Adjuvant Chemotherapy With UFT/LV Versus UFT/LV Plus PSK in Stage II/III Colorectal Cancer.

BACKGROUND/AIM: Uracil-tegafur+leucovorin (UFT/LV), an oral adjuvant therapy for stage II/III colorectal cancer, is non-inferior to standard weekly fluorouracil and folinate. Although polysaccharide K (PSK) has been evaluated as a postoperative adjuvant colorectal cancer drug, its efficacy remains unclear. This randomized phase II trial compared UFT/LV+PSK with UFT/LV as adjuvant chemotherapy. PATIENTS AND METHODS: Between April 2011 and August 2016, 186 patients who underwent radical resection randomly received 6 months of UFT/LV (Group A: 300 mg/m2/day UFT and 75 mg/day LV, every 35 days for five cycles), 6 months of UFT/LV+PSK (Group B: standard UFT/LV regimen and daily administration of 3 g/day of PSK), or 12 months of UFT/LV+PSK (Group C). The primary endpoint was the 3-year disease-free survival. RESULTS: Groups A, B, and C consisted of 37, 75, and 74 patients, of which treatment was completed by 33 (89.2%), 63 (84.9%), and 53 (70.4%) patients, respectively (p=0.0279). Adverse event incidence for all grades were 59.5%, 52.1%, and 59.2%, and for grade ≥3 were 13.5%, 9.6%, and 9.9%, respectively. The 3-year disease-free survival rates were 72.5%, 82.2%, and 74.2%, respectively, with no significant differences. The preoperative lymphocyte ratio did not significantly differ between groups. CONCLUSION: UFT/LV+PSK is comparable to UFT/LV therapy in terms of prognostic efficacy and reduced adverse effects. Thus, UFT/LV+PSK is a useful adjuvant chemotherapy option for patients with high-risk stage II/III colorectal cancer.

Lenalidomide treatment of Japanese patients with myelodysplastic syndromes with 5q deletion: a post-marketing surveillance study.

Lenalidomide was approved in Japan for the treatment of patients with myelodysplastic syndromes associated with a 5q deletion (del 5q-MDS) in August 2010. A post-marketing surveillance (PMS) study enrolled 173 patients with del 5q-MDS who started lenalidomide treatment between August 2010 and September 2011 (mean ± standard deviation [SD] age 72.4 ± 9.0 years) and observed for up to 6 cycles or 6 months. Adverse drug reactions (ADRs) and serious ADRs were reported in 78.0% and 50.9% of patients. The most commonly observed ADRs were thrombocytopenia or platelet count decreased (46.2%), neutropenia or neutrophil count decreased (42.2%), and rash (23.1%). Of 114 patients who were red blood cell transfusion-dependent at baseline, 39 (34.2%) achieved transfusion independence during lenalidomide treatment. Of 173 patients, 19 (11.0%) had confirmed acute myeloid leukemia (AML) progression during the study. Moreover, long-term follow-up (3 years) was available for 68 of the 173 patients, of whom 12 (17.6%) progressed to AML during the additional period. This PMS study investigated the safety and effectiveness of lenalidomide in patients with del 5q-MDS. No new safety concerns were noted in routine clinical use in Japan and no evidence was found for an increased risk of AML progression following lenalidomide treatment.

Gangrenous ischemic colitis localized to the cecum: a case report.

BACKGROUND: Ischemic colitis affects the left colon in elderly individuals and localization on the right side, especially in the cecum, is rare. We report a case of gangrenous ischemic colitis localized in the cecum of a patient undergoing hemodialysis. CASE PRESENTATION: A 73-year-old man had been undergoing hemodialysis for chronic renal failure caused by diabetic nephropathy. He experienced frequent vomiting, diarrhea, and abdominal pain. Contrast-enhanced computed tomography revealed thickening of the cecal wall, poor enhancement, dilation of the cecum, and intrahepatic portal emphysema. No obvious abnormal findings were observed in the appendix. The patient was diagnosed with cecal necrosis and ileocecal resection was performed. Histopathological examination revealed gangrenous ischemic colitis of the cecum. He was discharged 12 days after surgery without postoperative complications. CONCLUSION: It is important to consider the possibility of ischemic colitis of the right colon in the event of renal failure requiring dialysis, to ensure that opportunities for surgical intervention are not missed.

Large retroperitoneal leiomyoma developed from the pelvic floor to the buttocks.

Retroperitoneal leiomyoma is a very rare disease, with little reported information on its origin. Herein, we report a case of a large retroperitoneal leiomyoma that developed from the pelvic floor. A 44-year-old woman had a large mass protruding outside the body from the right hip. Imaging revealed a large tumor developing from the pelvic floor to the buttocks. It was difficult to identify the place of origin. Upon preoperative biopsy, the patient was diagnosed with retroperitoneal leiomyoma. Tumor removal with abdominoperineal and partial vaginal resection was performed. Based on the histological findings of the surgical specimens, she was diagnosed with a retroperitoneal leiomyoma (gynecologic type) via immunohistochemistry, the tumor cells were positive for αSMA, desmin, estrogen receptor(ER), and progesterone receptor(PgR), but negative for myoglobin, S-100, CD34, and MIB-1.This is a case of a large retroperitoneal leiomyoma that was successfully removed via abdominoperineal and partial vaginal resection.

PD-L1 upregulation is associated with activation of the DNA double-strand break repair pathway in patients with colitic cancer.

Ulcerative colitis (UC) is a DNA damage-associated chronic inflammatory disease; the DNA double-strand break (DSB) repair pathway participates in UC-associated dysplasia/colitic cancer carcinogenesis. The DSB/interferon regulatory factor-1 (IRF-1) pathway can induce PD-L1 expression transcriptionally. However, the association of PD-L1/DSB/IRF-1 with sporadic colorectal cancer (SCRC), and UC-associated dysplasia/colitic cancer, remains elusive. Therefore, we investigated the significance of the PD-L1/DSB repair pathway using samples from 17 SCRC and 12 UC patients with rare UC-associated dysplasia/colitic cancer cases by immunohistochemical analysis. We compared PD-L1 expression between patients with SCRC and UC-associated dysplasia/colitic cancer and determined the association between PD-L1 and the CD8+ T-cell/DSB/IRF-1 axis in UC-associated dysplasia/colitic cancer. PD-L1 expression in UC and UC-associated dysplasia/colitic cancer was higher than in normal mucosa or SCRC, and in CD8-positive T lymphocytes in UC-associated dysplasia/colitic cancer than in SCRC. Moreover, PD-L1 upregulation was associated with γH2AX (DSB marker) and IRF-1 upregulation in UC-associated dysplasia/colitic cancer. IRF-1 upregulation was associated with γH2AX upregulation in UC-associated dysplasia/colitic cancer but not in SCRC. Multicolour immunofluorescence staining validated γH2AX/IRF-1/PD-L1 co-expression in colitic cancer tissue sections. Thus, immune cell-induced inflammation might activate the DSB/IRF-1 axis, potentially serving as the primary regulatory mechanism of PD-L1 expression in UC-associated carcinogenesis.

Low level of stromal lectin-like oxidized LDL receptor 1 and CD8+ cytotoxic T-lymphocytes indicate poor prognosis of colorectal cancer.

BACKGROUND: Lectin-like oxidized LDL receptor-1 (LOX-1) has been identified as a new marker for functional myeloid-derived suppressor cells (MDSCs) that exhibit an immunosuppressive phenotype in the tumor microenvironment (TME). However, the role of LOX-1+ cells in the TME of colorectal cancer (CRC) remains unknown. AIM: This study aimed to determine the expression and significance of LOX-1 in the TME of clinical CRC specimens. METHODS AND RESULTS: We performed immunohistochemical and genetic analyses of LOX-1, CD8, KRAS, and BRAF in 128 resected CRC specimens and determined the expression of IFN-γ and IL-10 using real-time reverse transcription-polymerase chain reaction. We analyzed the correlation between LOX-1, TME factors, gene alteration, clinicopathological factors, and disease prognosis. The co-expression pattern of LOX-1, hematopoietic markers, and a fibroblast marker was evaluated using multiplex immunofluorescence staining. Low stromal LOX-1 expression and low intratumoral CD8+ cytotoxic T-lymphocyte (CTL) status correlated with poor prognosis. Moreover, stromal LOX-1-low/CD8+ CTL-low status was the most important independent prognostic factor of poor overall survival. Most of the LOX-1+ stromal cells were positive for CD163+ , indicating they were CD163+ M2 macrophages. CONCLUSIONS: The MDSC marker, LOX-1, was mainly expressed by M2 macrophages in CRC tissues. LOX-1+ macrophages and CD8+ CTLs may serve as useful biomarkers for predicting the prognosis of CRC.

Sacral and Rectal Necrosis after Carbon Ion Radiotherapy Reconstructed with Transpelvic Rectus Abdominis Flap.

Carbon ion radiotherapy (CIRT) has been used for malignant tumors that are difficult to excise surgically, such as sacral chordoma, and the success of its outcomes is attributable to the high dose concentration and biological effects. CIRT has produced successful clinical outcomes, and it is considered to have fewer adverse effects on surrounding normal tissues; moreover, complications have been rarely reported. We describe a 75-year-old woman with a full-thickness sacral defect, who had received CIRT for sacral chordoma 3 years earlier. Computed tomography showed sacral bone destruction, and a colonoscopy revealed rectal necrosis. Rectectomy in addition to sacral bone resection was necessary, which resulted in a huge sacral defect of slightly anxious viability. We performed reconstruction of the sacral defect by using pedicled vertical rectus abdominis myocutaneous (VRAM) flap, obliterating sacral defects and intrapelvic dead space that occurred after rectectomy. Six months after surgery, the wound had healed well, and no complication was observed. Sacral complications after CIRT may affect surrounding normal tissues such as the rectum, and it would be difficult to reconstruct the resulting complications. The vertical rectus abdominis myocutaneous flap is considered useful for the simultaneous obliteration of sacral defects and intrapelvic dead space after CIRT.

Prognostic significance of ß2-adrenergic receptor expression in patients with surgically resected colorectal cancer.

PURPOSE: The ß2-adrenergic receptor (ß2AR) is highly expressed in various human cancers. The prognostic significance of its expression in patients with colorectal cancer (CRC) remains unclear. The aim of this study was to assess the prognostic role of ß2AR expression in patients with surgically resected CRC. METHODS: One hundred and forty-seven patients with surgically resected CRC were examined using immunohistochemistry. The expression of ß2AR was assessed in the specimens of resected primary tumors. RESULTS: ß2AR was expressed in 52.3% of the patients' tumors. ß2AR expression was significantly associated with T factor, N factor, and tumor cell proliferation (Ki-67 labeling index). Univariate analysis demonstrated that T factor, N factor, tumor stage, lymphatic permeation, vascular invasion, perineural invasion, ß2AR expression, and Ki-67 labeling index were significant prognostic factors for worse disease-free survival (DFS); all but T factor were also significant predictors for worse overall survival (OS). Multivariate analysis confirmed that expression of ß2AR was a significant prognostic marker for predicting worse DFS and OS. CONCLUSION: ß2AR expression was identified as a significant independent prognostic factor in patients with surgically resected CRC.

Significance of RAS mutations in pulmonary metastases of patients with colorectal cancer.

BACKGROUND: RAS/BRAF mutations of colorectal cancer (CRC) play a crucial role in carcinogenesis and cancer progression and need to be considered for the therapeutic strategy choice. We used next-generation-sequencing (NGS) technology to assess RAS/BRAF mutation differences between primary CRC and corresponding pulmonary metastases (PMs). METHODS: We examined the mutation statuses of the KRAS 12/13/61/146, NRAS 12/13/61/146, and BRAF 600 codons in genomic DNA from fresh-frozen or formalin-fixed paraffin-embedded tissues derived from 34 primary lesions and 52 corresponding PMs from 36 patients with CRC. RESULTS: We found RAS mutations in 76% (26/34) of primary CRC lesions and in 86% (31/36) of PMs. While 27% (7/26) of the primary CRC RAS mutations were heterogeneous, all the RAS mutations in PMs were homogeneous. Of the mutations in PMs, 71% (22/31) were KRAS G>A transitions, of which 82% (18/22) were KRAS G12D or G13D. The RAS mutation discordance between primary tumors and PMs was 12.1% (4/33). RAS mutations with the same genotyping were detected in all synchronous and metachronous PMs from 9 patients. We found no BRAF mutations in either primary or pulmonary tissues. CONCLUSION: Our NGS analysis suggests that RAS mutations of PM of patients with CRC are more common than initially thought. The presence of KRAS mutations in CRC specimens, especially G12D or G13D mutations, seems to promote PM formation.

STMN1 accumulation is associated with dysplastic and neoplastic lesions in patients with ulcerative colitis.

Ulcerative colitis (UC) is thought to be associated with precancerous lesions that can ultimately lead to colon cancer. Therefore, diagnostic markers for colorectal dysplasia and cancer are urgently needed for patients with UC. Stathmin 1 (STMN1) is a novel cancer biomarker that is also a novel target for treatment in several cancers, including colon cancer. However, few studies have investigated the relationship between STMN1 expression and clinical features in colorectal dysplasia and cancer in patients with UC. The present study examined the clinical significance of STMN1 expression in colorectal dysplasia and cancer with UC. The present study performed an immunohistochemical analysis of 31 clinical colorectal samples from eight patients with colorectal dysplasia and/or cancer to assess the relationships between STMN1 expression and clinicopathological features including mismatch repair protein expression, rate of Ki-67 positivity, differentiation level, TNM stage, and UC duration. STNM1 expression was detected in 95.7% of dysplastic and cancerous lesions, whereas p53, the current diagnostic marker, was not expressed in 39.1% of dysplastic and cancerous lesions. Furthermore, STMN1 expression was associated with a high rate of positivity for Ki-67, a proliferation marker. Our data suggest that STMN1 in the colonic mucosa of UC patients may be useful as an early diagnostic marker of dysplasia and colitic cancer.

Role of Amino Acid Transporter Expression as a Prognostic Marker in Patients With Surgically Resected Colorectal Cancer.

BACKGROUND/AIM: L-type amino acid transporter 1 (LAT1) is highly expressed in various human cancers. However, the clinicopathological significance of LAT1 and 4F2 cell surface antigen (4F2hc) in patients with colorectal cancer (CRC) is unknown. The aim of this study was to clarify the prognostic significance of LAT1 expression in CRC patients who underwent surgical resection. MATERIALS AND METHODS: Samples from one hundred and forty-seven patients were examined by immunohistochemistry. The expression of LAT1 and 4F2hc, and the Ki-67 labeling index were assessed using resected tumor specimens. RESULTS: The positive expression of LAT1 and 4F2c was 80% (118/147) and 58% (86/147) (p<0.01), respectively. The expression of LAT1 was identified as an independent significant marker linked to worse prognosis in patients with CRC, and was correlated with tumor cell proliferation, tumor aggressiveness, and metastasis. Moreover, LAT1 was closely associated with the expression of 4F2hc and phosphorylation of the mTOR pathway. CONCLUSION: LAT1 is a significant molecular marker used to predict prognosis after surgical resection of CRC patients.

A novel one-step lens cleaning device using air and water flow for endoscopic surgery.

In a surgical operation requiring endoscopy, it is essential to obtain a clear endoscopic view. However, it is often disturbed by the contamination on the lens during the surgery. No device can clean the lens surface simply and completely. Many surgeons are hampered by the impaired view and the distraction by the repeated cleaning of the lens. Therefore, we developed a novel endoscope cleaning device to address this problem. The device was made of 3D-printed rubber-like plastic. It contains a syringe filled with saline and an aspiration system. It would be used intraoperatively to wash the lens surface in a few seconds with rapid flow of water and air. The cleaning ability of the device was evaluated using mayonnaise with adenosine triphosphate (ATP) as a model contaminant. The gauze-wiping maneuver was selected as control. After each maneuver, the clarity of the endoscopic view was evaluated, and residual contaminants were assessed quantitatively with ATP assay. The cleaning device obtained a crisp and clear view and eliminated the contaminant on the lens every time after a single cleaning maneuver. The gauze-wiping maneuver required for the lens to be wiped at least three times to obtain a clear view, and even then, some contaminants remained. Repeated contamination and cleaning using gauze led to accumulation of contaminants on the lens, which resulted in difficulty in cleaning the lens as the operation proceeded. The cleaning device did not show such accumulation. Our novel cleaning device with air and water flow has been shown to wash out the lens contaminants completely and immediately in a simple manner. It is expected to improve the safety and cost-effectiveness of endoscopic surgery.

Successful surgical treatment of left atrioesophageal fistula following atrial ablation.

A 69-year-old male had catheter-based ablation for atrial fibrillation. He was admitted with high fever and had neurological disorder; he was diagnosed with atrioesophageal fistula by CT scan. Intraoperative findings showed that the fistula existed adjacent to the left lower pulmonary vein with a vegetation. The esophageal fistula was repaired, and the left atrial fistula was closed. A nasogastric tube tip was placed in the esophagus for decompression and advanced into the stomach for nutritional support. After vomiting, the patient showed loss of consciousness and left hemiplegia. CT scan revealed a micro-air embolism to the brain. The nasogastric tube tip was pulled back into the esophagus. Gastrointestinal fiberscopy showed a pinhole at the fistula, and a percutaneous endoscopic gastrostomy was made. After conservative treatment, the esophageal fistula was closed and mediastinitis was improved. He was discharged with a little neurological deficit.

Prognostic Significance of Inflammatory and Nutritional Parameters in Patients with Esophageal Cancer.

BACKGROUND: We evaluated the following preoperative prognostic factors in patients who underwent esophagectomy for esophageal cancer: C-Reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), serum albumin, prognostic nutritional index (PNI), and body mass index (BMI). PATIENTS AND METHODS: This retrospective study included 173 men and 19 women with a mean age of 65.8 years (range=42-86 years) who were scheduled to undergo esophagectomy for esophageal cancer. The association of CRP, NLR, albumin, PNI, and BMI with various clinicopathological factors and prognosis were evaluated. RESULTS: Univariate analysis revealed that male sex, depth of invasion, nodal metastasis, pStage, high CRP, low PNI, high NLR, and low BMI were significant risk factors for a poor prognosis. Multivariate analysis identified depth of invasion, pStage, and BMI as significant prognostic factors in the Cox proportional hazard model. CONCLUSION: The preoperative nutritional status affected the postoperative survival time in patients with esophageal cancer. In particular, a low BMI was an independent prognostic factor for poorer survival in the multivariate analysis.

Securing the surgical field in laparoscopic pancreatectomy using a Penrose drain and Endo Close.

INTRODUCTION: We adopted the use of Penrose drains and Endo Close to secure a good surgical field during laparoscopic pancreatectomy. METHODS: We used a Penrose drain with threads ligated on both ends to suspend the stomach. We then pulled the threads out of the body from the side of the trocar or from besides the xiphisternum by using Endo Close. In most cases, 2 Penrose drains were used to retract the stomach. When the greater omentum on the left side of the cardia still blocks the surgical field, we sewed the posterior wall of the stomach onto the dome of the diaphragm. RESULTS: The use of 2 Penrose drains and Endo Close were effective to retract the stomach in most cases. However, in 3 cases, we needed to additionally sew the stomach onto the diaphragm to fully open up the field. CONCLUSION: This is a simple and effective method to ensure a good surgical field.

Laparoscopic resection of a paraganglioma located on the border of the thoracic and abdominal cavities using a transabdominal-transdiaphragmatic approach.

We treated a 64-year-old woman with high blood pressure. Catecholamine metabolite levels were elevated in the blood and urine. CT revealed a densely stained tumor on the right side of the descending aorta dorsal to the inferior vena cava. PET-CT revealed abnormal accumulation of (18) F-fluorodeoxyglucose, and (123) I-meta-iodo-benzylguanidine uptake was apparent on scintigraphy. The tumor was determined to be a paraganglioma located on the border between the thoracic and abdominal cavities, and laparoscopic tumorectomy was performed. The patient was placed in the left lateral position. The right lobe of the liver was turned over, and we cut the diaphragm to expose the front of the tumor. We resected the straight artery flowing in from the aorta and removed the tumor safely. Herein, we describe the removal of a paravertebral paraganglioma located in the border of the thoracic and abdominal cavities with a laparoscopic transabdominal-transdiaphragmatic approach.

Modified Pringle Maneuver Applicable for Laparoscopic Hepatectomy.

INTRODUCTION: We present a widely applicable technique of the modified Pringle maneuver to reduce blood loss for laparoscopic hepatectomy. METHODS: We use a drip-infusion tube and wrap it around the hepatoduodenal ligament. In the modified Pringle maneuver ① (m-Pringle ①), we use a 60 cm long tube. Both ends of the tube are led out from the side of the umbilical port, then pulled and clipped with Pean forceps to interrupt blood flow. In the modified Pringle maneuver ② (m-Pringle ②), we use a 20 cm long tube with silk threads tied at both ends. The threads were led extraperitoneally in the same manner. RESULTS: Although blood flow was sufficiently interrupted, CO2 leak occurred in 14 of 60 cases in m-Pringle ①. Blood flow was interrupted and intra-abdominal pressure was kept in all 10 patients in m-Pringle ②. CONCLUSIONS: These maneuvers require no extra port, and tube pulling and releasing is readily performed from outside the body.

[Peritoneal disseminated recurrence after total gastrectomy for perforated gastric malignant lymphoma--a case report].

We reported a case of peritoneal disseminated recurrence after total gastrectomy for perforated gastric malignant lymphoma. A 73-year-old man underwent total gastrectomy for perforated gastric diffuse large B cell lymphoma on day 5 of RCHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone) chemotherapy. He has rejected chemotherapy and received no additional treatment after gastrectomy. Computer tomography 13 months after surgery revealed peritoneal dissemination and abdominal lymph node metastasis. R-CHOP chemotherapy was performed, and after 4 courses of chemotherapy, peritoneal dissemination and metastatic abdominal lymph nodes disappeared. Chemotherapy was discontinued for a time, however, the tumors relapsed 2 months after stopping chemotherapy. He underwent chemotherapy with etoposide, but died of tumor progression 21 months after gastrectomy.

[Histological complete response in a case of advanced gastric cancer treated by neo-adjuvant chemotherapy with S-1/CDDP].

A 59-year-old male was found to have advanced gastric cancer with multiple lymph node metastasis including para-aortic lymph nodes(cT3, cN3, cM0, cH0, cP0, cStage IV). Since curative surgery was deemed not feasible, we tried neoadjuvant chemotherapy expecting downstaging of the tumor. S-1(120 mg/body)was orally administered for three weeks followed by one week rest, and CDDP(60 mg/m2)was administered on day 8. Three courses of treatment resulted in a marked shrinkage of the primary lesion and a reduction of lymph nodes. He was judged as clinical PR by RECIST, and a radical resection was considered possible. Laparotomy revealed neither ascites nor peritoneal dissemination, and he underwent total gastrectomy, splenectomy and D2+para-aortic lymph node dissection with curative intent. The histological diagnosis revealed complete disappearance of cancer cells in the primary lesion of the stomach and lymph nodes, confirming a pathological complete response. The patient has been alive for six months without recurrence.