Fertility-sparing surgery for women with stage I cervical cancer of 4 cm or larger: a systematic review

Violante Di Donato,Giuseppe Caruso,Carolina Maria Sassu,Giusi Santangelo,Giorgio Bogani,Francesco Plotti,Flavia Sorbi,Giorgia Perniola,Innocenza Palaia,Gianluca Terrin,Roberto Angioli,Pierluigi Benede 대한부인종양학회 2021 Journal of Gynecologic Oncology Vol.32 No.6

Objective: To investigate current evidence on oncological, fertility and obstetric outcomes of patients with stage I cervical cancer of 4 cm or larger undergoing fertility-sparing surgery (FSS). Methods: Systematic review of studies including women affected by stage I cervical cancer ≥4 cm who underwent FSS. Main outcome measures: disease-free survival (DFS), overall survival (OS), pregnancy rate, live birth rate, premature delivery rate. Results: Fifteen studies met all eligibility criteria for this systematic review, involving48 patients affected by cervical cancer ≥4 cm who completed FSS. Three patients (6.3%) experienced a recurrence and one of them (2.1%) died of disease. The 5-year DFS rate was 92.4%. The 5-year OS rate was 97.6%. A significantly shorter 5-year DFS was reported for high-risk patients (G3, non-squamous histotype, diameter ≥5 cm) compared with low-risk (74.7% vs. 100%; log-rank test, p=0.024). Data about fertility outcomes were available for 12 patients. Five patients out of 12 (41.7%) attempted to conceive with an estimated pregnancy rate of 80%, a live birth rate of 83.3% and a premature delivery rate of 20%. Conclusion: Women with high tumor grade, aggressive histology and tumor size ≥5 cm have a higher risk of recurrence. Oncologic outcomes are encouraging among low-risk patients; however, the lack of high-quality studies makes it difficult to draw any firm conclusions. Prospective multicentric clinical trials with a proper selection of inclusion/exclusion criteria should be conducted in women with low-risk factors, strong desire to preserve their fertility and high likelihood to conceive.

The age-adjusted Charlson comorbidity index as a predictor of survival in surgically treated vulvar cancer patients

Violante Di Donato,Zoe Page,Carlotta Bracchi,Federica Tomao,Angela Musella,Giorgia Perniola,PierLuigi Benedetti Panici 대한부인종양학회 2019 Journal of Gynecologic Oncology Vol.30 No.1

Objective: To evaluate the impact of age-adjusted Charlson comorbidity index (ACCI) in predicting disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS) among surgically treated patients with vulvar carcinoma. The secondary aim is to evaluate its impact as a predictor of the pattern of recurrence. Methods: We retrospectively evaluated data of patients that underwent surgical treatment for vulvar cancer from 1998 to 2016. ACCI at the time of primary surgery was evaluated and patients were classified as low (ACCI 0–1), intermediate (ACCI 2–3), and high risk (>3). DFS, OS and CSS were analyzed using the Kaplan-Meir and the Cox proportional hazard models. Logistic regression model was used to assess predictors of distant and local recurrence. Results: Seventy-eight patients were included in the study. Twelve were classified as low, 36 as intermediate, and 30 as high risk according to their ACCI. Using multivariate analysis, ACCI class was an independent predictor of worse DFS (hazard ratio [HR]=3.04; 95% confidence interval [CI]=1.54–5.99; p<0.001), OS (HR=5.25; 95% CI=1.63–16.89; p=0.005) and CSS (HR=3.79; 95% CI=1.13–12.78; p=0.03). Positive nodal status (odds ratio=8.46; 95% CI=2.13–33.58; p=0.002) was the only parameter correlated with distant recurrence at logistic regression. Conclusion: ACCI could be a useful tool in predicting prognosis in surgically treated vulvar cancer patients. Prospective multicenter trials assessing the role of ACCI in vulvar cancer patients are warranted.

Immunotherapy in endometrial cancer: new scenarios on the horizon

Chiara Di Tucci,Carmela Capone,Giulia Galati,Valentina Iacobelli,Michele C Schiavi,Violante Di Donato,Ludovico Muzii,Pierluigi Benedetti Panici 대한부인종양학회 2019 Journal of Gynecologic Oncology Vol.30 No.3

This extensive review summarizes clinical evidence on immunotherapy and targeted therapy currently available for endometrial cancer (EC) and reports the results of the clinical trials and ongoing studies. The research was carried out collecting preclinical and clinical findings using keywords such as immune environment, tumor infiltrating lymphocytes, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, immune checkpoint inhibitors, anti-PD-1/PD-L1 antibodies and others' on PubMed. Finally, we looked for the ongoing immunotherapy trials on ClinicalTrials.gov. EC is the fourth most common malignancy in women in developed countries. Despite medical and surgical treatments, survival has not improved in the last decade and death rates have increased for uterine cancer in women. Therefore, identification of clinically significant prognostic risk factors and formulation of new rational therapeutic regimens have great significance for enhancing the survival rate and improving the outcome in patients with advanced or metastatic disease. The identification of genetic alterations, including somatic mutations and microsatellite instability, and the definition of intracellular signaling pathways alterations that have a major role in in tumorigenesis is leading to the development of new therapeutic options for immunotherapy and targeted therapy.

Ovarian Cancer: Interplay of Vitamin D Signaling and miRNA Action

Attar, Rukset,Gasparri, Maria Luisa,Di Donato, Violante,Yaylim, Ilhan,Halim, Talha Abdul,Zaman, Farrukh,Farooqi, Ammad Ahmad Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.8

Increasing attention is being devoted to the mechanisms by which cells receive signals and then translate these into decisions for growth, death, or migration. Recent findings have presented significant breakthroughs in developing a deeper understanding of the activation or repression of target genes and proteins in response to various stimuli and of how they are assembled during signal transduction in cancer cells. Detailed mechanistic insights have unveiled new maps of linear and integrated signal transduction cascades, but the multifaceted nature of the pathways remains unclear. Although new layers of information are being added regarding mechanisms underlying ovarian cancer and how polymorphisms in VDR gene influence its development, the findings of this research must be sequentially collected and re-interpreted. We divide this multi-component review into different segments: how vitamin D modulates molecular network in ovarian cancer cells, how ovarian cancer is controlled by tumor suppressors and oncogenic miRNAs and finally how vitamin D signaling regulates miRNA expression. Intra/inter-population variability is insufficiently studied and a better understanding of genetics of population will be helpful in getting a step closer to personalized medicine.

Fertility-sparing treatment for intramucous, moderately differentiated, endometrioid endometrial cancer: a Gynecologic Cancer Inter-Group (GCIG) study

Francesca Falcone,Umberto Leone Roberti Maggiore,Violante Di Donato,Anna Myriam Perrone,Luigi Frigerio,Giuseppe Bifulco,Stephan Polterauer,Paolo Casadio,Gennaro Cormio,Valeria Masciullo,Mario Malzoni 대한부인종양학회 2020 Journal of Gynecologic Oncology Vol.31 No.5

Objective: ‘The Endometrial Cancer Conservative Treatment (E.C.Co.). A multicentre archive’is a worldwide project endorsed by the Gynecologic Cancer Inter-Group, aimed at registeringconservatively treated endometrial cancer (EC) patients. This paper reports the oncologicaland reproductive outcomes of intramucous, G2, endometrioid EC patients from this archive. Methods: Twenty-three patients (Stage IA, G2, endometrioid EC) were enrolled betweenJanuary 2004 and March 2019. Primary and secondary endpoints were, respectively, completeregression (CR) and recurrence rates, and pregnancy and live birth rates. Results: A median follow-up of 35 months (9–148) was achieved. Hysteroscopic resection(HR) plus progestin was adopted in 74% (17/23) of cases. Seventeen patients showed CR(median time to CR, 6 months; 3-13). Among the 6 non-responders, one showed persistenceand 5 progressed, all submitted to definitive surgery, with an unfavorauble outcome in one. The recurrence rate was 41.1%. Ten (58.8%) complete responders attempted to conceive, ofwhom 3 achieved at least one pregnancy with a live-birth. Two out of the 11 candidate patientsunderwent definitive surgery, while the remaining 9 have so far refused. To date, 22 patientsshow no evidence of disease, and one is still alive with disease. Conclusions: Fertility-sparing treatment seems to be feasible even in G2 EC, although cautionshould be kept considering the potential pathological undergrading or non-endometrioid histology misdiagnosis. The low rate of attempt to conceive and of compliance to definitivesurgery underline the need for a ‘global’ counselling extended to the follow-up period.

Dealing Naturally with Stumbling Blocks on Highways and Byways of TRAIL Induced Signaling

Rana, Aamir,Attar, Rukset,Qureshi, Muhammad Zahid,Gasparri, Maria Luisa,Donato, Violante Di,Ali, Ghulam Muhammad,Farooqi, Ammad Ahmad Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.19

In-depth analysis of how TRAIL signals through death receptors to induce apoptosis in cancer cells using high throughput technologies has added new layers of knowledge. However, the wealth of information has also highlighted the fact that TRAIL induced apoptosis may be impaired as evidenced by experimental findings obtained from TRAIL resistant cancer cell lines. Overwhelmingly, increasing understanding of TRAIL mediated apoptosis has helped in identifying synthetic and natural compounds which can restore TRAIL induced apoptosis via functionalization of either extrinsic or intrinsic pathways. Increasingly it is being realized that biologically active phytochemicals modulate TRAIL induced apoptosis, as evidenced by cell-based studies. In this review we have attempted to provide an overview of how different phytonutrients have shown efficacy in restoring apoptosis in TRAIL resistant cancer cells. We partition this review into how the TRAIL mediated signaling landscape has broadened over the years and how TRAIL induced signaling machinery crosstalks with autophagic protein networks. Subsequently, we provide a generalized view of considerable biological activity of coumarins against a wide range of cancer cell lines and how coumarins (psoralidin and esculetin) isolated from natural sources have improved TRAIL induced apoptosis in resistant cancer cells. We summarize recent updates on piperlongumine, phenethyl isothiocyanate and luteolin induced activation of TRAIL mediated apoptosis. The data obtained from pre-clinical studies will be helpful in translation of information from benchtop to the bedside.

Tumor Infiltrating Lymphocytes in Ovarian Cancer

Gasparri, Maria Luisa,Attar, Rukset,Palaia, Innocenza,Perniola, Giorgia,Marchetti, Claudia,Donato, Violante Di,Farooqi, Ammad Ahmad,Papadia, Andrea,Panici, Pierluigi Benedetti Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.9

Several improvements in ovarian cancer treatment have been achieved in recent years, both in surgery and in combination chemotherapy with targeting. However, ovarian tumors remain the women's cancers with highest mortality rates. In this scenario, a pivotal role has been endorsed to the immunological environment and to the immunological mechanisms involved in ovarian cancer behavior. Recent evidence suggests a loss of the critical balance between immune-activating and immune-suppressing mechanisms when oncogenesis and cancer progression occur. Ovarian cancer generates a mechanism to escape the immune system by producing a highly suppressive environment. Immune-activated tumor infiltrating lymphocytes (TILs) in ovarian tumor tissue testify that the immune system is the trigger in this neoplasm. The TIL mileau has been demonstrated to be associated with better prognosis, more chemosensitivity, and more cases of optimal residual tumor achieved during primary cytoreduction. Nowadays, scientists are focusing attention on new immunologically effective tumor biomarkers in order to optimize selection of patients for recruitment in clinical trials and to identify relationships of these biomarkers with responses to immunotherapeutics. Assessing this point of view, TILs might be considered as a potent predictive immunotherapy biomarker.

Sentinel node mapping in endometrial cancer

Giorgio Bogani,Andrea Giannini,Enrico Vizza,Francesco Raspagliesi,Violante Di Donato 대한부인종양학회 2024 Journal of Gynecologic Oncology Vol.35 No.1

Nodal status is one of the most important prognostic factors for patients with apparentearly stage endometrial cancer. The role of retroperitoneal staging in endometrial cancer iscontroversial. Nodal status provides useful prognostic data, and allows to tailor the needof postoperative treatments. However, two independent randomized trials showed thatthe execution of (pelvic) lymphadenectomy increases the risk of having surger y-relatedcomplication without improving patients’ outcomes. Sentinel node mapping aims toachieve data regarding nodal status without increasing morbidity. Sentinel node mappingis the removal of first (clinically negative) lymph nodes draining the uterus. Several studiessuggested that sentinel node mapping is not inferior to lymphadenectomy in identif yingpatients with nodal disease. More importantly, thorough ultrastaging sentinel node mappingallows the detection of low volume disease (micrometastases and isolated tumor cells), thatare not always detectable via conventional pathological examination. Therefore, the adoptionof sentinel node mapping guarantees a higher identification of patients with nodal diseasethan lymphadenectomy. Further evidence is needed to assess the value of various adjuvantstrategies in patients with low volume disease and to tailor those treatments also on the basisof the molecular and genomic characterization of endometrial tumors.

Comparison of Anogenital Distance and Correlation with Vulvo-vaginal Atrophy: A Pilot Study on Premenopausal and Postmenopausal Women

( Lavinia Domenici ),( Angela Musella ),( Carlotta Bracchi ),( Francesca Lecce ),( Michele Carlo Schiavi ),( Vanessa Colagiovanni ),( Violante Di Donato ),( Claudia Marchetti ),( Federica Tomao ),( In 대한폐경학회 2018 대한폐경학회지 Vol.24 No.2

Objectives: Anogenital distance (AGD) represents the space between labia posterior commissure and anus. This was pilot study to investigate how menopause and so lack of oestrogens affects AGD. Methods: A total of 109 patients were enrolled. AGD was measured in lithotomy position using sterile paper ruler. Anogenital index (AGI) was used to control 2 variables of height and weight (body mass index, kg/m2). Vaginal health index (VHI) was used to evaluate vaginal wellness. Female sexual function index (FSFI) questionnaire was administered to all women to evaluate the impact of menopause on their sexual function. Results: AGD (30.87 ± 2.98 vs. 17.57 ± 2.18; P = 0.0001) and AGI (1.40 ± 0.21 vs. 0.70 ± 0.15; P = 0.0001) were both significantly lower in the postmenopausal group. Postmenopausal women were affected by vulvovaginal atrophy (VVA) significantly. Thus, VHI scores were dramatically worse in postmenopausal group (23.95 ± 1.28 vs. 10.75 ± 3.41; P = 0.0001) as well as FSFI results (32.68 ± 2.25 vs. 19.78 ± 5.46; P = 0.0001). Conclusions: This study confirms that AGD in post-menopausal women was significantly shorter than AGD in premenopausal women, correlating with an increase of VVA and sexual impairment. Changes of AGD and AGI demonstrated to predict hormonal changes that may occur after menopause. (J Menopausal Med 2018;24:108-112)

Systematic lymph node dissection during interval debulking surgery for advanced epithelial ovarian cancer: a systematic review and meta-analysis

Giuseppe Caruso,Innocenza Palaia,Giorgio Bogani,Federica Tomao,Giorgia Perniola,Pierluigi Benedetti Panici,Ludovico Muzii,Violante Di Donato 대한부인종양학회 2022 Journal of Gynecologic Oncology Vol.33 No.5

Objective: To evaluate the efficacy and safety of systematic lymph node dissection (SyLND) at the time of interval debulking surgery (IDS) for advanced epithelial ovarian cancer (AEOC). Methods: Systematic literature review of studies including AEOC patients undergoing SyLND versus selective lymph node dissection (SeLND) or no lymph node dissection (NoLND) after neoadjuvant chemotherapy (NACT). Primary endpoints included progression-free survival (PFS) and overall survival (OS). Secondary endpoints included severe postoperative complications, lymphocele, lymphedema, blood loss, blood transfusions, operative time, and hospital stay. Results: Nine retrospective studies met the eligibility criteria, involving a total of 1,660 patients: 827 (49.8%) SyLND, 490 (29.5%) SeLND, and 343 (20.7%) NoLND. The pooled estimated hazard ratios (HR) for PFS and OS were, respectively, 0.88 (95% confidence interval [CI]=0.65–1.20; p=0.43) and 0.80 (95% CI=0.50–1.30; p=0.37). The pooled estimated odds ratios (ORs) for severe postoperative complications, lymphocele, lymphedema, and blood transfusions were, respectively, 1.83 (95% CI=1.19–2.82; p=0.006), 3.38 (95% CI=1.71– 6.70; p<0.001), 7.23 (95% CI=3.40–15.36; p<0.0001), and 1.22 (95% CI=0.50–2.96; p=0.67). Conclusion: Despite the heterogeneity in the study designs, SyLND after NACT failed to demonstrate a significant improvement in PFS and OS and resulted in a higher risk of severe postoperative complications.