[A Case of Long-Term Survival in Gastric Cancer with Multiple Liver Metastases Successfully Treated by Conversion Surgery after S-1 plus Cisplatin Combination Therapy].

A 49-year-old man was diagnosed with advanced gastric cancer, with a chief complaint of epigastric discomfort. Computed tomography revealed multiple liver metastases. S-1 plus cisplatin therapy was administered as first-line chemotherapy, and after 4courses, the liver metastases markedly reduced. Total gastrectomy with D2 lymphadenectomy and a needle biopsy of segment 2 of the liver were performed. Histopathological examination revealed no viable cancer cells in the resected stomach, lymph nodes, or liver tissue. The primary tumor was defined as Grade 3 by histopathological examination. Adjuvant chemotherapy with S-1 was administered for 1 year. The patient is alive without recurrence more than 6 years after surgery.

Lateral lymph node metastasis in a patient with T1 upper rectal cancer treated by lateral lymph node dissection: a case report and brief literature review.

BACKGROUND: Lateral lymph node (LLN) metastasis may occur in patients with advanced rectal cancers of which the lower margins are located at or below the peritoneal reflection. However, LLN metastasis from a T1 rectal cancer is rare. Here, we report a case of LLN metastasis from a T1 upper rectal cancer that was successfully treated by sequential LLN dissection. CASE PRESENTATION: A 56-year-old man was referred to our hospital for the treatment of a T1 upper rectal cancer. We performed a laparoscopic low anterior resection. Histological examination showed a moderately differentiated adenocarcinoma with submucosal layer invasion; the invasion depth was classified as head invasion, without vessel or lymph duct invasion. Tumor budding was classified as grade 1. A total of six lymph nodes were harvested, and no lymph node metastases were detected. The postoperative course was uneventful. At 6 months after surgery, however, the serum carcinoembryonic antigen levels were elevated, and abdominal computed tomography (CT) revealed swollen lymph nodes in the right internal and common iliac artery area. Positron emission tomography with CT revealed hot spots in the same lesions. A retrospective re-evaluation of the preoperative CT images revealed no apparent swollen lymph nodes; however, an unusual soft tissue area was detected around the right internal iliac artery. A right LLN dissection was performed. Fifteen lymph nodes were resected, and histologically, metastases of adenocarcinoma were identified in 3 nodes. The postoperative course was again uneventful. The patient was given 12 cycles of adjuvant chemotherapy with FOLFOX (fluorouracil, leucovorin, and oxaliplatin). The patient remains healthy and with no signs of recurrence at 30 months after the second surgery. CONCLUSIONS: LLN metastasis occurs very rarely in patients with T1 upper rectal cancer and no risk factors for lymph node metastasis; however, a careful perioperative examination of the LLN should be performed. In cases involving LLN metastasis, a LLN dissection may be a therapeutic option if performed with curative intent.

[A Case with Solitary Brain Metastatic Tumor from Colon Cancer].

We report a rare long-surviving case of solitary brain metastasis from colon cancer. The patient was a 64-year-old female. She had undergone laparoscopic right hemicolectomy for ascending colon cancer in October 2012(pStage III b). She was discharged from the hospitalin a satisfactory state, but 26 days after the operation, she was transported to the emergency department for systemic tonic-clonic convulsions. Magnetic resonance imaging revealed solitary metastatic tumor in the brain, but there were no metastatic lesions in other organs. Metastatic lesion was small and complete removal was considered to be difficult. Thus, we planned stereotactic radiosurgery for the metastases, and then regimen of mFOLFOX6 plus Bmab, tegafur-uracil plus Leucovorin were administered. As a means of evaluating recurrence of brain metastasis, methionine positron emission tomography(methionine PET)was also performed, and the patient has survived for 54 months since the surgery, to date, without recurrence. Cases with brain metastasis of colorectal cancer often have metastases involving other organs and are considered to have a poor prognosis. For solitary brain metastasis, long-term survival can be obtained with multidisciplinary treatments, and methionine PET is considered to be usefulfor recurrence evaluation after radiation treatment.

Hyperacute peripheral neuropathy is a predictor of oxaliplatin-induced persistent peripheral neuropathy.

PURPOSE: Chronic peripheral neuropathy is a major adverse response to oxaliplatin-containing chemotherapy regimens, but there are no established risk factors pertaining to it. We investigated the efficacy of hyperacute peripheral neuropathy (HAPN) as a predictor of oxaliplatin-induced persistent peripheral neuropathy (PPN). METHODS: Forty-seven cases of stage III colorectal cancer who received adjuvant chemotherapy with oxaliplatin after curative surgery between January 2010 and August 2014 were retrospectively reviewed. HAPN was defined as acute peripheral neuropathy (APN) occurring on day 1 (≤24 h after oxaliplatin infusion) of the first cycle. PPN was defined as neuropathy lasting >1 year after oxaliplatin discontinuation. RESULTS: The average total dose of oxaliplatin was 625.8 mg/m2, and the average relative dose intensity was 66.7%. Twenty-two of the 47 patients (46.8%) had PPN and 13 (27.7%) had HAPN. Male sex, treatment for neuropathy, HAPN, and APN were significantly more frequent in patients with PPN (p = 0.013, 0.02, <0.001, and 0.023, respectively). There was no significant difference in the total oxaliplatin dose between patients with and without PPN (p = 0.061). Multivariate analyses revealed total dose of oxaliplatin and HAPN as independent predictors of PPN [p = 0.015; odds ratio (OR) = 1.005, 95% confidence interval (CI), 1.001-1.009 and p = 0.001; OR = 75.307, 5.3-1070.123, respectively]. The total dose of oxaliplatin was relatively lower in patients with HAPN than that in those without HAPN in the PPN-positive group (not significant, p = 0.068). CONCLUSION: HAPN was found to be a predictor of oxaliplatin-induced PPN.

Laparoscopic colectomy for a patient with congenital renal agenesis.

We present a very rare case of laparoscopic colectomy for a patient with ascending colon cancer and an agenetic right kidney. A 57-year-old man visited our institute for further evaluation for a positive fecal occult blood test. Approximately, 20 years earlier, the right kidney of the patient was found to be congenitally absent. A physical examination indicated no anatomical anomalies in his genitourinary system, and the renal function was within the normal range. Total colonoscopy revealed a cancer of the ascending colon and laparoscopic colectomy was performed. The right colon was mobilized by lateral-to-medial extension of a retroperitoneal dissection between the fusion fascia and the anterior renal fascia. The right testicular vessels were preserved without injury to the anterior renal fascia; however, the right ureter could not be detected. The operation was performed safely. Thus, we believe that in patients with congenital unilateral renal agenesis, the anterior renal fascia is present, and laparoscopic ipsilateral colectomy can be safely performed in such patients.

Loss of Smad3 gives rise to poor soft callus formation and accelerates early fracture healing.

Smad3 is an intracellular signaling molecule in the transforming growth factor ß (TGF-ß) pathway that serves as a regulator of chondrogenesis and osteogenesis. To investigate the role of the TGF-ß/Smad3 signaling in the process of fracture healing, an open fracture was introduced in mouse tibiae, and the histology of the healing process was compared between wild-type (WT) and Smad3-null (KO) mice. In KO mice, the bone union formed more rapidly with less formation of cartilage in the callus and eventually the fracture was repaired more rapidly than in WT mice. Alkaline phosphatase staining showed that osteoblastic differentiation in the fracture callus was promoted in KO mice. Additionally, TRAP staining and the TUNEL assay revealed that the induction of osteoclasts and apoptotic cells was significantly promoted in the healing callus of KO mice. Sox9 expression clearly decreased at both mRNA and protein levels in the early stage of fracture in KO mice. In contrast, the expression of genes for osteogenesis and osteoclast formation increased from day 5 until day 14 post-fracture in KO mice compared to WT mice. From these results, we concluded that the loss of TGF-ß/Smad3 signaling promoted callus formation by promoting osteogenesis and suppressing chondrogenesis, which resulted in faster fracture healing.

A wound protector shields incision sites from bacterial invasion.

BACKGROUND: Superficial surgical site infection (SSI) can be caused by bacterial invasion during surgery. We investigated whether bacteria are found at the wound margin during surgery and whether a wound protector (WP; Alexis® Wound Retractor; Applied Medical, Rancho Santa Margarita, CA) contributes to preventing invasion of the incision margin. METHODS: We studied 272 patients who underwent gastrointestinal surgery (115 gastric, 157 colorectal, including emergency operations) between October 2005 and July 2007. The WP was used in all operations. After the intra-abdominal procedures were complete, bacterial swabs were taken from the abdominal cavity side of the WP and from the incision margin and used to prepare smears and cultures. After the swabbing, peritoneal lavage was performed using 3,000-5,000 mL of physiologic saline, and, after suture of the fascia, 500-1,000 mL of physiologic saline was used to irrigate the subcutaneous tissue. RESULTS: Nine gastric surgery patients and 15 colorectal surgery patients had positive cultures from the abdominal cavity. No patients had positive cultures from the incision margin. Of the 24 patients with positive cultures, three suffered SSIs, all of whom had undergone colorectal surgery. Of the patients who had negative cultures, SSI occurred in only one patient, who had undergone colorectal surgery. CONCLUSIONS: These results suggest that the WP protects an incision site from bacterial invasion.

A case of pathological complete response of advanced rectal cancer to preoperative chemoradiotherapy using S-1.

In patients with advanced rectal cancer, preoperative chemoradiotherapy is superior to postoperative chemoradiotherapy because of causing less toxicity and achieving higher rates of sphincter preservation and curative resection. We treated a patient who had advanced rectal cancer with preoperative chemotherapy using S-1 and concurrent radiotherapy. S-1 was orally administered at a dose of 100 mg/day during the first cycle (two-week on and one week off). During the third cycle, radiotherapy was initiated concurrently and a total dose of 45 Gy was given. The most severe adverse event was grade 3 leukopenia during the third cycle. On day 42 after completing radiotherapy, low anterior resection with diverting colostomy was performed. Histological examination found no viable cancer cells in the resected specimens, including the primary tumor site and lymph nodes. Thus, a pathological complete response was achieved. Postoperatively, anastomotic leakage occurred, but it was resolved with transanal drainage. Preoperative chemoradiotherapy using S-1 contributed to sphincter preservation and curative resection in this patient. This regimen was both effective and well-tolerated, suggesting that it could be useful for advanced rectal cancer.

Trps1 functions downstream of Bmp7 in kidney development.

During embryonic development, the mesenchyme of the lungs, gut, kidneys, and other tissues expresses Trps1, an atypical member of the GATA-type family of transcription factors. Our previous work suggested the possibility that Trps1 acts downstream of bone morphogenic protein 7 (Bmp7), which is essential for normal renal development. To examine the role of Trps1 during early renal development, we generated Trps1-deficient mice and examined their renal histology. Compared with wild-type mice, Trps1-deficient newborn mice had fewer tubules and glomeruli, an expanded renal interstitium, and numerous uninduced metanephric mesenchymal cells, which resulted in fewer nephrons. In wild-type kidneys, Trps1 expression was present in ureteric buds, cap mesenchyme, and renal vesicles, whereas Trps1 was virtually absent in Bmp7-deficient kidneys. Furthermore, Trps1-deficient kidneys had low levels of Pax2 and Wt1, which are markers of condensed mesenchymal cells, suggesting that a lack of Trps1 affects the differentiation of cap mesenchyme to renal vesicles. In cultured metanephric mesenchymal cells, Bmp7 induced Trps1 and E-cadherin and downregulated vimentin. Knockdown of Trps1 with small interference RNA inhibited this Bmp7-induced mesenchymal-to-epithelial transition. Last, whole-mount in situ hybridization of Wnt9b and Wnt4 demonstrated prolonged branching of ureteric buds and sparse cap mesenchyme in the kidneys of Trps1-deficient mice. Taken together, these findings suggest that normal formation of nephrons requires Trps1, which mediates mesenchymal-to-epithelial transition and ureteric bud branching during early renal development.

TNF-alpha deficiency accelerates renal tubular interstitial fibrosis in the late stage of ureteral obstruction.

TNF-alpha and TGF-beta1 have a complementary relationship in fibrogenesis. This study was performed to investigate the role of TNF-alpha in renal tubular interstitial fibrosis. We compared the extent of renal tubular interstitial fibrosis after unilateral ureteral obstruction (UUO) between wild-type and TNF-alpha-deficient mice by using immunohistochemistry, enzyme-linked immunoassay, and the real-time polymerase chain reaction (PCR). In comparison with wild-type mice, there was no significant difference in the extent of renal fibrosis in the TNF-alpha-deficient mice at 2 weeks after UUO. By 4 weeks after UUO, however, fibrosis marked an increase in the TNF-alpha-deficient mice to exceed that in the wild-type mice. Immunohistochemistry, enzyme-linked immunoassay, and real-time PCR demonstrated an increase of extracellular matrix in the kidneys of TNF-alpha-deficient mice that was caused by upregulation of the expression of TGF-beta1 and Snail, which in turn resulted from an increase of infiltrating macrophages. Real-time PCR revealed an increase in expression of the TNF-alpha type 2 receptor at 4 weeks after UUO, which explained the difference in the extent of renal fibrosis between TNF-alpha-deficient and wild-type mice. In the chronic stage of renal fibrosis, TNF-alpha suppresses the infiltration of macrophages by inducing TNF-alpha type 2 receptor expression, resulting in the amelioration of fibrosis.

Trps1 deficiency enlarges the proliferative zone of growth plate cartilage by upregulation of Pthrp.

We have reported that elongation of the columnar proliferative zone of long bone growth plates in Trps1-/- mice during the late fetal stage in the previous study [1]. Since expression of Trps1 protein was found to overlap with that of mRNAs for Indian hedgehog (Ihh), PTH/PTHrP receptor (PPR), and PTHrP, we hypothesized that Trps1 may inhibit the hypertrophic differentiation of chondrocytes by interacting with the Ihh/PTHrP feedback loop. To investigate whether Trps1 has a role in this Ihh/PTHrP feedback loop, we compared the growth plates of Trps1-/- mice and wild-type (Trps1+/+) mice. Immunohistochemistry showed that Trps1 protein was strongly expressed in the periarticular and prehypertrophic zones of the fetal growth plate in wild-type mice on embryonic day 18.5 (E18.5). On the other hand, Ihh, PPR, and PTHrP mRNAs were predominantly expressed in the prehypertrophic zone at this stage of development. While expression of Ihh and PPR by prehypertrophic chondrocytes was unaffected in the growth plates of Trps1-/- mice, the range of PTHrP expression was expanded toward the proliferating zone in these mice. Quantitative real-time PCR analysis demonstrated upregulation of PTHrP in the epiphyseal growth plates of Trps1-/- mice. Furthermore, promoter analysis combined with the chromatin immunoprecipitation (ChIP) assay demonstrated that direct binding of Trps1 to the PTHrP promoter suppressed the transcription of PTHrP. Finally, organ culture of E14.5 tibiae in the absence or the presence of Pthrp revealed that the proliferative zone of the tibial growth plate was elongated by culture with Pthrp compared to that of control tibiae. Taken together, these data provide the first genetic evidence that lack of Trps1 leads to overexpression of PTHrP, and that Trps1 is required to maintain the normal organization of chondrocytes in the growth plate.

Trps1 plays a pivotal role downstream of Gdf5 signaling in promoting chondrogenesis and apoptosis of ATDC5 cells.

Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant skeletal disorder caused by mutations of TRPS1. Based on the similar expression patterns of Trps1 and Gdf5, we hypothesized a possible functional interaction between these two molecules. Using a chondrogenic cell line (ATDC5), we investigated the association of Gdf5-mediated signaling pathways with Trps1 and the phenotypic changes of ATDC5 cells due to over-expression or suppression of Trps1. Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1. Trps1-overexpressing ATDC5 (O/E) cells differentiated into chondrocytes more quickly than mock-infected control cells, whereas cells transfected with dn-Alk6 showed slower differentiation. On the other hand, O/E cells showed an increase of apoptosis along with the up-regulation of cleaved caspase 3 and down-regulation of Bcl-2, whereas dn-Alk6 cells showed suppression of apoptosis. In conclusion, Trps1 acts downstream of the Gdf5 signaling pathway and promotes the differentiation and apoptosis of ATDC5 cells.

Randomized, controlled investigation of the anti-infective properties of the Alexis retractor/protector of incision sites.

BACKGROUND: We prospectively investigated whether the wound-protective Alexis (Applied Medical, Rancho Santa Margarita, CA) wound retractor was effective in preventing surgical site infection (SSI). METHODS: We examined the actual condition of SSI in a 12-month randomized, controlled trial consisting of 221 patients who had undergone nontraumatic gastrointestinal surgery. The patients were divided into a With Alexis retractor group (n = 111) and a Without Alexis retractor group (n = 110). We also analyzed SSI separately on the basis of surgical sites such as gastric surgery or colorectal surgery. RESULTS: Overall estimation showed a significant decrease in wound infection (superficial incisional SSI) in the With Alexis retractor group. In the analysis based on surgical sites, a significant decrease in wound infection was noted in the With Alexis retractor group, the members of which had undergone colorectal surgery. There was no significant difference between the two groups in the occurrence of organ/space SSI, including anastomotic leak or intraperitoneal abscess. CONCLUSION: It was suggested that the use of the Alexis wound retractor would protect surgical wounds from contamination by bacteria and thus prevent infection.

Endoscopic microwave coagulation therapy of postoperative hemorrhage from a stapled anastomosis.

We experienced three cases of postoperative hemorrhage from a stapled gastrointestinal anastomosis, and established endoscopic microwave coagulation therapy (EMCT) with a cylinder-type electrode. We were able to treat postoperative hemorrhage over the entire circumference of stapled anastomosis successfully. Two patients had undergone a lower third thoracic esophagogastrectomy through a left thoraco-abdominal approach for gastric cancer in the cardia, while the other case had undergone Billroth I gastrectomy. They each had fresh bleeding from the stapled anastomosis after the operation. Emergency endoscopic examination was immediately performed. Endoscopy revealed bleeding on the suture line. We performed hemostasis endoscopically with microwave coagulation therapy safely. They were discharged from the hospital without complications such as leakage and stenosis. Since EMCT with the cylinder-type electrode can coagulate shallowly and widely, it is very effective for hemorrhage from a stapled anastomosis.

[Microwave coagulation therapy for unresectable colorectal metastatic liver tumor].

INTRODUCTION: We evaluate the utility of microwave coagulation therapy (MCT) for the patients with unresectable liver metastasis from colorectal cancers. METHODS: Forty-four patients unresectable synchronous colorectal hepatic metastasis between January 1, 1989 and December 31, 2000, were enrolled in the present study. The patients courses were followed until March, 2002. To evaluate the efficacy of MCT for unresectable liver metastasis from colorectal cancers, a retrospective comparative study was done between a MCT with CT (hepatic arterial trans-infusion chemotherapy and/or systemic chemotherapy) group and a CT group. The background factors were examined included the maximum tumor diameter, the number of liver metastasis and disease of other metastatic sites, which influenced the outcome. RESULTS AND CONCLUSION: The survival curves of the patients with unresectable synchronous colorectal hepatic metastasis undergoing MCT with CT and CT alone were significantly different (p = 0.03). No significant differences were found in the background factors that had a prognostic influence. It is confirmed that using MCT can prolong the survival rate for the patients with unresectable synchronous colorectal hepatic metastasis.