Multicystic mesothelioma: Operative and long-term outcomes with cytoreductive surgery and hyperthermic intra peritoneal chemotherapy.

BACKGROUND: Multicystic peritoneal mesothelioma (MCPM) is an extremely rare disease with 40-50% rate of recurrence after surgical debulking. Due to the recurrent nature of the disease, the option of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) was offered for this condition. In the present study we aimed to describe the outcomes of this strategy in a single center cohort. METHODS: We retrospectively reviewed a prospectively collected database of all patients with MCPM that underwent the combined procedure in our center. Clinical presentation, operative procedures and outcomes were reviewed. RESULTS: Between August 1997 and October 2017, 19 patients with MCPM underwent 20 cytoreduction and HIPEC procedures in our center. The majority of the patients were females (n = 17, 89%), and mean age was 42, as reported in other series. Disease extent, as measured by mean peritoneal carcinomatosis index (PCI) was 15.5 ± 9.9 and total number of procedures performed 6.7 ± 2.6. Major complications occurred in 3 (15%) patients, with no perioperative mortality. After a median of follow-up of 69 months (range 4-220) all patients were alive and 4 patients had recurrence (21%). Patients with high PCI (defined by median PCI) had shorter recurrence free survival (RFS) than patient with low PCI (mean RFS = 106.4 ± 6.6 for high PCI vs. 125.6 ± 34.1 for low PCI, p = 0.03). CONCLUSION: Cytoreduction and HIPEC offer low recurrence rate and prolonged mean RFS for patients with MCPM. The combined procedure can be offered with acceptable morbidity in specialized centers.

The Role of Ki-67 and Pre-cytoreduction Parameters in Selecting Diffuse Malignant Peritoneal Mesothelioma (DMPM) Patients for Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND: We conducted a prognostic analysis of preoperative parameters and Ki-67 determination to develop selection criteria for cytoreductive surgery (CRS) and HIPEC in patients with diffuse malignant peritoneal mesothelioma (DMPM). METHODS: DMPM patients treated with CRS and HIPEC at NCI of Milan participated in this study. Multivariate analysis was conducted using Cox proportional hazard model and conditional inference tree method to select independent predictors of overall survival (OS) from the followings pre-cytoreduction parameters: age, sex, ECOG performance status, Charlson comorbidity index, previous systemic chemotherapy, CA-125, histological subtype (epithelioid vs. biphasic/sarcomatoid), Ki-67 (determined with immunohistochemistry), and peritoneal cancer index (PCI). RESULTS: A total of 117 patients (male/female: 67/50) with median age of 60.5 (range 22-75) years were included. Eighty-three patients had ECOG performance status = 0, median Charlson comorbidity index was 4 (range 2-9), and 102 cases had epithelioid subtype. Median Ki-67 was 5 % (range 1-60). Ninety-four (80.3 %) cases were optimally cytoreduced. The Cox analysis identified Ki-67, PCI, and histological subtype as independent prognosticators of OS. Conditional inference tree method identified three prognostic subsets: (I) Ki-67 ≤ 9 %; (II) Ki-67 > 9 % and PCI ≤ 17; and (III) Ki-67 > 9 % and PCI > 17. The median OS for subsets I, II, and III were, 86.6, 63.2, and 10.3 months, respectively. CONCLUSIONS: Ki-67 is a powerful prognosticator that allows, along with PCI, and histological subtype, a good prediction of OS in patients with DMPM. Patients with Ki-67 > 9 % and PCI > 17 are unlikely to benefit from the procedure and should be considered for other treatment protocols.

Diffuse malignant peritoneal mesothelioma: long-term survival with complete cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND: Prognosis of diffuse malignant peritoneal mesothelioma (DMPM) has been recently improved by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). As with other peritoneal surface malignancies, the survival benefit is maximal when a complete surgical cytoreduction is achieved, but additional factors predicting long-term outcome are still poorly understood. We sought to investigate outcome and prognostic factors in patients with DMPM treated by complete cytoreduction and HIPEC. METHODS: From a prospective database, we selected 108 patients with DMPM undergoing complete cytoreduction (residual tumour nodules ≤2.5 mm) and closed-abdomen HIPEC with cisplatin and doxorubicin or mitomycin-C. Twenty-seven patient-, tumour- and treatment-related variables were assessed by multivariate analysis with respect to overall (OS) and progression-free (PFS) survival. A panel of immunohistochemical markers was tested. RESULTS: Operative mortality was 1.9% and major morbidity 38.9%. Median follow-up was 48.8 months (95% confidence interval (CI) 37.1-60.6). Median OS and PFS were 63.2 months (95%CI 29.6-96.7) and 25.1 months (95%CI 5.1-45.1). The survival curve reached a plateau after 7 years, representing 19 actual survivors of 39 patients (43.6%) with potential follow-up ≥7 years. Cytokeratin 5/6, calretinin, Wilms tumour-1 (WT-1), podoplanin and epithelial growth factor receptor (EGFR) were mostly positive. At multivariate analysis, epithelial histological subtype, negative lymph-nodes, ≤10% Ki67-positive cells correlated with both increased OS and PFS. Positive podoplanin correlated to increased PFS. CONCLUSIONS: After complete cytoreduction and HIPEC, prognosis of DMPM is primarily dependent on pathologic and biologic features. Patients with DMPM surviving ≥7 years appeared to be cured. Cure rate was 43.6%. Proliferative index and podoplanin may be used for prognostic stratification.

Cytoreductive surgery with selective versus complete parietal peritonectomy followed by hyperthermic intraperitoneal chemotherapy in patients with diffuse malignant peritoneal mesothelioma: a controlled study.

BACKGROUND: Combined treatment involving peritonectomy procedures, multivisceral resections, and hyperthermic intraperitoneal chemotherapy (HIPEC) has reportedly resulted in survival benefit for peritoneal surface malignancies, including diffuse malignant peritoneal mesothelioma (DMPM). Many unanswered questions remain regarding the surgical options in the management of DMPM. The aim of this case­control study was to assess the impact of the type and extent of parietal peritonectomy on survival and operative outcomes. METHODS: Thirty patients with DMPM undergoing selective parietal peritonectomy (SPP) of macroscopically involved regions, and 30 matched patients undergoing routine complete parietal peritonectomy (CPP), regardless of disease distribution, were retrospectively identified from a prospective database. RESULTS: Groups were comparable for all characteristics, except for a higher proportion of patients treated before July 2003 and undergoing preoperative systemic chemotherapy in the SPP group. Median follow-up was 86.2 months in the SPP group and 50.3 months in the CPP group. Median overall survival was 29.6 months in the SPP group and not reached in the CPP group; 5-year overall survival was 40.0% and 63.9%, respectively (P = 0.0269). At multivariate analysis, CPP versus SPP was recognized as an independent predictor of better prognosis, along with complete cytoreduction, negative lymph nodes, epithelial histology, and lower MIB-1 labelling index. Morbidity and reoperation rates were not different between groups. No operative mortality occurred. In 12 of 24 patients undergoing CPP, pathologic examination detected disease involvement on parietal surfaces with no evident tumor at surgical exploration. CONCLUSIONS: CPP improved survival in patients with DMPM undergoing combined treatment. This information may contribute to standardize surgical options for DMPM and other peritoneal malignancies.

Receptor tyrosine kinase and downstream signalling analysis in diffuse malignant peritoneal mesothelioma.

Our aim was to assess the activation profile of EGFR, PDGFRB and PDGFRA receptor tyrosine kinases (RTK) and their downstream effectors in a series of cryopreserved diffuse malignant peritoneal mesothelioma (DMPM) surgical specimens to discover the targets for drug inhibition. We also made a complementary analysis of the cytotoxic effects of some kinase inhibitors on the proliferation of the human peritoneal mesothelioma STO cell line. We found the expression/phosphorylation of EGFR and PDGFRB in most of the tumours, and PDGFRA activation in half. The expression of the cognate ligands TGF-α, PDGFB and PDGFA in the absence of RTK mutation and amplification suggested the presence of an autocrine/paracrine loop. There was also evidence of EGFR and PDGFRB co-activation. RTK downstream signalling analysis demonstrated the activation/expression of ERK1/2, AKT and mTOR, together with S6 and 4EBP1, in almost all the DMPMs. No KRAS/BRAF mutations, PI3KCA mutations/amplifications or PTEN inactivation were observed. Real-time polymerase chain reaction revealed the decreased expression of TSC1 c-DNA in half of the tumours. In vitro cytotoxicity studies showed the STO cell line to be resistant to gefitinib and sensitive to sequential treatment with RAD001 and sorafenib; these findings were consistent with the presence of the KRAS mutation G12D in these cells although it was not detectable in the original tumour. Our results highlight the ligand-dependent activation and co-activation of EGFR and PDGFRB, as well as a connection between these activated RTKs and the downstream mTOR pathway, thus supporting the role of combined treatment with RTK and mTOR inhibitors in DMPM.

Lymph node metastases in diffuse malignant peritoneal mesothelioma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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

Pseudomyxoma peritonei: biological features are the dominant prognostic determinants after complete cytoreduction and hyperthermic intraperitoneal chemotherapy.

OBJECTIVE: To investigate outcome and prognostic factors in patients with pesudomyxoma peritonei (PMP) treated by complete cytoreduction and hyperthermic intraperitoneal chemotherapy. BACKGROUND: After comprehensive treatment, prognosis of PMP is predominantly dependent on the completeness of cytoreduction. Once complete cytoreduction is achieved, additional factors predicting long-term outcome are still poorly understood. METHODS: From a prospective database, we selected 102 patients undergoing complete cytoreduction (residual tumor nodules < or =2.5 mm) and closed-abdomen hyperthermic intraperitoneal chemotherapy with mitomycin-C and cisplatin. Previously, 22 patients had systemic chemotherapy. PMP was histologically classified into disseminated peritoneal adenomucinosis, peritoneal mucinous carcinomatosis (PMCA), and intermediate/discordant group. Twenty-one patient-, tumor-, and treatment-related variables were assessed by multivariate analysis with respect to overall (OS) and progression-free (PFS) survival. The following immunohistochemical markers were tested: cytokeratin (CK)-7, CK-20, CDX-2, MUC-2, and MUC-5AC. RESULTS: Operative mortality was 1%. Seventy-eight patients were diagnosed with disseminated peritoneal adenomucinosis, 24 with PMCA, none with intermediate/discordant group. For the overall series, median follow-up, 5-year OS, and PFS were 45 months (range 1-110), 84.4%, and 48.3%, respectively. In most cases, CK20, CDX-2, and MUC-2 were diffusely positive, whereas CK-7 and MUC-5AC were variably expressed. At multivariate analysis, previous systemic chemotherapy and PMCA correlated to both worse OS and PFS, elevated serum CA125 only to worse PFS. CK20, CDX-2, and MUC-2 expression correlated to prognosis at univariate analysis. CONCLUSIONS: After complete cytoreduction and hyperthermic intraperitoneal chemotherapy, prognosis of PMP is primarily dependent on pathologic and biologic features. MUC-2, CK-20, and CDX-2 may be related to the disease biology. Understanding PMP molecular basis may facilitate personalized treatment.

Diffuse malignant mesothelioma of the peritoneum: a clinicopathological study of 35 patients treated locoregionally at a single institution.

BACKGROUND: In the current study, the authors report the clinicopathologic features of patients with peritoneal diffuse malignant mesothelioma (DMM) who were treated in a uniform fashion at a single institution to assess prognostic factors. METHODS: Thirty-five patients were treated with cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). The tumors were classified into epithelial, sarcomatoid, and biphasic types. Immunohistochemistry stains were performed for calretinin, WT-1, pCEA, Ber-EP4, epidermal growth factor receptor (EGFR), p16, matrix metalloprotease-2 (MMP-2), and MMP-9. Statistical correlation was evaluated for age, gender, completeness of cytoreduction (CC), tumor histotype, mitotic count (MC), necrosis, nuclear grade (NG), and biologic markers with regard to overall survival (OS) and progression-free survival (PFS). RESULTS: The patient group was comprised of 15 men and 20 women with a median age of 52 years (range, 24-73 yrs). Twenty-five patients underwent optimal cytoreduction. There were 32 epithelial tumors and 3 biphasic tumors, and 3 patients had an NG of 1, 19 had an NG of 2, and 13 had an NG of 3. The mean MC was 14.1 (range, 0-160 per 50 high-power fields). Necrosis was present in 11 cases. All the tumors were found to be positive for calretinin and WT-1 and were negative for pCEA and Ber-EP4. The NG and MC were found to be significantly associated with OS (P = 0.02 and P = 0.01, respectively) whereas CC was found to be associated with both OS (P = 0.05) and PFS (P = 0.03). No biologic markers were found to be of prognostic significance. CONCLUSIONS: The results of the current study indicate that NG, MC, and CC may be useful prognostic factors in patients treated with CRS and IPHP. The expression of EGFR, MMP-2, and MMP-9 and absent and/or reduced expression of p16 in DMMs confirms the results of previous studies suggesting their role in tumor pathogenesis and kinetics.

High response rate and manageable toxicity with an intensive, short-term chemotherapy programme for Burkitt's lymphoma in adults.

UNLABELLED: A very short, intensive paediatric chemotherapy programme was tested in a consecutive monoinstitutional group of 22 adult Burkitt's lymphoma (BL) patients. After a 5-week induction phase of weekly infusions consisting of vincristine, cyclophosphamide, doxorubicin, high-dose (HD) methotrexate (MTX) plus leukovorin rescue, and intrathecal MTX or cytarabine (ARA-C), a consolidation phase including HD ARA-C plus cisplatin was given. Responding patients achieving less than complete response (CR) after completion of the initial induction phase, were promptly shifted to a high-dose, stem cell supported sequential chemotherapy schema (R-HDS). PATIENT CHARACTERISTICS: median age, 35.5 (range 18-76) years; Ann Arbor stage I-II/III-IV, 11/11; bulky disease, 15 patients; LDH > or = 460 U/l, 11 patients. The median duration of the chemotherapy programme was 62 d (range, 43-94 d). Seventeen patients achieved a CR (77%), one patient died of progressive disease and four partial responders following induction were converted to CR following R-HDS. Of 17 patients in CR, one died of infectious toxicity while in CR, and one relapsed at 30 months and died of progressive disease. After a median follow-up of 28.7 months (range, 6-158 months), 16 patients (73%) were in continued CR. Overall survival and progression-free survival were 77% [95% confidence interval (CI), 52-99%] and 68% (95% CI, 43-99%) respectively. Confirmation of these excellent efficacy and feasibility results by larger, multicentre and prospective studies is warranted.