Impact of Light Shielding on Photo-Degradation of Dacarbazine during the Preparation Process.

Dacarbazine (DTIC) is converted to the photo-degradation product 4-diazoimidazole-5-carboxamide (Diazo-IC) by light. Diazo-IC production is often responsible for the pain reactions observed during peripheral intravenous infusion of DTIC in clinical settings. Although light shielding during infusion decreases the photo-degradation of DTIC, its usefulness for the preparation of DTIC has not yet been fully clarified. The aim of this study was to investigate the light conditions during the preparation of DTIC solution in the compounding room from the viewpoint of the production amount of Diazo-IC. DTIC solution was prepared in the compounding room. Various light and temperature conditions and dissolving solutions during the preparation were investigated. The amounts of DTIC and Diazo-IC in solutions were determined using an HPLC coupled to UV detection. The photo-degradation of DTIC was estimated by the amount of Diazo-IC. Diazo-IC production in the dissolving solutions increased in a time-dependent manner at 4 and 25°C under light shielding. Light exposure during the dissolving process did not affect the DTIC and Diazo-IC concentrations. Light shielding during dissolution did not alter the Diazo-IC production until 4 h after dilution. In conclusion, short duration light exposure did not affect Diazo-IC production. These findings suggest that light shielding is not needed in the preparation of DTIC in the compounding room from the viewpoint of Diazo-IC production.

Influence of cytochrome P450 genotype on the plasma disposition of prochlorperazine metabolites and their relationships with clinical responses in cancer patients.

Background Oral prochlorperazine, a dopamine D2 receptor antagonist, is largely metabolized to sulphoxide, 7-hydroxylate and N-desmethylate by cytochrome P450s (CYPs). This study evaluated the influence of CYP genotype on the plasma dispositions of prochlorperazine and its metabolites and their relationships with antiemetic efficacy and prolactin elevation in cancer patients. Methods Forty-eight cancer patients treated with oral prochlorperazine were enrolled. Plasma prochlorperazine and its metabolites concentrations and serum prolactin concentration were determined at 12 h after the evening dosing. The genotypes of CYP2C19, CYP2D6 and CYP3A5 and the incidences of nausea and vomiting were investigated. Results The plasma concentrations of the prochlorperazine metabolites were weakly correlated with that of the parent drug. The CYP genotypes did not affect the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine and its metabolites were not associated with the incidences of nausea and vomiting. The incidence of vomiting was significantly higher in females than in males. The serum prolactin concentration was weakly correlated with the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine metabolites rather than the parent drug had a weaker relation to serum prolactin concentration. Conclusions The CYP genotypes did not affect the plasma dispositions of prochlorperazine and its metabolites. The prochlorperazine metabolites did not have a strong effect on antiemetic efficacy, while they were slightly associated with prolactin secretion in cancer patients.

[Long-Term Survivor of a Barrett's Esophageal Adenocarcinoma, Who Underwent Three Times Surgical Resection and MultidisciplinaryTherapyfor Lymph Node Recurrences - Report of a Case].

We report a case of a 42-year-old man who underwent 3 times surgical resection for lymph nodes recurrence and multidisciplinary therapy for Stage IV b Barrett's esophageal adenocarcinoma, and was well 6 years and 3 months after the first resection. The prognosis of the recurrence cases after radical recection of the esophageal cancer is extremely poor. Long-term prognosis may be obtained in few patients, but the cases are squamous cell carcinoma in most of the reported cases. The number of Barrett's esophageal adenocarcinoma patients is increasing, but it is not many. There is little reports, and there is no fixed treatment policy.

[A Patient with Stage IV Gastric Cancer Who Survived More Than Five Years after Gastrectomy].

The prognosis of patients with Stage IV gastric cancer is generally poor. The 5-year overall survival rate is less than 10%. The patient was a 73-year-old man with Stage IV gastric cancer. Before chemotherapy, peritoneal dissemination was observed using staging laparoscopy. The patient received first-line chemotherapy with TS-1 plus CDDP. Renal function worsened and consequently the therapy was stopped. He received 3 courses of chemotherapy with weekly PTX. The peritoneal dissemination had disappeared by the second staging laparoscopy and he underwent distal gastrectomy. The final diagnosis was pT4a, ly2, v1, pN2(4/16),M0, fStage III B. The patient received adjuvant chemotherapy of TS-1 for 4 years and 8months after gastrectomy. More than 5 year after gastrectomy, the patient is alive without recurrence.

Spleen preservation versus splenectomy in laparoscopic total gastrectomy with D2 lymphadenectomy for gastric cancer: A comparison of short-term outcomes.

INTRODUCTION: Splenic hilar lymph node dissection via a splenectomy for advanced proximal gastric cancer remains controversial. Recently, a laparoscopic spleen-preserving hilar lymph node dissection procedure was described in several publications. To assess the feasibility and safety of spleen-preserving laparoscopic total gastrectomy with D2 lymphadenectomy (LTG-D2), the present retrospective study compared the short-term surgical outcomes between spleen preservation and splenectomy during laparoscopic D2 total gastrectomy (LTG-D2S). METHOD: This study included 59 patients who underwent LTG-D2 and 19 patients who underwent LTG-D2S. RESULTS: The mean operation time did not significantly differ between the LTG-D2 and LTG-D2S groups (339.4 ± 56.8 vs 356.8 ± 46.0 min). The mean blood loss tended to be smaller in the LTG-D2 group than in the LTG-D2S group (105.9 ± 89.7 vs 210.0 ± 149.5 mL). The mean number of retrieved lymph nodes did not significantly differ between the LTG-D2 and LTG-D2S groups (39.9 ± 17.0 vs 40.6 ± 14.9), and the mean number of retrieved lymph nodes at the splenic hilum also did not significantly differ between the LTG-D2 and LTG-D2S groups (1.3 ± 1.7 vs 2.4 ± 2.6). Mild pancreatic fistula occurred in three cases (5%) in the LTG-D2 group and in three cases (15.8%) in the LTG-D2S group. CONCLUSION: A LTG-D2 is feasible in terms of the short-term outcomes. However, the indications for this complicated procedure should be considered carefully.

Triple-incision laparoscopic distal gastrectomy for the resection of gastric cancer: comparison with conventional laparoscopy-assisted distal gastrectomy.

INTRODUCTION: Reduced port surgery and single-port surgery are currently in the spotlight as next-generation, minimally invasive surgical techniques. We performed a triple-incision laparoscopic distal gastrectomy (TIL-DG) for gastric cancer as a reduced port surgery. METHOD: A total of 76 patients underwent a TIL-DG. A D1+ or D2 lymph node dissection was performed, and the Roux-en-Y method was used for reconstruction. The short-term patient outcomes of the TIL-DG group were compared with those of the conventional laparoscopy-assisted distal gastrectomy group (59 cases) to evaluate the feasibility of TIL-DG. RESULTS: No significant differences were observed between the TIL-DG group and the laparoscopy-assisted distal gastrectomy group in terms of mean operative time, blood loss, and the length of the postoperative hospital stay. The mean number of retrieved regional lymph nodes in the TIL-DG group was slightly higher than that in the laparoscopy-assisted distal gastrectomy group. CONCLUSION: A triple-incision laparoscopic distal gastrectomy is a feasible and safe procedure.

Impact of genetic and non-genetic factors on clinical responses to prochlorperazine in oxycodone-treated cancer patients.

BACKGROUND: The contributions of DRD2 and OPRM1 genetic variants to clinical responses to prochlorperazine remain to be clarified in opioid-treated patients. We evaluated the clinical responses to prochlorperazine based on non-genetic and genetic factors in oxycodone-treated patients. METHODS: Seventy Japanese cancer patients starting oral prochlorperazine together with oxycodone were enrolled. Predose plasma prochlorperazine concentrations and serum prolactin concentrations were determined. The incidences of oxycodone-induced nausea and vomiting were monitored for 2weeks. RESULTS: Plasma prochlorperazine concentration and oxycodone daily dose were not associated with the incidences of nausea and vomiting. The incidence of nausea was significantly higher in the DRD2 TaqIA A1A2+A1A1 group than in the A2A2 group. The incidence of vomiting was significantly higher in females than in males. Before and after the prochlorperazine administration, the serum prolactin concentration was significantly higher in female patients than in male patients. The serum prolactin concentration was weakly correlated with prochlorperazine concentration and was significantly higher in the OPRM1 118AA group than in the AG+GG group. CONCLUSIONS: DRD2 TaqIA and female gender altered the prophylactic antiemetic efficacy of prochlorperazine. OPRM1 A118G together with plasma exposure of prochlorperazine and gender affected prolactin secretion in oxycodone-treated patients.

Cancer cachexia raises the plasma concentration of oxymorphone through the reduction of CYP3A but not CYP2D6 in oxycodone-treated patients.

This study evaluated the plasma concentrations of oxycodone and its demethylates and opioid-induced adverse effects based on cachexia stage in cancer patients receiving oxycodone. Seventy patients receiving oxycodone for cancer pain were enrolled. Cachexia was evaluated using the Glasgow Prognostic Score (GPS). Predose plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined at the titration dose. Opioid-induced adverse effects were monitored for 2 weeks after the titration. Plasma concentrations of oxycodone and oxymorphone but not noroxycodone in patients with a GPS of 2 were significantly higher than that with a GPS of 0. The metabolic ratios of noroxycodone but not oxymorphone to oxycodone in patients with a GPS of 1 and 2 were significantly lower than in those with a GPS of 0. A higher GPS was associated with a higher incidence of somnolence, while the GPS did not affect the incidence of vomiting. Plasma concentrations of oxycodone and oxymorphone were not associated with the incidence of adverse effects. In conclusion, cancer cachexia raised the plasma exposures of oxycodone and oxymorphone through the reduction of CYP3A but not CYP2D6. Although the cachexia elevated the incidence of somnolence, alterations in their pharmacokinetics were not associated with the incidence.

Laparoscopic introduction of a center rod using a Nelaton catheter during laparoscopic esophagogastrostomy.

During laparoscopic proximal gasterctomy, the difficulty associated with the use of a circular stapler for esophagogastrectomy is not only the fixation of the anvil, but also the laparoscopic manipulation of the body of the circular stapler. We have developed a new approach to the laparoscopic introduction of the center rod using a Nelaton catheter. After transection of the esophagus, the stomach is pulled out through an umbilical minilaparotomy. The proximal gastrectomy is performed extracorporeally, and a Nelaton catheter is passed through a small incision at the lower body of the stomach and a small penetrating wound at the point of the esophagogastrostomy. The Nelaton catheter is attached to the center rod of the circular stapler. The center rod can be guided to the appropriate point laparoscopically by the Nelaton catheter. Between January 2009 and May 2010, 11 patients underwent this procedure, successfully. This technique was useful for laparoscopic proximal gastrectomy.

Impact of cachexia on pharmacokinetic disposition of and clinical responses to oxycodone in cancer patients.

PURPOSE: Cancer cachexia is characterized by hypoalbuminemia and with the hepatic production of acute-phase proteins in response to malignant growth. The aim of this study was to evaluate the influence of cachexia on the pharmacokinetic disposition of and clinical responses to oxycodone in cancer patients. METHODS: Forty-seven Japanese patients receiving oxycodone extended-release tablets as a starting opioid for cancer pain were enrolled in this study. Cachexia was evaluated using the Glasgow Prognostic Score (GPS). Predose plasma concentrations of oxycodone and noroxycodone were determined at the titration dose. RESULTS: Seven patients had a GPS of 0, 21 a GPS of 1, and 19 had a GPS of 2. A higher GPS was significantly correlated with a higher oxycodone concentration and a lower concentration ratio of noroxycodone to oxycodone and significantly associated with a lower incidence of dose escalation and a higher incidence of central adverse reactions. Serum albumin, but not α(1)-acid glycoprotein and C-reactive protein, was inversely correlated with the free fraction of oxycodone. Serum albumin concentration was significantly associated with the incidence of dose escalation. In contrast, the free fraction of oxycodone and acute-phase proteins were not related to the clinical responses. CONCLUSIONS: Cachexia had an effect on oxycodone metabolism and the clinical responses to oxycodone. The observed reduction in serum albumin concentration was associated with dose escalation. These findings suggest that cachexia affects the clinical responses to oxycodone through metabolic and nutritional disorders in cancer patients.

Simultaneous determination of prochlorperazine and its metabolites in human plasma using isocratic liquid chromatography tandem mass spectrometry.

Oral prochlorperazine (PCZ), an antiemetic, undergoes extensive first-pass metabolism. The study developed a simultaneous analytical method for PCZ and its major metabolites, prochlorperazine sulfoxide (PCZSO), N-demethylprochlorperazine (NDPCZ) and 7-hydroxyprochlorperazine (PCZOH), in human plasma using an isocratic liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Deproteinized plasma specimens were separated using a 3 µm particle size octadecylsilyl column, and the run time was 10 min. The calibration curves were linear over the concentration ranges of 0.01-40 µg/L for PCZ, NDPCZ and PCZOH, and 0.05-80 µg/L for PCZSO. The intra- and inter-assay precisions and accuracies were within 7.0 and 99-104% and within 9.0 and 99-105%, respectively. The lower limits of quantification in human plasma were 10 ng/L for PCZ, NDPCZ and PCZOH, and 50 ng/L for PCZSO. The validated method was applied to the determination of plasma samples in 37 cancer patients receiving PCZ. Large interindividual variations were observed in plasma concentrations of PCZ, PCZSO, NDPCZ and PCZOH (relative standard deviation, 89.4, 88.7, 86.4 and 78.2%, respectively). In conclusion, this simultaneous LC-MS/MS method with acceptable analytical performance can be helpful for evaluating the pharmacokinetics of PCZ, including the determination of its metabolites in cancer patients and in clinical research.

Laparoscopic-assisted low and ultralow anterior resection for lower rectal cancer using the simple "Rectum Catcher" device and an intra-operative colonoscopy.

PURPOSE: We report the feasible technique in lower rectal surgery. MATERIALS AND METHODS: The Rectum Catcher (Matsumoto et al. in Surg Endosc 22:1905-1909, 2008) is made of stainless steel, with a circle of diameter 6 mm punched out at a distance of 5 mm from the top and covered with a short-cut T-tube. A vessel tape is inserted into the stainless steel and the short-cut T-tube. The rectum is grasped using the Rectum Catcher at a proximal rectum of the cancer, and the location of the cancer is confirmed using an intra-operative colonoscopy. In the next step, the Rectum Catcher is applied at the distal rectum of the cancer, and which easily occludes the rectum, and we confirm that the cancer is not at the distal rectum from the Rectum Catcher, using an intra-operative colonoscopy. The rectal lumen is irrigated. Then, the linear cutter is positioned just distal rectum to the Rectum Catcher, and the rectum is transected adequately. RESULTS: From January 2009 to the present, this study included 18 patients undergoing laparoscopic-assisted low and ultralow anterior resection for lower rectal cancer, using the Rectum Catcher and an intra-operative colonoscopy. Using the Rectum Catcher and an intra-operative colonoscopy, we can easily make a decision of the location of rectal cancer in lower rectum and irrigation of rectal lumen can be easily performed to safely cut the bowel being occluded, in the narrow laparoscopic view of the pelvic cavity. CONCLUSION: The combination between the Rectum Catcher and an intra-operative colonoscopy is useful for performing laparoscopic rectal surgery.

CYP3A5*3 affects plasma disposition of noroxycodone and dose escalation in cancer patients receiving oxycodone.

The aim of this study was to evaluate the plasma dispositions of oxycodone and its demethylates and dose escalation based on genetic polymorphisms of CYP2D6, CYP3A5, ABCB1, and OPRM1 in cancer patients receiving oxycodone. Sixty-two Japanese cancer patients receiving oxycodone extended-release tablets were enrolled. Predose plasma concentrations (C(12)) of oxycodone, noroxycodone, and oxymorphone were determined at the titrated dose. Daily oxycodone escalation rate was evaluated as the opioid escalation index (OEI). Genetic variants did not significantly alter oxycodone C(12). Oxymorphone C(12) and its ratio to oxycodone C(12) were significantly higher in CYP2D6 extensive metabolizers than in intermediate metabolizers but did not affect dose escalation. In contrast, noroxycodone C(12) and its ratio to oxycodone C(12) were significantly higher in the CYP3A5*1 carrier group than in the *3/*3 group. The OEI was significantly higher in the CYP3A5*3/*3 group than in the *1 carrier group. No significant difference was observed in the OEI in the other genetic variants. Noroxycodone C(12) was higher in the dose escalation group as compared to the nonescalation group and significantly affected the incidence of dose escalation. In conclusion, CYP3A5*3 altered the plasma disposition of noroxycodone, which was inversely affecting the dose escalation in cancer patients receiving oxycodone.

The simple "Rectum Catcher" device is a useful tool for laparoscopic-assisted high and lower rectal surgery.

BACKGROUND: This report describes our experience in 13 patients with rectal cancer along with a general overview of the use of the simple "Rectum Catcher" device in high and lower rectal surgery. MATERIALS AND METHODS: The Rectum Catcher is made of stainless steel (length 40 cm, caliber 7 mm), with a circle of diameter 6 mm punched out at a distance of 5 mm from the top and covered with a short-cut T-tube (length 1 cm, caliber 6 mm) (SILKOLATEX T-tube, 8 mm; Willy Rusch AG, Germany). A vessel tape (width 9 mm, length 120 cm; Kawano Seisakusho, Chiba, Japan) is inserted into the stainless steel and the short-cut T-tube. The Rectum Catcher is inserted into the abdominal cavity through the 12-mm trocar (Ethicon Endo Surgery) and a vessel tape is circled the rectum and pulled to catch it. Thirteen patients with rectal cancer were operated laparoscopically using the Rectum Catcher at our hospital. RESULTS: From January 2007 to the present, this study included 13 patients (5 men and 8 women) undergoing laparoscopic-assisted high anterior resection (Lap-HAR, five patients), low anterior resection (Lap-LAR: six patients), and abdominoperineal resection (Lap-APR: two patients) for rectal cancer, using the Rectum Catcher. Using the Rectum Catcher, easy maneuverability of the rectum and irrigation of rectal lumen can be easily performed to safely cut the bowel being occluded, in the narrow laparoscopic view of the pelvic cavity. CONCLUSION: In our experience, the simple Rectum Catcher device is safe and useful for performing laparoscopic assisted high and lower rectal surgery.