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.

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.

Optic nerve sheath diameter, strain ratio, and shear wave elastography

Ilenia Di Paola,Mario Graziano,Donato Rosa 대한초음파의학회 2022 ULTRASONOGRAPHY Vol.41 No.4

ROS in cancer therapy: the bright side of the moon

Bruno Perillo,Marzia Di Donato,Antonio Pezone,Erika Di Zazzo,Pia Giovannelli,Giovanni Galasso,Gabriella Castoria,Antimo Migliaccio 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-

Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. It is now well accepted that moderate levels of ROS are required for several cellular functions, including gene expression. The production of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymatic and nonenzymatic pathways in the same cells. Moderate increases of ROS contribute to several pathologic conditions, among which are tumor promotion and progression, as they are involved in different signaling pathways and induce DNA mutation. However, ROS are also able to trigger programmed cell death (PCD). Our review will emphasize the molecular mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer. Specifically, we will report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells.

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.

Arterial Stiffness in Patients with Deep and Lobar Intracerebral Hemorrhage

Maurizio Acampa,Francesca Guideri,Ilaria Di Donato,Rossana Tassi,Giovanna Marotta,Giuseppe Lo Giudice,Paolo D’Andrea,Giuseppe Martini 대한뇌졸중학회 2014 Journal of stroke Vol.16 No.3

Background and Purpose Intracerebral hemorrhage (ICH) accounts for approximately 10% of stroke cases. Hypertension may play a role in the pathogenesis of ICH that occurs in the basal ganglia, thalamus, pons, and cerebellum, but not in that of lobar ICH. Hypertension contributes to decreased elasticity of arteries, thereby increasing the likelihood of rupture in response to acute elevation in intravascular pressure. This study aimed to evaluate arterial stiffness (using the arterial stiffness index [ASI]) in patients with deep (putaminal and thalamic) ICH in comparison with patients with lobar ICH. Methods We enrolled 64 patients (mean±SD age: 69.3±10.7 years; 47 men and 17 women) among 73 who referred consecutively to our department for intraparenchymal hemorrhage and underwent brain computed tomography (CT) and cerebral angio-CT. In all the subjects, 24-hour heart rates and blood pressures were monitored. The linear regression slope of diastolic on systolic blood pressure was assumed as a global measure of arterial compliance, and its complement (1 minus the slope), ASI, has been considered as a measure of arterial stiffness. Results In the patients with deep ICH, ASI was significantly higher than in the patients with lobar ICH (0.64±0.19 vs. 0.53±0.17, P=0.04). Conclusions Our results suggest that in deep ICH, arterial stiffening represents a possible pathogenetic factor that modifies arterial wall properties and contributes to vascular rupture in response to intravascular pressure acute elevation. Therapeutic strategies that reduce arterial stiffness may potentially lower the incidence of deep hemorrhagic stroke.

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.