Flume experiments were conducted to measure bed morphology adjustments in sand/gravel and sand/silt sediment mixtures during repeated hydrographs and to link these changes to sediment transport ...patterns over multiple time scales. Sediment composition and hydrograph flow magnitude greatly influenced channel morphology, which impacted sediment yield, hysteresis, and transport predictions. Bed load yields were larger and more variable for the sand/silt mixture, as gravel in the sand/gravel sediment inhibited grain entrainment, limited bed form growth, and acted to stabilize the bed. Hysteresis patterns varied due to bed form and surface structure adjustments, as well as the stabilizing effect of antecedent low flows. Using half the data set, a dimensionless fractional transport equation was derived based on excess shear stress. Dimensionless reference shear stresses were estimated in two ways: as bulk values from all transport measurements and by applying a separate limb approach in which values were estimated for each limb of each hydrograph. For the other half of the data set, transport predictions with the separate limb approach were more accurate than those from six existing transport equations and the fractional relationship applied with bulk reference shear stresses. Thus, hydrograph limb‐dependent dimensionless reference shear stress links changing bed morphology and sediment transport, providing a parameter to improve transport predictions during individual flood events and in unsteady flow regimes. This approach represents a framework with which to develop site‐specific transport relationships for varying flow regimes, particularly in cases where detailed bed morphology measurements are not feasible and heterogeneous sediment complicates bed structure over time.
Key Points:
Bed morphology and sediment transport studied during unsteady flow sequences
Separate limb reference shear stresses improved sediment transport predictions
Reference shear stress effectively linked transport to changing bed morphology
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
It has been recently hypothesized that many of the signals detected in genome-wide association studies (GWAS) to T2D and other diseases, despite being observed to common variants, might in fact ...result from causal mutations that are rare. One prediction of this hypothesis is that the allelic associations should be population-specific, as the causal mutations arose after the migrations that established different populations around the world. We selected 19 common variants found to be reproducibly associated to T2D risk in European populations and studied them in a large multiethnic case-control study (6,142 cases and 7,403 controls) among men and women from 5 racial/ethnic groups (European Americans, African Americans, Latinos, Japanese Americans, and Native Hawaiians). In analysis pooled across ethnic groups, the allelic associations were in the same direction as the original report for all 19 variants, and 14 of the 19 were significantly associated with risk. In summing the number of risk alleles for each individual, the per-allele associations were highly statistically significant (P<10(-4)) and similar in all populations (odds ratios 1.09-1.12) except in Japanese Americans the estimated effect per allele was larger than in the other populations (1.20; P(het) = 3.8×10(-4)). We did not observe ethnic differences in the distribution of risk that would explain the increased prevalence of type 2 diabetes in these groups as compared to European Americans. The consistency of allelic associations in diverse racial/ethnic groups is not predicted under the hypothesis of Goldstein regarding "synthetic associations" of rare mutations in T2D.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND: Checkpoint kinase 2 is a tumor suppressor gene in the deoxyribonucleic acid damage checkpoint system that may be mutated in several cancers. Patients with germline checkpoint kinase 2 ...mutations and multiple colon polyps were noted during routine care, and genetic testing is recommended for patients with as few as 10 lifetime polyps. OBJECTIVE: This study assessed whether checkpoint kinase 2 is associated with attenuated or oligopolyposis and characterized the gastrointestinal clinicopathologic profile. DESIGN: Retrospective observational study. SETTINGS: Records from patients harboring germline checkpoint kinase 2 mutations from 1999-2020 were reviewed. PATIENTS: A total of 45 patients with germline checkpoint kinase 2 mutations with endoscopic examinations. MAIN OUTCOME MEASURES: Description of clinicopathologic variables. RESULTS: Twenty-five of 45 patients had polyps: 3 with only upper gastrointestinal polyps, 17 with only lower gastrointestinal polyps and 5 with both upper and lower gastrointestinal polyps. The most common germline checkpoint kinase 2 mutations in patients with polyps were p.S428F (n = 10), p.I157T (n = 4) and p.T476M (n = 2), with other mutations present in 1 patient each. Among patients with lower gastrointestinal polyps, 9 had adenomas, 6 had serrated polyps, 1 had an inflammatory polyp and 6 had both adenomatous and serrated polyps. Three patients (p.I157T, n = 2; p.R117G, n = 1) had >10 adenomas, and 1 (p.G259fs) had 18 serrated polyps. Five patients (11.1%) developed colorectal adenocarcinoma, including 2 with >10 adenomas. Five patients with p.S428F (50%) exclusively had right- sided adenomas. LIMITATIONS: Single-center descriptive study. CONCLUSIONS: Germline checkpoint kinase 2 mutations should be considered in patients with polyposis. The preponderance of right- sided adenomas in patients with p.S428F mutations suggests the importance of right-sided colonoscopy in these patients. See Video Abstract
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KISLJ, NUK, OILJ, PNG, SAZU, UL, UM, UPUK
Aims
Pre‐exposure prophylaxis (PrEP) consists of combination antiretroviral therapy and is increasingly utilized to prevent human immunodeficiency virus (HIV) in high‐risk populations. Two index ...cases noted during routine care showed markedly increased duodenal villous surface apoptosis in patients on PrEP. We sought to examine the prevalence of this finding and identify any clinicopathologic correlations.
Methods
Gastrointestinal biopsy specimens from 23 male patients aged 18–40 years taking PrEP and 23 control patients were reviewed. Patients with HIV, inflammatory gastrointestinal diseases, and celiac disease were excluded. Apoptoses were counted on surface epithelium and deep crypts. The highest apoptotic body count per tissue fragment was recorded. Clusters were defined as groups of ≥5 apoptoses. Apoptotic counts between patients taking PrEP and controls were compared using t‐tests.
Results
In PrEP patients, the median age was 35 years (range 25–40) and 83% (19/23) were white. The control patients were demographically similar (median age: 32 years range 23–40; 70% 16/23 white). Duodenal apoptosis in villous surface epithelium was increased in PrEP patients, with 14/23 (60.9%) patients having ≥10 surface apoptoses compared to 2/23 (8.7%) controls (P = 2.1 × 10−3) and 14/23 (61%) having clusters compared to 3/23 (13%) controls (P = 2.0 × 10−3). There was no significant association between increased surface apoptosis or clusters and clinical symptoms or duration of PrEP use.
Conclusion
Markedly increased villous surface apoptosis, particularly in clusters, is often seen in the duodenum of patients taking PrEP. Although the mechanism and significance are unknown, knowledge of this peculiar finding may prevent unnecessary additional testing.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
While oesophageal squamous cell carcinoma remains infrequent in Western populations, the incidence of oesophageal adenocarcinoma (EAC) has increased sixfold to eightfold over the past four decades. ...We aimed to characterise oesophageal cancer-specific and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs). DESIGN: To identify regulatory elements, we profiled fresh-frozen oesophageal normal samples, tumours and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modelling was performed to establish (super)-enhancers landscapes and interconnected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs were investigated by ChIP-Seq, circularised chromosome conformation capture sequencing and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo.
We found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of oesophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signalling pathways, some of which may be exploited pharmacologically (eg, leukemia inhibitory factor (LIF) pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by four master TFs-ELF3, KLF5, GATA6 and EHF-which promoted each other's expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival.
By establishing cancer-specific and subtype-specific features of the EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.
OBJECTIVES:To describe the survival outcome of patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) who have a pathologic complete response (pCR) ...following neoadjuvant chemoradiation.
BACKGROUND:Patients with BR/LA-PDAC are often treated with neoadjuvant chemoradiation in an attempt to downstage the tumor. Uncommonly, a pCR may result.
METHODS:A retrospective review of a prospectively maintained database was performed at a single institution. pCR was defined as no viable tumor identified in the pancreas or lymph nodes by pathology. A near complete response (nCR) was defined as a primary tumor less than 1 cm, without nodal metastasis. Overall survival (OS) and disease-free survival (DFS) were reported.
RESULTS:One hundred eighty-six patients with BR/LA-PDAC underwent neoadjuvant chemoradiation and subsequent pancreatectomy. Nineteen patients (10%) had a pCR, 29 (16%) had an nCR, and the remaining 138 (74%) had a limited response. Median DFS was 26 months in patients with pCR, which was superior to nCR (12 months, P = 0.019) and limited response (12 months, P < 0.001). The median OS of nCR (27 months, P = 0.003) or limited response (26 months, P = 0.001) was less than that of pCR (more than 60 months). In multivariable analyses pCR was an independent prognostic factor for DFS (HR = 0.45; 0.22–0.93, P = 0.030) and OS (HR=0.41; 0.17–0.97, P = 0.044). Neoadjuvant FOLFIRINOX (HR=0.47; 0.26–0.87, P = 0.015) and negative lymph node status (HR=0.57; 0.36–0.90, P = 0.018) were also associated with improved survival.
CONCLUSIONS:Patients with BR/LA-PDAC who had a pCR after neoadjuvant chemoradiation had a significantly prolonged survival compared with those who had nCR or a limited response.
Patients with inflammatory bowel disease (IBD) are at an increased risk for colorectal cancer. Currently, dysplasia is the best marker of CRC risk. Assessing dysplasia is a challenging task for ...pathologists as the longstanding inflammation causes marked reactive cytologic changes and architectural distortion. Recent descriptions of nonconventional types of dysplasia in IBD have added to the complexity. In this review, we focus on the clinical, endoscopic, histologic, and molecular findings in lesions with serrated epithelium. Serrated epithelial change (SEC), sessile serrated lesion (SSL)-like, serrated lesion-not otherwise specified (SL-NOS), and traditional serrated adenoma (TSA)-like lesions all typically occur in patients with longstanding IBD with mean ages in the fifth-sixth decade. SEC is often encountered in nontargeted biopsies while the others form visible polyps. While serrated lesions have significant histologic overlap, subtle differences can help pathologists separate them. SEC has markedly distorted architecture with crypts losing perpendicular orientation to the muscularis mucosae. The crypts are goblet cell–rich and have irregular serrations that involve the full length of the crypt. SSL-like lesions are goblet cell poor and have microvesicular cytoplasm. Like their sporadic counterpart in non-IBD patients, these lesions have lateral growth at the crypt bases. TSA-like lesions are characterized by their villous architecture, ectopic crypts, pink cytoplasm, and hyperchromatic elongated nuclei. We also explore molecular findings that help in distinguishing these lesions, current knowledge on the association of each of these lesions with dysplasia and CRC, and future research needed to better characterize these entities.
•Colon biopsies from inflammatory bowel disease (IBD) patients can show several types of serrated epithelium (flat or endoscopically visible).•Sessile serrated lesion-like and traditional serrated adenoma-like lesions arising in IBD patients are probably the same as sporadic ones.•Serrated epithelial change, when defined based on strict morphologic criteria, differs from those above, harboring TP53 mutations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Capecitabine is a commonly used oral chemotherapeutic agent. Gastrointestinal (GI) side effects are clinically well-known, however, the histopathologic changes have not been comprehensively studied. ...This study describes the largest case series (8 patients) characterizing the histopathology of capecitabine-induced GI injury. All patients were adults (median age: 64.5 y, range: 61 to 76 y) and there was gender parity. Patients were receiving treatment for malignancies of the colorectum (n=5), breast (n=1), pancreas (n=1), and appendix (n=1). All had GI symptoms, including 7 with diarrhea and abdominal pain and 1 with melena. Five of 8 (63%) showed graft-versus-host disease (GVHD)-like histologic changes in small intestinal and/or colonic biopsies characterized by crypt disarray and dropout, crypt atrophy, dilated crypts lined by attenuated epithelium, and increased crypt apoptosis. Neuroendocrine cell aggregates were present in 4 of 5 cases. Four of 5 showed patchy prominence in lamina propria eosinophils. One patient receiving concomitant radiation therapy had a small intestinal biopsy showing regenerative changes. Two patients had histologically unremarkable biopsies. On follow-up, capecitabine was discontinued or dose-reduced in all patients. Three of 5 patients with a GVHD-like pattern had clinical improvement, whereas 2 died shortly after biopsy. One with regenerative changes also had radiation dose reduction and improved clinically. Two with unremarkable biopsies improved symptomatically. In summary, capecitabine-related GI injury shows a GVHD-like pattern. Knowledge of this is important to confirm the diagnosis as patients typically improve with dose reduction or discontinuation of the drug.
New Names for Old Tumors Wong, Mary; Waters, Kevin M; Guindi, Maha ...
American journal of clinical pathology,
2021-Apr-26, Volume:
155, Issue:
5
Journal Article
Peer reviewed
Abstract
Objectives
Previous studies described “clear cell” hepatocellular carcinoma (HCC), although definitions have varied. New clear cell subtypes of HCC have been proposed, including chromophobe ...(C-HCC), steatohepatitic (SH-HCC), and steatotic (S-HCC), and this study assessed the utility and clinical-pathologic profile of these subtypes.
Methods
Current histologic definitions, including 3 separate proposed definitions for SH-HCC, were applied to tumors previously characterized as clear cell HCC. Histologic and clinical variables were analyzed.
Results
Of 66 HCCs, 51 (77%) were classified using modern definitions, including 34 SH-HCCs, 15 S-HCCs, and 2 C-HCCs. Compared with the most permissive SH-HCC definition, the other 2 definitions designated 30 and 25 SH-HCCs (−12% and −26% cases, respectively). Unsurprisingly, S-HCC and SH-HCC were associated with steatotic clear cells (P < .0001). S-HCC was also more typically early type and low grade (P = .0017). The remaining unclassified clear cell HCCs were associated with flocculent (rather than steatotic or optically clear) cytoplasm (P < .0001) but otherwise demonstrated no discrete clinical-pathologic profile.
Conclusions
Current definitions could be used to reclassify the majority of “clear cell” HCCs. The subtypes are significantly correlated with a few variables, suggesting valid differences of the subtypes, although additional study is warranted, particularly to standardize the definition of SH-HCC.
This review seeks to summarise the steps in the path from reflux oesophagitis to Barrett oesophagus to oesophageal adenocarcinoma. The epidemiology, clinical presentation, definitions, pathological ...features, diagnostic pitfalls, and emerging concepts are reviewed for each entity. The histological features of reflux oesophagitis can be variable and are not specific. Cases of reflux oesophagitis with numerous eosinophils are difficult to distinguish from eosinophilic oesophagitis and other oesophagitides with eosinophils (Crohn's disease, medication effect, and connective tissue disorders). In reflux oesophagitis, the findings are often most pronounced in the distal oesophagus, the eosinophils are randomly distributed throughout the epithelium, and eosinophilic abscesses and degranulated eosinophils are rare. For reflux oesophagitis with prominent lymphocytes, clinical history and ancillary clinical studies are paramount to distinguish reflux oesophagitis from other causes of lymphocytic oesophagitis pattern. For Barrett oesophagus, the definition remains a hotly debated topic for which the requirement for intestinal metaplasia to make the diagnosis is not applied unanimously across the globe. Assessing for dysplasia is a challenging aspect of the histological interpretation that guides clinical management. We describe the histological features that we find useful in making this evaluation. Oesophageal adenocarcinoma has been steadily increasing in incidence and has a poor prognosis. The extent of invasion can be overdiagnosed due to a duplicated muscularis mucosae. We also describe the technical factors that can lead to challenges in distinguishing the mucosal and deep margins of endoscopic resections. Lastly, we give an overview of targeted therapies with emerging importance and the ancillary tests that can identify the cases best suited for each therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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