Publications by authors named "Michele De Simone"

48 Publications

A Phase I Dose Escalation Study of Oxaliplatin, Cisplatin and Doxorubicin Applied as PIPAC in Patients with Peritoneal Carcinomatosis.

Cancers (Basel) 2021 Mar 3;13(5). Epub 2021 Mar 3.

Unit of Surgical Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an innovative laparoscopic intraperitoneal chemotherapy approach with the advantage of a deeper tissue penetration. Thus far, oxaliplatin has been administered at an arbitrary dose of 92 mg/m, cisplatin at 7.5 mg/m and doxorubicin 1.5 mg/m. This is a model-based approach phase I dose escalation study with the aim of identifying the maximum tolerable dose of the three different drugs. The starting dose of oxaliplatin was 100 mg/m; cisplatin was used in association with doxorubicin: 15 mg/m and 3 mg/m were the respective starting doses. Safety was assessed according to Common Terminology Criteria for Adverse Events (CTCAE version 4.03). Thirteen patients were submitted to one PIPAC procedure. Seven patients were treated with cisplatin and doxorubicin and 6 patients with oxaliplatin; no dose limiting toxicities and major side effects were found. Common adverse events included postoperative abdominal pain and nausea. The maximum tolerable dose was not reached. The highest dose treated cohort (oxaliplatin 135 mg/m; cisplatin 30 mg/m and doxorubicin 6 mg/m) tolerated PIPAC well. Serological analyses revealed no trace of doxorubicin at any dose level. Serum levels of cis- and oxaliplatin reached a peak at 60-120 min after PIPAC and were still measurable in the circulation 24 h after the procedure. Cisplatin and doxorubicin may be safely used as PIPAC at a dose of 30 mg/m and 6 mg/m, respectively; oxaliplatin can be used at an intraperitoneal dose of 135 mg/m. The dosages achieved to date are the highest ever used in PIPAC.
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http://dx.doi.org/10.3390/cancers13051060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958944PMC
March 2021

Neither ACEIs nor ARBs are associated with respiratory distress or mortality in COVID-19 results of a prospective study on a hospital-based cohort.

Intern Emerg Med 2020 Nov 23;15(8):1477-1484. Epub 2020 Sep 23.

Emergency Department Gavardo Hospital, Brescia, Italy.

Considerable concern has emerged for the potential harm in the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor inhibitors (ARBs) in COVID-19 patients, given that ACEIs and ARBs may increase the expression of ACE2 receptors that represent the way for coronavirus 2 to entry into the cell and cause severe acute respiratory syndrome. Assess the effect of ACEI/ARBs on outcome in COVID-19 patients. Hospital-based prospective study. A total of 431 patients consecutively presenting at the Emergency Department and found to be affected by COVID-19 were assessed. Relevant clinical and laboratory variables were recorded, focusing on the type of current anti hypertensive treatment. Outcome variables were NO, MILD, SEVERE respiratory distress (RD) operationally defined and DEATH. Hypertension was the single most frequent comorbidity (221/431 = 51%). Distribution of antihypertensive treatment was: ACEIs 77/221 (35%), ARBs 63/221 (28%), OTHER than ACEIs or ARBs 64/221 (29%). In 17/221 (8%) antihypertensive medication was unknown. The proportion of patients taking ACEIs, ARBs or OTHERs who developed MILD or SEVERE RD was 43/77 (56%), 33/53 (52%), 39/64 (61%) and 19/77 (25%), 16/63 (25%) and 16/64 (25%), respectively, with no statistical difference between groups. Despite producing a RR for SEVERE RD of 2.59 (95% CI 1.93-3.49), hypertension was no longer significant in a logistic regression analysis that identified age, CRP and creatinine as the sole independent predictors of SEVERE RD and DEATH. ACEIs and ARBs do not promote a more severe outcome of COVID-19. There is no reason why they should be withheld in affected patients.
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http://dx.doi.org/10.1007/s11739-020-02500-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508677PMC
November 2020

Letter to the Editor.

Updates Surg 2020 Aug 27. Epub 2020 Aug 27.

Surgical Oncology, Candiolo Cancer Institute, Str. Provinciale 142, km 3.95, Candiolo, 10060, Turin, Italy.

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http://dx.doi.org/10.1007/s13304-020-00867-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450149PMC
August 2020

Cytoreductive Surgery for Heavily Pre-Treated, Platinum-Resistant Epithelial Ovarian Carcinoma: A Two-Center Retrospective Experience.

Cancers (Basel) 2020 Aug 10;12(8). Epub 2020 Aug 10.

Candiolo Cancer Institute, FPO-IRCCS-Candiolo, 10060 Torino, Italy.

Few retrospective studies have shown a benefit in selected patients affected by heavily pre-treated, platinum-resistant ovarian carcinomas (PROCs) who have undergone cytoreduction at relapse. However, the role of tertiary and quaternary cytoreductive surgery is not fully defined. Our aim was to evaluate survival and surgical morbidity and mortality after maximal cytoreduction in this setting. We evaluated all consecutive patients undergoing cytoreduction for platinum-resistance over an 8-year period (2010-2018) in two different centers. Fifty patients (median age 52.5 years, range 34-75) were included; the median number of previous chemotherapy lines was three (range 1-7) and the median number of previous surgeries was one (range 1-4). Completeness of cytoreduction (CC = 0) was achieved in 22 patients (44%). Rates of major operative morbidity and 30-day mortality were 38% and 8%, respectively. Median follow-up was 35 months. The absence of tumor residual (CC = 0) was associated with a significantly better overall survival (OS) compared to the CC > 0 subgroup (median OS 32.9 months (95% CI 21.6-44.2) vs. 4.8 months (95% CI n.a.-9.8), hazard ratio (HR) 4.21 (95% CI 2.07-8.60), < 0.001). Optimal cytoreduction is feasible and associated with promising OS in selected, heavily pre-treated PROCs. Further prospective studies are required to better define the role of surgery in platinum-resistant disease.
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http://dx.doi.org/10.3390/cancers12082239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464658PMC
August 2020

Improved Outcome Prediction for Appendiceal Pseudomyxoma Peritonei by Integration of Cancer Cell and Stromal Transcriptional Profiles.

Cancers (Basel) 2020 Jun 8;12(6). Epub 2020 Jun 8.

Candiolo Cancer Institute-FPO, IRCCS, Strada Prov. 142, km 3.95, I-10060 Candiolo (TO), Italy.

In recent years, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have substantially improved the clinical outcome of pseudomyxoma peritonei (PMP) originating from mucinous appendiceal cancer. However, current histopathological grading of appendiceal PMP frequently fails in predicting disease outcome. We recently observed that the integration of cancer cell transcriptional traits with those of cancer-associated fibroblasts (CAFs) improves prognostic prediction for tumors of the large intestine. We therefore generated global expression profiles on a consecutive series of 24 PMP patients treated with CRS plus HIPEC. Multiple lesions were profiled for nine patients. We then used expression data to stratify the samples by a previously published "high-risk appendiceal cancer" (HRAC) signature and by a CAF signature that we previously developed for colorectal cancer, or by a combination of both. The prognostic value of the HRAC signature was confirmed in our cohort and further improved by integration of the CAF signature. Classification of cases profiled for multiple lesions revealed the existence of outlier samples and highlighted the need of profiling multiple PMP lesions to select representative samples for optimal performances. The integrated predictor was subsequently validated in an independent PMP cohort. These results provide new insights into PMP biology, revealing a previously unrecognized prognostic role of the stromal component and supporting integration of standard pathological grade with the HRAC and CAF transcriptional signatures to better predict disease outcome.
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http://dx.doi.org/10.3390/cancers12061495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352410PMC
June 2020

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with Oxaliplatin, Cisplatin, and Doxorubicin in Patients with Peritoneal Carcinomatosis: An Open-Label, Single-Arm, Phase II Clinical Trial.

Biomedicines 2020 Apr 30;8(5). Epub 2020 Apr 30.

Candiolo Cancer Institute, Unit of Surgical Oncology, FPO-IRCCS, 10060 Candiolo, Italy.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an innovative approach for treating peritoneal carcinomatosis that applies chemotherapeutic drugs into the peritoneal cavity as an under-pressure airflow. It improves local bioavailability of cytostatic drugs as compared to conventional intraperitoneal chemotherapy. The aim of this study is to prove feasibility, efficacy and safety of this new treatment. Patients included in the analysis underwent at least two single port PIPAC procedures; drugs used were Oxaliplatin for colorectal cancers and Cisplatin + Doxorubicin for ovarian, gastric, and primary peritoneal cancers. The primary endpoint was the Disease Control Rate according to the RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Secondary significant endpoints were overall and progression free survival, tumor regression on histology, and quality of life. Safety and tolerability were assessed according to the Common Terminology Criteria for Adverse Events 4. Sixty-three patients were enrolled in this trial. Forty patients (100 PIPAC) were eligible for analysis. Twenty patients were undergoing systemic chemotherapy. Fourteen patients reported an objective response (35%). Median overall survival was 18.1 months; median progression-free survival was 7.4 months. Minor morbidity was observed in seven procedures. Grade 3 complications occurred in two patients, and grade 4 in one patient submitted to reoperation. Single-port PIPAC is feasible, safe, and easy to perform. The combined treatment based on systemic chemotherapy and PIPAC does not induce significant hepatic and renal toxicity and can be considered a valid therapeutic option in patients with advanced peritoneal disease. Further studies on the use of PIPAC alone, possibly with different drug dosages, may define the real effectiveness of the procedure.
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http://dx.doi.org/10.3390/biomedicines8050102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277495PMC
April 2020

Short-term outcome of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy used as treatment of colo-rectal carcinomatosis: a multicentric study.

Updates Surg 2020 Mar 15;72(1):163-170. Epub 2019 Nov 15.

Department of Surgical Oncology, Candiolo Cancer Insitute, SP 142, 10060, Candiolo, Torino, Italy.

The aim of this study is to assess the morbidity and mortality related to cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colo-rectal carcinomatosis. A retrospective multi-institutional study from seven Italian Centers was performed. One hundred and seventy-two patients, submitted to cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) to treat carcinomatosis of colorectal origin, were recorded. Postoperative morbidity was evaluated in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Post-operative mortality was evaluated as patients' death within 60 days from surgical procedures. Predictors of morbidity were evaluated with univariate and multivariate analyses. Post-operative morbidity occurred in 83 patients (48.3%): grades 1-2 in 29 cases (16.9%), and grades 3-4 in 54 (31.4%). Mortality occurred in four cases (2.3%). Number of anastomoses (OR 1.45; 95% CI 1.05-2.00; p = 0.024), number of blood transfusions (OR 1.31; 95% CI 1.11-1.54; p = 0.001) and chemotherapy regimen [Oxaliplatin (OX): OR 2.87; 95% CI 1.22-6.75; p = 0.015] remained, in multivariate analysis, in a statistically significant correlation with overall morbidity. The only variable that was proven to have statistically significant correlation with 3-4 morbidity was the number of blood transfusions (OR 1.25; 95% CI 1.07-1.46; p = 0.005). Morbidity and mortality do not preclude the use of CRS plus HIPEC in the treatment of peritoneal carcinomatosis of colorectal origin.
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http://dx.doi.org/10.1007/s13304-019-00691-8DOI Listing
March 2020

Precision oncotherapy based on liquid biopsies in multidisciplinary treatment of unresectable recurrent rectal cancer: a retrospective cohort study.

J Cancer Res Clin Oncol 2020 Jan 16;146(1):205-219. Epub 2019 Oct 16.

Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, 67100, L'Aquila, Italy.

Background: Third line innovative systemic treatments and loco-regional chemotherapy by hypoxic pelvic perfusion (HPP) have both been proposed for the treatment of unresectable not responsive recurrent rectal cancer (URRC). In the present study, we have compared the safety and efficacy of HPP/target therapy, using drug regimens selected by liquid biopsy precision oncotherapy, to third-line systemic therapy based on tissue specimens precision oncotherapy.

Methods: HPP/target therapy regimens were selected based on precision oncotherapy, including assays for chemosensitivity and viability, and qRT-PCR for tumor-related gene expression. In the control group, systemic third-line and further lines of therapy were defined according to clinical and biological parameters.

Results: From 2007 to 2019, 62 URRC patients were enrolled, comprised of 43 patients in the HPP/target-therapy group and 19 patients in the systemic therapy control group. No HPP related complications were reported and the most common adverse events were skin and bone marrow toxicity. In the HPP/target-therapy group, the ORR was 41.8% whereas in the systemic therapy control group was 15.8%. DCR of the HPP/target-therapy group was significantly improved over the systemic therapy group (P = 0.001), associated with a PFS of 8 vs 4 months (P = 0.009), and OS of 20 vs 8 months (P = 0.046).

Conclusions: The present data indicate that in URCC patients, the integration of HPP/target-therapy and precision oncotherapy based upon liquid biopsy is as effective and efficacious as third-line treatment in local disease control and, therefore, deserves to be further assessed and compared to conventional systemic treatments in future prospective randomized trials.
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http://dx.doi.org/10.1007/s00432-019-03046-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942036PMC
January 2020

A Comprehensive PDX Gastric Cancer Collection Captures Cancer Cell-Intrinsic Transcriptional MSI Traits.

Cancer Res 2019 11 4;79(22):5884-5896. Epub 2019 Oct 4.

First Department of General Surgery, Borgo Trento Hospital, University of Verona, Verona, Italy.

Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein-Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/ genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell-intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel "druggable" targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell-intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis. SIGNIFICANCE: This study reports a multilevel platform of gastric cancer PDXs and identifies a MSI gastric signature that could contribute to the advancement of precision medicine in gastric cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1166DOI Listing
November 2019

Exploring the Use of Pegylated Liposomal Doxorubicin (Caelyx) as Pressurized Intraperitoneal Aerosol Chemotherapy.

Front Pharmacol 2019 25;10:669. Epub 2019 Jun 25.

Unit of Surgical Oncology, Candiolo Cancer Institute, IRCCS-FPO, Candiolo, Italy.

Peritoneal carcinomatosis is a common metastatic pattern in ovarian, gastric, colorectal, and appendiceal cancer; systemic chemotherapy is the current standard of care for peritoneal metastatic disease; however, in a subset of patients its beneficial effect remains questionable. More effective perioperative chemotherapy is needed. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new treatment that applies chemotherapeutic drugs into the peritoneal cavity as an aerosol under pressure. It's a safe and feasible approach that improves local bioavailability of chemotherapeutic drugs as compared with conventional intraperitoneal chemotherapy. Till now the drugs used in PIPAC for the treatment of the peritoneal carcinomatosis (PC) are cisplatin, doxorubicin, and oxaliplatin; as of yet, there are no data comparing different drug formulations and dosage schedules of PIPAC. Pegylated liposomal doxorubicin 1.5 mg/sm was aerosolized in PIPAC procedures. Pharmacokinetics analysis of 10 procedures performed with conventional doxorubicin solution at the dose of 1.5 mg/m were compared to 15 procedures with the same dose of pegylated liposomal doxorubicin (PLD). Significant differences between experimental groups were detected by one-way ANOVA followed by Bonferroni correction; a p value < 0.05 was considered statistically significant. A statistically different doxorubicin tissue concentration was observed for the doxorubicin solution compared to pegylated liposomal doxorubicin in the right parietal peritoneum and right diaphragm. In the Caelyx series a mean tissue concentration of 1.27 ± 1.33 mg/g was reported, while in the second one we registered a mean concentration of 3.1 ± 3.7 mg/g. The delivery of nano-particles in PIPAC was feasible, but pegylated liposomal concentrations are lower than standard doxorubicin formulation. Probably mechanical and physical properties of pressurized aerosol chemotherapy might alter their stability and cause structural disintegration.
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http://dx.doi.org/10.3389/fphar.2019.00669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603215PMC
June 2019

PIPAC-OV3: A multicenter, open-label, randomized, two-arm phase III trial of the effect on progression-free survival of cisplatin and doxorubicin as Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) vs. chemotherapy alone in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

Pleura Peritoneum 2018 Sep 25;3(3):20180114. Epub 2018 Sep 25.

Charité University Medicine, Berlin, Germany.

Background: Recurrent, platin-resistant ovarian cancer (rPROC) has a poor survival. Even with the AURELIA trial, which is the best available treatment today, progression-free survival (PFS) is still only 6.7 months from the start of the second-line chemotherapy. Innovative, effective therapies are urgently needed. Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a novel drug delivery system for administering drugs into the abdomen. PIPAC with cisplatin and doxorubicin (PIPAC C/D) may be safely used at an intraperitoneal dose of 10.5 mg/m and 2.1 mg/m, respectively. Systemic toxicity of this therapy is low. In a phase II trial with 53 women, 62 % patients had an objective tumor response. Tumor regression on histology was observed in 76 % patients who underwent all three PIPACs. Randomized phase III studies are now required to evaluate the effect of PIPAC C/D compared to other standard treatments (sequential or simultaneous applications with systemic chemotherapy).

Methods: The present phase III study is a prospective, open, randomized, multicentric pivotal trial. A total of 244 patients will be randomly assigned (1:1) to the control (A) or to the experimental (B) group. Group A: Systemic palliative chemotherapy, physician's best choice (monotherapy consisting of pegylated liposomal doxorubicin or topotecan or gemcitabine or paclitaxel weekly. Bevacizumab can be used in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin). Group B: Intraperitoneal chemotherapy, 3×PIPAC C/D, performed every 6 weeks. Combination with systemic therapy is not allowed. Treatment is continued until disease progression, death, or patient refusal. In case of progression, no recommendation for further therapy is given by protocol. Patients are allowed to receive PIPAC C/D or systemic chemotherapy after study termination. The primary endpoint is PFS (according to RECIST v1.1) or death from any cause. The co-primary endpoint is the health-related quality of life (HRQoL) measured as the global health status (GHS, QLQ-30 of EORTC). Secondary outcomes comprise overall survival, safety (CTCAE 5.0), and tumor response according to peritoneal regression grading score (PRGS).

Discussion: We expect PIPAC C/D to control peritoneal disease and preserve the QoL on this subset of patients.

Trial Registration: The EudraCT number 2018-003664-31.
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http://dx.doi.org/10.1515/pp-2018-0114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405004PMC
September 2018

A predictive score for optimal cytoreduction at interval debulking surgery in epithelial ovarian cancer: a two- centers experience.

J Ovarian Res 2018 May 30;11(1):42. Epub 2018 May 30.

Candiolo Cancer Institute FPO-IRCCS, Strada Provinciale 142 km 3.95, 10060, Candiolo, TO, Italy.

Background: Optimal cytoreduction (macroscopic Residual Tumor, RT = 0) is the best survival predictor factor in epithelial ovarian cancer (EOC). It doesn't exist a consolidated criteria to predict optimal surgical resection at interval debulking surgery (IDS). The aim of this study is to develop a predictive model of complete cytoreduction at IDS.

Methods: We, retrospectively, analyzed 93 out of 432 patients, with advanced EOC, underwent neoadjuvant chemotherapy (NACT) and IDS from January 2010 to December 2016 in two referral cancer centers. The correlation between clinical-pathological variables and residual disease at IDS has been investigated with univariate and multivariate analysis. A predictive score of cytoreduction (PSC) has been created by combining all significant variables. The performance of each single variable and PSC has been reported and the correlation of all significant variables with progression free survival (PFS) has been assessed.

Results: At IDS, 65 patients (69,8%) had complete cytoreduction with no residual disease (R = 0). Three criteria independently predicted R > 0: age ≥ 60 years (p = 0.014), CA-125 before NACT > 550 UI/dl (p = 0.044), and Peritoneal Cancer Index (PCI) > 16 (p < 0.001). A PSC ≥ 3 has been associated with a better accuracy (85,8%), limiting the number of incomplete surgeries to 16,5%. Moreover, a PCI > 16, a PSC ≥ 3 and the presence of R > 0 after IDS were all significantly associated with shorter PFS (p < 0.001, p < 0.001 and p = 0.004 respectively).

Conclusions: Our PSC predicts, in a large number of patients, complete cytoreduction at IDS, limiting the rate of futile extensive surgeries in case of presence of residual tumor (R > 0). The PSC should be prospectively validated in a larger series of EOC patients undergoing NACT-IDS.
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http://dx.doi.org/10.1186/s13048-018-0415-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975698PMC
May 2018

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: morbidity and postoperative outcomes.

Minerva Chir 2019 Jun 28;74(3):195-202. Epub 2018 Mar 28.

Unit of Surgical Oncology, Candiolo Institute for Cancer Research and Care, Candiolo, Turin, Italy.

Background: Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) represents a treatment option for peritoneal surface malignancies. Even if it has been reported that this new approach improved survival of selected patients, it is still associated with high morbidity and mortality rates.

Methods: From October 1995 to December 2017, over 450 patients affected by peritoneal carcinomatosis (PC) underwent in our Institute CRS associated with HIPEC. For this preliminary analysis we considered 300 patients presenting PC of different origin: pseudomyxoma peritonei (PMP, N.=98), epithelial ovarian cancer (EOC, N.=87), peritoneal mesothelioma (DMPM, N.=49) and colorectal cancer (CRC, N.=66). Postoperative morbidity and mortality were studied in order to identify possible risk factors.

Results: The morbidity rate was 36.3% in all procedures (109/300). According to the Clavien-Dindo Classification, 67 cases (22.3%) were associated with grade I-II complications and 35 cases (11.7%) with grade III-IV. Surgical and medical complication rates were 8.3% (25/300) and 11.3% (34/300), respectively. The mortality rate was 2.3%. Reoperation was needed in 28 patients (9.3%). The operative time, the number of anastomosis, of peritonectomy procedures, of visceral resections performed and the PCI value resulted the most statistically significant factors influencing postoperative morbidity and mortality.

Conclusions: The risks of perioperative morbidity and mortality after CRS and HIPEC are analogous to any other major gastrointestinal surgery. CRS and HIPEC should remain a treatment option for highly-selected patients in whom a curative or life prolonging treatment is a pursuit and should be performed in high volume specialized institutions.
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http://dx.doi.org/10.23736/S0026-4733.18.07649-6DOI Listing
June 2019

Rituximab Treatment Prevents Lymphoma Onset in Gastric Cancer Patient-Derived Xenografts.

Neoplasia 2018 05 23;20(5):443-455. Epub 2018 Mar 23.

Department of Medical Sciences, University of Torino, Italy.

Patient-Derived Xenografts (PDXs), entailing implantation of cancer specimens in immunocompromised mice, are emerging as a valuable translational model that could help validate biologically relevant targets and assist the clinical development of novel therapeutic strategies for gastric cancer. More than 30% of PDXs generated from gastric carcinoma samples developed human B-cell lymphomas instead of gastric cancer. These lymphomas were monoclonal, Epstein Barr Virus (EBV) positive, originated tumorigenic cell cultures and displayed a mutational burden and an expression profile distinct from gastric adenocarcinomas. The ability of grafted samples to develop lymphomas did not correlate with patient outcome, nor with the histotype, the lymphocyte infiltration level, or the EBV status of the original gastric tumor, impeding from foreseeing lymphoma onset. Interestingly, lymphoma development was significantly more frequent when primary rather than metastatic samples were grafted. Notably, the development of such lympho-proliferative disease could be prevented by a short rituximab treatment upon mice implant, without negatively affecting gastric carcinoma engraftment. Due to the high frequency of human lymphoma onset, our data show that a careful histologic analysis is mandatory when generating gastric cancer PDXs. Such care would avoid misleading results that could occur if testing of putative gastric cancer therapies is performed in lymphoma PDXs. We propose rituximab treatment of mice to prevent lymphoma development in PDX models, averting the loss of human-derived samples.
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http://dx.doi.org/10.1016/j.neo.2018.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915970PMC
May 2018

Analysis of patient selection policy and pattern of recurrence after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal carcinomatosis.

Minerva Chir 2018 Apr 1;73(2):133-141. Epub 2018 Feb 1.

Unit of Surgical Oncology, Candiolo Cancer Institute, IRCCS-FPO, Candiolo, Turin, Italy.

Background: Actual cure rate and patterns of recurrence after cytoreductive surgery (CRS) associated to hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with colorectal peritoneal carcinomatosis (PC) are not yet well explored. Moreover, the selection policy to this resource-consuming treatment is still a matter of debate.

Methods: From a dataset of 400 CRS+HIPEC performed between October 1996 and December 2015, we selected 54 consecutive patients with colorectal PC. Exclusion criteria were age>70, PS>2, or disease progression during chemotherapy. From 2004, we also excluded patients with both PCI>16 and poor prognostic factors of primary tumor (i.e. T4, N2 and G3) and only proceeded to HIPEC in case of optimal cytoreduction. Prognostic factors, cure rate and patterns of recurrence were investigated, comparing the two time periods.

Results: After 2004, median overall survival was 52 months, with a 40% 5-year survival. Completeness of cytoreduction, primary tumor histology and time period were independent prognostic factors. Median recurrence-free survival was 16 months. A relapse was detected in 41 out of 46 patients with optimal cytoreduction. Main sites of first relapse were peritoneum (73%), and distant metastases (37%), mainly to liver and lungs. Peritoneal and liver/lung metastases presented as isolated recurrence in 73% and 58% of cases, respectively.

Conclusions: By a selection policy based on patient, disease extension and primary tumor factors, a median survival higher than 50 months can be expected. Most patients will eventually recur, mainly in the peritoneum. The pattern of recurrence suggests a potential role for more effective intraperitoneal therapies and repeat surgical treatments.
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http://dx.doi.org/10.23736/S0026-4733.18.07547-8DOI Listing
April 2018

Low-dose Pressurized Intrathoracic Aerosol Chemotherapy (PITAC) as an Alternative Therapy for Pleuropulmonary Involvement in Pseudomyxoma Peritonei.

Anticancer Res 2018 02;38(2):929-932

Unit of Surgical Oncology, Candiolo Cancer Institute, IRCCS - FPO, Candiolo, Italy.

Background/aim: Pseudomyxoma peritonei (PMP) is a rare disease characterized by mucinous ascites and widespread peritoneal implants. It usually originates from the rupture of an adenoma/adenocarcinoma of the appendix. Although this tumor is only superficially invasive and does not metastasize, it could be a fatal disease. Extra-abdominal spread of PMP is an unusual occurrence with few reports in medical literature.

Case Report: A 50-year-old man was diagnosed with PMP according to the findings of thorax and abdomen CT scan and cytologic and histological examinations. The radiological exam showed irregular thickening on the surface of left diaphragmatic and parietal pleura.

Results: First, cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy (HIPEC) for the abdominal disease was performed. Histopathological examination confirmed the diagnosis of low grade PMP. The radiological evaluation performed 5 months later showed a dimensional increase in pleural nodules. The treatment consisted of an extensive intrathoracic cytoreductive surgery in combination with pressurized intra-thoracic aerosol chemotherapy (PITAC). Postoperative course was uneventful.

Conclusion: PMP with pleural extension is a rare phenomenon and carries an unfavourable prognosis. Due to the rarity of this presentation, its correct treatment is still unclear. We present a therapeutic approach to be applied in selected patients.
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http://dx.doi.org/10.21873/anticanres.12305DOI Listing
February 2018

Is Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Justified for Biphasic Variants of Peritoneal Mesothelioma? Outcomes from the Peritoneal Surface Oncology Group International Registry.

Ann Surg Oncol 2018 Mar 19;25(3):667-673. Epub 2017 Dec 19.

Surgical Oncology Service, Department of General Surgery, Wake Forest Baptist Health, Winston-Salem, NC, USA.

Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has dramatically improved the survival of patients with epithelioid peritoneal mesothelioma. It is unknown if CRS/HIPEC is indicated for the more aggressive biphasic mesothelioma variant.

Methods: A retrospective analysis of the Peritoneal Surface Oncology Group International (PSOGI) registry including data from 33 centers was performed. Survival was reviewed based on mesothelioma type, completion of cytoreduction, and volume of disease.

Results: Overall, 484 of 1165 (41.5%) CRS/HIPEC procedures with complete CC0 and CC1 cytoreductions were analyzed; 450 (93%) procedures were performed for epithelioid mesotheliomas, while 34 (7%) were performed for biphasic mesotheliomas. For patients with CC0 resection, 5-year survival was 64.5 and 50.2% (median 7.8 and 6.8 years; p = 0.015) for epithelioid and biphasic mesotheliomas, respectively, while inclusion of CC1 resections in the analysis resulted in inferior 5-year survival of 62.9% and 41.6% (median 7.8 and 2.8 years; p = 0.0012), respectively. Incomplete CC2 resections for biphasic primaries resulted in a median survival of 4.3 months. Univariate analysis of the biphasic cohort indicated Peritoneal Cancer Index (PCI; p = 0.015), CC status of resection (p < 0.0001), and Ki67 (p = 0.04) as predictors of survival. Systemic chemotherapy before (p = 0.55) or after (p = 0.7) CRS/HIPEC did not influence survival. In multivariate analysis, only PCI (p = 0.03) and CC (p = 0.04) remained significant.

Conclusions: Long-term survival is achievable in patients with low-volume biphasic mesothelioma after complete macroscopic cytoreduction. Biphasic peritoneal mesotheliomas should not be considered as an absolute contraindication for CRS/HIPEC if there is low-volume disease and if complete cytoreduction can be achieved.
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http://dx.doi.org/10.1245/s10434-017-6293-5DOI Listing
March 2018

Impact of a risk-based follow-up in patients affected by gastrointestinal stromal tumour.

Eur J Cancer 2017 06 24;78:122-132. Epub 2017 Apr 24.

Sarcoma Unit, Division of Medical Oncology Candiolo Cancer Institute - FPO, IRCCS, Strada Provinciale 142, Km 3.95, 10060 Candiolo, TO, Italy; University of Torino, Department of Oncology, Regione Gonzole, 10, 10043 Orbassano, TO, Italy. Electronic address:

Background: Follow-up aims to precociously identify recurrences, metastases or treatment-related adverse events so as to undertake the appropriate therapy. Guidelines admit lack of knowledge on optimal surveillance schedule, but suggest follow-up based on experts' opinion and risk stratification. To identify the impact, if any, of regular follow-up, we interrogated our prospectively collected database whether early detection of recurrences affected both clinical management and, likely, the outcome.

Patients And Methods: We required information to be available on primary surgery and ≥3°years of follow-up for non-recurring patients. We analysed recurrence characteristics (asymptomatic versus symptomatic, low- versus high tumour burden) and computed tomography (CT) scan counts to detect one recurrence. Kaplan-Meier method estimated recurrence-free survival (RFS), post-recurrence progression-free survival (PR-PFS), and disease-specific overall survival (OS). Comparisons used Hazard ratios (HR) with 95% confidence intervals (CIs). Multivariate analyses employed the Cox proportional hazards model. All tests were two-sided.

Results: Between 01/2001 and 12/2012 we found 233 study-eligible patients. Estimated 5- and 10-year RFS were 61.8% and 50.4%, respectively. After a 68-month median follow-up, we observed 94 (40.3%) recurrences [73/94 (77.7%) asymptomatic versus 21/94 (22.3%) symptomatic and 45/94 (47.9%) low- versus 49/94 (52.1%) high tumour burden]. Multivariate analysis revealed that symptomatic and high tumour burden recurrences were highly predictive of both worse PR-PFS (HR:3.19, P < 0.001; HR:2.80, P = 0.003, respectively) and OS (HR:3.65, P < 0.001; HR:2.38, P = 0.026, respectively). Finally, 29 second (primary) cancers were detected during follow-up.

Conclusions: Regular follow-up detects recurrences at an earlier stage and may be associated with a better PR-PFS and OS for these patients. In the absence of randomised trials, these evidences support follow-up effort and cost.
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http://dx.doi.org/10.1016/j.ejca.2017.03.025DOI Listing
June 2017

1st Evidence-based Italian consensus conference on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinosis from ovarian cancer.

Tumori 2017 Nov 20;103(6):525-536. Epub 2017 Apr 20.

Abdominal Oncology Department, Fondazione Giovanni Pascale, IRCCS, Naples - Italy.

Ovarian cancer (OC) remains relatively rare, although it is among the top 4 causes of cancer death for women younger than 50. The aggressive nature of the disease and its often late diagnosis with peritoneal involvement have an impact on prognosis. The current scientific literature presents ambiguous or uncertain indications for management of peritoneal carcinosis (PC) from OC, both owing to the lack of sufficient scientific data and their heterogeneity or lack of consistency. Therefore, the Italian Society of Surgical Oncology (SICO), the Italian Society of Obstetrics and Gynaecology, the Italian Association of Hospital Obstetricians and Gynaecologists, and the Italian Association of Medical Oncology conducted a multidisciplinary consensus conference (CC) on management of advanced OC presenting with PC during the SICO annual meeting in Naples, Italy, on September 10-11, 2015. An expert committee developed questions on diagnosis and staging work-up, indications, and procedural aspects for peritonectomy, systemic chemotherapy, and hyperthermic intraperitoneal chemotherapy for PC from OC. These questions were provided to 6 invited speakers who answered with an evidence-based report. Each report was submitted to a jury panel, representative of Italian experts in the fields of surgical oncology, gynecology, and medical oncology. The jury panel revised the reports before and after the open discussion during the CC. This article is the final document containing the clinical evidence reports and statements, revised and approved by all the authors before submission.
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http://dx.doi.org/10.5301/tj.5000623DOI Listing
November 2017

Single-port access for Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC): technique, feasibility and safety.

Pleura Peritoneum 2016 Dec 15;1(4):217-222. Epub 2016 Dec 15.

Unit of Surgical Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.

Background: Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a drug delivery system for treatment of peritoneal metastasis (PM). A limitation of this technique is the non-access rate (10-15 %) due to peritoneal adhesions. The aim of the study was to assess feasibility and safety of the single-port access technique for PIPAC.

Methods: Single-center, pilot study. Case series, retrospective analysis on 17 patients with PM of various origin treated with intraperitoneal cisplatin, doxorubicin and/or oxaliplatin administered as PIPAC. Single-port access was attempted in all patients by minilaparotomy.

Results: Twenty-nine PIPAC procedures were performed. Nine patients were subjected to 1 PIPAC, four patients to 2 PIPAC and four patients to 3 PIPAC. Access to peritoneal cavity was possible in all cases. There was no bowel access lesion. Tightness of the abdomen (CO-flow = 0) was achieved in all cases. No postoperative complications according to CTCAE (Common Terminology Criteria for Adverse Events)>2 were observed, no re-laparotomies required and no postoperative mortality recorded.

Conclusions: Single port-access is feasible and safe for PIPAC. Potential advantages over multiple trocars technique are a lower non-access rate, a lower risk of bowel lesions and a better tightness of the abdomen. This has now to be confirmed in a comparative study.
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http://dx.doi.org/10.1515/pp-2016-0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386499PMC
December 2016

Cytoreduction (Peritonectomy Procedures) Combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Advanced Ovarian Cancer: Retrospective Italian Multicenter Observational Study of 511 Cases.

Ann Surg Oncol 2017 Apr 28;24(4):914-922. Epub 2016 Nov 28.

Department of Surgery 'P. Valdoni', Sapienza University of Rome, Rome, Italy.

Purpose: The aim of this study was to help with the process of selecting patients with advanced ovarian cancer to undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) by analyzing outcome data at distinct clinical time points reflecting the natural history of the disease.

Methods: In a retrospective Italian multicenter study investigating patients with advanced ovarian cancer who underwent CRS plus HIPEC between 1998 and 2014, we analyzed data for consecutive patients at eight treatment time points: primary debulking surgery (PDS); interval debulking surgery after partial response, after no response, and after a pathologic complete response to neoadjuvant chemotherapy; first recurrence with a progression-free interval >12, <12 months, or >12 months in patients who underwent further chemotherapy before CRS and HIPEC; and patients who underwent two or more CRS procedures and chemotherapy lines before CRS and HIPEC.

Results: The 511 enrolled patients underwent 3373 procedures; 72.6% achieved complete cytoreduction, with an overall major morbidity of 17.4%. At a median follow-up of 53.8 months, overall survival (OS) was 54.2 months (95% confidence interval [CI] 44-58.4) and progression-free (PFS) survival was 16.6 months (95% CI 14.7-19.1). Outcome analysis in patients in whom CRS plus HIPEC was used for primary advanced cancer or recurrent ovarian cancer showed significant differences in OS and PFS according to the time points analyzed. Multivariate analysis identified completeness of CRS, Peritoneal Cancer Index, and the times when patients underwent CRS plus HIPEC as independent prognostic factors.

Conclusions: This selective information on survival should help in interpreting the findings from ongoing randomized studies focusing on CRS plus HIPEC in patients with advanced ovarian cancer.
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http://dx.doi.org/10.1245/s10434-016-5686-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339330PMC
April 2017

Safety and feasibility of pressurized intraperitoneal aerosol chemotherapy (PIPAC) associated with systemic chemotherapy: an innovative approach to treat peritoneal carcinomatosis.

World J Surg Oncol 2016 Apr 29;14:128. Epub 2016 Apr 29.

Unit of Surgical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Strada Provinciale 142, km 3.95, 10060, Candiolo, TO, Italy.

Background: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new treatment that applies chemotherapeutic drugs into the peritoneal cavity as an aerosol under pressure. It improves local bioavailability of chemotherapeutic drugs as compared with conventional intraperitoneal chemotherapy. It has been proved to be safe and feasible if performed as an exclusive treatment in patients affected by peritoneal carcinomatosis. The first results in patients treated with PIPAC associated with systemic chemotherapy are presented.

Methods: Between June 2015 and February 2016, 57 PIPAC applications with oxaliplatin or cisplatin + doxorubicin every 6 weeks at 37 °C and 12 mmHg for 30 min were performed. Forty PIPAC procedures performed in 14 patients were included in this study; thirteen patients were undergoing systemic chemotherapy with a wash-out interval of at least 2 weeks before and 1 week after each PIPAC. Safety, tolerability, and postoperative complications were assessed by collection of adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) 2.

Results: Forty PIPAC administrations were performed in 14 patients with no major perioperative complications. CTCAE grades 1 and 2 were observed after six and eight procedures, respectively, for abdominal pain and nausea. Renal and hepatic functions were not impaired; no cumulative renal toxicity was observed after repeated PIPAC procedures in association with systemic chemotherapy.

Conclusions: These preliminary data show that the association of PIPAC and systemic chemotherapy does not induce significant hepatic and renal toxicity. It allows inclusion of patients with extraperitoneal disease or at a high risk of developing it. Further studies are needed to assess whether this combination therapy could become part of the standard treatment for peritoneal carcinomatosis.
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http://dx.doi.org/10.1186/s12957-016-0892-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850728PMC
April 2016

Xenopatients show the need for precision medicine approach to chemotherapy in ovarian cancer.

Oncotarget 2016 May;7(18):26181-91

Department of Oncology, University of Torino, Candiolo, Torino, Italy.

Platinum-based chemotherapy is the recommended first-line treatment for high-grade serous (HGS) epithelial ovarian cancer (EOC). However, most patients relapse because of platinum refractory/resistant disease. We aimed at assessing whether other drugs, commonly used to treat relapsed HGS-EOC and poorly active in this clinical setting, might be more effective against chemotherapy-naïve cancers. We collected couples of HGS-EOC samples from the same patients before and after neo-adjuvant platinum-based chemotherapy. Samples were propagated as Patient Derived Xenografts (PDXs) in immunocompromised mice ("xenopatients"). Xenopatients were treated in parallel with carboplatin, gemcitabine, pegylated liposomal doxorubicin (PLD) and trabectedin. PDXs derived from a naïve HSG-EOC showed responsiveness to carboplatin, trabectedin and gemcitabine. The PDXs propagated from a tumor mass of the same patient, grown after carboplatin therapy, did no longer respond to trabectedin and gemcitabine and showed heterogeneous response to carboplatin. In line, the patient experienced clinically platinum-sensitivity first and then discordant responses of different tumor sites to platinum re-challenge. Loss of PDX responsiveness to drugs was associated with 4-fold increase of NR2F2 gene expression. PDXs from another naïve tumor showed complete response to PLD, which was lost in the PDXs derived from a mass grown in the same patient after platinum-based chemotherapy. This patient showed platinum refractoriness and responded poorly to PLD as second-line treatment. PDX response to PLD was associated with high expression of TOP2A protein. PDXs demonstrated that chemotherapy-naïve HGS-EOC might display susceptibility to agents not used commonly as first line treatment. Data suggest the importance of personalizing also chemotherapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041973PMC
http://dx.doi.org/10.18632/oncotarget.8325DOI Listing
May 2016

Iterative procedures combining cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for isolated peritoneal recurrence.

Int J Hyperthermia 2014 Dec;30(8):565-9

Unit of Surgical Oncology, Candiolo Cancer Institute , Fondazione del Piemonte per l'Oncologia, Istituto di Ricerca e Cura del Cancro a carattere Scientifico , Turin and.

Purpose: The aim of this study was to analyse feasibility, morbidity and outcome of repeat complete cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC). CRS combined with HIPEC is becoming the gold standard treatment for resectable peritoneal carcinomatosis in highly selected patients. As yet treatment of isolated peritoneal recurrence with iterative CRS and HIPEC has not been thoroughly explored.

Materials And Methods: We selected 16 patients presenting isolated peritoneal recurrence who had undergone iterative CRS and HIPEC from a dataset of 322 CRS associated with HIPEC performed between 1996 and 2012.

Results: Peritoneal carcinomatosis (PC) was due to colorectal and ovarian cancer, peritoneal mesothelioma and pseudomyxoma peritonei (PMP). Disease-free survival (DFS) was 13 months after the first procedure and 13.7 months after the second one. Overall morbidity rate was 43.7% (7/16) for all patients, with grade III-IV complications in three patients (18.7%).

Conclusions: Iterative procedures combining cytoreductive surgery and HIPEC are feasible with acceptable morbidity and mortality rates in strictly selected patients. DFS following repeated CRS and HIPEC is comparable to that registered after the first procedure.
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http://dx.doi.org/10.3109/02656736.2014.974693DOI Listing
December 2014

Radiofrequency vessel-sealing system versus the clamp-crushing technique in liver transection: results of a prospective randomized study on 100 consecutive patients.

HPB (Oxford) 2014 Aug 28;16(8):707-12. Epub 2014 Jan 28.

Department of Surgical Oncology, Institute for Cancer Research and Treament (IRCC), Candiolo (TO), Italy.

Background: Liver transection is considered a critical factor influencing intra-operative blood loss. A increase in the number of complex liver resections has determined a growing interest in new devices able to 'optimize' the liver transection. The aim of this randomized controlled study was to compare a radiofrequency vessel-sealing system with the 'gold-standard' clamp-crushing technique.

Methods: From January to December 2012, 100 consecutive patients undergoing a liver resection were randomized to the radiofrequency vessel-sealing system (LF1212 group; N = 50) or to the clamp-crushing technique (Kelly group, N = 50).

Results: Background characteristics of the two groups were similar. There were not significant differences between the two groups in terms of blood loss, transection time and transection speed. In spite of a not-significant larger transection area in the LF1212 group compared with the Kelly group (51.5 versus 39 cm(2) , P = 0.116), the overall and 'per cm(2) ' blood losses were similar whereas the transection speed was better (even if not significantly) in the LF1212 group compared with the Kelly group (1.1 cm(2) /min versus 0.8, P = 0.089). Mortality, morbidity and bile leak rates were similar in both groups.

Conclusions: The radiofrequency vessel-sealing system allows a quick and safe liver transection similar to the gold-standard clamp-crushing technique.
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http://dx.doi.org/10.1111/hpb.12207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113252PMC
August 2014

MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer liver metastases.

Ann Surg 2013 Jun;257(6):1089-95

Laboratory of Oncogenomics, IRC@C: Institute for Cancer Research at Candiolo, Italy.

Objective: Upon colon cancer metastasis resection in liver, disease outcome is heterogeneous, ranging from indolent to very aggressive, with early recurrence. The aim of this study is to investigate the capability of metastasis associated in colon cancer 1 (MACC1) levels measured in liver metastasis specimens to predict further recurrence of the disease.

Methods: Gene expression and gene dosage of MACC1, hepatocyte growth factor (HGF), and hepatocyte growth factor receptor (MET) were assessed using quantitative realtime polymerase chain reaction on a cohort of 64 liver metastasis samples from patients with complete follow-up of 36 months and detailed clinical annotation. The most relevant mutations associated to prognosis in colorectal cancer, KRAS, and PIK3CA were assessed on the same specimens with Sanger sequencing.

Results: Receiver operating characteristic (ROC) analysis revealed that MACC1 mRNA abundance is a good indicator of metastatic recurrence (AUC = 0.65, P < 0.05), whereas no such results were obtained with MET and HGF, nor with gene dosage. Generation of MACC1-based risk classes was capable of successfully separating patients into poor and good prognosis subgroups [hazard ratio (HR) = 5.236, 95% confidence interval (CI) = 1.2068-22.715, P < 0.05]. Also KRAS mutation was significantly associated with higher risk of recurrence (HR = 2.07, 95% CI = 1.048-4.09, P < 0.05). Cox regression multivariate analysis supported the independence of MACC1, but not KRAS, from known prognostic clinical information (Node Size HR = 3.155, 95% CI = 1.4418-6.905, P < 0.001, Preoperative carcinoembryonic antigen HR = 2.359, 95% CI = 1.0203-5.452, P < 0.05, MACC1 HR = 7.2739, 95% CI = 1.6584-31.905, P < 0.01).

Conclusions: MACC1, a new easily detectable biomarker in cancer, is an independent prognostic factor of recurrence after liver resection of colorectal cancer metastasis.
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http://dx.doi.org/10.1097/SLA.0b013e31828f96bcDOI Listing
June 2013

Mechanisms inducing low bone density in Duchenne muscular dystrophy in mice and humans.

J Bone Miner Res 2011 Aug;26(8):1891-903

Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.

Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro-computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patients showed low bone mineral density (BMD) Z-scores and high bone-resorption marker and serum IL-6. Human primary osteoblasts from healthy donors incubated with 10% sera from DMD patients showed decreased nodule mineralization. Many osteogenic genes were downregulated in these cultures, including osterix and osteocalcin, by a mechanism blunted by an IL-6-neutralizing antibody. In contrast, the mRNAs of osteoclastogenic cytokines IL6, IL11, inhibin-βA, and TGFβ2 were increased, although only IL-6 was found to be high in the circulation. Consistently, enhancement of osteoclastogenesis was noted in cultures of circulating mononuclear precursors from DMD patients or from healthy donors cultured in the presence of DMD sera or IL-6. Circulating IL-6 also played a dominant role in osteoclast formation because ex vivo wild-type calvarial bones cultured with 10% sera of MDX mice showed increase osteoclast and bone-resorption parameters that were dampen by treatment with an IL-6 antibody. These results point to IL-6 as an important mediator of bone loss in DMD and suggest that targeted anti-IL-6 therapy may have a positive impact on the bone phenotype in these patients.
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http://dx.doi.org/10.1002/jbmr.410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150693PMC
August 2011

Treatment of peritoneal carcinomatosis from colonic cancer by cytoreduction, peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC). Experience of ten years.

In Vivo 2010 Jan-Feb;24(1):79-84

Department of General and Oncological Surgery, San Giuseppe Hospital, Viale Boccaccio, 12, 50053 Empoli (Florence), Italy.

Introduction: Peritoneal carcinomatosis (PC) is one of the routes of dissemination of abdominal neoplasms and is generally considered a lethal disease, with a poor prognosis by conventional chemotherapeutic treatments. While systemic chemotherapy has little impact on the treatment of peritoneal disease, some centers have reported encouraging results with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). This approach is based on surgical cytoreduction of the primary tumour, peritonectomy (stripping of implants on the peritoneal surface) and HIPEC. The rationale of this treatment, after macroscopic disease removal, is to obtain an elevated and persistent drug concentration in the peritoneal cavity, with limited systemic effects. Many studies have reported encouraging results on overall survival (OS) and the disease-free interval in patients affected by PC.

Patients And Methods: From October 1997 to November 2008, 411 operations for PC were performed in our institution; in 232 cases, cytoreduction plus HIPEC was carried out. Out of 72 operations for colonic cancer: 40 cytoreductions plus HIPEC, 12 cytoreductions+ EPIC (early postoperative intraperitoneal chemotherapy) and 16 debulking or explorative laparoscopies/laparotomies were performed. For the present study, the 40 patients who had undergone cytoreduction plus HIPEC for PC of colorectal cancer (CRC) were considered.

Results: The complication rate was 55% (22/40) and mortality rate 2.5% (1/40). The specific features of both groups were considered for the survival curves and complication rates, with special reference to the peritoneal carcinomatosis index (PCI; range 0, absence of disease to 39) and completeness of cytoreduction score (CCR; 0, no residual tumor, to CCR 3, residual nodules greater than 25 mm). In Group A, patients operated on prior to 2002, the median survival time was 16.7 months compared to 24.6 months for Group B, those operated on after 2002. The poor survival of Group A seemed to be related to higher PCI and CCR scores.

Conclusion: Correct patient selection based on a maximum PCI of 16, associated with complete cytoreduction (CCR-0), produced encouraging results in our experience. To improve this encouraging survival outcome, it is very important to unify the surgical experience of expertise centres. Our results also suggest the need for an integrated approach to this condition to identify the correct aspect of the surgical domain and results that may be influencing the prognosis and the evolution of this patients.
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April 2010