Toshiya Nagasaki

High expression of dihydropyrimidine dehydrogenase in lung adenocarcinoma is associated with mutations in epidermal growth factor receptor: implications for the treatment of non--small-cell lung cancer using 5-fluorouracil.

BACKGROUND It has been shown that 5-fluorouracil (5-FU) sensitivity in patients with non-small-cell lung cancer (NSCLC) is associated with epidermal growth factor receptor (EGFR) mutation status. However, the relationship between dihydropyrimidine dehydrogenase (DPD), a 5-FU degrading enzyme, and EGFR mutation status is unknown. Here, we focus on clinicopathologic factors and in vitro correlations between DPD expression and EGFR mutation status. PATIENTS AND METHODS EGFR mutations and messenger RNA (mRNA) levels of DPD and thymidylate synthase (TS) were analyzed in 47 resected NSCLC tumors by laser-capture microdissection. In addition, relationships between EGFR mutation status and the immunohistochemical expression of DPD and TS in 49 patients with primary NSCLC who were treated with a 5-FU derivative of S-1 postoperatively were examined. Correlations among clinicopathologic factors were evaluated. The effect of epidermal growth factor on DPD expression was also investigated in vitro in various cell lines. RESULTS Adenocarcinoma in situ showed significantly higher DPD mRNA levels and more EGFR mutation frequency than other histological types (P < .05). DPD immunopositive cases were more frequently observed in adenocarcinoma, in females, and in nonsmokers. DPD immunopositive cases were correlated with EGFR mutation status (P < .003). The prognoses of wild-type EGFR and mutated EGFR populations were similarly favorable with postoperative S-1 treatment, which overcomes the problem of 5-FU degradation in mutated EGFR. In vitro, EGFR-mutated cell lines showed high DPD mRNA and protein expression. CONCLUSION High DPD expression was shown to be correlated with EGFR mutation in adenocarcinoma cells and tissues. Clinicians should take this finding into consideration when using 5-FU to treat patients with NSCLC.

Analysis of 5-Fluorouracil–Related Enzymes in Pulmonary Neuroendocrine Carcinoma: Differences in Biological Properties Compared to Epithelial Carcinoma

BACKGROUND Dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), and thymidylate synthase (TS) levels correlate with sensitivity and resistance to 5-fluorouracil (5-FU). Few data are available on these enzymes in pulmonary neuroendocrine carcinoma, because 5-FU appears to have minimal effect on such carcinomas. PATIENTS AND METHODS This study investigated 5-FU-related enzymes in large-cell neuroendocrine carcinoma (LCNEC; n = 31) and small-cell lung carcinoma (SCLC; n = 15), comparing expression levels with epithelial carcinomas including adenocarcinoma (ADC; n = 34) and squamous cell carcinoma (SCC; n = 13) obtained from 93 patients with primary lung tumors. Levels of 5-FU-related enzyme mRNA were analyzed by laser capture microdissection, compared with immunohistochemical findings and correlated with clinicopathologic factors. RESULTS LCNEC and SCLC showed significantly higher TS and OPRT mRNA levels than ADC. SCLC exhibited significantly higher TS mRNA levels than LCNEC (P = .002). LCNEC displayed significantly lower DPD mRNA levels than ADC (P < .001), with a similar tendency in SCLC. SCC showed significantly lower DPD (P < .01) and higher OPRT (P < .001) mRNA levels than ADC. When we divide the data by pathology into epithelial carcinoma and neuroendocrine carcinoma, malignant potentials and prognoses correlated with mRNA levels in epithelial carcinoma, but not in neuroendocrine carcinoma. Immunohistochemically, neuroendocrine carcinomas were immunonegative for DPD. A significant correlation was found between enzymatic mRNA and protein expression for DPD (R = .500) and a weak correlation was observed for TS (R = .294). CONCLUSION Neuroendocrine carcinomas show characteristic patterns of expression for 5-FU-related enzymes, including low DPD mRNA and protein level and high TS mRNA level compared with adenocarcinomas. These results partially explain why 5-FU-based chemotherapy shows minimal efficacy against SCLC. Conversely, clinicopathological data and survival analysis indicates that 5-FU-related enzymes themselves might not affect the malignant potential of neuroendocrine carcinoma. Expressional differences in 5-FU-related enzymes among pathologies may provide valuable information for tailor-made chemotherapy.

Epidermal growth factor signals regulate dihydropyrimidine dehydrogenase expression in EGFR-mutated non-small-cell lung cancer

BackgroundIt has been shown that epidermal growth factor receptor (EGFR) mutation status is associated with 5-fluorouracil (5-FU) sensitivity in non-small-cell lung cancer (NSCLC). However, the relationship between EGFR mutation status and dihydropyrimidine dehydrogenase (DPD), a 5-FU degrading enzyme, is unknown.MethodsWe elucidated the crosstalk among the EGFR signal cascade, the DPD gene (DPYD), and DPD protein expression via the transcription factor Sp1 and the effect of EGFR mutation status on the crosstalk.ResultsIn the PC9 (exon19 E746-A750) study, EGF treatment induced up-regulation of both Sp1 and DPD; gefitinib, an EGFR-tyrosine kinase inhibitor (EGFR-TKI), and mithramycin A, a specific Sp-1 inhibitor, suppressed them. Among EGFR-mutated (PC9, HCC827; exon19 E746-A750 and H1975; exon21 L858R, T790M, gefitinib resistant) and -non-mutated (H1437, H1299) cell lines, EGF administration increased DPYD mRNA expression only in mutated cells (p < 0.05). Accordingly, gefitinib inhibited DPD protein expression only in PC9 and HCC827 cells, and mithramycin A inhibited it in EGFR-mutated cell lines, but not in wild-type. FU treatment decreased the level of cell viability more in gefitinib-treated EGFR-TKI sensitive cell lines. Further, combination treatment of FU and mithramycin A suppressed cell viability even in a gefitinib resistant cell line.ConclusionsThe EGFR signal cascade regulates DPD expression via Sp1 in EGFR mutant cells. These results might be a step towards new therapies targeting Sp1 and DPD in NSCLC with different EGFR mutant status.

Predictive parameters of intraoperative blood loss in patients who underwent pancreatectomy.

BACKGROUND/AIMS Despite recent advances in surgical techniques, blood loss is an important factor associated with postoperative outcomes in pancreatectomy. It is useful to identify risk factors of increased blood loss. METHODOLOGY The clinical records of 161 patients who underwent an elective pancreatectomy for peripancreatic diseases between 1994 and March 2011 were retrospectively examined. Univariate and multivariate analysis of clinicopathological and surgical parameters influencing intraoperative blood loss were performed. We determined the cut-off value of the amount of blood loss based on the analyzed results. RESULTS The mean and median blood loss was 1346±901 and 1070 mL, respectively. Red cell blood transfusion was performed in 72 patients (45%). Based on ROC analysis, the predictive value of blood loss in patients who received red cell blood transfusion was 880 mL (p <0.001); however, blood loss was not significantly associated with postoperative complications (p = 0.40). The cut-off level of estimated amount of blood loss in the present study was set at 880 mL. Male patients, fatty pancreas, higher serum alkaline phosphatase level, longer operating time, performance of pancreaticoduodenectomy (PD) and combined resections of adjacent major vessels were associated with significantly more increased blood loss (p <0.05). Based on multivariate analysis, longer operation time over 480 minutes and performance of PD were significantly associated with increased blood loss (p <0.05). CONCLUSIONS Attempting to reduce operating time in cases of PD is necessary to reduce intraoperative blood loss.

Skeletal muscle loss is an independent negative prognostic factor in patients with advanced lower rectal cancer treated with neoadjuvant chemoradiotherapy

Background The impact of body composition on the short- or long-term outcomes of patients with surgically treated advanced rectal cancer after neoadjuvant chemoradiotherapy remains unclear. This study examined the correlation between low skeletal muscle mass and morbidity and survival in patients with advanced lower rectal cancer. Methods We enrolled 144 clinical stage II/III patients with advanced lower rectal cancer who underwent neoadjuvant chemoradiotherapy followed by curative resection between 2004 and 2011. The cross-sectional skeletal muscle area at the third lumbar vertebra (L3) level was evaluated by computed tomography before chemoradiotherapy, and this was normalized by the square of the height to obtain the skeletal muscle index. Low skeletal muscle mass was defined as the sex-specific lowest quartile of the L3 skeletal muscle index. The association between low skeletal muscle mass and morbidity, relapse-free survival, or overall survival was assessed. Results Low skeletal muscle mass was identified in 37 (25.7%) patients. Age and body mass index were associated with low skeletal muscle mass. By multivariate analysis, we found that low skeletal muscle mass was independently associated with poor overall survival (hazard ratio = 2.93; 95%CI: 1.11–7.71; p = 0.031) and relapse-free survival (hazard ratio = 2.15; 95%CI: 1.06–4.21; p = 0.035), but was not associated with the rate of postoperative complications. Conclusions Low skeletal muscle mass is an independent negative prognostic factor for relapse-free and overall survival in patients with advanced lower rectal cancer treated with neoadjuvant chemoradiotherapy.

Laparoscopic right hemicolectomy for a colon cancer patient with an ileal conduit: Colectomy for patient with ileal conduit

Here, we describe our experience of laparoscopic surgery in a colon cancer patient with an ileal conduit. To our knowledge, this is the second case presented in the English‐language literature. A 71‐year‐old woman with a history of both open anterior exenteration with ileal conduit reconstruction for bladder cancer and open cholecystectomy for cholecystitis was diagnosed with ascending colon cancer (cT3N1M0). Laparoscopic right hemicolectomy with conduit preservation was planned. After adhesiolysis, complete mesocolic excision and central vascular ligation were achieved laparoscopically without injury to the conduit or other structures. Laparoscopic surgery for patients with an ileal conduit can be technically demanding. A preoperative plan based on preoperative imaging and the patient’s previous operative record is crucial, especially when considering the optimal balance between oncological radicality and functional outcomes.

Simultaneous laparoscopic left hemicolectomy and spleen-preserving distal pancreatectomy for descending colon cancer with pancreatic invasion: Lap colectomy with distal pancreatectomy

Here, we describe laparoscopic colectomy with spleen‐preserving distal pancreatectomy for descending colon cancer with pancreatic tail invasion. A 69‐year‐old man with descending colon cancer staged as clinical state IIIC (cT4b [pancreas] N1M0) underwent definitive laparoscopic surgery that was performed in collaboration with surgeons who specialize in laparoscopic colorectal and hepatobiliary‐pancreatic laparoscopy. After the left colon was mobilized, tumor infiltration of the pancreas, but not the splenic vessels, was confirmed, and the spleen was preserved. The procedures were safely completed laparoscopically, without intraoperative and postoperative complications. Laparoscopic multivisceral resection could be a treatment option for similar patients but only when performed by multidisciplinary specialists.

Laparoscopic repair of bowel herniation into the space between the obturator nerve and the umbilical artery after pelvic lymphadenectomy for cervical cancer: Entocele after pelvic lymphadenectomy

Bowel herniation through the space between the exposed structures after pelvic lymphadenectomy is a very rare cause of postoperative bowel obstruction. Here, a case of laparoscopic release of bowel migration into the space after pelvic lymphadenectomy is described. This is the seventh such reported case in the world. A 38‐year‐old woman who had a history of undergoing laparoscopic radical hysterectomy and bilateral pelvic lymphadenectomy for cervical cancer was diagnosed with strangulated bowel obstruction. Emergency laparoscopic surgery was performed, and bowel migration into the space between the right umbilical artery and the obturator nerve was detected. The loop of strangulated bowel was released laparoscopically, and bowel blood flow was improved. To prevent recurrence of bowel migration, the umbilical artery was resected. It is very important to consider the possibility of bowel herniation into the space between exposed structures in patients with bowel obstruction after minimally invasive pelvic lymphadenectomy.