to 59, 60 to 69, and 70 years or older.A cohort of 2237 patients with NSCLC was studied. Of the 2237 participants, 1939 (87%) had histologically confirmed adenocarcinoma, 269 (12%) had NSCLC not otherwise specified, and 29 (1%) had squamous histologic findings; 1396 (63%) had either stage IIIB or IV cancers; and median (range) age was 62 (20-95) years. We found that gene mutations for EGFR (P = .02) and ALK (P < .001) were associated with cancer diagnosis at a younger age, and a similar trend existed for ERBB2 (P = .15) and ROS1 (P = .10) but not BRAF V600E (P = .43). Among patients tested for all 5 targetable genomic alterations (n = 1325), younger age was associated with an increased frequency of a targetable genotype (P < .001). Those diagnosed at 50 years or younger have a 59% increased likelihood of harboring a targetable genotype. While presence of a potentially targetable genomic alteration treated with a targeted agent was associated with improved survival, the youngest and oldest age groups had similarly poor outcomes even when a targetable genotype was present.Younger age is associated with an increased likelihood of harboring a targetable genotype and is an underappreciated clinical biomarker in NSCLC. The survival of young patients with NCSLC is unexpectedly poor compared with other age groups, suggesting more aggressive disease biology. These findings underscore the importance of comprehensive genotyping, including next-generation sequencing, in younger patients with lung cancer.
Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon cancer (CC): NCCTG Intergroup Phase III Trial N0147.
Authors: R. M. Goldberg, D. J. Sargent, S. N. Thibodeau, M. R. Mahoney, A. F. Shields, E. Chan, S. Gill, M. S. Kahlenberg, S. Nair, S. R. Alberts
Journal: Journal of Clinical Oncology (2010)

3508 Background: FOLFOX is standard adjuvant therapy for resected stage III CC. N0147 assessed the potential benefit of Cmab added to FOLFOX in resected stage III CC. Initially N0147 enrolled pts regardless of KRAS status; here we report efficacy and toxicity results in mKRAS pts prior to an amendment requiring prospective KRAS testing. Methods: Pts were randomized to 12 biweekly courses of oxaliplatin 85 mg/m2 d1, with leucovorin 400 mg/m2, 5FU 400 mg/m2 bolus IV, then 46-hr IV 5FU 2,400 mg/m2 on d1-2 (mFOLFOX6), without (arm A) or with Cmab (arm D) 250 mg/m2 d1&8, with Cmab at 400 mg/m2, cycle 1, d1. Tumors were centrally tested for KRAS. This analysis focuses on pts with mKRAS CC. The primary endpoint was 3-yr disease free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. Results: 658 pts with mKRAS CC were enrolled prior to the prospective collection of KRAS (Arm A, 340; Arm D, 318). Median follow-up is 22.4 months. 3-yr DFS favored FOLFOX alone (HR 1.48, 95% CI 1.08-2.03; p=0.02). No benefit of Cmab was observed in any of the subgroups assessed. OS also favored FOLFOX alone (HR 1.67, CI 1.00-2.80; p=0.07). Increased toxicity and greater differences in outcomes were observed in pts aged ≥ 70 (Table). Conclusions: The addition of Cmab to mFOLFOX6 resulted in impaired DFS and a trend toward impaired OS in mKRAS resected stage III CC pts. While some between-arm difference in toxicity and ability to complete the full course of FOLFOX were observed, it is unlikely these factors could account in whole for the poorer outcome with Cmab added to mFOLFOX6 in pts with mKRAS CC. Supported by NIH Grant CA25224, Bristol-Myers Squibb, ImClone, aanofi-aventis, and Pfizer. Overall Age < 70 (n=566) Age >=70 (n=92) F F+C p F F+C p F F+C p 3-yr DFS 70.3 62.3 0.02 68.0 63.8 0.08 84.4 51.5 0.04 3-yr OS 86.1 79.1 0.07 85.9 81.8 0.20 88.0 65.4 0.10 On-study mortality 0.59 1.9 0.13 0.69 1.82 0.22 0 2.3 0.28 Any Gr ≥ 3 AE 52.7 68.9 <0.001 51.9 67.6 0.0002 57.1 76.7 0.05 Gr ≥ 3 diarrhea 7.5 14.8 0.003 6.7 13.1 0.01 12.2 25.6 0.10 Gr ≥ 4 neutropenia 11.1 12.9 0.48 9.5 13.1 0.18 20.4 11.6 0.26 Completed 12 cycles 73.7 68.0 0.11 74.8 68.5 0.10 66.7 65.1 0.88 Abbreviations: F, FOLFOX; F+C = FOLFOX + Cmab; p, p value. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Bristol-Myers Squibb, Celgene, Genentech, ImClone Systems, Pfizer, sanofi-aventis Bristol-Myers Squibb, sanofi-aventis Agensys, Amgen, Bristol-Myers Squibb, EMD Serono, Genentech, Idera, ImClone Systems, Lilly, Pfizer, Plexxikon, Roche, sanofi-aventis
Human cancer cells respond to cytosolic nucleic acids via enhanced production of interferon-β and apoptosis
Authors: Shan Zhu, Yuan Qiao, Jing Wu, Guoxia Zang, Yong-Jun Liu, Jingtao Chen
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts The innate immune system utilizes pattern-recognition receptors (PRRs) to detect the invasion of pathogens and initiate host antimicrobial responses. Recently, it was reported that human cancer cells also expressed PRRs, and responded to cytosolic nucleic acids via the production
Drug-Coated Balloon Versus Standard Balloon for Superficial Femoral Artery In-Stent Restenosis
Authors: Hans Krankenberg, Thilo Tübler, Maja Ingwersen, Michael Schlüter, Dierk Scheinert, Erwin Blessing, Sebastian Sixt, Arne Kieback, Ulrich Beschorner, Thomas Zeller
Journal: Circulation (2015)

Drug-coated balloon angioplasty (DCBA) was shown to be superior to standard balloon angioplasty (POBA) in terms of restenosis prevention for de novo superficial femoral artery disease. For in-stent restenosis, the benefit of DCBA over POBA remains uncertain.One hundred nineteen patients with superficial femoral artery in-stent restenosis and chronic limb ischemia were recruited over 34 months at 5 German clinical sites and prospectively randomized to either DCBA (n=62) or POBA (n=57). Mean lesion length was 82.2±68.4 mm. Thirty-four (28.6%) lesions were totally occluded; 30 (25.2%) were moderately or heavily calcified. Clinical and duplex ultrasound follow-up was conducted at 6 and 12 months. The primary end point of recurrent in-stent restenosis assessed by ultrasound at 6 months was 15.4% (8 of 52) in the DCBA and 44.7% (21 of 47) in the POBA group (P=0.002). Freedom from target lesion revascularization was 96.4% versus 81.0% (P=0.0117) at 6 months and 90.8% versus 52.6% (P<0.0001) at 12 months, respectively. At 12 months, clinical improvement by ≥1 Rutherford category without the need for target lesion revascularization was observed in 35 of 45 DCBA patients (77.8%) and 23 of 44 POBA patients (52.3%; P=0.015). No major amputation was needed. Two patients in the DCBA and 3 patients in the POBA group died. No death was procedure related.DCBA for superficial femoral artery in-stent restenosis is associated with less recurrent restenosis and a better clinical outcome than POBA without an apparent difference in safety.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01305070.
Delay In Onset Of First Transfusion and Increased Risk Of Graft Rejection In β Thalassemia Patients Undergoing a HLA Matched Related Allogeneic Stem Cell Transplant
Authors: Vikram Mathews, Abhijeet Ganapule, Kavitha M Lakshmi, Biju George, Aby Abraham, Auro Viswabandya, Alok Srivastava
Journal: Blood (2013)
Improving the resilience and workforce of health systems for women’s, children’s, and adolescents’ health
Authors: James Campbell, Giorgio Cometto, Kumanan Rasanathan, Edward Kelley, Shamsuzzoha Syed, Pascal Zurn, Luc de Bernis, Zoe Matthews, David Benton, Odile Frank, Andrea Nove
Journal: BMJ (2015)

To achieve the sustainable development goals related to maternal, child, and adolescent health, countries need to integrate targeted interventions within their national health strategies and leverage them into financing, workforce, and monitoring capacity across the system, say <b>James Campbell and colleagues</b>.