Andrea Giannini

The Role of Tumor Biomarkers in Tailoring the Approach to Advanced Ovarian Cancer

Growing evidence has demonstrated the role of mutations of tumor biomarkers in diagnosing and treating epithelial ovarian cancer. This review aims to analyze recent literature on the correlation between tumor biomarkers and chemotherapy in nonmucinous ovarian cancer, providing suggestions for personalized treatment approaches. An extensive literature search was conducted to identify relevant studies and trials. BRCA1/2 mutations are central in homologous recombination repair deficiency (HRD) in ovarian cancer, but several other genetic mutations also contribute to varying cancer risks. While the role of MMR testing in ovarian cancer is debated, it is more commonly linked to non-serous ovarian cancer, often associated with Lynch syndrome. A significant proportion of ovarian cancer patients have HRD, affecting treatment decisions in both first-line (especially in advanced stages) and second-line therapy due to HRD’s connection with platinum-based therapy and PARP inhibitors’ response. However, validated genetic tests to identify HRD have not yet been universally implemented. There is no definitive therapeutic algorithm for advanced ovarian cancer, despite ongoing efforts and multiple proposed tools. Future research should focus on expanding the utility of biomarkers, reducing resistance, and increasing the actionable biomarker pool.

Targeting BRAF pathway in low-grade serous ovarian cancer

Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities including ovarian carcinomas. In the recent years, several inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Low grade serous ovarian carcinoma, is a rare gynecological tumor which shows favorable overall survival, compared to the general ovarian cancer population, but worrying resistance to conventional chemotherapies. The clinical behavior of low grade serous ovarian carcinoma reflects the different gene profile compared to high-grade serous carcinoma:

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.

Sentinel node mapping in endometrial cancer

Nodal status is one of the most important prognostic factors for patients with apparent early stage endometrial cancer. The role of retroperitoneal staging in endometrial cancer is controversial. Nodal status provides useful prognostic data, and allows to tailor the need of postoperative treatments. However, two independent randomized trials showed that the execution of (pelvic) lymphadenectomy increases the risk of having surgery-related complication without improving patients' outcomes. Sentinel node mapping aims to achieve data regarding nodal status without increasing morbidity. Sentinel node mapping is the removal of first (clinically negative) lymph nodes draining the uterus. Several studies suggested that sentinel node mapping is not inferior to lymphadenectomy in identifying patients with nodal disease. More importantly, thorough ultrastaging sentinel node mapping allows the detection of low volume disease (micrometastases and isolated tumor cells), that are not always detectable via conventional pathological examination. Therefore, the adoption of sentinel node mapping guarantees a higher identification of patients with nodal disease than lymphadenectomy. Further evidence is needed to assess the value of various adjuvant strategies in patients with low volume disease and to tailor those treatments also on the basis of the molecular and genomic characterization of endometrial tumors.

The role of L1CAM as predictor of poor prognosis in stage I endometrial cancer: a systematic review and meta-analysis

Molecular and genomic profiling in endometrial cancer is increasing popularity. L1 cell adhesion molecule (L1CAM) is frequently mutated in endometrial cancer. In this paper, we aim to evaluate the prognostic role of L1CAM in patients with stage I endometrial cancer. We performed a systematic review and meta-analysis searching in PubMed (MEDLINE), EMBASE, and Web of Science database to identify studies reporting the expression of L1CAM in endometrial cancer. The primary endpoint measure was to assess and evaluate the impact of L1CAM on survival outcomes. This study was performed according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement. Five studies were included. The pooled results suggested that L1CAM expression influences survival outcomes in stage I endometrial cancer. High L1CAM expression correlated with worse disease-free survival (HR 4.11, 95% CI 1.02-16.59, p = 0.047) and overall survival (HR 3.62, 95% CI 1.32-9.31, p = 0.012). High L1CAM level was also associated with a more aggressive FIGO grade and with older age. This systematic review supported that L1CAM have a prognostic role in stage I endometrial cancer, thus providing a potential useful tool for tailoring the need of adjuvant therapy.

Factors in malignant transformation of ovarian endometriosis: A narrative review

Endometriosis is a common estrogen-dependent inflammatory disease with a chronic course and a tendency to recur. The association between endometriosis and cancer has been studied for several years. Numerous reports have demonstrated a strong association between specific ovarian malignancies and endometriotic lesions. Atypical endometriosis has been widely described as a malignant precursor to ovarian epithelial tumors, particularly clear cell carcinomas and endometrioid carcinomas. These histological types associated with endometriosis develop predominantly in the ovary rather than in extragonadal sites. The detailed molecular mechanism of etiology remains unclear. Recent studies have analyzed the genetic and molecular mechanisms involved in endometriosis-associated ovarian cancer. A critical role appears to be played by a carcinogenic model based on iron-induced oxidative stress, which is typical of the endometriosis microenvironment. It has been hypothesized that trans-tubal reflux of blood, endometrial cells and associated iron-induced oxidative stress underlie the development of endometriosis-associated ovarian cancer. However, the multifactorial mechanisms of this malignant transformation are not fully understood. The aim of this review is to summaries the current epidemiological, histopathological, genetic and molecular findings in the progression of endometriosis-associated ovarian cancer.

Robotic-assisted, laparoscopic, and vaginal hysterectomy in morbidly obese patients with endometrial hyperplasia and endometrial cancer

Hysterectomy for endometrial hyperplasia and endometrial cancer in morbidly obese patients is challenging. Here, we reported data regarding three minimally invasive approaches. This is a multicenter retrospective study evaluating 30-day and 90-day surgery-related outcomes of morbidly obese patients (those with BMI > 40kg/m Charts of 95 morbidly obese patients who underwent surgery for endometrial cancer were retrieved. Overall, robotic-assisted, laparoscopic, and vaginal surgeries were performed in 35 (36.8%), 38 (40%), and 22 (23.2%) patients, respectively. Patients having robotic-assisted surgery experienced longer operative time than patients having vaginal and laparoscopic approaches ( Robotic-assisted, laparoscopic, and vaginal surgery represent three safe and feasible minimally invasive approaches to manage morbidly obese patients with endometrial hyperplasia and endometrial cancer.

Novel Insights into Molecular Mechanisms of Endometrial Diseases

Endometrial diseases are the most common gynecological pathologies in Western Countries [...]

Age-Adjusted Charlson Comorbidity Index Predicts Survival in Endometrial Cancer Patients

<b><i>Objective:</i></b> Comorbidity scores are increasingly used to reduce potential confounding in oncologic research. This is of paramount importance in endometrial cancer (EC) since it is characterized by quite indolent behavior. Here, we aim to evaluate the impact of various comorbidities and concurrent medications used on survival outcomes, adopting the age-adjusted Charlson comorbidity index (A-CCI). <b><i>Design:</i></b> This is an observational study. Charts of 257 EC patients were retrieved. <b><i>Methods:</i></b> We retrospectively evaluated data of patients who underwent surgical treatment for EC. A-CCI was calculated by summing the weighted comorbidities and age of each patient. A binomial value was assigned to different comorbidities and different drugs. Oncologic outcomes were evaluated using Cox proportional hazard models adjusted for age. <b><i>Results:</i></b> A-CCI ≥3 correlated with more aggressive tumor features (47.6% vs. 26.8%, <i>p</i> = 0.001), higher risk of recurrence (29.7% vs. 11.6%, <i>p</i> = 0.001), death (20.7% vs. 7.1%, <i>p</i> = 0.002), and death due to disease (16.6% vs. 6.3%, <i>p</i> = 0.012). Considering comorbidities and drugs at parsimonious multivariable analysis model: cardiac disease, liver disease, and proton pump inhibitors (PPIs) use were independent predictors of disease-free survival. Cardiac disease, autoimmune disease, and PPIs use were independent predictors of overall survival. Diabetes was the only independent predictor for cause-specific survival. <b><i>Limitations:</i></b> The major limitation of the present study is its retrospective nature and the relatively small sample size that limit the possibility to have firm conclusions. <b><i>Conclusion:</i></b> Patients with EC are characterized by a high burden of comorbidities. Comorbidities are associated directly with survival outcomes. Further attention is needed to improve the active management of comorbidities soon after EC treatments. Interventional studies are needed to improve patients’ outcomes.

Cold Knife Versus Carbon Dioxide for the Treatment of Preinvasive Cervical Lesion

Background and Objectives: Cervical cancer (CC) represents a significant health concern worldwide, particularly for younger women. Cold knife (CK) conization and carbon dioxide (CO2) laser conization are two techniques commonly used to remove pre-invasive lesions, offering a potential curative intent in cases of incidental diagnosis of CC. This study aimed to assess the clinical implications and pathological outcomes of CK vs. CO2 laser conization for pre-invasive lesions. Materials and Methods: We retrospectively analyzed women who underwent CO2 or CK conization for high-grade preinvasive lesions (CIN2/3, CIS and AIS) between 2010 and 2022. Patient demographics, surgical details and pathological outcomes were collected. Pregnancy outcomes, including composite adverse obstetric rates, and oncological follow-up data, were also obtained. Results: In all, 1270 women were included; of them, 1225 (96.5%) underwent CO2, and 45 (3.5%) underwent CK conization. Overall, the rate of positive endocervical or deep margins was lower with CO2 laser compared to CK (4.3% vs. 13.3%, p = 0.015). Incidental CC was diagnosed in 56 (4.4%) patients, with 35 (62.5%) squamous and 21 (46.6%) adenocarcinomas. In a multivariate regression model, the relative risk for positive endocervical or deep margins is significantly greater in cases of incidental diagnosis of CC (p < 0.01). In cases of incidental diagnosis of CC, we found that the probabilities of having either positive endocervical or deep margins after CO2 laser or CK conization are similar, with a higher risk in case of adenocarcinoma lesion. Among women with CC, 42 (75%) opted for radical treatment, while 14 (25%) underwent a follow-up. Only one woman (7.1%) in the follow-up group, who had undergone CK conization, experienced a composite adverse obstetric outcome. No recurrences were observed after a median follow-up of 53 months. Conclusions: CO2 laser conization achieved a lower positive margin rate overall. CK and CO2 conization appear to be equivalent oncological options for incidental CC.

Reproductive Outcomes in Young Women with Early-Stage Cervical Cancer Greater than 2 cm Undergoing Fertility-Sparing Treatment: A Systematic Review

Background and Objectives: Despite advancements in detection and treatment, cervical cancer remains a significant health concern, particularly among young women of reproductive age. Limited data exists in the literature regarding fertility-sparing treatment (FST) of cervical cancers with tumor sizes greater than 2 cm. The objective of this systematic review was to evaluate the reproductive outcomes of women diagnosed with cervical cancer greater than 2 cm who underwent FST. Materials and Methods: A comprehensive search of the literature was carried out on the following databases: MEDLINE, EMBASE, Global Health, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), the Health Technology Assessment Database, and Web of Science. Only original studies (retrospective or prospective) that reported reproductive outcomes of patients with cervical cancer >2 cm were considered eligible for inclusion in this systematic review (CRD42024521964). Studies describing only the oncologic outcomes, involving FST for cervical cancers less than 2 cm in size, and case reports were excluded. Results: Seventeen papers that met the abovementioned inclusion criteria were included in the present systematic review. In total, 443 patients with a cervical cancer larger than 2 cm were included in this systematic review. Eighty pregnancies occurred, with 24 miscarriages and 54 live births. Conclusions: FST appears to be a viable option for women of childbearing age diagnosed with cervical cancer larger than 2 cm. However, careful consideration is advised in interpreting these encouraging results, as they are subject to limitations, such as variability in study designs and potential biases. In addition, reproductive outcomes should be further cross-referenced with oncologic outcomes to clarify the potential risk–benefit ratio. It is critical to conduct further research using standardized approaches and larger participant groups to strengthen the validity of the conclusions drawn.

The giant steps in surgical downsizing toward a personalized treatment of vulvar cancer

AbstractThe present article aims to highlight the importance of changes of personalized surgical treatment for vulvar cancer. Current international literature regarding surgical treatment of vulvar cancer was evaluated. This included several studies and systematic reviews. Radical surgery approach, such as en bloc resection, was the first therapeutic option and the standard care for many years, even if burdened with a high complication rate and frequently disfiguring. Taussing and Way introduced radical vulvectomy approach with en bloc bilateral inguinal‐femoral lymphadenectomy; modified radical vulvectomy was developed, with a wide radical excision of the primary tumor. The role of inguinofemoral lymphadenectomy (mono or bilateral) changed in the years too, particularly with the advent of SLN biopsy as minimally invasive surgical approach for lymph node staging, in patients with unifocal cancer <4 cm, without suspicious groin nodes. More personalized and conservative surgical approach, consisting of wide local or wide radical excisions, is necessary to reduce complications as lymphedema or sexual disfunction. The optimal surgical management of vulvar cancer needs to consider dimensions, staging, depth of invasion, presence of carcinoma at the surgical margins of resection and grading, with the goal of making the treatment as individualized as possible.

Evaluation of Surgical Outcomes of Abdominal Radical Hysterectomy and Total Laparoscopic Radical Hysterectomy for Cervical Cancer: A Retrospective Analysis of Data Collected before the LACC Trial

Although a surgical approach is one of the key treatments for stages IA1-IIA2, results of the Laparoscopic Approach to Cervical Cancer (LACC) published in 2018 radically changed the field, since minimally invasive surgery was associated with a four-fold higher rate of recurrence and a six-fold higher rate of all-cause death compared to an open approach. We aimed to evaluate surgical outcomes of abdominal radical hysterectomy (ARH) and total laparoscopic radical hysterectomy (TLRH) for cervical cancer, including data collected before the LACC trial. In our retrospective analysis, operative time was significantly longer in TLRH compared to ARH (p < 0.0001), although this disadvantage could be considered balanced by lower intra-operative estimated blood loss in TLRH compared with ARH (p < 0.0001). In addition, we did not find significant differences for intra-operative (p = 0.0874) and post-operative complication rates (p = 0.0727) between ARH and TLRH. This was not likely to be influenced by age and Body Mass Index, since they were comparable in the two groups (p = 0.0798 and p = 0.4825, respectively). Finally, mean number of pelvic lymph nodes retrieved (p = 0.153) and nodal metastases (p = 0.774), as well as death rate (p = 0.5514) and recurrence rate (p = 0.1582) were comparable between the two groups. Future studies should be aimed at assessing whether different histology/grades of cervical cancer, as well as particular subpopulations, may have significantly different outcomes using minimally invasive surgery or laparotomy, with or without neoadjuvant chemotherapy.

Radical Hysterectomy for Early Stage Cervical Cancer

Radical hysterectomy and plus pelvic node dissection are the primary methods of treatment for patients with early stage cervical cancer. During the last decade, growing evidence has supported the adoption of a minimally invasive approach. Retrospective data suggested that minimally invasive surgery improves perioperative outcomes, without neglecting long-term oncologic outcomes. In 2018, the guidelines from the European Society of Gynaecological Oncology stated that a “minimally invasive approach is favored” in comparison with open surgery. However, the phase III, randomized Laparoscopic Approach to Cervical Cancer (LACC) trial questioned the safety of the minimally invasive approach. The LACC trial highlighted that the execution of minimally invasive radical hysterectomy correlates with an increased risk of recurrence and death. After its publication, other retrospective studies investigated this issue, with differing results. Recent evidence suggested that robotic-assisted surgery is not associated with an increased risk of worse oncologic outcomes. The phase III randomized Robotic-assisted Approach to Cervical Cancer (RACC) and the Robotic Versus Open Hysterectomy Surgery in Cervix Cancer (ROCC) trials will clarify the pros and cons of performing a robotic-assisted radical hysterectomy (with tumor containment before colpotomy) in early stage cervical cancer.

New Advances in Cervical Cancer: From Bench to Bedside

Cervical cancer is the most common gynecologic malignancy and the fourth most common cancer in women worldwide. Over the last two decades, minimally invasive surgery (MIS) has emerged as the mainstay in the surgical management of early-stage cervical cancer, bringing advantages such as a lower operative morbidity and shorter hospital stay compared to open surgery, while maintaining comparable oncologic outcomes in numerous retrospective studies. Considering oncological patients, it is mandatory to assess the oncological outcomes and safety of this type of surgery. Moreover, there are different future outlooks on cervical cancer therapy, based on immunotherapy, target therapy, and poly-ADP-ribose polymerases (PARP) inhibitors in combination with each other, and in combination with standard chemotherapy and radiotherapy. The goal is to find an approach that is as personalized as possible.

Minimally Invasive Surgery for Cervical Cancer: Should We Look beyond Squamous Cell Carcinoma?

Robotic-assisted single-port and multi-port surgical staging in early-stage endometrial cancer: a propensity matched comparison.

Robotic-assisted surgery has emerged as an effective method for managing endometrial cancer. Recently, the new Da Vinci Single-Port (SP) was developed with the aim of minimizing surgery-related morbidity, using a single-port approach. The present research evaluated outcomes of apparent early-stage endometrial cancer patients undergoing single- and multi-port robotic-assisted surgery. This is a retrospective study. Data of consecutive patients affected by early-stage endometrial cancer who had robotic-assisted staging (including hysterectomy, bilateral salpingo-oophorectomy and nodal staging) with Da Vinci SP were matched 1:1 with a cohort of patients undergoing robotic-assisted surgery with the multi-port Da Vinci Xi. The matching was conducted by a propensity-score comparison. Fifty patient pairs (50 undergoing single-port surgical staging vs. 50 undergoing multiple-port surgical staging) were included. Demographic and baseline characteristics were balanced between groups. Median (skin to skin) operative time (minutes) was similar between groups (120 (range, 70-229) in the single-port vs. 115 (range, 60-205) in the multi-port group; p = 0.367). Estimated blood loss was comparable between groups (p = 0.317). No intra-operative complications or intra-operative blood transfusions were recorded. The median length of hospital stay was similar between groups (p = 0.269). Overall, 10 (10 %) patients developed 90-day surgery-related complications: six (12 %) and four (8 %) in the single- and multi-port group, respectively (p = 0.740). One (2 %) and two (4 %) patients experienced severe (grade 3 or more) 90-day complications after single- and multi-port robotic-assisted staging (p = 1.00). Introducing Da Vinci SP appears to be safe and feasible. The single-port approach does not increase operative time and complication rates in comparison to the multi-port robotic-assisted system.

Surgical outcomes and morbidity in open and videoendoscopic inguinal lymphadenectomy in vulvar cancer: A systematic review and metanalysis”

Surgical evaluation of inguinal lymph nodes is essential to correctly guide the adjuvant treatment of vulvar cancer patients. Open inguinal lymphadenectomy (OIL) approach is the preferred route, while the videoendoscopic inguinal lymphadenectomy (VEIL) seems to be associated with better results. This meta-analysis aimed to compare the surgical outcomes of OIL vs VEIL in vulvar cancer. The meta-analysis was conducted according to the PRISMA guideline. The search string included the following keywords: "(vulvar cancer) AND ((inguinal) OR (femoral)) AND ((lymph node dissection) OR (lymphadenectomy))". Three double-blind researchers independently extracted data. Seventeen studies were considered eligible for the analysis. Seven studies were included in the OIL group and ten studies in the VEIL group. A total of 372 groins were included in OIL group and 197 groins in VEIL group. 153 groins (41.1 %) in the OIL group and 25 groins (12.6 %) in the VEIL group developed major complications. The analysis of all lymphatic and wound complications showed that VEIL had a lower rate of lymphatic and wound complications. Estimated blood loss (p = 0.4), hospital stay (p = 0.18), time of drainage (p = 0.74), number of lymph node excised (p = 0.74) did not show significant difference between the two approaches. VEIL route may be a valid alternative to OIL route with no differences in terms of surgical outcomes, except for operative time that is shorter for OIL. Future analysis of randomized controlled trials in this specific patient population are warranted to confirm these results.

Hormone replacement therapy in gynecological cancer survivors and BRCA mutation carriers: a MITO group survey

Early iatrogenic menopause in gynecological cancer survivors and BRCA mutation (BRCAm) carriers undergoing risk-reducing salpingo-oophorectomy (RRSO) is a major health concern. Hormone replacement therapy (HRT) is the most effective remedy, but remains underused in clinical practice. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) group promoted a national survey to investigate the knowledge and attitudes of healthcare professionals regarding the prescription of HRT. The survey consisted of a self-administered, multiple-choice 45-item questionnaire, available online to all MITO members for 2 months starting from January 2022. A total of 61 participants completed the questionnaire (47 out of 180 MITO centers; compliance: 26.1%). Most respondents were female (73.8%), younger than 50 years (65.6%), and gynecologic oncologists (55.7%), working in public general hospitals (49.2%). An 84.4% of specialists actively discuss HRT with patients and 51.0% of patients ask the specialist for an opinion on HRT. The rate of specialists globally in favor of prescribing HRT was 22.9% for ovarian cancer, 49.1% for cervical cancer, and 8.2% for endometrial cancer patients. Most respondents (70.5%) believe HRT is safe for BRCA-mutated patients after RRSO. Nearly 70% of physicians prescribe systemic HRT, while 23.8% prefer local HRT. Most specialists recommend HRT for as long as there is a benefit and generally for up to 5 years. Real-world data suggest that many healthcare professionals still do not easily prescribe HRT for gynecological cancer survivors and BRCA mutation carriers after RRSO. Further efforts are required to implement the use of HRT in clinical practice and to support both clinicians in recommending HRT and patients in accepting it.