Outcome of Pancreaticoduodenectomy at Low-Volume Centre in Tier-II City of India

Abstract

Currently, pancreaticoduodenectomy (PD) is considered a common and feasibly performed surgery for periampullary tumours, but it is still a high-risk surgical procedure with potential morbidity and mortality rates. Previously, it was emphasised for the need of high-volume centres to perform specialised surgery such as PD. The authors have made an attempt to know the relation between low-volume centre and outcomes of PD. The study was conducted in a Tier-II city referral hospital located in Karnataka, India. A total of 37 patients with suspected periampullary neoplasms underwent surgical exploration with curative intent over a period of 4 years, i.e. from May 2012 to May 2016. Out of 37 patients, 26 underwent PD, either classic Whipple resection (n = 01) or pylorus-preserving modification (n = 25). In 11 patients, resection was not possible, where biliary and gastric drainage procedures were done. All patients were treated by standardised post-operative care protocols for pancreatic resection used at our centre. We recorded the perioperative outcome along with demographics, indications for surgery, and pre- and intra-operative factors of PD. Post-operative pancreatic fistulae were evident in 4 patients. Two patients had hepaticojejunostomy leak. One patient had chyle leak. Three patients had infection at the surgical site. One patient had post-operative pneumonia leading to mortality. None of the patients had post-op haemorrhage. The surgeon volume and surgeon experience may have minimal contributing factor in post-operative morbidity, especially if there is availability of well-equipped ICU and imaging facilities, along with well-experienced personnel like oncosurgeon, anaesthesiologist, intensivist, radiologist, and nursing staff. There is a need of a multicentre study from Tier-II city hospitals/low-volume centres and high-volume centres to come with perioperative surgical outcomes following PD.

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A Multi-Institutional Validation of Gleason Score Derived from Tissue Microarray Cores

Abstract

To test the agreement between high-grade PCa at RP and TMA, and the ability of TMA to predict BCR. Validation of concordance between tissue microarray (TMA) and radical prostatectomy (RP) high-grade prostate cancer (PCa) is crucial because latter determines the treated natural history of PCa. We hypothesized that TMA Gleason score is in agreement with RP pathology and capable of accurately predicting biochemical recurrence (BCR). Data were provided from a multi-institutional Canadian sample of 1333 TMA and RP specimens with complete clinicopathological data. First, rate of agreement between TMA and high-grade Gleason at RP or biopsy and RP was tested. Second, ability of RP, TMA and biopsy to predict BCR was compared. Multivariable (MVA) Cox regression models were fitted and BCR rates were illustrated with Kaplan-Meier plots. Agreement between RP and TMA and between RP and biopsy was 72.6% (95% CI:69.7–75.5) and 60.4% (95% CI:57.2–63.6), respectively. In MVA predicting BCR, the accuracy for RP, TMA and biopsy was 0.73, 0.72 and 0.68, respectively. TMA added discriminatory ability among exclusively low-grade Gleason RP patients (p = 0.02), but did not improve BCR discrimination in exclusive high-grade PCa RP patients (p = 0.8). TMA Gleason grade accurately reflects presence of high-grade Gleason in RP specimen, accurately predicts BCR rates after RP and improves prediction of BCR in low-grade Gleason patients at RP.

https://ift.tt/2uRIJBJ

A Multi-Institutional Validation of Gleason Score Derived from Tissue Microarray Cores

Abstract

To test the agreement between high-grade PCa at RP and TMA, and the ability of TMA to predict BCR. Validation of concordance between tissue microarray (TMA) and radical prostatectomy (RP) high-grade prostate cancer (PCa) is crucial because latter determines the treated natural history of PCa. We hypothesized that TMA Gleason score is in agreement with RP pathology and capable of accurately predicting biochemical recurrence (BCR). Data were provided from a multi-institutional Canadian sample of 1333 TMA and RP specimens with complete clinicopathological data. First, rate of agreement between TMA and high-grade Gleason at RP or biopsy and RP was tested. Second, ability of RP, TMA and biopsy to predict BCR was compared. Multivariable (MVA) Cox regression models were fitted and BCR rates were illustrated with Kaplan-Meier plots. Agreement between RP and TMA and between RP and biopsy was 72.6% (95% CI:69.7–75.5) and 60.4% (95% CI:57.2–63.6), respectively. In MVA predicting BCR, the accuracy for RP, TMA and biopsy was 0.73, 0.72 and 0.68, respectively. TMA added discriminatory ability among exclusively low-grade Gleason RP patients (p = 0.02), but did not improve BCR discrimination in exclusive high-grade PCa RP patients (p = 0.8). TMA Gleason grade accurately reflects presence of high-grade Gleason in RP specimen, accurately predicts BCR rates after RP and improves prediction of BCR in low-grade Gleason patients at RP.

https://ift.tt/2uRIJBJ

Outcome of Pancreaticoduodenectomy at Low-Volume Centre in Tier-II City of India

Abstract

Currently, pancreaticoduodenectomy (PD) is considered a common and feasibly performed surgery for periampullary tumours, but it is still a high-risk surgical procedure with potential morbidity and mortality rates. Previously, it was emphasised for the need of high-volume centres to perform specialised surgery such as PD. The authors have made an attempt to know the relation between low-volume centre and outcomes of PD. The study was conducted in a Tier-II city referral hospital located in Karnataka, India. A total of 37 patients with suspected periampullary neoplasms underwent surgical exploration with curative intent over a period of 4 years, i.e. from May 2012 to May 2016. Out of 37 patients, 26 underwent PD, either classic Whipple resection (n = 01) or pylorus-preserving modification (n = 25). In 11 patients, resection was not possible, where biliary and gastric drainage procedures were done. All patients were treated by standardised post-operative care protocols for pancreatic resection used at our centre. We recorded the perioperative outcome along with demographics, indications for surgery, and pre- and intra-operative factors of PD. Post-operative pancreatic fistulae were evident in 4 patients. Two patients had hepaticojejunostomy leak. One patient had chyle leak. Three patients had infection at the surgical site. One patient had post-operative pneumonia leading to mortality. None of the patients had post-op haemorrhage. The surgeon volume and surgeon experience may have minimal contributing factor in post-operative morbidity, especially if there is availability of well-equipped ICU and imaging facilities, along with well-experienced personnel like oncosurgeon, anaesthesiologist, intensivist, radiologist, and nursing staff. There is a need of a multicentre study from Tier-II city hospitals/low-volume centres and high-volume centres to come with perioperative surgical outcomes following PD.

https://ift.tt/2GDbnMJ

Genomic and Functional Approaches to Understanding Cancer Aneuploidy

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Alison M. Taylor, Juliann Shih, Gavin Ha, Galen F. Gao, Xiaoyang Zhang, Ashton C. Berger, Steven E. Schumacher, Chen Wang, Hai Hu, Jianfang Liu, Alexander J. Lazar, Andrew D. Cherniack, Rameen Beroukhim, Matthew Meyerson
Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy.

Graphical abstract

Teaser

Analyzing >10,000 human cancers, Taylor et al. show that aneuploidy is correlated with somatic mutation rate, expression of proliferation genes, and decreased leukocyte infiltration. Loss of chromosome arm 3p is common in squamous cancers, but deletion of chromosome 3p reduces cell proliferation in vitro.


https://ift.tt/2qb7V1i

Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Yang Liu, Nilay S. Sethi, Toshinori Hinoue, Barbara G. Schneider, Andrew D. Cherniack, Francisco Sanchez-Vega, Jose A. Seoane, Farshad Farshidfar, Reanne Bowlby, Mirazul Islam, Jaegil Kim, Walid Chatila, Rehan Akbani, Rupa S. Kanchi, Charles S. Rabkin, Joseph E. Willis, Kenneth K. Wang, Shannon J. McCall, Lopa Mishra, Akinyemi I. Ojesina, Susan Bullman, Chandra Sekhar Pedamallu, Alexander J. Lazar, Ryo Sakai, Vésteinn Thorsson, Adam J. Bass, Peter W. Laird
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.

Graphical abstract

Teaser

Liu et al. analyze 921 gastrointestinal (GI) tract adenocarcinomas and find that hypermutated tumors are enriched for insertions/deletions, upper GI tumors with chromosomal instability harbor fragmented genomes, and a group of genome-stable colorectal tumors are enriched in mutations in SOX9 and PCBP1.


https://ift.tt/2IvA1uY

A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Ashton C. Berger, Anil Korkut, Rupa S. Kanchi, Apurva M. Hegde, Walter Lenoir, Wenbin Liu, Yuexin Liu, Huihui Fan, Hui Shen, Visweswaran Ravikumar, Arvind Rao, Andre Schultz, Xubin Li, Pavel Sumazin, Cecilia Williams, Pieter Mestdagh, Preethi H. Gunaratne, Christina Yau, Reanne Bowlby, A. Gordon Robertson, Daniel G. Tiezzi, Chen Wang, Andrew D. Cherniack, Andrew K. Godwin, Nicole M. Kuderer, Janet S. Rader, Rosemary E. Zuna, Anil K. Sood, Alexander J. Lazar, Akinyemi I. Ojesina, Clement Adebamowo, Sally N. Adebamowo, Keith A. Baggerly, Ting-Wen Chen, Hua-Sheng Chiu, Steve Lefever, Liang Liu, Karen MacKenzie, Sandra Orsulic, Jason Roszik, Carl Simon Shelley, Qianqian Song, Christopher P. Vellano, Nicolas Wentzensen, John N. Weinstein, Gordon B. Mills, Douglas A. Levine, Rehan Akbani
We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.

Teaser

By performing molecular analyses of 2,579 TCGA gynecological (OV, UCEC, CESC, and UCS) and breast tumors, Berger et al. identify five prognostic subtypes using 16 key molecular features and propose a decision tree based on six clinically assessable features that classifies patients into the subtypes.


https://ift.tt/2JnGEk9

Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer

Publication date: Available online 29 March 2018
Source:Cancer Cell
Author(s): Ying-Nai Wang, Heng-Huan Lee, Chao-Kai Chou, Wen-Hao Yang, Yongkun Wei, Chun-Te Chen, Jun Yao, Jennifer L. Hsu, Cihui Zhu, Haoqiang Ying, Yuanqing Ye, Wei-Jan Wang, Seung-Oe Lim, Weiya Xia, How-Wen Ko, Xiuping Liu, Chang-Gong Liu, Xifeng Wu, Huamin Wang, Donghui Li, Laura R. Prakash, Matthew H. Katz, Yaan Kang, Michael Kim, Jason B. Fleming, David Fogelman, Milind Javle, Anirban Maitra, Mien-Chie Hung
Pancreatic ribonuclease (RNase) is a secreted enzyme critical for host defense. We discover an intrinsic RNase function, serving as a ligand for epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase (RTK), in pancreatic ductal adenocarcinoma (PDAC). The closely related bovine RNase A and human RNase 5 (angiogenin [ANG]) can trigger oncogenic transformation independently of their catalytic activities via direct association with EGFR. Notably, high plasma ANG level in PDAC patients is positively associated with response to EGFR inhibitor erlotinib treatment. These results identify a role of ANG as a serum biomarker that may be used to stratify patients for EGFR-targeted therapies, and offer insights into the ligand-receptor relationship between RNase and RTK families.

Graphical abstract

Teaser

Wang et al. identify angiogenin (ANG) as a ligand for epidermal growth factor receptor (EGFR). ANG-mediated EGFR activation can trigger oncogenic transformation, and high ANG in the plasma of pancreatic adenocarcinoma patients positively correlates with response to the EGFR inhibitor erlotinib.


https://ift.tt/2uT195c

GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth

Publication date: Available online 29 March 2018
Source:Cancer Cell
Author(s): Leanne Li, Qiqun Zeng, Arjun Bhutkar, José A. Galván, Eva Karamitopoulou, Daan Noordermeer, Mei-Wen Peng, Alessandra Piersigilli, Aurel Perren, Inti Zlobec, Hugh Robinson, M. Luisa Iruela-Arispe, Douglas Hanahan
Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). Here, we establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells. Furthermore, we distilled genome-wide expression profiles orchestrated by the NMDAR-GKAP signaling axis, identifying transcriptome signatures in tumors with low/inhibited NMDAR activity that significantly associate with favorable patient prognosis in several cancer types.

Graphical abstract

Teaser

Li et al. show that GKAP, a scaffold protein of NMDAR, and its downstream effectors FMRP and HSF1 play important roles in the invasive growth of pancreatic tumors. In several cancer types, low NMDAR activity, based on a transcriptomic signature, associates with favorable patient prognosis.


https://ift.tt/2q5L7QM

lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Zehua Wang, Bo Yang, Min Zhang, Weiwei Guo, Zhiyuan Wu, Yue Wang, Lin Jia, Song Li, Wen Xie, Da Yang
We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129–283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo.

Graphical abstract

Teaser

Wang et al. characterize the epigenetic landscape of lncRNAs genes across a large number of human tumors and cancer cell lines and observe recurrent hypomethylation of lncRNA genes, including EPIC1. EPIC1 RNA promotes cell-cycle progression by interacting with MYC and enhancing its binding to target genes.


https://ift.tt/2uMDzXP

Genomic and Functional Approaches to Understanding Cancer Aneuploidy

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Alison M. Taylor, Juliann Shih, Gavin Ha, Galen F. Gao, Xiaoyang Zhang, Ashton C. Berger, Steven E. Schumacher, Chen Wang, Hai Hu, Jianfang Liu, Alexander J. Lazar, Andrew D. Cherniack, Rameen Beroukhim, Matthew Meyerson
Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy.

Graphical abstract

Teaser

Analyzing >10,000 human cancers, Taylor et al. show that aneuploidy is correlated with somatic mutation rate, expression of proliferation genes, and decreased leukocyte infiltration. Loss of chromosome arm 3p is common in squamous cancers, but deletion of chromosome 3p reduces cell proliferation in vitro.


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Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Yang Liu, Nilay S. Sethi, Toshinori Hinoue, Barbara G. Schneider, Andrew D. Cherniack, Francisco Sanchez-Vega, Jose A. Seoane, Farshad Farshidfar, Reanne Bowlby, Mirazul Islam, Jaegil Kim, Walid Chatila, Rehan Akbani, Rupa S. Kanchi, Charles S. Rabkin, Joseph E. Willis, Kenneth K. Wang, Shannon J. McCall, Lopa Mishra, Akinyemi I. Ojesina, Susan Bullman, Chandra Sekhar Pedamallu, Alexander J. Lazar, Ryo Sakai, Vésteinn Thorsson, Adam J. Bass, Peter W. Laird
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.

Graphical abstract

Teaser

Liu et al. analyze 921 gastrointestinal (GI) tract adenocarcinomas and find that hypermutated tumors are enriched for insertions/deletions, upper GI tumors with chromosomal instability harbor fragmented genomes, and a group of genome-stable colorectal tumors are enriched in mutations in SOX9 and PCBP1.


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A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Ashton C. Berger, Anil Korkut, Rupa S. Kanchi, Apurva M. Hegde, Walter Lenoir, Wenbin Liu, Yuexin Liu, Huihui Fan, Hui Shen, Visweswaran Ravikumar, Arvind Rao, Andre Schultz, Xubin Li, Pavel Sumazin, Cecilia Williams, Pieter Mestdagh, Preethi H. Gunaratne, Christina Yau, Reanne Bowlby, A. Gordon Robertson, Daniel G. Tiezzi, Chen Wang, Andrew D. Cherniack, Andrew K. Godwin, Nicole M. Kuderer, Janet S. Rader, Rosemary E. Zuna, Anil K. Sood, Alexander J. Lazar, Akinyemi I. Ojesina, Clement Adebamowo, Sally N. Adebamowo, Keith A. Baggerly, Ting-Wen Chen, Hua-Sheng Chiu, Steve Lefever, Liang Liu, Karen MacKenzie, Sandra Orsulic, Jason Roszik, Carl Simon Shelley, Qianqian Song, Christopher P. Vellano, Nicolas Wentzensen, John N. Weinstein, Gordon B. Mills, Douglas A. Levine, Rehan Akbani
We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.

Teaser

By performing molecular analyses of 2,579 TCGA gynecological (OV, UCEC, CESC, and UCS) and breast tumors, Berger et al. identify five prognostic subtypes using 16 key molecular features and propose a decision tree based on six clinically assessable features that classifies patients into the subtypes.


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Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer

Publication date: Available online 29 March 2018
Source:Cancer Cell
Author(s): Ying-Nai Wang, Heng-Huan Lee, Chao-Kai Chou, Wen-Hao Yang, Yongkun Wei, Chun-Te Chen, Jun Yao, Jennifer L. Hsu, Cihui Zhu, Haoqiang Ying, Yuanqing Ye, Wei-Jan Wang, Seung-Oe Lim, Weiya Xia, How-Wen Ko, Xiuping Liu, Chang-Gong Liu, Xifeng Wu, Huamin Wang, Donghui Li, Laura R. Prakash, Matthew H. Katz, Yaan Kang, Michael Kim, Jason B. Fleming, David Fogelman, Milind Javle, Anirban Maitra, Mien-Chie Hung
Pancreatic ribonuclease (RNase) is a secreted enzyme critical for host defense. We discover an intrinsic RNase function, serving as a ligand for epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase (RTK), in pancreatic ductal adenocarcinoma (PDAC). The closely related bovine RNase A and human RNase 5 (angiogenin [ANG]) can trigger oncogenic transformation independently of their catalytic activities via direct association with EGFR. Notably, high plasma ANG level in PDAC patients is positively associated with response to EGFR inhibitor erlotinib treatment. These results identify a role of ANG as a serum biomarker that may be used to stratify patients for EGFR-targeted therapies, and offer insights into the ligand-receptor relationship between RNase and RTK families.

Graphical abstract

Teaser

Wang et al. identify angiogenin (ANG) as a ligand for epidermal growth factor receptor (EGFR). ANG-mediated EGFR activation can trigger oncogenic transformation, and high ANG in the plasma of pancreatic adenocarcinoma patients positively correlates with response to the EGFR inhibitor erlotinib.


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GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth

Publication date: Available online 29 March 2018
Source:Cancer Cell
Author(s): Leanne Li, Qiqun Zeng, Arjun Bhutkar, José A. Galván, Eva Karamitopoulou, Daan Noordermeer, Mei-Wen Peng, Alessandra Piersigilli, Aurel Perren, Inti Zlobec, Hugh Robinson, M. Luisa Iruela-Arispe, Douglas Hanahan
Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). Here, we establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells. Furthermore, we distilled genome-wide expression profiles orchestrated by the NMDAR-GKAP signaling axis, identifying transcriptome signatures in tumors with low/inhibited NMDAR activity that significantly associate with favorable patient prognosis in several cancer types.

Graphical abstract

Teaser

Li et al. show that GKAP, a scaffold protein of NMDAR, and its downstream effectors FMRP and HSF1 play important roles in the invasive growth of pancreatic tumors. In several cancer types, low NMDAR activity, based on a transcriptomic signature, associates with favorable patient prognosis.


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lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer

Publication date: Available online 2 April 2018
Source:Cancer Cell
Author(s): Zehua Wang, Bo Yang, Min Zhang, Weiwei Guo, Zhiyuan Wu, Yue Wang, Lin Jia, Song Li, Wen Xie, Da Yang
We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129–283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo.

Graphical abstract

Teaser

Wang et al. characterize the epigenetic landscape of lncRNAs genes across a large number of human tumors and cancer cell lines and observe recurrent hypomethylation of lncRNA genes, including EPIC1. EPIC1 RNA promotes cell-cycle progression by interacting with MYC and enhancing its binding to target genes.


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Atezolizumab in Metastatic Urothelial Carcinoma Outside Clinical Trials: Focus on Efficacy, Safety, and Response to Subsequent Therapies

Abstract

Background

Little is known about the outcomes, safety, and response to subsequent therapies of patients with metastatic urothelial carcinoma (mUC) treated with atezolizumab outside clinical trials.

Objectives

The objectives of the study include to report the clinical efficacy and safety of atezolizumab, and the response to future therapies in clinical practice outside clinical trials.

Patient and Methods

This is a retrospective, single-center study including consecutive patients with confirmed mUC who received at least one dose of atezolizumab 1200 mg every 3 weeks between May 2016 and April 2017.

Results

Seventy-nine patients, median age 72 years (range 29–93), 71% men and 76% ECOG PS 0–1, were identified. Most patients (79%) had primary cancer in the bladder, 62% had prior surgery, and 75% received at least one prior line of treatment (34 patients had prior cisplatin-based chemotherapy). Best response included 18% partial response, 29% stable disease, and 53% progressive disease. Patients were on atezolizumab for a median of 2.7 months (95%CI, 1.8–3.6) and median PFS was 3.2 months (95%CI, 1.6–4.8). A total of 33 (42%) patients had significant (any cause) AEs, including grade 4 hyperbilirubinemia in two patients; no toxic deaths were reported. At time of data analysis, only 18% of patients received at least one subsequent line of treatment for a median of 1.8 months (95%CI, 0.0–5.0) while 42% were referred to palliative care/hospice or died.

Conclusions

Patients with mUC who progressed on atezolizumab were unlikely to receive subsequent systemic treatments and the benefit of those treatments appeared limited in our cohort. The findings may impact timing and designs of clinical trials in mUC.

https://ift.tt/2uOYAkG

Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer

Abstract

BACKGROUND

Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors are driven by amplification or mutation of HER2.

MATERIALS AND METHODS

This paper reviews the role of HER2 as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type.

RESULTS

While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology.

CONCLUSION

HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients.

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Clinical challenges of glioma and pregnancy: a systematic review

Abstract

Introduction

This review aims to summarize challenges in clinical management of concomitant gliomas and pregnancy and provides suggestions for this management based on current literature.

Methods

PubMed and Embase databases were systematically searched for studies on glioma and pregnancy. Observational studies and articles describing expert opinions on clinical management were included. The strength of evidence was categorized as arguments from observational studies, consensus in expert opinions, or single expert opinions. Risk of bias was assessed by the Newcastle-Ottawa Scale (NOS).

Results

27 studies were selected, including 316 patients with newly diagnosed (n = 202) and known (n = 114) gliomas during pregnancy. The median sample size was 6 (range 1–65, interquartile range 1–9). Few recommendations originated from observational studies; the remaining arguments originated from consensus in expert opinions.

Conclusion

Findings from observational studies of adequate quality include (1) There is no known effect of pregnancy on survival in low-grade glioma patients; (2) Pregnancy can provoke clinical deterioration and tumor growth on MRI; (3) In stable women at term, there is no benefit of cesarean section over vaginal delivery, with respect to adverse events in mother or child. Unanswered questions include when pregnancy should be discouraged, what best monitoring schedule is for both mother and fetus, and if and how chemo- and radiation therapy can be safely administered during pregnancy. A multicenter individual patient level meta-analysis collecting granular information on clinical management and related outcomes is needed to provide scientific evidence for clinical decision-making in pregnant glioma patients.

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Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer

Abstract

BACKGROUND

Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors are driven by amplification or mutation of HER2.

MATERIALS AND METHODS

This paper reviews the role of HER2 as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type.

RESULTS

While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology.

CONCLUSION

HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients.

https://ift.tt/2Ix9i12

Clinical challenges of glioma and pregnancy: a systematic review

Abstract

Introduction

This review aims to summarize challenges in clinical management of concomitant gliomas and pregnancy and provides suggestions for this management based on current literature.

Methods

PubMed and Embase databases were systematically searched for studies on glioma and pregnancy. Observational studies and articles describing expert opinions on clinical management were included. The strength of evidence was categorized as arguments from observational studies, consensus in expert opinions, or single expert opinions. Risk of bias was assessed by the Newcastle-Ottawa Scale (NOS).

Results

27 studies were selected, including 316 patients with newly diagnosed (n = 202) and known (n = 114) gliomas during pregnancy. The median sample size was 6 (range 1–65, interquartile range 1–9). Few recommendations originated from observational studies; the remaining arguments originated from consensus in expert opinions.

Conclusion

Findings from observational studies of adequate quality include (1) There is no known effect of pregnancy on survival in low-grade glioma patients; (2) Pregnancy can provoke clinical deterioration and tumor growth on MRI; (3) In stable women at term, there is no benefit of cesarean section over vaginal delivery, with respect to adverse events in mother or child. Unanswered questions include when pregnancy should be discouraged, what best monitoring schedule is for both mother and fetus, and if and how chemo- and radiation therapy can be safely administered during pregnancy. A multicenter individual patient level meta-analysis collecting granular information on clinical management and related outcomes is needed to provide scientific evidence for clinical decision-making in pregnant glioma patients.

https://ift.tt/2q9DpnS

Assessment of Radiology Training During Radiation Oncology Residency

Abstract

A strong foundation in diagnostic imaging is essential to the practice of radiation oncology. This study evaluated radiology training in radiation oncology residency. An online survey was distributed to current radiation oncology residents in the USA by e-mail in 2017. Responses were summarized using frequency and percentages and compared with chi-square test and Spearman's rank correlation when appropriate. One hundred five residents completed the survey. Although most residents felt that a strong knowledge base in diagnostic radiology was moderately or extremely important (87%, n = 90/104), the majority were only somewhat confident in their radiology skills (61%, n = 63/104) and were only somewhat, minimally, or not at all satisfied with their training (79%, n = 81/103). Although there was an association between increasing post-graduate training and confidence level (p = 0.01062, ρ = 0.24959), the majority of graduating residents feel only somewhat confident in radiology skills (63%, n = 12/19). Residents were most commonly exposed to radiology via multidisciplinary conferences (96%, n = 100/104), though only 15% (n = 16/104) of residents ranked these as the most beneficial component of their radiology training and 13% (n = 13/101) of residents felt these were the least beneficial. Most residents (60%, n = 63/105) believe there is a need for dedicated radiology training during residency, preferring monthly formal didactics (68%, n = 71/105) co-taught by a radiologist and radiation oncologist (58%, n = 61/105). Radiation oncology residents feel their radiology training is suboptimal, suggesting a need for more guidance and standardization of radiology curriculum. A preferred option may be monthly didactics co-taught by radiologists and radiation oncologists; however, future studies should assess the effectiveness of this model.

https://ift.tt/2IvYTCO

Assessment of Radiology Training During Radiation Oncology Residency

Abstract

A strong foundation in diagnostic imaging is essential to the practice of radiation oncology. This study evaluated radiology training in radiation oncology residency. An online survey was distributed to current radiation oncology residents in the USA by e-mail in 2017. Responses were summarized using frequency and percentages and compared with chi-square test and Spearman's rank correlation when appropriate. One hundred five residents completed the survey. Although most residents felt that a strong knowledge base in diagnostic radiology was moderately or extremely important (87%, n = 90/104), the majority were only somewhat confident in their radiology skills (61%, n = 63/104) and were only somewhat, minimally, or not at all satisfied with their training (79%, n = 81/103). Although there was an association between increasing post-graduate training and confidence level (p = 0.01062, ρ = 0.24959), the majority of graduating residents feel only somewhat confident in radiology skills (63%, n = 12/19). Residents were most commonly exposed to radiology via multidisciplinary conferences (96%, n = 100/104), though only 15% (n = 16/104) of residents ranked these as the most beneficial component of their radiology training and 13% (n = 13/101) of residents felt these were the least beneficial. Most residents (60%, n = 63/105) believe there is a need for dedicated radiology training during residency, preferring monthly formal didactics (68%, n = 71/105) co-taught by a radiologist and radiation oncologist (58%, n = 61/105). Radiation oncology residents feel their radiology training is suboptimal, suggesting a need for more guidance and standardization of radiology curriculum. A preferred option may be monthly didactics co-taught by radiologists and radiation oncologists; however, future studies should assess the effectiveness of this model.

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Unicentric epithelioid hemangioendothelioma of the calcaneus: a case report and review of literature

Abstract

Background

This review of the literature combined with a clinical case will allow the illustration of a favorable outcome of this variable low grade malignancy, display a role for limb salvage surgery with intralesional treatment, and offer a clinical example of epithelioid hemangioendothelioma, a rare malignancy.

Case presentation

The case report presents a case of solitary epithelioid hemangioendothelioma (EHE) of the calcaneus in a 60-year-old male. Primary vascular tumors of the bone are rare; however, EHE is one of the most common primary malignant vascular tumors to occur in bone. A review of the literature found few cases that involved the calcaneus; those cases found that involved the calcaneus were either part of a multifocal or metastatic disease process. Our case presents a 45-month clinical follow-up of solitary EHE in the calcaneus treated with surgical excision by curettage and cementing.

Conclusion

This case has clinical follow-up greater than 2 years post-operatively and could be a guide for treatment of a rare disorder with a substantial paucity of literature.

https://ift.tt/2GBzZFt

Unicentric epithelioid hemangioendothelioma of the calcaneus: a case report and review of literature

Abstract

Background

This review of the literature combined with a clinical case will allow the illustration of a favorable outcome of this variable low grade malignancy, display a role for limb salvage surgery with intralesional treatment, and offer a clinical example of epithelioid hemangioendothelioma, a rare malignancy.

Case presentation

The case report presents a case of solitary epithelioid hemangioendothelioma (EHE) of the calcaneus in a 60-year-old male. Primary vascular tumors of the bone are rare; however, EHE is one of the most common primary malignant vascular tumors to occur in bone. A review of the literature found few cases that involved the calcaneus; those cases found that involved the calcaneus were either part of a multifocal or metastatic disease process. Our case presents a 45-month clinical follow-up of solitary EHE in the calcaneus treated with surgical excision by curettage and cementing.

Conclusion

This case has clinical follow-up greater than 2 years post-operatively and could be a guide for treatment of a rare disorder with a substantial paucity of literature.

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Cost‐effectiveness of the BRECONDA decision aid for women with breast cancer: Results from a randomized controlled trial

Psycho-Oncology, EarlyView.


https://ift.tt/2GEhMqH

Cost‐effectiveness of the BRECONDA decision aid for women with breast cancer: Results from a randomized controlled trial

Psycho-Oncology, EarlyView.


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PAM50 and risk of recurrence scores for interval breast cancers

Breast cancers detected after a negative breast screening examination and prior to the next screening are referred to as interval cancers. These cancers generally have poor clinical characteristics compared to screen-detected cancers, but associations between interval cancer and genomic cancer characteristics are not well understood. Mammographically-screened women diagnosed with primary invasive breast cancer from 1993-2013 (n=370) were identified by linking the Carolina Breast Cancer Study and the Carolina Mammography Registry. Among women with a registry-identified screening mammogram 0-24 months before diagnosis, cancers were classified as screen-detected (N=165) or interval-detected (N=205). Using logistic regression, we examined the association of mode of detection with cancer characteristics (clinical, IHC, and genomic), overall, and in analyses stratified on mammographic density and race. Interval cancer was associated with large tumors (> 2 cm) (OR=2.3; 95% C.I.: 1.5, 3.7), positive nodal status (OR=1.8; 95% C.I.: 1.1, 2.8), and triple negative subtype (OR=2.5; 95% C.I.: 1.1, 5.5). Interval cancers were more likely to have non-Luminal A subtype (OR=2.9; 95% C.I.: 1.5, 5.7), while screen-detected cancers tended to be more indolent (96% had low risk of recurrence genomic scores; 71% were PAM50 Luminal A). When stratifying by mammographic density and race, associations between interval detection and poor prognostic features were similar by race and density status. Strong associations between interval cancers and poor-prognosis genomic features (non-Luminal A subtype and high risk of recurrence score) suggest that aggressive tumor biology is an important contributor to interval cancer rates.

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Orchestrating Ribosomal Subunit Coordination to Control Stem Cell Fate

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Eesha Sharma, Benjamin J. Blencowe
The mechanisms responsible for maintaining ribosomal component stoichiometry, which is critical during cell fate transitions, are currently not well understood. In this issue of Cell Stem Cell, Corsini et al. (2018) demonstrate that the transcription and splicing-associated factor HTATSF1 controls stem cell fate by coordinately regulating ribosomal protein and RNA production.

Teaser

The mechanisms responsible for maintaining ribosomal component stoichiometry, which is critical during cell fate transitions, are currently not well understood. In this issue of Cell Stem Cell, Corsini et al. (2018) demonstrate that the transcription and splicing-associated factor HTATSF1 controls stem cell fate by coordinately regulating ribosomal protein and RNA production.


https://ift.tt/2EmgJ95

Coordinated Control of mRNA and rRNA Processing Controls Embryonic Stem Cell Pluripotency and Differentiation

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Nina S. Corsini, Angela M. Peer, Paul Moeseneder, Mykola Roiuk, Thomas R. Burkard, Hans-Christian Theussl, Isabella Moll, Juergen A. Knoblich
Stem cell-specific transcriptional networks are well known to control pluripotency, but constitutive cellular processes such as mRNA splicing and protein synthesis can add complex layers of regulation with poorly understood effects on cell-fate decisions. Here, we show that the RNA binding protein HTATSF1 controls embryonic stem cell differentiation by regulating multiple aspects of RNA processing during ribosome biogenesis. HTATSF1, in a complex with splicing factor SF3B1, controls intron removal from ribosomal protein transcripts and regulates ribosomal RNA transcription and processing, thereby controlling 60S ribosomal abundance and protein synthesis. HTATSF1-dependent protein synthesis is essential for naive pre-implantation epiblast to transition into post-implantation epiblast, a stage with transiently low protein synthesis, and further differentiation toward neuroectoderm. Together, these results identify coordinated regulation of ribosomal RNA and protein synthesis by HTATSF1 and show that this essential mechanism controls protein synthesis during early mammalian embryogenesis.

Graphical abstract

Teaser

Corsini et al. identify the splicing factor HTATSF1 as a regulator of intron retention specifically in ribosomal proteins and of ribosomal RNA transcription and processing to modulate levels of overall protein synthesis. They further demonstrate that HTATSF1-mediated protein synthesis dynamics control embryonic stem cell pluripotency and neuroectoderm differentiation.


https://ift.tt/2EnqvaY

Building Bonds: Cancer Stem Cells Depend on Their Progeny to Drive Tumor Progression

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Sree Deepthi Muthukrishnan, Alvaro G. Alvarado, Harley I. Kornblum
Little is currently known about how cancer stem-like cells (CSCs) interact with their more restricted progeny. In this issue of Cell Stem Cell, Wang et al. (2018) demonstrate a novel bidirectional signaling axis between CSCs and their progeny that is mediated by brain-derived neurotrophic factor and VGF accelerating glioma progression.

Teaser

Little is currently known about how cancer stem-like cells (CSCs) interact with their more restricted progeny. In this issue of Cell Stem Cell, Wang et al. (2018) demonstrate a novel bidirectional signaling axis between CSCs and their progeny that is mediated by brain-derived neurotrophic factor and VGF accelerating glioma progression.


https://ift.tt/2GY2n3K

To Be Young at Heart

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Patrick C.H. Hsieh, Timothy J. Kamp
Recently in Cell, Mohamed et al. (2018) report a cell-cycle regulator gene cocktail identified from young cardiomyocytes that enables mouse, rat, and human cardiomyocyte proliferation and promotes heart regeneration after infarction, defying the non-dividing nature of adult mammalian cardiomyocytes and implying a new way to treat or prevent heart failure.

Teaser

Recently in Cell, Mohamed et al. (2018) report a cell-cycle regulator gene cocktail identified from young cardiomyocytes that enables mouse, rat, and human cardiomyocyte proliferation and promotes heart regeneration after infarction, defying the non-dividing nature of adult mammalian cardiomyocytes and implying a new way to treat or prevent heart failure.


https://ift.tt/2GEbBz4

The Rules of Successful Speed Dating Are Complex, Even for Super-Enhancers

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Raymond Poot
Super-enhancers (SEs) are important for regulating cell identity genes and oncogenes, but correctly assigning target genes to SEs is difficult. Recently in Cell Reports, Lopes Novo et al. (2018) map interactions between SEs and promoters and observe a significant rewiring of complex SE-promoter networks between different pluripotent states.

Teaser

Super-enhancers (SEs) are important for regulating cell identity genes and oncogenes, but correctly assigning target genes to SEs is difficult. Recently in Cell Reports, Lopes Novo et al. (2018) map interactions between SEs and promoters and observe a significant rewiring of complex SE-promoter networks between different pluripotent states.


https://ift.tt/2GVhF9A

Sending Cancer into the Fetal Position

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Hannah A. Pizzato, Deepta Bhattacharya
Malignant cells gain the ability to self-renew and reacquire expression of proteins associated with embryonic development. In this issue of Cell Stem Cell, Kooreman et al. (2018) demonstrate that vaccination of mice with syngeneic inactivated iPSCs generates T cell immunity against embryonic antigens and provides resistance to several different types of cancers.

Teaser

Malignant cells gain the ability to self-renew and reacquire expression of proteins associated with embryonic development. In this issue of Cell Stem Cell, Kooreman et al. (2018) demonstrate that vaccination of mice with syngeneic inactivated iPSCs generates T cell immunity against embryonic antigens and provides resistance to several different types of cancers.


https://ift.tt/2GAvI0P

De Novo DNA Methylation: Marking the Path from Stem Cell to Neural Fate

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Ayana Sawai, Jeremy S. Dasen
DNA methylation is an epigenetic mark that plays pivotal roles in gene regulation, but its functions in neural fate decisions are poorly understood. In this issue of Cell Stem Cell, Ziller et al. (2018) show that the de novo methyltransferase Dnmt3a ensures efficient generation of motor neurons from stem cells.

Teaser

DNA methylation is an epigenetic mark that plays pivotal roles in gene regulation, but its functions in neural fate decisions are poorly understood. In this issue of Cell Stem Cell, Ziller et al. (2018) show that the de novo methyltransferase Dnmt3a ensures efficient generation of motor neurons from stem cells.


https://ift.tt/2GSRHDR

Mentoring the Next Generation: Fiona Watt

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4

Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Fiona Watt about her views.



https://ift.tt/2El33uJ

Human Pluripotent Stem Cell-Derived Endoderm for Modeling Development and Clinical Applications

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Loukia Yiangou, Alexander D.B. Ross, Kim Jee Goh, Ludovic Vallier
The liver, lung, pancreas, and digestive tract all originate from the endoderm germ layer, and these vital organs are subject to many life-threatening diseases affecting millions of patients. However, primary cells from endodermal organs are often difficult to grow in vitro. Human pluripotent stem cells thus hold great promise for generating endoderm cells and their derivatives as tools for the development of new therapeutics against a variety of global healthcare challenges. Here we describe recent advances in methods for generating endodermal cell types from human pluripotent stem cells and their use for disease modeling and cell-based therapy.

Teaser

In this Protocol Review, Yiangou et al. describe recent advances in methods for generating endodermal cell types from human pluripotent stem cells and their use for disease modeling and cell-based therapy.


https://ift.tt/2GVGjXB

Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Xiuxing Wang, Briana C. Prager, Qiulian Wu, Leo J.Y. Kim, Ryan C. Gimple, Yu Shi, Kailin Yang, Andrew R. Morton, Wenchao Zhou, Zhe Zhu, Elisabeth Anne Adanma Obara, Tyler E. Miller, Anne Song, Sisi Lai, Christopher G. Hubert, Xun Jin, Zhi Huang, Xiaoguang Fang, Deobrat Dixit, Weiwei Tao, Kui Zhai, Cong Chen, Zhen Dong, Guoxin Zhang, Stephen M. Dombrowski, Petra Hamerlik, Stephen C. Mack, Shideng Bao, Jeremy N. Rich
Glioblastoma is the most lethal primary brain tumor; however, the crosstalk between glioblastoma stem cells (GSCs) and their supportive niche is not well understood. Here, we interrogated reciprocal signaling between GSCs and their differentiated glioblastoma cell (DGC) progeny. We found that DGCs accelerated GSC tumor growth. DGCs preferentially expressed brain-derived neurotrophic factor (BDNF), whereas GSCs expressed the BDNF receptor NTRK2. Forced BDNF expression in DGCs augmented GSC tumor growth. To determine molecular mediators of BDNF-NTRK2 paracrine signaling, we leveraged transcriptional and epigenetic profiles of matched GSCs and DGCs, revealing preferential VGF expression by GSCs, which patient-derived tumor models confirmed. VGF serves a dual role in the glioblastoma hierarchy by promoting GSC survival and stemness in vitro and in vivo while also supporting DGC survival and inducing DGC secretion of BDNF. Collectively, these data demonstrate that differentiated glioblastoma cells cooperate with stem-like tumor cells through BDNF-NTRK2-VGF paracrine signaling to promote tumor growth.

Graphical abstract

Teaser

Wang et al. investigate reciprocal signaling between glioma stem cells and their differentiated glioblastoma cell progeny. The authors demonstrate that differentiated tumor cells promote the glioblastoma hierarchy and tumor growth through a paracrine feedback loop of neurotrophin signaling in cooperation with stem cell-like tumor cells.


https://ift.tt/2EnRRNW

Chromatin Accessibility Dynamics during Chemical Induction of Pluripotency

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Shangtao Cao, Shengyong Yu, Dongwei Li, Jing Ye, Xuejie Yang, Chen Li, Xiaoshan Wang, Yuanbang Mai, Yue Qin, Jian Wu, Jiangping He, Chunhua Zhou, He Liu, Bentian Zhao, Xiaodong Shu, Chuman Wu, Ruiping Chen, Waiyee Chan, Guangjin Pan, Jiekai Chen, Jing Liu, Duanqing Pei
Despite its exciting potential, chemical induction of pluripotency (CIP) efficiency remains low and the mechanisms are poorly understood. We report the development of an efficient two-step serum- and replating-free CIP protocol and the associated chromatin accessibility dynamics (CAD) by assay for transposase-accessible chromatin (ATAC)-seq. CIP reorganizes the somatic genome to an intermediate state that is resolved under 2iL condition by re-closing previously opened loci prior to pluripotency acquisition with gradual opening of loci enriched with motifs for the OCT/SOX/KLF families. Bromodeoxyuridine, a critical ingredient of CIP, is responsible for both closing and opening critical loci, at least in part by preventing the opening of loci enriched with motifs for the AP1 family and facilitating the opening of loci enriched with SOX/KLF/GATA motifs. These changes differ markedly from CAD observed during Yamanaka-factor-driven reprogramming. Our study provides insights into small-molecule-based reprogramming mechanisms and reorganization of nuclear architecture associated with cell-fate decisions.

Graphical abstract

Teaser

Cao et al. report an efficient protocol for chemical induction of pluripotency and its chromatin accessibility dynamics, which links small molecules and the reorganization of nuclear architecture in the context of cell-fate decisions.


https://ift.tt/2JkUXpK

A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Marcella Cesana, Michael H. Guo, Davide Cacchiarelli, Lara Wahlster, Jessica Barragan, Sergei Doulatov, Linda T. Vo, Beatrice Salvatori, Cole Trapnell, Kendell Clement, Patrick Cahan, Kaloyan M. Tsanov, Patricia M. Sousa, Barbara Tazon-Vega, Adriano Bolondi, Federico M. Giorgi, Andrea Califano, John L. Rinn, Alexander Meissner, Joel N. Hirschhorn, George Q. Daley
While gene expression dynamics have been extensively cataloged during hematopoietic differentiation in the adult, less is known about transcriptome diversity of human hematopoietic stem cells (HSCs) during development. To characterize transcriptional and post-transcriptional changes in HSCs during development, we leveraged high-throughput genomic approaches to profile miRNAs, lincRNAs, and mRNAs. Our findings indicate that HSCs manifest distinct alternative splicing patterns in key hematopoietic regulators. Detailed analysis of the splicing dynamics and function of one such regulator, HMGA2, identified an alternative isoform that escapes miRNA-mediated targeting. We further identified the splicing kinase CLK3 that, by regulating HMGA2 splicing, preserves HMGA2 function in the setting of an increase in let-7 miRNA levels, delineating how CLK3 and HMGA2 form a functional axis that influences HSC properties during development. Collectively, our study highlights molecular mechanisms by which alternative splicing and miRNA-mediated post-transcriptional regulation impact the molecular identity and stage-specific developmental features of human HSCs.

Graphical abstract

Teaser

Human hematopoietic stem cells (HSCs) display substantial transcriptional diversity during development. Here, we investigated the contribution of alternative splicing to such diversity by analyzing the dynamics of a key hematopoietic regulator, HMGA2. Next, we showed that CLK3, by regulating the splicing pattern of HMGA2, reinforces an HSC-specific program.


https://ift.tt/2JlJF4y

Human Hippocampal Neurogenesis Persists throughout Aging

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Maura Boldrini, Camille A. Fulmore, Alexandria N. Tartt, Laika R. Simeon, Ina Pavlova, Verica Poposka, Gorazd B. Rosoklija, Aleksandar Stankov, Victoria Arango, Andrew J. Dwork, René Hen, J. John Mann
Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal dentate gyrus (DG) region, although concurrent changes in these parameters are not well studied. Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis. It is possible that ongoing hippocampal neurogenesis sustains human-specific cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience.

Graphical abstract

Teaser

Boldrini et al. find persistent adult neurogenesis in humans into the eighth decade of life, despite declines in quiescent stem cell pools, angiogenesis, and neuroplasticity. Over a 65-year age span, proliferating neural progenitors, immature and mature granule neurons, glia, and dentate gryus volume were unchanged.


https://ift.tt/2Eo3EM9

Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Ryo Yamamoto, Adam C. Wilkinson, Jun Ooehara, Xun Lan, Chen-Yi Lai, Yusuke Nakauchi, Jonathan K. Pritchard, Hiromitsu Nakauchi
Aging is linked to functional deterioration and hematological diseases. The hematopoietic system is maintained by hematopoietic stem cells (HSCs), and dysfunction within the HSC compartment is thought to be a key mechanism underlying age-related hematopoietic perturbations. Using single-cell transplantation assays with five blood-lineage analysis, we previously identified myeloid-restricted repopulating progenitors (MyRPs) within the phenotypic HSC compartment in young mice. Here, we determined the age-related functional changes to the HSC compartment using over 400 single-cell transplantation assays. Notably, MyRP frequency increased dramatically with age, while multipotent HSCs expanded modestly within the bone marrow. We also identified a subset of functional cells that were myeloid restricted in primary recipients but displayed multipotent (five blood-lineage) output in secondary recipients. We have termed this cell type latent-HSCs, which appear exclusive to the aged HSC compartment. These results question the traditional dogma of HSC aging and our current approaches to assay and define HSCs.

Graphical abstract

Teaser

Yamamoto et al. explore age-related changes to HSC function through large-scale clonal analysis using single-cell transplantation. They find large increases in myeloid-restricted repopulating progenitors (MyRPs) as well as a population of MyRPs that display a broader differentiation capacity only in secondary transplants, suggesting additional mechanisms contributing to hematopoietic aging.


https://ift.tt/2H0u6AW

Regenerative Rehabilitation: Applied Biophysics Meets Stem Cell Therapeutics

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): Thomas A. Rando, Fabrisia Ambrosio




https://ift.tt/2GG12eN

Vascular Tissue Engineering: Progress, Challenges, and Clinical Promise

Publication date: 5 April 2018
Source:Cell Stem Cell, Volume 22, Issue 4
Author(s): H.-H. Greco Song, Rowza T. Rumma, C. Keith Ozaki, Elazer R. Edelman, Christopher S. Chen




https://ift.tt/2JmNKpf

Functional-guided radiotherapy using knowledge-based planning

There are two significant challenges when implementing functional-guided radiotherapy using 4DCT-ventilation imaging: (1) lack of knowledge of realistic patient specific dosimetric goals for functional lung and (2) ensuring consistent plan quality across multiple planners. Knowledge-based planning (KBP) is positioned to address both concerns.

https://ift.tt/2q7KJRt

Initiating a Robotic Thyroidectomy Program in India

Abstract

Robotic surgery has been successfully used for many surgical indications in head and neck surgery. Robotic thyroidectomy is getting accepted worldwide, but the majority of the literature is from South Korea. The purpose of the paper is to review and give a personal perspective on how a robotic thyroidectomy program was initiated in a tertiary care academic medical institution in India. Advantages of robotic approaches are the three-dimensional visualization, precision, dexterity, and surgeon ergonomics. Cost is an important concern. Training includes basic robotics skill training, cadaveric training, observership, and hands-on training. Sufficient preclinical and clinical training is essential before embarking onto the newer surgical modality. Surgeon credentialing, though institution dependent, has specific guidelines. Case selection is the key, especially in the initial learning curve. The authors prefer the retroauricular approach for robotic thyroidectomy, and our initial experience in the first ten cases of total thyroidectomy was encouraging.

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via IFTTT

Initiating a Robotic Thyroidectomy Program in India

Abstract

Robotic surgery has been successfully used for many surgical indications in head and neck surgery. Robotic thyroidectomy is getting accepted worldwide, but the majority of the literature is from South Korea. The purpose of the paper is to review and give a personal perspective on how a robotic thyroidectomy program was initiated in a tertiary care academic medical institution in India. Advantages of robotic approaches are the three-dimensional visualization, precision, dexterity, and surgeon ergonomics. Cost is an important concern. Training includes basic robotics skill training, cadaveric training, observership, and hands-on training. Sufficient preclinical and clinical training is essential before embarking onto the newer surgical modality. Surgeon credentialing, though institution dependent, has specific guidelines. Case selection is the key, especially in the initial learning curve. The authors prefer the retroauricular approach for robotic thyroidectomy, and our initial experience in the first ten cases of total thyroidectomy was encouraging.

https://ift.tt/2qbWYvw

Association of Muscle and Adiposity Measured by CT With Survival in Patients With Breast Cancer

This observational study examines associations of sarcopenia, muscle radiodensity, and adiposity with overall mortality in nonmetastatic breast cancer.

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Linking Mismatch Repair Mutation With Age at Gynecological Cancer Onset in Lynch Syndrome

To the Editor We read with interest the article by Ryan et al suggesting that patients with truncating MLH1 mutations develop endometrial cancer (EC) at a later age compared with those with nontruncating mutations and that surveillance guidelines should be adapted to accommodate these findings. This is a relevant observation because interfamilial variance of the Lynch phenotype is a well-known problem and a tailor-made surveillance program would benefit patients. However, we believe that it is too early to draw such rigorous conclusions.

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Management of Metastatic Melanoma in 2018

This Insights discusses management strategies for metastatic melanoma using the most recent therapeutic options.

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Obesity, Body Composition, and Breast Cancer

The role of obesity in breast cancer development has been known for decades, but better and larger studies over time have uncovered more details about the complex association. There is strong evidence that obesity and weight gain during adulthood are associated with increased risk of postmenopausal breast cancer, particularly among women not using menopausal hormone therapy. On the other hand, obesity during adolescence and young adulthood is associated with reduced premenopausal breast cancer risk. Over time we also learned that what we have historically known about these associations only applies to hormone receptor–positive tumors (ie, estrogen receptor [ER]-positive and/or progesterone receptor–positive tumors). The literature on obesity and breast cancer prognosis is more recent and smaller, but currently an active research area. There is growing evidence that obesity is associated with higher breast cancer–specific and overall mortality in both women who are premenopausal and postmenopausal, with associations stronger among those with morbid obesity (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared] ≥40). Furthermore, associations may vary by race/ethnicity, depending on the adiposity measure used. Fewer studies have evaluated associations by hormone receptor status, and most had limited statistical power, particularly for estrogen receptor (ER)-negative tumors. Overall, the evidence for higher mortality associated with obesity tends to be consistent for ER-positive tumors, but inconsistent for ER-negative and triple-negative breast cancer.

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Oral Ketamine vs Placebo in Patients With Cancer-Related Neuropathic Pain

This multicenter randomized clinical trial compares oral ketamine with placebo for treating neuropathic pain in patients with cancer.

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Linking Mismatch Repair Mutation With Age at Gynecological Cancer Onset in Lynch Syndrome—Reply

In Reply We are grateful for the opportunity to respond to Bogani and colleagues about our report of an association between type of mismatch repair mutation and age of cancer onset in Lynch syndrome. They correctly state that neither endometrial nor ovarian cancers are single disease entities; their histological subtypes reflect vast differences in their biological characteristics, clinical behavior, and prognosis. They point out that if Lynch syndrome–associated gynecological cancers are heterogeneous, they might pursue different clinical courses, and a unified approach to cancer surveillance may not be appropriate.

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Linking Mismatch Repair Mutation With Age at Gynecological Cancer Onset in Lynch Syndrome

To the Editor We read with interest the article by Ryan and colleagues. We applaud the authors' excellent investigation. The research shows the association between mutated genes (MLH1, MSH2, MSH6, or PMS2) and type of mutation (ie, truncated, splicing, large rearrangement) in one of the mismatch repair genes and the age at onset of Lynch syndrome–associated malignant neoplasms.

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Long-term Accuracy of Breast Cancer Risk Assessment Combining Classic Risk Factors and Breast Density

This cohort study reports the long-term accuracy of the Tyler-Cuzick model combined with breast density in assessment of risk for breast cancer among women in a state registry.

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Clinical Trials in Medical Center Advertising

This Viewpoint evaluates whether there is benefit for medical centers to advertise the opportunity for clinical trial participation.

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Quality of life and anterior resection syndrome after surgery for mid to low rectal cancer: a cross-sectional study

Publication date: Available online 4 April 2018
Source:European Journal of Surgical Oncology
Author(s): Loris Trenti, Ana Galvez, Sebastiano Biondo, Alejandro Solis, Francesc Vallribera-Valls, Eloy Espin-Basany, Alvaro Garcia-Granero, Esther Kreisler
BackgroundThe aim of this study was to analyze the quality of life (QoL), low anterior resection syndrome (LARS) and fecal incontinence after surgery for mid to low rectal cancer and its relationship with the type of surgical procedure performed.MethodsA cross-sectional cohort survey study of 358 patients operated on for mid to low rectal cancer. Patients were included in three groups: abdominoperineal resection (APR), low mechanical colorectal anastomosis (CRA) and hand-sewn coloanal anastomosis (CAA). The QLQ-C30/CR29 questionnaires, LARS and Vaizey scores were used to study QoL and defecatory dysfunction. Multivariable analysis was used to estimate the prognostic effect of the variables on QoL and LARS scores.Results62.6% of the patients answered the survey. The global QoL score was similar among APR, CRA and CAA. Patients' body image perception was significantly worse after APR than after CRA or CAA. LARS score was better in CRA group (p=0.002). A major LARS was observed in 83.3% of the patients who underwent CAA and in 56.6% of the patients who underwent CRA. No relationship between surgical procedures and the global QoL score was observed. Neoadjuvant radiotherapy (p=0.048) and CAA (p=0.005) were associated with a major LARS. The Vaizey score was higher for CAA than for CRA (p=0.036).ConclusionsThough CAA group presents worse LARS and higher faecal incontinence scores respect CRA patients, and APR is related with a worse body image, global QoL was similar in the three groups.



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An Atypical Case of Bartonella henselae Osteomyelitis and Hepatic Disease

Bartonella henselae is a Gram-negative bacterium and the causative agent of cat scratch disease (CSD). Atypical presentations of B. henselae that involve the musculoskeletal, hepatosplenic, cardiac, or neurologic systems are rare. In this case report, we describe a case of B. henselae osteomyelitis involving bilateral iliac bones complicated by hepatic lesions in a 12-year-old immunocompetent female patient. Although B. henselae is a rare cause of osteomyelitis, it should be considered when patients who present with fever, pain, and lymphadenopathy do not respond to routine osteomyelitis therapy.

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Comparison of plasma ctDNA and tissue/cytology-based techniques for the detection of EGFR mutation status in advanced NSCLC: Spanish data subset from ASSESS

Abstract

Purpose

The analysis of epidermal growth factor receptor (EGFR) mutations in many patients with advanced non-small-cell lung cancer (aNSCLC) has provided the opportunity for successful treatment with specific, targeted EGFR tyrosine kinase inhibitors. However, this therapeutic decision may be challenging when insufficient tumor tissue is available for EGFR mutation testing. Therefore, blood surrogate samples for EGFR mutation analysis have been suggested.

Methods

Data were collected from the Spanish cohort of patients in the large, non-interventional, diagnostic ASSESS study (NCT01785888) evaluating the utility of circulating free tumor-derived DNA from plasma for EGFR mutation testing. The incidence of EGFR mutation in Spain and the level of concordance between matched tissue/cytology and plasma samples were evaluated.

Results

In a cohort of 154 eligible patients, EGFR mutations were identified in 15.1 and 11.0% of tumor and plasma samples, respectively. The most commonly used EGFR mutation testing method for the tumor tissue samples was the QIAGEN Therascreen^® EGFR RGQ PCR kit (52.1%). Fragment Length Analysis + PNA LNA Clamp was used for the plasma samples. The concordance rate for EGFR mutation status between the tissue/cytology and plasma samples was 88.8%; the sensitivity was 45.5%, and the specificity was 96.7%.

Conclusions

The high concordance between the different DNA sources for EGFR mutation testing supports the use of plasma samples when tumor tissue is unavailable.

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Postoperative intra-abdominal infection is an independent prognostic factor of disease-free survival and disease-specific survival in patients with stage II colon cancer

Abstract

Background

Recurrence occurs in up to 20% of patients with stage II colon cancer operated on for cure. Although postoperative intra-abdominal infection has been linked with an increased risk of recurrence, the association is controversial. The aim was to investigate the impact of postoperative intra-abdominal infection on disease-free survival and disease-specific survival in patients with stage II colon cancer.

Methods

Patients undergoing elective surgery for colon cancer stage II, between 2003 and 2014, were included. Patients with anastomotic leak or intra-abdominal abscess were included in the infection group. We used the Kaplan–Meier method to represent the distribution of survival and the Cox proportional hazards model to estimate the contribution of relevant clinicopathological factors with prognosis.

Results

Postoperative intra-abdominal infection was diagnosed in 37 of 363 (10.2%) patients. Perioperative blood transfusion was more frequent in patients with infection (p = 0.008). Overall 5-year disease-free survival rate was 85.1%. Disease-free survival at 5 years was lower in patients with postoperative intra-abdominal infection (52.8 vs 88.7%; p < 0.001), perineural invasion (p = 0.001), lymphovascular invasion (p = 0.001), pT4 (p = 0.013), and in patients with adjuvant chemotherapy (p = 0.013). Multivariate analysis showed that postoperative intra-abdominal infection (HR 4.275; p < 0.001), perineural invasion (HR 2.230; p = 0.007), and lymphovascular invasion (HR 2.052; p = 0.016) were all significant independent predictors of reduced disease-free survival. Regarding specific survival, independent significant prognostic factors were the number of lymph nodes, lymphovascular invasion, and postoperative intra-abdominal infection.

Conclusion

In this series of patients with stage II colon cancer, postoperative intra-abdominal infection has an independent negative impact on disease-free survival and disease-specific survival.

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Recurrent non-functioning pituitary adenomas: a review on the new pathological classification, management guidelines and treatment options

Abstract

At least 50% of surgically resected non-functioning pituitary adenomas (NFPA) recur. Either early or late adjuvant radiotherapy is highly efficacious in controlling recurrent NFPA but associates potentially burdensome complications like hypopituitarism, vascular complications or secondary neoplasm. Reoperation is indicated in bulky tumor rests compressing the optic pathway. To date, no standardized medical therapy is available for recurrent NFPA although cabergoline and temozolomide show promising results. Guidelines on the management of recurrent NFPAs are now available. The new 2017 WHO pituitary tumor classification, based on immunohistochemistry and transcription factor assessment, identifies a group of aggressive NFPA variants that may benefit from earlier adjuvant therapy. Nevertheless, NFPA patients exhibit a reduced overall life expectancy largely due to hypopituitarism and treatment-related morbidity. The management of recurrent NFPA benefits from a multidisciplinary teamwork of surgeons, endocrinologists, radiation oncologists, ophthalmologists, pathologists and neuro-radiologists in order to provide individualized therapy and anticipate deterioration.

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Comparison of plasma ctDNA and tissue/cytology-based techniques for the detection of EGFR mutation status in advanced NSCLC: Spanish data subset from ASSESS

Abstract

Purpose

The analysis of epidermal growth factor receptor (EGFR) mutations in many patients with advanced non-small-cell lung cancer (aNSCLC) has provided the opportunity for successful treatment with specific, targeted EGFR tyrosine kinase inhibitors. However, this therapeutic decision may be challenging when insufficient tumor tissue is available for EGFR mutation testing. Therefore, blood surrogate samples for EGFR mutation analysis have been suggested.

Methods

Data were collected from the Spanish cohort of patients in the large, non-interventional, diagnostic ASSESS study (NCT01785888) evaluating the utility of circulating free tumor-derived DNA from plasma for EGFR mutation testing. The incidence of EGFR mutation in Spain and the level of concordance between matched tissue/cytology and plasma samples were evaluated.

Results

In a cohort of 154 eligible patients, EGFR mutations were identified in 15.1 and 11.0% of tumor and plasma samples, respectively. The most commonly used EGFR mutation testing method for the tumor tissue samples was the QIAGEN Therascreen^® EGFR RGQ PCR kit (52.1%). Fragment Length Analysis + PNA LNA Clamp was used for the plasma samples. The concordance rate for EGFR mutation status between the tissue/cytology and plasma samples was 88.8%; the sensitivity was 45.5%, and the specificity was 96.7%.

Conclusions

The high concordance between the different DNA sources for EGFR mutation testing supports the use of plasma samples when tumor tissue is unavailable.

https://ift.tt/2IwxTDr

Postoperative intra-abdominal infection is an independent prognostic factor of disease-free survival and disease-specific survival in patients with stage II colon cancer

Abstract

Background

Recurrence occurs in up to 20% of patients with stage II colon cancer operated on for cure. Although postoperative intra-abdominal infection has been linked with an increased risk of recurrence, the association is controversial. The aim was to investigate the impact of postoperative intra-abdominal infection on disease-free survival and disease-specific survival in patients with stage II colon cancer.

Methods

Patients undergoing elective surgery for colon cancer stage II, between 2003 and 2014, were included. Patients with anastomotic leak or intra-abdominal abscess were included in the infection group. We used the Kaplan–Meier method to represent the distribution of survival and the Cox proportional hazards model to estimate the contribution of relevant clinicopathological factors with prognosis.

Results

Postoperative intra-abdominal infection was diagnosed in 37 of 363 (10.2%) patients. Perioperative blood transfusion was more frequent in patients with infection (p = 0.008). Overall 5-year disease-free survival rate was 85.1%. Disease-free survival at 5 years was lower in patients with postoperative intra-abdominal infection (52.8 vs 88.7%; p < 0.001), perineural invasion (p = 0.001), lymphovascular invasion (p = 0.001), pT4 (p = 0.013), and in patients with adjuvant chemotherapy (p = 0.013). Multivariate analysis showed that postoperative intra-abdominal infection (HR 4.275; p < 0.001), perineural invasion (HR 2.230; p = 0.007), and lymphovascular invasion (HR 2.052; p = 0.016) were all significant independent predictors of reduced disease-free survival. Regarding specific survival, independent significant prognostic factors were the number of lymph nodes, lymphovascular invasion, and postoperative intra-abdominal infection.

Conclusion

In this series of patients with stage II colon cancer, postoperative intra-abdominal infection has an independent negative impact on disease-free survival and disease-specific survival.

https://ift.tt/2GYcTYY

Recurrent non-functioning pituitary adenomas: a review on the new pathological classification, management guidelines and treatment options

Abstract

At least 50% of surgically resected non-functioning pituitary adenomas (NFPA) recur. Either early or late adjuvant radiotherapy is highly efficacious in controlling recurrent NFPA but associates potentially burdensome complications like hypopituitarism, vascular complications or secondary neoplasm. Reoperation is indicated in bulky tumor rests compressing the optic pathway. To date, no standardized medical therapy is available for recurrent NFPA although cabergoline and temozolomide show promising results. Guidelines on the management of recurrent NFPAs are now available. The new 2017 WHO pituitary tumor classification, based on immunohistochemistry and transcription factor assessment, identifies a group of aggressive NFPA variants that may benefit from earlier adjuvant therapy. Nevertheless, NFPA patients exhibit a reduced overall life expectancy largely due to hypopituitarism and treatment-related morbidity. The management of recurrent NFPA benefits from a multidisciplinary teamwork of surgeons, endocrinologists, radiation oncologists, ophthalmologists, pathologists and neuro-radiologists in order to provide individualized therapy and anticipate deterioration.

https://ift.tt/2IxJwdf

The effect of dose escalation for large squamous cell carcinomas of the anal canal

Abstract

Purpose

Chemoradiation allows for organ preservation in patients with anal cancer, but patients with large tumors (> 5 cm) have elevated rates of locoregional recurrence. With conformal radiation techniques, there is interest in dose escalation to decrease local recurrence in patients with large tumor size.

Methods/patients

The National Cancer Database (NCDB) was used to identify patients with anal cancer from 2004 to 2013 with tumors > 5 cm. Adult patients who received definitive chemoradiation were included. Patients with prior resection were excluded. High dose was defined as greater than or equal to 5940 cGy. Statistical analyses were performed using logistic regression, Kaplan–Meier, and Cox proportional hazards for overall survival (OS).

Results

In total, 1349 patients were analyzed with 412 (30.5%) receiving high-dose radiation therapy (RT). 5-year OS was 58 and 60% for high and standard dose RT, respectively (p = 0.9887). On univariate analysis, high-dose RT was not associated with improved OS (HR = 0.998, CI 0.805–1.239, p = 0.9887). On multivariate analysis, high-dose RT (HR = 0.948, CI 0.757–1.187, p = 0.6420) was not associated with improved OS but older age (HR = 1.535, CI 1.233–1.911, p = 0.0001), male sex (HR = 1.695, CI 1.382–2.080, p < 0.0001), comorbidities (HR = 1.389, CI 1.097–1.759, p = 0.0064), and long RT (HR = 1.299, CI 1.047–1.611, p = 0.0173) were significantly associated with decreased OS.

Conclusions

There was no observed difference in OS for dose escalation of anal cancers > 5 cm in this population-based analysis. Differences in local control and salvage therapy cannot be assessed through the NCDB. Whether dose escalation of large tumors may improve local control and colostomy-free survival remains an important question and is the subject of ongoing trials.

https://ift.tt/2GUANoa

Dosimetry study of 18 F-FMISO + PET/CT hypoxia imaging guidance on intensity-modulated radiation therapy for non-small cell lung cancer

Abstract

Objectives

This study was to evaluate the feasibility of simultaneous integrated boost on tumor hypoxia area by studying the dosimetric change of hypoxia imaging guidance on intensity-modulated radiation therapy for non-small cell lung cancer (NSCLC).

Methods

Five NSCLC patients with large hypoxic volume participated in this study. FDG PET/CT images were fused with CT localization images to delineate gross tumor volume. FMISO PET/CT images were fused with CT localization images to delineate hypoxic biological target volume (BTV) (tissue maximum ratio ≥ 1.3) by threshold. BTV was irradiated with 72, 78 and 84 Gy, respectively, 30 times. The dosimetry differences were compared in target volume and organ at risk between simultaneous integrated boost plans and conventional radiotherapy plans.

Results

Dosages on BTV of NSCLC hypoxic area were increased to 72, 78 and 84 Gy, respectively, by simultaneous integrated boost intensity-modulated radiation therapy. There was no obvious difference in dosage distributions on original target volume compared with those in conventional radiotherapy. Dosages on main organ at risk in chest met the dosimetric constraint, and there was no significant difference compared with those in conventional radiotherapy.

Conclusion

It is feasible in dosiology that the dosages in NSCLC hypoxic area were added to 72, 78 and 84 Gy by simultaneous integrated boost with the guidance of ¹⁸F-FMISO PET/CT.

https://ift.tt/2Ixuiox

Pathology findings and clinical outcomes after risk reduction salpingo-oophorectomy in BRCA mutation carriers: a multicenter Spanish study

Abstract

Objective

To determine the incidence of serous tubal intraepithelial carcinoma (STIC) after risk reduction salpingo-oophorectomy(RRSO), and to describe oncological outcomes after RRSO.

Materials and methods

BRCA pathogenic mutation carriers who had undergone an RRSO were evaluated in this retrospective multicenter observational study. Patients were only included when fallopian tubes were analyzed following the protocol for Sectioning and Extensively Examining the FIMbria (SEE-FIM). Surgeries were performed between June 2010 and April 2017 at eight Spanish hospitals.

Results

A total of 359 patients met the inclusion criteria. STIC was diagnosed in 3 (0.8%) patients; one of them underwent surgical staging due to positive peritoneal washing, with absence of disease at the final pathology report. None of the three patients received adjuvant chemotherapy and were free of disease at last follow-up. Fallopian tube and ovarian carcinoma were diagnosed in 5 (1.4%) and 1 (0.3%), respectively. At a median (range) follow-up time of 29 (3–92) months, five patients had a newly diagnosed breast cancer. Other types of cancer, which were diagnosed during the follow-up time, included: serous primary peritoneal carcinoma (n = 1), serous endometrial carcinoma (n = 1), colon (n = 1), pancreas (n = 1), jaw (n = 1), and lymphoma (n = 1). Seven patients died due to different types of cancer: breast (n = 4), pancreas (n = 1), jaw (n = 1), and colon (n = 1).

Conclusion

The incidence of STIC after RRSO in BRCA mutation carriers is low (0.8%) and it presents an excellent oncological outcome. Patients after RRSO, however, run the risk to develop other types of cancer during follow-up and should be properly advised before the prophylactic surgery.

https://ift.tt/2GUAJEW

Childhood and adolescent lymphoma in Spain: incidence and survival trends over 20 years

Abstract

Background

Lymphoma is the third most common malignancy in children (0–14 years) and the first in adolescents (15–19 years). This population-based study—the largest ever done in Spain—analyses incidence and survival of lymphomas among Spanish children and adolescents.

Patients and methods

1664 lymphoma cases (1983–2007) for incidence and 1030 for survival (1991–2005) followed until 31/12/2010, were provided by 11 cancer registries. Age-adjusted incidence rates (ASRw) to the world standard population were obtained; incidence trends were modelled using the Joinpoint programme, observed survival (OS) was estimated with Kaplan–Meier and trends tested with a log-rank test. Results are presented according to the International Classification of Childhood Cancer-3.

Results

In Spain, the ASRw_0–14 for lymphomas was 17.5 per 1.000.000 child-years and 50.0 the specific rate for adolescents. Overall incidence increased significantly during 1983–1997 with no increases thereafter. Patients over 9 years old showed significant rising trends for all subtypes, except for Burkitt lymphoma (BL) in adolescents. During 2001–2005 (age 0–19 years), 5-year OS was 94 (90–98), 73 (64–83) and 86 (78–94) for Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and BL, respectively. No improvement in survival was found. The incidence in Spain was higher than overall European rates, but within the range of that in Southern Europe. Comparing OS in Spain 1991–1995 and 2001–2005 with results for Europe of the Automated Childhood Cancer Information System (ACCIS) (1988–1997) and the European cancer registry-based study on survival and care of cancer patients (EUROCARE) (2000–2007), it was similar for HL and lower for NHL and BL.

Conclusions

Systematic monitoring and analysis of lymphoma paediatric data would provide clinical and epidemiological information to improve the health care of these patients and the outcomes for these malignancies in Spain.

https://ift.tt/2IvJHFK

The effect of dose escalation for large squamous cell carcinomas of the anal canal

Abstract

Purpose

Chemoradiation allows for organ preservation in patients with anal cancer, but patients with large tumors (> 5 cm) have elevated rates of locoregional recurrence. With conformal radiation techniques, there is interest in dose escalation to decrease local recurrence in patients with large tumor size.

Methods/patients

The National Cancer Database (NCDB) was used to identify patients with anal cancer from 2004 to 2013 with tumors > 5 cm. Adult patients who received definitive chemoradiation were included. Patients with prior resection were excluded. High dose was defined as greater than or equal to 5940 cGy. Statistical analyses were performed using logistic regression, Kaplan–Meier, and Cox proportional hazards for overall survival (OS).

Results

In total, 1349 patients were analyzed with 412 (30.5%) receiving high-dose radiation therapy (RT). 5-year OS was 58 and 60% for high and standard dose RT, respectively (p = 0.9887). On univariate analysis, high-dose RT was not associated with improved OS (HR = 0.998, CI 0.805–1.239, p = 0.9887). On multivariate analysis, high-dose RT (HR = 0.948, CI 0.757–1.187, p = 0.6420) was not associated with improved OS but older age (HR = 1.535, CI 1.233–1.911, p = 0.0001), male sex (HR = 1.695, CI 1.382–2.080, p < 0.0001), comorbidities (HR = 1.389, CI 1.097–1.759, p = 0.0064), and long RT (HR = 1.299, CI 1.047–1.611, p = 0.0173) were significantly associated with decreased OS.

Conclusions

There was no observed difference in OS for dose escalation of anal cancers > 5 cm in this population-based analysis. Differences in local control and salvage therapy cannot be assessed through the NCDB. Whether dose escalation of large tumors may improve local control and colostomy-free survival remains an important question and is the subject of ongoing trials.

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Dosimetry study of 18 F-FMISO + PET/CT hypoxia imaging guidance on intensity-modulated radiation therapy for non-small cell lung cancer

Abstract

Objectives

This study was to evaluate the feasibility of simultaneous integrated boost on tumor hypoxia area by studying the dosimetric change of hypoxia imaging guidance on intensity-modulated radiation therapy for non-small cell lung cancer (NSCLC).

Methods

Five NSCLC patients with large hypoxic volume participated in this study. FDG PET/CT images were fused with CT localization images to delineate gross tumor volume. FMISO PET/CT images were fused with CT localization images to delineate hypoxic biological target volume (BTV) (tissue maximum ratio ≥ 1.3) by threshold. BTV was irradiated with 72, 78 and 84 Gy, respectively, 30 times. The dosimetry differences were compared in target volume and organ at risk between simultaneous integrated boost plans and conventional radiotherapy plans.

Results

Dosages on BTV of NSCLC hypoxic area were increased to 72, 78 and 84 Gy, respectively, by simultaneous integrated boost intensity-modulated radiation therapy. There was no obvious difference in dosage distributions on original target volume compared with those in conventional radiotherapy. Dosages on main organ at risk in chest met the dosimetric constraint, and there was no significant difference compared with those in conventional radiotherapy.

Conclusion

It is feasible in dosiology that the dosages in NSCLC hypoxic area were added to 72, 78 and 84 Gy by simultaneous integrated boost with the guidance of ¹⁸F-FMISO PET/CT.

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