Experience with peritoneal mesothelioma at the Milan National Cancer Institute

Deraco, Marcello; Baratti, Dario; Cabras, Antonello D.; Zaffaroni, Nadia; Perrone, Federica; Villa, Raffaella; Jocollè, Jenny; Balestra, Maria Rosaria; Kusamura, Shigeki; Laterza, Barbara; Pilotti, Silvana

doi:10.4251/wjgo.v2.i2.76

Cited by 23 publications

(8 citation statements)

References 49 publications

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“…In this context, TMM have been proposed to represent a reservoir of candidate targets for the development of novel therapeutic interventions for the disease [32]. …”

Section: Discussionmentioning

confidence: 99%

miR-380-5p-mediated repression of TEP1 and TSPYL5 interferes with telomerase activity and favours the emergence of an “ALT-like” phenotype in diffuse malignant peritoneal mesothelioma cells

et al. 2017

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BackgroundUnderstanding the molecular/cellular underpinnings of diffuse malignant peritoneal mesothelioma (DMPM), a fatal malignancy with limited therapeutic options, is of utmost importance for the fruitful management of the disease. In this context, we previously found that telomerase activity (TA), which accounts for the limitless proliferative potential of cancer cells, is prognostic for disease relapse and cancer-related death in DMPM patients. Consequently, the identification of factors involved in telomerase activation/regulation may pave the way towards the development of novel therapeutic interventions for the disease. Here, the capability of miR-380-5p, a microRNA negligibly expressed in telomerase-positive DMPM clinical specimens, to interfere with telomerase-mediated telomere maintenance and, hence, with cancer cell growth was assessed on preclinical models of DMPM.MethodsDMPM cells were transfected with a miR-380-5p synthetic precursor, and the effects of miRNA replacement were evaluated in terms of growing capability, induction of apoptosis and interference with TA. Reiterated weekly transfections were also performed in order to analyse the phenotype arising upon prolonged miR-380-5p reconstitution in DMPM cells.ResultsThe ectopic expression of miR-380-5p elicited a remarkable inhibition of TA and resulted in DMPM cell growth impairment and apoptosis induction. In particular, we demonstrated for the first time that these effects were the result of a molecular circuitry converging on telomerase associated protein 1 (TEP1), where the miRNA was able to target the gene both directly in unconventional targeting modality and indirectly via p53 accumulation consequent to miRNA-mediated downregulation of testis-specific protein, Y-encoded-like 5 gene. Moreover, miR-380-5p did not cause telomere attrition and cell growth arrest in long-term DMPM transfectants, which in turn showed slightly elongated telomeres and molecular features (e.g. c-circle DNA and reduced expression levels of chromatin remodeler ATRX) resembling an alternative lengthening of telomeres (ALT) phenotype.ConclusionsmiR-380-5p interferes with TA in DMPM cells by targeting TEP1. Notably, in the long-term setting, miR-380-5p-mediated impairment of TA did not result in telomere attrition. Instead, a phenotype reminiscent of ALT emerged in DMPM cells as possible compensatory pathway that safeguards DMPM cell growth, an event that may be regarded as a potential resistance mechanism to anticancer therapies based on telomerase inhibitors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0510-3) contains supplementary material, which is available to authorized users.

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“…In this context, TMM have been proposed to represent a reservoir of candidate targets for the development of novel therapeutic interventions for the disease [32]. …”

Section: Discussionmentioning

confidence: 99%

miR-380-5p-mediated repression of TEP1 and TSPYL5 interferes with telomerase activity and favours the emergence of an “ALT-like” phenotype in diffuse malignant peritoneal mesothelioma cells

et al. 2017

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“…Only patients with performance status (PS) < 2, in according with Eastern Cooperative Oncology Group (ECOG) (11) with primary PC (pseudomixoma peritonei and mesothelioma) and secondary (from ovarian, GI and selected cases of sarcoma origin), with possible complete cytoreduction and without extraperitoneal disease are selected to undergo CRS-HIPEC. Surgical and anaesthesiological procedures have been well assessed and standardized (12,13).…”

Section: Materials and Methods Materials And Methodsmentioning

confidence: 99%

The St Constantin Hospital's initial experience with CRS-HIPEC

Moldovan¹,

Pocreaţă²,

Moldovan³

et al. 2015

JTMR

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Introduction: Cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is a spreading technique for the treatment of peritoneal carcinomatosis, a technique that is associated with high morbidity and mortality rates. We report retrospectively the experience of St Constantin Hospital Brasov, underlining the good results obtained in terms of both reduction of complications and oncologic outcome. Methods: Between Juin 2013 and October 2015, 32 patients with a median age of 55.6 years, underwent 34 CRS-HIPEC combined procedures. Results: CCR-0 resection was achieved in 19/34 of patients, CCR-1 in 8/34 of patients and CCR-2 in 7/34 of patients, with a median operative time of 560 minutes (range 400-620 minutes). Median hospital stay was 9 days(4 days in laparoscopic HIPEC-20 days). Total morbidity rate was 40%, with WHO grade 3 and 4 morbidity rate 0 and the 30 days mortality was 0. With a median follow up of 11.8 months, the overall survival (OS) rate was 62%. Gastrointestinal (GI) origin in contrast with ovarian origin and peritoneal cancer index (PCI) higher than 19 showed a worst prognosis in terms of both OS and Progression Free Survival (PFS). Conclusions. In a referral surgical oncology centre, CRS-HIPEC related perioperative mortality and morbidity can be reduced with a multidisciplinary patient management and a correct patient selection for this procedure. Our single centre retrospective series confirm the advantage in PFS and OS of the combined treatment CRS-HIPEC in the management of peritoneal carcinomatosis.

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“…Urano et al showed an excellent in vitro and in vivo thermal augmentation of cisplatin [56]. Current applied cisplatin-based HIPEC regimens are the "Sugarbaker Regimen" [57] and the "National Cancer Institute Milan Regimen" [58] ( Table 3). …”

Section: Cisplatinmentioning

confidence: 99%

Overview of the optimal perioperative intraperitoneal chemotherapy regimens used in current clinical practice

Speeten

Lemoine

Sugarbaker

2017

Pleura and Peritoneum

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Peritoneal surface malignancy (PSM) is a common manifestation of digestive and gynecologic malignancies alike. At present, patients with isolated PSM are treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The combination of CRS and intraperitoneal (IP) chemotherapy should now be considered standard of care for PSM from appendiceal epithelial cancers, colorectal cancer and peritoneal mesothelioma. Although there is a near universal standardization regarding the CRS, we are still lacking a much-needed standardization among the various IP chemotherapy treatment modalities used today in clinical practice. Pharmacologic evidence should be generated to answer important questions raised by the myriad of variables associated with IP chemotherapy.

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Experience with peritoneal mesothelioma at the Milan National Cancer Institute

Cited by 23 publications

References 49 publications

miR-380-5p-mediated repression of TEP1 and TSPYL5 interferes with telomerase activity and favours the emergence of an “ALT-like” phenotype in diffuse malignant peritoneal mesothelioma cells

miR-380-5p-mediated repression of TEP1 and TSPYL5 interferes with telomerase activity and favours the emergence of an “ALT-like” phenotype in diffuse malignant peritoneal mesothelioma cells

The St Constantin Hospital's initial experience with CRS-HIPEC

Overview of the optimal perioperative intraperitoneal chemotherapy regimens used in current clinical practice

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