Neoadjuvant chemotherapy prior to radical hysterectomy in locally advanced cervical cancer: a systematic review and meta-analysis.

OBJECTIVE: The objective of this systematic review was to evaluate the effect of different types of neoadjuvant chemotherapy regimens, in terms of optimal pathological response and oncological outcomes, in patients with locally advanced cervical cancer. METHODS: A systematic search of the literature was performed. MEDLINE through PubMed and Embase databases were searched from inception to June 2023. The study was registered in PROSPERO (ID number CRD42023389806). All women with a pathological diagnosis of locally advanced cervical cancer (International Federation of Gynecology and Obstetrics (FIGO) 2009 classification stages IB2-IVA), any age or histology, who underwent intravenous neoadjuvant chemotherapy before radical surgery, and articles only in English language, were included. We conducted a meta-analysis for optimal pathological response after surgery and survival outcomes. The risk of bias was assessed using the Newcastle-Ottawa scale and the Risk of Bias 2 (RoB) tools. The review methods and results were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: 25 studies with a total number of 1984 patients fulfilled the eligibility criteria of our review and were included for data extraction and efficacy analysis. When compared with a two-drug regimen, the three-drug combination including cisplatin, paclitaxel, and ifosfamide or anthracyclines showed superior efficacy in terms of optimal pathological response with an odds ratio of 0.38 (95% CI 0.24 to 0.61, p<0.0001), with no difference in disease-free survival (hazard ratio (HR) 0.72, 95% CI 0.50 to 1.03, I2=0%, p=0.07) and higher overall survival (HR 0.63, 95% CI 0.41 to 0.97, I2=0%, p=0.03). CONCLUSIONS: The three-drug combination of cisplatin, paclitaxel, and ifosfamide or anthracyclines showed a higher rate of complete or optimal partial response, with the triple regimens having an advantage over the platinum-based schedules in terms of overall survival. Neoadjuvant chemotherapy followed by radical surgery should not be considered a standard of care in locally advanced cervical cancer.

Outcomes of High-Grade Cervical Dysplasia with Positive Margins and HPV Persistence after Cervical Conization.

The objective of this work is to assess the 5-year outcomes of patients undergoing conization for high-grade cervical lesions that simultaneously present as risk factors in the persistence of HPV infection and the positivity of surgical resection margins. This is a retrospective study evaluating patients undergoing conization for high-grade cervical lesions. All patients included had both positive surgical margins and experienced HPV persistence at 6 months. Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR). The charts of 2966 patients undergoing conization were reviewed. Among the whole population, 163 (5.5%) patients met the inclusion criteria, being at high risk due to the presence of positive surgical margins and experiencing HPV persistence. Of 163 patients included, 17 (10.4%) patients developed a CIN2+ recurrence during the 5-year follow-up. Via univariate analyses, diagnosis of CIN3 instead of CIN2 (HR: 4.88 (95%CI: 1.10, 12.41); p = 0.035) and positive endocervical instead of ectocervical margins (HR: 6.44 (95%CI: 2.80, 9.65); p < 0.001) were associated with increased risk of persistence/recurrence. Via multivariate analyses, only positive endocervical instead of ectocervical margins (HR: 4.56 (95%CI: 1.23, 7.95); p = 0.021) were associated with worse outcomes. In this high-risk group, positive endocervical margins is the main risk factor predicting 5-year recurrence.

Development of a Nomogram Predicting the Risk of Persistence/Recurrence of Cervical Dysplasia.

Background: Cervical dysplasia persistence/recurrence has a great impact on women's health and quality of life. In this study, we investigated whether a prognostic nomogram may improve risk assessment after primary conization. Methods: This is a retrospective multi-institutional study based on charts of consecutive patients undergoing conization between 1 January 2010 and 31 December 2014. A nomogram assessing the importance of different variables was built. A cohort of patients treated between 1 January 2015 and 30 June 2016 was used to validate the nomogram. Results: A total of 2966 patients undergoing primary conization were analyzed. The median (range) patient age was 40 (18-89) years. At 5-year of follow-up, 6% of patients (175/2966) had developed a persistent/recurrent cervical dysplasia. Median (range) recurrence-free survival was 18 (5-52) months. Diagnosis of CIN3, presence of HR-HPV types, positive endocervical margins, HPV persistence, and the omission of HPV vaccination after conization increased significantly and independently of the risk of developing cervical dysplasia persistence/recurrence. A nomogram weighting the impact of all variables was built with a C-Index of 0.809. A dataset of 549 patients was used to validate the nomogram, with a C-index of 0.809. Conclusions: The present nomogram represents a useful tool for counseling women about their risk of persistence/recurrence after primary conization. HPV vaccination after conization is associated with a reduced risk of CIN2+.

Low-Pressure Laparoscopy Using the AirSeal System versus Standard Insufflation in Early-Stage Endometrial Cancer: A Multicenter, Retrospective Study (ARIEL Study).

The aim of our study was to evaluate the benefits of a low-pressure insufflation system (AirSeal) vs. a standard insufflation system in terms of anesthesiologists' parameters and postoperative pain in patients undergoing laparoscopic surgery for early-stage endometrial cancer. This retrospective study involved five tertiary centers and included 152 patients with apparent early-stage disease who underwent laparoscopic surgical staging with either the low-pressure AirSeal system (8−10 mmHg, n = 84) or standard laparoscopic insufflation (10−12 mmHg, n = 68). All the intraoperative anesthesia variables evaluated (systolic blood pressure, end-tidal CO2, peak airway pressure) were significantly lower in the AirSeal group. We recorded a statistically significant difference between the two groups in the median NRS scores for global pain recorded at 4, 8, and 24 h, and for overall shoulder pain after surgery. Significantly more women in the AirSeal group were also discharged on day one compared to the standard group. All such results were confirmed when analyzing the subgroup of women with a BMI >30 kg/m2. In conclusion, according to our preliminary study, low-pressure laparoscopy represents a valid alternative to standard laparoscopy and could facilitate the development of outpatient surgery.

Neoadjuvant Chemotherapy Prior Fertility-Sparing Surgery in Women with FIGO 2018 Stage IB2 Cervical Cancer: A Systematic Review.

Nowadays, the optimal management of patients with cervical cancers measuring 2-4 cm desiring to maintain fertility is still uncertain. In this systematic review, we assessed the reliability of neoadjuvant chemotherapy (NACT) prior to fertility-sparing (FS) surgery in International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB2 cervical cancer, in terms of pathologic response, oncological and obstetric outcomes. The review of the literature was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data, using MEDLINE and PubMed, were searched for from 1 January 2005 up to 1 December 2020. We identified 20 articles and 114 women with IB2 disease, possible candidates for NACT prior to FS surgery. However, uterine conservation was achieved only in 76.7% of them. Patients reached optimal pathological response to NACT in 60.9% of cases and a TIP (cisplatin, ifosfamide and paclitaxel) regime was related to the best response. Suboptimal response to NACT appeared to be an independent negative prognostic factor. Up to 9.2% of patients recurred with a median 7.4-months DFS, and 4.6% of patients died of disease. Fifty percent of women tried to conceive after treatment and NACT prior to conization appeared to be the most promising alternative to upfront radical trachelectomy in terms of obstetric outcomes. In conclusion, NACT prior to FS surgery is an option, but the literature about this issue is still weak and FS should be carefully discussed with patients.

Fetal disseminated intravascular coagulopathy, hydrops and massive umbilical vein thrombosis consequence of a rare placental condition: multifocal chorangiomatosis.

Purpose: Villous capillary lesions are rare abnormal placental developmental conditions which include chorangiosis, chorangiomatosis, chorangioma and a rare variant of the latter called multiple chorangioma syndrome. The causes of villous capillary lesion are not completely clear but appear to involve excessive angiogenesis. MATERIALS AND METHODS: In this paper we start illustrating our experience of multifocal chorangiomatosis with the newborn affected by massive umbilical vein thrombosis, disseminated intravascular coagulopathy and hydrops, going to a literature review of cases available.Results: Two other similar cases have been previously published in literature. Comparing clinical characteristics and fetal outcomes, we confirm the association with unfavorable neonatal outcome mentioned in literature. Our case is the first characterized by severe hemolytic anemia, thrombocytopenia, heart congestion with the overlap of disseminated intravascular coagulopathy and massive umbilical vein thrombosis and congenital anomalies. CONCLUSIONS: Our clinical case and the review of literature highlight how multifocal chorangiomatosis, within the three subgroups identified, is the rarer form with distinct placental features and the worst outcomes for neonates. No cases of multifocal chorangiomatosis have never been described prenatally and, for further studies, could be reasonable investigate the involvement of some growth factors like vascular endothelial growth factor and placental growth factor that could lead to a detection of a subgroup of patient at higher risk to manifest placental vascular lesions and the follow fetal and maternal complications.

The impact of orthotopic reconstruction on female sexuality and quality of life after radical cystectomy for non-malignant bladder conditions.

OBJECTIVE: To review the literature on the impact on female quality of life and sexual function of orthotopic reconstruction after radical cystectomy for non-malignant bladder conditions. Radical cystectomy is commonly required to treat malignant conditions but may also be considered for the treatment of non-malignant diseases. These heterogeneous group of disorders includes interstitial cystitis, painful bladder syndrome, neurogenic bladder, haemorrhagic/ radiation cystitis, endometriosis and refractory genitourinary fistula. Treatment begins with non-invasive medical therapies but, in non-responder cases, a surgical solution should be considered. Such invasive techniques include urinary diversion and reconstructive procedures that have an impact on healthrelated quality of life, physical, social, and mental status. MATERIALS AND METHODS: This narrative review research was done using the PubMed database up until 2020, July. All papers referring to cystectomy for benign indication were considered. RESULTS: In comparison to other reconstructive options, orthotopic neobladder allows the restoration of a normal self-image and consequently it is the most suitable procedure when a surgical reconstruction is necessary for non-malignant conditions. However, women can face many disorders that impact on everyday life, such as voiding dysfunction or sexual activity problems. CONCLUSIONS: Scant data is available about quality of life, sexual life and self-perception in women treated by cystectomy for benign conditions and most literature is dedicated to those indicators in cancer patients. More research is needed to understand the tolerability and the quality of life results of the female population affected by benign conditions undergoing this kind of surgical approach.

Targeting the NLRP3 Inflammasome as a New Therapeutic Option for Overcoming Cancer.

Inflammasomes are multiprotein complexes that regulate the maturation and secretion of the proinflammatory cytokines interleukin-1beta (IL-1ß and interleukin-18 (IL-18) in response to various intracellular stimuli. As a member of the inflammasomes family, NLRP3 is the most studied and best characterized inflammasome and has been shown to be involved in several pathologies. Recent findings have made it increasingly apparent that the NLRP3 inflammasome may also play a central role in tumorigenesis, and it has attracted attention as a potential anticancer therapy target. In this review, we discuss the role of NLRP3 in the development and progression of cancer, offering a detailed summary of NLRP3 inflammasome activation (and inhibition) in the pathogenesis of various forms of cancer. Moreover, we focus on the therapeutic potential of targeting NLRP3 for cancer therapy, emphasizing how understanding NLRP3 inflammasome-dependent cancer mechanisms might guide the development of new drugs that target the inflammatory response of tumor-associated cells.

High-risk HPV-positive and -negative high-grade cervical dysplasia: Analysis of 5-year outcomes.

OBJECTIVE: To evaluate the outcomes of high-risk (HR) HPV-positive and -negative women affected by high-grade cervical dysplasia. METHODS: This is a retrospective multi-institutional study. Medical records of consecutive patients with high-grade cervical dysplasia undergoing conization between 2010 and 2014 were retrieved. All patients included had at least 5 years of follow-up. A propensity-score matching was adopted in order to reduce the presence of confounding factors between groups. Kaplan-Meir and Cox hazard models were used to estimate 5-year outcomes. RESULTS: Overall, data of 2966 women, affected by high-grade cervical dysplasia were reviewed. The study population included 1478 (85%) and 260 (15%) women affected by HR-HPV-positive and HR-HPV-negative high-grade cervical dysplasia. The prevalence of CIN2 and CIN3 among the HR-HPV-positive and -negative cohort was similar (p = 0.315). Patients with HR-HPV-positive high-grade cervical dysplasia were at higher risk of 5-year recurrence (after primary conization) that HR-HPV-negative patients (p < 0.001, log-rank test). Via multivariate analysis, HR-HPV-negative women were at low risk of recurrence (HR: 1.69 (95%CI: 1.05, 4.80); p = 0.018, Cox Hazard model). A propensity-score matched comparison was carried out in order to reduce biases that are related to the retrospective study design. In comparison to HR-HPV-negative patients, thosewith HR-HPV-positive CIN3 was associate with a 8-fold increase in the risk of recurrence (p < 0.001, log-rank test). CONCLUSIONS: HR-HPV-negative high-grade cervical dysplasia is not uncommon, accounting for 15% of our study population. Those patients experience more favorable outcomes than patients with documented HR-HPV infection(s). Further prospective studies are needed to corroborate our data.

Assessing the Long-Term Role of Vaccination against HPV after Loop Electrosurgical Excision Procedure (LEEP): A Propensity-Score Matched Comparison.

Background: Primary prevention through vaccination is a prophylactic approach aiming to reduce the risk of developing human papillomavirus (HPV)-related lesions. No mature and long-term data supported the adoption of vaccination in women undergoing conization. Methods: This is a retrospective multi-institutional study. Charts of consecutive patients undergoing conization between 2010 and 2014 were collected. All patients included had at least 5 years of follow-up. We compared outcomes of patients undergoing conization plus vaccination and conization alone. A propensity-score matching algorithm was applied in order to reduce allocation biases. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. Results: Overall, charts of 1914 women were analyzed. The study group included 116 (6.1%) and 1798 (93.9%) women undergoing conization plus vaccination and conization alone, respectively. Five-year recurrence rate was 1.7% (n = 2) and 5.7% (n = 102) after conization plus vaccination and conization alone, respectively (p = 0.068). After the application of a propensity-score matching, we selected 100 patients undergoing conization plus vaccination and 200 patients undergoing conization alone. The crude number of recurrences was 2 (2%) and 11 (5.5%) for patients undergoing conization plus vaccination and conization alone, respectively (p = 0.231). Vaccination had no impact on persistent lesions (no negative examination between conization and new cervical dysplasia; p = 0.603), but reduced the risk of recurrent disease (patients who had at least one negative examination between conization and the diagnosis of recurrent cervical dysplasia; p = 0.031). Conclusions: Patients having vaccination experience a slightly lower risk of recurrence than women who had not, although not statistically significantly different. Further evidence is needed to assess the cost effectiveness of adopting vaccination in this setting.

Recurrence rate after loop electrosurgical excision procedure (LEEP) and laser Conization: A 5-year follow-up study.

OBJECTIVE: Conization aims to remove pre-neoplastic lesions of the uterine cervix. Several techniques for conization have been compared, but evidence regarding the most effective therapeutic option is scant. Here, we aimed to compare the recurrence rate following laser conization and loop electrosurgical excision procedure (LEEP) in patients with high-grade cervical dysplasia (HSIL/CIN2+). METHODS: This is a retrospective multi-institutional study. Medical records of consecutive patients with HSIL/CIN2+ undergoing conization between 2010 and 2014 were retrieved. A propensity-score matching (PSM) was applied in order to reduce allocation bias. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. RESULTS: Overall, 2966 patients had conization over the study period, including 567 (20%) and 2399 (80%) patients having laser conization and LEEP, respectively. Looking at predictors of recurrence, diagnosis of CIN3 (HR:3.80 (95%CI:2.01,7.21); p < 0.001) and HPV persistence (HR:1.81 (95%CI:1.11,2.96); p < 0.001) correlated with an increased risk of recurrence. After applying a PSM we selected 500 patients undergoing laser conization and 1000 undergoing LEEP. Patients undergoing LEEP were at higher risk of having positive surgical margins in comparison to patients undergoing laser conization (11.2% vs. 4.2%). The risk of having persistence of HPV was similar between the two groups (15.0% vs. 11.6%;p = 0.256). Five-year recurrence rate was 8.1% and 4% after LEEP and laser conization, respectively (p = 0.023). HPV persistence was the only factor associated with [5-]year recurrence after both laser conization (p = 0.003) and LEEP (p = 0.001). CONCLUSIONS: HPV persistence is the only factor associated with an increased risk of recurrence after either laser conization or LEEP. Owing to the lack of data regarding obstetrical outcomes, we are not able to assess the best therapeutic option for women with cervical dysplasia.

Data on correction of pelvic organ prolapse by laparoscopic lateral suspension with mesh: A clinical series.

This DIB article provides additional data on laparoscopic lateral suspension with mesh for correcting pelvic organ prolapse. Data come from a multicentric sample of Italian women (https://doi.org/10.1016/j.ejogrb.2019.07.025). Data are collected retrospectively. Descriptive and raw data on surgery and descriptive and raw data on symptoms of pelvic organ prolapse pre-surgery and post-surgery are provided. Kaplan-Meier curves and scores of 7-items King's Health Questionnaire for quality of life assessment are also reported.

Correction of pelvic organ prolapse by laparoscopic lateral suspension with mesh: A clinical series.

OBJECTIVE: Illustrating the outcomes of laparoscopic lateral suspension by mesh for pelvic organ prolapse repair. STUDY DESIGN: A retrospective observational study was conducted collecting medical records of 48 patients treated between May 2016 and April 2018 in two different centers in Italy. Pre- and post-operative clinical evaluations as well as patients' satisfaction scores were considered. Patients were followed for two years. Statistical analysis was determined using the chi-square test in intention-to-treat and per-protocol analyses, while Kaplan-Meier curves were built for assessing the prolapse recurrence and the symptoms recurrence. The Steel-Dwass test for pairwise comparisons was used to compare median scores from the King's General Health Perception Questionnaire answers. RESULTS: Regarding the anatomical result, the outcome was either optimal or satisfactory (PoP-Q ≤1) at 12 months in 92% of patients for anterior compartment, in 100% for apical compartment, and in 75% for posterior compartment (intention-to-treat). Kaplan-Meier curves depicted a repair of prolapse in 70% of cases, with better outcomes for the anterior and the apical compartment. Patient self-perception of health was over 80% at each follow-up evaluation. CONCLUSION: Laparoscopic lateral suspension is a reasonable technique for treatment of pelvic organ prolapse. Further studies are needed to prove such a technique versus alternative surgeries.

Laparoscopic Approach in Management of Renal Cell Carcinoma During Pregnancy: State of the Art.

Renal cell carcinoma (RCC) is extremely rare in pregnant women. However, this is one of the most reported urologic tumors during pregnancy. The aim of this review was to evaluate RCC during pregnancy in terms of epidemiology, risk factors, diagnosis, natural history of disease, and the safety of laparoscopic approach in the management of this tumor. RCC presentation is frequently made incidentally during an ultrasonography performed for other reasons, such as hydronephrosis owing to non-neoplastic causes. The optimal time for surgery during pregnancy and the consequences of surgery on the maternal and fetal well-being are major considerations. Risks for adverse pregnancy outcomes should be explained, and the patient's decision about pregnancy termination should be considered. Ultrasound is good in diagnosing renal masses, with a sensitivity comparable to that of computed tomography only for exophytic masses larger than 3 cm. Magnetic resonance imaging is reproducible and a good, though expensive, alternative to computed tomography scans for the evaluation of renal lesions in pregnant women. Radical nephrectomy or nephron-sparing surgery are essential treatments for management of RCC. Laparoscopic surgery has historically been considered dangerous during pregnancy and avoided whenever possible, because of concerns regarding surgery-related risks, such as uterine injury, miscarriage, teratogenesis, preterm birth, and hypercapnia. The laparoscopic treatment during pregnancy is becoming increasingly accepted where feasible with low morbidity. However, the combination of a multidisciplinary approach, multi-specialty communication, and skilled surgeons can give the best possible outcomes for mother and fetus.

Artificial intelligence estimates the impact of human papillomavirus types in influencing the risk of cervical dysplasia recurrence: progress toward a more personalized approach.

The objective of this study was to determine whether the pretreatment human papillomavirus (HPV) genotype might predict the risk of cervical dysplasia persistence/recurrence. Retrospective analysis of prospectively collected data of consecutive 5104 women who underwent the HPV-DNA test were matched with retrospective data of women undergoing either follow-up or medical/surgical treatment(s) for genital HPV-related infection(s). Artificial neuronal network (ANN) analysis was used in order to weight the importance of different HPV genotypes in predicting cervical dysplasia persistence/recurrence. ANN simulates a biological neuronal system from both the structural and functional points of view: like neurons, ANN acquires knowledge through a learning-phase process and allows weighting the importance of covariates, thus establishing how much a variable influences a multifactor phenomenon. Overall, 5104 women were tested for HPV. Among them, 1273 (25%) patients underwent treatment for HPV-related disorders. LASER conization and cervical vaporization were performed in 807 (59%) and 386 (30%) patients, respectively, and secondary cervical conization in 45 (5.5%). ANN technology showed that the most important genotypes predicting cervical dysplasia persistence/recurrence were HPV-16 (normalized importance: 100%), HPV-59 (normalized importance: 51.2%), HPV-52 (normalized importance: 47.7%), HPV-18 (normalized importance: 32.8%) and HPV-45 (normalized importance: 30.2%). The pretreatment diagnosis of all of those genotypes, except HPV-45, correlated with an increased risk of cervical dysplasia persistence/recurrence; the pretreatment diagnosis was also arrived at using standard univariate and multivariable models (P<0.01). Pretreatment positivity for HPV-16, HPV-18, HPV-52 and HPV-59 might correlate with an increased risk of cervical dysplasia persistence/recurrence after treatment. These data might be helpful during patients' counseling and to implement new vaccination programs.

Potential impact of introducing a nonavalent HPV vaccination.

OBJECTIVE: To test the theoretical utility of incorporating nonavalent vaccination against HPV into a clinical setting. METHODS: The present retrospective study included data from consecutive patients who underwent HPV-DNA testing between January 1, 1998, and December 31, 2015. Changes in the prevalence of different HPV types were assessed during three periods (T1, 1998-2003; T2, 2004-2009; and T3, 2010-2015) using XY analysis. RESULTS: The study included a total of 13 665 patients. Overall, 1361, 5130, and 7174 patients were included in the T1, T2, and T3 periods, respectively. The quadrivalent vaccine would have potentially protected against HPV in 71.5% (973/1361), 46.5% (2385/5130), and 26.5% (1901/7174) of patients in T1, T2, and T3, respectively (P<0.001 for trend). The nonavalent vaccine could have protected against HPV in 92.5% (1259/1361), 72.3% (3709/5130), and 58.1% (4168/7174) of patients in T1, T2, and T3, respectively (P<0.001 for trend). The proportion of patients with genital dysplasia grade 2+ who did not have infections with HPV genotypes covered by the quadrivalent or nonavalent vaccines increased across the three periods (P<0.001 for trend). For all study periods, the protection provided by the nonavalent vaccine would have been superior to the quadrivalent vaccine (χ2 test P<0.001). CONCLUSION: The introduction of a nonavalent vaccine could improve protection against HPV infections and HPV-related genital dysplasia.

Invasive Paget Disease of the Vulva.

OBJECTIVE: Extramammary Paget disease of the vulva (EPDV) is a rare occurrence with an indolent and relapsing course. Progression to invasion occurs in 4% to 19% of cases. The aim of this study is to report clinical-pathological features and outcomes of patients treated for invasive EPDV. METHODS: Data of consecutive patients treated between 2000 and 2017 for invasive EPDV were reviewed. RESULTS: Among 79 patients with EPDV, 10 (12.7%) presented a microinvasive or invasive form at first diagnosis or during follow-up. All of them underwent upfront radical surgery; 7 (70%) received subsequent radiotherapy, chemotherapy, or both. The mortality rate was 40%. The recurrence rate after treatment for invasive forms was 60%, with a mean time to first recurrence of 20 (range, 5-36) months. CONCLUSIONS: Our study confirms that invasive EPDV remains a rare gynecological neoplasm with a poor prognosis. Multicentre trials or well-organized prospective data collection could improve the knowledge about the management of invasive EPDV.