tbuckley/cabot-search huggingface dataset:
Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease
Authors: Michael M. Boyiadzis, John M. Kirkwood, John L. Marshall, Colin C. Pritchard, Nilofer S. Azad, James L. Gulley
Journal: Journal for ImmunoTherapy of Cancer (2018)

The U.S. Food and Drug Administration (FDA) recently approved pembrolizumab, an anti- programmed cell death protein 1 cancer immunotherapeutic, for use in advanced solid tumors in patients with the microsatellite-high/DNA mismatch repair-deficient biomarker. This is the first example of a tissue-agnostic FDA approval of a treatment based on a patient's tumor biomarker status, rather than on tumor histology. Here we discuss key issues and implications arising from the biomarker-based disease classification implied by this historic approval.
A phase I fixed-dose feasibility study of MK615 and gemcitabine in patients with advanced or metastatic pancreatic cancer.
Authors: Ichiro Moriyama, Fumiyoshi Ikejiri, Koshi Kawakami, Masaya Inoue, Satoshi Kumanomido, Matsuda Shinichiro, Fumimasa Takahashi, Shunsuke Ito, Yusuke Okada, Hiroshi Mochida, Yasumasa Shimazaki, Norimi Ugata, Takahiro Okada, Yumi Jo, Chie Onishi, Tsutomu Takahashi, Takaaki Miyake, Ritsuro Suzuki, Junji Suzumiya
Journal: Journal of Clinical Oncology (2018)

510 Background: The medical agent MK615 is produced from Japanese apricot and contains a number of cyclic triterpenes. Antitumor activity of MK615 and its additive effect when combined with gemcitabine in pancreatic cancer cell line. MIAPaCa-2 was previously reported by our group. The objective of this phase I trial was to evaluate safety and feasibility of combined MK615 and gemcitabine therapy in patients with advanced or metastatic pancreatic cancer. Methods: Patients with untreated pancreatic cancer or those who underwent chemotherapy without gemcitabine were enrolled. Gemcitabine was infused at 1000 mg/m2 over 30 minutes once weekly for 3 weeks of each 28-day treatment cycle. Three packets of MK615 were orally administered daily during each 28-day treatment cycle, until any discontinuation criteria were met. If severe toxicity occurred, dose was reduced. Results: All five patients enrolled were evaluable for toxicity and response. Median age was 72 (54-79) years. Three patients had performance status (PS) 0, one had PS 1, and one PS 2. Three of five patients had been treated with chemotherapy; two with FOLFIRINOX and one with S-1. One of five patients treated had grade 4 neutropenia and two were administered granulocyte-colony stimulating factor. No patient had febrile neutropenia or adverse event leading to death. Relative dose intensity was 96.6% and 69.8% for MK615 and gemcitabine, respectively. No patients had objective response (complete response + partial response), while 2 of 5 patients (40%) had disease control (objective response + stable disease). Conclusions: Combined MK615 and gemcitabine therapy was well-tolerated and showed antitumor activity in patients previously treated without gemcitabine or untreated patients with advanced or metastatic pancreatic cancer. Currently, we are planning phase II trials for elderly or frail people.
Safety of administration of bevacizumab within a week from placement of a totally implantable central venous port system.
Authors: Tetsuhito Muranaka, Yoshito Komatsu, Masataka Yagisawa, Yasuyuki Kawamoto, Hiroshi Nakatsumi, Satoshi Yuki, Naoya Sakamoto
Journal: Journal of Clinical Oncology (2018)

589 Background: Totally implantable central venous port systems (TICVP) are easy to implant on an in- or outpatient basis and provide reliable, long-lasting central venous access for treatment of intravenous anti-cancer chemotherapy in patients with cancer but it is needed to cut 3cm of patients’ skin at the operation. Bevacizumab is one of the anti vascular endothelial growth factor (ant-VEGF) antibody which is known to improve overall survival in patients with colorectal cancer but have a side effect of delayed wound healing. There are few reports about the safety of administration of bevacizumab in a short period of time from the small surgery such as placement of TICVP. Methods: Patients who were placed TICVP in Department of Gastroenterology of Hokkaido University Hospital from July 2009 to December 2016. We planned to compare the rate of post-operative wound dehiscence (POWD) and surgical site infection (SSI) between patients who administered bevacizumab within a week from placement of TICVP (Group A) and the other patients (Group B). Patients who didn’t receive any chemotherapy after placement of TICVP were excluded. Results: We found 432 patients who implanted TICVP, and excluded 32 patients who didn’t receive any chemotherapy. 50 patients were assigned to Group A and 350 patients were assigned to Group B. Median age in both group were 67.5 in Group A and 65 in Group B. The averages of operation time were 38.7 (+/-19.3) minutes in Group A and 36.4 (+/-19.5) minutes in Group B. Prophylactic antibiotics were given to 27 patients (54%) in Group A and 146 patients (48.7%) in Group B. The rate of POWD was 0.0% (0/50) in Group A vs 1.1% (4/350) in Group B ( p = 0.45 ) , and the rate of SSI was 0.0%(0/50) in Group A vs 1.1% (4/350) in Group B ( p = 0.45 ) . The average of operation time of patients with and without POWD was 56.4 minutes and 36.7 minutes (p = 0.013). Conclusions: In our study, it was found that there is no significant increase of incidence by administration of bevacizumab within a short period from placement of TICVP. The long operation time tends to increase the rate of POWD.
MRI-Guided Intravenous Alteplase for Stroke — Still Stuck in Time
Authors: Tudor G. Jovin
Journal: New England Journal of Medicine (2018)

Time is a critical determinant of patient eligibility for intravenous thrombolysis in acute stroke. In such patients, intravenous alteplase is routinely administered up to 4.5 hours after the onset of symptoms, but even within this window, earlier treatment leads to better outcomes. Restriction of treatment to fixed times has limitations, since the time of symptom onset often cannot be ascertained, particularly in patients who wake up from sleep with a neurologic deficit. Furthermore, most patients arrive at the hospital more than 4.5 hours after symptom onset, which renders only a minority of patients eligible for treatment. The duration of symptoms . . .
Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study
Authors: F. Valenzuela, N.J. Korman, R. Bissonnette, N. Bakos, T.-F. Tsai, M.K. Harper, W.C. Ports, H. Tan, A. Tallman, H. Valdez, A.C. Gardner
Journal: British Journal of Dermatology (2018)

Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open‐label extension study of tofacitinib in psoriasis are reported. To evaluate the long‐term safety and durability of efficacy of tofacitinib in adults with moderate‐to‐severe chronic plaque psoriasis. Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75). Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient‐years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52–62% of patients and PASI 75 by 56–74% of patients at each study visit through month 54. In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).
<i>Notes from the Field:</i> Investigation of an Outbreak of <i>Salmonella</i> Paratyphi B Variant L(+) tartrate + (Java) Associated with Ball Python Exposure — United States, 2017
Authors: Vikram Krishnasamy, Lauren Stevenson, Lia Koski, Marilee Kellis, Betsy Schroeder, Madhura Sundararajan, Stephen Ladd-Wilson, Ashley Sampsel, Mike Mannell, Andrew Classon, Darlene Wagner, Kelley Hise, Heather Carleton, Eija Trees, Linda Schlater, Kristina Lantz, Megin Nichols
Journal: MMWR Morbidity and Mortality Weekly Report (2018)
Abstract 15443: Unexpected Role of PCSK9 in Human Pluripotent Stem Cells and Their Differentiation
Authors: Salam Idriss, Amandine Caillaud, Aurore Girardeau, Benoite Champon, Amandine David, Lucie Arnaud, Matthieu Pichelin, Cedric Le May, Annik Prat, Anne Camus, Nabil G Seidah, Bertrand Cariou, Karim Si-Tayeb
Journal: Circulation (2016)

Introduction: We previously showed that patient-derived induced pluripotent stem cells (hiPSCs) differentiated into hepatocytes is a relevant model to study the impact of PCSK9 gain-of-function (GO...
Clinical and molecular characteristics of younger versus older patients with colorectal cancer.
Authors: Pritish Iyer, Kit Wong, Christopher Hanyoung Lieu, Jason Henry, Sarah Lindsey Davis, Karyn A. Goodman, Kurtis Davies, Dara Aisner, Wells A. Messersmith, Stephen Leong
Journal: Journal of Clinical Oncology (2018)

630 Background: Although overall incidence of colorectal cancer is declining, the incidence for young patients (age &lt; 50) with colon cancer is increasing. Reasons for this rise are unclear. Understanding clinical and molecular differences between younger and older cohorts can help guide both patient education strategies and future research into the mechanisms of this phenomenon. Methods: A retrospective analysis of patients diagnosed with colon cancer between 2008 and 2015 who underwent molecular tumor profiling via next-gen sequencing of 26 commonly mutated genes at the University of Colorado. Data collected by chart review includes demographic, pathologic, treatment course, and outcomes. Age group cutoffs for data analysis were set at &lt; 50, 50-65, and &gt; 65 based on screening guidelines and average age of diagnosis Results: We evaluated a total of 242 patients, stage I (n = 1), stage II (n = 65), stage III (n = 68), stage IV (n = 105). Mean age was 59.5 (range 27 to 89). A higher percentage of younger patients were non-smokers (77% of youngest cohort vs 46% of oldest cohort, p &lt; 0.001) and had a non-significant trend towards male gender (youngest cohort 63.8% male, oldest cohort 43.4% male, p = 0.065). Younger patients had similar body mass index (BMI) compared to older patients (BMI 27 vs 25.7, p = 0.35). Younger patients had higher rates of rectal cancer (42% vs 21%, p = 0.01) and lower rates of proximal/right sided colon cancer (20% vs 46.5%, p = 0.014). Younger patients also had lower rates of MSI-H tumors (8% vs 14%, p = 0.01). Finally, younger patients had significantly lower rates of APC (43.1% vs 69.3%, p = 0.009) and BRAF (3.5% vs 19.7%, p = 0.004) mutations. Conclusions: Younger patients ( &lt; 50 years old) with colorectal cancer had lower rates of tobacco use and no difference in obesity rates compared to older patients. In addition, although APC and BRAF mutations were lower in younger patients, there were no mutations that were more prevalent in the young cohort. Therefore, further research into lifestyle factors (specific diet/exercise patterns) or alternative molecular mechanisms are needed.
Abstract 14395: A Common Genetic Variant Within SCN10A Modulates DNA Methylation of SCN5A Promoters
Authors: Naoya Hironobe, Yukiko Nakano, Takehito Tokuyama, Akinori Sairaku, Hiroya Matsumura, Shunsuke Tomomori, Michitaka Amioka, Yasuki Kihara
Journal: Circulation (2016)

Risk stratification of Brugada syndrome (BrS) remains controversial and the majority of BrS patients have no genetic explanation. In a recent genome-wide association study (GWAS),  SCN10A  (rs10428132; T>G) single nucleotide polymorphisms (SNPs) were reported to be associated with BrS. We replicated the association of  SCN10A  (rs10428132) in our Japanese BrS patients and investigated the mechanism of pathogenesis. We genotyped the rs10428132 in 95 Japanese patients with BrS and 1,978 healthy controls. Subsequently, we examined whether the  SCN10A  SNP was related to  SCN5A  promoter methylation. Transverse sections of a septal site of the RV outflow tract were obtained by biopsy from 21 patients out of the BrS subjects and the 14 CpG dinucleotides in the SCN5A promoter by direct Sanger sequencing of the PCR amplicons of bisulfite treated DNA. The minor allele frequency of rs10428132 was significantly higher in BrS than the controls (P = 2.7x10 -14 , odds ratio (OR) 3.0). The PQ interval was longer in patients with the  SCN10A  risk allele than in those without as previously reported (CC: 157 ± 2.5 ms, CT: 172 ± 5.3 ms, TT: 172 ± 3.5 ms,  P  = 1.8x10 -3 ). The rate of the methylation was higher in BrS patients with risk allele T than those without (GG: 6% vs. GT: 11.6% and TT 11.4%, respectively, P=0.03). The results suggested that the  SCN10A  SNP may modulate the SCN5A expression through  SCN5A  promoter methylation. The risk genotype of the  SCN10A  SNP may contribute to decrease  SCN5A  expression by promoting  SCN5A  promoter methylation and eventually be more likely develop BrS.
Abstract IA08: Somatic p53 mutations drive development of triple-negative breast cancer with evolutionarily distinct metastases
Authors: Yun Zhang, Shunbin Xiong, Guillermina Lozano
Journal: Cancer Research (2018)

Abstract Breast cancer is a heterogeneous disease generally comprising four molecular subtypes: luminal A, luminal B, HER-2 enriched, and basal-like. Basal-like breast cancers, the majority of which are triple-negative breast cancers (TNBCs), are the most aggressive with the poorest prognosis and no targeted therapies. The majority of these tumors (80-88%) have mutations in the TP53 tumor suppressor, which suggests an important role for TP53 mutations in tumor initiation and progression. We have created two novel conditional mutant p53 alleles in the mouse, p53wm-R172H and p53wm-R245W. These alleles are wild type, but in response to Cre-mediated recombination, they produce p53R172H and p53R245W proteins that correspond to p53R175H and p53R248W hot spot mutants in human TNBCs. In a somatic breast cancer model, p53 mutations in a few mammary epithelial cells were generated using intraductal injection of Ad-Cre. Importantly, the stroma and immune cells retain wild type p53. p53wm-R172H/+ mice rarely developed breast cancer while p53wm-R172H/fl (includes the p53R172H mutation and a p53-null allele) and p53wm-R245W/+ readily developed breast carcinomas, a subset of which are TNBCs that metastasized to the lung and liver, common sites of human breast cancer metastasis. Whole-exome sequencing of p53R245W tumors revealed different evolution patterns for metastases. These models most closely simulate the genesis of TNBCs and will thus be invaluable in testing novel therapeutic combinations. Citation Format: Yun Zhang, Shunbin Xiong, Guillermina Lozano. Somatic p53 mutations drive development of triple-negative breast cancer with evolutionarily distinct metastases [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA08.
Air Pollution and Mortality in the Medicare Population
Authors: Frederick W. Lipfert
Journal: JAMA (2018)

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Impact of microsatellite instability (MSI) on tumor clonal evolution in metastatic colorectal cancer (mCRC).
Authors: Jason Willis, Maria Pia Morelli, Van Karlyle Morris, Jonathan Loree, Michael Lam, Allan Andresson Lima Pereira, Kanwal Pratap Singh Raghav, Bryan K. Kee, Eduardo Vilar Sanchez, Cathy Eng, Shanequa Manuel, Shadarra Crosby, Robert A. Wolff, Richard B. Lanman, AmirAli Talasaz, Filip Janku, Michael J. Overman, Scott Kopetz
Journal: Journal of Clinical Oncology (2018)

616 Background: For mCRC, the contribution of clinical and pathologic factors to concordance between formalin-fixed, paraffin-embedded (FFPE) tissue-based and ctDNA-based mutation profiling remains unclear. MSI is hypothesized to confer a higher rate of somatic alteration resulting in clonal evolution over time compared to microsatellite stable (MSS) patients, but this has not been previously confirmed. Methods: All mCRC patients were consented for a prospective genomic matching protocol (Assessment of Targeted Therapies Against Colorectal Cancer [ATTACC]) using CLIA-certified platforms. Archived tumor DNA from primary or metastatic tissue was sequenced on a 46- or 50-gene panel (Ion Torrent). Paired ctDNA samples were isolated from blood and sequenced with an ultra high-sensitivity assay (Guardant360). Mutation data were normalized by excluding genomic regions not covered on both platforms and were filtered to remove germline or synonymous variants. Results: An initial cohort of 139 patients was included in our analyses, with a median of two lines of intervening chemotherapy between FFPE and plasma DNA collection; 6 (4.3%) of the patients had MSI (MSI-H) mCRC. We detected 472 total mutations in either tissue or ctDNA, with a global concordance rate of 34.5%. Global concordance was not associated with tissue source, nor treatment with specific standard cytotoxic and/or biologic agents. Mutations detected in MSI-H CRC showed significantly greater discordance compared to MSS CRC (OR = 2.5, p = 0.025). This finding was validated using an independent cohort of 17 MSI-H mCRC patients (OR = 2.78, p = 0.00015). Among recurrently altered genes, we found that MSI-H cases were significantly more likely to have gained new TP53 mutations (OR = 8.17, p = 0.001) and to have lost PIK3CA mutations (OR = 8.04, p = 0.036) in ctDNA compared to MSS cases. Conclusions: MSI correlates with discordance between tissue DNA and ctDNA-based mutation profiling, which suggests that MSI-H CRC undergoes distinct patterns of clonal evolution including acquisition of new TP53 mutations. This may have implications for targeted and immunologic therapies in this unique population, and suggests a utility for repeated molecular testing.
David Oliver: Are comparisons between acute healthcare and the aviation industry invidious?
Authors: David Oliver
Journal: BMJ (2018)

Much of the inspiration for establishing the Healthcare Safety Investigation Branch in 2016 came from Jeremy Hunt’s wish to learn from the aviation industry. Significantly, Keith Conradi, who had been chief investigator for the Air Accidents Investigation Branch (AAIB), was appointed the new unit’s chief investigator.

It’s easy to understand the desire for the NHS to learn from airlines. Commercial aviation has a relentless focus on safety: learning from incidents and ensuring safety is central to staff training and values. Most of all, aviation supports an open culture of learning and reporting in which staff who report concerns are protected.

During the …
A prospective evaluation of universal tumor testing strategies for Lynch syndrome in endometrial cancer.
Authors: Kari Lassen Ring, Amanda S. Bruegl, Brittany A.L. Batte, Molly S Daniels, Mark F. Munsell, Karen H. Lu, Russell Broaddus
Journal: Journal of Clinical Oncology (2014)

5512 Background: Screening for Lynch Syndrome (LS) in endometrial cancer (EC) has traditionally been based on early age at diagnosis and family history. Universal tumor testing has been proposed given poor sensitivity of referral criteria and low referral rates. While immunohistochemistry (IHC) is cost effective and widely available, no prospective evaluation of concordance between screening strategies has been completed in EC to define the optimal approach. Our objective was to perform a prospective, population-based evaluation of universal tumor testing in EC to evaluate concordance between microsatellite instability (MSI) and IHC. Methods: MSI and IHC for expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) were performed prospectively on all EC undergoing surgical staging from August 2012 to August 2013 (n=184). PCR-based MLH1 methylation analysis was performed on tumors with IHC loss of MLH1. Results: Forty-five tumors (24.9%) were MSI-H and 50 tumors (27.2%) had loss of ≥1 MMR protein on IHC. Overall concordance between MSI analysis and IHC was 93.9% (CI 89.4 – 96.9); however, 11 patients (6.1%) had discordant tumor studies. One of 45 MSI-H tumors (2.2%) had intact IHC for all 4 proteins and demonstrated MLH1 methylation. Five of 50 tumors (10.0%) with loss of ≥1 MMR protein on IHC were MS-stable (MSS). Three of these 5 tumors had heterogeneous loss of MLH1 and PMS2 and 1 tumor had complete loss of expression of MLH1 and PMS2. All 4 tumors had MLH1 methylation and presumed sporadic. One MSS tumor had isolated MSH6 loss and a confirmed germline mutation in MSH6. Five tumors (2.8%) were MSI-L, 4 of which had intact IHC. Of these 4, 2 had no germline mutation detected in MSH6, 1 had a variant of unknown significance (VUS) in MSH6, and one did not undergo germline testing. One MSI-L tumor had loss of MLH1 and PMS2, with MLH1 methylation. Conclusions: Overall concordance between MSI and IHC was high in this prospective EC population. However, 6.1% of patients had discordant tumor studies and 2 of 5 patients without MLH1 methylation had a confirmed germline mutation or VUS. Heterogeneous loss of expression on IHC and MSI-L tumors present clinical caveats that are not well defined in EC and warrant further evaluation.
Views and experiences with regard to antibiotic use of hospitalized patients in five European countries: a qualitative descriptive study
Authors: V. Zanichelli, A.A. Monnier, G. Tebano, B.M. Stanić, I.C. Gyssens, C. Pulcini, V. Vlahović-Palčevski, M. Schindler, S. Harbarth, M. Hulscher, B.D. Huttner
Journal: Clinical Microbiology and Infection (2018)