Although mesothelin and osteopontin showed their potential usefulness in diagnosing and assessing prognosis of pleura mesothelioma patients, no information is available for DMPM [22]. The clinical role of serum markers was studied in 60 patients with DMPM treated at the Istituto Nazionale Tumori (INT) in Milan, Italy. Baseline diagnostic sensitivity was 53.3 % for cancer antigen (CA)125, 0 for CEA, 3.8 % for CA19.9, and 48.5 % for CA15.3 [23]. These data may help in the initial evaluation of peritoneal tumors from unknown site of origin. When therapy response was assessed, CA125 normalized after adequate CRS plus HIPEC in 21/22 patients with elevated baseline levels. CA125 remained high in all patients with persistent macroscopic disease after surgery. Also, CA125 became positive in 12/12 patients with elevated baseline levels, developing disease progression after adequate CRS plus HIPEC. A borderline prognostic significance for baseline CA125 levels was observed only in individuals not previously treated with systemic chemotherapy (sCHT).

In a large collaborative study, the most significant prognostic factors were epithelial subtype, no node metastases, completeness of cytoreduction (CC), and administration of HIPEC [33]. In pattern-of-failure analysis, the small bowel was the site most commonly involved at recurrence; residual tumor > 2.5 mm was the only independent risk factor for recurrence [38]. CC has consistently been one of the most predominant prognostic factors. It is related to the extent of peritoneal involvement and surgeon skill to remove all peritoneal disease [1–3, 32–34]. Lymph node metastases are rare in DMPM but correlate with poor outcome. This supports the necessity that any suspicious node be systematically removed during the CRS procedure [32, 33].

Biphasic and sarcomatoid histological variants are correlated with poor prognosis, although their clinical utility as prognostic factors is limited by their rarity [1]. Other pathological prognostic variables are nuclear/nucleolar size, depth of tumor invasion, and mitotic count.

In the above-mentioned series, a Ki67-positive cell rate < 10 % correlated at multivariate analysis with better OS and PFS [37]. The role of proliferative index for prognostic stratification was confirmed in an exhaustive clinicopathological analysis by Deraco et al. (personal communication) using the technology of tissue microarray (TMA), results of which were presented at the Ninth International Symposium on Locoregional Cancer Therapies, Steamboat Springs, CO, USA, 15–17 February 2014.

In DMPM, molecular and cellular mechanisms underlying the proliferative potential and resistance to therapy are still poorly understood. The biology of this disease has been thoroughly investigated by clinical and basic science researchers at Milan INT during the last decade. It has been demonstrated that p16 expression is frequently absent or reduced in patients with DMPM and that EGFR overexpression is more common in peritoneal than in pleural forms. However, no correlation with prognosis of overexpression of EGFR and matrix metalloproteases (MMP)-2 and -9 was found in patients treated in our institution [39].

Telomerase activity (TA) is expressed in the majority of DMPM and negatively impacts prognosis [40]. In DMPM specimens from 38 patients undergoing various therapies; we assessed TA using the telomeric repeat amplification protocol. The alternative lengthening of telomeres (ALT) mechanisms were studied by assaying ALT-associated promyelocytic leukemia nuclear bodies. ALT or TA alone was found in 18.2 % and 63.6 % of cases, respectively; both ALT and TA were positive in two cases. In the overall series, TA expression was significantly associated with disease relapse (p = 0.018) and cancer-related death (p =0.045); ALT was not associated with outcome. In a subset analysis, the prognostic relevance of TA was confirmed in patients uniformly treated by CRS plus HIPEC.

Overexpression of cytoprotective factors, including survivin and members of the inhibitors of apoptosis protein (IAP) family, were demonstrated by Zaffaroni et al. [5]. Those authors analyzed DMPM proliferative and apoptotic features and tested a survivin knockdown approach in a human DMPM cell line. DMPM cells were transfected with small-interfering RNA (siRNA) targeting survivin messenger RNA (mRNA). Survivin expression, growth rate, and ability to undergo spontaneous and drug-induced apoptosis was measured, showing low proliferation rates and poor apoptotic activity in DMPM cells. Survivin was expressed in 91 % of cases and the other IAPs in 69–100 %. Transfection of DMPM cells with survivin siRNA resulted in a survivin inhibition, a timedependent cell-growth decrease, and an enhancement of spontaneous and druginduced apoptosis. These results suggest that survivin may be a potential target for biological treatments in DMPM.