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Introduction  Multivisceral resections (MVRs) in gastric cancer are potentially curable in selected patients in whom clear resection margins are possible. However, there are still uncertain data on their feasibility and safety considering short- and long-term results. The study compares survival, morbidity, mortality, and other secondary outcomes between standard and MVRs for gastric cancer. Materials and Methods  A monocentric retrospective study in patients with gastric adenocarcinoma, covering 2004 to 2020. Of the 336 operable cases, 101 patients underwent MVRs. The remaining 235 underwent standard gastric resections (SGRs), of which 173 patients were in stage T3/T4. To compare survival, a control group of 101 patients with palliative procedures was used-bypass anastomosis or exploration. Results  MVR had a lower survival rate than the SGR but significantly higher than the palliative procedures. The predominant gender in MVR was male (72.3%), with a mean age of 61 years. The perioperative mortality was 3.96% ( n  = 4), and the overall median survival was 28.1 months. The most frequently resected organs were the spleen (67.3%), followed by the pancreas (32.7%) and the liver (20.8%). In 56.4% of the cases two organs were resected, in 28.7% three organs, and in 13.9% four organs. The main complication was bleeding (9.9%). The major postoperative complications in the MVR were 14.85%, and in the SGR 6.4% ( p  < 0.05). Better long-term results were observed in patients who underwent R0 resections compared with R1. Conclusion  Multiorgan resections are characterized by poorer survival and a higher complication rate than gastrectomies. On the other hand, they have better long-term outcomes than palliative procedures. However, MVRs are admissible when performed by an experienced surgical team in high-volume centers., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

We report the transmission of acute myeloid leukemia (AML) undetected at donation from a deceased organ donor to two kidneys and one liver recipients. We reviewed the medical records, and performed molecular analyses and whole exome sequencing (WES) to ascertain AML donor origin and its molecular evolution. The liver recipient was diagnosed 11 months after transplantation and died from complications 2 months later. The two kidney recipients (R1 and R2) were diagnosed 19 and 20 months after transplantation and both received treatment for leukemia. R1 died of complications 11 months after diagnosis, while R2 went into complete remission for 44 months, before relapsing. R2 died 10 months later of complications from allogenic bone marrow transplantation. Microsatellite analysis demonstrated donor chimerism in circulating cells from both kidney recipients. Targeted molecular analyses and medical records revealed NPM1 mutation present in the donor and recipients, while FLT3 was mutated only in R1. These findings were confirmed by WES, which revealed additional founder and clonal mutations, and HLA genomic loss in R2. In conclusion, we report the first in-depth genomic analysis of AML transmission following solid organ transplantation, revealing distinct clonal evolution, and providing a potential molecular explanation for tumor escape., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Abstract., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hemobilia is an extremely rare cause of upper gastrointestinal bleeding. It often has intermittent manifestation, which may lead to significant diagnostic delay. In 65% of the cases, the causes are iatrogenic, in 7% the cause is malignancy, in 5% - gallstones, in 8% it is inflammation (cholecystitis, parasites, reflux cholangitis), vascular abnormality is the cause in 7% (most commonly pseudoaneurysm of the hepatic artery), and pancreatic pseudocyst causes hemobilia in 1%. In almost all cases, the bleeding originates from intrahepatic or extrahepatic bile ducts, and rarely from the pancreas., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: We present a comparative analysis of survival, complications and major risk factors in patients who underwent surgery for pancreatic head carcinoma. Methods: This is a single-centre retrospective study aimed to evaluate clinical, surgical and pathoanatomical features of 467 patients who underwent radical surgery for pancreatic head carcinoma between September 2004 and October 2019. The series includes 88 patients (18.8%) with venous resections for borderline resectable pancreatic adenocarcinoma. Results: The estimated median survival rates were statistically significant with 19.3 months in pancreatoduodenal venous resections (VR) and 26.9 months in pancreatoduodenal resections (PDR), respectively (p=0.047). On the other hand, one, three, and five-year survival rates of 46.6%, 17.6% and 8.3% in VR, and 53.6%, 20.8%, 14.9% in PDR were not statistically significant (p=0.13, 0.5 and 0.11 respectively). Survival rates comparison in PDR, VR, and palliative procedures (PP) between the three groups showed statistical significance (p 0.05). The clinically relevant postoperative complications in venous resections (13.6%) vs. 14.8% in PDR were not statistically significant (p=0.77). Postoperative bleeding and reoperation (p 0.05) are independent prognostic factors for worse outcomes. There was no statistically significant relationship between survival and presence of vascular invasion (p=0.581). Conclusions: When performed by experienced surgeons at specialized high-volume centres, pancreatoduodenal resections combined with venous resection and reconstruction are reliable and safe surgical procedures., (Celsius.)

Background: Tumours involving the supra-renal segment of IVC have dismal prognosis if left untreated. Currently, aggressive surgical management is the only potentially curative treatment but is associated with relatively high morbidity and mortality. This study aims to evaluate perioperative factors, associated with adverse postoperative outcomes, based on the perioperative characteristics and type of IVC reconstruction., Methods: We identified 44 consecutive patients, who underwent supra-renal IVC resection with a mean age of 57.3 years. Isolated resection of IVC was performed in four patients, concomitant liver resection was performed in 27 patients and other associated resection in 13 patients. Total vascular exclusion was applied in 21 patients, isolated IVC occlusion in 11 patients. Neither venovenous bypass (VVB) nor hypothermic perfusion was used in any of the cases., Results: The mean operative time was 205 min (150-324 min) and the mean estimated blood loss was 755 ml (230-4500 ml). Overall morbidity was 59% and major complications (Dindo-Clavien ≥ III) occurred in 11 patients (25%). The 90-day mortality was 11% (5pts). Intraoperative haemotransfusion was significantly associated with postoperative general complications (p < 0,001). With a mean follow-up of 26.2 months, the actuarial 1-, 3- and 5-year survival is 69%, 34%, and 16%, respectively., Conclusions: IVC resection and reconstruction in the aspect of aggressive surgical management of malignant disease confers a survival advantage in patients, often considered unresectable. When performed in experienced centres it is associated with acceptable morbidity and mortality.

Purpose: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution., Patients and Methods: We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial., Results: The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia ( n = 1); seizure, somnolence, and delirium ( n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia ( n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects., Conclusions: Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690., (©2020 American Association for Cancer Research.)

Despite decades of research and an enormity of resultant data, cancer remains a significant public health problem. New tools and fresh perspectives are needed to obtain fundamental insights, to develop better prognostic and predictive tools, and to identify improved therapeutic interventions. With increasingly common genome-scale data, one suite of algorithms and concepts with potential to shed light on cancer biology is phylogenetics, a scientific discipline used in diverse fields. From grouping subsets of cancer samples to tracing subclonal evolution during cancer progression and metastasis, the use of phylogenetics is a powerful systems biology approach. Well-developed phylogenetic applications provide fast, robust approaches to analyze high-dimensional, heterogeneous cancer data sets. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Mutations detected in cancers are often divided into "drivers" and "passengers." We suggest that this classification is potentially misleading for purposes of early detection and prevention. Specifically, some mutations are frequent in tumors and thus appear to be drivers, but are poor predictors of cancer; other mutations are individually rare and thus appear to be passengers, but may collectively explain a large proportion of risk. The assumptions bundled into the terms "driver" and "passenger" can lead to misunderstandings of neoplastic progression, with unintended consequences including overdiagnosis, overtreatment, and failure to identify the true sources of risk. We argue that samples from healthy, benign, or neoplastic tissues are critical for evaluating the risk of future cancer posed by mutations in a given gene. Cancer Prev Res; 9(5); 335-8. ©2016 AACR., (©2016 American Association for Cancer Research.)

When multiple samples are taken from the neoplastic tissues of a single patient, it is natural to compare their mutation content. This is often done by bulk genotyping of whole biopsies, but the chance that a mutation will be detected in bulk genotyping depends on its local frequency in the sample. When the underlying mutation count per cell is equal, homogenous biopsies will have more high-frequency mutations, and thus more detectable mutations, than heterogeneous ones. Using simulations, we show that bulk genotyping of data simulated under a neutral model of somatic evolution generates strong spurious evidence for non-neutrality, because the pattern of tissue growth systematically generates differences in biopsy heterogeneity. Any experiment which compares mutation content across bulk-genotyped biopsies may therefore suggest mutation rate or selection intensity variation even when these forces are absent. We discuss computational and experimental approaches for resolving this problem.

Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) datafile. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011-2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted.

Cancer results from a sequence of genetic and epigenetic changes which lead to a variety of abnormal phenotypes including increased proliferation and survival of somatic cells, and thus, to a selective advantage of pre-cancerous cells. The notion of cancer progression as an evolutionary process has been experiencing increasing interest in recent years. Many efforts have been made to better understand and predict the progression to cancer using mathematical models; these mostly consider the evolution of a well-mixed cell population, even though pre-cancerous cells often evolve in highly structured epithelial tissues. In this study, we propose a novel model of cancer progression that considers a spatially structured cell population where clones expand via adaptive waves. This model is used to assess two different paradigms of asexual evolution that have been suggested to delineate the process of cancer progression. The standard scenario of periodic selection assumes that driver mutations are accumulated strictly sequentially over time. However, when the mutation supply is sufficiently high, clones may arise simultaneously on distinct genetic backgrounds, and clonal adaptation waves interfere with each other. We find that in the presence of clonal interference, spatial structure increases the waiting time for cancer, leads to a patchwork structure of non-uniformly sized clones, decreases the survival probability of virtually neutral (passenger) mutations, and that genetic distance begins to increase over a characteristic length scale L(c). These characteristic features of clonal interference may help to predict the onset of cancers with pronounced spatial structure and to interpret spatially-sampled genetic data obtained from biopsies. Our estimates suggest that clonal interference likely occurs in the progression of colon cancer, and possibly other cancers where spatial structure matters.

Barrett's esophagus is a condition in which the normal stratified squamous epithelium of the distal esophagus is replaced by intestinal metaplasia. For more than three decades, the prevailing clinical paradigm has been that Barrett's esophagus is a complication of symptomatic reflux disease that predisposes to esophageal adenocarcinoma. However, no clinical strategy for cancer prevention or early detection based on this paradigm has been proven to reduce esophageal adenocarcinoma mortality in a randomized clinical trial in part because only about 5% to 10% of individuals with Barrett's esophagus develop esophageal adenocarcinoma. Recent research indicates that Barrett's metaplasia is an adaptation for mucosal defense in response to chronic reflux in most individuals. The risk of progressing to esophageal adenocarcinoma is determined by development of genomic instability and dynamic clonal evolution in the distal esophagus modulated by host and environmental risk and protective factors, including inherited genotype. The challenge for investigators of Barrett's esophagus lies in integrating knowledge about genomic instability and clonal evolution into clinical management to increase the lifespan and quality of life of individuals with this condition., (©2011 AACR.)

Barrett's esophagus (BE) is a premalignant intermediate to esophageal adenocarcinoma, which develops in the context of chronic inflammation and exposure to bile and acid. We asked whether there might be common genomic alterations that could be identified as potential clinical biomarker(s) for BE by whole genome profiling. We detected copy number alterations and/or loss of heterozygosity at 56 fragile sites in 20 patients with premalignant BE. Chromosomal fragile sites are particularly sensitive to DNA breaks and are frequent sites of rearrangement or loss in many human cancers. Seventy-eight percent of all genomic alterations detected by array-CGH were associated with fragile sites. Copy number losses in early BE were observed at particularly high frequency at FRA3B (81%), FRA9A/C (71.4%), FRA5E (52.4%), and FRA 4D (52.4%), and at lower frequencies in other fragile sites, including FRA1K (42.9%), FRAXC (42.9%), FRA 12B (33.3%), and FRA16D (33.3%). Due to the consistency of the region of copy number loss, we were able to verify these results by quantitative PCR, which detected the loss of FRA3B and FRA16D, in 83% and 40% of early molecular stage BE patients, respectively. Loss of heterozygosity in these cases was confirmed through pyrosequencing at FRA3B and FRA16D (75% and 70%, respectively). Deletion and genomic instability at FRA3B and other fragile sites could thus be a biomarker of genetic damage in BE patients and a potential biomarker of cancer risk.

Guanine-rich nucleic acids are known to form highly stable G-quadruplex structures, also known as G-quartets. Recently, there has been a tremendous amount of interest in studying G-quadruplexes owing to the realization of their biological importance. G-rich sequences (GRSs) capable of forming G-quadruplexes are found in the vicinity of polyadenylation regions and are involved in regulating 3' end processing of mammalian pre-mRNAs. G-rich motifs are also known to play an important role in alternative, tissue-specific splicing by interacting with hnRNP H protein subfamily. Whether quadruplex structure directly plays a role in regulating RNA processing events requires further investigation. To date there has not been a comprehensive effort to study G-quadruplexes near RNA processing sites. We have applied a computational approach to map putative Quadruplex forming GRSs within the transcribed regions of a large number of alternatively processed human and mouse gene sequences that were obtained as fully annotated entries from GenBank and RefSeq. We have used the computed data to build the GRSDB database that provides a unique avenue for studying G-quadruplexes in the context of RNA processing sites. GRSDB website offers visual comparison of G-quadruplex distribution patterns among all the alternative RNA products of a gene with the help of dynamic graphics. At present, GRSDB contains data from 1310 human and mouse genes, of which 1188 are alternatively processed. It has a total of 379,223 predicted G-quadruplexes, of which 54,252 are near RNA processing sites. GRSDB is a good resource for researchers interested in investigating the functional relevance of G-quadruplexes, especially in the context of alternative RNA processing. It can be accessed at http://bioinformatics.ramapo.edu/grsdb/.