tbuckley/cabot-search huggingface dataset:
Immune profiling of BRCA-mutated breast cancers.
Authors: Jeremy Meyer Force, Sarah Abbott, Gloria Broadwater, Ilona Stashko, Kelly E. Westbrook, Gretchen Genevieve Kimmick, Sarah LeNoir Sammons, Terry Hyslop, Heather Ann Brauer, Afshin Mashadi-Hossein, Jennifer Kay Plichta, Eun-Sil Shelley Hwang, Noah D. Kauff, Kent J. Weinhold, Smita Nair, Edgardo Castellar, Paul Kelly Marcom
Journal: Journal of Clinical Oncology (2018)

585 Background: Increased tumor infiltrating lymphocytes (TILs) are predictive and prognostic for improved outcomes in breast cancers. Increased tumor mutational burden can be immune activating. BRCA-mutated (BRCA+) breast cancers may have increased tumor mutational burden compared to BRCA wildtype (BRCA-). Immune system responses to BRCA+ breast cancers have not been well described. The primary aim of our study was to assess tumor infiltrating immune cells in early stage breast cancers with and without germline BRCA mutations. Methods: Here we report TILs and genomic profiling from our full study cohort. Assuming the %TILs in the BRCA- group was 20% we determined 124 early stage breast cancers with and without BRCA mutations was needed to detect a 20% difference in TILs between cohorts to attain 80% power with a one-side alpha of 0.05. We identified 124 early stage untreated breast cancers with BRCA mutations (n = 62) and without (n = 62). Our BRCA- control group were matched by hormone receptor (HR) status followed by age then stage. TILs were measured on pretreatment H&E slides. A NanoString BC360 panel was applied to RNA isolated from 80 breast cancers (BRCA+ = 39; BRCA- = 41). Results: Compared to BRCA- early stage breast cancers, median TILs were increased in the BRCA+ cohort (median 5 vs 10, p = 0.007). BRCA+/HR- samples did not have more TILs compared to BRCA-/HR- (median 10 vs 15, p = 0.10). BRCA+/HR+ had increased TILs compared to BRCA-/HR+ (median 1 vs 5, p = 0.005). An 18 gene RNA tumor immune score (TIS) moderately correlated with TILs (R2= 0.339, p < 0.001), was increased in BRCA+ cancers (p = 0.29), but was primarily elevated in those with a basal-like phenotype (p < 0.001). Conclusions: Early stage BRCA+ breast cancers have increased TILs compared to BRCA-. TILs are significantly more abundant in BRCA+/HR+ breast cancers, which might be explained by an increased basal-like phenotype. TIS moderately correlates with TILs. TIS is increased in BRCA+ breast cancers, but reaches significance in the basal-like phenotype. Many BRCA+/HR+ cancers with luminal phenotypes had increased TILs and elevated TIS. To guide development of immunomodulating therapies in BRCA+ cancers, further immune analyses should be investigated in hereditary breast cancers and compared to sporadic cancers.
<i>TMPRSS2-ERG</i> Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in <i>PTEN</i> and <i>TP53</i>-Mutated Prostate Cancer
Authors: Alexandra M. Blee, Yundong He, Yinhui Yang, Zhenqing Ye, Yuqian Yan, Yunqian Pan, Tao Ma, Joseph Dugdale, Emily Kuehn, Manish Kohli, Rafael Jimenez, Yu Chen, Wanhai Xu, Liguo Wang, Haojie Huang
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Deletions or mutations in PTEN and TP53 tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor ERG is observed in approximately 50% of all prostate cancers, many of which also harbor PTEN and TP53 alterations. However, the role of ERG in lineage plasticity of PTEN/TP53–altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance. Experimental Design: We generated a Pten-negative/Trp53-mutated/ERG-overexpressing mouse model of prostate cancer and integrated RNA-sequencing with ERG chromatin immunoprecipitation-sequencing (ChIP-seq) to identify pathways regulated by ERG in the context of Pten/Trp53 alteration. We investigated ERG-dependent sensitivity to the antiandrogen enzalutamide and cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib in human prostate cancer cell lines, xenografts, and allografted mouse tumors. Trends were evaluated in TCGA, SU2C, and Beltran 2016 published patient cohorts and a human tissue microarray. Results: Transgenic ERG expression in mice blocked Pten/Trp53 alteration–induced decrease of AR expression and downstream luminal epithelial genes. ERG directly suppressed expression of cell cycle–related genes, which induced RB hypophosphorylation and repressed E2F1-mediated expression of mesenchymal lineage regulators, thereby restricting adenocarcinoma plasticity and maintaining antiandrogen sensitivity. In ERG-negative tumors, CDK4/6 inhibition delayed tumor growth. Conclusions: Our studies identify a previously undefined function of ERG to restrict lineage plasticity and maintain antiandrogen sensitivity in PTEN/TP53–altered prostate cancer. Our findings suggest ERG fusion as a biomarker to guide treatment of PTEN/TP53-altered, RB1-intact prostate cancer. Clin Cancer Res; 24(18); 4551–65. ©2018 AACR.
Anesthesia Care Handovers and Risk of Adverse Outcomes—Reply
Authors: Philip M. Jones, Salimah Z. Shariff, Duminda N. Wijeysundera
Journal: JAMA (2018)

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Endogenous and Exogenous Opioids in Pain
Authors: Gregory Corder, Daniel C. Castro, Michael R. Bruchas, Grégory Scherrer
Journal: Annual Review of Neuroscience (2018)

Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein-coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (β-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system. We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.
Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function
Authors: Benjamin Lazarus, Aozhou Wu, Jung-Im Shin, Yingying Sang, G. Caleb Alexander, Alex Secora, Lesley A. Inker, Josef Coresh, Alex R. Chang, Morgan E. Grams
Journal: JAMA Internal Medicine (2018)

Approximately 1 million patients in the United States with type 2 diabetes mellitus and mild-to-moderate kidney disease do not receive guideline-directed therapy with metformin. This may reflect uncertainty regarding the risk of acidosis in patients with chronic kidney disease.
Fulvestrant efficacy in artificial menopausal hormone receptor positive and HER 2 negative metastatic breast cancer patients under 50 years old.
Authors: Caglayan Geredeli, Sener Cihan, Nurgul Yasar, Abdullah Sakin, Orcun Can, Şaban Seçmeler, Serdar Arıcı, Cumhur Demir
Journal: Journal of Clinical Oncology (2018)

e13000 Background: This study investigated the efficacy of fulvestrant in premenopausal patients with metastatic breast cancer who developed artificial menopause using a luteinizing hormone releasing hormone analogue. Methods: This retrospective study was conducted at the Istanbul Okmeydani Education and Research Hospital. Those patients receiving 3.6 mg of goserelin acetate for 28 days and 500 mg of intramuscular fulvestrant for 28 days were included. Results: A total of 37 patients were evaluated, with a median age of 39 years old (range 27–49) and a median follow-up time of 20 months (0–78). The estrogen receptor positivity was 83.8%, and the progesterone receptor positivity was 86.5%. Of these patients, 86.5% had invasive ductal carcinoma, 5.4% had invasive lobular carcinoma, and 8.1% had other histological types. Bone metastasis was found in 83.8% of the patients, lung metastasis in 21.6%, lymph node metastasis in 16.2%, liver metastasis in 13.5%, and brain metastasis in 5.4%. On average, the fulvestrant series number was 2.4 (min 1, max 4), and the mean fulvestrant cure number was 12.3 (min 1, max 38). Beforehand, 83.8% of the patients used hormonal therapy. The progression-free survival (PFS) was a median of 12 months after starting the fulvestrant; it was 51.6% at 12 months, 32.9% at 24 months, and 20.5% at 36 months. The PFS was relatively shorter in those with brain metastases, but there was no statistically significant difference. The median PFS was 12 months in 2 series and 8 months in 3 and later series, which was statistically significant (p = 0.025). The overall survival (OS) was a median of 77 months; it was 86% at 12 months, 63% at 36 months, and 56% at 60 months. The median OS of the 2nd line was 20 months. No grade 3-4 toxic effects were observed. Conclusions: As in naturally postmenopausal patients, fulvestrant was found to be effective and tolerable in patients treated with artificial menopausal hormone receptor-positive metastatic breast cancer under the age of 50. The fulvestrant was more effective in those who did not previously receive hormonal therapy.
Efficacy and safety of sofosbuvir plus ribavirin for Korean patients with hepatitis C virus genotype 2 infection: A retrospective multi-institutional study
Authors: Young Min Kim, Suk Bae Kim, Il Han Song, Sae Hwan Lee, Hong Soo Kim, Tae Hee Lee, Young Woo Kang, Seok Hyun Kim, Byung Seok Lee, Hee Bok Chae, Myeong Jun Song, Ji Woong Jang, Soon Young Ko, Jae Dong Lee
Journal: Clinical and Molecular Hepatology (2018)

Sofosbuvir plus ribavirin is a standard treatment for patients infected with chronic hepatitis C virus (HCV) genotype 2 in Korea. The purpose of this study was to examine the efficacy and safety of this treatment in Korean patients with chronic HCV genotype 2 infection.
What is the risk‐benefit ratio of long‐term antipsychotic treatment in people with schizophrenia?
Authors: Christoph U. Correll, Jose M. Rubio, John M. Kane
Journal: World Psychiatry (2018)

The long‐term benefit‐to‐risk ratio of sustained antipsychotic treatment for schizophrenia has recently been questioned. In this paper, we critically examine the literature on the long‐term efficacy and effectiveness of this treatment. We also review the evidence on the undesired effects, the impact on physical morbidity and mortality, as well as the neurobiological correlates of chronic exposure to antipsychotics. Finally, we summarize factors that affect the risk‐benefit ratio. There is consistent evidence supporting the efficacy of antipsychotics in the short term and mid term following stabilization of acute psychotic symptoms. There is insufficient evidence supporting the notion that this effect changes in the long term. Most, but not all, of the long‐term cohort studies find a decrease in efficacy during chronic treatment with antipsychotics. However, these results are inconclusive, given the extensive risk of bias, including increasing non‐adherence. On the other hand, long‐term studies based on national registries, which have lower risk of bias, find an advantage in terms of effectiveness during sustained antipsychotic treatment. Sustained antipsychotic treatment has been also consistently associated with lower mortality in people with schizophrenia compared to no antipsychotic treatment. Nevertheless, chronic antipsychotic use is associated with metabolic disturbance and tardive dyskinesia. The latter is the clearest undesired clinical consequence of brain functioning as a potential result of chronic antipsychotic exposure, likely from dopaminergic hypersensitivity, without otherwise clear evidence of other irreversible neurobiological changes. Adjunctive psychosocial interventions seem critical for achieving recovery. However, overall, the current literature does not support the safe reduction of antipsychotic dosages by 50% or more in stabilized individuals receiving adjunctive psychosocial interventions. In conclusion, the critical appraisal of the literature indicates that, although chronic antipsychotic use can be associated with undesirable neurologic and metabolic side effects, the evidence supporting its long‐term efficacy and effectiveness, including impact on life expectancy, outweighs the evidence against this practice, overall indicating a favorable benefit‐to‐risk ratio. However, the finding that a minority of individuals diagnosed initially with schizophrenia appear to be relapse free for long periods, despite absence of sustained antipsychotic treatment, calls for further research on patient‐level predictors of positive outcomes in people with an initial psychotic presentation.
Endoscopic submucosal dissection for large protruding colorectal neoplasms: it still is a challenging procedure!
Authors: Eun-Jung Lee
Journal: Endoscopy (2018)

See also: Short-term outcomes following endoscopic submucosal dissection of large protruding colorectal neoplasmsEndoscopy eFirstDOI: 10.1055/s-0043-123578
Re: Effectiveness of and overdiagnosis from mammography screening in the Netherlands : Population based study
Authors: Sabine Siesling, Linda de Munck
Journal: BMJ (2017)

Objective: To analyse stage specific incidence of breast cancer in the Netherlands where women have been invited to biennial mammography screening since 1989 (ages 50-69) and 1997 (ages 70-75), and to assess changes in breast cancer mortality and quantified overdiagnosis. Design: Population based study. Setting: Mammography screening programme, the Netherlands. Participants: Dutch women of all ages, 1989 to 2012. Main outcome measures: Stage specific age adjusted incidence of breast cancer from 1989 to 2012. The extra numbers of in situ and stage 1 breast tumours associated with screening were estimated by comparing rates in women aged 50-74 with those in age groups not invited to screening. Overdiagnosis was estimated after subtraction of the lead time cancers. Breast cancer mortality reductions during 2010-12 and overdiagnosis during 2009-11 were computed without (scenario 1) and with (scenario 2) a cohort effect on mortality secular trends. Results: The incidence of stage 2-4 breast cancers in women aged 50 or more was 168 per 100 000 in 1989 and 166 per 100 000 in 2012. Screening would be associated with a 5% mortality reduction in scenario 1 and with no influence on mortality in scenario 2. In both scenarios, improved treatments would be associated with 28% reductions in mortality. Overdiagnosis has steadily increased over time with the extension of screening to women aged 70-75 and with the introduction of digital mammography. After deduction of clinical lead time cancers, 32% of cancers found in women invited to screening in 2010-12 and 52% of screen detected cancers would be overdiagnosed. Conclusions: The Dutch mammography screening programme seems to have little impact on the burden of advanced breast cancers, which suggests a marginal effect on breast cancer mortality. About half of screen detected breast cancers would represent overdiagnosis.
Leveraging the electronic health record (EHR) to support survivorship care planning for bone marrow transplant (BMT) survivors.
Authors: Mandy Swiecichowski, Amye Tevaarwerk, Mark Juckett, James Edward Haine, Kirsten Norslien, Jessica Becher, Bethaney Campbell, Eneida Mendonca, Mary Sesto
Journal: Journal of Clinical Oncology (2018)

57 Background: BMT survivors are underrepresented in survivorship research, yet are at high risk for complications. Practice guidelines are vague, non-BMT clinicians are inadequately informed, and communication between BMT and non-BMT clinicians is inconsistent. Our objective is to develop EHR-integrated survivorship care planning that is user-centered, supports non-BMT clinician and survivor needs, but does not adversely impact clinical workflow. Methods: A multidisciplinary team of clinicians (primary care, oncology, BMT), engineers, and EHR analysts used a systems engineering approach to identify barriers and facilitators to BMT survivorship care planning. The team identified patient data categories to include in BMT survivorship care plan (SCP) templates, as well as examined tasks, technology, workflows and individual roles and responsibilities necessary to support care planning. Results: Facilitators include: potential for EHR to discretely capture individual diagnosis and treatment data to create accurate SCPs addressing survivor and primary care information needs. Barriers are: lack of EHR inter-operability which prevents sharing of patient data outside the BMT center’s EHR system, reliance on manual entry of critical data elements into the SCP (i.e. majority of the 88 patient data categories, identified by the team, are non-discrete in the EHR), inefficient or absent survivorship workflows, lack of resources (including time, dedicated clinical staff, space, SCP content), poorly defined roles and responsibilities for survivorship care provision, and lack of evidence-based BMT survivorship guidelines. Conclusions: Work system barriers impede use of the EHR to support survivorship care planning. Steps to overcome barriers: design discrete fields in the EHR to support patient-level data capture, re-engineer existing workflows to support survivorship care planning, obtain BMT program consensus on SCP content, and evaluate user-centeredness of SCPs. This research has the potential to improve feasibility and sustainability of survivorship care planning activities, resulting in improved communication and care coordination for BMT survivors.
Polymorphisms within the Toll-like receptor 4 (TLR4) gene are associated with HBeAg-negative status and spontaneous HBsAg seroconversion in females with chronic hepatitis B virus (HBV) infections
Authors: Eleni Koukoulioti, Janett Fischer, Stephan Bohm, Balazs Fueloep, Eckart Schott, Renate Heyne, Thomas Berg, Florian van Bommel
Journal: Hepatology (2016)
Fabrication and application of supine MRI-based 3D brest surgical guide for precise breast conserving surgery in breast cancer patients.
Authors: Beomseok Ko, Sae Byul Lee, jong Won Lee, hee Jeong Kim, Sung-Bae Kim, Hak-Hee Kim, Gyungyub Gong, Sangwook Lee, Kim Namkug, Sei-Hyun Ahn, Byung Ho Sohn
Journal: Journal of Clinical Oncology (2018)

e12612 Background: It is known that the accuracy magnetic Resonance Imaging (MRI) is higher than that of mammography or ultrasound in confirming the area of breast cancer. However, using conventional methods, it is difficult to mark the area of the tumor observed on MRI in the breast. We have developed a breast surgical guide that can mark a range of tumor directly on the breast using three-dimensional printing technology based on supine MRI. This study analyzed the results of patients who underwent BCS using a 3D printing breast surgical guide (3D-BSG) based on supine MRI. Methods: From MRI images, morphological shapes of breasts and tumors were modeled. The prepared digital model was saved in stereolithography file format and then exported to a 3D printer. 3D-BSG is designed to be able to mark the skin and attach the dye injecting column to mark the around the tumor. To obtain tumor free margin, intraoperative frozen sections were identified in several cavities and re-excision was performed if tumor positive. Results: During July 2017 to January 2018, 49 patients were enrolled, and one patient had bilateral breast cancer and BSG was applied in 50 cases. Most tumors (90%) were removed with adequate surgical margin. In five cases, tumor was positive in resection margin from frozen biopsy performed during surgery, all of which were DCIS. In this case, re-excision was performed and there was no conversion to mastectomy. The final pathologic result was tumor negative in margin. The median size of the long axis of the tumor was 1.5 cm (range, 0.5 to 6.5 cm) and the median size of the long axis of the removed breast tissue was 5.3 cm (range, 1.5 to 11.5 cm). The distance between tumor and resection margin was 1.2 cm (range, 0.1 to 7.0 cm). Conclusions: In BCS, the application of the supine MRI based 3D-BSG showed low rates of positive margins. Unlike conventional localization techniques, application of 3D-BSG does not cause pain to the patient, has no radiation exposure, and has no time required for the localization procedure, so it is expected that its application will increase in the future. Clinical trial information: KCT0002375.
PADA-1: A randomized, open label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with hormone therapy driven by circulating DNA <i>ESR1</i> mutation monitoring in ER-positive, HER2-negative metastatic breast cancer patients.
Authors: Francois Clement Bidard, Renaud Sabatier, Frederique Berger, Barbara Pistilli, Florence Dalenc, Thibault De La Motte Rouge, Jean-Sebastien Frenel, Coraline Dubot, Sylvain Ladoire, Jean-Marc Ferrero, Laetitia Stefani, Alain Lortholary, Anne-Claire Hardy-Bessard, Julien Grenier, Sibille Everhard, Emmanuelle Jeannot, Charlotte Proudhon, Jérôme Lemonnier, Suzette Delaloge, Thomas Denis Bachelot
Journal: Journal of Clinical Oncology (2018)

TPS1105 Background: Palbociclib (Pal) combined with an aromatase inhibitor (AI) is a standard of care as first line therapy in estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). The efficacy of Pal+AI may be however limited by the onset of ESR1 mutations during therapy as a mechanism of resistance to AI, while pre-clinical and retrospective clinical data suggest that ESR1-mutated clones remain sensitive to fulvestrant (Ful). Rising ESR1 mutation levels might be detected in ctDNA several months before actual tumor progression. This clinical utility trial tests whether switching from AI-Pal to Ful-Pal after the onset of rising ESR1 mutations will turn into a clinical benefit for patients; the safety of these treatments will also be evaluated. Methods: Main inclusion criteria are patients with ER+ HER2-MBC with no prior systemic treatment for metastatic disease, no visceral crisis and theoretical AI-sensitivity. In the first step, all patients (N=800) are treated with Pal+AI; ESR1 mutations in ctDNA are tracked by ddPCR (targeting E380, L536, Y537 and D538 ER hotspots) at baseline, after 1 cycle of treatment and then every other cycle. Upon the detection of rising ESR1 mutation(s) in blood, patients without RECIST tumor progression proceed to the second step and are randomized (1:1) between the continuation of the same regimen or a switch to Pal+Ful. In a third step, patients that were randomized in standard regimen arm may crossover to Pal+Ful following tumor progression. The co-primary objectives of this ethically approved trial (NCT03079011), conducted in France by UCBG with GINECO, are (i) treatment safety (steps 1 to 3) and (ii) PFS in the two treatment arms (step 2). The 1st patient was included in March 2017; as of January 2018, 426 patients have been included. Clinical trial information: NCT03079011.