Matteo Morotti

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.

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.

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.

Risks factors for anastomotic leakage in advanced ovarian cancer: A systematic review and meta-analysis

This systematic review and meta-analysis aimed to summarise the available evidence on the pre- and intra-operative risk factors for anastomotic leakage (AL) after bowel resection and anastomosis for ovarian cancer (OC). We searched online databases from Pubmed, Scopus, ScienceDirect, and Cochrane Library from inception to October 2020. Pre- and intra-operative risk factors for AL were considered as the primary outcomes. Research heterogeneity and bias were evaluated by I The overall AL rate after OC surgery (median ± SD) was 5.3 ± 12% (277 AL on 5178 anastomoses). Thirteen non-randomised studies were included in the meta-analysis enrolling a total of 3274 patients. Pre albumin level ≤ 3 gr/dl, multiple bowel resections and primary cytoreductive surgery were associated with a significantly high risk of AL with a pooled OR of 5.29 (95% CI: 1.51-18.59), OR = 4.4 (95% CI: 1.19-16.66) and OR = 1.71 (95% CI: 1.05-2.77), respectively. Optimal cytoreduction, ASA score, ascites, and protective stoma were not associated with an increased risk of AL. Based on the best available evidence, preoperative albumin level <3 gr/dl, multiple bowel resections and primary cytoreductive surgery were associated with an increased risk for AL after bowel surgery for OC.

Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING

In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1-mutated (BRCA1

Bevacizumab, Atezolizumab, and Acetylsalicylic Acid in Recurrent, Platinum-Resistant Ovarian Cancer: The EORTC 1508-GCG Phase II Study

Abstract Purpose: Treatment options for patients with platinum-resistant ovarian cancer (PROC) are limited, and new therapeutic strategies are urgently needed. This phase II, randomized, multicentre trial evaluated the safety and activity of the anti–PD-L1 antibody atezolizumab (atezo) combined with the VEGF inhibitor bevacizumab (bev) and the irreversible cyclooxygenase 1/2 inhibitor aspirin [acetylsalicylic acid (ASA)] in PROC. Patients and Methods: Patients were randomized to bev monotherapy 15 mg/kg (arm 1), atezo 1,200 mg plus placebo (pbo; arm 2), atezo 1,200 mg plus ASA 320 mg/daily (arm 3), bev 15 mg/kg plus atezo 1,200 mg plus pbo (arm 4), or bev 15 mg/kg plus atezo 1,200 mg plus ASA 320 mg/daily (arm 5). Primary endpoint was progression-free survival at 6 months (PFS-6) according to RECIST v1.1 assessed by a local investigator. Secondary objectives included overall survival, PFS, second PFS (PFS2), and tolerability. Time to first subsequent therapy (TFST) was evaluated in a post hoc analysis. Results: In arms 1 (bev), 4 (bev–atezo–pbo), and 5 (bev–atezo–ASA), there were 7/32 [21.9%, 70% confidence interval (CI), 14.0–32.0], 8/32 (25.0%, 70% CI, 16.6–35.3), and 8/32 (25.0%, 70% CI, 16.6–35.3) patients alive and progression-free at 6 months. The primary objective was not reached in any arm. Median PFS and response rates were 2.3 for bev monotherapy, 4.1 for bev–atezo–pbo, and 4.0 months for bev–atezo–ASA and 10%, 19%, and 15%, respectively. Two patients achieved an ongoing complete response lasting for more than 5 years from randomization (1 in bev–atezo–pbo and 1 in bev–atezo–ASA). A post hoc analysis of TFST suggested benefit of adding bev to atezo–ASA (P &amp;lt; 0.001). Tumor-infiltrating lymphocytes (TIL) increased in the atezo-containing arms after the first two cycles, and increased TIL were associated with a significantly longer TFST. Conclusions: The addition of ASA to bev plus atezo was well-tolerated but did not improve efficacy in PROC. Relative to bev alone, the bev plus atezo combination numerically improved PFS. Exploratory translational analyses suggest clinical benefit in a subgroup of patients characterized by high TIL infiltration and PD-L1–positive tumors at baseline.

Contribution of Preserving the Superior Left Colic Artery to the Vascularization of the Descending Colon Prior to Colorectal Anastomosis During Left-Sided or Rectal Resections for Colorectal or Ovarian Cancer. (Revascularisation Colique)

Colorectal cancers and ovarian cancers are respectively the 2nd and 5th cause of cancer mortality in France. Surgical resection is a crucial step in the therapeutic management of colorectal cancers. For advanced ovarian cancers, the objective of cytoreductive surgery is to obtain complete macroscopic resection with no visible residual disease. One or more digestive resections are often required to achieve this goal of complete surgery (usually a modified posterior pelvic exenteration with colorectal resection). A ligation of the inferior mesenteric artery at its origin is classically performed in left colectomies and rectal resection for colorectal cancers. This allows the resection of the colorectal segment with a complete mesocolic lymphadenectomy until the origin of the inferior mesenteric artery and a good mobilization of the descending colon to allow its anastomosis to the underlying rectal stump. This ligation of the inferior mesenteric artery at its origin is also frequently performed in cases of modified posterior pelvic exenteration for ovarian cancer. Recently, several studies suggest that arterial ligation of the inferior mesenteric artery could be performed below the emergence of the left colic artery. Its preservation requiring a meticulous vascular dissection would allow a better vascularization of the descending colon and of the colorectal anastomosis without affecting the carcinologic quality of the resection and the number of resected lymph-nodes. Indeed, the most feared complication during colorectal anastomosis is the anastomotic leakage whose rates are on average 15% in rectal cancer with low anastomosis and 6% in ovarian cancers. Verifying the adequate vascularization of the descending colon before performing the colorectal anastomosis is a crucial step in reducing the risk of postoperative fistula. However, quantifying this vascularization is challenging, and several techniques can be used to assess it. The gold standard technique involves measuring arterial pressure using a catheter inserted into the marginal artery of the descending colon. Other non-invasive techniques also use Doppler studies to calculate pressure in the marginal artery or assess oxygen saturation using a sterile sensor. Studies have shown that the use of indocyanine green in colorectal surgery, particularly to evaluate perfusion before the creation of an anastomosis, significantly reduces the rate of anastomotic leakage. Indocyanine green is a fluorescent dye that, after intravenous injection, binds to plasma proteins and allows tissue perfusion to be visualized using a fluorescence system. The objective of this project is to show that the preservation of the left colic artery is possible and allows a better vascularization of the descending colon before colorectal anastomosis.