Yonemura Y, Tsukiyama G, Miyata R, Sako S, Endou Y, Hirano M, Mizumoto A, Matsuda T, Takao N, Ichinose M, Miura M, Hagiwara A, Li Y.

NPO Organization to Support Peritoneal Dissemination Treatment.

Abstract

A total of 521 patients with peritoneal carcinomatosis (PC) were treated by peritonectomy and perioperative chemotherapy. Each of the 95, 58, 316, 31, 10 and 11 patients were from gastric, colorectal, appendiceal, ovarian, small bowel cancer and mesothelioma, respectively. The distribution and volume of PC are recorded by the Sugarbaker peritoneal carcinomatosis index( PCI). Peritonectomy was performed with a radical resection of the primary tumor and all gross PC with involved organs, peritoneum, or tissue that was deemed technically feasible and safe for the patient. The postoperative major complication of grade 3 was found in 14%, and total 30 – day mortality was 2.7%. The survival of gastric cancer patients with a PCI score ≤ 6 was significantly better than those with a PCI score ≥ 7. In appendiceal neoplasm, patients with PCI score less than 28 showed significantly better survival than those with PCI score greater than 29. The survival of colorectal cancer patients with a PCI score ≥ 11 was significantly poorer than those with a PCI score ≤ 10. Among the various prognostic factors in appendiceal neoplasm and gastric cancer patients, CC – 0 complete cytoreduction was the most important independent prognostic factor. Peritonectomy is done to remove macroscopic disease and perioperative intraperitoneal chemotherapy to eradicate microscopic residual disease aiming to remove disease completely with a single procedure. Peritonectomy combined with perioperative chemotherapy may achieve long – term survival in a selected group of patients with PC. The higher mortality rate underlines this necessarily strict selection that should be reserved to experienced institutions.

Cavallaro A, Berretta M, Lo Menzo E, Cavallaro V, Zanghì A, Di Vita M, Cappellani A.

Department of Surgery, University of Catania, Catania, Italy.

Abstract

Benign multicystic peritoneal mesothelioma (BMPM) is a rare disease with good short-term prognosis and rare malignant transformation. However, its biological significance remains unexplained. A neoplastic origin is considered by many authors to require a surgical excision, based on the high recurrence and progressive growth rate of the tumors. However, alternative or integrative treatment options have also been proposed. A 45-year-old woman presented to our unit with a history of occasional discomfort and pain in the left hip. On physical examination, we noticed a tough-elastic, fixed mass located in the iliac fossa. Computed tomography scan detected a mass with multiseptated cystic-like areas. Due to the similarity of these findings to a primitive sarcomatous tumor of the retroperitoneum, an arteriographic study was also performed. The patient underwent en bloc resection of the mass, including a segment of the sigmoid colon. The final pathologic diagnosis was cystic mesothelioma. Further studies are needed to better understand the etiology and pathogenesis of this rare disease, and to define a more tailored treatment plan.

Keywords: Benign multicystic peritoneal mesothelioma – Calretinin – Cytokeratin

Ana Slipicevic, MSca, Geir Frode Øy, MScb, Inger Cecilie Askildt, BSca, Arild Holth, BSca, Ellen Hellesylt, BSca, Vivi Ann Flørenes, PhDa, Ben Davidson, MD, PhD

Division of Pathology, Norwegian Radium Hospital, Rikshospitalet Medical Center, N-0310 Oslo, Norway.

Abstract

We recently reported on higher expression of the insulin-like growth factor pathway genes IGF-II and IGFBP3 in serous ovarian/peritoneal carcinoma compared to malignant peritoneal mesothelioma. The present study analyzed the diagnostic and clinical role of these proteins in serous effusions. Effusions (n = 327), including 294 carcinomas (205 ovarian, 48 breast, 17 cervical/endometrial, 12 lung, 12 gastrointestinal/genitourinary) and 33 malignant mesotheliomas, were immunostained for insulin-like growth factor-II and insulin-like growth factor binding protein-3. Surgical ovarian carcinoma (n = 124) and peritoneal mesothelioma (n = 18) specimens were additionally studied. Insulin-like growth factor binding protein-3 levels were measured in 148 effusion supernatants (114 ovarian carcinomas, 18 breast carcinomas, 16 mesotheliomas) using enzyme-linked immunosorbent assay. Insulin-like growth factor binding protein-3 promoter methylation was analyzed in 11 ovarian carcinoma effusions. Insulin-like growth factor binding protein-3 (P = .002) and insulin-like growth factor-II (P < .001) expression by immunohistochemistry was significantly higher in carcinomas compared to mesotheliomas, with diagnostic sensitivity of 77% and 70% and specificity of 55% and 70%, respectively. In surgical specimens, insulin-like growth factor binding protein-3 expression was higher in ovarian carcinomas compared to peritoneal mesotheliomas (P = .007), whereas insulin-like growth factor-II expression was comparable (P = .505). Insulin-like growth factor binding protein-3 levels by enzyme-linked immunosorbent assay were comparable in the 3 analyzed cancer types. Insulin-like growth factor binding protein-3 promoter methylation was found in 6 of 11 effusions. High insulin-like growth factor binding protein-3 expression in prechemotherapy and high insulin-like growth factor-II expression in postchemotherapy ovarian carcinoma effusions correlated with poor overall survival (P = .031 and P = .024, respectively). Insulin-like growth factor-II expression in postchemotherapy effusions was an independent prognostic factor in Cox multivariate analysis (P = .04). In conclusion, insulin-like growth factor-II and insulin-like growth factor binding protein-3 are more frequently expressed in metastatic carcinomas compared to mesothelioma in effusions but are less specific than currently used markers. Insulin-like growth factor-II and insulin-like growth factor binding protein-3 may be novel prognostic markers in metastatic ovarian carcinoma.

Keywords: Insulin-like growth factor, Effusions, Carcinoma, Mesothelioma, Survival

Passot G, Cotte E, Brigand C, Beaujard AC, Isaac S, Gilly FN, Glehen O.

Service de chirurgie générale digestive et endocrinienne, centre hospitalier Lyon Sud (CHLS) – Lyon.

Abstract

Diffuse malignant peritoneal mesothelioma is a rare and lethal disease. Locoregional treatments combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) seem to improve prognosis.

Methods: Cytoreductive surgery and HIPEC was performed in 22 patients at the Centre Hospitalier-Lyon Sud between 1989 and 2006. A retrospective analysis of survival was carried out to assess clinical and histological prognostic factors.

Results: Nineteen patients with diffuse malignant peritoneal mesothelioma were included (16 epithelial, 3 biphasic and 3 multicystic forms). Sixteen patients presented stage 3 or 4 peritoneal carcinomatosis according to the Gilly classification. Optimal cytoreductive surgery was performed for 11 patients (complete macroscopic resection or residual tumor nodules less than 2.5mm). No post-operative deaths occurred but 9 patients (47%) presented grade III or IV post-operative complications. The overall median survival was 36.9 months; completeness of cytoreduction was the only significant prognostic factor.

Conclusion: Cytoreductive surgery combined with HIPEC may improve the length of survival for patients with diffuse malignant peritoneal mesothelioma; such patients should be treated in specialized centers.

Keywords: Peritoneal Mesothelioma , Treatment , Cytoreductive surgery , Hyperthermic intraperitoneal chemotherapy

Moore AJ, Parker RJ, Wiggins J.

Department of Respiratory Medicine, Wexham Park Hospital, Wexham, Slough, Berkshire, UK. a.moore@ic.ac.uk

Abstract

Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10-20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational “environmental” exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis.

Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M.

Laboratory of Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.

Abstract

Ovarian cancer and malignant mesothelioma frequently express both mesothelin and CA125 (also known as MUC16) at high levels on the cell surface. The interaction between mesothelin and CA125 may facilitate the implantation and peritoneal spread of tumors by cell adhesion, whereas the detailed nature of this interaction is still unknown. Here, we used truncated mutagenesis and alanine replacement techniques to identify a binding site on mesothelin for CA125. We examined the molecular interaction by Western blot overlay assays and further quantitatively analyzed by enzyme-linked immunosorbent assay. We also evaluated the binding on cancer cells by flow cytometry. We identified the region (296-359) consisting of 64 amino acids at the N-terminal of cell surface mesothelin as the minimum fragment for complete binding activity to CA125. We found that substitution of tyrosine 318 with an alanine abolished CA125 binding. Replacement of tryptophan 321 and glutamic acid 324 with alanine could partially decrease binding to CA125, whereas mutation of histidine 354 had no effect. These results indicate that a conformation-sensitive structure of the region (296-359) is required and sufficient for the binding of mesothelin to CA125. In addition, we have shown that a single chain monoclonal antibody (SS1) recognizes this CA125-binding domain and blocks the mesothelin-CA125 interaction on cancer cells. The identified CA125-binding domain significantly inhibits cancer cell adhesion and merits evaluation as a new therapeutic agent for preventing or treating peritoneal malignant tumors.

Baratti D, Kusamura S, Cabras AD, Dileo P, Laterza B, Deraco M.

Department of Surgery, National Cancer Institute, Milan, Italy.

Abstract

Improved survival has been reported for diffuse malignant peritoneal mesothelioma (DMPM) treated by cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). The issue of treatment failure has never been extensively addressed. The present study assessed the failure pattern, management, and outcome of progressive DMPM following comprehensive treatment. Clinical data on 70 patients with DMPM undergoing cytoreduction and HIPEC were prospectively collected; after a median follow-up of 43 months, disease progression occurred in 38 patients. Progressive disease distribution in 13 abdominopelvic regions was analyzed. In 28 patients undergoing adequate cytoreduction (residual tumor < or =2.5 mm), clinicopathological factors correlating to disease progression in each region were investigated. Median time to progression was 9 months [95% confidence interval (CI) 1.6-35.9]. Median survival from progression was 8 months (95% CI 4-16.2). The failure pattern was categorized as peritoneal progression (n = 31), liver metastases (n = 1), abdominal lymph-node involvement (n = 2), pleural seeding (n = 4). Small bowel was the single site most commonly involved (n = 27). Residual tumor < or =2.5 mm (versus no visible) was the only independent risk factor for disease progression in epigastric region (P = 0.047), upper ileum (P = 0.029), upper jejunum (P = 0.034), and lower jejunum (P = 0.002). Progressive disease was treated with second HIPEC in 3 patients, debulking in 4, systemic chemotherapy in 16, and supportive care in 15. At multivariate analysis, time to progression <9 months (P = 0.009), poor performance status (P = 0.005), and supportive care (P = 0.003) correlated to reduced survival from progression. We conclude that minimal residual disease, compared with macroscopically complete cytoreduction, correlated to failure in critical anatomical areas, suggesting the need for maximal cytoreductive surgical efforts. In selected patients, aggressive management of progressive disease seems worthwhile.

Miao N, Pingpank JF, Alexander HR, Royal R, Steinberg SM, Quezado MM, Beresnev T, Quezado ZM.

Department of Anesthesia and Surgical Services, National Institutes of Health Clinical Center, National Institutes of Health, 10 Center Drive, MSC-1512, Building 10, Room 2C624, Bethesda, MD 20892-1512, USA.

Abstract

Cytoreductive surgery and continuous hyperthermic peritoneal perfusion (CHPP) involve the conduct of a complex surgical procedure and delivery of high-dose hyperthermic chemotherapy to the peritoneum. This therapeutic modality has been shown to benefit patients with peritoneal carcinomatosis resulting from gastrointestinal and ovarian tumors and mesothelioma. However, it is unknown whether the primary disease (mesothelioma versus peritoneal carcinomatosis) affects hemodynamic and metabolic perturbations during the course of CHPP with cisplatin. We examined the perioperative course of patients undergoing CHPP with cisplatin and evaluated the effect of primary diagnosis (mesothelioma versus peritoneal carcinomatosis) on hemodynamic and metabolic parameters in response to peritoneal perfusion. Sixty-nine mesothelioma and 100 peritoneal carcinomatosis patients underwent 169 consecutive cytoreduction and CHPP procedures with general anesthesia. During CHPP, patients from both groups developed significant increases in central venous pressure, and heart rate, decreases in mean arterial pressure (all P < 0.0001), metabolic acidosis with significant decreases in pH and bicarbonate (P < 0.0001), deterioration of gas exchange with significant increases in PaCO₂ and oxygen alveolar–arterial gradient (P < 0.0001), and significant increases in activated partial thromboplastin time (aPTT) and prothrombin time (PT) and decreases in hematocrit and platelet counts (all P < 0.0001). However, patients with mesothelioma had lesser increases in temperature (P < 0.01) and heart rate (P < 0.0001) and lesser decreases in hematocrit (P = 0.0013) during CHPP and greater decreases in sodium bicarbonate (P = 0.0082) after completion of CHPP compared with patients with peritoneal carcinomatosis. We conclude that the transient hemodynamic and metabolic perturbations associated with cytoreductive surgery and CHPP with cisplatin can vary according to the primary diagnosis (mesothelioma versus peritoneal carcinomatosis) warranting this therapy.

Carteni G, Manegold C, Garcia GM, Siena S, Zielinski CC, Amadori D, Liu Y, Blatter J, Visseren-Grul C, Stahel R.

Cardarelli Hospital, Medical Oncology, Via Cardarelli 9, 80100 Naples, Italy. giacomo.carteni@ospedalecardarelli.it

Abstract

Aim: Peritoneal mesothelioma (PM) has rarely been studied. The Expanded Access Program (EAP) provided access to 109 patients with PM.

Methods: This was a nonrandomized, open-label study conducted in chemo-naïve or previously treated patients with PM not amenable to curative surgery. Patients received pemetrexed (PEM) 500mg/m2 alone or with cisplatin (CIS) 75mg/m2 or carboplatin (CARBO) AUC 5 every 21 days, supplemented with standard vitamin B12, folate, and dexamethasone.

Results: Response rates (95% CI) for PEM, PEM/CIS, and PEM/CARBO were 12.5% (3.5, 29.0), 20.0% (7.7, 38.6), and 24.1% (10.3, 43.5), respectively. Median survival for PEM was 10.3 months. One-year survival rates for PEM/CIS and PEM were 57.4% (95% CI: 10.3, 100) and 41.5% (95% CI: 4.6, 78.4), respectively, and were not available for PEM/CARBO. Anemia was the most common serious adverse event (6.4%). Neutropenia (34.6%) was the most frequent CTC grade 3 or 4 toxicity reported.

Concluding statement: PEM with or without a platinum agent was both active and well tolerated in patients with peritoneal mesothelioma.

Keywords: Peritoneal mesothelioma, Pemetrexed, Platinum, Cisplatin, Carboplatin, Compassionate-use program, Expanded Access Program (EAP).

Chua TC, Yan TD, Morris DL.

Department of Surgery, University of New South Wales, St George Hospital, Kogarah, Sydney, NSW, Australia.

Abstract

Aims: Peritoneal mesothelioma is a rapidly progressing malignancy with a median survival of 6-12 months. Palliative surgery, chemotherapy and radiotherapy are futile and have not shown to improve survival. This paper reports the outcomes of cytoreductive surgery (CRS) and Hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of this disease.

Patients and Methods: An observational study of 20 patients with peritoneal mesothelioma treated with CRS and HIPEC at the St George Hospital, Sydney, Australia. Survival analysis was performed using the Kaplan-Meier method and comparison using the Log Rank test.

Results: There were six females. The mean age was 55.7 (9.0) years. The median survival was 29.5 (0.46-87.2) months with 1- and 3-year survival of 78.2% and 46.3%, respectively. Survival was found to be influenced by completeness of cytoreduction (P = 0.02) and histological subtype (P = 0.01). Patients with epitheloid peritoneal mesothelioma who had a CC0 had a median survival of 87.2 months.

Conclusion: CRS and HIPEC is a treatment option for peritoneal mesothelioma. Patients with epithelioid tumor who undergo complete cytoreduction may potentially benefit from this procedure.

Keywords: cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, mesothelioma, peritoneal neoplasms, peritonectomy