HSF-1/miR-145-5p transcriptional axis enhances hyperthermic intraperitoneal chemotherapy efficacy on peritoneal ovarian carcinosis.

Hyperthermic intraperitoneal administration of chemotherapy (HIPEC) increases local drug concentrations and reduces systemic side effects associated with prolonged adjuvant intraperitoneal exposure in patients affected by either peritoneal malignancies or metastatic diseases originating from gastric, colon, kidney, and ovarian primary tumors. Mechanistically, the anticancer effects of HIPEC have been poorly explored. Herein we documented that HIPEC treatment promoted miR-145-5p expression paired with a significant downregulation of its oncogenic target genes c-MYC, EGFR, OCT4, and MUC1 in a pilot cohort of patients with ovarian peritoneal metastatic lesions. RNA sequencing analyses of ovarian peritoneal metastatic nodules from HIPEC treated patients unveils HSF-1 as a transcriptional regulator factor of miR-145-5p expression. Notably, either depletion of HSF-1 expression or chemical inhibition of its transcriptional activity impaired miR-145-5p tumor suppressor activity and the response to cisplatin in ovarian cancer cell lines incubated at 42 °C. In aggregate, our findings highlight a novel transcriptional network involving HSF-1, miR145-5p, MYC, EGFR, MUC1, and OCT4 whose proper activity contributes to HIPEC anticancer efficacy in the treatment of ovarian metastatic peritoneal lesions.

Gastric Cancer (GC) with Peritoneal Metastases (PMs): An Overview of Italian PSM Oncoteam Evidence and Study Purposes.

Gastric cancer (GC) continues to be one of the leading types of malignancies worldwide, despite an ongoing decrease in incidence. It is the fifth most frequent type of cancer in the world and the fourth leading cause of cancer death. Peritoneal metastases (PMs) occur in 20-30% of cases during the natural history of the disease. Systemic chemotherapy (SC) is undoubtedly the standard of care for patients with GC and PMs. However, with the development of highly effective regimens (SC combined with intraperitoneal chemotherapy), significant tumor shrinkage has been observed in many patients with synchronous GC and PMs, allowing some to undergo curative resection "conversion surgery" with long-term survival. In recent years, there has been growing interest in intraperitoneal chemotherapy for PMs, because the reduced drug clearance associated with the peritoneal/plasma barrier allows for direct and prolonged drug exposure with less systemic toxicity. These procedures, along with other methods used for peritoneal surface malignancies (PSMs), can be used in GCs with PMs as neoadjuvant chemotherapy or adjuvant treatments after radical surgery or as palliative treatments delivered either laparoscopically or-more recently-as pressurized intraperitoneal aerosol chemotherapy. The great heterogeneity of patients with stage IV gastric cancer did not allow us to carry out a systemic review; therefore, we limited ourselves to providing readers with an overview to clarify the indications and outcomes of integrated treatments for GCs with PMs by analyzing reports from the international clinical literature and the specific experiences of our oncoteam.

Complications and Mortality Rate of Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy: Italian Peritoneal Surface Malignancies Oncoteam Results Analysis.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy may significantly improve survival for selected patients with peritoneal surface malignancies, but it has always been criticized due to the high incidence of postoperative morbidity and mortality. METHODS: Data were collected from nine Italian centers with peritoneal surface malignancies expertise within a collaborative group of the Italian Society of Surgical Oncology. Complications and mortality rates were recorded, and multivariate Cox analysis was used to identify risk factors. RESULTS: The study included 2576 patients. The procedure was mostly performed for ovarian (27.4%) and colon cancer (22.4%). The median peritoneal cancer index was 13. Overall postoperative morbidity and mortality rates were 34% and 1.6%. A total of 232 (9%) patients required surgical reoperation. Multivariate regression logistic analysis identified the type of perfusion (p ≤ 0.0001), body mass index (p ≤ 0.0001), number of resections (p ≤ 0.0001) and colorectal resections (p ≤ 0.0001) as the strongest predictors of complications, whereas the number of resections (p ≤ 0.0001) and age (p = 0.01) were the strongest predictors of mortality. CONCLUSIONS: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is a valuable option of treatment for selected patients with peritoneal carcinomatosis providing low postoperative morbidity and mortality rates, if performed in high-volume specialized centers.

Cytoreductive Surgery (CRS) and HIPEC for Advanced Ovarian Cancer with Peritoneal Metastases: Italian PSM Oncoteam Evidence and Study Purposes.

Ovarian cancer is the eighth most common neoplasm in women with a high mortality rate mainly due to a marked propensity for peritoneal spread directly at diagnosis, as well as tumor recurrence after radical surgical treatment. Treatments for peritoneal metastases have to be designed from a patient's perspective and focus on meaningful measures of benefit. Hyperthermic intraperitoneal chemotherapy (HIPEC), a strategy combining maximal cytoreductive surgery with regional chemotherapy, has been proposed to treat advanced ovarian cancer. Preliminary results to date have shown promising results, with improved survival outcomes and tumor regression. As knowledge about the disease process increases, practice guidelines will continue to evolve. In this review, we have reported a broad overview of advanced ovarian cancer management, and an update of the current evidence. The future perspectives of the Italian Society of Surgical Oncology (SICO) are discussed conclusively.

Laparoscopic Cytoreduction Combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Peritoneal Surface Malignancies (PSM): Italian PSM Oncoteam Evidence and Literature Review.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has gained increasing acceptance in clinical practice. Performing CRS and HIPEC laparoscopically represents a challenging and intriguing technical evolution. However, the experiences are limited, and the evidence is low. This retrospective analysis was performed on patients treated with laparoscopic CRS-HIPEC within the Italian Peritoneal Surface Malignancies Oncoteam. Clinical, perioperative, and follow-up data were extracted and collected on prospectively maintained databases. We added a systematic review according to the PRISMA method for English-language articles through April 2022 using the keywords laparoscopic, hyperthermic, HIPEC, and chemotherapy. From 2016 to 2022, fourteen patients were treated with Lap-CRS-HIPEC with curative intent within the Italian centers. No conversion to open was observed. The median duration of surgery was 487.5 min. The median Peritoneal Cancer Index (PCI) was 3, and complete cytoreduction was achieved in all patients. Two patients (14.3%) had major postoperative complications, one requiring reintervention. After a median follow-up of 16.9 months, eleven patients were alive without disease (78.6%), two patients developed recurrence (14.3%), and one patient died for unrelated causes (7.1%). The literature review confirmed these results. In conclusion, current evidence shows that Lap-CRS-HIPEC is feasible, safe, and associated with a favorable outcome in selected patients. An accurate patient selection will continue to be paramount in choosing this treatment.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal metastasis of non-primary origin.

PURPOSE: The objective of this study was to analyze the role of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy that has developed in the treatment of patients with peritoneal metastasis of non-primary origin. METHODS: Patients who underwent treatment for secondary gastrointestinal and ovarian malignancies over a 20-year period were reviewed. Survival curves were estimated by the Kaplan-Meier product limit method and the log-rank test was used to assess differences between subgroups. RESULTS: The study included 293 patients. The most common histology was ovarian cancer (56.3%). Median PCI was 16 and CC0-1 resection was obtained in 88.1% of cases. Grade III and IV complications occurred in 12 patients (4.1%) and 47 patients (16%), respectively. The 30- and 60-day mortality rate was 1.3% (4 patients) and 2.4% (7 patients). Five-year OS was 21.7%, 73.6%, 42.1%, and 0 for colorectal, appendiceal, ovarian, and gastric cancer (p = < 0.0001), respectively, whereas 5-year DFS was 12.4%, 48.4%, 24.3%, and 0 (p = < 0.0001), respectively. Survival outcomes were significantly higher for CC0 in each subgroup of patients. CONCLUSION: Despite being a complex procedure, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy should be considered a safe treatment with acceptable postoperative morbidity and mortality rates, if performed in high-volume centers. Good survival outcomes have been increasingly obtained in selected patients with peritoneal metastasis of non-primary origin.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer with Synchronous Peritoneal Metastases: Multicenter Study of 'Italian Peritoneal Surface Malignancies Oncoteam-S.I.C.O.'

BACKGROUND: The development of multimodality treatment, including cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC), has led to promising results in selected patients with peritoneal disease of gastric origin. The aim of this study was to investigate the short- and long-term outcomes of CRS/HIPEC in the treatment of synchronous peritoneal metastasis in gastric cancer. METHODS: The Italian Peritoneal Surface Malignancies Oncoteam-S.I.C.O. retrospective registry included patients with synchronous peritoneal malignancy from gastric cancer submitted to gastrectomy with CRS and HIPEC between 2005 and 2018 from 11 high-volume, specialized centers. RESULTS: A total of 91 patients with a median age of 58 years (range 26-75) were enrolled. The median overall survival (OS) time for the whole group of patients was 20.2 months (95% confidence interval [CI] 11.8-28.5] and the median recurrence-free survival (RFS) was 7.3 months (95% CI 4-10.6). The completeness of cytoreduction score (CCS) of 0 and Peritoneal Cancer Index (PCI) score of ≤ 6 groups showed a significantly better long-term survival (median OS 40.7 and 44.3 months, respectively) compared with the incomplete resected groups (median OS 10.7 months, p = 0.003) and PCI score of > 6 group (median OS 13.4 months, p = 0.005). A significant difference was observed in the survival rate according to neoadjuvant treatment (untreated patients: 10.7 months, 95% CI 5.1-16.2; treated patients: 35.3 months, 95% CI 2.8-67.8; p = 0.022). CONCLUSIONS: In referral centers, CRS and HIPEC after neoadjuvant treatment significantly improved survival in selected patients. Patients with a PCI score ≤ 6, complete cytoreduction, negative nodal involvements, and negative cytology had encouraging results, showing a clinically meaningful survival.

Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis from Epithelial Ovarian Cancer: A 20-Year Single-Center Experience.

Despite improvement in treatments, the peritoneum remains the primary site of relapse in most ovarian cancer cases. Patients who underwent cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis from epithelial ovarian cancer were reviewed. Kaplan-Meier curves and multivariate Cox analyses were used to identify survival rates and prognostic factors. This study included 158 patients. The procedure was mostly performed for recurrent disease (46.8%) and high-grade serous carcinoma (58.2%). The median peritoneal cancer index was 14, and complete cytoreduction was obtained in 87.9% of cases. Grade IV morbidity occurred in 15.2% of patients, mostly requiring surgical reoperation, and one patient (0.6%) died within 90 days. The median follow-up was 63.5 months. The Kaplan-Meier 5-year overall survival (OS) and disease-free survival (DFS) rates were 42.1% and 24.3%, respectively. Multiple regression logistic analyses demonstrated that the completeness of cytoreduction (CC) score (p ≤ 0.0001), pancreatic resection (p ≤ 0.0001) and number of resections (p = 0.001) were significant factors influencing OS; whereas the CC score (p ≤ 0.0001) and diaphragmatic procedures (p = 0.01) were significant for DFS. The addition of hyperthermic intraperitoneal chemotherapy to standard multimodality therapy may improve outcomes in both primary and recurrent epithelial ovarian cancer without impairing early postoperative results, but the exact timing has not yet been established. Prospective randomized studies will clarify the role and indications of this approach.

Feasibility of diaphragmatic interventions in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis: A 20-year experience.

INTRODUCTION: Complete cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is an effective treatment for improving prognosis of selected patients with peritoneal carcinomatosis. The addiction of diaphragmatic procedures may increase the incidence of postoperative respiratory complications. Our goal was to evaluate the early postoperative results following diaphragmatic surgery. METHODS: Prospectively collected data of patients undergoing diaphragmatic surgery between January 2000 and January 2020 were retrospectively analyzed. Chest drains were routinely placed in all cases. Demographics, clinical and perioperative features were evaluated. RESULTS: The study included 222 patients. Peritoneal stripping and full-thickness resections were performed in 165 and 57 cases, respectively. Women and ovarian tumours represented the vast majority of cases. Overall postoperative mortality and morbidity rates were 1.3% (3 patients) and 43.2% (96 patients), respectively. Specific diaphragmatic surgery-related complications was 9.4% (21 patients). No pleural effusion and pneumothotrax occurred. The incidence of pneumonia was 1.8% (4 patients), each due to systemic bacterial origin, 2 (0.9%) of which required Intensive Care Unit-readmission. Postoperative bleeding was observed in 15 (6.7%) cases, 12 (5.4%) of which required reoperation. A comparison with 105 patients who operated during the same period without diaphragmatic surgery was performed and by multivariate analysis, Peritoneal Cancer Index, histology and overall morbidity resulted significantly associated with diaphragmatic surgery. CONCLUSION: Diaphragmatic surgery during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is often required in order to obtain complete resection. It may be associated with higher postoperative morbidity, especially bleeding, but routine placement of chest drains may reduce the incidence of adverse respiratory events.

European single-center experience on 356 operated patients for gastric cancer.

AIM: Surgery in association with lymphadenectomy is the treatment of choice for the gastric adenocarcinoma. Aim is to report our experience in the surgical treatment of gastric cancer in a European center. MATERIAL AND METHODS: A prospectively maintained database identified 515 patients. Staging laparoscopy was performed to rule out peritoneal carcinomatosis in suspicious cases. Type of surgery and lymphadenectomy were determined according to the Japanese guidelines and pathological staging according to the TNM classification. Survival was analysed using the Kaplan-Meier method. RESULTS: Staging laparoscopy avoided 150 (29.1%) unnecessary laparotomies. A total of 356 patients underwent surgery with curative intent. Overall postoperative morbidity and mortality rates were 16.8% and 5.9%, respectively. Two hundred-fifty-one patients (70%) were T3-T4. Negative lymph-nodes were observed in 71 patients (19.9%). One-hundred- seventy-nine were at least stage III. At a mean follow-up of 80.6 months, the overall and disease-free survival rates were 54.4% and 50.6%, respectively. The survival stratification based on the type of lymphadenectomy showed an overall survival rate of 43% and 65.5% in case of D1 and D2 lymphadenectomy, respectively. Based on the tumor stage the overall survival rate was 90%, 62.7%, 36.4% and the disease-free survival was 90%, 54.3%, 31.3%, for stage I, II and III, respectively. CONCLUSIONS: Total or subtotal gastrectomy with D2 lymphadenectomy and adjuvant therapy for the treatment of locally advanced gastric cancer proved a valuable strategy. Staging laparoscopy is recommended. KEY WORDS: Gastric cancer, Laparoscopy, Lymphadenectomy, Prognosis, Surgery.

Cross-sectional analysis of circulating tumor DNA in primary colorectal cancer at surgery and during post-surgery follow-up by liquid biopsy.

BACKGROUND: Liquid biopsy (LB) in early-stage, non-metastatic colorectal cancer (CRC) must be sensitive enough to detect extremely low circulating tumor DNA (ctDNA) levels. This challenge has been seldom and non-systematically investigated. METHODS: Next generation sequencing (NGS) and digital PCR (dPCR) were combined to test tumor DNAs (tDNAs) and paired ctDNAs collected at surgery from 39 patients, 12 of whom were also monitored during the immediate post-surgery follow up. Patients treated for metastatic disease (n = 14) were included as controls. RESULTS: NGS and dPCR concordantly (100% agreement) called at least one single nucleotide variant (SNV) in 34 tDNAs, estimated differences in allelic frequencies being negligible (±1.4%). However, despite dPCR testing, SNVs were only detectable in 15/34 (44.1%) ctDNAs from patients at surgery, as opposed to 14/14 (100%) metastatic patients. This was likely due to striking differences (average 10 times, up to 500) in ctDNA levels between groups. NGS revealed blood-only SNVs, suggesting spatial heterogeneity since pre-surgery disease stages, and raising the combined NGS/dPCR sensitivity to 58.8%. ctDNA levels at surgery correlated with neither tumor size, stage, grade, or nodal status, nor with variant abundance in paired tDNA. LB sensitivity reached 63.6% when ctDNA was combined with CEA. Finally, persistence and absence of ctDNA on the first conventional (month 3) post-surgery follow-up were associated with fast relapse and a disease-free status in 3 and 7 patients, respectively. CONCLUSIONS: A simple clinical NGS/dPCR/CEA combination effectively addresses the LB challenge in a fraction of non-metastatic CRC patients.

Transanal drainage tube: alternative option to defunctioning stoma in rectal cancer surgery?

BACKGROUND: Anastomotic leakage (AL) remains the most dreaded complication after rectal cancer surgery. The aim of this study was to evaluate the role of transanal drainage tube in reducing the incidence, severity and hospital costs respect to defunctioning stoma (DS). METHODS: Considering 429 patients consecutively operated for rectal adenocarcinoma, the tube was placed in 275 (Group A) and not placed in 154 (Group B) patients. A DS was created in a subgroup of 54 patients among the latter. RESULTS: The incidence of AL was significantly higher in Group B (P=0.007). In patients with DS, the incidence was higher than Group A (P=NS). Grade C complications were significantly higher in Group B (P=0.006) and Grade B complications were significantly higher in patients with DS (P=0.03). Estimated economic benefit was 4,000 Euros for each patient. CONCLUSIONS: Transanal drainage tube may be a safe and effective alternative to DS in many cases. The incidence of leakage and Grade C complications are reduced albeit not significantly but Grade B complications are significantly lower. Although the AL incidence was similar in our experience, the tube allows to avoid a stoma-related consequence and the need for reversal procedure with economic benefit.

An 18-Year Experience in Diagnostic Laparoscopy of Peritoneal Carcinomatosis: Results from 744 Patients.

BACKGROUND: Despite accurate preoperative imaging assessment, optimal cytoreductive surgery with hyperthermic intraperitoneal chemotherapy remains unfeasible in many patients with peritoneal carcinomatosis at the time of surgery. The aim of this study was to evaluate the role of diagnostic laparoscopy in the selection of candidates. METHODS: Prospectively collected data of all patients undergoing diagnostic laparoscopy in our Department were retrospectively analyzed. Demographics and perioperative features as well as operative details and outcome were evaluated. RESULTS: The study included 744 consecutive patients. Primary ovarian tumors were the most common indications, followed by gastric tumors and recurrent colorectal cancers. The procedure was successfully completed in 99.73% of cases. Approximately two thirds of them (68%) had undergone previous surgical procedures. The presence of ascites was recorded in 482 patients (64.78%). A total of 374 (50.3%) patients were excluded from surgical exploration. Among those who eventually underwent surgery, CC0 resection was obtained in 64.6% (239) of cases. Understaging of peritoneal carcinomatosis was observed in 11 patients (1.48%). Postoperative mortality was null and 5 (0.8%) complications were observed. Three (0.4%) port-site metastases were recorded at the beginning of the experience. CONCLUSION: Diagnostic laparosocopy is a safe and feasible tool able to improve the selection of patients eligible for cytoreduction with hyperthermic intraperitoneal chemotherapy, at the same time allowing avoiding a significant number of unnecessary laparotomies.

Upfront debulking surgery versus interval debulking surgery for advanced tubo-ovarian high-grade serous carcinoma and diffuse peritoneal metastases treated with peritonectomy procedures plus HIPEC.

BACKGROUND: Whether patients with advanced tubo-ovarian high-grade serous cancer (HGSC) fare better after upfront debulking surgery (UDS) or neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) remains controversial. METHODS: We studied patients with HGSC who underwent UDS or NACT-IDS between July 2000 and December 2015, with peritonectomy procedures combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Clinical reports were included peritoneal cancer index (PCI), NACT responses, surgical complexity score (SCS), completeness of cytoreduction (CC), complete follow-up with timing, site, and treatment of recurrence. Outcome measures were morbidity, progression-free survival (PFS), PFS2, and overall survival during a mean 5-year follow-up. RESULTS: A total of 34 patients (23.6%) underwent UDS and 110 (76.4%) NACT-IDS both combined with HIPEC. At a median 66.3-month follow-up, patients who underwent UDS or NACT-IDS had similar outcomes. NACT subgroup responses correlated with PCI, SCS, morbidity, and CC. Patients who underwent UDS had lower recurrence rates than those who responded partly or poorly to NACT (PFS, P < .04; PFS2, P < .01). Despite HIPEC, the peritoneal disease recurred in 42.5% of the overall patients. CONCLUSION: In patients with primary HGSC who undergo UDS or NACT-IDS, despite similar outcomes, peritonectomy procedures combined with HIPEC seem unable to prevent peritoneal recurrence.

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

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.