tbuckley/cabot-search huggingface dataset:
Abstract 18124: Delayed Staged Palliation Does Not Affect Clinical Outcomes for Children With Hypoplastic Left Heart Syndrome and Variants
Authors: Devin Chetan, Christoph Haller, Steven M Schwartz, Christopher A Caldarone, Glen S Van Arsdell, Osami Honjo
Journal: Circulation (2016)

Introduction:  Impact of delayed stage II and/or Fontan palliation on survival and Fontan physiology is not well understood.   Hypothesis:  Delayed staged palliation results in lower survival and worse Fontan outcomes.   Methods:  All 232 patients with HLHS undergoing stage I palliation from 2000-2011 were reviewed (Figure). The clinical course for patients who had delayed stage II (>7 months) or Fontan (>3.5 years) was documented. Patients were classified as having either minor or significant reasons for delayed palliation. Rates of on-time and overall Fontan completion, survival, transplant, and post-Fontan failure were compared between patients who did not meet (G1; n=28) and met (G2; n=125) conventional stage II palliation timelines. Rates of post-Fontan failure were also compared for patients who did not meet (G3; n=44) and met (G4; n=74) conventional Fontan completion timelines.   Results:  Delayed stage II palliation resulted in equivalent rates of on-time (G1: 15 [53.6%] vs G2: 59 [47.2%]; p=0.54) and delayed (G1: 10 [35.7%] vs G2: 34 [27.2%]; p=0.37) Fontan completion, with no difference noted between rates of delay because of minor or significant reasons (p   Conclusions:  Delayed timing of stage II and Fontan palliation did not impact survival or Fontan failure. While close followup and sensible rehabilitation strategy are likely contributors to equivalent outcomes, this result may partly be due to patients who never reached subsequent palliation because of inter-stage death or transplant.
Clinical significance and therapeutic potential of targeting B7-H3 in pancreatic cancer
Authors: Ichiro Yamato, Masayuki Sho, Takeo Nomi, Takahiro Akahori, Hiromichi Kanehiro, Miyuki Azuma, Hideo Yagita, Yoshiyuki Nakajima
Journal: Cancer Research (2008)

1518  B7-H3, a new member of the B7 family, has been reported to provide both positive and negative signals to T cells under various physiological and pathological circumstances. To date, the precise role of B7-H3 in tumor immunity remains largely unknown. In this study, we investigated the expression of B7-H3 in human pancreatic cancer and therapeutic potential of targeting B7-H3 as a novel immunotherapy. First, we examined the expression of B7-H3 on 67 pancreatic cancer tissues by immunohistochemistry. Positive staining was seen both on the cell membrane and in the cytoplasm of cancer cells in almost all patients. Thus, data suggested that B7-H3 might be a critical regulator and potential target for immunotherapy against pancreatic cancer. Toward clinical application, we evaluated therapeutic efficacy of targeting B7-H3 in vivo. To this end, we utilized a murine pancreatic cancer cell line, PAN02, and employed a blocking anti-mouse B7-H3 mAb (MJ-18). By MTS assay, we did not see any direct effect of mAb on the tumor growth in vitro. Then, PAN02 was orthotopically implanted in the pancreas of the syngeneic C57BL/6 mice. On the next day of tumor implantation, anti-B7-H3 mAb treatment was started (0.3mg, three times a week for 3 weeks). The treatment induced substantial antitumor effect and significantly inhibited tumor growth compared to controls (tumor volume at 4 weeks; anti-B7-H3 mAb, n=10, 144.6±13.3 mm3, control, n=9, 320.4±36.1mm3, P=0.0002). Real-time PCR analysis further revealed that B7-H3 blockade promoted T cell infiltration and also downregulated VEGF in tumors, suggesting that B7-H3 blockade induce local immune activation and inhibit tumor angiogenesis, thereby resulting in tumor regression. Finally, we examined the efficacy of combination therapy of B7-H3 blockade and conventional chemotherapy. We used gemcitabine that is currently standard chemotherapeutic agent for pancreatic cancer. Gemcitabine treatment (0.8mg, every three days, 5 times) had a modest antitumor effect (n=5, 108.6±9.3 mm3, P=0.0011). Interestingly, B7-H3 blockade and gemcitabine exerted significant synergistic effect on pancreatic cancer, resulting in substantial response without overt toxicity (n=5, 27.1±4.9 mm3, P
Comprehensive genomic profiling to merge precision medicine with immunotherapy.
Authors: Stephen Lyle, Julie Y Tse, Ruobai Sun, Xiu Huang, Meaghan Russell, Jane Jiang, Dana Vuzman, Alexei Protopopov, Cheryl Eifert
Journal: Journal of Clinical Oncology (2017)

e23108 Background: Immunotherapy is rapidly emerging as one of the most promising therapeutic options in clinical oncology. However, not all patients will respond to immune-oncology drugs and diagnostic assays are urgently needed to identify biomarkers that predict response to these therapies. We developed an assay that utilizes next generation sequencing data to simultaneously determine different types of somatic changes in tumors. The assay was designed, in part, to facilitate identification of cancer patients most likely to respond to immunotherapies by detecting 1) CD274 (PD-L1) copy number alterations, 2) viral infections (HPV16/18 and EBV), 3) microsatellite instability (MSI), and 4) tumor mutation burden. Methods: We developed a 435-gene panel assay (CancerPlex) with the goal of identifying all the genomic changes that inform treatment decisions with the highest possible accuracy. We thoroughly evaluated the performance of the assay using reference samples that represent all classes of genetic variation, including SNPs, indels, copy number changes, rearrangements, HPV/EBV infection and MSI. FFPE clinical samples were also evaluated to assess the ability of the assay to detect genetic variation in complex, heterogeneous tumors. Results: The assay has excellent performance, with a mean sensitivity of 99.4% and specificity of 99.9% for detecting somatic mutations with an allele fraction as low as 10%. The assay identified the MSI status of colorectal tumors with the same sensitivity as immunohistochemistry but with greater sensitivity than PCR. We also showed that calculating tumor mutation burden using the 435-gene panel predicts response to pembrolizumab as effectively as using whole exome sequencing. Among 892 patients across all tumor types, 6.8% were identified as candidates for immunotherapy based upon high tumor mutation burden and/or MSI status. Conclusions: The capacity of the 435-gene panel to determine all of the critical genetic changes, tumor mutation burden, MSI status, CD274 (PD-L1) CNVs, and HPV/EBV status has important ramifications for patient treatment strategies, including identification of patients who are more likely to benefit from immune checkpoint inhibitor therapies.
High somatic mutation and neoantigen burden are correlated with decreased progression-free survival in multiple myeloma
Authors: A Miller, Y Asmann, L Cattaneo, E Braggio, J Keats, D Auclair, S Lonial, S J Russell, A K Stewart
Journal: Blood Cancer Journal (2017)

Abstract Tumor-specific mutations can result in immunogenic neoantigens, both of which have been correlated with responsiveness to immune checkpoint inhibitors in highly mutagenic cancers. However, early results of single-agent checkpoint inhibitors in multiple myeloma (MM) have been underwhelming. Therefore, we sought to understand the relationship between mutation and neoantigen landscape of MM patients and responsiveness to therapies. Somatic mutation burden, neoantigen load, and response to therapy were determined using interim data from the MMRF CoMMpass study (NCT01454297) on 664 MM patients. In this population, the mean somatic and missense mutation loads were 405.84( s =608.55) and 63.90( s =95.88) mutations per patient, respectively. There was a positive linear relationship between mutation and neoantigen burdens ( R 2 =0.862). The average predicted neoantigen load was 23.52( s =52.14) neoantigens with an average of 9.40( s =26.97) expressed neoantigens. Survival analysis revealed significantly shorter progression-free survival (PFS) in patients with greater than average somatic missense mutation load ( N =163, 0.493 vs 0.726 2-year PFS, P =0.0023) and predicted expressed neoantigen load ( N =214, 0.555 vs 0.729 2-year PFS, P =0.0028). This pattern is maintained when stratified by disease stage and cytogenetic abnormalities. Therefore, high mutation and neoantigen load are clinically relevant risk factors that negatively impact survival of MM patients under current standards of care.
Response to erlotinib and prognosis for patients with de novo epidermal growth factor receptor (<i>EGFR</i>) T790M mutations.
Authors: Gregory J. Riely, Helena Alexandra Yu, Maria E. Arcila, Matthew David Hellmann, Marc Ladanyi, Mark G. Kris
Journal: Journal of Clinical Oncology (2013)

8018 Background: A secondary mutation in exon 20 of EGFR, T790M, is the most common cause of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR mutant lung cancers. De novo EGFR T790M mutations in TKI-naïve patients are rare when assessed by standard genotyping methods. The response to EGFR TKIs in patients with de novo EGFR T790M mutations is unknown. Methods: Patients with EGFRmutations were identified through routine testing, using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing. Clinical characteristics, progression free survival (PFS) from start of EGFR TKI and overall survival (OS) were obtained from the medical record. Results: From 2008-2012, we observed EGFR T790M in 21 tumors from 20 patients who had not previously been treated with an EGFR TKI representing &lt;2% of all tumors with identified EGFR mutations. Two patients are included in reports from the Lung Cancer Mutation Consortium. The median age at lung cancer diagnosis was 57 (range 35-90). 55% presented with stage IV disease. 60% were women. 65% were never-smokers. In all cases, T790M occurred concurrently with another EGFR mutation, L858R (76%, 16/21) or exon 19 deletion (24%, 5/21). Compared to a contemporary cohort of 593 patients with EGFR mutations, in these patients with de novo EGFR T790M, L858R was more frequent than exon 19 deletion (p=0.003). Thirteen patients received erlotinib monotherapy as treatment for metastatic disease. Their response rate (CR+PR) was 9% (1/11, 95% Confidence Interval: 0-40%). SD was observed in 36% (4/11). The median progression-free survival was 3 months and the median overall survival was 16 months. Conclusions: De novo EGFR T790M mutations are rare and occur most commonly with EGFR L858R. Overall survival for patients with de novo EGFR T790 mutations is shorter than what is seen in patients with EGFR exon 19 deletions or L858R, and appears more similar to EGFR wild-type patients. Response rate to EGFR TKI in these patients is low. EGFR TKI therapy for patients with de novo EGFR T790M appears to have limited objective benefit and should be considered only after standard cytotoxic chemotherapy.
Outcomes following resection of periampullary adenocarcinoma as a function of body composition assessed on preoperative CT.
Authors: Oliver F. Bathe, Tariq Al-Manasra, Elizabeth Tobola, Santiago Salazar, Derek Leugner, Francis R. Sutherland, Chad Ball, Elijah Dixon, Vickie E Baracos
Journal: Journal of Clinical Oncology (2015)

e15289 Background: Cachexia is a common manifestation of pancreatic cancer and other periampullary adenocarcinomas. Sarcopenia (low muscle mass) is one manifestation of cachexia. Reduced skeletal muscle attenuation on CT scan also often accompanies cachexia, and this is thought to be related to fat infiltration of skeletal muscle (myosteatosis). We postulated that changes in body composition that signify cachexia adversely affect perioperative outcomes and survival. Methods: 123 patients who underwent a Whipple pancreaticoduodenectomy for pancreatic adenocarcinoma or a non-pancreatic periampullary adenocarcinoma had a preoperative CT scan available for analysis. Muscle cross sectional areas and attenuation values were measured at the level of the third lumbar vertebra. Muscle area was normalized for stature. Sarcopenia was defined as muscle index (cm2/m2) below the 25th percentile for each gender. Reduced muscle attenuation was defined as muscle attenuation below the 25thpercentile. Results: Myosteatosis (but not sarcopenia) was associated with a higher incidence of anastomotic leak and delayed gastric emptying. Sarcopenia was associated with a diminished overall survival (P = 0.04, HR 1.635). Reduced muscle attenuation was also associated with reduced survival (P = 0.02, HR 1.729). Neither sarcopenia nor reduced muscle attenuation affected disease-free survival. On multivariate analysis, reduced muscle attenuation, high BMI, and pancreatic adenocarcinoma were associated with diminished overall survival. Factors significantly associated with reduced muscle attenuation included older age, sarcopenia, a higher BMI, diabetes, markedly elevated CA 19-9 and higher Charleson comorbidity index. Conclusions: Sarcopenia and reduced skeletal muscle attenuation (indicators of cachexia) adversely impact survival after resection of pancreatic and periampullary adenocarcinomas. Further investigation will be required to understand the tumor and host-related factors that drive these changes in body composition.
Clinical features and outcomes of reversible posterior encephalopathy syndrome following bevacizumab treatment.
Authors: Mitsuhiko Iwamoto, Shiori Inoue, Kanako Kawaguchi, Risa Terasawa, Hiroya Fujioka, Kosei Kimura, Kazuhisa Uchiyama
Journal: Journal of Clinical Oncology (2017)

e14045 Background: Reversible posterior leukoenchephalopathy syndrome (RPLS), also known as Posterior reversible encephalopathy syndrome (PRES) is a distinct clinicoradiological entity characterized by a constellation of clinical features, and a potentially devastating complication of bevacizumab treatment. Methods: Patients were identified from the published literature using ‘PubMed’ databases using the terms ‘bevacizumab’ or , ‘RPLS’ and ‘RPES’ from 2006 to 2016, who developed RPLS features within 3 weeks of bevacizumab treatment, who had brain imaging findings of focal vasogenic edema and radiologic proof of reversibility Results: A total of 22 cases of RPLS following the administration of bevacizumab have been reported. The mean age of these patients was 50 years (range 34–74 years), 6 of whom were male and 14 female. Headaches ( n = 11), seizures ( n = 10), visual disturbances ( n = 9) and nausea and vomiting ( n = 8) were the common presenting symptoms. In a majority of patients, an increase in blood pressure from their baseline values was observed during their hospitalization. RPLS occurred in 3 patients who received bevacizumab as monotherapy and the rest had received bevacizumab in combination with other chemotherapeutic agents (oxaliplatin, n = 8; fluorouracil, n = 6; leucovorin, n = 5; gemcitabine, n = 3; paclitaxel, n = 3; capecitabine, n = 3; doxorubicin, n = 2; carboplatin, n = 2; and irinotecan, n = 1). In 20 out of 22 patients, PRES resolved following withdrawal of bevacizumab and strict control of blood pressure. 3 patients also received prednisolone and mannitol as part of their treatment for RPLS. However, 2 out of 22 patients could not recover from severe coma, and died. Conclusions: A high level of suspicion for RPLS is advisable in patients who develop headache, seizures, visual disturbances, during bevacizumab treatment, either as monotherapy or in combination with other chemotherapeutic agents. These data support the need for close vigilance of neurological features and blood pressure monitoring of patients undergoing bevacizumab treatment. Prompt withdrawal of bevacizumab and blood pressure control appear to portend favorable outcomes in these patients.
PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2α-Targeting Therapy for Renal Cell Carcinoma
Authors: Hirofumi Yoshino, Nijiro Nohata, Kazutaka Miyamoto, Masaya Yonemori, Takashi Sakaguchi, Satoshi Sugita, Toshihiko Itesako, Satoshi Kofuji, Masayuki Nakagawa, Rajvir Dahiya, Hideki Enokida
Journal: Cancer Research (2017)

Abstract Continuous activation of hypoxia-inducible factor (HIF) is important for progression of renal cell carcinoma (RCC) and acquired resistance to antiangiogenic multikinase and mTOR inhibitors. Recently, HIF2α antagonists PT2385 and PT2399 were developed and are being evaluated in a phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC). However, resistance to HIF2α antagonists would be expected to develop. In this study, we identified signals activated by HIF2α deficiency as candidate mediators of resistance to the HIF2α antagonists. We established sunitinib-resistant tumor cells in vivo and created HIF2α-deficient variants of these cells using CRISPR/Cas9 technology. Mechanistic investigations revealed that a regulator of the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), was upregulated commonly in HIF2α-deficient tumor cells along with the serine biosynthesis pathway itself. Accordingly, treatment with a PHGDH inhibitor reduced the growth of HIF2α-deficient tumor cells in vivo and in vitro by inducing apoptosis. Our findings identify the serine biosynthesis pathway as a source of candidate therapeutic targets to eradicate advanced or metastatic ccRCC resistant to HIF2α antagonists. Cancer Res; 77(22); 6321–9. ©2017 AACR.
Liquid biopsies of plasma exosomal nucleic acids, plasma cell-free DNA, and survival of patients with advanced cancers.
Authors: Lino Moehrmann, Helen J. Huang, David S. Hong, Apostolia Maria Tsimberidou, Siqing Fu, Sarina Anne Piha-Paul, Vivek Subbiah, Daniel D. Karp, Aung Naing, Anne Krug, Daniel Enderle, Tina Priewasser, Mikkel Noerholm, Cathy Eng, Scott Kopetz, Johan Skog, Funda Meric-Bernstam, Filip Janku
Journal: Journal of Clinical Oncology (2017)

11551 Background: Blood-based liquid biopsies offer easy accessible genomic material for molecular diagnostics in cancer. Commonly used cell-free DNA (cfDNA) originates from dying cells. In contrast exosomal nucleic acid (exoNA) originates from living cells, which can better reflect underlying cancer biology. Methods: We isolated exoNA (EXO52) and cfDNA (QIAamp Circulating Nucleic Acid kit) from plasma of patients with progressing advanced cancers and tested for BRAF V600 , KRAS G12/G13 , and EGFR exon19del/L858R mutations using next-generation sequencing (EXO1000), droplet digital PCR (ddPCR, QX200) and BEAMing digital PCR. The results were compared to clinical testing of archival tumor tissue and correlated with survival. Results: Of the 43 patients (colorectal cancer, 20; melanoma, 8; non-small cell lung cancer, 6; ovarian cancer, 2; papillary thyroid cancer, 2; other cancers, 5) 41 had a mutation in the tumor tissue (20 [47%] BRAF mutation, 17 [40%] KRAS mutation and 4 [9%] EGFR mutation). Mutation testing of plasma exoNA from all 43 patients detected 39 (95%) of 41 mutations present in tumor tissue with 100% specificity. Mutation testing of plasma cfDNA from 39 patients using ddPCR detected 33 (89%) of 37 mutations present in tumor and testing of plasma cfDNA from 37 patients using BEAMing detected 34 (97%) of 35 mutations present in tumor tissue; however, both cfDNA methods reported an additional KRAS mutation not present in tumor tissue. Patients with high mutation allele frequency (MAF, &gt; median) had shorter median survival compared to patients with low MAF ( &lt; median) when using exoNA (5.9 vs. 11.8 months, P= 0.006), but not cfDNA ddPCR (6.0 vs. 7.4 months, P= 0.06) or cfDNA BEAMing (6.5 vs. 7.4 month, P= 0.07). High MAF in exoNA was an independent prognostic factor for survival in multicovariate analysis (HR 0.13, P= 0.017). Conclusions: Mutation testing of plasma exoNA for common BRAF, KRAS, and EGFR mutations has high sensitivity compared to clinical testing of archival tumor tissue and better specificity than PCR testing of plasma cfDNA. High MAF in exoNA is the independent prognostic factor for shorter survival.
Re: Ferdinando Fusco, Mohamed Abdel-Fattah, Christopher R. Chapple, et al. Updated Systematic Review and Meta-analysis of the Comparative Data on Colposuspensions, Pubovaginal Slings, and Midurethral Tapes in the Surgical Treatment of Female Stress Urinary Incontinence. Eur Urol 2017;72:567–91
Authors: Wael Agur, Jawad Freites
Journal: European Urology (2017)
The expression of pluripotency genes regulates properties of cancer stem cells in MCF-7 breast cancer model.
Authors: Regina R. Miftakhova, Aigul R Rakhmatullina, Rimma N. Mingaleeva, Ekaterina E Garanina, Svetlana F Khaiboullina, Albert A Rizvanov
Journal: Journal of Clinical Oncology (2017)

e23018 Background: More than 1.6 million cases of breast cancer (BC) are diagnosed annually worldwide. Despite advances in diagnoses and treatment, BC remains the third leading cause of death in women. Metastases and chemotherapy resistance are the main factors contributing to BC mortality. The ability of tumor cells to overcome the drug-induced growth inhibition is now linked to a unique population of cancer initiating tumor cells, often referred as cancer stem cells (CSC). CSC represent a small fraction of tumor cells, therefore, currently used isolation protocols have a low yield and are poorly reproducible, hampering research on the role of these cells in cancer chemoresistance. We propose a novel approach to generate large quantities of CSC-like cells by genetic reprogramming of non-stem cancer cells. Methods: We postulate that CSC-enriched cell line can be developed in vitro by upregulating of proteins controlling cancer cell pluripotency including Oct4, Sox2, NANOG, KLF4 and c-Myc. Increased transcriptional and translational activity of these genes in MCF-7 cells was demonstrated by real time-PCR and Western blot. Proliferation and migration of cells overexpressing Oct4, Sox2, NANOG, KLF4 and c-Myc were analyzed as well. Also, changes in CSC population counts and their sensitivity to chemotherapy were investigated using sphere formation assay. Results: We found that cell proliferation rate was correlated with the expression level of c-Myc and Oct4. Increased CSC counts were found in cells with overexpressed Oct4 (62.7%), KLF4 (97%) and NANOG (121.3%) proteins as compared to the parental cells. Overexpression of SOX2, NANOG and KLF4 significantly increased CSC resistance to docetaxel (83,3±6,8; 93,3±4,5 and 80,3±5,0 spheres respectively) when compared to the original cells (48,3±3,0 spheres). Conclusions: We conclude that overexpression of pluripotency proteins Oct4, Sox2, NANOG, KLF4 and c-Myc changes the CSC counts and proliferation capacity of BC cells. Acknowledgements: The study was funded by RFBR, according to the research project No. 16-34-60210 mol_а_dk, and by Russian Government Program of Competitive Growth of Kazan Federal University.
Quality and Safety in Health Care, Part XXXIII
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2017)

The transcatheter mitral valve procedure with the MitraClip device has been clinically available in much of Europe since 2008. In 2013, the Food and Drug Administration permitted MitraClip procedures to be done commercially for those patients with primary severe mitral regurgitation who were not surgical candidates. The COAPT trial is designed to see if the MitraClip procedure should be approved in the United States for those with secondary mitral regurgitation, although it has been used for that purpose in much of Europe for years.
Chimeric antigen receptor-modified T cells directed against CD19 in patients with relapsed or refractory CD19-positive B-cell lymphomas: interim analysis of a phase 1 study
Authors: Zhitao Ying, Xiaoyu Xiang, Yuqin Song, Ning Ding, Yufu Lin, Wen Zheng, Xiaopei Wang, Ningjing Lin, Meifeng Tu, Yan Xie, Chen Zhang, Weiping Liu, Lijuan Deng, Yanling Liu, Yunqiang Yue, Xueyun Yu, Hanzhi Liu, Panpan Duan, Mierzhati Mamuti, Xiaokai Guo, Feng Chen, Xiaoyan Wu, Junqing Zhang, Tingting Zhang, Xue F Huang, Lindsey Jones, Xi Kang, Si-Yi Chen, Jun Zhu
Journal: The Lancet Oncology (2017)