tbuckley/cabot-search huggingface dataset:
Addressing Generic-Drug Market Failures — The Case for Establishing a Nonprofit Manufacturer
Authors: Dan Liljenquist, Ge Bai, Gerard F. Anderson
Journal: New England Journal of Medicine (2018)

Interview with Dan Liljenquist on generic-drug market failures and the creation of a nonprofit drug manufacturer. (11:41)Download One market-based solution to stimulating competition in generic-drug markets is to establish a nonprofit manufacturer with the explicit mission of producing affordable versions of essential drugs and ensuring a stable supply of such products.
Did neoadjuvant chemotherapy provide better long term outcomes in borderline resectable with arterial involvement (BR-A PC)?
Authors: Kei Saito, Yousuke Nakai, Yoshihiro Sakamoto, Kazunaga Ishigaki, Naminatsu Takahara, Junichi Arita, Takeyuki Watadani, Hiroyuki Isayama, Kazuhiko Koike
Journal: Journal of Clinical Oncology (2018)

434 Background: Recently high rates of conversion (or adjuvant) surgery were reported after neoadjuvant chemo(radiation)therapy (NAC) for borderline or locally advanced pancreatic cancer (BR/LA PC) including our phase II trial of gemcitabine, S-1 and leucovorin (GSL) combination therapy for BR PC with arterial involvement (BR-A PC) and LA PC. In our phase II trial, a high recurrence rate of 78% was noted despite a high R0 resection of 76%. Herein, we conducted a retrospective analysis of BR-A PC who underwent NAC, upfront surgery and palliative chemotherapy to evaluate the long term outcomes of NAC. Methods: Consecutive patients with BR-A PC at the University of Tokyo Hospital were retrospectively studied. Clinical outcomes in patients who underwent (NAC group) were compared with those in patients who underwent upfront surgery or palliative chemotherapy (non-NAC group). NAC was introduced in our institution from January 2014. Results: A total of 45 patients (22 non-NAC and 23 NAC group) were diagnosed with BR-A PC between January 2008 and December 2016. There were no significant differences in patient characteristics between non-NAC group and NAC group: Median age of 63 vs. 64, male in 72% vs. 52%, Performance status of 0 in 63% vs. 65%, median pretreatment CA19-9 of 175 vs. 205 U/ml. In non-NAC group, 17 underwent palliative chemotherapy as follows 8 gemcitabine alone, 3 gemcitabine and S-1 combination chemotherapy and 6 other regimens. The remaining 5 patients underwent upfront surgery with an R0 resection rate of 80%. In NAC group, a median duration of neoadjuvant chemotherapy was 4 months. A total of 14 patients underwent surgical resection with an R0 resection rate of 76%. The remaining 9 patients had disease progression during NAC and received 2 nd line chemotherapy. The median follow-up time was 16.5 months in non-NAC group and 15.3 months in NAC group. The median overall survival (OS) were 19.3 vs. 21.9 months (p = 0.25). Conclusions: Both R0 resection rate and the median OS were comparable between non-NAC group and NAC group. An ideal regimen of NAC or its duration needs further investigation to prolong OS in BR-A PC.
IL1RAP potentiates multiple oncogenic signaling pathways in AML
Authors: Kelly Mitchell, Laura Barreyro, Tihomira I. Todorova, Samuel J. Taylor, Iléana Antony-Debré, Swathi-Rao Narayanagari, Luis A. Carvajal, Joana Leite, Zubair Piperdi, Gopichand Pendurti, Ioannis Mantzaris, Elisabeth Paietta, Amit Verma, Kira Gritsman, Ulrich Steidl
Journal: The Journal of Experimental Medicine (2018)

The surface molecule interleukin-1 receptor accessory protein (IL1RAP) is consistently overexpressed across multiple genetic subtypes of acute myeloid leukemia (AML) and other myeloid malignancies, including at the stem cell level, and is emerging as a novel therapeutic target. However, the cell-intrinsic functions of IL1RAP in AML cells are largely unknown. Here, we show that targeting of IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo, without perturbing healthy hematopoietic function or viability. Furthermore, we found that the role of IL1RAP is not restricted to the IL-1 receptor pathway, but that IL1RAP physically interacts with and mediates signaling and pro-proliferative effects through FLT3 and c-KIT, two receptor tyrosine kinases with known key roles in AML pathogenesis. Our study provides a new mechanistic basis for the efficacy of IL1RAP targeting in AML and reveals a novel role for this protein in the pathogenesis of the disease.
Acute Pancreatitis Following Peptide Receptor Radionuclide Therapy
Authors: Ioannis Karfis, Gwennaëlle Marin, Godelieve Machiels, Alain Hendlisz, Patrick Flamen
Journal: Clinical Nuclear Medicine (2018)

A 54-year-old man with grade 2 rectal neuroendocrine tumor and hepatic, pancreatic, and bone metastases was treated with Lu-DOTATATE as second-line therapy, after failure of somatostatin analogues. Two weeks after the first injection, he presented at the emergency department with acute pancreatitis. We hypothesized that this unusual adverse event, never been reported so far, was the result of acute tumor irradiation after PRRT, leading to peritumoral inflammation and edema with obstruction of an accessory pancreatic duct.
Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome
Authors: Alain Combes, David Hajage, Gilles Capellier, Alexandre Demoule, Sylvain Lavoué, Christophe Guervilly, Daniel Da Silva, Lara Zafrani, Patrice Tirot, Benoit Veber, Eric Maury, Bruno Levy, Yves Cohen, Christian Richard, Pierre Kalfon, Lila Bouadma, Hossein Mehdaoui, Gaëtan Beduneau, Guillaume Lebreton, Laurent Brochard, Niall D. Ferguson, Eddy Fan, Arthur S. Slutsky, Daniel Brodie, Alain Mercat
Journal: New England Journal of Medicine (2018)

The efficacy of venovenous extracorporeal membrane oxygenation (ECMO) in patients with severe acute respiratory distress syndrome (ARDS) remains controversial.
New approaches to WHO financing: the key to better health
Authors: Charles Clift, John-Arne Røttingen
Journal: BMJ (2018)

Dr Tedros's plans to reverse the trend towards earmarked funding are important but challenging, say Charles Clift and John-Arne Røttingen If the World Health Organization is to become more effective it needs to have greater flexibility on how it spends its funding. This is the argument that the organisation's director-general, Tedros Adhanom Ghebreyesus, has made repeatedly since taking office in July last year. Speaking at the WHO executive board meeting in January 2018, he said: "If we continue to operate under the same funding restrictions, we will produce the same results. No organisation can succeed when its budget and priorities are not aligned."1 In his opening speech at the 71st World Health Assembly he reiterated the call to reduce earmarking and avoid internal competition for donor funding.2 Currently around 80% of the funds WHO receives are earmarked for projects specified by the donor (box 1). The result is that many of its programmes are seriously underfunded, including those for non-communicable diseases and maternal and child health.3 Tedros is not necessarily asking for more money, but he believes the current system hampers WHO in meeting its members' aims. The reliance on voluntary contributions means fundraising is essentially devolved to individual departments and offices within WHO, stopping the organisation from operating as a coherent whole. The individual departments inevitably become more accountable to their external donors, who provide most of their funding, than to the management and leadership at WHO.4 As Tedros said last year: "By not working together we lose the synergy that is gained through joint working. But also, what one department does can actually undermine what another is trying to achieve."4 Box 1 ### WHO financingRETURN TO TEXT
Multiple functions of m6A RNA methylation in cancer
Authors: Yutian Pan, Pei Ma, Yu Liu, Wei Li, Yongqian Shu
Journal: Journal of Hematology & Oncology (2018)

First identified in 1974, m6A RNA methylation, which serves as a predominant internal modification of RNA in higher eukaryotes, has gained prodigious interest in recent years. Modifications of m6A are dynamic and reversible in mammalian cells, which have been proposed as another layer of epigenetic regulation similar to DNA and histone modifications. m6A RNA methylation is involved in all stages in the life cycle of RNA, ranging from RNA processing, through nuclear export, translation modulation to RNA degradation, which suggests its potential of influencing a plurality of aspects of RNA metabolism. All of the recent studies have pointed to a complicated regulation network of m6A modification in different tissues, cell lines, and space–time models. m6A methylation has been found to have an impact on tumor initiation and progression through various mechanisms. Furthermore, m6A RNA methylation has provided new opportunities for early stage diagnosis and treatment of cancers. Herein, we review the chemical basis of m6A RNA methylation, its multiple functions and potential significance in cancer.
Prevalence and impact of WHO group 3 pulmonary hypertension in advanced idiopathic nonspecific interstitial pneumonia
Authors: Christopher S. King, A. Whitney Brown, Oksana A. Shlobin, Nargues Weir, Matthew Libre, Domingo Franco-Palacios, Shahzad Ahmad, Steven D. Nathan
Journal: European Respiratory Journal (2018)

Pulmonary hypertension (PH) is associated with impaired quality of life, worsened functional status and increased mortality in idiopathic pulmonary fibrosis (IPF) [1]. The prevalence and clinical impact in other idiopathic interstitial pneumonias (IIPs) has not previously been reported. Given the prognostic significance of PH in IPF, we sought to determine the prevalence and severity of World Health Organization (WHO) group 3 PH in a cohort of patients with biopsy-proven idiopathic nonspecific interstitial pneumonia (NSIP). We recognised that the prevalence of PH in this population of patients with advanced NSIP would be an overestimation of the NSIP population at large, but felt that mandating surgical lung biopsy and right heart catheterisation (RHC) were the only way to ensure accurate diagnosis of NSIP and PH, respectively. Group 3 pulmonary hypertension commonly complicates idiopathic NSIP and is associated with adverse outcomes <http://ow.ly/jsa930jMaSD>
THU0237 Enbrel® (etanercept) in patients with psoriatic arthritis and psoriasis
Authors: PJ Mease, BS Goffe, J Metz, A VanderStoep, DJ Burge
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Results have been previously presented from a 12-week, double-blind placebo-controlled study of 60 patients with psoriatic arthritis (PsA) and psoriasis.<sup>1</sup> ENBREL was well tolerated and provided clinically significant benefit to patients with PsA and psoriasis. All patients could receive open-label ENBREL in a 24-week extension study. <h3>Objectives</h3> Observe the safety and clinical benefit of ENBREL in a longer-term open-label study. <h3>Methods</h3> In the extension study, as in the blinded study, we evaluated improvements in patients with PsA according to PsA response criteria (PsARC) and ACR criteria. Patients with psoriasis were evaluated using the Psoriasis Area and Severity Index (PASI). <h3>Results</h3> Fifty-eight patients from the 12-week study received open-label ENBREL in the 24-week extension study and were evaluated according to PsARC and ACR criteria. Thirty-seven patients with psoriasis were evaluated using the PASI. The original ENBREL patients sustained their improvement in both PsA and psoriasis in the extension study. The original placebo patients demonstrated similar improvements once they began receiving ENBREL. At 36 weeks of therapy, 81% of all patients achieved the PsARC, 74% achieved the ACR 20, and 55% achieved the ACR 50. The patients with psoriasis (n = 37) achieved median improvements of 62% in the PASI and 50% in the target lesion response. Of the 28 patients who were taking concomitant methotrexate (MTX) at baseline, 43% (12/28) have decreased their MTX dose and 25% (7/28) patients have discontinued MTX. Similarly, of 18 patients on corticosteroids at baseline, 67% (12/18) have decreased their steroid dose and 44% (8/18) have discontinued steroids. At 36 weeks, 28% of patients had zero tender joints, 41% had zero swollen joints, and 40% had a disability score of zero. ENBREL continued to be well tolerated, with no serious adverse events or infections and no increases in adverse events with extended exposure. <h3>Conclusion</h3> ENBREL continues to be safe and effective in reducing the clinical signs and symptoms of PsA and psoriasis for up to 36 weeks. <h3>Reference</h3> Mease PJ, Goffe BS, Metz J, <i>et al</i>. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial. Lancet 2000;356:385–90
Can looking at density differences between liver parenchyma and oligometastatic lesions predict outcomes and toxicities in patients receiving stereotactic body radiation therapy for metastatectomy?
Authors: Will Jin, Diego Augusto Santos Toesca, Evan Osmundson, Jenny Shaffer, Albert Koong, Daniel Tandel Chang
Journal: Journal of Clinical Oncology (2018)

479 Background: Stereotactic body radiation therapy (SBRT) has found utility in oligometastatic liver lesions by providing excellent local control in most patients. These tumors are not routinely biopsied to evaluate for histologic grade due to high risk of seeding. Non-invasive pre-treatment radiographic findings may be able to identify a subset of patients at higher risk of local recurrence. Methods: Retrospective review of an IRB-approved database of liver metastases treated with SBRT yielded 55 patients for final analysis. Liver parenchyma and metastatic liver lesions were contoured using MIM version 6.6.5. Receiver Operating Characteristic curves and mean values were used to generate binary cutoffs for toxicities and Kaplan-Meier analysis, respectively. Computer Tomography features, like density, skew, kurtosis, variance, and volume, based on our pre-SBRT planning liver protocol images and their relationship with outcomes and toxicities were examined. Results: Largepre-SBRT density differences between oligometastatic lesions and liver parenchyma, as measured by Hounsfield Units, was associated with a 3.248 increased risk of local failures (p = 0.027) and grade 3 or higher late non-hepatobiliary toxicities (p = 0.032). There were no associations with overall survival. Lesions with large variance in density was associated with grade 3 or higher acute hepatobiliary toxicities (p = 0.043). Conclusions: Density metrics in metastatic liver lesions are readily available in most treatment planning systems and may be a prognostic indicator of tumor aggressiveness. Higher radiation doses may be needed to reduce rates of local recurrence in these patients. Further studies should examine if post-treatment density metrics are dose-dependent and correlate with outcomes.
Improved survival with renal transplantation for end-stage renal disease due to granulomatosis with polyangiitis: data from the United States Renal Data System
Authors: Zachary S Wallace, Rachel Wallwork, Yuqing Zhang, Na Lu, Frank Cortazar, John L Niles, Eliot Heher, John H Stone, Hyon K Choi
Journal: Annals of the Rheumatic Diseases (2018)

Renal transplantation is the optimal treatment for selected patients with end-stage renal disease (ESRD). However, the survival benefit of renal transplantation among patients with ESRD attributed to granulomatosis with polyangiitis (GPA) is unknown.We identified patients from the United States Renal Data System with ESRD due to GPA (ESRD-GPA) between 1995 and 2014. We restricted our analysis to waitlisted subjects to evaluate the impact of transplantation on mortality. We followed patients until death or the end of follow-up. We compared the relative risk (RR) of all-cause and cause-specific mortality in patients who received a transplant versus non-transplanted patients using a pooled logistic regression model with transplantation as a time-varying exposure.During the study period, 1525 patients were waitlisted and 946 received a renal transplant. Receiving a renal transplant was associated with a 70% reduction in the risk of all-cause mortality in multivariable-adjusted analyses (RR=0.30, 95% CI 0.25 to 0.37), largely attributed to a 90% reduction in the risk of death due to cardiovascular disease (CVD) (RR=0.10, 95% 0.06-0.16).Renal transplantation is associated with a significant decrease in all-cause mortality among patients with ESRD attributed to GPA, largely due to a decrease in the risk of death to CVD. Prompt referral for transplantation is critical to optimise outcomes for this patient population.
Air Pollution and Mortality in the Medicare Population
Authors: Louis Anthony Cox
Journal: JAMA (2018)

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Use of Xpert MTB/RIF Ultra assays among paediatric tuberculosis experts in Europe
Authors: Paola Villanueva, Olaf Neth, Nicole Ritz, Marc Tebruegge
Journal: European Respiratory Journal (2018)

We read with interest the recent editorial by Cabibbe et al . [1], which highlights the importance of rapid molecular tuberculosis (TB) assays for patient care. Only few paediatric TB experts based in Europe had access to the Xpert MTB/RIF Ultra assay, a new generation molecular TB test, by the end of 2017 <http://ow.ly/ZgoF30jHShY>
The difference between the scope of a norm and its apparent source
Authors: Jonathan Birch
Journal: Behavioral and Brain Sciences (2018)

Abstract We should distinguish between the apparent source of a norm and the scope of the norm's satisfaction conditions. Wide-scope social norms need not be externalised, and externalised social norms need not be wide in scope. Attending to this distinction leads to a problem for Stanford: The adaptive advantages he attributes to externalised norms are actually advantages of wide-scope norms.
Rates of infection after colonoscopy and osophagogastroduodenoscopy in ambulatory surgery centres in the USA
Authors: Peiqi Wang, Tim Xu, Saowanee Ngamruengphong, Martin A Makary, Anthony Kalloo, Susan Hutfless
Journal: Gut (2018)

Objective Over 15 million colonoscopies and 7 million osophagogastroduodenoscopies (OGDs) are performed annually in the USA. We aimed to estimate the rates of infections after colonoscopy and OGD performed in ambulatory surgery centres (ASCs). Design We identified colonoscopy and OGD procedures performed at ASCs in 2014 all-payer claims data from six states in the USA. Screening mammography, prostate cancer screening, bronchoscopy and cystoscopy procedures were comparators. We tracked infection-related emergency department visits and unplanned in-patient admissions within 7 and 30 days after the procedures, examined infection sites and organisms and analysed predictors of infections. We investigated case-mix adjusted variation in infection rates by ASC. Results The rates of postendoscopic infection per 1000 procedures within 7 days were 1.1 for screening colonoscopy, 1.6 for non-screening colonoscopy and 3.0 for OGD; all higher than screening mammography (0.6) but lower than bronchoscopy (15.6) and cystoscopy (4.4) (p &lt; 0.0001). Predictors of postendoscopic infection included recent history of hospitalisation or endoscopic procedure; concurrence with another endoscopic procedure; low procedure volume or non-freestanding ASC; younger or older age; black or Native American race and male sex. Rates of 7-day postendoscopic infections varied widely by ASC, ranging from 0 to 115 per 1000 procedures for screening colonoscopy, 0 to 132 for non-screening colonoscopy and 0 to 62 for OGD. Conclusion We found that postendoscopic infections are more common than previously thought and vary widely by facility. Although screening colonoscopy is not without risk, the risk is lower than diagnostic endoscopic procedures.
Talimogene Laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: a case series
Authors: Lillian Sun, Pauline Funchain, Jung Min Song, Patricia Rayman, Charles Tannenbaum, Jennifer Ko, Michael Mcnamara, C. Marcela Diaz-Montero, Brian Gastman
Journal: Journal for ImmunoTherapy of Cancer (2018)

Talimogene Laherparepvec (T-VEC) is an oncolytic virus approved as an intratumoral therapy for treating unresectable stage IIIB-IV metastatic melanoma. The mechanisms of action for T-VEC and checkpoint inhibitor are highly complementary. Recent studies have shown that combining checkpoint inhibitor therapy with T-VEC injection can lead to improved response rates for stage IIIB-IV melanoma patients.We reviewed 10 consecutive cases of stage IIIC to stage IVM1b melanoma patients that received T-VEC plus checkpoint inhibitor(s) therapy (pembrolizumab, ipilimumab/nivolumab, or nivolumab) treated between June 2016 and August 2017 at the Cleveland Clinic with a median follow-up of 7 months (range: 4 to 13 months). Responses of injected (on-target) and uninjected (off-target) lesions were evaluated according to RECIST 2.0.The overall response rate for on-target lesions was 90%, with 6 patients experiencing a complete response in injected lesions. Two patients had off-target lesions, which were completely resolved after treatment. Blood samples were tested for 3 complete responders and 2 partial responders. CD4:CD8 ratio and frequencies of circulating PD1+ CD4 and CD8 T cells were elevated in complete responders but not partial responders. One patient died due to causes unrelated to melanoma and one patient died of progression of the disease.Our data suggest that combining checkpoint inhibitor(s) with T-VEC injection may provide a synergistic efficacy for patients with unresectable melanoma. We observed a better overall response rate and complete response rate compared to published studies on similar therapeutic regimens.