Risk of Proctectomy After Ileorectal Anastomosis in Familial Adenomatous Polyposis in the Modern Era.

BACKGROUND: Prophylactic surgery for familial adenomatous polyposis has evolved over several decades. Restorative proctocolectomy with IPAA provides an alternative to total abdominal colectomy with ileorectal anastomosis. We have previously shown that the rate of proctectomy and rectal cancer after total abdominal colectomy with ileorectal anastomosis in the "pre-pouch era" was 32% and 13%, respectively. OBJECTIVE: To determine the rate of proctectomy and rectal cancer among familial adenomatous polyposis patients and relative rectal sparing (fewer than 20 rectal polyps) selected for total abdominal colectomy with ileorectal anastomosis in the modern era. DESIGN: Retrospective cohort study. SETTING: Single tertiary care institution with a hereditary colorectal cancer registry. PATIENTS: Patients with familial adenomatous polyposis who underwent total abdominal colectomy with ileorectal anastomosis between 1993 and 2020. MAIN OUTCOME MEASURES: Incidence of proctectomy for any indication and rectal cancer. RESULTS: A total of 197 patients with a median age of 24 years (range, 10-67) were included. The median follow-up after total abdominal colectomy with ileorectal anastomosis was 13 years (interquartile range, 6-17). Sixteen patients (8%) underwent proctectomy. Indications included rectal cancer in 6 patients (3%; 2 stage I and 4 stage III), polyps with high-grade dysplasia in 4 (2%), progressive polyp burden in 3 (1.5%), defecatory dysfunction in 2 (1%), and anastomotic leak in 1 (0.5%). Among 30 patients (18%) with 20 or more rectal polyps at the time of total abdominal colectomy with ileorectal anastomosis, 8 patients (26%) underwent proctectomy and 3 patients developed rectal cancer (10%). Among 134 patients (82%) with fewer than 20 polyps, 8 patients (6%) underwent proctectomy and 3 patients developed rectal cancer (2%). Number of rectal polyps at the time of total abdominal colectomy with ileorectal anastomosis was associated with the likelihood of proctectomy (OR 1.1, p < 0.001) but not incident rectal cancer ( p = 0.3). LIMITATION: Retrospective data collection. CONCLUSIONS: Patients with familial adenomatous polyposis selected for total abdominal colectomy with ileorectal anastomosis by rectal polyp number have low rates of proctectomy and rectal cancer compared to historical controls. With appropriate selection criteria and surveillance, total abdominal colectomy with ileorectal anastomosis remains an important and safe treatment option for patients with familial adenomatous polyposis. See Video Abstract . RIESGO DE PROCTECTOMA DESPUS DE ANASTOMOSIS ILEORRECTAL EN POLIPOSIS ADENOMATOSA FAMILIAR EN LA ERA MODERNA: ANTECEDENTES:La cirugía profiláctica para la poliposis adenomatosa familiar (PAF) ha evolucionado durante varias décadas. La proctocolectomía restauradora con anastomosis anal con bolsa ileal (IPAA) proporciona una alternativa a la colectomía abdominal total con anastomosis ileorrectal (TAC/IRA). Anteriormente hemos demostrado que la tasa de proctectomía y cáncer de recto después de TAC/IRA en la era "pre-bolsa" era del 32% y el 13%, respectivamente.OBJETIVO:Determinar la tasa de proctectomía y cáncer de recto entre pacientes con PAF y pacientes con preservación rectal relativa (<20 pólipos rectales) seleccionados para TAC/IRA en la era moderna.DISEÑO:Estudio de cohorte retrospectivo.ÁMBITO:Institución única de atención terciaria con un registro de cáncer colorrectal hereditario.PACIENTES:Pacientes con PAF que se sometieron a TAC/IRA entre 1993 y 2020.MEDIDAS DE RESULTADO PRINCIPALES:Incidencia de proctectomía por cualquier indicación y cáncer de recto.RESULTADOS:Se incluyeron 197 pacientes con una mediana de edad de 24 años (rango 10-67). La mediana de seguimiento tras TAC/IRA fue de 13 años (RIC 6-17). 16 pacientes (8%) fueron sometidos a proctectomía. Las indicaciones incluyeron cáncer de recto en 6 (3%) (2 en estadio I y 4 en estadio III); pólipos con displasia de alto grado en 4 (2%); carga progresiva de pólipos en 3 (1,5%), disfunción defecatoria en 2 (1%); y fuga anastomótica en 1 (0,5%). Entre 30 pacientes (18%) con ≥20 pólipos rectales en el momento de TAC/IRA, 8 pacientes (26%) se sometieron a proctectomía y 3 pacientes desarrollaron cáncer de recto (10%). Entre 134 pacientes (82%) con <20 pólipos, 8 pacientes (6%) se sometieron a proctectomía y 3 pacientes desarrollaron cáncer de recto (2%). El número de pólipos rectales en el momento de TAC/IRA se asoció con la probabilidad de proctectomía (OR 1,1, p <0,001), pero no con la incidencia de cáncer de recto (p = 0,3).LIMITACIÓN:Recopilación de datos retrospectivos.CONCLUSIÓN:Los pacientes con PAF seleccionados para TAC/IRA por el número de pólipos rectales tienen tasas bajas de proctectomía y cáncer de recto en comparación con los controles históricos. Con criterios de selección y vigilancia adecuados, TAC/IRA sigue siendo una opción de tratamiento importante y segura para los pacientes con PAF. (Pre-proofed version ).

Tofacitinib Is Associated With Increased Risk of Postoperative Venous Thromboembolism in Patients With Ulcerative Colitis.

BACKGROUND: In 2019, the Food and Drug Administration issued a black box warning for increased risk of venous thromboembolism in patients with rheumatoid arthritis exposed to tofacitinib. There are limited data regarding postoperative venous thromboembolism risk in patients with ulcerative colitis exposed to tofacitinib. OBJECTIVE: To assess whether preoperative exposure to tofacitinib is associated with increased odds of postoperative venous thromboembolism. DESIGN: Retrospective review. SETTINGS: Tertiary academic medical center. PATIENTS: Consecutive patients exposed to tofacitinib within 4 weeks before total abdominal colectomy or total proctocolectomy, with or without ileostomy, from 2014 to 2021, matched 1:2 for tofacitinib exposure or no exposure. INTERVENTION: Tofacitinib exposure versus no exposure. MAIN OUTCOME MEASURES: Ninety-day postoperative venous thromboembolism rate. RESULTS: Forty-two patients with tofacitinib exposure and 84 case-matched patients without tofacitinib exposure underwent surgery for medically refractory ulcerative colitis. Nine (22.0%) tofacitinib-exposed patients and 7 (8.5%) unexposed patients were diagnosed with venous thromboembolism within 90 days of surgery. In univariate logistic regression, patients exposed to tofacitinib had 3.01 times increased odds of developing venous thromboembolism within 90 days after surgery compared to unexposed patients ( p = 0.04; 95% CI, 1.03-8.79). Other venous thromboembolism risk factors were not significantly associated with venous thromboembolisms. Venous thromboembolisms in both groups were most commonly portomesenteric vein thromboses (66.7% in the tofacitinib-exposed group and 42.9% in the unexposed group) and were diagnosed at a mean of 23.2 days (range, 3-90 days) postoperatively in the tofacitinib-exposed group and 7.9 days (1-19 days) in the unexposed group. There were no statistically significant differences in location or timing between the 2 groups. LIMITATIONS: Retrospective nature of the study and associated biases. Reliance on clinically diagnosed venous thromboembolisms may underreport the true incidence rate. CONCLUSIONS: Tofacitinib exposure before surgery for medically refractory ulcerative colitis is associated with 3 times increased odds of venous thromboembolism compared with patients without tofacitinib exposure. See Video Abstract . TOFACITINIB SE ASOCIA CON UN MAYOR RIESGO DE TROMBOEMBOLISMO VENOSO POSTOPERATORIO EN PACIENTES CON COLITIS ULCEROSA: ANTECEDENTES:En 2019, la FDA emitió una advertencia de recuadro negro sobre un mayor riesgo de tromboembolismo venoso en pacientes con artritis reumatoide expuestos a tofacitinib. Hay datos limitados sobre el riesgo de tromboembolismo venoso postoperatorio en pacientes con colitis ulcerosa expuestos a tofacitinib.OBJETIVO:Evaluar si la exposición preoperatoria a tofacitinib se asocia con mayores probabilidades de tromboembolismo venoso postoperatorio.DISEÑO:Revisión retrospectiva.LUGARES:Centro médico académico terciario.PACIENTES:Pacientes consecutivos expuestos a tofacitinib dentro de las 4 semanas previas a la colectomía abdominal total o proctocolectomía total, con o sin ileostomía, entre 2014 y 2021, emparejados 1:2 para exposición a tofacitinib o ninguna exposición.INTERVENCIÓN(S):Exposición a tofacitinib versus ninguna exposición.PRINCIPALES MEDIDAS DE RESULTADO:Tasa de tromboembolismo venoso posoperatorio a los 90 días.RESULTADOS:Cuarenta y dos pacientes con exposición a tofacitinib y 84 pacientes de casos similares sin exposición a tofacitinib se sometieron a cirugía por colitis ulcerosa médicamente refractaria. Nueve (22,0%) pacientes expuestos a tofacitinib y 7 (8,5%) pacientes no expuestos fueron diagnosticados con tromboembolismo venoso dentro de los 90 días posteriores a la cirugía. En la regresión logística univariada, los pacientes expuestos a tofacitinib tuvieron 3,01 veces más probabilidades de desarrollar un tromboembolismo venoso dentro de los 90 días posteriores a la cirugía en comparación con los no expuestos ( p = 0,04, IC del 95 %: 1,03-8,79). Otros factores de riesgo de tromboembolismo venoso no se asociaron significativamente con el tromboembolismo venoso. Los tromboembolismos venosos en ambos grupos fueron más comúnmente trombosis de la vena portomesentérica (66,7% en los expuestos a tofacitinib y 42,9% en los no expuestos) y se diagnosticaron en una media de 23,2 días (rango, 3-90 días) después de la operación en los expuestos a tofacitinib y 7,9 días. (1-19 días) en los grupos no expuestos, respectivamente. No hubo diferencias estadísticamente significativas en la ubicación o el momento entre los dos grupos.LIMITACIONES:Carácter retrospectivo del estudio y sesgos asociados. La dependencia de tromboembolismos venosos diagnosticados clínicamente puede subestimar la tasa de incidencia real.CONCLUSIONES:La exposición a tofacitinib antes de la cirugía para la colitis ulcerosa médicamente refractaria se asocia con probabilidades 3 veces mayores de tromboembolismo venoso en comparación con los pacientes sin exposición a tofacitinib. (Traducción-Dr. Mauricio Santamaria ).

Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex.

The anaphase-promoting complex (APC/C) orchestrates progression through mitosis by decorating cell-cycle regulators with ubiquitin chains. To nucleate chains, the APC/C links ubiquitin to a lysine in substrates, but to elongate chains it modifies lysine residues in attached ubiquitin moieties. The mechanism enabling the APC/C, and ubiquitin ligases in general, to switch from lysine residues in substrates to specific ones in ubiquitin remains poorly understood. Here, we determine the topology and the mechanism of assembly for the ubiquitin chains mediating functions of the human APC/C. We find that the APC/C triggers substrate degradation by assembling K11-linked ubiquitin chains, the efficient formation of which depends on a surface of ubiquitin, the TEK-box. Strikingly, homologous TEK-boxes are found in APC/C substrates, where they facilitate chain nucleation. We propose that recognition of similar motifs in substrates and ubiquitin enables the APC/C to assemble ubiquitin chains with the specificity and efficiency required for tight cell-cycle control.

DNA methylome in pancreatic cancer identified novel promoter hyper-methylation in NPY and FAIM2 genes associated with poor prognosis in Indian patient cohort.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading cancers worldwide and has a poor survival, with a 5-year survival rate of only 8.5%. In this study we investigated altered DNA methylation associated with PDAC severity and prognosis. METHODS: Methylome data, generated using 450 K bead array, was compared between paired PDAC and normal samples in the TCGA cohort (n = 9) and our Indian cohort (n = 7). The total Indian Cohort (n = 75) was split into cohort 1 (n = 7), cohort 2 (n = 22), cohort 3 (n = 26) and cohort 4 (n = 20).Validation of differential methylation (6 selected CpG loci) and associated gene expression for differentially methylated genes (10 selected gDMs) were carried out in separate validation cohorts, using MSP, RT-PCR and IHC correlations between methylation and gene expression were observed in TCGA, GTEx cohorts and in validation cohorts. Kaplan-Meier survival analysis was done to study differential prognosis, during 2-5 years of follow-up. RESULTS: We identified 156 DMPs, mapped to 91 genes (gDMs), in PDAC; 68 (43.5%) DMPs were found to be differentially methylated both in TCGA cohort and our cohort, with significant concordance at hypo- and hyper-methylated loci. Enrichments of "regulation of ion transport", "Interferon alpha/beta signalling", "morphogenesis and development" and "transcriptional dysregulation" pathways were observed among 91 gDMs. Hyper-methylation of NPY and FAIM2 genes with down-regulated expression in PDAC, were significantly associated with poor prognosis in the Indian patient cohort. CONCLUSIONS: Ethnic variations among populations may determine the altered epigenetic landscape in the PDAC patients of the Indian cohort. Our study identified novel differentially methylated genes (mainly NPY and FAIM2) and also validated the previously identified differentially methylated CpG sites associated with PDAC cancer patient's survival. Comparative analysis of our data with TCGA and CPTAC cohorts showed that both NPY and FAIM2 hyper-methylation and down-regulations can be novel epigenetically regulated genes in the Indian patient population, statistically significantly associated with poor survival and advanced tumour stages.

Commission on Cancer Facility Type is Associated with Overall Survival in Patients with Gastric Adenocarcinoma in the United States.

BACKGROUND: In the United States, "high-volume" centers for gastric cancer treat significantly fewer cases per year compared with centers in Asia. Factors associated with oncologic outcomes, aside from volume, are poorly understood. METHODS: Patients with gastric adenocarcinoma between 2004 and 2015 were analyzed in the NCDB cohort. Commission on Cancer facility types were classified as either Academic/Research Programs (ARP) or Non-Academic Programs (NAP). Factors associated with treatment at facility type were assessed by logistic regression. Overall survival was compared between facility types by Cox proportional hazard models. RESULTS: Thirty-nine percent of patients were treated at ARPs. In multivariable analysis, patients treated at ARPs were younger, healthier (Charlson-Deyo score), and had lower AJCC stage. Treatment at an ARP was associated with superior median OS compared with treatment at a NAP (17.3 months vs. 11.1 months, respectively, P < 0.001,) and in each stage of disease. Treatment of stages II and III patients at ARPs increased over time. Among patients with stages II and III disease, adherence to therapy guidelines was higher and postoperative mortality was lower at ARPs. CONCLUSION: Although patients at ARPs tend to have favorable characteristics, superior overall survival may also be due to better adherence to therapy guidelines and capacity to rescue after surgical complications.

Current management of succinate dehydrogenase-deficient gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are increasingly recognized as having diverse biology. With the development of tyrosine kinase inhibitors molecularly matched to oncogenic KIT and PDGFRA mutations, GISTs have become a quintessential model for precision oncology. However, about 5-10% of GIST lack these driver mutations and are deficient in succinate dehydrogenase (SDH), an enzyme that converts succinate to fumarate. SDH deficiency leads to accumulation of succinate, an oncometabolite that promotes tumorigenesis. SDH-deficient GISTs are clinically unique in that they generally affect younger patients and are associated with GIST-paraganglioma hereditary syndrome, also known as Carney-Stratakis Syndrome. SDH-deficient GISTs are generally resistant to tyrosine-kinase inhibitors, the standard treatment for advanced or metastatic GIST. Thus, surgical resection is the mainstay of treatment for localized disease, but recurrence is common. Clinical trials are currently underway investigating systemic agents for treatment of advanced SDH-deficient GIST. However, further studies are warranted to improve our understanding of SDH-deficient GIST disease biology, natural history, surgical approaches, and novel therapeutics.

A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients.

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is a cancer of the exocrine pancreas and 5-year survival rates remain constant at 7%. Along with PDAC, Periampullary Adenocarcinoma (PAC) accounts for 0.5-2% of all gastrointestinal malignancies. Genomic observations were well concluded for PDAC and PACs in western countries but no reports are available from India till now. METHODS: Targeted Next Generation Sequencing were performed in 8 (5 PDAC and 3 PAC) tumour normal pairs, using a panel of 412 cancer related genes. Primary findings were replicated in 85 tumour samples (31 PDAC and 54 PAC) using the Sanger sequencing. Mutations were also validated by ASPCR, RFLP, and Ion Torrent sequencing. IHC along with molecular dynamics and docking studies were performed for the p.A138V mutant of TP53. Key polymorphisms at TP53 and its associated genes were genotyped by PCR-RFLP method and association with somatic mutations were evaluated. All survival analysis was done using the Kaplan-Meier survival method which revealed that the survival rates varied significantly depending on the somatic mutations the patients harboured. RESULTS: Among the total 114 detected somatic mutations, TP53 was the most frequently mutated (41%) gene, followed by KRAS, SMAD4, CTNNB1, and ERBB3. We identified a novel hotspot TP53 mutation (p.A138V, in 17% of all patients). Low frequency of KRAS mutation (33%) was detected in these samples compared to patients from Western counties. Molecular Dynamics (MD) simulation and DNA-protein docking analysis predicted p.A138V to have oncogenic characteristics. Patients with p.A138V mutation showed poorer overall survival (p = 0.01). So, our finding highlights elevated prevalence of the p53p.A138V somatic mutation in PDAC and pancreatobiliary PAC patients. CONCLUSION: Detection of p.A138V somatic variant in TP53 might serve as a prognostic marker to classify patients. It might also have a role in determining treatment regimes. In addition, low frequency of KRAS hotspot mutation mostly in Indian PDAC patient cohort indicates presence of other early drivers in malignant transformation.

Differential methylation landscape of pancreatic ductal adenocarcinoma and its precancerous lesions.

BACKGROUND: Pancreatic cancer is one of the most lethal diseases with an incidence almost equal to the mortality. In addition to having genetic causes, cancer can also be considered an epigenetic disease. DNA methylation is the premier epigenetic modification and patterns of aberrant DNA methylation are recognized to be a common hallmark of human tumor. In the multistage carcinogenesis of pancreas starting from precancerous lesions to pancreatic ductal adenocarcinoma (PDAC), the epigenetic changes play a significant role. DATA SOURCES: Relevant studies for this review were derived via an extensive literature search in PubMed via using various keywords such as pancreatic ductal adenocarcinoma, precancerous lesions, methylation profile, epigenetic biomarkers that are relevant directly or closely associated with the concerned area of our interest. The literature search was intensively done considering a time frame of 20 years (1998-2018). RESULT: In this review we have highlighted the hypermethylation and hypomethylation of the precancerous PDAC lesions (pancreatic intra-epithelial neoplasia, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm and chronic pancreatitis) and PDAC along with the potential biomarkers. We have also achieved the early epigenetic driver that leads to progression from precancerous lesions to PDAC. A bunch of epigenetic driver genes leads to progression of precancerous lesions to PDAC (ppENK, APC, p14/5/16/17, hMLH1 and MGMT) are also documented. We summarized the importance of these observations in therapeutics and diagnosis of PDAC hence identifying the potential use of epigenetic biomarkers in epigenetic targeted therapy. Epigenetic inactivation occurs by hypermethylation of CpG islands in the promoter regions of tumor suppressor genes. We listed all hyper- and hypomethylation of CpG islands of several genes in PDAC including its precancerous lesions. CONCLUSIONS: The concept of the review would help to understand their biological effects, and to determine whether they may be successfully combined with other epigenetic drugs. However, we need to continue our research to develop more specific DNA-demethylating agents, which are the targets for hypermethylated CpG methylation sites.

Loss of the PTCH1 tumor suppressor defines a new subset of plexiform fibromyxoma.

BACKGROUND: Plexiform fibromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor. These so-called "benign" tumors often present with upper GI bleeding and gastric outlet obstruction. It was recently demonstrated that approximately one-third of PF have activation of the GLI1 oncogene, a transcription factor in the hedgehog (Hh) pathway, via a MALAT1-GLI1 fusion protein or GLI1 up-regulation. Despite this discovery, the biology of most PFs remains unknown. METHODS: Next generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded (FFPE) samples of PF specimens collected from three institutions (UCSD, NCI and OHSU). Fresh frozen tissue from one tumor was utilized for in vitro assays, including quantitative RT-PCR and cell viability assays following drug treatment. RESULTS: Eight patients with PF were identified and 5 patients' tumors were analyzed by NGS. An index case had a mono-allelic PTCH1 deletion of exons 15-24 and a second case, identified in a validation cohort, also had a PTCH1 gene loss associated with a suspected long-range chromosome 9 deletion. Building on the role of Hh signaling in PF, PTCH1, a tumor suppressor protein, functions upstream of GLI1. Loss of PTCH1 induces GLI1 activation and downstream gene transcription. Utilizing fresh tissue from the index PF case, RT-qPCR analysis demonstrated expression of Hh pathway components, SMO and GLI1, as well as GLI1 transcriptional targets, CCND1 and HHIP. In turn, short-term in vitro treatment with a Hh pathway inhibitor, sonidegib, resulted in dose-dependent cell killing. CONCLUSIONS: For the first time, we report a novel association between PTCH1 inactivation and the development of plexiform fibromyxoma. Hh pathway inhibition with SMO antagonists may represent a target to study for treating a subset of plexiform fibromyxomas.

Frequent rectal gastrointestinal stromal tumor recurrences in the imatinib era: Retrospective analysis of an International Patient Registry.

INTRODUCTION: Rectal gastrointestinal stromal tumor (GIST) is rare and comprises about 3% of GIST. METHODS: Registry data was collected by the Life Raft Group June 1976 to November 2017. All patients had a histologic GIST diagnosis. Demographic, clinicopathologic, and clinical outcome data were patient reported. Recurrence-free survival (RFS) was analyzed using the Kaplan-Meier method and Cox regression analysis. RESULTS: Of 1798 patients in the database, 48 had localized rectal GIST (2.7%). Patients were frequently male (58.3%) and non-Hispanic whites (58.3%). Median age at diagnosis was 52 years. Most patients (77%) were diagnosed in the imatinib era (2001 to current). Over half (54.2%) of the cohort had mutation testing and all profiled tumors possessed KIT mutations (exon 9: 7.7%, exon 11: 88.5%, and exon 13: 3.8%). Most evaluable patients (26/28; 92.9%) had high-risk disease (modified NIH criteria) and nearly all patients (95.8%) received imatinib. Median follow-up was 8.8 years (range, 0.3-30.7) and overall RFS was 8.0 years (95% CI, 2.9-13.1). Thirty-two percent (12/37) of patients in the post-imatinib era developed recurrent disease. Diagnosis in the imatinib era was associated with improved RFS (HR = 0.22, 95% CI, 0.08-0.62; P = .004) in the multivariable model. CONCLUSION: We find that disease recurrence remains prevalent in one-third of patients treated during the imatinib-era.

Regulation of ubiquitin chain initiation to control the timing of substrate degradation.

Processive reactions, such as transcription or translation, often proceed through distinct initiation and elongation phases. The processive formation of polymeric ubiquitin chains can accordingly be catalyzed by specialized initiating and elongating E2 enzymes, but the functional significance for this division of labor has remained unclear. Here, we have identified sequence motifs in several substrates of the anaphase-promoting complex (APC/C) that are required for efficient chain initiation by its E2 Ube2C. Differences in the quality and accessibility of these chain initiation motifs can determine the rate of a substrate's degradation without affecting its affinity for the APC/C, a mechanism used by the APC/C to control the timing of substrate proteolysis during the cell cycle. Based on our results, we propose that initiation motifs and their cognate E2s allow E3 enzymes to exert precise temporal control over substrate degradation.

Electron Trapping from Interactions between Laser-Driven Relativistic Plasma Waves.

Interactions of large-amplitude relativistic plasma waves were investigated experimentally by propagating two synchronized ultraintense femtosecond laser pulses in plasma at oblique crossing angles to each other. The electrostatic and electromagnetic fields of the colliding waves acted to preaccelerate and trap electrons via previously predicted, but untested injection mechanisms of ponderomotive drift and wake-wake interference. High-quality energetic electron beams were produced, also revealing valuable new information about plasma-wave dynamics.

Genetic Alterations of Periampullary and Pancreatic Ductal Adenocarcinoma: An Overview.

Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies of all solid cancers. Precancerous lesions for PDAC include PanIN, IPMNs and MCNs. PDAC has a poor prognosis with a 5-year survival of approximately 6%. Whereas Periampulary AdenoCarcinoma (PAC) having four anatomic subtypes, pancreatic, Common Bile Duct (CBD), ampullary and duodenum shows relative better prognosis. The highest incidence of PDAC has been reported with black with respect to white population. Similarly, incidence rate of PAC also differs with different ethnic populations. Several lifestyle, environmental and occupational exposures including long-term diabetes, obesity, and smoking, have been linked to PDAC, however, for PAC the causal risk factors were poorly described. It is now clear that PDAC and PAC are a multi-stage process resulting from the accumulation of genomic alterations in the somatic DNA of normal cells as well as inherited mutations. Approximately 10% of PDAC have a familial inheritance. Germline mutations in CDKN2A, BRCA2, STK11, PALB2, PRSS1, etc., as well as certain syndromes have been well associated with predisposition to PDAC. KRAS, CDKN2A, TP53 and SMAD4 are the 4 "mountains" (high-frequency driver genes) which have been known to earliest somatic alterations for PDAC while relatively less frequent in PAC. Our understanding of the molecular carcinogenesis has improved in the last few years due to extensive research on PDAC which was not well explored in case of PAC. The genetic alterations that have been identified in PDAC and different subgroups of PAC are important implications for the development of genetic screening test, early diagnosis, and prognostic genetic markers. The present review will provide a brief overview of the incidence and prevalence of PDAC and PAC, mainly, increased risk in India, the several kinds of risk factors associated with the diseases as well as required genetic alterations for disease initiation and progression.

A computed tomography radiogenomic biomarker predicts microvascular invasion and clinical outcomes in hepatocellular carcinoma.

UNLABELLED: Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is an independent predictor of poor outcomes subsequent to surgical resection or liver transplantation (LT); however, MVI currently cannot be adequately determined preoperatively. Radiogenomic venous invasion (RVI) is a contrast-enhanced computed tomography (CECT) biomarker of MVI derived from a 91-gene HCC "venous invasion" gene expression signature. Preoperative CECTs of 157 HCC patients who underwent surgical resection (N = 72) or LT (N = 85) between 2000 and 2009 at three institutions were evaluated for the presence or absence of RVI. RVI was assessed for its ability to predict MVI and outcomes. Interobserver agreement for scoring RVI was substantial among five radiologists (κ = 0.705; P < 0.001). The diagnostic accuracy, sensitivity, and specificity of RVI in predicting MVI was 89%, 76%, and 94%, respectively. Positive RVI score was associated with lower overall survival (OS) than negative RVI score in the overall cohort (P < 0.001; 48 vs. >147 months), American Joint Committee on Cancer tumor-node-metastasis stage II (P < 0.001; 34 vs. >147 months), and in LT patients within Milan criteria (P < 0.001; 69 vs. >147 months). Positive RVI score also portended lower recurrence-free survival at 3 years versus negative RVI score (P = 0.001; 27% vs. 62%). CONCLUSION: RVI is a noninvasive radiogenomic biomarker that accurately predicts histological MVI in HCC surgical candidates. Its presence on preoperative CECT is associated with early disease recurrence and poor OS and may be useful for identifying patients less likely to derive a durable benefit from surgical treatment.

The Radiogenomic Risk Score: Construction of a Prognostic Quantitative, Noninvasive Image-based Molecular Assay for Renal Cell Carcinoma.

PURPOSE: To evaluate the feasibility of constructing radiogenomic-based surrogates of molecular assays (SOMAs) in patients with clear-cell renal cell carcinoma (CCRCC) by using data extracted from a single computed tomographic (CT) image. MATERIALS AND METHODS: In this institutional review board approved study, gene expression profile data and contrast material-enhanced CT images from 70 patients with CCRCC in a training set were independently assessed by two radiologists for a set of predefined imaging features. A SOMA for a previously validated CCRCC-specific supervised principal component (SPC) risk score prognostic gene signature was constructed and termed the radiogenomic risk score (RRS). It uses the microarray data and a 28-trait image array to evaluate each CT image with multiple regression of gene expression analysis. The predictive power of the RRS SOMA was then prospectively validated in an independent dataset to confirm its relationship to the SPC gene signature (n = 70) and determination of patient outcome (n = 77). Data were analyzed by using multivariate linear regression-based methods and Cox regression modeling, and significance was assessed with receiver operator characteristic curves and Kaplan-Meier survival analysis. RESULTS: Our SOMA faithfully represents the tissue-based molecular assay it models. The RRS scaled with the SPC gene signature (R = 0.57, P < .001, classification accuracy 70.1%, P < .001) and predicted disease-specific survival (log rank P < .001). Independent validation confirmed the relationship between the RRS and the SPC gene signature (R = 0.45, P < .001, classification accuracy 68.6%, P < .001) and disease-specific survival (log-rank P < .001) and that it was independent of stage, grade, and performance status (multivariate Cox model P < .05, log-rank P < .001). CONCLUSION: A SOMA for the CCRCC-specific SPC prognostic gene signature that is predictive of disease-specific survival and independent of stage was constructed and validated, confirming that SOMA construction is feasible.

Wavefront-correction for nearly diffraction-limited focusing of dual-color laser beams to high intensities.

We demonstrate wavefront correction of terawatt-peak-power laser beams at two distinct and well-separated wavelengths. Simultaneous near diffraction-limited focusability is achieved for both the fundamental (800 nm) and second harmonic (400 nm) of Ti:sapphire-amplified laser light. By comparing the relative effectiveness of various correction loops, the optimal ones are found. Simultaneous correction of both beams of different color relies on the linear proportionality between their wavefront aberrations. This method can enable two-color experiments at relativistic intensities.

Generation of 9 MeV γ-rays by all-laser-driven Compton scattering with second-harmonic laser light.

Gamma-ray photons with energy >9 MeV were produced when second-harmonic-generated laser light (3 eV) inverse-Compton-scattered from a counterpropagating relativistic (~450 MeV) laser-wakefield-accelerated electron beam. Two laser pulses from the same laser system were used: one to accelerate electrons and one to scatter. Since the two pulses play very different roles in the γ-ray generation process, and thus have different requirements, a novel laser system was developed. It separately and independently optimized the optical properties of the two pulses. This approach also mitigated the deleterious effects on beam focusing that generally accompany nonlinear optics at high peak-power levels.

Adaptive-feedback spectral-phase control for interactions with transform-limited ultrashort high-power laser pulses.

Fourier-transform-limited light pulses were obtained at the laser-plasma interaction point of a 100-TW peak-power laser in vacuum. The spectral-phase distortion induced by the dispersion mismatching between the stretcher, compressor, and dispersive materials was fully compensated for by means of an adaptive closed-loop. The coherent temporal contrast on the sub-picosecond time scale was two orders of magnitude higher than that without adaptive control. This novel phase control capability enabled the experimental study of the dependence of laser wakefield acceleration on the spectral phase of intense laser light.