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Introduction Up to one-fifth of patients with colorectal cancer will develop peritoneal metastases, frequently without other districts' involvement. Despite the recent unsuccesses of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer peritoneal metastases treatment, the rationale in the prophylactic setting remains strong. Several clinical and pharmacokinetic data suggest that the efficacy of intraperitoneal chemotherapy is highest when the disease is microscopic. However, robust evidence demonstrating whether the addition of HIPEC for high-risk colorectal cancers offers better control of local recurrence is lacking. Methods and analysis This is a multicentre randomised phase 3 trial comparing prophylactic surgery plus HIPEC CO2 with mitomycin, over standard surgical excision in patients with colorectal cancer at high risk of peritoneal carcinomatosis; 388 patients will be included in this study. The primary objective is to compare the efficacy of prophylactic surgery (radical colorectal resection, omentectomy, appendectomy, round ligament of the liver resection and bilateral adnexectomy) plus HIPEC CO2 with mitomycin and standard surgery in terms of local recurrence-free survival. The main secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. The primary endpoint will be described with a cumulative incidence function and will be analysed with Grey test to take account of the competing risks. DFS and OS will be described with the Kaplan-Meier method. Ethics and dissemination This trial has been evaluated by the Italian Medicines Agency, local ethics committees and will be submitted to the Ministry of Health to notify the start of the trial according to the regulation of trials on devices with CE mark/certification. The results will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal, whatever the findings. Trial registration number NCT03914820.

Peritoneal dissemination from colorectal cancer (CRC) has long been associated with unfavorable prognosis. However, in the last decades, the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was able to obtain up to 30% 5-year survival rate in selected centers. Despite the wide diffusion of CRS and HIPEC, until now, there are no clear recommendations on the drug of choice for HIPEC nor its technique, and safety and efficacy data of HIPEC regimens and techniques are lacking. We performed a retrospective analysis of a prospectively maintained database of 26 CRS and mitomycin C HIPEC with CO2 recirculation (HIPEC-CO2) for CRC peritoneal metastasis (PM) performed at our center. The main endpoints were morbidity, mortality, the temperature of perfusate during HIPEC and metabolic changes throughout the procedure. Morbidity was assessed by analysis of postoperative adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Continuous variables of Arterial Blood Gas (ABG) analysis at three time-points were compared by the Student t test. There were no postoperative deaths. The overall grade 3–4 CTCAE complications rate at 30 days was 38.4%, with ten severe adverse events occurring to six (23.0%) patients. The temperature within HIPEC perfusion maintained between 41 and 42 °C in all cases and we experienced no HIPEC-related intraoperative complications. We observed a significant difference between all baseline and pre-HIPEC ABG parameters evaluated but no statistically significant differences between pre- and post-HIPEC ABG outcomes. This study shows that mitomycin C HIPEC-CO2 is feasible and has a safety profile comparable to that of other HIPEC techniques reported in the literature. Further research is needed to validate prospectively the safety and efficacy of this technique.

Purpose: Careful patient selection plays a crucial role in avoiding overtreatment and further increases survival rates in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer (CRC) with peritoneal metastases (PM). Methods: The clinical and molecular factors influencing survival in patients who had undergone CRS with HIPEC between January 2015 and December 2018 were analyzed. Results: Sixty-six patients underwent CRS with HIPEC during the study period. The median overall survival (OS) was 36 months, with a 3-year OS of 43%. Multivariate analysis revealed increased PCI (HR: 1.21; 95% CI: 1.02–1.41; p = 0.020), right-sided primary tumor (HR: 3.01; 95% CI: 1.27–7.13; p = 0.017), and BRAF V600E mutation (HR: 4.55; 95% CI: 1.21–17.21; p = 0.025) as independent predictors for worse OS. Conclusion: In addition to confirming the prognostic role of PCI, our study extends the role of BRAF mutation and right primary tumor location as markers for worse prognosis.

Introduction: Patients with peritoneal metastasis frequently develop malignant bowel obstruction (MBO). Medical palliative management is preferred but often fails. Conversely, the role of palliative surgery remains unclear and debated. This study aims to identify patients who could benefit from invasive surgical interventions and factors associated with successful surgical palliation. Materials and Methods: In this retrospective study, 98 consecutive patients who underwent palliative surgery for MBO over 5 years were reviewed. We evaluate as the primary outcome surgical failure to select patients who could benefit from palliative surgery, avoiding unnecessary surgery. A prognostic score was developed based on a logistic regression model to identify patients at risk of surgical failure. The score was evaluated for overall accuracy by receiver operating characteristic curve analysis. Results: Palliative surgery was achieved in 76 (77.5%) patients. The variables that were found to be significant factors for surgical failure are recurrent disease (P = 0.015), absence of bowel obstruction (P < 0.001), absence of bowel distension (P < 0.001), and mesenteric involvement (P = 0.001) and retraction (P < 0.001). The absence of bowel distension (P = 0.046) and bowel obstruction (P = 0.012) emerged as independent predictors of surgical failure. Carcinomatosis level assessment for peritoneum score, based on these factors, was built to evaluate the risk of surgical failure. Conclusion: Our proposed scoring system might help select patients most likely to benefit from palliative surgery.

Background: Cytoreductive surgery (CRS) and hypertermic intraperitoneal chemotherapy (HIPEC) represent the most effective strategy to manage peritoneal metastases (PM). This systematic review and meta-analysis aimed to assess the impact of body composition on clinical outcomes in patients with PM. Methods: A systematic literature search was performed using Medline, Web of Science and EMBASE databases from inception to the 20st August 2020. Data were independently extracted by 3 authors. Newcastle-Ottawa Scale was used to assess quality and risk of bias of studies. Pooled analyses were performed using Mantel-Haenszel method to estimate overall effect size with mean differences or odd ratios (ORs) and 95% confidence interval (CI). The primary outcome was postoperative complication (POC) rate, while secondary outcomes were severe POC and postoperative mortality. Results: A total of 4 studies were included in the systematic review and meta-analysis, including 582 patients. A significant association between low skeletal muscle mass and POC was found (OR 1.45, 95% CI 1.04 to 2.03; p = 0.03), while no differences were found in terms operative time, estimated blood loss, length of hospital stay, and postoperative mortality (p > 0.05). Conclusions: Low skeletal muscle mass at diagnosis is a valid prognostic factor for POC development in colorectal and PM patients undergoing CRS. Prospective and larger studies are needed to better investigate the role of CT scan derived body composition and to understand how to implement this tool in clinical practice.

Background: Systemic chemotherapy for pancreatic adenocarcinoma (PDAC) and cholangiocarcinoma (CC) with peritoneal metastases (PM) is affected by several pharmacological shortcomings and low clinical efficacy. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is expected to maximize exposure of peritoneal nodules to antiblastic agents. This study aims to evaluate safety and efficacy of PIPAC for PM of PDAC and CC origin. Methods: This is a retrospective analysis of consecutive PDAC and CC cases with PM treated with PIPAC at two European referral centers for peritoneal disease. We prospectively recorded from August 2016 to May 2019 demographic, clinical, surgical, and oncological data. We performed a feasibility and safety assessment and an efficacy analysis based on clinical and pathological regression. Results: Twenty patients with PM from PDAC (14) and CC (six) underwent 45 PIPAC administrations. Cisplatin–doxorubicin or oxaliplatin were administered to eight and 12 patients, respectively. We experienced one intraoperative complication (small bowel perforation) and 18 grade 1–2 postoperative adverse events according to Common Terminology Criteria for Adverse Events version 4.0. A pathological regression was recorded in 50% of patients (62% in the cisplatin–doxorubicin cohort and 42% in the oxaliplatin one). Median survival from the first PIPAC was 9.7 and 10.9 months for PDAC and CC, respectively. Conclusion: PIPAC resulted feasible and safe without relevant toxicity issues, with both cisplatin–doxorubicin and oxaliplatin. The pathological response observed supports the evidence of antitumoral activity. Despite the study limitations, these outcomes are encouraging, recommending PIPAC in prospective, controlled trials in the palliative setting or the first line chemotherapy for PM from PDAC and CC.

We present major elements compositions and volatiles contents of olivine-hosted melt inclusions from Etna volcano (Italy), which extend the existing database with the aim of interpreting the chemical variability of Etnean magmas over the last 15 ka. Olivine phenocrysts were selected from the most primitive Fall Stratified (FS) eruptive products of picritic composition (Mg# = 67–70, Fo89–91), the Mt. Spagnolo eccentric lavas (Mg# = 52–64, Fo82–88) and among the more recent 2002–2013 eruptive products (Mg# = 33–53, Fo68–83). Crystal fractionation and degassing processes were modeled at temperatures of 1050–1300 °C, pressures <500 MPa, and oxygen fugacity between 1 and 2 log units above the nickel-nickel oxide buffer, in order to interpret melt inclusions data. Melt inclusions show a great variability in major elements chemistry (e.g., 44–57 wt% SiO2, 3–16 wt% CaO, 4–13 wt% FeO, 2–12 wt% MgO, 1–6 wt% K2O), designating a continuous differentiation trend from FS toward 2013 entrapped melts, which is mostly reproduced by the fractional crystallization of olivine + spinel + clinopyroxene ± plagioclase, in order of appearance. Volatile contents in the glass inclusions are also extremely variable, with maxima up to 6 wt% H2O and 0.6 wt% CO2 in FS melt inclusions, and up to 0.43 wt% S in Mt. Spagnolo inclusions. H2O and CO2 contents in the melt inclusions suggest minimum entrapment depths of 4–19 km (below crater level) for FS inclusions and <10 km for the 2002–2013 trachybasalts. Petrological arguments coupled to the modeling of fractional crystallization and degassing processes concur to suggest that magmas from Mt. Spagnolo and the recent eruptions may be produced by differentiation from the most primitive volatile-rich FS magma along variable P-T paths, occasionally accompanied by secondary processes as crustal assimilation, mixing, and CO2 flushing. We do not exclude the occurrence of source processes at Etna, e.g., variable degrees of mantle melting and/or variabl

INTRODUCTION: Systemic chemotherapy offers poor control over peritoneal disease, maybe as a consequence of restricted drug availability within the abdominal cavity. Locoregional chemotherapy may overcome these shortcomings but its administration is limited to a few patients with confined peritoneal spread. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) emerged in the last years as a novel method of intraperitoneal drug administration.EVIDENCE ACQUISITION: We report a meta-analysis of published studies on PIPAC safety and pathological anti-tumoral efficacy on PC from various tumor entities, with the aim of providing more evidence to support further research. This systematic review and meta-analysis were designed, conducted and reported according to the PRISMA statement.EVIDENCE SYNTHESIS: An overall pathological response rate of 43.7% was calculated on a total of 668 patients who underwent 1480 PIPAC cycles across the 20 studies. Pooled severe adverse events rate (CTCAE grade 3-4) was 10% and seven deaths across all studies were reported, of which only four were related to PIPAC.CONCLUSIONS: PIPAC is a safe procedure which has a relevant anti-tumoral activity on peritoneal carcinomatosis. Further studies, even in the early stage of disease, are awaited to assess the clinical benefit of PIPAC. This review may serve as a reliable basis for future research.

The major elements, trace elements and Sr and Nd isotopes of selected Etnean primitive rocks (<15kyBP) were studied in order to characterize their mantle source. The noble-gas geochemistry of fluid inclusions in minerals from the same lavas was also investigated. The major element compositions of whole rocks and minerals showed that these products are among the most primitive at Mt. Etna, comprising 6.3-17.5wt.% MgO. The variable LREE (Light Rare Earth Elements) enrichment relative to MORB (Mid-Ocean Ridge Basalt) (Lan/Ybn=11-26), together with the patterns of certain trace-element ratios (i.e., Ce/Yb versus Zr/Nb and Th/Y versus La/Yb), can be attributed to varying degrees of melting of a common mantle source. Numerical simulations performed with the MELTS program allowed the melting percentages associated with each product to be estimated. This led us to recalculate the hypothetical parental trace-element content of the Etnean mantle source, which was common to all of the investigated rocks. The characteristics of the Sr, Nd and He isotopes confirmed the primitive nature of the rocks, with the most-depleted and primitive lava being that of Mt. Spagnolo (SPA; 143Nd/144Nd=0.512908 87Sr/86Sr=0.703317-0.703325 and 3He/4He=7.6 Ra), and highlighted the similarity of the mantle sources feeding the volcanic activity of Mt. Etna and the Hyblean Plateau (a region to the south of Mt. Etna and characterized by older magmatism than Mt. Etna). The coupling of noble gases and trace elements suggests an origin for the investigated Etnean lavas from melting of a Hyblean-like mantle, consisting of a two-component source where a peridotitic matrix is veined by 10% pyroxenite. A variable degree of mantle contamination by crustal-like fluids, probably related to subduction, is proposed to explain the higher Sr-isotope and lower Nd-isotope values in some rocks (143Nd/144Nd up to 0.512865 and 87Sr/86Sr up to 0.703707). This process probably occurred in the source prior to magma gener

The Peloritani Mountains are a fragment of an orogen variably attributed to the Alpine or Hercynian orogeny. On the basis of Ar-39-Ar-40, U-Pb and Rb-Sr dating, the main metamorphism of the two medium-high grade metamorphic units, the Mela and Aspromonte Units, and most of the thrusting responsible for stacking the orogenic edifice are seen to be Hercynian. The main thrusting of the Aspromonte Unit over the lower grade units took place at 301+/-2 Ma. Brittle deformation during Tertiary reactivation of Hercynian thrust planes did not generate any rejuvenation of white micas in the studied sector. Our dataset shows a great complexity and we propose to unravel it by considering different levels of information. To first order, the Mela and Aspromonte Units differ in their metamorphic paths and their geochronological evolution. The Mela Unit shows generally younger ages (Carboniferous) than the Aspromonte Unit and, unlike the latter, was extensively retrogressed in greenschist facies. The Aspromonte Unit is itself geochronologically heterogeneous. Proterozoic ages are preserved both in titanite and in amphibole relics of one tectonic subunit; Devonian to Carboniferous amphibole ages are found in different other subunits; tertiary overprint is minor and spatially limited. We propose to consider the chronologically heterogeneous subunits as accreted pre-Hercynian terranes amalgamated late during the Hercynian orogeny. Micas in both units give scattered Mesozoic Ar-39-Ar-40 and Rb-Sr ages, with evidence for heterochemical mica generations. We interpret them as a result of widespread hydrothermal circulation event(s). Tertiary overprint is generally absent, with the exception of a small area near Messina where biotite and muscovite underwent a complex recrystallisation history in the interval between 48 and 61 Ma