Synchronous cutaneous malignant peripheral nerve sheath tumor and jejunal gastrointestinal stromal tumor and submucosal angiomyolipoma in type 1 neurofibromatosis: A case report and literature review.

RATIONALE: Type 1 neurofibromatosis (NF1) is one of the most prevalent genetic conditions. NF1 is characterized by cutaneous plexiform neurofibromas and café au lait skin pigmentation, and is inherited in an autosomal dominant trait with mutation in the neurofibromin 1 gene on chromosome 17. Neurofibromin is involved in Ras proto-oncogene regulation. Accordingly, NF1 may lead to malignancies, with a lifetime cancer risk of 60%. Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality due to NF1. The relevance of gastrointestinal stromal tumor (GIST) in NF1 is increasingly being reported in the literature and NF1-associated GIST has been identified to have an alternative molecular pathogenesis. PATIENT CONCERNS: A 62-years-old female had a 7 × 5 cm growing back mass in the background of various sized cutaneous neurofibromas with café au lait spots. Computed tomography performed in the workup revealed a 4.1 cm enhancing mass near the ileal mesentery. DIAGNOSES: NF1 affected by cutaneous MPNST of the back, and synchronous GIST and submucosal angiomyolipoma (AML) of the jejunum. INTERVENTIONS: The patient underwent laparoscopic jejunal mass excision, and excision and flap coverage for the back mass owing to the suspicion of multiple MPNSTs. However, the abdominal masses were diagnosed as GIST and AML following confirmation of the immunohistochemical profiles. Accordingly, the patient was administered adjuvant radiotherapy to the MPNST after surgery. OUTCOMES: Symptomatic improvements were achieved, and no subsequent relapses were observed. LESSONS: Although MPNST and GIST are not rare neoplasm in NF1, only 2 case reports have been published on the synchronous occurrence of these tumors. Moreover, no case report has been published on AML in NF1, except 1 renal AML in segmental neurofibromatosis. Identifying the clinical and pathologic significances of the NF1 is important to achieve improved diagnostic accuracy.

Treatment shortening of drug-sensitive pulmonary tuberculosis using high-dose rifampicin for 3 months after culture conversion (Hi-DoRi-3): a study protocol for an open-label randomized clinical trial.

BACKGROUND: The standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted. METHODS: This study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited. DISCUSSION: This study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB. TRIAL REGISTRATION: ClinicalTrials.gov NCT04485156 . Registered on July 24, 2020.

Upregulation of prostaglandin E2 by inducible microsomal prostaglandin E synthase-1 in colon cancer.

PURPOSE: Prostaglandin E2 (PGE2) is known to promote carcinogenesis and cancer progression in colon cancer. Enzymes involved in the metabolism of PGE2 include cyclooxygenase (COX)-2, microsomal prostaglandin E synthase-1 (mPGES-1), and 15-prostaglandin dehydrogenase (15-PGDH). The current study aims to determine how PGE2 is expressed by examining patients with colorectal cancer and evaluating colon cancer cells to gain insight into changes in relevant enzymes upon induction of PGE2. METHODS: The concentration of PGE2 was measured in tumor tissues and adjacent normal mucosal tissues of 26 patients with colon cancer. The expression of COX-1, COX-2, mPGES-1, and 15-PGDH proteins was measured. The concentration of PGE2 in FET colon cancer cells was measured both in the initial status and after stimulation by tumor necrosis factor (TNF)-α. The expression levels of PGE2-related enzymes were measured as well. RESULTS: There was no significant difference in the average concentration of PGE2, which was measured at 453.1 pg/mL in cancer tissues and 401.2 pg/mL in normal mucosa. Among PGE2-related enzymes, 15-PGDH was expressed at a lower level in tumor cells than in normal mucosa. In colon cancer cells, PGE2 was found to be upregulated upon stimulation by TNF-α, which led to strong induction of mPGES-1 without any change in the expression of COX-2 among the PGE2-related enzymes. CONCLUSION: These results demonstrated that PGE2 can be induced by stimuli such as TNF-α, and suggest that activation of mPGES-1 is more closely related than that of COX-2 in the induction of PGE2 on colon cancer.

Delamanid, Bedaquiline, and Linezolid Minimum Inhibitory Concentration Distributions and Resistance-related Gene Mutations in Multidrug-resistant and Extensively Drug-resistant Tuberculosis in Korea.

BACKGROUND: Delamanid, bedaquiline, and linezolid have recently been approved for the treatment of multidrug- and extensively drug-resistant (MDR and XDR, respectively) tuberculosis (TB). To use these drugs effectively, drug susceptibility tests, including rapid molecular techniques, are required for accurate diagnosis and treatment. Furthermore, mutation analyses are needed to assess the potential for resistance. We evaluated the minimum inhibitory concentrations (MICs) of these three anti-TB drugs for Korean MDR and XDR clinical strains and mutations in genes related to resistance to these drugs. METHODS: MICs were determined for delamanid, bedaquiline, and linezolid using a microdilution method. The PCR products of drug resistance-related genes from 420 clinical Mycobacterium tuberculosis strains were sequenced and aligned to those of M. tuberculosis H37Rv. RESULTS: The overall MICs for delamanid, bedaquiline, and linezolid ranged from ≤0.025 to >1.6 mg/L, ≤0.0312 to >4 mg/L, and ≤0.125 to 1 mg/L, respectively. Numerous mutations were found in drug-susceptible and -resistant strains. We did not detect specific mutations associated with resistance to bedaquiline and linezolid. However, the Gly81Ser and Gly81Asp mutations were associated with resistance to delamanid. CONCLUSIONS: We determined the MICs of three anti-TB drugs for Korean MDR and XDR strains and identified various mutations in resistance-related genes. Further studies are needed to determine the genetic mechanisms underlying resistance to these drugs.

Comparison of efficacy and safety between endoscopic submucosal dissection and transanal endoscopic microsurgery for the treatment of rectal tumor.

Background/Aim: To compare the treatment efficacy and safety between endoscopic submucosal dissection (ESD) and transanal endoscopic microsurgery (TEM) for the treatment of rectal epithelial tumors, including large adenoma, cancer, and subepithelial tumors (SET). Patients and Methods: We conducted a retrospective analysis of the medical records of 71 patients with rectal tumors who were treated with ESD (48 patients) or TEM (23 patients) from January 2013 to December 2015. The patient group comprised 56 patients with epithelial tumors and 15 patients with SET. Treatment efficacy such as en bloc resection, procedure time, local recurrence, hospital stay, additional procedure rate, and safety between the treatment groups were evaluated and analyzed. Results: There were no significant differences in tumor size, location, macroscopic appearance, and histological depth between ESD and TEM groups. For ESD compared to TEM in rectal epithelial tumors, en bloc resection rates were 95% vs. 93.7% and R0 resection rates were 92.5% vs. 87.5% (P = 0.617); in rectal SET, en bloc resection rates were 100% vs. 100% and R0 resection rates were 87% vs. 85% (P = 0.91). The procedure time was 71.5 ± 51.3 min vs. 105.6 ± 28.2 min (P = 0.016) for epithelial tumors and 32.13 ± 13.4 min vs. 80.71 ± 18.35 min (P = 0.00) for SET, respectively. Hospital stay was 4.3 ± 1.2 days vs. 5.8 ± 1.8 days (P = 0.001) for epithelial tumors and 4.1 ± 4.1 days vs. 5.5 ± 2 days (P = 0.42) for rectal SET, respectively. There were no significant differences between recurrence rates, additional procedure rates, and complications in the two groups. Conclusions: ESD and TEM are both effective and safe for the treatment of rectal epithelial tumors and SET because of favorable R0 resection rates and recurrence rates. However, the ESD group showed shorter procedure times and hospital stays than the TEM group. Therefore, ESD should be considered more preferentially than TEM in the treatment of large rectal epithelial tumors and SET.

Management Outcomes of Colonoscopic Perforations Are Affected by the General Condition of the Patients.

PURPOSE: The management of a colonoscopic perforation (CP) varies from conservative to surgical. The objective of this study was to evaluate the outcomes between surgical and conservative treatment of patients with a CP. METHODS: From 2003 to 2016, the medical records of patients with CP were retrospectively reviewed. Patients were divided into 2 groups depending on whether they initially received conservative or surgical treatment. RESULTS: During the study period, a total of 48 patients with a CP were treated. Among them, 5 patients had underlying colorectal cancer and underwent emergency radical cancer surgery; these patients were excluded. The mean age of the remaining 43 patients was 64.5 years old, and the most common perforation site was the sigmoid colon (15 patients). The initial conservative care group included 16 patients, and the surgery group included 27 patients. In the conservative group, 5 patients required conversion to surgery (failure rate: 5 of 16 [31.3%]). Of the surgery group, laparoscopic surgery was performed on 19 patients and open surgery on 8 patients, including 2 conversion cases. Major postoperative complications developed in 11 patients (34.4%), and postoperative mortality developed in 4 patients (12.5%). The only predictor for poor prognosis after surgery was a high American Society of Anesthesiologists physical status classification. CONCLUSION: In this study, conservative treatment for patients with a CP had a relatively high failure rate. Furthermore, surgical treatment showed significant rates of complications and mortality, which depended on the general status of the patients.

Surgical Outcomes and Risk Factors in Patients Who Underwent Emergency Colorectal Surgery.

PURPOSE: Emergency colorectal surgery has high rates of complications and mortality because of incomplete bowel preparation and bacterial contamination. The authors aimed to evaluate the surgical outcomes and the risk factors for the mortality and the complication rates of patients who underwent emergency surgery to treat colorectal diseases. METHODS: This is a prospective study from January 2014 to April 2016, and the results are based on a retrospective analysis of the clinical results for patients who underwent emergency colorectal surgery at Chosun University Hospital. RESULTS: A total of 99 patients underwent emergency colorectal surgery during the study period. The most frequent indication of surgery was perforation (75.8%). The causes of disease were colorectal cancer (19.2%), complicated diverticulitis (21.2%), and ischemia (27.2%). There were 27 mortalities (27.3%). The major morbidity was 39.5%. Preoperative hypotension and perioperative blood transfusion were independent risk factors for both morbidity and mortality. CONCLUSION: These results revealed that emergency colorectal surgeries are associated with significant morbidity and mortality. Furthermore, the independent risk factors for both morbidity and mortality in such patiients were preoperative hypotension and perioperative transfusion.

Synchronous Primary Anorectal Melanoma and Sigmoid Adenocarcinoma.

A primary anorectal malignant melanoma is a rare tumor. Moreover, cases involving a synchronous anorectal melanoma and colon adenocarcinoma are extremely rare. The authors report a case of a synchronous anorectal melanoma and sigmoid adenocarcinoma in an 84-year-old man. The regions of the anorectal melanoma showed melanocytic nevi in the adjacent mucosa of the anal canal and rectum. A dysplastic nevus was also identified in the anal mucosa. This case demonstrates that an anorectal melanoma can arise from pre-existing anorectal melanocytic lesions.

Outcomes and Risk Factors Affecting Mortality in Patients Who Underwent Colorectal Emergency Surgery.

PURPOSE: Emergency colorectal surgery has a high risk of mortality and morbidity because of incomplete bowel preparation, bacterial proliferation, and contamination. In this study, we investigated the outcomes and the risk factors affecting mortality in patients who had undergone emergency surgery for the treatment of various colorectal diseases. METHODS: This study is a retrospective analysis of prospectively collected data to survey the clinical results for patients who had undergone emergency colorectal surgery from January 2014 to December 2014. We analyzed various clinicopathologic factors, which were divided into 3 categories: preoperative, intraoperative, and postoperative. RESULTS: A total of 50 patients had undergone emergency colorectal surgery during the time period covered by this study. Among them, 10 patients (20%) died during the postoperative period. A simple linear regression analysis showed that the risk factors for mortality were old age, preoperative hypotension, and a high American Society of Anesthesiologist (ASA) score. Moreover, a multiple linear regression analysis showed a high ASA score and preoperative hypotension to be independent risk factors. CONCLUSION: In this study, emergency colorectal surgery showed a relatively high mortality rate. Furthermore, the independent risk factors for mortality were preoperative hypotension and high ASA score; thus, patients with these characteristics need to be evaluated more carefully and receive better care if the mortality rate is to be reduced.

Giant ascending colonic diverticulum presenting with intussusception.

Diverticular disease of the colon is a common disease, and its incidence is increasing gradually. A giant colonic diverticulum (GCD) is a rare entity and is defined as a diverticulum greater than 4 cm in size. It mainly arises from the sigmoid colon, and possible etiology is a ball-valve mechanism permitting progressive enlargement. A plain abdominal X-ray can be helpful to make a diagnosis initially, and a barium enema and abdominal computed tomography may confirm the diagnosis. Surgical intervention is a definite treatment for a GCD. We report a case of an ascending GCD presenting with intussusception in a young adult.

Right side fixation of sigmoid colon with a hepato-sigmoidocolic fistula in patient with hepatocellular carcinoma and midgut malrotation.

The location of the sigmoid colon varies within the abdominal cavity, but its mesocolon is fixed to the left side. Right side fixation of the sigmoid colon is a very rare congenital positional anomaly. In addition, it has been reported that hepatocolic fistula is also a very rare disease that may present lower gastrointestinal bleeding. Here, the authors describe a case of a 71-year-old man who underwent surgery for hepato-sigmoidocolic fistula complicated by hepatocellular carcinoma and the right side fixation of the sigmoid colon.

Prognostic implication of 15-hydroxyprostaglandin dehydrogenase down-regulation in patients with colorectal cancer.

PURPOSE: Prostaglandin (PG) E2 is known to be closely related to cancer progression and is inactivated by 15-hydroxyprostaglandin dehydrogenase (PGDH). 15-PGDH is shown to have tumor suppressor activity and to be down-regulated in various cancers, including colorectal cancer (CRC). Therefore, we evaluated the expression of 15-PGDH and its prognostic effect in patients with CRC. METHODS: 15-PGDH expression was examined by using immunohistochemistry in 77 patients with CRC. Its prognostic significance was statistically evaluated. RESULTS: Negative 15-PGDH expression was noted in 55.8% of the 77 cases of CRC. 15-PGDH expression showed no correlation with any of the various clinicopathologic parameters. The status of lymph node metastasis, tumor-node-metastasis stages, and pre-operative carcinoembryonic antigen levels showed significant prognostic effect. However, univariate analysis revealed down-regulation of 15-PGDH not to be a predictor of poor survival. The 5-year overall survival rate was 71.7% in the group with positive expression of 15-PGDH and 67.1% in the group with negative expression of 15-PGDH, but this difference was not statistically significant (P = 0.751). CONCLUSION: 15-PGDH was down-regulated in 55.8% of the colorectal cancer patients. However, down-regulation of 15-PGDH showed no prognostic value in patients with CRC. Further larger scale or prospective studies are needed to clarify the prognostic effect of 15-PGDH down-regulation in patients with colorectal cancer.

Prognostic significance of cytosolic phospholipase A2 expression in patients with colorectal cancer.

PURPOSE: Cyclooxygenase-2 is believed to be an important enzyme in the pathogenesis of colorectal cancer (CRC). Cytosolic phospholipase A2 (cPLA2), also, have been suggested to be related to the carcinogenesis of CRC. The aim of this study was to investigate cPLA2 expression and its relationship with prognostic significance in CRC. METHODS: Eighty-eight patients with colorectal cancer who underwent curative surgery were enrolled in this study. cPLA2 was examined in 88 primary CRCs by immunohistochemistry and we compared their expression with clinicopathologic findings, recurrence and survival in patients with CRC. RESULTS: The expression of cPLA2 was positive in 54.5% (48/88). The expression of cPLA2 was not correlated with clinicopathologic parameters. However, cPLA2 expression was significantly related with vascular endothelial growth factor expression. Kaplan-Meier analysis didn't show any clinical significance in disease-free survival and overall survival according to cPLA2 expression. CONCLUSION: These results suggest that cPLA2 expression was not associated with the prognosis of CRC. However, further large-scale studies are needed to clarify the prognostic effect of cPLA2 in CRC.

Up-regulation of cyclooxygenase-2-derived prostaglandin E(2) in colon cancer cells resistant to 5-fluorouracil.

PURPOSE: It has been suggested that constitutive up-regulation of cyclooxygenase (COX)-2 is associated with resistance to apoptosis, increased angiogenesis, and increased tumor invasiveness in various cancers including colon cancer. There are many factors involved in the resistance to 5-fluorouracil (5-FU) in colon cancer. However, little is known about the role of COX-2 in acquired resistance to 5-FU in colon cancer. METHODS: Hence we investigated whether COX-2 contribute to acquired resistance to 5-FU in colon cancer cells, using cytotoxicity assay for cell survival, reverse transcription-polymerase chain reaction (RT-PCR) for vascular endothelial growth factor (VEGF), quantitative RT-PCR for COX-1 and COX-2, and enzyme-linked immunosorbent assay for PGE(2). RESULTS: The 5-FU resistant colon cancer cells, SNU-C5/5FUR, showed increased expression of COX-2, prostaglandin E(2) (PGE(2)), and VEGF, compared to its parental cell (SNU-C5). By treatment with meloxicam, the expression of PGE(2) and VEGF was reduced significantly in the resistant cells, but not in the parent cells. CONCLUSION: These results demonstrate that COX-2 derived PGE(2) is up-regulated and COX-2 inhibitor may have an anti-angiogenic effect in the colon cancer cells resistant to 5-FU.

Impacts of cytosolic phospholipase A2, 15-prostaglandin dehydrogenase, and cyclooxygenase-2 expressions on tumor progression in colorectal cancer.

PURPOSE: In addition to cyclooxygenase-2 (COX-2) which is related to prostaglandin E2 synthesis, other enzymes such as cytosolic phospholipase A2 (cPLA2), microsomal prostaglandin E2 synthase-1 (mPGES-1), and 15-prostaglandin dehydrogenase (15-PGDH) have been suggested to be related to carcinogenesis of colorectal cancer (CRC). The aim of this study was to investigate the roles of cPLA2, COX-2, mPGES-1, and 15-PGDH in tumor progression. MATERIALS AND METHODS: cPLA2, COX-2, mPGES-1, 15-PGDH, and vascular endothelial growth factor (VEGF) expressions were immunohistochemically examined in 89 CRC, and their expressions were compared with each other or clinicopathologic parameters as well as VEGF as tumor progression parameters. RESULTS: cPLA2 was expressed in 54.5%, COX-2 in 80.5%, mPGES-1 in 96.4%, 15-PGDH in 46.1%, and VEGF in 65.9%. The expression of cPLA2 correlated with VEGF expression. COX-2 expression was correlated with the depth of invasion, tumor stage, cPLA2, and VEGF expressions. Moreover, VEGF revealed the highest expression in the tissues positive for both cPLA2 and COX-2. Furthermore, 15-PGDH expression was inversely correlated with VEGF expression. CONCLUSION: The present study demonstrates that cPLA2 and mPGES-1, in addition to COX-2, are constitutively overexpressed, and that 15-PGDH might be attenuated in colorectal cancer. Furthermore, cPLA2 and 15-PGDH as well as COX-2 could have an important role in tumor progression.

Significance of p-STAT3 expression in human colorectal adenocarcinoma.

To examine the relationship between p-STAT3 and the clinicopathological parameters of colorectal adenocarcinoma (CRA), we initially conducted immunohistochemical (IHC) analyses on formalin-fixed tissues. A total of 127 invasive CRA, 20 colorectal adenomas and 20 normal mucosae were obtained. To clarify the validity of p-STAT3 as determined by the IHC analysis, quantitative real-time PCR was performed on fresh samples from 51 CRA-4 carcinomas in situ, 47 invasive CRA and on 51 normal mucosae. IHC analyses were conducted after formalin fixation from 51 CRA for comparison. The statistically significant difference of immunoreactivity for p-STAT3 between the CRA and adenoma, and between the CRA and normal mucosae was identified. Among the 174 CRA, p-STAT3 immunoreactivity significantly correlated with the T- and clinical stage. Among the 47 invasive CRA, the expression of STAT3 as determined by real-time PCR significantly correlated with tumor size, M stage and clinical stage. The overall findings of the real-time PCR analyses correlated with the findings of the IHC analyses. These findings suggest that p-STAT3 expression has an important role related to the tumorigenesis and tumor progression of CRAs. Moreover, IHC analysis is a reliable and useful modality of assessing the status of p-STAT3 expression in formalin-fixed samples.

Epigenetic mechanisms involved in differential MDR1 mRNA expression between gastric and colon cancer cell lines and rationales for clinical chemotherapy.

BACKGROUND: The membrane transporters such as P-glycoprotein (Pgp), the MDR1 gene product, are one of causes of treatment failure in cancer patients. In this study, the epigenetic mechanisms involved in differential MDR1 mRNA expression were compared between 10 gastric and 9 colon cancer cell lines. METHODS: The MDR1 mRNA levels were determined using PCR and real-time PCR assays after reverse transcription. Cytotoxicity was performed using the MTT assay. Methylation status was explored by quantification PCR-based methylation and bisulfite DNA sequencing analyses. RESULTS: The MDR1 mRNA levels obtained by 35 cycles of RT-PCR in gastric cancer cells were just comparable to those obtained by 22 cycles of RT-PCR in colon cancer cells. Real-time RT-PCR analysis revealed that MDR1 mRNA was not detected in the 10 gastric cancer cell lines but variable MDR1 mRNA levels in 7 of 9 colon cancer cell lines except the SNU-C5 and HT-29 cells. MTT assay showed that Pgp inhibitors such as cyclosporine A, verapamil and PSC833 sensitized Colo320HSR (colon, highest MDR1 expression) but not SNU-668 (gastric, highest) and SNU-C5 (gastric, no expression) to paclitaxel. Quantification PCR-based methylation analysis revealed that 90% of gastric cancer cells, and 33% of colon cancer cells were methylated, which were completely matched with the results obtained by bisulfite DNA sequencing analysis. 5-aza-2'-deoxcytidine (5AC, a DNA methyltransferase inhibitor) increased the MDR1 mRNA levels in 60% of gastric cells, and in 11% of colon cancer cells. Trichostatin A (TSA, histone deacetylase inhibitor) increased the MDR1 mRNA levels in 70% of gastric cancer cells and 55% of colon cancer cells. The combined treatment of 5AC with TSA increased the MDR1 mRNA levels additively in 20% of gastric cancer cells, but synergistically in 40% of gastric and 11% of colon cancer cells. CONCLUSION: These results indicate that the MDR1 mRNA levels in gastric cancer cells are significantly lower than those in colon cancer cells, which is at least in part due to different epigenetic regulations such as DNA methylation and/or histone deacetylation. These results can provide a better understanding of the efficacy of combined chemotherapy as well as their oral bioavailability.