Diffuse Malignant Peritoneal Mesothelioma Research Articles

Lymph Node Metastases in Diffuse Malignant Peritoneal Mesothelioma

Improved survival has been reported for diffuse malignant peritoneal mesothelioma (DMPM) treated by surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). The significance of lymph node involvement in this disease is still poorly understood. Prospectively collected clinical data on 83 consecutive patients with DMPM undergoing surgical cytoreduction and closed-abdomen HIPEC with cisplatin and doxorubicin were reviewed. Clinically suspicious lymph nodes were submitted to pathological examination. The impact of nodal involvement on survival was assessed by multivariate analysis; 14 clinicopathological control variables were tested. For the overall series, median follow-up was 52 months (range 1-126 months) and 5-year overall survival (OS) was 49.5%. Lymph nodes were submitted to pathological examination in 38 patients, being positive in 11 and negative in 27. Lymph nodes were not clinically suspicious and not sampled in 45 patients. Iliac (n = 7) and paracolic (n = 2) nodes were the most commonly involved nodes. OS was 18.0% for patients with pathologically positive nodes and 82.5% for those with pathologically negative nodes (P = 0.0024). On multivariate analysis, pathologically negative (versus positive/not assessed) nodes [hazard ratio (HR) = 2.81; 95% confidence interval (CI) = 1.12-7.05; P = 0.027], epithelial subtype (HR = 2.93; CI = 1.24-6.95; P = 0.015), mitotic count <or=5/50 high-power microscopic fields (HPF) (HR = 5.34; CI = 1.96-14.54; P = 0.001), and completeness of cytoreduction (HR = 2.06; CI = 1.19-3.56; P = 0.001) correlated with increased OS. Positive nodes (versus negative/not assessed) did not significantly correlate with survival. Pathologically negative nodes (as compared with pathological positive and not assessed), along with pathological and biological features, independently correlated with increased survival following comprehensive treatment. This suggests the need for careful node sampling when performing surgical cytoreduction for DMPM patients.

Diffuse Malignant Peritoneal Mesothelioma Presenting as Intestinal Obstruction

Diffuse malignant peritoneal mesothelioma (DMPM) represents 90% of all peritoneal forms of mesothelioma. It affects mainly patients 50-69 years old. In 50% of cases there is a history of asbestos exposure. The clinical presentation of the disease is not characteristic: nonspecific abdominal pain, weight loss, and abdominal distension are common. Ascites occurs in 90% of the patients. Bowel obstruction is a late manifestation. We present three patients with DMPM, without a history of asbestos exposure and without ascites, who presented with complete bowel obstruction. All patients underwent emergency operations, and palliative surgical procedures were performed. Each patient died within 3 to 6 months postoperatively.

Malignant peritoneal mesothelioma

Malignant mesothelioma is a highly aggressive neoplasm. The incidence of malignant mesothelioma is increasing worldwide. Diffuse malignant peritoneal mesothelioma (DMPM) represents one-fourth of all mesotheliomas. Association of asbestos exposure with DMPM has been observed, especially in males. The great majority of patients present with abdominal pain and distension, caused by accumulation of tumors and ascitic fluid. In the past, DMPM was considered a pre-terminal condition; therefore attracted little attention. Patients invariably died from their disease within a year. Recently, several prospective trials have demonstrated a median survival of 40 to 90 mo and 5-year survival of 30% to 60% after combined treatment using cytoreductive surgery and perioperative intraperitoneal chemotherapy. This remarkable improvement in survival has prompted new search into the medical science related to DMPM, a disease previously ignored as uninteresting. This review article focuses on the key advances in the epidemiology, diagnosis, staging, treatments and prognosis of DMPM that have occurred in the past decade.

Diffuse Malignant Peritoneal Mesothelioma: Failure Analysis Following Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

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.

Mésothéliome péritonéal : traitement par l’association chirurgie de cytoréduction et chimiothérapie hyperthermique intrapéritonéale

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

Consensus statement on peritoneal mesothelioma

Diffuse malignant peritoneal mesothelioma (DMPM) has been traditionally regarded as a rapidly lethal disease. Recently, several independent prospective trials have reported improved survival with an intensive loco-regional treatment strategy including cytoreductive surgery (CRS) along with peri-operative intra-peritoneal chemotherapy (PIC). However, most of the surgical data comes from mono-institutional phase I or II studies and there is a broad range of variability regarding inclusion criteria, cytoreductive surgical procedures, drugs, temperatures and methods of delivering the heated chemotherapy (open vs. closed abdomen). This manuscript critically analyze and discuss the results of a group of health care providers trying to achieve a consensus statement in the management of this group of patients. The main conflicting points regarding preoperative evaluation, patient eligibility, combined treatment methodology, postoperative follow-up and future investigational perspectives were summarized as a list of multiple-choice questions. A questionnaire was placed on the website of the "5(th) International Workshop on Peritoneal Surface Malignancies" and the group members voted via internet. The results were presented for further debate during a dedicated session of the Workshop. The general treatment guidelines and future investigational perspectives were defined.

Multiple Mechanisms of Telomere Maintenance Exist and Differentially Affect Clinical Outcome in Diffuse Malignant Peritoneal Mesothelioma

This study aims to investigate the prevalence of the two known telomere maintenance mechanisms, telomerase activity (TA) and alternative lengthening of telomeres (ALT), and to assess their prognostic relevance in diffuse malignant peritoneal mesothelioma (DMPM). In 44 DMPM specimens obtained from 38 patients, TA was determined using the telomeric repeat amplification protocol and ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies. The prognostic significance of telomere maintenance mechanisms was analyzed by Cox regression in the overall series and in a subset of 29 patients who underwent a uniform treatment regimen consisting of cytoreductive surgery and hyperthermic i.p. chemotherapy. Telomere maintenance mechanisms were detectable in 86.4% of DMPM: ALT or TA alone was found in 18.2% or 63.6% of lesions, respectively, whereas two cases (4.6%) were ALT+/TA+. TA and ALT proved to be inversely associated (P = 0.002). In the overall series, TA was prognostic for 4-year relapse (TA+ versus TA-, hazard ratio, 3.30; 95% confidence interval, 1.23-8.86; P = 0.018) and cancer-related death (TA+ versus TA-, hazard ratio, 3.56; 95% confidence interval, 1.03-12.51; P = 0.045), whereas ALT failed to significantly affect clinical outcome. These results held true also in the subset of patients submitted to uniform treatment with cytoreductive surgery and hyperthermic i.p. chemotherapy. Our results indicate that both known telomere maintenance mechanisms, TA and ALT, are present in DMPM and differentially affect patient prognosis.

Primary peritoneal mesotheliomas in children: a clinicopathological and immunohistochemical study of eight cases

To present eight cases of primary diffuse peritoneal malignant mesothelioma in children <15 years old, with a discussion of the pitfalls of this diagnosis in the paediatric age group. The cases were selected based on the following criteria: (i) primary peritoneal neoplasms confined grossly or radiographically to the abdominal cavity; (ii) negative history of previous or another associated malignancy; (iii) histopathological confirmation. All patients (five female, three male) presented clinically with symptoms of abdominal pain, distention and ascites. Grossly, the tumours showed multiple, diffuse peritoneal nodules. Histologically, seven cases corresponded to epithelioid mesotheliomas and one case displayed biphasic (epithelioid and spindle) cellular proliferation. Immunohistochemical studies for cytokeratin (CK) 5/6, calretinin and low-molecular-weight CK (CAM5.2) showed strong cytoplasmic positivity in the neoplastic cells. Three patients were treated by chemotherapy. On clinical follow-up, four patients with epithelioid mesotheliomas were alive and well from 12 to 18 months after initial diagnosis; one patient with a mixed (biphasic epithelioid/sarcomatoid) mesothelioma died of tumour 24 months after diagnosis. Peritoneal malignant mesothelioma in children is a rare condition that can introduce difficulties in histopathological diagnosis.

Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma

Tumors are a mixture of neoplastic and host stromal cells, which establish a microenvironment that contributes to tumor progression. In this study, the contribution of tumor-associated macrophages (TAMs) to tumor growth and metastasis was examined using an orthotopic, immunocompetent murine model of diffuse malignant peritoneal mesothelioma. The expression profile of cytokines and chemokines in solid tumors was consistent with a M2-polarized, TAM-mediated immunosuppressive microenvironment. TAMs were targeted using liposome-encapsulated clodronate (CLIP). Exposure of tumor spheroids to CM-DiI-labeled CLIP in situ confirms targeting of macrophages and not mesothelioma cells. Intraperitoneal (i.p.) delivery of CLIP produced apoptosis in tumor spheroids and solid tumors in contrast to delivery of liposome-encapsulated PBS or PBS. Mice received an i.p. injection of mesothelioma cells with CLIP delivered i.p. every 5 days. This treatment protocol produces a 4-fold reduction in the number of tumors, a 17-fold reduction in the relative tumor burden, and a 5-fold reduction in invasion and metastasis when compared with mice exposed to liposome-encapsulated PBS or PBS. Following transplantation of tumor spheroids and treatment with CLIP, mice showed a 4-fold reduction in the number of tumors and a 15-fold reduction in relative tumor burden. Mice bearing established tumors showed a 2-fold reduction in the number of tumors and relative tumor burden when exposed to half the previous dose of CLIP delivered by repeated i.p. injection. These reductions in tumor burden are statistically significant and identify TAMs as an important host-derived cell that contributes to growth, invasion, and metastasis in diffuse malignant peritoneal mesothelioma.

Acne inversa complicated by squamous cell carcinoma in association with diffuse malignant peritoneal mesothelioma arising in the absence of predisposing factors: a case report

Diffuse malignant peritoneal mesothelioma (DMPM) is a relatively rare neoplasm. Risk factors associated with its development include asbestos exposure, chronic irritation or inflammation of the peritoneum, abdominal radiotherapy, familial Mediterranean fever and simian virus 40. A familial segregation of this neoplasia has been reported in small villages of the Cappadocian region of Turkey, and it has been postulated that hereditary factors may predispose to mesothelioma, even with exposure to small amounts of asbestos. We report a case of DMPM, which apparently occurred in the absence of predisposing factors in a patient with a clinical history characterized by recurrent pre-sacral acne inversa of long duration. The association of this chronic inflammatory disease with DMPM has never been reported. The genetic locus for acne inversa has recently been identified within the 1p21.1-1q25.3 chromosomal region. Interestingly, frequent losses in chromosomal region 1p.21-22 have been found in mesothelioma as well. It is thus tempting to speculate that genetic mutations involving chromosome 1p.21-22 may account for the development of both diseases.

MUC4 is upregulated in ovarian carcinoma effusions and differentiates carcinoma cells from mesothelial cells

Using gene expression arrays, we recently showed that MUC4 expression is significantly higher in ovarian/primary peritoneal serous carcinoma (OC/PPC) compared to diffuse peritoneal malignant mesothelioma (DMPM). In the present study, we analyzed the anatomic site-related expression of MUC4 in OC/PPC and studied its prognostic role. We additionally studied the ability of MUC4 to differentiate between OC/PPC and reactive mesothelial cells (RMC). OC/PPC effusions (n = 142) and benign reactive effusions (n = 10) were immunostained for MUC4 expression. Immunoreactivity was scored in carcinoma cells and RMC and was compared with tumor cell expression in 60 previously studied primary carcinomas and solid metastases and analyzed for association with clinicopathologic parameters, including survival. MUC4 was detected in carcinoma cells in 141/142 (99%) effusions, with comparable expression in peritoneal and pleural effusions. RMC were present in 72 malignant effusions and were MUC4-negative in all specimens, as well as in the 10 reactive effusions. MUC4 expression in carcinoma cells in effusions was significantly higher than in primary carcinomas and solid metastases (P < 0.001). Higher MUC4 expression was seen in tumors from older (>60 year) patients (P = 0.049). No association was found between MUC4 expression and other clinicopathologic parameters, including survival. MUC4 is universally expressed in OC/PPC effusions and is upregulated at this anatomic site compared to primary carcinomas and solid metastases. The data in the present study, together with our earlier report, show that MUC4 is an excellent marker for differentiating OC/PPC from both benign and malignant mesothelial cells.

Malignant peritoneal mesothelioma: treatment with maximal cytoreductive surgery plus intraperitoneal chemotherapy

To report survival results in patients with diffuse malignant peritoneal mesothelioma (MPM) treated with maximal cytoreductive surgery followed by immediate intraperitoneal chemotherapy, and to compare them with the median survival of 12-24 months obtained with the standard treatment based on systemic chemotherapy. Twenty-six patients underwent this new regional approach and a median follow-up of 55 months was achieved after this treatment. Complete cytoreductive surgery (residual disease < 2 mm) was performed in all but one patient. Intraperitoneal chemotherapy was performed with hyperthermia (4245 degrees C) and oxaliplatin in 22 patients. The last 12 patients additionally received irinotecan. Data were prospectively verified and retrospectively analyzed. One patient died postoperatively (4%), and morbidity attained 54%. The median survival exceeded 100 months and the overall 5-year survival rate was 63%. This small series lacks the statistical power required to conduct a well-grounded study on prognostic factors, particularly as the completeness of the surgery is not analyzable here. However, the low-grade histological types had a better disease-free survival rate that was of borderline significance compared to their high-grade counterparts. This new approach combining complete cytoreductive surgery considerably increases the survival of patients with MPM compared with the standard treatment based on systemic chemotherapy.

Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Colorectal Carcinomatosis: If at First You Don't Succeed...

The management and outcomes of stage IV colorectal cancer have changed significantly over the past 5–10 years. The advent of relatively effective, multimodality regimens of 5-fluorouracil and leucovorin combined with cytotoxic agents (e.g., oxaliplatin or irinotecan) and targeted therapies (e.g., bevacizumab or cetuximab) has resulted in unprecedented rates of both tumor response and patient survival. Simultaneously the indications for surgery in the management of hepatic and pulmonary metastases from colorectal cancer continue to expand. However, for patients with carcinomatosis from colorectal cancer, the view remains generally nihilistic for a number of reasons. First, the historical life expectancy of patients with colorectal carcinomatosis was a dismal 6–7 months. Second, surgery has traditionally not been shown to play any significant role other than selective palliation. Third, despite the overall results of the more efficacious chemotherapy regimens, the actual benefit to patients with carcinomatosis has yet to be determined. Consequently, while evidence-based guidelines recommending neoadjuvant chemotherapy followed by surgery for the management of patients with hepatic and pulmonary metastases are readily available, there are no management guidelines for patients with carcinomatosis. Despite this daunting backdrop, significant efforts are being made to improve the outcome of patients with carcinomatosis. One such effort is the use of a combined treatment approach involving cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC). Currently, this approach is gaining recognition as a treatment option for a variety of peritoneal surface-based malignancies. Significant improvements in disease-free and overall survival from CRS and PIC have been demonstrated in patients with peritoneal dissemination of appendiceal and ovarian cancers and diffuse malignant peritoneal mesothelioma. In fact, CRS and PIC are considered by many to be the standard of care for select patients with peritoneal-based disease from these malignancies. CRS and PIC have also been used in the treatment of carcinomatosis from colorectal cancer with some centers publishing 5-year survival rates of 30% or higher. For such a historically hopeless clinical situation, these results seem almost miraculous. Consequently, and despite a paucity of high-level evidence, a consensus statement has been published advocating the use of CRS and PIC in select colorectal patients with carcinomatosis. In ‘‘Failure Analysis of Recurrent Disease Following Complete Cytoreduction and Perioperative Intraperitoneal Chemotherapy in Patients with Peritoneal Carcinomatosis from Colorectal Cancer,’’ Bijelic et al. 15 are the first to analyze the anatomic distribution, timing, and outcomes of recurrent peritoneal disease after complete cytoreduction and PIC for peritoneal carcinomatosis from colorectal cancer. The data are derived from a single-institution experience, spanning Received July 10, 2007; accepted July 11, 2007; published online: August 29, 2007. Address correspondence and reprint requests to: Paul F. Mansfield, MD; E-mail: ansmith@mdanderson.org

Advances in diffuse malignant peritoneal mesothelioma

Malignant mesothelioma is a highly aggressive neoplasm. The incidence of malignant mesothelioma is increasing worldwide. Diffuse malignant peritoneal mesothelioma (DMPM) represents one-fourth of all mesotheliomas. Association of asbestos exposure with DMPM has been observed, especially in males. A great majority of patients present with abdominal pain and distension, caused by accumulation of tumors and ascitic fluid. In the past, DMPM was considered a pre-terminal condition; therefore attracted little attention. Patients invariably died from their disease within a year. Recently, several prospective trials have demonstrated median survival of 40 to 90 months and 5-year survival of 30% to 60% after the combined treatment using cytoreductive surgery and perioperative intraperitoneal chemotherapy. This improvement in survival has prompted new searches into the medical science related to DMPM, a disease previously ignored as uninteresting. This review article focuses on the key advances in the epidemiology, diagnosis, staging, treatments and prognosis of DMPM that have occurred in the past decade.

SO13P CYTOREDUCTIVE SURGERY COMBINED WITH PERIOPERATIVE INTRAPERITONEAL CHEMOTHERAPY FOR DIFFUSE MALIGNANT PERITONEAL MESOTHELIOMA – ANALYSIS OF 100 CONSECUTIVE PATIENTS FROM A PROSPECTIVE DATABASE

Purpose Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and invariably fatal neoplasm. Some studies have shown that cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) achieved an improved survival, as compared to historical controls. However, prognostic factors for survival have not been well defined.Methodology One hundred patients with DMPM underwent CRS and PIC at the Washington Center Institute. The inclusion criteria for surgery consisted of histological diagnosis of DMPM, age &lt; 80 years, good performance status, and signed informed consent. All data were collected prospectively. Eight clinical and eight treatment‐related prognostic factors were analyzed for survival.Results The overall median survival was 52 months (range 1 to 148 months), with 1‐, 3‐, 5‐ and 7‐year survival of 78%, 55%, 46% and 39%, respectively. Univariate analysis showed that gender (p &lt; 0.001), peritoneal cancer index (p = 0.009), lymph node status (p &lt; 0.001), distant metastasis (p = 0.026), histological type (p &lt; 0.001), intraoperative blood loss (p = 0.035), completeness of cytoreduction (p &lt; 0.001), intraperitoneal chemotherapy regimen (p = 0.041), and redo cytoreductive surgery (p = 0.022) were significant for survival. Multivariate analysis demonstrated that female gender, absence of lymph node involvement, epithelial/multicystic type, and adequate cytoreduction were independently associated with an improved survival.Conclusions CRS and PIC showed an improved survival for DMPM, as compared to historical controls. Long‐term survival was associated with female gender, absence of lymph node involvement, epithelial or multicystic type and adequate cytoreduction.

Prognostic Significance of Histomorphologic Parameters in Diffuse Malignant Peritoneal Mesothelioma

Diffuse malignant peritoneal mesothelioma is currently regarded as a rare and lethal primary tumor arising from the peritoneal membrane. In the past, treatment plans with variable combinations of surgery and systemic chemotherapy were associated with a median survival of approximately 1 year. Standardized treatments using cytoreductive surgery and perioperative intraperitoneal chemotherapy have extended this survival. To critically analyze the prognostic significance of histomorphologic parameters as a determinant of survival. Sixty-two consecutive patients with diffuse malignant peritoneal mesothelioma in whom data were prospectively accumulated were retrospectively analyzed by 14 different histomorphologic parameters. The influences of these pathologic characteristics on survival were critically statistically evaluated. In a univariate analysis, histologic type, nuclear/nucleolar size, stroma, depth of invasion into the bowel, atypical mitoses, mitotic index, necrosis, lymph node involvement, and chromatin patterns were found to be significant. In the multivariate analysis, histologic type and nuclear/nucleolar size remained as determinant histomorphologic characteristics. Use of biphasic/sarcomatoid histologic type as a poor prognostic characteristic was limited in that only 8% of patients showed this histology. Histomorphologic parameters carry prognostic significance in predicting the survival of patients with diffuse malignant peritoneal mesothelioma when treated in a standardized fashion using cytoreductive surgery and perioperative intraperitoneal chemotherapy. Nuclear/nucleolar size was found to be a reliable histomorphologic assessment available to assess prognosis in these patients.

Prognostic significance of histomorphologic parameters in diffuse malignant peritoneal mesothelioma.

Abstract Context.—Diffuse malignant peritoneal mesothelioma is currently regarded as a rare and lethal primary tumor arising from the peritoneal membrane. In the past, treatment plans with variable combinations of surgery and systemic chemotherapy were associated with a median survival of approximately 1 year. Standardized treatments using cytoreductive surgery and perioperative intraperitoneal chemotherapy have extended this survival. Objective.—To critically analyze the prognostic significance of histomorphologic parameters as a determinant of survival. Design.—Sixty-two consecutive patients with diffuse malignant peritoneal mesothelioma in whom data were prospectively accumulated were retrospectively analyzed by 14 different histomorphologic parameters. The influences of these pathologic characteristics on survival were critically statistically evaluated. Results.—In a univariate analysis, histologic type, nuclear/nucleolar size, stroma, depth of invasion into the bowel, atypical mitoses, mitotic index...

Gene Expression Signatures Differentiate Ovarian/Peritoneal Serous Carcinoma from Diffuse Malignant Peritoneal Mesothelioma

Ovarian/primary peritoneal serous carcinoma (OC/PPC) and diffuse peritoneal malignant mesothelioma (DMPM) are highly aggressive tumors that are closely related morphologically and histogenetically. It remains unclear whether both tumors are molecularly distinct neoplasms. The current study compared global gene expression patterns in OC/PPC and DMPM. Ten OC/PPC and five DMPM effusions were analyzed for gene expression profiles using the Affymetrix U133 Plus 2 arrays and the dCHIP analysis program. Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry. Unsupervised hierarchical clustering using all 54,675 genes in the array classified the samples into two groups: DMPM specimens versus OC/PPC specimens. A total of 189 genes that were differentially expressed in these two groups were selected based on statistical significance. Genes overexpressed in DMPM (n = 68) included calretinin, vitronectin, claudin 15, alpha4 laminin, hyaluronan synthase 1, cadherin 11, RAB7, v-maf, and the epidermal growth factor-containing fibulin-like extracellular matrix protein 1. Genes overexpressed in OC/PPC (n = 121) included insulin-like growth factor II (IGF-II); IGF-II binding protein 3; cyclin E1; folate receptors 1 and 3; RAB25; MUC4; endothelin-1; CD24; kallikreins 6, 7, and 8; claudins 3, 4, and 6; Notch3; and MMP-7. Quantitative real-time PCR validated the differential expression of 13 genes, and immunohistochemistry confirmed the differences for four gene products. Expression profiling separates OC/PPC from DMPM and identifies a number of genes that are differentially expressed in these tumors. The molecular signatures unique to OC/PPC and DMPM should provide a molecular basis to study both tumors and new potential markers for facilitating their differential diagnosis.

Prognostic Indicators for Patients Undergoing Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Diffuse Malignant Peritoneal Mesothelioma†

This study evaluates clinical, radiological and histopathological prognostic indicators for survival of patients undergoing cytoreductive surgery and perioperative intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma (DMPM). Sixty-two consecutive patients with DMPM underwent cytoreduction and perioperative intraperitoneal chemotherapy at the Washington Cancer Institute. Twenty-six clinical, radiological and histopathological parameters were analyzed in univariate and multivariate analyses using overall survival as an endpoint. The overall survival was 79 months (range 1-143 months), with 1-, 3- and 5-year survival rates of 84%, 58% and 50%, respectively. The following 14 prognostic variables were significant for survival in the univariate analysis: gender (P = .045), peritoneal cancer index (P = .038), completeness of cytoreduction score (P = .010), interpretive CT findings of the small bowel and mesentery (P = .001), mesothelioma cell type (P < .001), mesothelioma nuclear size (P < .001), nuclear/cytoplasmic ratio (P < .001), mitotic count (P < .001), atypical mitosis (P < .001), chromatin pattern (P < .001), cellular necrosis (P < .001), perineural invasion (P = .037), stroma pattern (P < .001) and depth of invasion (P = .014). In the multivariate analysis, the only factor that was independently associated with an improved survival after cytoreduction and perioperative intraperitoneal chemotherapy was mesothelioma nuclear size. Mesothelioma nuclear size was the dominant factor determining overall survival in patients with DMPM. A histopathological staging system based on measurement of the nuclear size was proposed.

Morbidity and Mortality Assessment of Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Diffuse Malignant Peritoneal Mesothelioma—A Prospective Study of 70 Consecutive Cases

Although many reports regarding morbidity and mortality of cytoreductive surgery plus perioperative intraperitoneal chemotherapy are available, there are no prospective data on morbidity and mortality limited to patients with diffuse malignant peritoneal mesothelioma (DMPM). This prospective morbidity and mortality assessment was performed on 70 consecutive cytoreductive procedures with perioperative intraperitoneal chemotherapy for DMPM. Forty-seven adverse events by eight categories were rated from grades I to IV with increasing severity. Grade I morbidity was self-limiting; grade II required medical treatments; grade III required an invasive intervention; grade IV required returning to the operating room or intensive care management. Risk factors for grades III and IV morbidity were determined. The perioperative mortality rate was 3%. The grades III and IV morbidity rates were 27 and 14%, respectively. Primary colonic anastomosis (P = 0.028), more than four peritonectomy procedures (P = 0.015), duration of the operation of more than 7 h (P = 0.027) were the risk factors for grade IV morbidity. Survival analysis of these 70 patients was provided. The morbidity and mortality results for cytoreductive surgery and perioperative intraperitoneal chemotherapy for patients with DMPM were within the acceptable range for major gastrointestinal surgery. Grade IV morbidity was associated with more extensive cytoreduction.