Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes

Numerous driver mutations have been identified in colorectal cancer (CRC), but their relevance to the development of targeted therapies remains elusive. The secondary effects of pathogenic driver mutations on downstream signaling pathways offer a potential approach for the identification of therapeutic targets. We aimed to identify differentially expressed genes as potential drug targets linked to driver mutations.Somatic mutations and the gene expression data of 582 CRC patients were utilized, incorporating the mutational status of 39,916 and the expression levels of 20,500 genes. To uncover candidate targets, the expression levels of various genes in wild-type and mutant cases for the most frequent disruptive mutations were compared with a Mann-Whitney test. A survival analysis was performed in 2100 patients with transcriptomic gene expression data. Up-regulated genes associated with worse survival were filtered for potentially actionable targets. The most significant hits were validated in an independent set of 171 CRC patients.Altogether, 426 disruptive mutation-associated upregulated genes were identified. Among these, 95 were linked to worse recurrence-free survival (RFS). Based on the druggability filter, 37 potentially actionable targets were revealed. We selected seven genes and validated their expression in 171 patient specimens. The best independently validated combinations were DUSP4 (p = 2.6 × 10-12) in ACVR2A mutated (7.7%) patients; BMP4 (p = 1.6 × 10-04) in SOX9 mutated (8.1%) patients; TRIB2 (p = 1.35 × 10-14) in ACVR2A mutated patients; VSIG4 (p = 2.6 × 10-05) in ANK3 mutated (7.6%) patients, and DUSP4 (p = 7.1 × 10-04) in AMER1 mutated (8.2%) patients.The results uncovered potentially druggable genes in colorectal cancer. The identified mutations could enable future patient stratification for targeted therapy

A long-term survival case of adult undifferentiated embryonal sarcoma of liver

Undifferentiated embryonal sarcoma of the liver (USEL) is a rare malignant hepatic tumor with a poor prognosis that is usually observed in children (aged 6 to 10 years) and rarely seen in adults. We present a case of USEL in a 27-year-old woman with no previous history of the disease. Laboratory tests performed on admission showed that the patient had mildly elevated levels of aspartate aminotransferase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and γ-glutamyl transpeptidase. The levels of viral hepatitis and tumor serum markers were all within normal limits. Computed tomography showed a large mass involving the right lobe and the medial segment of the liver. Right trisectionectomy was performed. Microscopically, the tumor was composed of pleomorphic and polynuclear dyskaryotic cells in a myxoid stroma with focal eosinophilic globules and no clear differentiation to muscle. Histological diagnosis showed undifferentiated embryonal sarcoma. Adjuvant therapy with cisplatin, vincristine, doxorubicin, cyclophosphamide, and actinomycin D was initiated. We administered a high dose of etoposide to extract the patient's peripheral blood stem cells and performed radiation therapy and peripheral blood stem cell transplantation. At 5-year follow-up, the patient was alive without any evidence of recurrence. Here, we describe the clinical and histopathological features of USEL as well as the therapeutic options for USEL in adults with this disease

Hepatectomy is Beneficial in Select Patients with Multiple Hepatocellular Carcinomas

Background A single hepatocellular carcinoma (HCC) is a good indication for hepatic resection regardless of tumor size, but the surgical indications for cases with multiple HCCs remain unclear. Methods We retrospectively reviewed the outcomes of hepatectomies for Barcelona Clinic Liver Cancer (BCLC) stage 0, A, and B HCCs. We further subclassified stage A and B into A1 (single nodule = 10 cm), B1 (two to three nodules >3 cm), and B2 (four or more nodules). Results A total of 1088 patients were enrolled, comprising 88 stage 0, 750 stage A (A1: 485; A2: 190; A3: 75), and 250 stage B (B1: 166; B2: 84) cases. The 5-year overall survival (OS) rates for stage 0, A1, A2, A3, B1, and B2 patients were 70.4%, 74.2%, 63.8%, 47.7%, 47.5%, and 31.9%, respectively (p < 0.0001). Significant differences in OS were found between stages A1 and A2 (p = 0.0118), A2 and A3 (p = 0.0013), and B1 and B2 (p = 0.0050), but not between stages A3 and B1 (p = 0.4742). In stage B1 patients, multivariate analysis indicated that Child-Pugh B cirrhosis was the only independent prognostic factor for the OS outcome. Conclusions A hepatectomy should be considered for multiple HCCs if the number of tumors is three or fewer, especially in patients with no cirrhosis or in Child-Pugh A cases, because the long-term results are equivalent to those for a single HCC

Central Hepatectomy Versus Major Hepatectomy for Centrally Located Hepatocellular Carcinoma : A Propensity Score Matching Study

Background In terms of anatomical liver sectionectomy approaches, both a central hepatectomy (CH) and major hepatectomy (MH) are feasible options for a centrally located hepatocellular carcinoma (HCC). Methods We retrospectively reviewed the surgical outcomes of central HCC patients who underwent CH or MH. MH includes hemihepatectomy or trisectionectomy, whereas CH involves a left medial sectionectomy, right anterior sectionectomy, or central bisectionectomy. The surgical outcomes were compared before and after propensity score matching (PSM). Results A total of 233 patients were enrolled, including 132 in the CH group and 101 in the MH group. The MH group cases were pathologically more advanced and had poorer overall survival rates than the CH group. After PSM, 68 patients were selected into each group, both of which showed similar overall and recurrence-free survival outcomes. The CH group showed a tendency for a longer operation time; however, other perioperative outcomes were similar between the two groups. Multivariate analyses of our matched HCC patients revealed that the type of surgery (CH or MH) was not an independent prognostic factor. More patients in the matched CH group experienced a repeat hepatectomy for recurrence and no patients in this group underwent a preoperative portal vein embolization. Conclusions The short- and long-term surgical outcomes of CH and MH for a centrally located HCC are similar under a matched clinicopathological background. CH has the advantage of not requiring a preoperative portal vein embolization and increased chances of conducting a repeat hepatectomy for recurrence

Analysis of the risk factors for early death due to disease recurrence or progression within 1 year after hepatectomy in patients with hepatocellular carcinoma

Background: Liver resection for hepatocellular carcinoma (HCC) has the highest local controllability among all local treatments and results in a good survival rate. However, the recurrence rates of HCC continue to remain high even after curative hepatectomy Moreover, it has been reported that some patients with HCC have an early death due to recurrence. We analyzed the preoperative risk factors for early cancer death. Methods: Between 1997 and 2009, 521 consecutive patients who underwent hepatectomy for HCC at our center were assigned to group ED (death due to HCC recurrence or progression within 1 year after hepatectomy) and group NED (alive over 1 year after hepatectomy). Risk factors for early cancer death were analyzed. Results: Group ED included 48 patients, and group NED included 473 patients. The cause of death included cancer progression (150; 78.1%), operation-related (1; 0.5%), hepatic failure (15; 7.8%), and other (26; 13.5%). Between the ED and NED groups, there were significant differences in albumin levels, Child-Pugh classifications, anatomical resections, curability, tumor numbers, tumor sizes, macroscopic vascular invasion (portal vein and hepatic vein), alpha-fetoprotein (AFP) levels, AFP-L3 levels, protein induced by vitamin K absence or antagonism factor II (PIVKA-II) levels, differentiation, microscopic portal vein invasion, microscopic hepatic vein invasion, and distant metastasis by univariate analysis. Multivariate analysis identified specific risk factors, such as AFP level > 1,000 ng/ml, tumor number ≥ 4, tumor size ≥ 5 cm, poor differentiation, and portal vein invasion. With respect to the preoperative risk factors such as AFP level, tumor number, and tumor size, 3 (1.1%) of 280 patients with no risk factors, 12 (7.8%) of 153 patients with 1 risk factor, 24 (32.9%) of 73 patients with 2 factors, and 9 (60.0%) of 15 patients with 3 risk factors died within 1 year of hepatectomy (p 1,000 ng/ml, tumor number ≥ 4, and tumor size ≥ 5 cm, because patients with these preoperative risk factors tend to die within 1 year after hepatectomy; these patients might be better treated with other therapy

An intraductal papillary neoplasm of the bile duct mimicking a hemorrhagic hepatic cyst: a case report

An intraductal papillary neoplasm of the bile duct is a biliary, epithelium-lined, cystic lesion that exhibits papillary proliferation and rarely causes large hemorrhagic cystic lesions. Here, we report a case of an intraductal papillary neoplasm of the bile duct mimicking a hemorrhagic hepatic cyst in a middle-aged man with large hemorrhagic hepatic cysts who experienced abdominal pain and repeated episodes of intracystic bleeding. Following portal vein embolization, extended right hepatic lobectomy was performed, and intraoperative cholangiography revealed communication between the intracystic space and the hepatic duct. Although histological studies revealed that the large hemorrhagic lesion was not lined with epithelium, the surrounding multilocular lesions contained biliary-derived epithelial cells that presented as papillary growths without ovarian-like stroma. A diagnosis of oncocytic-type intraductal papillary neoplasm of the bile duct was made, and we hypothesized that intracystic bleeding with denudation of the lining epithelial cells might occur as the cystically dilated bile duct increased in size. Differential diagnosis between a hemorrhagic cyst and a cyst-forming intraductal papillary neoplasm of the bile duct with bleeding is difficult. However, an intraductal papillary neoplasm of the bile duct could manifest as multilocular hemorrhagic lesions; therefore, complete resection should be performed for a better prognosis

Significance of functional hepatic resection rate calculated using 3D CT/99mTcgalactosyl human serum albumin single-photon emission computed tomography fusion imaging

AIM: To evaluate the usefulness of the functional hepatic resection rate (FHRR) calculated using 3D computed tomography (CT)/(99m)Tc-galactosyl-human serum albumin (GSA) single-photon emission computed tomography (SPECT) fusion imaging for surgical decision making. METHODS: We enrolled 57 patients who underwent bi-or trisectionectomy at our institution between October 2013 and March 2015. Of these, 26 patients presented with hepatocellular carcinoma, 12 with hilar cholangiocarcinoma, six with intrahepatic cholangiocarcinoma, four with liver metastasis, and nine with other diseases. All patients preoperatively underwent three-phase dynamic multidetector CT and (99m)Tc-GSA scintigraphy. We compared the parenchymal hepatic resection rate (PHRR) with the FHRR, which was defined as the resection volume counts per total liver volume counts on 3D CT/(99m)Tc-GSA SPECT fusion images. RESULTS: In total, 50 patients underwent bisectionectomy and seven underwent trisectionectomy. Biliary reconstruction was performed in 15 patients, including hepatopancreatoduodenectomy in two. FHRR and PHRR were 38.6 +/- 19.9 and 44.5 +/- 16.0, respectively; FHRR was strongly correlated with PHRR. The regression coefficient for FHRR on PHRR was 1.16 (P 1000 mL, and/or macroscopic vascular invasion was significantly smaller than that for patients without these factors (0.73 +/- 0.19 vs 0.82 +/- 0.18, P = 3) occurred in 17 patients (29.8%). There was no case of surgery-related death. CONCLUSION: Our results suggest that FHRR is an important deciding factor for major hepatectomy, because FHRR and PHRR may be discrepant owing to insufficient hepatic inflow and congestion in patients with preoperative therapies, macroscopic vascular invasion, and/ or a tumor volume of > 1000 mL

Surgical management of hepatocellular carcinoma with tumor thrombi in the inferior vena cava or right atrium

Background: The prognosis for advanced hepatocellular carcinoma (HCC) with tumor thrombi in the inferior vena cava (IVC) or right atrium (RA) is poor, and there is no established effective treatment for this condition. Thus study aimed to evaluate the efficacy of surgical resection and prognosis after surgery for such cases. Methods: Between January 1990 and December 2012, 891 patients underwent hepatectomy for HCC at our institution. Of these, 13 patients (1.5%) diagnosed with advanced HCC with tumor thrombi in the IVC or RA underwent hepatectomy and thrombectomy. Data detailing the surgical outcome were evaluated and recurrence-free and overall survival rates were calculated using the Kaplan-Meier method. Results: Seven patients had an IVC thrombus and six had an RA thrombus. Extra-hepatic metastasis was diagnosed in 8 of 13 patients. Surgical procedures included three extended right lobectomies, three extended left lobectomies, five right lobectomies, and two sectionectomies. Right adrenal gland metastases were excised simultaneously in two patients. All IVC thrombi were removed under hepatic vascular exclusion and all RA thrombi were removed under cardiopulmonary bypass (CPB). Four patients (30.8%) experienced controllable postoperative complications, and there was no surgical mortality. The mean postoperative hospital stay for patients with IVC and RA thrombi was 23.6 +/- 12.5 days and 21.2 +/- 4.6 days, respectively. Curative resection was performed in 5 of 13 cases. The 1- and 3-year overall survival rates were 50.4%, and 21.0%, respectively, and the median survival duration was 15.3 months. The 1- and 3-year overall survival rates for patients who underwent curative surgical resection were 80.0% and 30.0%, respectively, with a median survival duration of 30.8 months. All patients who underwent curative resection developed postoperative recurrences, with a median recurrence-free survival duration of 3.8 months. The 1- year survival rate for patients who underwent noncurative surgery and had residual tumors was 29.2%, with a median survival duration of 10.5 months. Conclusions: Aggressive surgical resection for HCC with tumor thrombi in the IVC or RA can be performed safely and may improve the prognoses of these patients. However, early recurrence and treatment for recurrent or metastatic tumors remain unresolved issues

MicroRNAs in Colon Tissue of Pediatric Ulcerative Pancolitis Patients Allow Detection and Prognostic Stratification

Prevalence of inflammatory bowel disease has been on the rise in recent years, especially in pediatric populations. This study aimed to provide precise identification and stratification of pediatric patients with diagnosed ulcerative colitis (UC) according to the severity of their condition and the prediction for standard treatment according to the specific expression of candidate miRNAs. We enrolled consecutive, therapeutically naïve, pediatric UC patients with confirmed pancolitis. We examined formalin-fixed paraffin-embedded specimens of colonic tissue for the expression of 10 selected candidate miRNAs. We performed receiver operating characteristic curve analysis, using area under the curve and a logistic regression model to evaluate the diagnostic and predictive power of the miRNA panels. Sixty patients were included in the final analysis. As a control group, 18 children without macroscopic and microscopic signs of inflammatory bowel disease were examined. The combination of three candidate miRNAs (let-7i-5p, miR-223-3p and miR-4284) enabled accurate detection of pediatric UC patients and controls. A panel of four candidate miRNAs (miR-375-3p, miR-146a-5p, miR-223-3p and miR-200b-3p) was associated with severity of UC in pediatric patients and a combination of three miRNAs (miR-21-5p, miR-192-5p and miR-194-5p) was associated with early relapse of the disease. Nine patients out of the total were diagnosed with primary sclerosing cholangitis (PSC) simultaneously with ulcerative colitis. A panel of 6 candidate miRNAs (miR-142-3p, miR-146a-5p, miR-223-3p, let-7i-5p, miR-192-5p and miR-194-5p) identified those patients with PSC. Specific combinations of miRNAs are promising tools for potential use in precise disease identification and severity and prognostic stratification in pediatric patients with ulcerative pancolitis