Plasma exosomal microRNA-125b as a monitoring biomarker of resistance to mFOLFOX6-based chemotherapy in advanced and recurrent colorectal cancer patients.

Liquid biomarkers for the early detection of resistance to chemotherapy are important for improving prognosis. This study investigated the usefulness of plasma exosomal microRNA-125b (ex-miRNA-125b) for the early detection of resistance to modified fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)-based first-line chemotherapy in patients with advanced or recurrent (advanced/recurrent) colorectal cancer (CRC). First, ex-miRNAs associated with resistance to mFOLFOX6-based chemotherapy were profiled via miRNA microarray analysis. In this analysis, ex-miR-125b exhibited the greatest upregulation in patients with progressive disease (PD) compared with the findings for patients with stable disease (SD) and healthy controls. Next, another 55 patients with advanced/recurrent CRC who received mFOLFOX6-based first-line chemotherapy underwent a validation study of ex-miR-125b. Blood samples were collected before and during treatment until tumor progression. Ex-miRNA levels were measured via TaqMan microRNA assays. Patients with CRC had significantly higher ex-miR-125b levels than healthy controls. In patients with partial responses, ex-miR-125b levels at the Response Evaluation Criteria in Solid Tumors (RECIST) judgment point were significantly lower than those measured before treatment. In patients with SD, ex-miR-125b levels did not differ before and during treatment. In patients with PD, ex-miR-125b levels at the RECIST judgment point were significantly higher than those measured before treatment. These changes in ex-miR-125b levels were significantly different between groups even 1 month after the initiation of chemotherapy. Progression-free survival (PFS) was significantly worse in patients with high baseline ex-miR-125b levels than in those with low levels. In the Cox analysis, baseline ex-miR-125b levels and KRAS mutation were indicated to be independent prognostic factors for PFS. The present results suggest that plasma ex-miR-125b levels may be useful for the early detection of resistance to mFOLFOX6-based first-line chemotherapy. Furthermore, ex-miR-125b before chemotherapy is a predictive biomarker for PFS in patients with advanced/recurrent CRC.

A rare case of perivascular epithelioid cell tumor (PEComa) of the greater omentum.

BACKGROUND: A tumor composed exclusively or predominantly of human melanin black 45 (HMB45)-positive epithelioid cells is called a perivascular epithelioid cell tumor (PEComa). We report a very rare case of a PEComa of the greater omentum. CASE PRESENTATION: MRI conducted to examine the orthopedic disease of the patients, a 49-year-old Japanese woman, also identified a tumor in her pelvis. A CT scan revealed a tumor mass on the right side of the pelvic floor and clear nutrient vessels originating from the splenic and celiac arteries. An omental primary tumor or accessory spleen was thus suspected, and tumor resection was performed. The tumor was a light brown solid tumor with a smooth margin, measuring 5.2 × 3.8 × 3.5 cm. Histopathologically, the tumor was composed mainly of spindle and epithelioid cells, and large and small blood vessel formation was observed. In the immunohistochemical staining, tumor cells were positive for human melanin black 45 (HMB-45) and Melan-A and partially positive for alpha-smooth muscle actin. The final diagnosis was PEComa of the greater omentum. CONCLUSIONS: Although omental PEComa is very rare, it should be considered as a differential disease of an omental primary tumor.

Number of Lymph Nodes in Rectal Cancer is Correlated with Response to Preoperative Chemoradiotherapy but is not Associated with Patient Survival.

BACKGROUND/AIMS: We aimed to clarify the oncological significance of the number of lymph nodes in rectal cancers treated with preoperative chemoradiotherapy. METHODOLOGY: We studied 126 curatively operated patients with clinical T3-T4 and M0 rectal cancers. The number of lymph nodes and clinicopathological features were compared between the patients treated with surgery alone (OP group, n = 45) and those treated with preoperative chemoradiotherapy (50-50.4 Gy in 25-28 fractions with tegafur-uracil and leucovorin, CRT group, n = 81). Factors influencing lymph node count and its prognostic significance were analyzed. RESULTS: The CRT group had significantly fewer lymph nodes than the OP group (12.4 vs. 21.1, P < 0.0001). High histological regression of rectal lesions was significantly correlated with decreased lymph node count in the CRT group. In the OP group, the 5-year cancer-specific survival rate of the patients with 12 or more lymph nodes was significantly better than those with fewer than 12 lymph nodes (75.1% vs. 33.3%, P = 0.02); in the CRT group, on the other hand, these survival rates did not differ (84.5% vs. 77.5%, P = 0.6). CONCLUSIONS: The number of lymph nodes in rectal cancer was correlated with the response of primary rectal lesions to chemoradiotherapy, and was not associated with patient survival.

Clinicopathological and prognostic significance of the microRNA processing enzyme DICER1 mRNA expression in colorectal cancer patients.

The cytoplasmic ribonuclease DICER1 is one of the key enzymes in microRNA (miRNA) processing, essential for the production of mature miRNA. The effect of DICER1 expression in tumor cells on the prognosis of patients with several cancers has been examined with controversial results in various cancer types. In particular, the clinical significance of DICER1 expression in colorectal cancer (CRC) patients has yet to be determined. The aim of this study was to evaluate the correlation between the DICER1 mRNA levels and the clinicopathological characteristics and prognostic significance in CRC patients. Tumor and normal adjacent tumor tissues from 260 patients with CRC (Dukes' stage A: 40 cases, Dukes' B: 68 cases, Dukes' C: 88 cases and Dukes' D: 64 cases) were examined. The DICER1 mRNA levels were measured using the TaqMan real-time reverse transcription polymerase chain reaction (RT-PCR) method. The expression levels of DICER1 mRNAs showed a significant decrease in CRC tissues as compared to normal ones (P=0.039). A statistically significant association was observed between DICER1 mRNA expression and tumor size, depth of invasion, lymph node metastasis, lymphatic invasion and Dukes' stage. In Kaplan-Meier survival curve analysis, overall survival (OS) and disease-free survival (DFS) rates of patients with a low DICER1 mRNA expression were significantly worse compared to patients with a high DICER1 mRNA expression (OS P<0.001; DFS P<0.001). In the Cox multivariate analysis, DICER1 mRNA expression in CRC tissues was identified as an independent prognostic factor for OS [hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.13-0.64; P=0.001] and DFS (HR, 0.23; 95% CI, 0.10-0.48; P=0.001). This study demonstrated that a reduced DICER1 mRNA expression is associated with poor prognosis in CRC patients.

Prognostic significance of PDCD4 expression and association with microRNA-21 in each Dukes' stage of colorectal cancer patients.

Down-regulation of the novel tumor suppressor gene programmed cell death 4 (PDCD4) was demonstrated in several types of cancer and regulation by micro-RNA is gaining attention. However, the clinical significance of the PDCD4 gene in colorectal cancer (CRC) patients still remains unclear. In particular, the significance of PDCD4 mRNA expression in each tumor stage has not been reported. In this study, we evaluated the prognostic value of PDCD4 expression in each Dukes' stage of CRC patients. Furthermore, relationships between the PDCD4 mRNA and microRNA-21 (miR-21) were evaluated. Tumor tissues and normal adjacent tumor tissues from 326 patients with CRC (Dukes' stage A, 44 cases; Dukes' B, 118 cases; Dukes' C, 100 cases; Dukes' D, 64 cases) were examined. The PDCD4 mRNA was investigated by the quantitative real-time RT-PCR method and miR-21 was examined by TaqMan microRNA assays. The overall survival rates (OS) and disease-free survival rates (DFS) of low PDCD4 patients were significantly worse than those of patients with high expression. In analysis of each tumor stage, OS and DFS of patients with low PDCD4 levels were significantly worse than those with high PDCD4 levels in Dukes' stage B and C. In Dukes' stage D, patients with low PDCD4 expression showed a significant worse OS compared to those of patients with high PDCD4 expression. In contrast, no significant differences were seen between these groups in patients with Dukes' stage A. PDCD4 expression in CRC tissues was an independent prognostic factor in Dukes' stage B, C and D. Significant inverse correlations were demonstrated between PDCD4 and miR-21. The reduced PDCD4 mRNA expression is associated with poor prognosis in CRC patients with Dukes' stage B, C and D. Furthermore, PDCD4 mRNA levels were negatively regulated by miR-21in each tumor stage of CRC.

Prognostic significance of CTCs and CSCs of tumor drainage vein blood in Dukes' stage B and C colorectal cancer patients.

The clinical significance of circulating tumor cells (CTCs) including cancer stem cells (CSCs) (CTC/CSC) in the tumor drainage vein blood of patients with colorectal cancer (CRC) is unclear. In this study, we investigated the prognostic value of CTC/CSC that express carcinoembryonic antigen (CEA) cytokeratin 19 (CK19), CK20 and/or CD133 (CEA/CK/CD133) mRNA in the tumor drainage blood of CRC patients with Dukes' stage B and C. We examined tumor drainage blood from 197 patients with Dukes' stage B and C CRC. CTCs that expressed CEA, CK19, CK20 and CD133 mRNA were detected using the quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) assay. Each mRNA level was normalized with GAPDH mRNA levels. In the relationship between the expression of CEA/CK/CD133 in the tumor drainage blood and clinicopathological factors, a significant correlation was observed between CEA/CK/CD133 expression and Dukes' stage (p<0.041). In CRC patients with Dukes' stage B and C, disease-free (DFS) and overall survival (OS) of patients with CEA/CK/CD133 positive in the tumor drainage blood were significantly worse than that of marker gene negative patients. In contrast, in patients with Dukes' stage A, no significant differences were shown between these groups. By Cox progression analysis, it was shown that CEA/CK/CD133 mRNA in tumor drainage blood was an independent prognostic factor for DFS and OS in patients with Dukes' stage B and C. These results suggest that detecting CEA/CK/CD133 mRNA in tumor drainage blood by the real-time RT-PCR method would have a prognostic value in CRC patients with Dukes' stage B and C.

Radiation-induced apoptosis of peripheral blood lymphocytes is correlated with histological regression of rectal cancer in response to preoperative chemoradiotherapy.

PURPOSE: The response of rectal cancer to preoperative chemoradiotherapy (PRT) varies widely among patients, and predictors of the response remain to be elucidated. The purpose of this study is to investigate whether radiation-induced apoptosis (RIA) of peripheral blood lymphocytes (PBLs) reflects the underlying intrinsic radiosensitivity of rectal cancer. METHODS: Forty-one patients with clinical T3-4, M0 low rectal cancers, treated with PRT and curative surgery, were retrospectively studied. PBLs were obtained from blood samples of the patients, irradiated at 0, 2, 8, and 16 Gy in vitro, and analyzed for RIA by flow cytometry using Annexin V (AV) and propidium iodide (PI). The correlation of the RIA of PBLs and histological regression of rectal cancer in response to PRT was examined. RESULTS: Both the proportions of AV+/PI- PBLs (early apoptosis) and AV+/PI + PBLs (late apoptosis) were significantly higher in patients with high histological regression than in those with low histological regression. Age, sex, tumor size, and clinical T and N stages did not affect the RIA of PBLs. CONCLUSIONS: This study showed that the RIA of PBLs is correlated with the histological regression of rectal cancer in response to PRT and suggested that the radiosensitivity of rectal cancer might be estimated by the RIA of PBLs.

Tumor location is a prognostic factor in poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet-ring cell carcinoma of the colon.

PURPOSE: Cancers which arise in the proximal and distal colon are suggested to be different clinically, pathologically, and genetically. The aim of this study is to clarify whether clinical behavior of colonic poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet-cell carcinoma (Por/Muc/Sig cancers), minor and aggressive subpopulation in colonic cancers, differs in accordance with the tumor location. METHODS: A total of 3,175 patients with curatively resected colonic cancers were studied. Clinical and pathological features were compared between Por/Muc/Sig cancers and well or moderately differentiated adenocarcinomas (Wel/Mod cancers) and between proximal and distal cancers in each histologic type. RESULTS: Por/Muc/Sig cancers (n = 213) were more advanced in the TNM stage and showed worse disease-specific survival than Wel/Mod cancers (n = 2,692). In Por/Muc/Sig cancers, but not in Wel/Mod cancers, proximal cancers showed significantly better disease-specific survival than distal cancers (88.9% vs. 76.5%, p = 0.0234), and a multivariate analysis showed that proximal tumor location was an independent predictor of fair prognosis (hazard ratio (HR), 0.458; 95% confidence interval (CI), 0.218-0.961; p = 0.0390). In addition, female gender also was an independent predictor of fair prognosis in Por/Muc/Sig cancers (HR, 0.373; 95% CI, 0.151-0.922) and not in Wel/Mod cancers. CONCLUSIONS: Proximal Por/Muc/Sig cancers were suggested to be a distinct subpopulation with a favorable oncologic outcome. Tumor location and gender might be helpful in the risk stratification after curative surgery for Por/Muc/Sig cancers.

Skin metastasis from sigmoid colon cancer.

Skin metastases from visceral cancers are rare and the reported incidence from all visceral cancers is 1.4% to 10%. Skin metastases from colorectal cancers account for only 5% of metastatic skin cancers, among which scalp metastases are very rare. We describe a 53-year-old man with scalp metastasis derived from sigmoid colon cancer that was diagnosed and surgically resected in 2005. Metastatic lung tumors that developed thereafter were surgically resected and then chemotherapy was administered. However, metastatic brain tumors occurred in 2008, and these were treated by gamma-knife radiosurgery. Around the same time, a raised lesion that appeared on the scalp was diagnosed as skin metastasis and treated with best supportive care. Thereafter, the brain metastases continued to spread, and the patient died in October 2008.

A case of marked response to preoperative chemoradiotherapy for rectal cancer with para-aortic lymph node metastasis.

A 67-year-old man had rectal cancer with para-aortic lymph node metastasis. Prior to surgical resection, tegafur-uracil and leucovorin had been administered orally as chemotherapy, and radiotherapy (50.4 Gy) was applied for the rectum and para-aortic lymph nodes. Low anterior resection was then performed, followed by 45 cycles of chemotherapy in total. Enlargement of the left axillary lymph nodes was noted during treatment, but nodes shrank in response to treatment with bevacizumab + FOLFIRI (i.e., irinotecan + 5-fluorouracil/leucovorin). As of the time of writing, 36 months after diagnosis, no swelling of the para-aortic lymph nodes was evident and chemotherapy was being continued. This patient was alive after achieving response to neoadjuvant therapy comprising chemotherapy and irradiation of the para-aortic lymph nodes, along with postoperative chemotherapy. This therapeutic approach of preoperative chemotherapy plus irradiation of the primary lesion and para-aortic lymph nodes has potential as an effective treatment.

Severance of a ventriculoperitoneal shunt catheter implanted between the cerebral ventricle and peritoneal cavity, resulting in protrusion from the anus.

One rare complication of a ventriculoperitoneal (VP) shunt is perforation of the gastrointestinal tract by the catheter. We report a case in which the catheter severed spontaneously inside the peritoneal cavity, creating a communication between the intestinal tract and the peritoneal cavity. The patient was a 41-year-old man who presented with a VP shunt catheter protruding from the anus. Computed tomography showed that the VP shunt catheter, which had been put in place 25 years earlier, had severed spontaneously. The distal end had then perforated and entered the intestinal tract. The patient was hospitalized and emergency surgery was performed to repair the intestinal tract perforation caused by the end of the VP shunt catheter. Laparotomy revealed that the catheter had perforated the sigmoid colon. The VP shunt catheter was removed, and the perforation in the intestinal tract was closed by suturing. The patient was discharged on postoperative day 20.

A case of lung squamous cell carcinoma with metastases to the duodenum and small intestine.

Gastrointestinal metastasis of lung cancer is fairly rare, and metastasis to the duodenum is very uncommon. We report a case of duodenum and small intestine metastases of lung squamous cell carcinoma. The patient was a 66-year-old man. He was diagnosed with lung squamous cell carcinoma (T4N3M1 [mediastinum, cervical lymph node, and duodenum metastases], stage IV). He noted a sense of abdominal fullness on the evening of the day chemoradiotherapy was given, and emergency surgery was performed for suspected perforation of the digestive tract. Intraoperative findings included a tumor in the small intestine with a perforation at the tumor site; partial resection of the small intestine, including the tumor, was performed. Small intestine metastasis of lung cancer was diagnosed following histopathologic examination. When lung cancer patients complain of abdominal symptoms, it is important to consider gastrointestinal metastases in diagnosis and treatment.

Prognostic significance of adverse events associated with preoperative radiotherapy for rectal cancer.

PURPOSE: Adverse events may occur in patients receiving preoperative radiotherapy (PRT) for rectal cancers. The aim of this study is to clarify the clinical and pathological features of the patients with PRT-related adverse events, and the significance of the adverse events on the clinical outcome. METHODS: Seventy-five patients with T3 or T4 low rectal cancers curatively resected following PRT were studied. Thirty-one patients received radiotherapy, and 44 patients received chemoradiotherapy with tegafur-uracil and leucovorin. The total radiation dose was 50-50.4 Gy given in 25-28 fractions and the operation was performed 4-8 weeks after PRT. PRT-related adverse events were graded in accordance with the Common Terminology Criteria for Adverse Events v3.0. RESULTS: The most frequent adverse events were leukocytopenia and diarrhea, observed in 12% and 24% of patients, respectively. The majority of the leukocytopenia and diarrhea was grade 1-2 toxicity. Women experienced leukocytopenia more frequently than men (28% vs. 7%, p = 0.0317); however, no other predisposing factor for adverse events was recognized. Patients with leukocytopenia or diarrhea showed a better 5-year relapse-free survival rate than those without (94 ± 5% vs. 49 ± 9%, p = 0.00054), and the presence of these adverse events was an independent prognostic factor in a multivariate analysis. CONCLUSIONS: The presence of leukocytopenia or diarrhea was an independent predictor of a fair prognosis after curative operation following PRT, and thus these adverse events seem not to discourage oncologists and patients from considering PRT for rectal cancers.

Intestinal pneumatosis in which CT colonography was of significant diagnostic value: case report.

Intestinal pneumatosis refers to the presence of gas in the gastrointestinal wall. It is often difficult to clinically differentiate this condition from gastrointestinal perforation, sometimes resulting in emergency surgery. Imaging studies are important to establish the differential diagnosis. However, there have been few studies showing the efficacy of computed tomography (CT) colonography in diagnosing pneumatosis. We report a case of intestinal pneumatosis in which CT colonography was of significant diagnostic value. A 43-year-old man was referred to our hospital for a detailed investigation of multiple submucosal tumor-like lesions associated with multiple pneumatosis from the cecum to the ascending colon. These lesions were revealed by colonoscopy performed in another hospital on May 21, 2008. Abdominal 3-dimensional CT showed multiple pneumatic lesions from the cecum to the ascending colon, and the patient was diagnosed as having intestinal pneumatosis. The patient is being followed conservatively because he is asymptomatic.

A case of paracecal hernia.

A 63-year-old male patient suddenly suffered right lower abdominal pain. The patient had tenderness and rebound tenderness at the right lower abdomen. Marked small bowel dilatation and an intestinal obstruction were evident upon abdominal X-ray and abdominal computed tomography (CT) imaging. CT imaging also revealed a dilated small bowel cluster in a wrapped round shape in the right lower abdomen. The cecum and the ascending colon were displaced inward. Strangulation in the ileocecal region was suspected, and emergency surgery was performed. A part of the small bowel was incarcerated within the retrocecal recess, and the intestinal tract was strangulated in the hernia orifice, by which paracecal hernia was diagnosed. The strangulated intestinal tract was repositioned, and the orifice to the hernia was closed. Paracecal hernia is a rare disease; an internal hernia should always be considered in patients with ileus without a history of surgery.

A case of appendiceal Crohn's disease in which a laparoscopic appendectomy was performed.

A 74-year-old female had occasionally experienced right lower abdominal pain in the past. She underwent a barium enema examination during a medical checkup, which revealed a wall irregularity around the appendix, but the appendix itself was not visualized. The patient was referred to our hospital for possible appendiceal neoplasm. Colonoscopy revealed a tumor-like protrusion with marked redness at the entrance to the appendix. Pathologic analysis of biopsy specimens revealed only inflammatory cells. Differential diagnosis of appendiceal Crohn's disease or appendiceal neoplasm was made, and laparoscopic appendectomy was performed. Pathologic examination revealed inflammation in all layers of the appendiceal wall and noncaseating epithelioid cell granuloma, and a diagnosis of appendiceal Crohn's disease was made. The postoperative course was uneventful, and the patient was discharged from the hospital 3 days after surgery. No sign of recurrence has been observed up to now, 6 months after surgical treatment.