To determine if the degree of blood loss during resection of hepatocellular carcinoma (HCC) is predictive of recurrence and long-term survival.
Several studies have addressed the impact of blood ...transfusion on survival and recurrence after liver resection for HCC. However, the independent effect of intraoperative estimated blood loss (EBL) on oncologic outcome is unclear.
From our prospective database, we identified 192 patients who had a partial hepatectomy for HCC from 1985 to 2002. Clinicopathologic predictors of EBL were identified using logistic regression. Overall survival (OS), disease-specific survival (DSS), and recurrence free survival (RFS) were assessed using the Kaplan-Meier and Cox regression methods.
The median patient age was 64 (range, 19-86) and 66% were men. All patients had histologically proven HCC. The median follow-up time was 34 months (range, 1-297). Factors associated with increased EBL on multivariate analysis were male gender, vascular invasion, extent of hepatectomy, and operative time (P < 0.01). EBL and vascular invasion were independent predictors of OS and DSS. Only EBL was significantly associated with RFS on multivariate analysis (P = 0.02). Additionally, we found a significant inverse correlation between increasing levels of EBL and length of DSS (P = 0.01).
The magnitude of EBL during HCC resection is related to biologic characteristics of the tumor as well as the extent of surgery. Increased intraoperative blood loss during HCC resection is an independent prognostic factor for tumor recurrence and death.
Proteomic analyses indicate that STAT1 protein (signal transducer and activator of transcription 1 or transcription factor ISGF-3 components p91/p84) is upregulated in some colorectal cancers. This ...study examined 736 colorectal cancer patients for the expression of STAT1 protein in tissue specimens, including 614 early stage patients and 122 advanced stage patients. Tissue microarrays were constructed, and STAT1 expression was examined by immunohistochemistry and scored semi-quantitatively. Among all cases, 9% of cases displayed high levels of cytoplasmic expression of STAT1 and 15% of cases had positive nuclear expression. Based on statistical analyses of a cohort of 559 early stage patients with survival data and no neoadjuvant therapy, we found that high levels of cytoplasmic expression of STAT1 correlated with shorter survival time in early stage colorectal cancer, particularly of the microsatellite instability (MSI) subtype. Additional analysis of a 244-case cohort of colorectal cancers from the Cancer Genome Atlas found that STAT1 gene expression correlated positively with PD-L1 (CD274) and PD-1 (PDCD1) but had no correlation with KRAS or BRAF mutation status. STAT1 expression showed no clear correlation with any of the 4 clinical diagnostic markers of mismatch repair, MLH1, MSH2, MSH6, and PMS2, suggesting its potential as an independent outcome marker for MSI cancers. Our findings suggest that STAT1 may be used as a potential prognostic protein marker for stratifying the outcome risk of early stage MSI colorectal cancer.
Summary The patients with autoimmune pancreatitis usually present with jaundice and a pancreatic head mass, presumed to have pancreatic cancer, and they often undergo pancreatic resection. Elevated ...serum IgG4 levels (>135 mg/dL) help to distinguish autoimmune pancreatitis from pancreatic cancer. However, when the biopsy from a pancreatic mass shows dense chronic inflammation and fibrosis and the serum IgG4 level is not available, it presents a diagnostic dilemma whether it represents autoimmune pancreatitis or peritumoral pancreatitis. We performed IgG4 immunohistochemistry on 25 cases of autoimmune pancreatitis-lymphoplasmacytic sclerosing pancreatitis, 7 cases of autoimmune pancreatitis with granulocytic epithelial lesions, 8 cases of nonspecific pancreatitis, 15 cases of pancreatitis associated with pancreatic ductal adenocarcinoma, and 5 biopsies of pancreatic adenocarcinoma with variable inflammation. The distribution of IgG4-positive cells was noted in each case. Eighty-four percent (21/25) of autoimmune pancreatitis-LPSP cases showed diffuse and dense staining for IgG4, with more than 50 positive plasma cells per high-power field (range, 50-150 cells/hpf) in the highest density area. Most (5/7) cases of autoimmune pancreatitis-granulocytic epithelial lesions were negative for IgG4. Thirty-nine percent of nonspecific pancreatitis and peritumoral pancreatitis cases stained positive for IgG4, but the distribution was focal and none of the cases showed more than 50 IgG4-positive cells/hpf in the highest density area of IgG4 staining. IgG4-positive cells in peritumoral pancreatitis and nonspecific pancreatitis cases were closely associated with malignant glands and areas of acute inflammation in some cases. Using a cutoff of 50 IgG4-positive cells/hpf, the sensitivity of IgG4 staining for classical autoimmune pancreatitis-LPSP versus other types of pancreatitis was 84%, the specificity was 100%, and the P value was significant (<.0001). Hence, we conclude that diffuse and dense staining (>50 positive cells/hpf) for IgG4 is specifically seen in autoimmune pancreatitis-LPSP, and IgG4 staining along with the histologic features and serum IgG4 levels may be very helpful in diagnosing autoimmune pancreatitis.
Human noroviruses (HuNoVs) can often cause chronic infections in solid organ and haematopoietic stem cell transplant (HSCT) patients. Based on histopathological changes observed during HuNoV ...infections, the intestine is the presumed site of virus replication in patients; however, the cell types infected by HuNoVs remain unknown. The objective of this study was to characterize histopathological changes during HuNoV infection and to determine the cell types that may be permissive for HuNoV replication in transplant patients. We analysed biopsies from HuNoV-infected and non-infected (control) transplant patients to assess histopathological changes in conjunction with detection of HuNoV antigens to identify the infected cell types. HuNoV infection in immunocompromised patients was associated with histopathological changes such as disorganization and flattening of the intestinal epithelium. The HuNoV major capsid protein, VP1, was detected in all segments of the small intestine, in areas of biopsies that showed histopathological changes. Specifically, VP1 was detected in enterocytes, macrophages, T cells and dendritic cells. HuNoV replication was investigated by detecting the non-structural proteins, RdRp and VPg. We detected RdRp and VPg along with VP1 in duodenal and jejunal enterocytes. These results provide critical insights into histological changes due to HuNoV infection in immunocompromised patients and propose human enterocytes as a physiologically relevant cell type for HuNoV cultivation.
The Cancer Genome Atlas data on colorectal carcinoma have provided a comprehensive view of the tumor's genomic alterations and their tumorigenic roles. Tumor morphology, however, has not been fully ...integrated into the analysis. The aim of this study was to explore relevant associations between tumor morphology and the newly characterized genomic alterations in colorectal carcinoma. Two hundred and seven colorectal carcinomas that had undergone whole-exome sequencing as part of The Cancer Genome Atlas project and had adequate virtual images in the cBioPortal for Cancer Genomics constituted our study population. Upon analysis, a tight association between ‘microsatellite instability-high histology' and microsatellite instability-high (P<0.001) was readily detected and helped validate our image-based histology evaluation. Further, we showed, (1) among all histologies, the not otherwise specified type had the lowest overall mutation count (P<0.001 for entire cohort, P<0.03 for the microsatellite-instable group), and among the microsatellite-instable tumors, this type also correlated with fewer frameshift mutations in coding mononucleotide repeats of a defined set of relevant genes (P<0.01); (2) cytosine phosphate guanine island methylator phenotype-high colorectal cancers with or without microsatellite instability tended to have different histological patterns: the former more often mucinous and the latter more often not otherwise specified; (3) mucinous histology was associated with more frequent alterations in BRAF, PIK3CA, and the transforming growth factor-β pathway when compared with non-mucinous histologies (P<0.001, P=0.01, and P<0.001, respectively); and (4) few colorectal cancers (<9%) exhibited upregulation of immune-inhibitory genes including major immune checkpoints; these tumors were primarily microsatellite-instable (up to 43%, vs <3% in microsatellite-stable group) and had distinctly non-mucinous histologies with a solid growth. These morphology–molecular associations are interesting and propose important clinical implications. The morphological patterns associated with alterations of immune checkpoint genes bear the potential to guide patient selection for clinical trials that target immune checkpoints in colorectal cancer, and provide directions for future studies.
Background Patients undergoing liver resection for colorectal cancer liver metastasis (CRCLM) are often treated with chemotherapy before surgery. However, the associations between chemotherapy, liver ...injury, perioperative outcomes, and other confounding factors remain unclear. This study investigates the effect of preoperative chemotherapy for CRCLM on nontumoral liver histology and perioperative outcomes in a contemporary cohort. Study Design Five hundred six patients underwent hepatic resection for CRCLM between April 2003 and March 2007. Histologic evaluation of nontumoral liver parenchyma for sinusoidal dilatation, steatosis, and steatohepatitis was performed in 384 cases for which tissue was available. Patient factors, tumor characteristics, chemotherapy regimens, histology of nontumoral liver, and perioperative morbidity were analyzed. Results Two hundred fifty patients (65%) received preoperative chemotherapy for a median duration of 24 weeks. Irinotecan, increased body mass index (BMI), and diabetes mellitus (DM) were associated with hepatic steatosis and steatohepatitis. Sinusoidal dilatation was not associated with chemotherapy or any clinicopathologic factors. Perioperative blood transfusion was independently associated with an increased risk of any complication. Major postoperative complications were independently associated with major (≥3 segments) resections (57%) and perioperative blood transfusion. The use of any preoperative chemotherapy decreased the odds of major complications. Liver-related complications were independently associated with major resection and blood transfusion, but not with chemotherapy. Three postoperative deaths (0.8%) occurred, all in patients who were not treated with chemotherapy and had no evidence of liver injury. Conclusions With appropriate patient selection, liver resection for CRCLM can be safely performed in patients treated with preoperative chemotherapy.
Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that is often associated with a poor prognosis. Methylation levels of genomic repeats such as LINE-1 elements have ...been recognized as independent factors for increased cancer-related mortality. The methylation status of LINE-1 elements in early-onset CRC has not been analyzed previously.
We analyzed 343 CRC tissues and 32 normal colonic mucosa samples, including 2 independent cohorts of CRC diagnosed ≤ 50 years old (n=188), a group of sporadic CRC >50 years (MSS n=89; MSI n=46), and a group of Lynch syndrome CRCs (n=20). Tumor mismatch repair protein expression, microsatellite instability status, LINE-1 and MLH1 methylation, somatic BRAF V600E mutation, and germline MUTYH mutations were evaluated.
Mean LINE-1 methylation levels (± SD) in the five study groups were early-onset CRC, 56.6% (8.6); sporadic MSI, 67.1% (5.5); sporadic MSS, 65.1% (6.3); Lynch syndrome, 66.3% (4.5) and normal mucosa, 76.5% (1.5). Early-onset CRC had significantly lower LINE-1 methylation than any other group (p<0.0001). Compared to patients with <65% LINE-1 methylation in tumors, those with ≥ 65% LINE-1 methylation had significantly better overall survival (p=0.026, log rank test).
LINE-1 hypomethylation constitutes a potentially important feature of early-onset CRC, and suggests a distinct molecular subtype. Further studies are needed to assess the potential of LINE-1 methylation status as a prognostic biomarker for young people with CRC.
Understanding the molecular and phenotypic profile of colorectal cancer (CRC) in West Africa is vital to addressing the regions rising burden of disease. Tissue from unselected Nigerian patients was ...analyzed with a multigene, next-generation sequencing assay. The rate of microsatellite instability is significantly higher among Nigerian CRC patients (28.1%) than patients from The Cancer Genome Atlas (TCGA, 14.2%) and Memorial Sloan Kettering Cancer Center (MSKCC, 8.5%, P < 0.001). In microsatellite-stable cases, tumors from Nigerian patients are less likely to have APC mutations (39.1% vs. 76.0% MSKCC P < 0.001) and WNT pathway alterations (47.8% vs. 81.9% MSKCC, P < 0.001); whereas RAS pathway alteration is more prevalent (76.1% vs. 59.6%, P = 0.03). Nigerian CRC patients are also younger and more likely to present with rectal disease (50.8% vs. 33.7% MSKCC, P < 0.001). The findings suggest a unique biology of CRC in Nigeria, which emphasizes the need for regional data to guide diagnostic and treatment approaches for patients in West Africa.
The pathology of biliary carcinomas is diverse with different gross and histological features in tumors arising in the different segments of the biliary system. Various epidemiological risk factors, ...varied genetic makeup, and tissue microenvironment are contributory factors. As biliary tumors have been shown to be a part of the Lynch syndrome tumor spectrum, it is plausible to speculate that DNA mismatch repair (MMR) deficiency plays a role in biliary tumors. Literature data suggest that DNA MMR deficiency indeed occurs in these tumors, albeit infrequently with the reported frequencies (weighted for sample size) of high level microsatellite instability (MSI) being 5% each for gallbladder carcinoma and carcinoma of extra-hepatic bile ducts, and 10% each for intrahepatic cholangiocarcinoma and ampullary carcinoma. Importantly, the presence of MMR deficiency in these tumors has been shown to have different implications with regard to its association with Lynch syndrome, tumor histological features, and other clinical characteristics, when compared with non-biliary tumors or among the biliary tumors from the different segments of the biliary system. Ongoing and future efforts that utilize large scale sequencing techniques and aim at detecting actionable molecular targets should emphasize a multidisciplinary approach that integrates genomic discoveries with not only functional studies but also studies of tumor pathology and the tumor's clinical and biological behavior.
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