Marcus Q. Bernardini

Treatment Strategy and Residual Disease as Determinants of Survival in Stage IVB High‐Grade Serous Ovarian Cancer: A Retrospective Cohort Study

ABSTRACT Background and Objective Stage IVB high‐grade serous ovarian cancer (HGSOC) carries a poor prognosis. We aimed to: (1) describe the characteristics and survival of patients treated with primary cytoreductive surgery (PCS), interval cytoreductive surgery (ICS) or chemotherapy alone, (2) investigate the correlation between disease distribution and treatment type, and (3) evaluate the impact of cytoreductive surgery (CS) “aggressiveness” and outcome on survival. Methods A single‐center retrospective cohort study of Stage IVB HGSOC patients. Demographics, tumor characteristics, treatment including “aggressive” CS (upper abdominal and extraperitoneal procedures), and outcomes were analyzed using descriptive statistics and survival analysis, with nonparametric tests and Cox‐proportional hazard models. Results Of 110 patients, 24 (22%) underwent PCS, 73 (66%) ICS, and 13 (12%) chemotherapy alone. Median overall survival (OS) was 76.2 (PCS), 36.9 (ICS), and 20.1 months (chemotherapy alone) ( p  = 0.014). Supradiaphragmatic lymph‐node metastasis differed across groups ( p  = 0.042). “Aggressive” CS was performed in 53.6% of the surgical cohort, with 54.86% no‐gross‐residual (NGR), 34% optimal ≤ 1 cm ≤ and 11.3% suboptimal/aborted surgical outcome. Median OS post CS for NGR, optimal ≤ 1 cm, and suboptimal was 67.55, 35.26, and 20.97 months, respectively ( p  = 0.006). Conclusions OS for Stage IVB HGSOC follows a hierarchical pattern: PCS, ICS, and chemotherapy. Disease distribution guides treatment and residual tumor after CS correlates with survival.

Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors

The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti-tumor responses. This apparent dichotomy highlights the need to better understand differences in the ILC composition and phenotype within different tumor types that could drive seemingly opposite anti-tumor responses. Here, we characterized the frequency and phenotype of various ILC subsets in melanoma metastases and primary epithelial ovarian tumors. We observed high PD-1 expression on ILC subsets isolated from epithelial ovarian tumor samples, while ILC populations in melanoma samples express higher levels of LAG-3. In addition, we found that the frequency of cytotoxic ILCs and NKp46

Molecular Classification of Endometrial Cancers Using an Integrative DNA Sequencing Panel

ABSTRACT Background and Objectives Adoption of molecular classification in endometrial cancer (EC) into clinical practice remains challenging due to complexity in coordination of multiple assays. We aimed to develop a simple molecular technique to classify ECs into four subgroups using our custom‐designed targeted sequencing panel. Methods Patients with newly diagnosed ECs were prospectively recruited from three cancer centres in Ontario, Canada. Using our panel, 181 ECs were sequenced. Variants were analysed for pathogenicity and clinicopathologic information was collected through medical records retrospectively. Results Of 181, 86 (48%) were mismatch repair deficient (MMRd), of which 62 (72%) harboured MLH1 promoter methylation and 24 (28%) had pathogenic variants in MMR genes. Of single classifiers, three (1.8%) had pathogenic POLE ( POLE mut), 15 (9%) had TP53 mutations (p53abn) and 61 (37%) had no specific molecular profile subtype (NSMP). Sixteen (9%) had more than one molecular classifying feature, with eight (4%) MMRd‐p53abn, six (3%) POLE mut‐MMRd, one (0.5%) POLE mut‐MMRd‐p53abn and one (0.5%) POLE mut‐p53abn. When MMRd group was further subclassified according to mechanism of MMR loss, MLH1 promoter methylated group had worse outcomes than those with somatic MMR pathogenic variants. Conclusions Our panel can classify ECs into four subgroups through a simplified process and can be implemented reflexively in clinical practice.

A prospective comparison of costs between robotics, laparoscopy, and laparotomy in endometrial cancer among women with Class III obesity or higher

AbstractBackground and ObjectivesTo compare the immediate operating room (OR), inpatient, and overall costs between three surgical modalities among women with endometrial cancer (EC) and Class III obesity or higher.MethodsA multicentre prospective observational study examined outcomes of women, with early stage EC, treated surgically. Resource use was collected for OR costs including OR time, equipment, and inpatient costs. Median OR, inpatient, and overall costs across surgical modalities were analyzed using an Independent‐Samples Kruskal–Wallis Test among patients with BMI ≥ 40.ResultsOut of 520 women, 103 had a BMI ≥ 40. Among women with BMI ≥ 40: median OR costs were $4197.02 for laparotomy, $5524.63 for non‐robotic assisted laparoscopy, and $7225.16 for robotic‐assisted laparoscopy (p < 0.001) and median inpatient costs were $5584.28 for laparotomy, $3042.07 for non‐robotic assisted laparoscopy, and $1794.51 for robotic‐assisted laparoscopy (p < 0.001). There were no statistically significant differences in the median overall costs: $10 291.50 for laparotomy, $8412.63 for non‐robotic assisted laparoscopy, and $9002.48 for robotic‐assisted laparoscopy (p = 0.185).ConclusionThere was no difference in overall costs between the three surgical modalities in patient with BMI ≥ 40. Given the similar costs, any form of minimally invasive surgery should be promoted in this population.

Generation of an Inhibitory NK Cell Subset by TGF-β1/IL-15 Polarization

Abstract NK cells have been shown to exhibit inflammatory and immunoregulatory functions in a variety of healthy and diseased settings. In the context of chronic viral infection and cancer, distinct NK cell populations that inhibit adaptive immune responses have been observed. To understand how these cells arise and further characterize their immunosuppressive role, we examined in vitro conditions that could polarize human NK cells into an inhibitory subset. TGF-β1 has been shown to induce regulatory T cells in vitro and in vivo; we therefore investigated if TGF-β1 could also induce immunosuppressive NK-like cells. First, we found that TGF-β1/IL-15, but not IL-15 alone, induced CD103+CD49a+ NK-like cells from peripheral blood NK cells, which expressed markers previously associated with inhibitory CD56+ innate lymphoid cells, including high expression of GITR and CD101. Moreover, supernatant from ascites collected from patients with ovarian carcinoma also induced CD103+CD49a+ NK-like cells in vitro in a TGF-β–dependent manner. Interestingly, TGF-β1/IL-15–induced CD103+CD56+ NK-like cells suppressed autologous CD4+ T cells in vitro by reducing absolute number, proliferation, and expression of activation marker CD25. Collectively, these findings provide new insight into how NK cells may acquire an inhibitory phenotype in TGF-β1–rich environments.

Treatment outcomes and predictive factors in patients ≥70 years old with advanced ovarian cancer

AbstractObjectiveTo evaluate treatment outcomes, survival, and predictive factors in patients ≥70 with advanced epithelial ovarian cancer (AEOC).MethodsA retrospective single institution cohort study of women ≥70 with Stage III–IV AEOC between 2010 and 2018. Patients had either primary cytoreductive surgery (PCS), neoadjuvant chemotherapy (NACT) with interval cytoreductive surgery (ICS), chemotherapy alone, or no treatment. Demographics, surgical outcome, complications, and survival outcome were compared between groups.ResultsAmong 248 patients, 69 (27.7%) underwent PCS, 99 (39.9%) had ICS, 56 (22.5%) had chemotherapy alone. Twenty‐four (9.6%) remained untreated. Optimal cytoreduction (≤1 cm) was achieved in 72.4% of PCS and 77.8% of NACT/ICS (p = 0.34), without difference in grade ≥3 postoperative complications (15.9% vs. 9.1%, p = 0.37). Progression‐free survival (PFS) was 23.5 months in PCS and 15.0 months in ICS patients (hazard ratio [HR]: 1.4, p = 0.041). Patients in the surgical arms, PCS or ICS, had better 2‐year overall survival (OS) compared to chemotherapy alone (79%, 68%, 41%, respectively, HR: 3.58, p < 0.001). In a subgroup analysis, patients ≥80 had improved 2‐year OS when treated with NACT compared to PCS (82% vs. 57%) and a trend toward improved PFS. Age, stage, and CA‐125 were determinants of undergoing PCS.ConclusionIn patients ≥70 with AEOC, surgery should not be deferred based on age alone. Fit, well selected patients ≥70 can benefit from PCS, while patients ≥80 might benefit from NACT over PCS.

Using a machine learning algorithm to predict outcome of primary cytoreductive surgery in advanced ovarian cancer

AbstractObjectiveTo develop a machine learning (ML) algorithm to predict outcome of primary cytoreductive surgery (PCS) in patients with advanced ovarian cancer (AOC)MethodsThis retrospective cohort study included patients with AOC undergoing PCS between January 2017 and February 2021. Using radiologic criteria, patient factors (age, CA‐125, performance status, BRCA) and surgical complexity scores, we trained a random forest model to predict the dichotomous outcome of optimal cytoreduction (<1 cm) and no gross residual (RD = 0 mm) using JMP‐Pro 15 (SAS). This model is available at https://ipm-ml.ccm.sickkids.ca.ResultsOne hundred and fifty‐one patients underwent PCS and randomly assigned to train (n = 92), validate (n = 30), or test (n = 29) the model. The median age was 58 (27–83). Patients with suboptimal cytoreduction were more likely to have an Eastern Cooperative Oncology Group 3–4 (11% vs. 0.75%, p = 0.004), lower albumin (38 vs. 41, p = 0.02), and higher CA125 (1126 vs. 388, p = 0.012) than patients with optimal cytoreduction (n = 133). There were no significant differences in age, histology, stage, or BRCA status between groups. The bootstrap random forest model had AUCs of 99.8% (training), 89.6%(validation), and 89.0% (test). The top five contributors were CA125, albumin, diaphragmatic disease, age, and ascites. For RD = 0 mm, the AUCs were 94.4%, 52%, and 84%, respectively.ConclusionOur ML algorithm demonstrated high accuracy in predicting optimal cytoreduction in patients with AOC selected for PCS and may assist decision‐making.

Incidence of adverse events in minimally invasive vs open radical hysterectomy in early cervical cancer: results of a randomized controlled trial

Standard treatment of early cervical cancer involves a radical hysterectomy and retroperitoneal lymph node dissection. The existing evidence on the incidence of adverse events after minimally invasive vs open radical hysterectomy for early cervical cancer is either nonrandomized or retrospective. The purpose of this study was to compare the incidence of adverse events after minimally invasive vs open radical hysterectomy for early cervical cancer. The Laparoscopic Approach to Carcinoma of the Cervix trial was a multinational, randomized noninferiority trial that was conducted between 2008 and 2017, in which surgeons from 33 tertiary gynecologic cancer centers in 24 countries randomly assigned 631 women with International Federation of Gynecology and Obstetrics 2009 stage IA1 with lymph-vascular invasion to IB1 cervical cancer to undergo minimally invasive (n = 319) or open radical hysterectomy (n = 312). The Laparoscopic Approach to Carcinoma of the Cervix trial was suspended for enrolment in September 2017 because of an increased risk of recurrence and death in the minimally invasive surgery group. Here we report on a secondary outcome measure: the incidence of intra- and postoperative adverse events within 6 months after surgery. Of 631 randomly assigned patients, 536 (85%; mean age, 46.0 years) met inclusion criteria for this analysis; 279 (52%) underwent minimally invasive radical hysterectomy, and 257 (48%) underwent open radical hysterectomy. Of those, 300 (56%), 91 (16.9%), and 69 (12.8%) experienced at least 1 grade ≥2 or ≥3 or a serious adverse event, respectively. The incidence of intraoperative grade ≥2 adverse events was 12% (34/279 patients) in the minimally invasive group vs 10% (26/257) in the open group (difference, 2.1%; 95% confidence interval, -3.3 to 7.4%; P=.45). The overall incidence of postoperative grade ≥2 adverse events was 54% (152/279 patients) in the minimally invasive group vs 48% (124/257) in the open group (difference, 6.2%; 95% confidence interval, -2.2 to 14.7%; P=.14). For early cervical cancer, the use of minimally invasive compared with open radical hysterectomy resulted in a similar overall incidence of intraoperative or postoperative adverse events.