tbuckley/cabot-search huggingface dataset:
AML relapse following allogeneic hematopoietic stem cell transplant: a single center experience.
Authors: Andrea O. Akpoguma, Connie Grobe, Sarah C Mott, Margarida De Magalhaes-Silverman
Journal: Journal of Clinical Oncology (2015)

e18002 Background: As non-relapse mortality following allogeneic hematopoietic stem cell transplantation (HSCT) continues to improve, relapse remains a major cause of death. There remains controversy as to the best salvage approach. Herein, we report a retrospective analysis on outcome of AML patients (pts) who relapsed after allogeneic HSCT. Methods: A total of 209 pts with AML underwent allogeneic HSCT from 2003 through 2014 at our institution. Of these, 73 (35%) pts relapsed after first transplant and were included in the analysis. Median age was 55 years (range 18-74) with 31 of 73 pts transplanted in advanced phase. The sources of graft were HLA-id sibling in 34 pts and unrelated donor in 39. The preparative regimen was myeloablative in 51 pts and reduced intensity in 22. Relapse was hematologic in 59 pts, extramedullary in 9 pts and both in 4. Fifty three of these pts were treated with salvage therapies containing chemotherapy alone (n = 12), donor lymphocyte infusions (DLI) alone (n = 6), chemotherapy plus DLI (n = 18), hypomethylating agents (n = 9), or other (n = 8). Twenty pts received palliative/no therapy. Survival estimates were obtained using the Kaplan-Meier method and comparisons were performed with log-rank tests. Fisher’s exact test was used to examine the association between salvage therapy and response after salvage. Results: There was not a significant difference in time to relapse when comparing preparative regimens (myeloablative vs reduced intensity, p = 0.66) or transplant type (related vs unrelated, p = 0.72). The post-relapse median OS for all patients was 1.9 months. Patients who received salvage therapy had a median OS of 3.2 months vs 0.5 months without therapy (p < 0.01). Among patients who receive salvage treatment, there was not a significant difference in response when comparing salvage therapies (p = 0.23). Only 4 pts are alive at 4, 40, 26 and 92 months after relapse. Conclusions: AML relapsing after allogeneic HSCT is associated with very poor outcome and salvage treatments result in complete response in a very small number of pts with no single therapy consistently resulting in durable remissions.
Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).
Authors: Simon Yuen Fai Fu, Elie Ritch, Cameron Herberts, Steven Yip, Daniel Khalaf, Evan W Warner, Sinja Taavitsainen, Matti Annala, Gillian Vandekerkhove, Igal Kushnir, Cristiano Ferrario, Alexander William Wyatt, Kim N. Chi
Journal: Journal of Clinical Oncology (2019)

5072 Background: A small proportion of metastatic PC exhibit outlier somatic mutation (mut) rates exceeding the average of 4.4 mut/Mb. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing from a panel of PC genes using plasma cell-free DNA samples collected from metastatic castration-resistant prostate cancer (mCRPC) pts and calculated somatic mutation burden. HM samples were additionally subjected to whole exome sequencing to determine trinucleotide mutational signatures and microsatellite instability (MSI). Clinical data was retrospectively collected and compared to a control cohort of 199 mCRPC pts. Results: 671 samples from 434 pts had ctDNA &gt; 2% and were evaluable. 32 samples from 24 pts had &gt; 11 mut/Mb and fell above the 95 th percentile for mutation burden with a median mutation burden of 34 mut/Mb. 11 pts had deleterious mutations or homozygous deletions in mismatch repair (MMR) genes and 4 further pts had evidence of MMR deficiency (MMRd) from mutational signatures and MSI status. The remaining 9 pts had either BRCA2 mutations (n = 4), Kataegis (localized hypermutation, n = 3), or undefined causes for HM (n = 2). The incidence of MMRd was 3.5% (15/434), and germline MMRd was 0.2% (1/434). For MMRd pts with available clinical data (10/15) at diagnosis, the median age was 73.6 y, 70% had Gleason score ≥8, and 50% presented with M1 disease. Comparing the MMRd with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9–11.4) vs. 18.2 m (95% CI 15.1–21.3), p = 0.001; median time from CRPC to death was 13.1 m (95% CI 0.3–25.9) vs. 40.1 m (95% CI 32.4–47.8), p &lt; 0.001. Conclusions: HM and MMRd can be identified using liquid biopsy and could help to select pts for immunotherapy.
TFL Deletion Induces Incredible CXCL13 Secretion and Cachexia in Vavp-Bcl2Transgenic Mice
Authors: Kentaro Minagawa, Kanako Wakahashi, Fukui Chie, Shinichiro Nishikawa, Noboru Asada, Yuko Kawano, Hiroki Kawano, Tomohide Suzuki, Shinichi Ishii, Yoshio Katayama, Toshimitsu Matsui
Journal: Blood (2018)
A prospective phase II trial of gemcitabine plus axitinib in patients with sarcomatoid type renal carcinoma.
Authors: Inkeun Park, Hyo Jin Lee, Woo Kyun Bae, Shinkyo Yoon, Jae-Lyun Lee
Journal: Journal of Clinical Oncology (2019)

616 Background: Sarcomatoid renal cell carcinoma (SRCC) is a rare but very aggressive type of RCC. The treatment option for SRCC is very limited, and there have been anecdotal reports of very good responders to gemcitabine or vascular endothelial growth factor receptor tyrosine kinaase inhibitors (VEGFR TKI). We conducted multicenter phase 2 trial of gemcitabine plus axitinib (GX) in patients (pts) with recurrent or metastatic SRCC to evaluate its efficacy and safety. Methods: Eligibility criteria included histologically confirmed metastatic or recurrent RCC with sarcomatoid component of 25% or more on resected kidney or exclusive sarcomatoid carcinoma on needle biopsy, ECOG PS 0-2, measurable lesion by RECIST v1.1, and adequate cardiac, hepatic, renal and bone marrow function. Pts with uncontrolled hypertension, prior exposure to gemcitabine or VEGFR TKI were exclude. Pts received gemcitabine 1,000 mg/m2 intravenously on days 1 and 8 by 3-week cycle and axitinib 5 mg twice daily. The primary endpoint was objective response rate (ORR) according to RECIST v1.1, and secondary end points were progression-free survival (PFS), overall survival (OS), and toxicity. Results: Twenty-five pts were enrolled between Oct 2014 and Aug 2018. Median age was 61 (range 33-80), and 84% was male. ECOG PS were 1 (92%) and 2 (8%), and 52% had prior nephrectomy. Clear cell carcinoma was the most common histology of carcinoma component, and median percentage of sarcomatoid component was 90% (25-100%). Pts belonged to intermediate (28%) and poor (72%) risk group according to IMDC risk stratification. Median 6 cycles of GX were administered, and 56%, 28%, and 12% of pts achieved PR, SD, and PD, respectively, with an ORR of 56% and median duration of response of 2.5 months. With a median follow-up duration of 21.4 mo, median PFS was 4.9 mo (95% CI, 3.5-13.3), and median OS was 8.4 months (95% CI 3.5-13.3 months). Most adverse events were manageable, and no unexpected toxicities were found. One pt died of grade 5 pneumonia. Conclusions: GX showed promising efficacy in pts with SRCC. GX might be considered as one of treatment options for pts with SRCC, although efficacy of GX should be confirmed in larger trial.
Stabilized Peptide HDAC Inhibitors Derived from HDAC1 Substrate H3K56 for the Treatment of Cancer Stem–Like Cells <i>In Vivo</i>
Authors: Dongyuan Wang, Wenjun Li, Rongtong Zhao, Longjian Chen, Na Liu, Yuan Tian, Hui Zhao, Mingsheng Xie, Fei Lu, Qi Fang, Wei Liang, Feng Yin, Zigang Li
Journal: Cancer Research (2019)

FDA-approved HDAC inhibitors exhibit dose-limiting adverse effects; thus, we sought to improve the therapeutic windows for this class of drugs. In this report, we describe a new class of peptide-based HDAC inhibitors derived from the HDAC1-specific substrate H3K56 with improved nonspecific toxicity compared with traditional small-molecular inhibitors. We showed that our designed peptides exerted superior antiproliferation effects on cancer stem-like cells with minimal toxicity to normal cells compared with the small-molecular inhibitor SAHA, which showed nonspecific toxicity to normal and cancer cells. These peptide inhibitors also inactivated cellular HDAC1 and HDAC6 and disrupted the formation of the HDAC1, LSD1, and CoREST complex. In ovarian teratocarcinoma (PA-1) and testicular embryonic carcinoma (NTERA-2) cell xenograft animal models (5 mice/group, 50 mg/kg, every other day, intraperitoneal injection), these peptides inhibited tumor growth by 80% to 90% with negligible organ (heart, liver, spleen, lung, kidney, brain) lesions. These results represent the first attempt to design chemically stabilized peptide inhibitors to investigate HDAC inhibition in cancer stem-like cells. These novel peptide inhibitors have significantly enhanced therapeutic window and offer promising opportunities for cancer therapy. SIGNIFICANCE: Selective antiproliferative effects of stabilized peptide HDAC inhibitors toward cancer stem-like cells provide a therapeutic alternative that avoids high nonspecific toxicity of current drugs.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/1769/F1.large.jpg.
Prognostic role of PD-L1 expression in patients with advanced renal cell carcinoma (RCC) treated with sunitinib.
Authors: Clara Iglesias, Rodrigo Ignacio Cereceda García, Lucía Rodríguez Arias, Felipe Jose Alvarez Manceñido, Verónica Blanco Lorenzo, Laura Faez, Maria Pilar Solis-Hernandez, Sara Fernández, Alfonso Revuelta, David Gómez, Jorge del Río Fernández, Sena Valcárcel González, Debora Corina Contreras Toledo, Luka Mihic Góngora, Emilio Esteban
Journal: Journal of Clinical Oncology (2019)

603 Background: the prognosis and treatment of advanced RCC has improved over the last decade due to a number of effective anti-angiogenic and immune checkpoint inhibitors (ICPI) therapies. Certain clinical factors, such as low Karnofsky status (≤ 70%); less than a one year period from diagnosis to treatment administration; low serum hemoglobin; high corrected serum calcium; high lactate dehydrogenase; elevated neutrophil count or platelet count exceeding the upper limit of the normal range, have been able to stratify patients into three distinct prognostic groups: favorable (zero risk factors), intermediate (one to two), and poor risk (more than two). Nowadays, the relationship between PD-L1 expression with treatment response and the survival rate of RCC is a current topic of interest. Methods: a retrospective analysis of 182 patients with advanced RCC who received sunitinb in a single Institution has been conducted with the aim of analyzing PD-L1 as a prognostic factor. To carry out the immunohistochemical analysis, microscopy samples have been treated with the PD-L1 IHC 22C3 pharmDx assay, which is intended to measure the percentage of PD-L1 expression in the primary tumor tissue. Results: a total of 65 patients with primary tumor tissue sampling, who were never treated with (ICPI), were analyzed. Among these, 95% were considered as intermediate or poor risk and 47% had PD-L1 expression. The results have shown that PD-L1 expression is associated with worse progression-free survival (PFS) and overall survival (OS). In patients with no expression of PD-L1, the median PFS was 16.89 months (95% confidence interval 11.0 – 40.87 months) and 12.61 months for those with some % of PD-L1 expression (4.43 – 53.09). (χ² = 1.16; Pr &gt; χ² = 0.20). Likewise, the median OS was 42.28 months (13.76 – 68.13) for patients with no expression of PD-L1 and 24.60 months for those with some % of PD-L1 expression (13.76- not reached) ( χ ² = 0.12; Pr &gt; χ ² = 0.73). Conclusions: patients treated with sunitinib who express PD-L1, have shown shorter PFS and OS. Its validation as an independent prognostic factor, with regard to other standard clinical parameters, must be considered in order to develop a more tailored approach to treatment decision.
Overall survival in platinum-sensitive recurrent ovarian cancer: Findings from a multinational medical record review.
Authors: Jerzy Tyczynski, Sarah Williams, Noolie Gregory, Mandy Garratt, Ilian Tchakov, Keith L. Davis, James A. Kaye, Jennifer Korsnes, Jan Lewis
Journal: Journal of Clinical Oncology (2015)

e16547 Background: Overall survival (OS) in platinum-sensitive recurrent ovarian cancer (PSR OC) has been assessed in recent trials of platinum-based regimens and novel targeted agents. However, OS data are still limited for women with PSR OC in real-world settings. Methods: We retrospectively reviewed a sample of medical records from 3 countries (United Kingdom [UK], Canada [CAN], Netherlands [NL]). Women determined to have serous PSR OC (progression-free interval of ≥ 6 months after 1st-line platinum completion) during 2009-2013 were selected. For pts receiving 2nd-line therapy (1st treatment for PSR OC), OS was assessed via Kaplan-Meier from 2nd-line start until death or last record for all regimens combined and for carboplatin + paclitaxel specifically. For pts not starting 2nd-line, OS was assessed from date of PSR OC determination. Results: 421 pts were analyzed (n = 312 UK, 73 CAN, 36 NL; median age: 61, 60, 60 years; stage IV at presentation: 20%, 5%, 14%). The majority of pts (73%, 62%, 81%) received 2nd-line therapy, most commonly carboplatin + paclitaxel (31%, 40%, 62% of initiators). Median time to 2nd-line start was 1 month from relapse. OS estimates are provided in the table. Medians not reached and confidence limits not estimable noted by “-”. Conclusions: In this review, median OS from PSR OC determination and from 2nd-line initiation was consistent with recent reports. In the UK, OS from 2nd-line carboplatin + paclitaxel (37 months) was similar to the 33 months reported in the CALYPSO trial. OS was longer, however, in CAN (52 months), indicating possible selection of a better prognostic group, evidenced by the smaller proportion of CAN pts presenting with stage IV disease. That at least 20% of pts did not receive 2nd-line therapy combined with shorter OS in these pts may highlight a need for better treatment options. No. events, median OS (95% CI) in months Start time All UK CAN NL PSR OC determination (pts not receiving 2nd-line therapy) 78, 34 (30, -) 48, 37 (30, -) 16, - (25, -) 14, 18 (6, 26) 2nd-line initiation (all regimens) 56, 40 (32, -) 34, 40 (19, -) 13, 52 (23, -) 9, 40 (19, -) 2nd-line carboplatin + paclitaxel initiation 23, 52 (32, 52) 15, 37 (32, -) 5, 52 (20, 52) 3, - (19, -)
Abstract MP15: Validation of Phenotyping Algorithms for Stroke From Electronic Health Records Using Natural Language Processing
Authors: Yiqing Zhao, Suyang Fu, Nicholas B Larson, Paul A Decker, Alanna M Chamberlain, Veronique L Roger, Hongfang Liu, Suzette J Bielinski
Journal: Circulation (2019)

Background: Accurate identification of stroke cases from electronic health record (EHR) is needed for efficient and valid clinical and epidemiology research. A number of studies have evaluated the validity of using ICD-9 and ICD-10 codes for stroke identification. Previous research results show that sensitivity and positive predictive value (PPV) for stroke identification is the lowest among all other cerebrovascular diseases, with notable differences observed by stroke pathological subtypes. While most prevalent cerebrovascular disease cases can be detected using 430-438/I60-I69 collectively, more accurate and comprehensive stroke phenotyping algorithm is needed to identify incident stroke cases from EHR. In our work, we compared case identification results using ICD-codes exclusively with ICD plus a natural language processing (NLP) algorithm. Methods: We developed the NLP part of our stroke algorithm using a list of expert provided stroke-related keywords, which covers transient ischemic attack (TIA), ischemic stroke, and hemorrhagic stroke. We validated the hybrid (ICD+NLP) algorithm and compared it with ICD-exclusive algorithm in a previously established atrial fibrillation cohort (n=5,062). Clinical notes and ICD codes of all patients after the incident AF event were reviewed by two nurse abstracters to confirm new stroke incidences. All past clinical notes and ICD codes of a subset of patients (n=402) were reviewed to confirm lifetime (prior and current) stroke cases. Manual abstraction results were considered the gold standard for evaluation of ICD only and ICD+NLP automatic extraction. Sensitivity and positive predictive values (PPV) of both algorithms were calculated. Results: Among 5,062 patients, 593 patients were confirmed to have suffered a stroke after atrial fibrillation while 4,469 patients were confirmed with no EHR evidence of stroke after AF. The ICD-exclusive algorithm had a sensitivity of 47.2% and a PPV of 47.8% for detecting new stroke incidences. The hybrid stroke algorithm achieved a sensitivity of 92.4% and a PPV of 60.6% for extraction of incident stroke. For extraction of lifetime stroke cases, the hybrid approach achieved a sensitivity of 93.9% and a PPV of 88.7%. Performance of new stroke incidence extraction is limited because past/current stroke mentions in clinical notes are difficult to distinguish by our NLP algorithm (may be a future direction). Conclusions: We developed and validated a stroke algorithm that performed well for identifying incident and lifetime stroke cases. The addition of NLP into the stroke algorithm improved the sensitivity and PPV of compared to an ICD-exclusive algorithm.
Abstract P250: Changes in Glycemia and Blood Lipids Following a 4 Month Mhealth Walking Intervention
Authors: Benjamin E Hook, Catherine L Jarrett, Jennifer L Herbold, Wesley J Tucker, Jane C Hurley, Michael Todd, Nishat Bhuiyan, Jacqueline A Fernandez, Marc A Adams, Siddhartha S Angadi
Journal: Circulation (2016)

Introduction: Walking interventions focused on increasing step counts are typically associated with salutary effects on glycemia, fasting insulin, insulin resistance and blood lipids which may be in turn associated with improvements in cardiorespiratory fitness (peak oxygen uptake [[Unable to Display Character: &amp;#8211;]] VO 2peak ) and vascular stiffness. We hypothesized that a novel 4-month, behavioral economics-based walking intervention would have favorable effects on glucose homeostasis and blood lipids and that these in turn would be related to VO 2peak and vascular stiffness (carotid femoral pulse wave velocity [[Unable to Display Character: &amp;#8211;]] cfPWV). Methods: We carried out secondary analyses on a subsample of sedentary, overweight/obese adults who participated in a 4-month, 2x2, randomized-controlled walking intervention examining the effects of goal setting (static v. adaptive goals) and rewards (immediate v. delayed) on steps/day (N=96). Fasting blood samples (n=58) were collected from participants before and after the intervention. Premenopausal females were in the follicular phase of their menstrual cycles. Lipid and glucose levels were measured using an automated chemistry analyzer, while insulin was measured using radio-immunoassay. Homeostatic model of insulin resistance (HOMA-IR) was calculated using the following formula (HOMA-IR=glucose x insulin / 405). We examined associations [partial correlations (adjusted for age)] between changes in blood biomarkers and VO 2peak and cfPWV, irrespective of group, and we used linear mixed models to examine between-group differences in levels of and change in biomarker outcomes. Results: Groups did not differ in overall levels of, or degree of change in, biomarker outcomes (all p&gt;0.05). Mean changes, irrespective of group, in biomarkers were as follows: glucose Δ= 0.74± 4.5mg/dl; insulin Δ= 0.09 ± 4.1 μU/ml; total cholesterol Δ= 0.24 ± 20.6 mg/dl; HDL-C Δ= 0.27 ± 5.1 mg/dl; LDL-C Δ= 1.3 ± 19.9 mg/dl; triglycerides Δ= 1.7 ± 27.2 mg/dl; HOMA-IR Δ = -.0548 ± 1.05). We found no significant associations between change in biomarker levels and change in VO 2peak or change in cfPWV (all correlation coefficients &lt; 0.15; p &gt; 0.05). Conclusion: A 4-month, behavioral economics-based mHealth intervention focused on increasing steps/day did not bring about favorable changes on markers of glycemia, insulin resistance and blood lipids.
Gut mucosal virome alterations in ulcerative colitis
Authors: Tao Zuo, Xiao-Juan Lu, Yu Zhang, Chun Pan Cheung, Siu Lam, Fen Zhang, Whitney Tang, Jessica Y L Ching, Risheng Zhao, Paul K S Chan, Joseph J Y Sung, Jun Yu, Francis K L Chan, Qian Cao, Jian-Qiu Sheng, Siew C Ng
Journal: Gut (2019)

The pathogenesis of UC relates to gut microbiota dysbiosis. We postulate that alterations in the viral community populating the intestinal mucosa play an important role in UC pathogenesis. This study aims to characterise the mucosal virome and their functions in health and UC.Deep metagenomics sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on the rectal mucosa of 167 subjects from three different geographical regions in China (UC=91; healthy controls=76). Virome and bacteriome alterations in UC mucosa were assessed and correlated with patient metadata. We applied partition around medoids clustering algorithm and classified mucosa viral communities into two clusters, referred to as mucosal virome metacommunities 1 and 2.In UC, there was an expansion of mucosa viruses, particularly Caudovirales bacteriophages, and a decrease in mucosa Caudovirales diversity, richness and evenness compared with healthy controls. Altered mucosal virome correlated with intestinal inflammation. Interindividual dissimilarity between mucosal viromes was higher in UC than controls. Escherichia phage and Enterobacteria phage were more abundant in the mucosa of UC than controls. Compared with metacommunity 1, metacommunity 2 was predominated by UC subjects and displayed a significant loss of various viral species. Patients with UC showed substantial abrogation of diverse viral functions, whereas multiple viral functions, particularly functions of bacteriophages associated with host bacteria fitness and pathogenicity, were markedly enriched in UC mucosa. Intensive transkingdom correlations between mucosa viruses and bacteria were significantly depleted in UC.We demonstrated for the first time that UC is characterised by substantial alterations of the mucosa virobiota with functional distortion. Enrichment of Caudovirales bacteriophages, increased phage/bacteria virulence functions and loss of viral-bacterial correlations in the UC mucosa highlight that mucosal virome may play an important role in UC pathogenesis.
Targeting BCL-2, BCL-XL, BCL-W and MDM2 in B-Cell Acute Lymphoblastic Leukemia Is Highly Effective Ex Vivo
Authors: Helena Hohtari, Shady Awad, Olli Dufva, Swapnil Potdar, Caroline A Heckman, Krister Wennerberg, Satu Mustjoki, Kimmo Porkka
Journal: Blood (2018)