tbuckley/cabot-search huggingface dataset:
Advancing into the details of pulmonary haemodynamics during exercise
Authors: Gabor Kovacs, Horst Olschewski
Journal: European Respiratory Journal (2018)

Pulmonary haemodynamics during exercise may help us to understand why patients are severely limited despite relatively moderate pathological findings at rest. Recently, a European Respiratory Society task force presented the expert consensus on clinical experience and published studies over the past 50 years in this field [1], and suggested a definition of "exercise pulmonary hypertension" (exercise PH). In contrast to previous guidelines [2], this expert statement does not consider an isolated increase of mean pulmonary arterial pressure (MPAP) over a certain threshold during exercise as pathological. Instead, "exercise PH" is characterised by an excessive increase of MPAP in relation to the increase in pulmonary blood flow during exercise. Recent clinical studies allow better understanding of changes in pulmonary haemodynamics during exercise in different disease entities <http://ow.ly/129o30lwHP2>
End of life care for oncology patients in a community academic setting.
Authors: Ryan Mayo, Usman Shah
Journal: Journal of Clinical Oncology (2018)

e22010 Background: Multicenter quality studies have shown that earlier end of life discussions and palliative care can lead to better outcomes for oncology patients including improved quality of life, improved quantity of life and easier bereavement adjustment for the family. End of life (EOL) metrics in the last 30 days of life are a critical component of the CMS MIPS program in oncology. Methods: Using our electronic medical record, 2217 cases of deaths of cancer patients in 2016 were compiled. Of these, the most common primary site cases were reviewed to determine if the patient died from cancer and analyzed for multiple EOL metrics. These included primary malignancies of brain, breast, esophageal, gastric, pancreatic, rectum, and melanoma. Results: 499 patients who died from cancer were evaluable. In the last 30 days of life, 308 (61%) of the patients were admitted to the hospital, 308 (62%) were seen in the ED, 127 (25%) were admitted to the ICU, and 90 died in an inpatient setting (18%). 11 patients (2%) received chemotherapy in the last 14 days of life. 388 (78%) patients were referred to palliative care (PC) while 114 patients (23%) did not receive hospice services before death. Of patients referred to PC, 388 were evaluable at the end of life and EOL metrics were similar to 111 patients not seen by PC. Patients referred to PC were stratified by time from referral to death. 189 patients were referred 30 days or less before death: rates of hospitalization, ED visits, ICU admission and hospice < 3 days were 88%, 87%, 40% and 22% respectively. 27% of patients were not admitted to hospice services. Of 199 patients who were referred greater than 30 days before death, rates of hospitalization, ED visits, ICU admission and hospice < 3 days were 42%, 43%, and 13% and 11% respectively. 14% of patients were not admitted to hospice services. Conclusions: Our health network has a high percentage of patient’s who are receiving PC and then hospice services at the end of life. The data suggests that EOL metrics do not positively correlate with PC referral and evaluation. However, increased time from PC referral to death did correlate with improved EOL metrics. Early PC referral in the course of therapy is likely to decrease aggressive intensive care in the last 30 days of life.
Association of circulating tumor DNA clearance during treatment with improved progression-free survival in advanced non-small cell lung cancer patients.
Authors: Shun Lu, Yong Song, Zhanhong Xie, Min Li, Zhengfei Zhu, LI LIU, Xiaorong Dong, Yuan Chen, Di Zheng, Weixin Zhao, Jian Hua Chang, Meiling Jin, Jie Hu, Gangling Tong, Chuangzhou Rao, Haiyan Xu, Lu Zhang, Xinru Mao, Han Han-Zhang, Hao Liu
Journal: Journal of Clinical Oncology (2017)

11528 Background: Currently, response assessment of patients with non-small cell lung cancer (NSCLC) primarily relies on imaging scans, which do not reflect biological processes at the molecular level. We utilized circulating tumor DNA (ctDNA) coupled with capture-based ultra deep next generation sequencing to conduct dynamic monitoring of treatment response, thus evaluating the ability of ctDNA as a tumor clonal response biomarker. Methods: We performed capture-based sequencing on longitudinal plasma samples, including baseline and a minimum of 2 evaluation points, obtained from 88 patients with advanced NSCLC using a ctDNA panel, spanning 160KB of human genome and consisting of critical exons and introns from 168 genes. This real world study comprises a highly heterogeneous cohort with a mixture of prior treatment exposure. Results: At baseline, treatment-naïve patients often harbor solo driver mutation; in contrast, patients with prior treatments are more likely to harbor concurrent driver mutations. Patients who received molecular targeted therapy according to the baseline sequencing results have a longer progression-free survival (PFS) (p = 0.0001), demonstrating the value of ctDNA in directing treatment. During subsequent evaluations, we observed 74% concordance rate between molecular and radiographic responses. Furthermore, our data revealed that during follow-up, patients with at least one time of undetectable ctDNA are associated with a longer PFS (p = 5.52e -6 ), regardless the type of treatment commenced. Among 44 patients who had at least one time of undetectable ctDNA, 39 achieved partial response or stable disease as their best response. Collectively, this phenomenon reflects clonal response, thus demonstrating the biological nature underlying the clinical response assessed by imaging modalities. Conclusions: This real world study demonstrates that patients with at least one time of ctDNA clearance during subsequent evaluation are associated with a longer PFS. Our study warrants further investigations to explore the value of ctDNA clearance as a surrogate endpoint of efficacy and as a risk stratification factor.
Human Papillomavirus Testing in Head and Neck Carcinomas: ASCO Clinical Practice Guideline Endorsement of the College of American Pathologists Guideline
Authors: Carole Fakhry, Christina Lacchetti, Lisa M. Rooper, Richard C. Jordan, Danny Rischin, Erich M. Sturgis, Diana Bell, Mark W. Lingen, Seema Harichand-Herdt, John Thibo, Jose Zevallos, Bayardo Perez-Ordonez
Journal: Journal of Clinical Oncology (2018)

The College of American Pathologists produced an evidence-based guideline on testing, application, interpretation, and reporting of human papillomavirus (HPV) and surrogate marker tests in head and neck carcinomas that was determined to be relevant to the American Society of Clinical Oncology (ASCO) membership.The College of American Pathologists HPV Testing in Head and Neck Carcinomas guideline was reviewed by ASCO content experts for clinical accuracy and by methodologists for developmental rigor. On favorable review, an ASCO Expert Panel was convened to review the guideline contents and recommendations.The ASCO Expert Panel determined that the recommendations from the HPV Testing in Head and Neck Carcinomas guideline, published in 2018, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the guideline and added minor qualifying statements.It is recommended that HPV tumor status should be determined for newly diagnosed oropharyngeal squamous cell carcinomas. HPV tumor status testing may be performed by surrogate marker p16 immunohistochemistry either on the primary tumor or from cervical nodal metastases only if an oropharyngeal primary tumor is present. The threshold for positivity is at least 70% nuclear and cytoplasmic expression with at least moderate to strong intensity. Additional confirmatory testing may be done at the discretion of the pathologist and/or treating clinician. Pathologists should not routinely determine HPV tumor status in nonsquamous carcinomas of the oropharynx or non-oropharyngeal squamous cell carcinomas of the head and neck. When there is uncertainty of histologic type or whether a poorly differentiated oropharyngeal tumor is nonsquamous, HPV tumor status testing may be warranted and at the discretion of the pathologist and/or treating clinician. Additional information is available at: www.asco.org/head-neck-cancer-guidelines .
Development and validation of a risk assessment tool for symptomatic BKV infection.
Authors: Ala Abudayyeh, Maen Abdelrahim, Heather Y. Lin, Valda D Page, Gabriela Rondon, Borje Andersson, Charles Martinez, Jeffery Tarrand, Dimitrios P Kontoyiannis, David Marin, A.Osama Gaber, Betul Oran, Roy Chemaly, Amanda Leigh Olson, Roy B. Jones, Uday R. Popat, Elizabeth J. Shpall, Katayoun Rezvani
Journal: Journal of Clinical Oncology (2018)

7057 Background: BKV, is a member of the family Polyomaviridae. BKV has been associated with increased morbidity and mortality secondary to late hemorrhagic cystitis, ureteral stenosis, and nephropathy. In our retrospective published study of 2477 SCT patients, 38.1% had developed renal impairment, and BKV viruria was present in 25%. In addition, BKV was found to be an independent predictor of chronic kidney disease and poor survival. Using the same cohort we derived a risk grading system to quantify risk of symptomatic BKV without having to use a complex statistical model and further validated it with another retrospective cohort of 442 allogeneic SCT patients. We hypothesize that our risk grading system will accurately identify the patients at risk of symptomatic BKV at day 30 post allogeneic stem cell transplant. Methods: Using the three variables (conditioning regimen, HLA donor status, & underlying cancer diagnosis) that were significant predictors for symptomatic BKV derived from our initial study, we developed a risk scoring system, using the methods described by Sullivan and colleagues. A nomogram of the sub distribution hazard model with death as a competing risk was constructed as a visualizing aid to obtain predicted probability of BK infection manually. We further stratified the patients based on their risk score into low, moderate, and high risk using 33th percentile of the risk score as the cutoff point, and into low and high risk using 99th percentile of the risk score as the cutoff points Results: The risk score was significantly associated with symptomatic BKV (P < 0.0001). Specifically, at 30-days post STC, the Low risk (≤7) patients had 9% chance of developing symptomatic BKV, while the high risk top 1% ( 9 patients) of the population had 56% of developing symptomatic BKV. This was confirmed in the cohort of 442 allogeneic SCT patients. Conclusions: We have created and validated a grading system for symptomatic BKV to predict risk at day 30 post allogeneic SCT. Using this grading system we would hope to identify high risk patients for BKV and treat prophylactically using BKV Cytotoxic T cell therapies and prevent reactivation which is highly associated with increased morbidity, mortality, and kidney function decline.
Activity of targeted therapy after failure of first-line immunotherapy in BRAF-mutant metastatic melanoma.
Authors: Cathy Yi Xia, Daniel Ying Wang, Robert Mason, Jessica Louise Smith, Meredith Ann McKean, Serigne Lo, Alexander David Guminski, Georgina V. Long, Matteo S. Carlino, Victoria Atkinson, Michael Millward, Jennifer Leigh McQuade, Rodabe Navroze Amaria, Douglas Buckner Johnson, Alexander M. Menzies
Journal: Journal of Clinical Oncology (2018)

9532 Background: There are limited data regarding the best sequence of targeted and immunotherapy in patients (pts) with BRAF-mutant melanoma. Some studies suggest lower activity of immunotherapy after BRAF/MEK inhibitors (BRAF/MEKi), but there are no data examining BRAF/MEKi after immunotherapy. Methods: Consecutive patients with BRAF-mutant metastatic melanoma from 6 centers treated with 1 or more lines of immunotherapy then subsequent BRAF/MEKi were identified. Disease characteristics, treatment details, RECIST response and survival data were retrospectively examined. If pts ceased BRAF/MEKi for toxicity prior to first response assessment, response was deemed progressive disease (PD). Results: 79 pts were included, with V600E (85%), V600K (13%), V600M (1%) and V600R (1%) mutations. 56% pts were treated with first-line ipilimumab, 21% with PD1 antibodies, 15% with combination ipilimumab/nivolumab, and 5% with other PD1 combinations. Median duration of immunotherapy was 10.9 weeks, and best response was partial response (PR) in 11%, stable disease (SD) in 17%, and PD in 72% pts. 20% of pts had 1 or more further lines of systemic treatment prior to BRAF/MEKi. At commencement of BRAF/MEKi, median age was 60 years, 68% were stage M1c, 25% had brain metastases, 57% had elevated LDH, 24% were ECOG 2/3. Median interval from last dose of immunotherapy was 6 weeks. 55 (70%) pts received combination BRAF+MEKi, 22 (28%) BRAFi alone, and 2 (3%) MEKi alone. 10/79 (13%) pts ceased BRAF/MEKi due to toxicity, 2 prior to first response, and median treatment duration was 21 weeks. 59% pts had a RECIST response (5% CR), 11% had SD and 29% had PD. Median PFS was 4.4 months (3.5 - 6.2). 65% pts had subsequent treatment, including PD1 antibodies in 50%. Median OS from BRAF/MEKi commencement was 18.0 months (14.6 - 40.3), and 39% were alive at 3 years. In the 35 (44%) pts that had received prior PD1 antibodies, the response rate was 66%, median PFS 4.1 months (2.4 - 6.8) and median OS 13.6 months (10.2 – NR). Conclusions: BRAF/MEKi have efficacy in pts previously treated with immunotherapy. Despite pts having more adverse disease characteristics than seen in first line trials, response rates may be similar, however PFS appears shorter.
Characterization of immune related hepatitis (irH) from immune checkpoint inhibitors (ICIs).
Authors: Justine Vanessa Cohen, Joseph Misdraji, Michael Dougan, Riley Fadden, Krista M. Rubin, Aleigha Lawless, Kerry Lynn Reynolds, Donald P. Lawrence, Meghan Mooradian, Keith Flaherty, Ryan J. Sullivan
Journal: Journal of Clinical Oncology (2018)

3087 Background: Immune related hepatitis (irH) occurs in a subset of patients receiving ICIs. Although the pathologic features of irH have been described, no studies have correlated the histologic findings on liver biopsy with steroid responsiveness. Methods: 25 patients with cancer (22 melanoma, 1 cutaneous squamous cell carcinoma, 1 glioblastoma, 1 non-small cell lung cancer) who had a liver biopsy for elevated transaminases were included. 23 patients received anti-PD1, anti-CTLA4 or a combination of ICI with a non-ICI agent. 2 patients underwent biopsies after targeted therapy. Liver biopsies were reviewed for pattern of injury. Steroid response and requirement for secondary immunosuppression was determined from clinical notes. The pattern of hepatic injury was correlated with response to steroids. Results: 15 biopsies showed evidence of lobular injury that was often centrizonal, but in some was panlobular, with a histiocytic inflammatory response. In 6, the histiocytes formed granulomas that were loose, well-formed, or fibrin ring type. 5 of the 15 had central vein endothelialitis. Another 3 patients had mild lobular or portal inflammation without typical features of irH. 2 patients had cholestatic patterns, with portal edema, duct injury, or pericholangitis. 2 had fatty liver disease. 3 remaining patients had non-inflammatory patterns of hepatocyte injury such as hepatocyte cytoplasmic rarefaction. 19 (76%) patients required steroids and 6 (24%) required secondary immunosuppression. 11 (73%) of the 15 cases with characteristic irH were steroid responsive (resolution of transaminitis with < 2 months). The 2 cholestatic cases were less responsive to steroids (one required > 2 months of steroids and the other required secondary immunosuppression). Patients with fatty liver and non-inflammatory injury had variable response to steroids. Conclusions: ICI hepatitis has a characteristic pattern of lobular injury with histiocytic infiltration, granuloma formation, and endothelialitis on liver biopsy is highly likely to be steroid responsive. A cholestatic pattern of injury predicts less steroid responsiveness. Non-inflammatory hepatic injury on liver biopsy has variable steroid responsiveness.
Allogeneic transplantation for advanced acute myelogenous leukemia: The value of complete remission.
Authors: Daniel Jordan Weisdorf, Heather R Millard, Mary M. Horowitz, Mary Eapen, Parvinder Hyare, Renee Ward, Hanna Jean Khoury, Marcos J.G. De Lima, Brenda M. Sandmaier, Mei-Jie Zhang
Journal: Journal of Clinical Oncology (2016)

7033 Background: Patients with AML failing to achieve complete remission (CR) or in first relapse (Rel1) can have extended leukemia control and survival following allogeneic hematopoietic cell transplantation (HCT). Transplantation in primary induction failure (PIF) or Rel1 versus additional treatment to achieve CR2 and thereafter HCT might yield similar outcomes, but modern data addressing this question is scarce. Methods: We studied patients who proceed to HCT, analyzing comparative survival by disease status: PIF (N = 1440), REL1 (N = 1256) and CR2 (N = 1986) in 2000 – 2013 and median follow up of 5 years. Results: Age, gender, donor, graft type, conditioning intensity and GVHD prophylaxis were similar in the three groups. CR2 patients were more likely to report performance scores of 90 or 100, de novo AML and longer duration CR1. Adverse cytogenetics was more common in PIF patients and duration of CR1 was shorter in REL1 than CR2. Mortality was higher for HCT in Rel1 compared to CR2 regardless of CR1 duration (RR 1.65, p < 0.0001). Similarly, mortality was higher for HCT in PIF compared to CR2 with CR1 duration < 6 (RR 1.26, p < 0.0001), 6-12 (RR 1.60, p < 0.0001) and > 12 months (RR 2.24, p < 0.0001). However, comparing PIF to Rel1, mortality was higher for HCTs in PIF compared to Rel1 with duration of CR1 > 12 months (RR 1.36, p < 0.0001) but not for Rel1 with duration of CR1 6-12 months. Mortality was lower for HCTs in PIF compared to Rel1 with duration of CR1 < 6 months (RR 0.76, p < 0.0001). The probabilities of overall survival by disease status, and adjusted for age, performance score, cytogenetic risk and donor type, the other factors associated with mortality risks are: 6 months: CR2 73 (71-75)%; REL1 53 (50-55)%; PIF 58 (56-61)% and at 2 years, CR2 50 (48-52)%; REL1 27 (24-29)%; PIF 29 (27-32)%. Conclusions: These data demonstrate superior survival for HCT in CR2 than either in REL1 or PIF. Yet HCT for selected patients in PIF or REL1 may still be valuable. These data can guide decision-making about the utility of additional salvage therapy vs. prompt HCT, even for patients not in CR, but should note intrinsically more treatable AML with favorable risk cytogenetics, longer CR1 duration and younger patients with better performance score.
Outcomes Among Patients With Atrial Fibrillation and Appropriate Anticoagulation Control
Authors: Anders Nissen Bonde, Laila Staerk, Christina J-Y. Lee, Naja Emborg Vinding, Casper N. Bang, Christian Torp-Pedersen, Gunnar Gislason, Gregory Y.H. Lip, Jonas Bjerring Olesen
Journal: Journal of the American College of Cardiology (2018)
Macrophage Inflammation, Erythrophagocytosis, and Accelerated Atherosclerosis in <i>Jak2</i> <sup> <i>V617F</i> </sup> Mice
Authors: Wei Wang, Wenli Liu, Trevor Fidler, Ying Wang, Yang Tang, Brittany Woods, Carrie Welch, Bishuang Cai, Carlos Silvestre-Roig, Ding Ai, Yong-Guang Yang, Andres Hidalgo, Oliver Soehnlein, Ira Tabas, Ross L. Levine, Alan R. Tall, Nan Wang
Journal: Circulation Research (2018)

The mechanisms driving atherothrombotic risk in individuals with JAK2 V617F ( Jak2 VF) positive clonal hematopoiesis or myeloproliferative neoplasms are poorly understood.The goal of this study was to assess atherosclerosis and underlying mechanisms in hypercholesterolemic mice with hematopoietic Jak2 VF expression.Irradiated low-density lipoprotein receptor knockout ( Ldlr-/-) mice were transplanted with bone marrow from wild-type or Jak2 VF mice and fed a high-fat high-cholesterol Western diet. Hematopoietic functions and atherosclerosis were characterized. After 7 weeks of Western diet, Jak2 VF mice showed increased atherosclerosis. Early atherosclerotic lesions showed increased neutrophil adhesion and content, correlating with lesion size. After 12 weeks of Western diet, Jak2 VF lesions showed increased complexity, with larger necrotic cores, defective efferocytosis, prominent iron deposition, and costaining of erythrocytes and macrophages, suggesting erythrophagocytosis. Jak2 VF erythrocytes were more susceptible to phagocytosis by wild-type macrophages and showed decreased surface expression of CD47, a "don't-eat-me" signal. Human JAK2VF erythrocytes were also more susceptible to erythrophagocytosis. Jak2 VF macrophages displayed increased expression and production of proinflammatory cytokines and chemokines, prominent inflammasome activation, increased p38 MAPK (mitogen-activated protein kinase) signaling, and reduced levels of MerTK (c-Mer tyrosine kinase), a key molecule mediating efferocytosis. Increased erythrophagocytosis also suppressed efferocytosis.Hematopoietic Jak2 VF expression promotes early lesion formation and increased complexity in advanced atherosclerosis. In addition to increasing hematopoiesis and neutrophil infiltration in early lesions, Jak2 VF caused cellular defects in erythrocytes and macrophages, leading to increased erythrophagocytosis but defective efferocytosis. These changes promote accumulation of iron in plaques and increased necrotic core formation which, together with exacerbated proinflammatory responses, likely contribute to plaque instability.
The role and optimal duration of adjuvant imatinib therapy in primary GIST patients.
Authors: Peter Arkhiri, Ivan S. Stilidi, Irina Poddubnaya, Sergey N. Nered, Vahan Yurikovich Bokhian, Ivan N. Peregorodiev, Maxim P. Nikulin
Journal: Journal of Clinical Oncology (2016)

e22510Background: According to the results of the SSG XVIII/AIO trial, adjuvant imatinib administered at 400 mg/day for the duration of 3 years is a standard treatment in patients with high risk of...