Haruaki Ishibashi

Effects of Neoadjuvant Intraperitoneal/Systemic Chemotherapy (Bidirectional Chemotherapy) for the Treatment of Patients with Peritoneal Metastasis from Gastric Cancer

Novel multidisciplinary treatment combined with neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS) and peritonectomy was developed. Ninety-six patients were enrolled. Peritoneal wash cytology was performed before and after NIPS through a port system. Patients were treated with 60 mg/m2 of oral S-1 for 21 days, followed by a 1-week rest. On days 1, 8, and 15, 30 mg/m2 of Taxotere and 30 mg/m2 of cisplatin with 500 mL of saline were introduced through the port. NIPS is done 2 cycles before surgery. Three weeks after NIPS, 82 patients were eligible to intend cytoreductive surgery (CRS) by gastrectomy + D2 dissection + periotnectomy to achieve complete cytoreduction. Sixty-eight patients showed positice cytology before NIPS, and the positive cytology results became negative in 47 (69%) patients after NIPS. Complete pathologic response on PC after NIPS was experienced in 30 (36.8%) patients. Stage migration was experienced in 12 patients (14.6%). Complete cytoreduction was achieved in 58 patients (70.7%). By the multivariate analysis, complete cytoreduction and pathologic response became a significantly good survival. However the high morbidity and mortality, stringent patient selection is important. The best indications of the therapy are patients with good pathologic response and PCI ≤ 6, which are supposed to be removed completely by peritonectomy.

Prognostic Factors of Peritoneal Metastases from Colorectal Cancer following Cytoreductive Surgery and Perioperative Chemotherapy

Background. Prolonged survival of patients affected by peritoneal metastasis (PM) of colorectal origin treated with complete cytoreduction followed by intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) has been reported. However, two-thirds of the patients after complete cytoreduction and perioperative chemotherapy (POC) develop recurrence. This study is to analyze the prognostic factors of PM from colorectal cancer following the treatment with cytoreductive surgery (CRS) + POC. Patients and Methods. During the last 8 years, 142 patients with PM of colorectal origin have been treated with CRS and perioperative chemotherapy. The surgical resections consisted of a combination of peritonectomy procedures. Results. Complete cytoreduction (CCR-0) was achieved at a higher rate in patients with peritoneal cancer index (PCI) score less than 10 (94.7%, 71/75) than those of PCI score above 11 (40.2%, 37/67). Regarding the PCI of small bowel (SB-PCI), 89 of 94 (91.5%) patients with ≤2 and 22 of 48 (45.8%) patients with SB-PCI ≥ 3 received CCR-0 resection (P < 0.001). Postoperative Grade 3 and Grade 4 complications occurred in 11 (7.7%) and 14 (9.9%). The overall operative mortality rate was 0.7% (1/142). Cox hazard model showed that CCR-0, SB-PCI ≤ 2, differentiated carcinoma, and PCI ≤ 10 were the independent favorite prognostic factors. Conclusions. Complete cytoreduction, PCI, SB-PCI threshold, and histologic type were the independent prognostic factors.

Late recurrence of benign multicystic peritoneal mesothelioma complicated with an incisional hernia.

Benign multicystic peritoneal mesothelioma (BMPM) is a rare disease arising from the peritoneal mesothelium. Here, we report a 57-year-old woman admitted to our unit with an incisional hernia fifteen years later following her first operation due to BMPM. Computerized tomography demonstrated a cystic appearing mass with intraabdominal extension in hernia sac. The patient underwent en bloc resection of the mass and hernia repair. An immunohistochemical analysis of the mass confirmed the recurrence of BMPM. Our case supports that BMPM has slowly progressive nature and can recur with complicated incisional hernia long time after primary resection. Diagnosis and long-term followup are crucial for clarifying the characteristics of this disease.

Trans-Lymphatic Metastasis in Peritoneal Dissemination

Mechanism of the formation of peritoneal metastasis (PM) through lymphatic vessels was studied. Materials and methods: Parietal peritoneum was divided into 8 regions, and specimens of each zone were removed from patients with PM. The specimens were stained with enzyme histochemical staining for alkaline phoshatase (ALPase) and 5-Nase activity, and with immunohistochemical staining with D2-40. Surface of the peritoneum and subperitoneal tissue were observed by a scanning electron mcirosopy. Results: Well-developed lymphatic lacunae were found in the shallow submesothelial layer of 7 regions except for the anterior abdominal wall. Lymphatic vessels were found in the deep submesothelial layer up to 200 micrometer from the peritoneal surface. The mesothelial stomata directly connect with the submesothelial lymphatic vessels through holes of the macula cribrifolmis. Migration of cancer cells through stoma was found, and cancer cells were detected in the submesothelial lymphatic lacunae. Lymphatic vessels are not found in the center of established PM, but were found in the adjacent normal tissue. In the subperitoneal tissue outside the PM, morphological findings suggesting lymphangiogenesis designated as cystic Lymphatic Island, ladder formation, budding, and extension of lymphatic vessels were found. Conclusion: The triplet structure consisting of mesothelial stomata, holes on macula cribriformis and submesothelial lymphatic lacunae is essential for the migration of peritoneal free cancer cells into the submesothelial lymphatic lacunae. The rout of the formation of PM through peritoneal lymphatic vessels was named as translymphatic metastasis.

Risk Factors for Recurrence after Complete Cytoreductive Surgery andPerioperative Chemotherapy in Peritoneal Metastases from GastricCancer

Background and objective: The aim of this study is to analyze anatomical distribution, timing and outcomes of recurrence after complete cytoreduction and perioperative chemotherapy for peritoneal metastasis from gastric cancer (GCPM). Method: Data of 193 GCPM patients who underwent a complete cytoreductive surgery (CRS) after treatment with neoadjuvant chemotherapy were entered into a prospective database and the recurrence was analyzed. Result: The median time to progression was 16.2 months, median overall survival (OS) was 21.6 months and 5-year survival rate was 18.1%. Five years after CRS, 11 patients were disease free survivors. Recurrence rate was 68.5% (126/184). Mutivariate analysis confirmed small bowel peritoneal cancer index of ≥3 and pathologic nonresponders after NAC as independent risk factors for recurrence. Patients were treated with systemic chemotherapy or second cytoreductive surgery for recurrence. However, survival after diagnosis of recurrence was poor with median survival of 2.9 months. The most common type of recurrence was diffuse peritoneal recurrence (71%, 90/126). Localized intra-abdominal recurrence was experienced in only 7 patients. Conclusion: Pathologic non-responders and small bowel PCI of ≥3 are independent risk factors for recurrence. Exploratory laparoscopy after NAC might be a useful strategy for the selection of patients for CRS.

5-Aminolevulinic Acid Fluorescence in Detection of Peritoneal Metastases

BACKGROUND The value of 5-aminolevulinic acid (ALA) in fluorescence detection of peritoneal metastases and the underlying mechanisms were evaluated in patients with peritoneal surface malignancies. MATERIALS AND METHODS Oral 5-ALA was administered at a concentration of 20 mg ⁄kg body weight with 50 ml of water 2 hours prior to surgery (n=115). The diagnostic value of 5-ALA based fluorescence production was evaluated following white light inspection during prior to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Then, peptide transporter PEPT1 (ALA influx transporter) and ATP-binding cassette transporter ABCG2 (porphyrin efflux transporter) gene expression was determined with quantitative real time (qRT)-PCR and pathological diagnoses confirmed for all tissue samples. RESULTS The 5-ALA based photodynamic detection rate was 17% for appendiceal mucinous neoplasms, 54% for colorectal cancers, 33% for gastric cancers, 67% for diffuse malign peritoneal mesotheliomas, and 89% for epithelial ovarian cancer of peritoneal metastases. 5-ALA was detected in all cases of peritoneal metastases originating from cholangiocarcinomas whereas it was not able to detect any in granulosa cell and gastrointestinal stromal tumor cases. Furthermore, PEPT1 was overexpressed whereas ABCG2 expression was downregulated in tumors detected with fluorescence. CONCLUSIONS 5-ALA provided 100% specificity and high sensitivity to detect peritoneal metastases in subgroups of patients with peritoneal surface mailgnancies. ALA influx transporter PEPT1 and porphyrin efflux transporter ABCG2 genes are important in tumor specific 5-ALA induced fluorescence in vivo. Further studies should clarify diagnostic utility of 5-ALA in peritoneal surface malignancies.

Phase II Study of a Comprehensive Treatment Using Perioperative Chemotherapy Combined with Cytoreductive Surgery for Curatively Resected Gastric Cancer Patients with Positive Peritoneal Wash Cytology

Patients with curatively resected gastric cancer patients with positive peritoneal wash cytology are called P0/Cy1 status. The aim of the present study is to verify the survival benefit of the comprehensive treatment for patients with P0/Cy1 status. Twenty gastric cancer patients were diagnosed as P0/Cy1 by laparoscopy or laparotomy, and were treated with a comprehensive treatment consisting of neoadjuvant intraperitoneal/systemic chemotherapy (NIPS), cytoreductive surgery (CRS) consisting of gastrectomy with lymph node dissection and peritonectomy, intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) and postoperative systemic chemotherapy. At the second look laparotomy, the peritoneal wash cytology became negative in 15 patients. No grade 3, 4, 5 complications were experienced after second look operations for CRS. Median follow-up time is 3.7 years. Eight patients died of recurrence, but the other 21 patients are alive without recurrence. Five-year survival rate was 42%. The present study demonstrated the efficacy and safety of the comprehensive treatment on the gastric cancer patients in P0/Cy1 status.

Photodynamic Detection of Peritoneal Metastases Using 5-Aminolevulinic Acid (ALA)

In the past, peritoneal metastasis (PM) was considered as a terminal stage of cancer. From the early 1990s, however, a new comprehensive treatment consisting of cytoreductive surgery and perioperative chemotherapy has been established to improve long-term survival for selected patients with PM. Among prognostic indicators after the treatment, completeness of cytoreduction is the most independent predictors of survival. However, peritoneal recurrence is a main cause of recurrence, even after complete cytoreduction. As a cause of peritoneal recurrence, small PM may be overlooked at the time of cytoreductive surgery (CRS), therefore, development of a new method to detect small PM is desired. Recently, photodynamic diagnosis (PDD) was developed for detection of PM. The objectives of this review were to evaluate whether PDD using 5-aminolevulinic acid (ALA) could improve detection of small PM.

Mechanisms of the Formation of Peritoneal Surface Malignancy on Omental Milky Spots from Low Grade Appendiceal Mucinous Carcinoma

Mechanisms of the Formation of Peritoneal Surface Malignancy on Omental Milky Spots from Low Grade Appendiceal Mucinous Carcinoma Purpose: Omental milky spot (OMS) is considered to have an important role in the formation of peritoneal surface malignancy (PSM). However, human OMS and cancer metastasis has not been fully clarified. The present study demonstrates the mechanisms of the formation of metastasis on the omental milky spots (OMS) from the low grade AMC. Methods and materials: To clarify the mechanism of the formation of peritoneal metastasis in low grade appendiceal mucinous carcinoma (AMC), 195 low grade AMC showing peritoneal cancer index (PCI) of ≤28 were studied for the distribution of peritoneal metastasis. Peritoneum was resected from 10 patients, and was prepared as whole-mount extending specimen. The specimens were studied by 5’-nucleotidase and alkaline phosphatase double stain and immunohistologic staining by D2-40, anti-CD31 and anti- Ki-67 monoclonal antibody. Furthermore, peritoneal parts were observed by scanning electron microscopy. Results: Pelvic and subdiaphragmatic peritoneum were involved in 164 (84%) and 143 (73%) patients. Greater omentum was involved in 135 (69%) patients. Under the SEM observation, no typical milky spots were observed on the peritoneum except for the greater omentum. Surface of OMS was covered with cuboidal mesothelial cells. Between the cuboidal mesothelial cells, many stomata were found. After digestion of OMS by 6N KOH, disk-like peritoneal pouch was detected at OMS. Small holes were found on the collagen plate covered on the bottom of the pouch. Below the pouch, initial lymphatic vessels closed to the pouch with stomata. Agglomerated blood capillaries distributed around the initial lymphatics. Metastasis foci were found around the stomata on OMS, but were not detected on the flat mesothelial cells on the greater omentum.. Conclusion: Peritoneal free cancer cells from low grade AMC may be adsorbed at stomata and adhere on the OMS. Then, they proliferate on OMS.

Management of Peritoneal Metastases Developed from Gastric Cancer:Laparascopic Hyperthermic Intraperitoneal Chemontherapy in NeoadjuvantSetting

Objective: Peritoneal Metastases (PM) of Gastric Cancer (GC) are lesions of peritoneal surfaces, which may cause the dissemination throughout the abdominal cavity. The role of laparoscopic Hyperthermic Intraperitoneal Chemotherapy (HIPEC) as neoadjuvant purpose in the management of PM of GC is undefined. Methods: Fifty patients were enrolled into this study with histopathological diagnosis of PM of GC referred to our center between 2012 and 2013 All patients were underwent two cycles of neoadjuvant laparoscopic HIPEC. At the second session of LHIPEC, ascites volume, cytological status and PCI levels were compared with those at the 1st LHIPEC. Results: There was no intraoperative complication and mortality after LHIPEC. Four patients developed mild azotemia of Grade 2. Amount of ascites were completely abolished or decreased in 22 of 34 (64.7%) and positive peritoneal cytology changed to be a negative in 14 of 20 (70%) patients at the 2nd LHIPEC. Complete response was in 6 (12%), and peritoneal cancer indices (PCI) were significantly reduced from 14.3 ± 10.2 at the 1st LHIPEC to 10.8 ± 10.5 at the 2nd LHIPEC (p<0.05). Furthermore, total PCI scores on small bowel mesentery at 1st and 2nd LHIPEC were 6.56 ± 2.92 and 5.25 ± 3.78 (P=0.016). Conclusions: This study identified two outcomes. Diagnostic and therapeutic laparoscopy can be performed safely in patients with PM of GC. Laparoscopic HIPEC can be applied as a neoadjuvant treatment modality in order to reduce the tumor burden and disease control until complete managements to be achieved in patients with PM of GC.