Spondylodiscitis after sacral colpopexy: diagnose early to treat earlier.

Spondylodiscitis following sacral colpopexy for Pelvic Organ Prolapse (POP) represents a rare complication with severe consequences. Authors performed a literature search, from 2000 to 2022, to set a narrative review of literature. Spondylodiscitis is an uncommon but dangerous side effect of a routine surgical treatment that needs to be identified and treated right away to prevent worsening clinical consequences. Suboptimal dissection of the sacral promontory and/or site infection are associated with spondylodiscitis. When spondylodiscitis is suspected, advanced imaging methods should be used, and surgical excision shouldn't be put off after a failed course of treatment. Authors presented a case-video of a 68-year-old woman who reported severe lower back pain 7 weeks after surgery, in which sacral spondylodiscitis was diagnosed and laparoscopically treated. In this case, a laparoscopic tack and mesh removal from promontory was carried out following the patient's continued lower back pain and the antibiotic therapy's incomplete radiological remission of spondylodiscitis. The patient's radiological findings and symptoms completely resolved two weeks following the procedure.

From 3D to 2D-4K laparoscopic sacral colpopexy: are we addicted to technology?

OBJECTIVE: A study analyzing perioperative outcomes related to a sudden switch from 3D to 2D-4K technology for laparoscopic sacral colpopexy by expert pelvic surgeons: are we addicted to technology? MATERIAL AND METHODS: After a sudden transition from 3D to 2D-4K laparoscopic technology, a total of 115 consecutive pelvic prolapse patients who underwent sacral colpopexy from June 2020 to September 2021 were retrospectively assessed from our database. Perioperative parameters, operative times (OT), and intraoperative difficulty scales were assessed. One-year follow-ups were analyzed for the study. Primary endpoints were OT; secondary endpoint was the evaluation of complications linked to this procedure. RESULTS: We found statistical differences in OT and intraoperative difficulty scales between medians of the last 3D procedures and the first ten 2D-4K surgeries, without differences between operators. Only after more than 20 surgeries, we observed no significant differences between 3D and 2D-4K sacral colpopexy. We observed no statistical differences in terms of anatomic failure, PGI-I, and intra-postoperative complications. CONCLUSION: The transition of urogynecology from an exclusive vaginal approach to 2D-3D-4K laparoscopy significantly increased the level of technology necessary for surgical treatment of prolapse. This could, as a result, lead to pelvic surgeons becoming increasingly dependent on technology.

Medicolegal and insurance issues regarding BRCA1 and BRCA2 gene tests in high income countries.

Hereditary breast and ovarian cancer syndrome is an autosomal dominant cancer susceptibility syndrome mainly due to variants in BRCA1 or BRCA2 genes. Patients presenting with BRCA1 or BRCA2 gene mutations have a lifetime risk of developing breast or ovarian cancer (80% and 40%, respectively). Genetic testing to explore the predisposition to develop cancer represents a pivotal factor in such cases, and this review wants to explore the main implications in terms of medicolegal liability and insurance issues. Medicolegal issues related to these diagnostic processes include: (a) failure to recommend the test; (b) failure to properly interpret the test; (c) failure to correctly translate results into clinical practice; (d) lack of informed consent; and (e) failure to refer patients to specialized genetic counseling. Such errors may lead to compensation since the legal burden inherent in the efficacy of prophylactic interventions is a proof that requires the so-called 'preponderance of the evidence'. Concerning insurance issues, the carriers of such alleles without cancer are healthy because the genetic predisposition is not a disease per se but represents a (relevant) health risk. However, disclosure of these conditions can be impelled by insurers. It can lead to so-called 'genetic discrimination' because insurance companies might use genetic information to limit insurance options or increase their costs. Many private and public healthcare funders do not cover risk reducing surgeries, even when recommended as part of a risk reduction management plan for BRCA gene mutation carriers. Here, positions on these matters from different high income countries are discussed, stressing the importance of a common supranational or international regulatory framework to reach a trade-off between the economic interests of insurers and the rights of carriers not to disclose extremely sensitive information.

Obesity paradox: is a high body mass index positively influencing survival outcomes in gynecological cancers? A systematic review and meta-analysis.

OBJECTIVE: Obesity represents an exponentially growing preventable disease leading to different health complications, particularly when associated with cancer. In recent years, however, an 'obesity paradox' has been hypothesized where obese individuals affected by cancer counterintuitively show better survival rates. The aim of this systematic review and meta-analysis is to assess whether the prognosis in gynecological malignancies is positively influenced by obesity. METHODS: This study adheres to PRISMA guidelines and is registered with PROSPERO. Studies reporting the impact of a body mass index (BMI) of >30 kg/m2 compared with <30 kg/m2 in patients with gynecological cancers listed in PubMed, Google Scholar and ClinicalTrials.gov were included in the analysis. The Quality Assessment of Diagnostic Accuracy Studies 2 tool (QUADAS-2) was used for quality assessment of the selected articles. RESULTS: Twenty-one studies were identified for the meta-analysis, including 14 108 patients with cervical, ovarian, or endometrial cancer. There was no benefit in 5-year overall survival for obese patients compared with non-obese patients (OR 1.2, 95% CI 1.00 to 1.44, p=0.05; I2=71%). When pooling for cancer sub-groups, there were no statistically significant differences in 5-year overall survival in patients with cervical cancer and 5-year overall survival and progression-free survival in patients with ovarian cancer. For obese women diagnosed with endometrial cancer, a significant decrease of 44% in 5-year overall survival (p=0.01) was found, with no significant difference in 5-year disease-free survival (p=0.78). CONCLUSION: According to the results of the present meta-analysis, a BMI of ≥30 kg/m2 does not have a positive prognostic effect on survival compared with a BMI of <30 kg/m2 in women diagnosed with gynecological cancers. The existence of the 'obesity paradox' in other fields, however, suggests the importance of further investigations with prospective studies.

Post-traumatic growth in oncological patients during the COVID-19 pandemic.

BACKGROUND: Post-traumatic growth (PTG) is defined as "positive psychological change experienced as a result of the struggle with highly challenging life circumstances". Diagnosis of cancer leads to many psychological challenges. The recent pandemic forced oncological patients to face other multiple stressors. Resilience is a target of interest for PTG. The aim of this study is to analyze relationships between cancer trauma, COVID-19 pandemic stress, PTG and resilience over time. PARTICIPANTS AND PROCEDURE: One hundred forty-six patients (124 females, 22 males) in active oncological treatment were enrolled from September 2020: 45.2% (n = 66) diagnosed with gynecological cancer, 23.3% (n = 34) with breast cancer, 15.1% (n = 22) with lung cancer, 16.5% (n = 24) with other cancers. We conducted a prospective longitudinal study on oncological patients evaluated at: diagnosis (T0), 6 (T1) and 12 months (T2) by means of the following self-administered tests: Distress Thermometer (DT), Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale Revised (IES-R), Post-traumatic Growth Inventory (PTGI), Perceived Stress Scale (PSS), Connor-Davidson Resilience Scale (CD-RISC). RESULTS: DT decreased over time (T0 vs. T2, p < .001). HADS decreased from T0 to T2 (p < .001). The PTG subscales regarding new possibilities and appreciating life improved comparing T0 vs. T2 (p = .029; p = .013), as well as the total index of PTG (p = .027). The IES avoidance subscale score decreased over time (T0 vs. T1, p = .035). CONCLUSIONS: For some patients, the cancer experience is characterized not only by psychological distress but also by the presence and growth of positive aspects, such as the tendency to positively reconsider the value and importance of life, health and social relationships.

Circulating tumor DNA as a biomarker for predicting progression-free survival and overall survival in patients with epithelial ovarian cancer: a systematic review and meta-analysis.

OBJECTIVES: Circulating tumor DNA (ctDNA) is emerging as a potential prognostic biomarker in multiple tumor types. However, despite the many studies available on small series of patients with ovarian cancer, a recent systematic review and meta-analysis is lacking. The objective of this study was to determine the association of ctDNA with progression-free-survival and overall survival in patients with epithelial ovarian cancer. METHODS: An electronic search was conducted using PubMed (MEDLINE), Embase, CENTRAL (Cochrane Library), and CINAHL-Complete from January 2000 to September 15, 2023. To be included in the analysis the studies had to meet the following pre-specified inclusion criteria: (1) evaluable ctDNA; (2) progression-free-survival and overall survival reported as hazard ratio (HR); and (3) the patient population had epithelial ovarian cancer at the time of ctDNA detection. We evaluated the association of ctDNA with progression-free survival and overall survival. Secondary outcomes focused on sub-group analysis of genomic alterations and international Federation of Gynecology and Obstetrics (FIGO) stage. RESULTS: A total of 26 studies reporting on 1696 patients with epithelial ovarian cancer were included. The overall concordance rate between plasma-based and tissue-based analyses was approximately 62%. We found that a high level of ctDNA in epithelial ovarian cancer was associated with worse progression-free survival (HR 5.31, 95% CI 2.14 to 13.17, p<0.001) and overall survival (HR 2.98, 95% CI 1.86 to 4.76, p<0.0001). The sub-group analysis showed a greater than threefold increase in the risk of relapse in patients with positive HOXA9 meth-ctDNA (HR 3.84, 95% CI 1.57 to 9.41, p=0.003). CONCLUSIONS: ctDNA was significantly associated with worse progression-free survival and overall survival in patients with epithelial ovarian cancer. Further prospective studies are needed. PROSPERO REGISTRATION NUMBER: CRD42023469390.

Endometrial cancer with positive sentinel lymph nodes: pathologic characteristics of metastases as predictors of extent of lymphatic dissemination and prognosis.

OBJECTIVES: To assess predictors of extensive lymph node dissemination and non-vaginal recurrence in patients with endometrial cancer with positive sentinel lymph nodes (SLNs). METHODS: Patients with endometrial cancer who underwent primary surgery with SLN mapping and had at least one positive node between October 2013 and May 2019 were included. Positive SLNs were reviewed, and cases were classified according to the location of the metastasis (extracapsular vs intracapsular), and the size of the largest SLN metastasis (isolated tumor cells, micrometastasis, macrometastasis). Associations were assessed based on fitting logistic regression models and Cox proportional hazards models. RESULTS: A total of 103 patients met the inclusion criteria: including 36 (34.9%) with isolated tumor cells, 27 (26.2%) with micrometastasis, and 40 (38.8%) with macrometastasis. Notably, 71.4% of patients exhibiting extracapsular SLN metastases had multiple positive SLNs (p=0.008). Extracapsular invasion (adjusted odds ratio (aOR) 5.81, 95% CI 1.4 to 23.6) and age (aOR=1.8, 95% CI 1.1 to 3.0) emerged as independent predictors of multiple positive SLNs. Among the 38 patients who underwent a backup pelvic lymphadenectomy, 18 (47.4%) presented with positive pelvic non-SLNs, a phenomenon more prevalent in patients with macrometastasis (p=0.004).Independent predictors of non-vaginal recurrence included SLN macrometastasis (adjusted hazard ratio (aHR) 3.3, 95% CI 1.3 to 8.3), non-endometrioid histology (aHR=3.7, 95% CI 1.5 to 9.3), and cervical stromal invasion (aHR=5.5, 95% CI 2.0 to 14.9). Among the 34 patients with isolated tumor cells and endometrioid histology, 3 (9%) experienced a recurrence, all of whom had not received any adjuvant chemotherapy or external beam radiotherapy. CONCLUSION: Patients with positive SLN macrometastasis are independently associated with extensive lymphatic dissemination and distant recurrences. The risk of multiple positive SLNs increases with the extracapsular location of the SLN metastasis and with age. Independent uterine pathologic predictors of non-vaginal recurrence are non-endometrioid histology and cervical stromal invasion.

Predicting the Risk of nOdal disease with histological and Molecular features in Endometrial cancer: the prospective PROME trial.

OBJECTIVE: To assess the role of histopathological and molecular features in predicting the risk of nodal metastases in apparent early-stage endometrial cancer patients undergoing sentinel node mapping. METHODS: This is a prospective trial. Consecutive patients with apparent early-stage endometrial cancer, undergoing laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and sentinel node mapping, were enrolled. Histological and molecular features were used to predict the node positivity. RESULTS: Charts of 223 apparent early-stage endometrial cancer patients were included in this study. Four (1.8%) patients were excluded from this study due to the lack of data about molecular features. Additionally, nine (4%) patients did not meet the inclusion criteria (due to the presence of peritoneal carcinomatosis or bulky nodes (the presence of p53 abnormality correlated with the presence of advanced stage disease (p<0.001)). The study population included 178 (84.8%) and 32 (15.2%) patients with endometrioid and non-endometrioid endometrial cancer, respectively. According to pathological uterine risk factors, 93 (44.3%), 45 (21.4%), 40 (19.1%), and 32 (15.2%) were classified as low, intermediate, intermediate-high, and high-risk, respectively. Using the surrogate molecular classification, 10 (4.8%), 42 (20%), 57 (27.1%), and 101 (48.1%) were included in the POLE mutated, p53 abnormal, MMRd/MSI-H, and NSMP, respectively. Overall, 41 (19.5%) patients were detected with positive nodes. Molecular features were not associated with the risk of having nodal metastases (OR 1.03, 95% CI 0.21 to 5.05, p=0.969 for POLE mutated; OR 0.788, 95% CI 0.32 to 1.98, p=0.602 for p53 abnormal; OR 1.14, 95% CI 0.53 to 2.42, p=0.733 for MMRd/MSI-H). At multivariable analysis, only deep myometrial invasion (OR 3.318, 95% CI 1.357 to 8.150, p=0.009) and lymphovascular space invasion (OR 6.584, 95% CI 2.663 to 16.279, p<0.001) correlated with the increased risk of positive nodes. CONCLUSION: Our data suggest that molecular classification does not seem useful to tailor the need of nodal dissection in apparent early-stage endometrial cancer. p53 abnormality predicts the risk of having advanced disease at presentation. Further external validation is needed. CLINICAL TRIAL REGISTRATION: NCT05793333.

Hormone Replacement Therapy in Post-Menopause Hormone-Dependent Gynecological Cancer Patients: A Narrative Review.

BACKGROUND: Advances in the treatment of gynecological cancer have led to improvements in survival but also an increase in menopausal symptoms, especially in young women with premature iatrogenic menopause. METHODS: A narrative review was performed to clarify the possibility of prescribing hormone replacement therapy (HRT) after hormone-dependent gynecological cancers (ovarian cancer [OC], cervical adenocarcinoma [AC], and endometrial cancer [EC]). RESULTS: HRT can be prescribed to patients with early-stage, grade I-II OC who experience bothersome menopausal symptoms non-responsive to alternative non-hormone therapy after optimal surgery. Caution should be exercised in administering HRT after serous borderline tumors and endometrioid OC, and HRT is not recommended in low-grade serous OC. HRT is not contraindicated in AC survivors. After surgery for EC, HRT can be prescribed in women with early-stage low-grade EC. There is not enough data to give indications to patients with advanced EC. CONCLUSIONS: HRT can be discussed with patients, evaluating the risks and benefits of hormone-dependent gynecological cancer. Counseling should be performed by gynecologic oncologists experienced in the management of these patients.

Preventing Bone Loss in Breast Cancer Patients: Designing a Personalized Clinical Pathway in a Large-Volume Research Hospital.

BACKGROUND: We assess the impact of bone health clinical management in breast cancer (BC) patients receiving adjuvant endocrine therapy and design a personalized clinical pathway to reduce bone loss in an Italian research hospital. METHODS: The primary endpoint was to assess (through the process improvement organizational method) the clinical pathway that post-surgical BC patients prescribed with endocrine therapy undergo to prevent bone loss. The secondary endpoint was to design a personalized clinical pathway for a prompt implementation of guidelines, to assess and possibly prescribe antiresorptive therapy. RESULTS: During the first year of the execution of the new Diagnostic Therapeutic Assistance Pathway, a 60% increase in Dual-Energy X-ray Absorptiometry evaluations within 30 days and a 39.5% increase in antiresorptive therapy prescription within 90 days (since the prescription of endocrine therapy) were shown, thus increasing patients' compliance. CONCLUSION: Case managers and bone health specialists in this context can improve patients' adherence to therapies and bone health, helping physicians to expand their collaboration.

Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

2023 FIGO staging system for endometrial cancer: The evolution of the revolution.

INTRODUCTION: Embracing the complex and diverse nature of the heterogenous group of malignancies that are included under the umbrella of "endometrial cancer" (EC) to better align prognosis with treatment recommendations, requires a more comprehensive staging system. Our goal at the development of the new FIGO staging was to provide 1) high accuracy in the predictive prognosis for a patient with EC, which is the genuine purpose of a staging system, and 2) identification of distinct treatment relevant subgroups. Since the publication of the 2009 staging system by the International Federation of Gynecology and Obstetrics (FIGO) 14  years ago (1, 2), our understanding of the biology and natural history of EC has undergone a radical transformation. The TGCA results in 2013 (3), and the many validation reports published since then (4-9), have taught us that "EC" is composed of at least four distinct molecularly defined diseases. Strong histopathologic markers reflecting tumor biology such as lymph vascular space invasion (LVSI) were identified. Importantly, anatomical borders were shown to lose their prognostic relevance for EC patients in the presence of dominant tumor biology-markers such as molecular subtypes/LVSI (10, 11). This emphasizes the integration of these novel markers into a prognostic staging system that aims to be relevant to patients. The 2023 FIGO staging system for EC harmonizes and integrates old and new knowledge on anatomic, histopathologic, and molecular features (12). It requires a change in our perception of a staging system, from a traditional purely anatomical borders-based system to an integrated staging system integrating anatomical borders and tumor biology as pivotal prognostic factors for EC patients while providing important information for treatment decision making. Therefore, the 2023 FIGO staging system demonstrates the logical next step in the evolution of the revolution in a patient-centric staging approach. Below, we elucidate the rationale for the FIGO 2023 endometrial cancer staging system.

The association of histopathologic features after neoadjuvant chemo-immunotherapy with clinical outcome: Sub-analyses from the randomized double-blinded, placebo-controlled, Phase III IMagyn050/GOG3015/ENGOT-ov39 study.

OBJECTIVE: Histopathologic characteristics after neoadjuvant chemotherapy (NACT) may correlate with outcome. This study evaluates histopathologic features after immunotherapy and NACT/bevacizumab, and associated clinical outcomes. METHODS: Evaluable tissue from IMagyn050/GOG3015/ENGOT-ov39 patients from prespecified anatomic sites from interval cytoreductive surgery (ICS) after NACT/bevacizumab plus atezolizumab/placebo underwent central histopathologic scoring and analyzed with clinical outcomes. RESULTS: The predefined population had 243 evaluable NACT patients, with 48.1% tumors being PD-L1-positive. No statistically significant differences in PFS (16.9 months vs. 19.2 months, p = 0.21) or OS (41.5 months vs. 45.1 months, p = 0.67) between treatment arms were seen. Substantial residual tumor (RT) (3+) was identified in 26% atezolizumab vs. 24% placebo arms (p = 0.94). Most showed no (1+) necrosis (82% vs. 96%, respectively, p = 0.69), moderate (2+) to severe (3+) fibrosis (71% vs. 75%, respectively, p = 0.82), and extensive (2+) inflammation (53% vs. 47% respectively, p = 0.48). No significant histopathologic differences were identified by tissue site or by arm. Multivariate analyses showed increased risk for progression with moderate and substantial RT (13.6 mon vs. 21.1 mon, hazard ratio 2.0, p < 0.01; 13.6 mon vs. 21.1 mon, HR 1.9, p < 0.01, respectively); but decreased risk for death with extensive inflammation (46.9 mon vs. 36.3 mon, HR 0.65, p = 0.02). Inflammation also correlated with greater likelihood of response to NACT/bevacizumab plus immunotherapy (odds ratio 2.9, p < 0.01). Modeling showed inflammation as a consistent but modest predictor for OS. CONCLUSIONS: Detailed histologic assessment of ICS specimens appear to identify characteristics, such as inflammation and residual tumor, that may provide insight to certain clinical outcomes. Future work potentially leveraging emerging tools may provide further insight into outcomes.

Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial.

BACKGROUND: Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

How BRCA and homologous recombination deficiency change therapeutic strategies in ovarian cancer: a review of literature.

About 50% of High Grade Serous Ovarian Cancer exhibit a high degree of genomic instability due to mutation of genes involved in Homologous Recombination (HRD) and such defect accounts for synthetic lethality mechanism of PARP inhibitors (PARP-i). Several clinical trials have shown how BRCA and HRD mutational status profoundly affect first line chemotherapy as well as response to maintenance therapy with PARP-i, hence Progression Free Survival and Overall Survival. Consequently, there is urgent need for the development of increasingly reliable HRD tests, overcoming present limitations, as they play a key role in the diagnostic and therapeutic process as well as have a prognostic and predictive value. In this review we offer an overview of the state of the art regarding the actual knowledge about BRCA and HRD mutational status, the rationale of PARPi use and HRD testing (current and in development assays) and their implications in clinical practice and in the treatment decision process, in order to optimize and choose the best tailored therapy in patients with ovarian cancer.

Alpelisib for PIK3CA-mutated advanced gynecological cancers: First clues of clinical activity.

OBJECTIVE: Recurrent gynecological tumors (e.g., endometrial, and ovarian cancers) are incurable diseases; therefore, new treatment options are urgently needed. The PTEN-AKT-PI3K pathway is frequently altered in these tumors, representing a potential treatment target. Alpelisib is an α-specific PI3K inhibitor approved in PIK3CA-mutated advanced breast cancer. We report outcomes from a large series of patients with PIK3CA-mutated gynecological cancers prospectively treated with alpelisib within a controlled program. METHODS: From April 2021 to December 2022, 36 patients with PIK3CA-mutated advanced gynecological cancers received alpelisib 300 mg orally once daily. Objective response (ORR) and disease control (DCR) rates provided measure of the antitumor activity of alpelisib, the primary objective of the study. RESULTS: Included patients had endometrial (17/36 [47%]), ovarian (10/36 [28%]), or other gynecological cancers (9/36 [25%]). Most patients had received 2-3 prior systemic treatments (endometrial, 47·2%; ovarian, 60%; other, 56%), and presented with visceral metastases at baseline (82%, 70%, and 56%, respectively). Overall, 17 different PIK3CA mutations were found, including 53% in the kinase domain (most commonly H1047R) and 36% in the helical domain (most commonly E545K). Overall, the ORR was 28% and DCR was 61%, with the greatest benefit observed in patients with endometrial cancer (35% and 71%, respectively). CONCLUSION: Alpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers.

Totally intracorporeal colorectal anastomosis (TICA) versus classical mini-laparotomy for specimen extraction, after segmental bowel resection for deep endometriosis: a single-center experience.

PURPOSE: The surgical approach to bowel endometriosis is still unclear. The aim of the study is to compare TICA to conventional specimen extractions and extra-abdominal insertion of the anvil in terms of both complications and functional outcomes. METHODS: This is a single-center, observational, retrospective study conducted enrolling symptomatic women underwent laparoscopic excision of deep endometriosis with segmental bowel resection between September 2019 and June 2022. Women who underwent TICA were compared to classical technique (CT) in terms of intra- and postoperative complications, moreover, functional outcomes relating to the pelvic organs were assessed using validated questionnaires [Knowles-Eccersley-Scott-Symptom (KESS) questionnaire and Gastro-Intestinal Quality of Life Index (GIQLI)] for bowel function. Pain symptoms were assessed using Visual Analogue Scale (VAS) scores. RESULTS: The sample included 64 women. TICA was performed on 31.2% (n = 20) of the women, whereas CT was used on 68.8% (n = 44). None of the patients experienced rectovaginal, vesicovaginal, ureteral or vesical fistula, or ureteral stenosis and uroperitoneum, and in no cases was it necessary to reoperate. Regarding the two surgical approaches, no significant difference was observed in terms of complications. As concerns pain symptoms at 6-month follow-up evaluations on stratified data, except for dysuria, all VAS scales reported showed significant reductions between median values, for both surgery interventions. As well, significant improvements were further observed in KESS scores and overall GIQLI. Only the GIQLI evaluation was significantly smaller in the TICA group compared to CT after the 6-month follow-up. CONCLUSIONS: We did not find any significant differences in terms of intra- or post-operative complications compared TICA and CT, but only a slight improvement in the Gastro-Intestinal Quality of Life Index in patients who underwent the CT compared to the TICA technique.

Shedding of Syncytiotrophoblast-Derived Extracellular Vesicles Is Increased in Placenta Previa and Accreta Spectrum.

Placenta accreta spectrum (PAS) refers to excessive placental invasion into the maternal uterus and it is associated with high risk of obstetric haemorrhage and adverse maternal-neonatal outcomes. Currently, no specific circulating biomarkers of PAS have been identified. Given that in PAS disorders, the depth and the extension of placental invasion into the uterus are expected to be increased, in this study, we analysed plasma levels of syncytiotrophoblast-derived extracellular vesicles (STBEVs) in women with placenta previa (PP), at a high risk of PAS disorders, and pregnant women with normal placentation. Venous blood samples were collected from 35 women with ultrasonographic diagnosis of PP and 35 women with normal placentation, matched for gestational age. Plasma samples were ultracentrifuged at 120.000 g to collect extracellular vesicles (EVs). To identify and quantify plasma placenta-derived EVs (or STBEVs), EVs were analysed by flow cytometry using a monoclonal antibody against placental alkaline phosphatase (PLAP). Plasma levels of STBEVs were significantly higher in PP patients compared to controls. Plasma levels of STBEVs in women with PP and PAS showed a trend to a higher concentration compared to women with PP without PAS, although not reaching a statistical significance. Circulating STBEVs are potential candidates as biological markers to be integrated to ultrasonography in the antenatal screening programme for PAS. More studies are needed to confirm our observation in a larger cohort of patients and to analyse a possible association between high circulating levels of STBEVs and PAS.

New windows of surgical opportunity for gynecological cancers in the era of targeted therapies.

Precision medicine through molecular profiling has taken a prominent role in the treatment of solid tumors and it is widely expected that this will continue to expand. With respect to gynecological cancers, a major change has particularly been observed in the treatment landscape of epithelial ovarian, endometrial, and cervical cancers. Regarding the former, maintenance therapy with either poly(ADP-ribose) polymerase inhibitors (PARPi) and/or bevacizumab has become an indispensable treatment option following the traditional combination of cytoreductive surgery and platinum-based chemotherapy. Considering endometrial cancer, the molecular classification system has now been incorporated into virtually every guideline available and molecular-directed treatment strategies are currently being researched, presumably leading to a further transformation of its treatment paradigm. After all, treatment with immune-checkpoint inhibitors that target the programmed cell death 1 (PD-1) receptor has already been shown to significantly improve disease outcomes in these patients, especially in those with mismatch repair deficient, microsatellite stability-high (MMRd-MSI-H) disease. Similarly, in recurrent/metastatic cervical cancer patients, these agents elicited improved survival rates when being added to platinum-based chemotherapy with or without bevacizumab. Interestingly, implications of these targeted therapies for surgical management have been touched on to a minor extent, but are at least as intriguing. This review therefore aims to address the wide-ranging opportunities the molecular tumor characteristics and their corresponding targeted therapies have to offer for the surgical management of epithelial ovarian, endometrial, and cervical cancers, both in the primary and recurrent setting.