Roberto Tozzi

The Impact of Neoadjuvant Chemotherapy on Ovarian Cancer Tumor Microenvironment: A Systematic Review of the Literature

Immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has shown limited efficacy in treating ovarian cancer (OC), possibly due to diverse T cell infiltration patterns in the tumor microenvironment. This review explores how neoadjuvant chemotherapy (NACT) impacts the immune landscape of OC, focusing on tumor-infiltrating lymphocytes (TILs), PD-1/PD-L1 expression, and their clinical implications. A comprehensive literature search across four databases yielded nine relevant studies. These studies evaluated stromal (sTILs) and intra-epithelial (ieTILs) TILs before and after NACT. sTIL responses varied, impacting prognostic outcomes, and ieTILs increased in some patients without clear survival associations. PD-L1 expression after NACT correlated with improved overall survival (OS), and increases in granzyme B+ and PD-1 correlated with longer progression-free survival (PFS). Remarkably, reduced FoxP3+ TILs post-NACT correlated with better prognosis. NACT often increases sTIL/ieTIL and CD8+ subpopulations, but their correlation with improved PFS and OS varies. Upregulation of co-inhibitory molecules, notably PD-L1, suggests an immunosuppressive response to chemotherapy. Ongoing trials exploring neoadjuvant ICIs and chemotherapy offer promise for advancing OC treatment. Standardized measurements assessing TIL density, location, and heterogeneity are crucial for addressing genetic complexity and immunological heterogeneity in OC.

Peritonectomy and resection of mesentery during Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer: A phase I-II trial

To describe the surgical technique, assess feasibility, efficacy, and safety of peritonectomy and/or resection of mesentery (P-Rme) during Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer (OC). In April 2009 we registered a protocol study on the safety and feasibility of P-Rme. In the period April 2009-December 2022, 687 patients with FIGO stage IIIC-IV ovarian cancer underwent VPD. One hundred and twenty-nine patients (18.7%) had extensive disease on the mesentery and underwent P-Rme. Feasibility was assessed as the number of procedures completed. Efficacy was measured as the rate of Complete Resection (CR). Safety was defined by the intra- and post-operative morbidity rate specifically associated with these procedures. In all patients P-Rme was successfully completed. P-me was performed in 82 patients and R-me in 47, both procedures in 23 patients. CR was achieved in all 129 patients with an efficacy of 100%. Intra-operatively 5 patients out of 129 experienced small bowel loop surgical devascularization. They required small bowel resection and anastomosis. The procedure specific morbidity was 3.8%. No post-operative complication was related to P-Rme. At 64 months median follow-up, survival outcomes in the study group were similar to patients in the control group. Overall, almost 20% of the VPD patients needed P-Rme to obtain a CR. P-Rme was a safe and effective step during VPD. The rate of CR in the study group was 100% achieved thanks to the addition of the P-Rme. No procedure specific post-operative complications occurred but 3.8% of the patients had unplanned additional surgery related to these procedures.

Sentinel node mapping in high-intermediate and high-risk endometrial cancer: Analysis of 5-year oncologic outcomes

To assess 5-year oncologic outcomes of apparent early-stage high-intermediate and high-risk endometrial cancer undergoing sentinel node mapping versus systematic lymphadenectomy. This is a multi-institutional retrospective, propensity-matched study evaluating data of high-intermediate and high-risk endometrial cancer (according to ESGO/ESTRO/ESP guidelines) undergoing sentinel node mapping versus systematic pelvic lymphadenectomy (with and without para-aortic lymphadenectomy). Survival outcomes were assessed using Kaplan-Meier and Cox proportional hazard methods. Overall, the charts of 242 patients with high-intermediate and high-risk endometrial cancer were retrieved. Data on 73 (30.1%) patients undergoing hysterectomy plus sentinel node mapping were analyzed. Forty-two (57.5%) and 31 (42.5%) patients were classified in the high-intermediate and high-risk groups, respectively. Unilateral sentinel node mapping was achieved in all patients. Bilateral mapping was achieved in 67 (91.7%) patients. Three (4.1%) patients had site-specific lymphadenectomy (two pelvic areas only and one pelvic plus para-aortic area), while adjunctive nodal dissection was omitted in the hemipelvis of the other three (4.1%) patients. Sentinel nodes were detected in the para-aortic area in eight (10.9%) patients. Twenty-four (32.8%) patients were diagnosed with nodal disease. A propensity-score matching was used to compare the aforementioned group of patients undergoing sentinel node mapping with a group of patients undergoing lymphadenectomy. Seventy patient pairs were selected (70 having sentinel node mapping vs. 70 having lymphadenectomy). Patients undergoing sentinel node mapping experienced similar 5-year disease-free survival (HR: 1.233; 95%CI: 0.6217 to 2.444; p = 0.547, log-rank test) and 5-year overall survival (HR: 1.505; 95%CI: 0.6752 to 3.355; p = 0.256, log-rank test) than patients undergoing lymphadenectomy. Sentinel node mapping does not negatively impact 5-year outcomes of high-intermediate and high-risk endometrial cancer. Further prospective studies are warranted.

Feasibility of laparoscopic Visceral-Peritoneal Debulking (L-VPD) in patients with stage III–IV ovarian cancer: the ULTRA-LAP trial pilot study

A non-randomized prospective clinical trial (ULTRA-LAP) was registered to test safety, side effects and efficacy of laparoscopic Visceral-Peritoneal Debulking (L-VPD) in patients with stage III-IV ovarian cancer (OC). A pilot study was designed to identify which OC patients are suitable to undergo L-VPD. Between March 2016 and October 2021, all consecutive patients with OC underwent exploratory laparoscopy (EXL). All patients whose disease was deemed amenable for a complete resection (CR) at imaging review and EXL, underwent VPD. In all patients a consistent attempt was made at completing L-VPD. Two hundred and eight OC had EXL in the study period: 121 underwent interval VPD and 87 up-front VPD. Overall, 158 patients had VPD by laparotomy (75.9%) and 50 (24.1%) had L-VPD, of which 34 patients as interval (iL-VPD) and 16 as up-front (uL-VPD). Intra- and post-operative morbidity was very low in the L-VPD group. CR rate was 98% in L-VPD group and 94% in VPD. Most common reason for conversion was diaphragmatic disease extending dorsally. In the pilot study of ULTRA-LAP, L-VPD was completed in 24,1% of OC. Initial analysis supports the feasibility of L-VPD in 2 groups of OC: those with no gross disease at interval surgery and those with gross visible disease at upfront or interval surgery, but limited to: pelvis (including recto-sigmoid), gastro colic omentum, peritoneum and diaphragm, the latter not requiring dorsal liver mobilization. Both groups had 100% feasibility and have been thus forth recruited to ULTRA-LAP. ClinicalTrials.gov Identifier: NCT05862740.

The Feasibility of Cardiophrenic Lymphnode Assessment and Removal in Patients Requiring Diaphragmatic Resection During Interval Debulking Surgery for Ovarian Cancer

Several studies have demonstrated the feasibility and role of bulky cardiophrenic lymph nodes (CPLNs) resection during primary debulking surgery (PDS) for stage IV ovarian cancer (OC). However, no studies, to date, investigated the accuracy and feasibility of CPLNs assessment and removal during interval debulking surgery (IDS) after neoadjuvant chemotherapy (NACT). A retrospective analysis of consecutive stage IV OC patients who underwent NACT followed by IDS with CPLNs assessment and/or resection from July 2017 to June 2018. Bulky CPLNs were considered for excision when a full-thickness diaphragmatic resection was required in order to achieve complete tumour resection. A total of 21 ovarian cancer stage IV patients treated with NACT followed by IDS were identified. Seven (33.3%) patients underwent CPLNs resection due to bulky appearance of the CPLNs at the intraoperative palpation. The final histological examination of the CPLNs reported metastatic disease in four (57%) of seven patients. Complete cytoreduction without residual disease was achieved in five cases (71.4%) while in two case (28.6%) optimal cytoreduction was performed. Intra-operative surgical complications occurred in one patient. One patient had a major postoperative complication (Clavien-Dindo 3). Two cases of postoperative cardiac arrhythmia were observed. CPLNs intraoperative assessment is less accurate during IDS compared to previous PDS studies. CPLNs removal during IDS after NACT for stage IV OC could be safely performed to achieve a complete resection.

Feasibility of laparoscopic diaphragmatic peritonectomy during Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer

To describe the surgical technique and evaluate the safety, feasibility and efficacy of laparoscopic diaphragmatic peritonectomy during Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer (OC). This report is part of a Service Evaluation Protocol (Trust number 3267) on laparoscopy in patients with OC following neo-adjuvant chemotherapy. Between April 2015 and November 2017, all patients underwent to exploratory laparoscopy and a selected court was offered laparoscopic VPD. Laparoscopic diaphragmatic surgery was considered if there was no full thickness involvement. Primary endpoints of this part of the study were the safety, feasibility and efficacy of laparoscopic diaphragmatic peritonectomy. We report the surgical technique and outcomes. Ninety-six patients underwent diaphragmatic surgery during the study period. Fifty patients (52.1%) had intra-operative exclusion criteria and/or full thickness diaphragmatic resection, 46 (47.9%) had peritonectomy and were included in the study. Laparoscopic diaphragmatic peritonectomy was performed in 21 patients (45.4%, group 1), while in 25 patients (54.6%, group 2) laparotomy was necessary. Extent of disease and complexity of surgery were similar. Reasons for conversions were disease coalescing the liver to the diaphragm preventing safe mobilization (22 patients) and accidental pleural opening (3 patients). Overall, intra- and post-operative morbidity was lower in group 1 and pulmonary specific morbidity was very low. Diaphragmatic peritonectomy can be safely accomplished by laparoscopy in almost half of the patients with OC whose disease is limited to the diaphragmatic peritoneum.

Interval Debulking Surgery for Advanced Ovarian Cancer in Elderly Patients (≥70 y): Does the Age Matter?

Elderly ovarian cancer (OC) patients are more likely to be managed suboptimally, with worse clinical outcomes as a result. Strategies to decrease morbidity are lacking. A total of 153 patients were referred during the study period. 114 patients underwent IDS after NACT (74.5%), 46 in Group 1 and 68 in Group 2. Elderly patients were more likely to receive more than three cycles of NACT prior to IDS compared to younger patients (39% vs. 19%, Older age should not preclude clinicians from offering ultra-radical resection to patients with advanced OC after NACT. In our series, elderly patients received the same treatment with similar outcomes to the younger group. Clinicians should be encouraged to use CPET for patients' selection following NACT.

Tozzi classification of diaphragmatic surgery in patients with stage IIIC–IV ovarian cancer based on surgical findings and complexity

To introduce a systematic classification of diaphragmatic surgery in patients with ovarian cancer based on disease spread and surgical complexity. For all consecutive patients who underwent diaphragmatic surgery during Visceral-Peritoneal debulking (VPD) in the period 2009-2017, we extracted: initial surgical finding, extent of liver mobilization and type of procedure. Combining these features, we aimed to classify the surgical procedures necessary to tackle different presentation of diaphragmatic disease. We also report histology, intra- and post-operative specific complication rate based on the classification. A total of 170 patients were included in this study, 110 (64.7%) had a peritonectomy, while 60 (35.3%) had a full thickness resection with pleurectomy. We identified 3 types of surgical procedures. Type I treated 28 out of 170 patients (16.5%) who only had anterior diaphragm disease, needed no liver mobilization, included peritonectomy and had no morbidity recorded. Type II pertained to 105 out of 170 patients (61.7%) who had anterior and posterior disease, needed partial and sometimes full liver mobilization, had a mix of peritonectomy and full thickness resection, and experienced 10% specific morbidity. Type III included 37 out of 170 patients (21.7%) who needed full mobilization of the liver, always had full thickness resection, and suffered 30% specific morbidity. Diaphragmatic surgery can be classified in 3 types. The adoption of this classification can facilitate standardization of the surgery, comparison of data and define the expertise required. Finally, this classification can be a benchmark to establish the training required to treat diaphragmatic disease.

Fertility-sparing vs hysterectomy for uterine STUMP: A pragmatic clinical study.

Uterine smooth muscle tumors of uncertain malignant potential (STUMP) are rare neoplasms with unpredictable clinical behavior. Optimal management, particularly in reproductive-aged women, remains controversial, with limited data comparing the safety of fertility-sparing versus hysterectomy. This multicentre retrospective cohort study included women aged 18-85 with histologically confirmed STUMP treated at 17 Italian gynecologic oncology centers from 2010 to 2023. Patients underwent either fertility-sparing surgery (myomectomy or hysteroscopic resection) or definitive surgery (hysterectomy ± salpingo-oophorectomy). Kaplan-Meier and Cox models were used to compare recurrence-free survival (RFS) and overall survival (OS). Median (range) follow-up was 51 (1-291) months. Among 401 women, 106 (26.4 %) received fertility-sparing treatment (mean [± SD] age: 35.3 ± 6.8 years) and 295 (73.6 %) underwent definitive surgery (mean [± SD] age: 47.7 ± 9.2). At total follow-up, recurrence occurred in 12.5 % of patients, predominantly within the pelvis. Median RFS was longer after definitive surgery than after fertility-sparing procedures (50.0 vs 42.5 months; HR 2.39 [95 % CI 1.36-4.19]), although this difference disappeared when benign (leiomyoma) recurrences were excluded (HR 1.74 [95 % CI 0.90-3.34]). At last available follow-up, 97.5 % of patients were alive, with no significant OS difference between treatment groups (HR 0.22 [95 % CI 0.27-1.79]). Outcomes were comparable across menopausal status and concurrent adnexal removal. Definitive surgery reduces recurrence risk, but long-term survival is similarly excellent after fertility-sparing surgery in appropriately selected women with STUMP. Conservative management represents a reasonable option for patients desiring fertility, provided they receive counseling regarding recurrence risk, diagnostic uncertainty, and the need for long-term surveillance.

ULTRA-LAP Trial: Laparoscopic Debulking Surgery (LDS) in Advanced Ovarian Cancer

ULTRA-LAP is a prospective study is to investigate the safety, efficacy and feasibility of laparoscopic debulking surgery (LDS) for the treatment of patients with advanced ovarian cancer. The outcomes to measure are: * Safety: the rate of patients experiencing intra- and post-operative early and late morbidities (within the hospitalization and up to 60 days from surgery) * Efficacy: the rate of patients in which the surgical target set pre-operatively (complete resection) is achieved by laparoscopy. * Feasibility: the rate of patients who have their procedure completed by laparoscopy Patients will undergo laparoscopic debulking surgery (LDS) if the surgical target can be met. If it cannot be achieved by laparoscopy the surgeon will convert to laparotomy.