Intraperitoneal chemotherapy for peritoneal metastases using sustained release formula of cisplatin-incorporated gelatin hydrogel granules.

PURPOSE: We previously reported the effectiveness of gelatin microspheres incorporating cisplatin in a mouse model of peritoneal metastases. In this study, we report our new complete sustained-release formula of gelatin hydrogel granules incorporating cisplatin (GHG-CDDP), which exerted a good anti-tumor effect with less toxicity. METHODS: GHG-CDDP was prepared without organic solvents to enable its future clinical use. The pharmaceutical characterization of GHG-CDDP was performed, and its in vivo degradability was evaluated. The anti-tumor effect was evaluated using a murine peritoneal metastasis model of the human gastric cancer MKN45-Luc cell line. RESULTS: Our new manufacturing process dramatically reduced the initial burst of CDDP release to approximately 2% (wt), while the previous product had a 25-30% initial burst. In intraperitoneal degradation tests, approximately 30% of GHG-CDDP remained in the murine abdominal cavity 7 days after intraperitoneal injection and disappeared within 3 weeks. GHG-CDDP significantly suppressed the in vivo tumor growth (p = 0.02) and prolonged the survival time (p = 0.0012) compared with the control. In contrast, free CDDP did not show a significant therapeutic effect at any dose. Weight loss and hematological toxicity were also significantly ameliorated. CONCLUSIONS: GHG-CDDP is a promising treatment option for peritoneal metastases through the complete sustained-release of CDDP with less systemic toxicity.

Antiadhesion effect of the C17 glycerin ester of isoprenoid-type lipid forming a nonlamellar liquid crystal.

Postoperative adhesion is a relevant clinical problem that causes a variety of clinical complications after abdominal surgery. The objective of this study is to develop a liquid-type antiadhesion agent and evaluate its efficacy in preventing tissue adhesion in a rat peritoneal adhesion model. The liquid-type agent was prepared by submicron-sized emulsification of C17 glycerin ester (C17GE), squalene, pluronic F127, ethanol, and water with a high-pressure homogenizer. The primary component was C17GE, which is an amphiphilic lipid of one isoprenoid-type hydrophobic chain and can form two phases of self-assembly nonlamellar liquid crystals. The C17GE agent consisted of nanoparticles with an internal inverted hexagonal phase when evaluated by small-angle X-ray scattering (SAXS) and cryo-transmission electron microscopy (cryo-TEM). Upon contact with the biological tissue, this agent formed a thin membrane with a bioadhesive property. After this agent was applied to a sidewall injury of rats, it showed a percentage average of adhesion significantly less than that obtained with the Seprafilm® antiadhesion membrane in a rat model. Additionally, the retention of the agent prolonged at the applied site in the peritoneal cavity of rats. In conclusion, the C17GE agent is promising as an antiadhesion material. STATEMENT OF SIGNIFICANCE: Postoperative adhesion remains a common adverse effect. Although various materials have been investigated, there are few products commercially available to prevent adhesion. For the sheet-type agent, it is inconvenient to be applied through small laparotomy, especially in laparoscopic surgery. Additionally, the liquid-type agent currently used requires a complicated procedure to spray at the targeted site. Our liquid-type antiadhesion agent can form liquid crystals and act as a thin membrane-like physical barrier between the peritoneum and tissues to prevent adhesion. Indeed, the antiadhesion agent used in our present study significantly prevents adhesion compared with the antiadhesion membrane most used clinically. Moreover, our agent is highly stable by itself and easy to use in laparoscopic surgery, thus leading to a promising new candidate as an antiadhesion material.

Short- and mid-term outcomes after early surgical training in laparoscopic colorectal cancer surgery: trainees' performance has no negative impact.

BACKGROUND: This study aimed to evaluate the safety and quality of laparoscopic colorectal cancer surgery undertaken by trainees. PATIENTS AND METHODS: From a prospectively maintained database, we identified 456 consecutive patients who underwent laparoscopic resection for colorectal cancer between 2006 and 2010. Short-term operative outcomes, relapse-free survival (RFS), and overall survival (OS) were compared between operations undertaken by the experts (E group) and trainees (T group). Multivariate analyses were performed for RFS and OS in stage II/III disease. RESULTS: Trainees performed 313 surgeries (68.6%) and completed the procedure by themselves in 297 cases (94.9%). Short-term outcomes, including operative time, blood loss, conversion, complication, mortality, and retrieval of less than 12 lymph nodes, were comparable between the E group and the T group. After a median follow-up period of 35 months, RFS and OS were similar between the two groups, with the exception of OS for stage II (3-year OS for E group versus T group, 96.9% versus 87.0%; P=.029); however, this difference disappeared after multivariate analyses. Multivariate analyses showed that positive resection margin and higher log carcinoembryonic antigen (CEA) levels were associated with lower RFS. Furthermore, increasing age, positive resection margin, higher log CEA levels, intraoperative surgeon exchange, rectal cancer, postoperative complications, absence of postoperative chemotherapy, and shorter operative time were associated with poor OS. CONCLUSIONS: Laparoscopic operations undertaken by trainees did not negatively affect short-term outcomes and were not associated with impaired mid-term oncologic outcomes. Our findings support early initiation of training in laparoscopic surgery for colorectal cancer treatment.

Parenchyma-sparing anatomical liver resection based on Hjortsjo's concept: a venous-drainage-guided approach to identify the ventral segment fissure.

PURPOSE: Anatomical liver resection is usually based on Couinaud's anatomical concept. In contrast, Hjortsjo's concept, which divides the right anterior section of the liver into ventral and dorsal segments by the vertical plane named the ventral segment fissure (VSF), has been rarely utilized for liver resection. Identification of the VSF is the most difficult step in liver resection based on Hjortsjo's concept. This study aimed to detail liver resection based on Hjortsjo's concept and report surgical outcomes of this procedure. METHODS: We reviewed the records of 166 consecutive patients who underwent liver resection between September 2009 and June 2012 at Kyoto Medical Center and identified seven liver resections in which Hjortsjo's concept was utilized. These patients consisted of four men and three women aged 55-79 years. Four patients had hepatocellular carcinoma and cirrhosis and three patients had metachronous colorectal liver metastasis. RESULTS: Liver resection along the VSF consisted of two extended left medial sectionectomies, three extended right posterior sectionectomies, and one Sg 7+8-dorsal resection by a venous-drainage-guided approach and one Sg 8-dorsal resection by a Glissonian approach. In all patients, the VSF was successfully identified as a congested or ischemic border on the liver surface. Mortality and major morbidity were nil. No patients underwent blood transfusion. After a median follow-up of 15 months, there were no deaths or local recurrence. CONCLUSIONS: Anatomical liver resection based on Hjortsjo's concept is feasible and advantageous over conventional liver resection because it preserves more parenchyma. The venous-drainage-guided approach is an effective method for identifying the VSF.

Laparoscopic resection for sigmoid and rectosigmoid colon cancer performed by trainees: impact on short-term outcomes and selection of suitable patients.

PURPOSE: This study aimed (1) to evaluate the impact of clinical factors, particularly operation by trainees, on the short-term outcomes of laparoscopic resection for sigmoid and rectosigmoid cancer, and (2) to determine patients suitable for operation by trainees. METHODS: From a prospectively maintained single-institution database, we identified 133 patients who underwent laparoscopic resection for sigmoid or rectosigmoid cancer between 2007 and 2010. Gender, age, body mass index (BMI), previous abdominal surgery, tumor location, tumor size, tumor stage, extent of lymph node dissection, and primary surgeon were evaluated using univariate and multivariate analyses to determine the predictive significance of these variables on surgical outcomes including operative time, blood loss, complication, postoperative stay, and retrieved lymph nodes. RESULTS: Multivariate analysis showed that location of the tumor in the rectosigmoid (p < 0.001), higher BMI (p < 0.001), operation by trainees (p < 0.001), male gender (p = 0.002), and greater tumor depth (p = 0.011) were independently predictive of longer operative time. Larger tumor size (p = 0.025) and higher BMI (p = 0.040) were independently predictive of greater blood loss. Larger tumor size was also related to longer postoperative stay (p = 0.001) and a greater number of retrieved lymph nodes (p = 0.001). CONCLUSIONS: This study identified operation by trainees as an independent risk factor for longer operative time but with no negative impact on any of the other outcomes. Female patients with a low BMI, sigmoid cancer, shallow tumor depth, and/or small tumor are suitable for operation by trainees.

[Oral capecitabine as postoperative adjuvant chemotherapy in stage III colon cancer patients].

Capecitabine(Xeloda®)has been a global standard drug for the treatment of colon cancer since large randomized controlled trials demonstrated its efficacy and safety in treating patients suffering from the disease. Few studies have been conducted to assess the effects of oral capecitabine treatment on Japanese patients. Therefore, we conducted this study to evaluate oral capecitabine as postoperative adjuvant chemotherapy in 50 patients who underwent surgery for stage III colon cancer at our department. Patients received an 8 courses treatment with capecitabine during the study, and the incidence of adverse events, treatment completion rate, and treatment compliance were assessed. Adverse events were reported in a total of 46 patients(92%). The most common adverse event was hand foot syndrome(HFS), reported in 39 patients(78%), whereas bone-marrow toxicity and diarrhea were reported in as few as 2(4%)and 3(6%)patients, respectively. Both these events were mild in severity, and no patients required hospitalization, nor were they associated with treatment-related deaths. The median treatment duration was 8 courses ranging from 3 to 8 courses, and the 8 courses treatment completion rate was 96%. The relative dose intensity, which was used as a treatment compliance index, is expressed as the actual dose taken by the patient divided by the dose planned at baseline. The median and mean of the relative dose intensity were 100%(ranging from 37% to 100%)and 93%, respectively. The results of this study showed that the safety profile of oral capecitabine therapy was generally favorable, with a lower incidence and lesser severity of life-threatening bone-marrow toxicity and diarrhea, although the treatment is still associated with frequent HFS. This is the great advantage of capecitabine when it is used as postoperative adjuvant chemotherapy for gastrointestinal cancer. Indeed, a satisfactory treatment completion rate was achieved in this study while maintaining a sufficient dose and treating HFS, by reducing the dose, interrupting treatment, or providing appropriate corrective measures.