An Analysis of Clinical, Surgical, Pathological and Molecular Characteristics of Endometrial Cancer According to Mismatch Repair Status. A Multidisciplinary Approach.

Since 2016, our hospital has applied tumor testing with immunohistochemistry (IHC) in endometrial cancer in order to detect mutations of mismatch repair genes (MMR). All cases with MMR deficiency proteins expression are sent for genetic testing, except those with MLH1 protein deficiency, in which case genetic testing is performed if negative for promoter hypermethylation. The primary aim of this study was to investigate the ability of our algorithm to identify Lynch syndrome (LS). The Secondary aims were to investigate the relationship between MMR status and clinicopathological features and prognosis of primary endometrial cancer (EC). From January 2016 to December 2018, 239 patients with EC were retrospectively analyzed and subdivided according to MMR status. Patients were divided in three groups: MMR proficient, LS and Lynch-like cancer (LLC). LS was characterized by a lower age and BMI, more use of contraceptive and less use of hormonal replacement therapy, nulliparity and a trend versus a better prognosis. LLC appeared more related to MMR proficient than LS and exhibited a more aggressive behavior. Our multidisciplinary approach permitted a correct diagnosis of germline mutation in patients with newly diagnosis EC and it confirmed clinicopathologic and prognostic characteristics of LS.

Cervical cancer in pregnancy: Analysis of the literature and innovative approaches.

Cervical cancer is one of the most common gynecological malignancies diagnosed during pregnancy although, fortunately, it is a rare event. In majority of cases, the management of cervical cancer in pregnant women is not different from nonpregnant women and prognosis seems not compromised by pregnancy. The association between cancer and pregnancy appears to be a significant challenge for women and specialists and the decisions about therapy must be individualized and taken by a multidisciplinary team. This review is focused on cervical cancer in pregnancy. The aim is to discuss the diagnosis, potential biomarkers and molecular aspects, therapeutic approaches, and prognosis from intraepithelial cervical neoplasia to invasive cervical cancer (early and advanced stages) in different gestational ages. We provide an overview of the current literature regarding the treatment strategies of concurrent pregnancy and cervical cancer cases and we propose some clinical advices to help clinicians to manage this condition. A mention about the effects of the conservative therapy (as conization) on fertility, the human papillomavirus vaccine in pregnant women and our center's experience with obstetrical and oncological outcomes are reported.

Electrochemotherapy pre-treatment in primary squamous vulvar cancer. Our preliminary experience.

BACKGROUND AND OBJECTIVES: Previous studies showed a local tumor control of 80% in patients with relapsed squamous cell vulvar cancer (V-SCC) treated with electrochemotherapy. These results encouraged electrochemotherapy use as neo-adjuvant treatment in V-SCC. The objective of this study was to evaluate the effectiveness of electrochemotherapy in reducing tumor burden in V-SCC. METHODS: Patients with histological diagnosis of primary V-SCC eligible for surgery were enrolled. Following accurate mapping of all the lesions, electrochemotherapy was performed. One month after electrochemotherapy clinical response was evaluated according to RECIST criteria and the type of surgery was confirmed or modified. Adjuvant therapies were prescribed depending on stage and pathological evaluation. RESULTS: We report the results from nine patients treated with electrochemotherapy before surgery. The median age was 64 years (range 51-81 years). Tumor response after electrochemotherapy was observed in seven patients (77.8%) with one CR and six PR, without complications. Tumor downsizing led to more conservative surgery in six patients (66.7%). At a median follow-up of 8 months (range 2-32 months) all patients were alive without disease. CONCLUSIONS: Our preliminary analysis suggests that ECT is a suitable treatment in patients with V-SCC before surgery, reducing the tumor size and the surgical resection.

Conservative treatment of early endometrial cancer.

Endometrial cancer is the most common cancer of the female genital tract in Europe and in the United States. Endometrial cancer has increased 21% in incidence since 2008, and the death rate has increased more than 100% over the past two decades. Approximately 15% of patients with endometrial cancer are pre-menopausal. The aim of this review is to discuss the conservative management of endometrial cancer. A number of studies largely support the conservative treatment of endometrial carcinoma (EC) in women desiring future fertility. We focus on the role of progestin hormonal therapy, including the risks associated with non-standard care, appropriate candidate selection, expected outcomes, various progestin agents and recommended follow-up.

Microbiological Retention on PTFE versus Silk Suture: A Quantitative Pilot Study in Third Molar Surgery.

Background: Mandibular third molar (M3M) removal and management of postoperative complications represent a common matter of interest in oral and maxillofacial surgery. This potential quantitative study assessed the ability of two types of surgical sutures, Silk and polytetrafluoroethylene polymer (PTFE), to carry aerobic and anaerobic bacteria on wounds after mandibular third molar surgery, with a collection of the stitches at the suture removal and study in the laboratory on the basis of colony-forming units. Methods: This prospective quantitative study sampled a total of 10 consecutive healthy patients for mandibular third molar surgery at the Oral Surgery School, Dentistry and Dental Prosthodontics, Department of Medical Biotechnologies, University of Siena, Siena, Italy. The mean age of the patients was 31 years (range 25-40 years), seven patients were male and three patients were female. Inclusion criteria were: presence of a partially impacted mandibular third molar. Exclusion criteria were: smoking and diabetes mellitus. Extraction of the mandibular third molar was performed under local anesthesia: after the third molar surgery, two sutures were applied on the surgical site distally to the second mandibular molar: one single 3/0 silk stitch; one single 3/0 PTFE stitch. No sutures were applied on the release incision. Sutures were removed after 7 days and were immediately conserved and sent to the laboratory to be rated on the basis of colony-forming units (CFUs). CFUs were evaluated and reported on GraphPad Prism and transformed into its base 10 logarithm. Data were analyzed with a non-parametric Wilcoxon test, and p-values < 0.05 were evaluated as statistically significant. Results: All the patients attended the suture removal date, and all the sutures were present in the site. None of the surgical sites presented dehiscence. No stitch loss was reported, and no patient reported mouth washing or tooth brushing in the surgery site. All interventions were uneventful and no major complications were reported after M3M surgery. Bacterial retention resulted as statistically greater in silk sutures rather than PTFE sutures, both in Brain Heart Infusion samples (p = 0.003) and Wilkins-Chalgren anaerobe samples (p = 0.002). Conclusions: We found the PTFE suture to be superior to the silk suture in a reduction in the bacterial biofilm in both aerobic and anaerobic evaluations after M3M surgery.

Optimal number of neoadjuvant chemotherapy cycles prior to interval debulking surgery in advanced epithelial ovarian cancer: a systematic review and meta-analysis of progression-free survival and overall survival.

OBJECTIVE: Neoadjuvant chemotherapy (NACT) represents a treatment option in patients with advanced epithelial ovarian cancer (AEOC) who are not good candidates for primary debulking surgery. Usually, 3 cycles of chemotherapy before surgery have been considered the best option for patient survival, although quite often some patients receive more than 3 cycles. The aim of this systematic review and meta-analysis was to identify the optimal number of NACT cycles reporting better survival in AEOC patients. METHODS: PubMed, Cochrane Library, and Scopus were searched for original articles that analyzed the relationship between the number of chemotherapy cycles and clinical outcomes in AEOC patients before interval debulking surgery (IDS). The main outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 22 studies comprising 7,005 patients diagnosed with AEOC were included in our analysis. In terms of survival, the reviewed studies dividing the patients in ≤3 NACT cycles vs. >3, showed a trend for a decrease in PFS and a significant reduction in OS with an increasing number of cycles, while a difference in both PFS and OS was revealed if early IDS included patients with 4 NACT cycles. These results should be interpreted with caution due to the complex characteristics of AEOC patients. CONCLUSION: In conclusion, our review and meta-analysis revealed that there is not enough evidence to determine the optimal number of NACT treatments before surgery. Further research in the form of well-designed randomized controlled trials is necessary to address this issue. TRIAL REGISTRATION: PROSPERO Identifier: CRD42022334959.

New insights in endometrial carcinogenesis.

Endometrial carcinoma is the most common cancer of the female genital tract in Europe and in the United States. Despite advances in defining the biology of endometrial carcinomas, there has been poor progress in determining markers that distinguish preinvasive endometrial proliferations. The aim of this review is to highlight the most recent studies regarding the molecular markers involved in endometrial adenocarcinoma pathogenesis and carcinogenesis. We focus on studies that describe markers with potential to progress from endometrial hyperplasia to invasive disease.

New players in ovarian cancer.

Ovarian cancer is the leading cause of gynecologic cancer mortality worldwide. The aim of this review is to highlight the most recent studies regarding ovarian cancer pathogenesis and the new therapeutic approaches against this insidious disease. We focus on the relevance of some cell cycle genes, transcription factors, and microRNAs in the carcinogenesis of ovarian cancer as well as on a new hypothesis for therapy using histone deacetylase inhibitors. We also report recent studies regarding some mechanisms of chemoresistance, a major obstacle in the treatment of ovarian cancer. Together these studies can improve our knowledge of ovarian cancer tumorigenesis and diagnosis providing new tools to hopefully defeat this deadly disease.

Role of Circulating miRNAs in Therapeutic Response in Epithelial Ovarian Cancer: A Systematic Revision.

Epithelial ovarian cancer (EOC) is one of the most lethal cancers worldwide, mostly due to nonspecific symptoms and a lack of screening tests, which, taken together, contribute to delayed diagnosis and treatment. The current clinical biomarker is serum CA-125, which allows the identification of most advanced primary and relapsed disease and correlates with disease burden; however, as well highlighted in the literature, CA-125 often lacks sensitivity and specificity, and is not helpful in monitoring chemotherapeutic response or in predicting the risk of relapse. Given that, the identification of novel biomarkers able to foster more precise medical approaches and the personalization of patient management represents an unmet clinical requirement. In this context, circulating miRNAs may represent an interesting opportunity as they can be easily detected in all biological fluids. This is particularly relevant when looking for non-invasive approaches that can be repeated over time, with no pain and stress for the oncological patient. Given that, the present review aims to describe the circulating miRNAs currently identified as associated with therapeutic treatments in OC and presents a complete overview of the available evidence.

Classification Systems of Endometrial Cancer: A Comparative Study about Old and New.

Endometrial cancer is the most common gynecological malignancy of the female reproductive organs. Historically it was divided into type I and type II, until 2013 when the Cancer Genome Atlas molecular classification was proposed. Here, we applied the different classification types on our endometrial cancer patient cohort in order to identify the most predictive one. We enrolled 117 endometrial cancer patients available for the study and collected the following parameters: age, body mass index, stage, menopause, Lynch syndrome status, parity, hypertension, type of localization of the lesion at hysteroscopy, type of surgery and complications, and presence of metachronous or synchronous tumors. The tumors were classified according to the European Society for Medical Oncology, Proactive Molecular Risk Classifier for Endometrial Cancer, Post-Operative Radiation Therapy in Endometrial Carcinoma, and Cancer Genome Atlas classification schemes. Our data confirmed that European Society for Medical Oncology risk was the strongest predictor of prognosis in our cohort. The parameters correlated with poor prognosis were the histotype, FIGO stage, and grade. Our study cohort shows that risk stratification should be based on the integration of histologic, clinical, and molecular parameters.

HPV vaccines: state of the art.

Cervical cancer is one of the most common types of cancer in women worldwide and is frequent in relatively young women. In the last decades, its incidence has decreased following the implementation of screening programs, mainly in developed countries. Cervical screening programs, while successful if properly carried out, are difficult and expensive to implement, especially in developing countries. Advances in the understanding of the role of human papillomavirus (HPV) in the etiology of high-grade cervical lesions and cervical cancer have led to the development and evaluation of two prophylactic HPV vaccines. Vaccination against the HPV, which is the major cause of cervical cancer, is a significant step forward. This review article provides a summary of the most recent studies related with the development and efficacy of the two HPV vaccines.

pRb2/p130 and VEGF expression in endometrial carcinoma in relation to angiogenesis and histopathologic tumor grade.

PURPOSE: Endometrial cancer is the most common gynecologic malignancy. Established prognostic factors are histologic grade, depth of myometrial invasion, and extrauterine spread including retroperitoneal lymph node metastases. Tumorigenesis is a multistep process involving different genetic changes resulting in uncontrolled cellular proliferation, inhibition of apoptosis, and enhanced vascular proliferation among other events. Angiogenesis, the formation of new blood vessels from a preexisting vascular network, is necessary for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. The pathogenesis of the angiogenetic phenotype may involve the inactivation of different tumor suppressor genes. EXPERIMENTAL DESIGN: We investigated the relationship between the expression levels of VEGF and the retinoblastoma family member pRb2/p130 in endometrial carcinoma in relation to histopathologic tumor grade in a cohort of 50 patients. RESULTS: We found that VEGF and pRB2/p130 expression were inversely correlated. Additionally, high grade tumors presented a significantly lower number of cells expressing pRb2/p130 when compared to low grade tumors. A significant positive correlation was found, by means of the Spearman coefficient, between VEGF expression and binary grading (0.450, p-value < 0.005) which is an architectural grading system that uses low-magnification assessment of amount of solid growth, pattern of invasion, and presence of necrosis to divide endometrioid carcinomas into low- and high-grade tumors. Additionally, we also found a negative correlation between pRb2/p130 expression levels and binary grading (-0.595, p-value < 0.005). Interestingly, we also found that VEGF and pRb2/p130 expression levels were not related to staging (p-value > 0.005). CONCLUSIONS: These results open up a new perspective including novel markers that, combined together, may be useful in patient screening for endometrial cancer aggressiveness.

Expression of cell-cycle-regulated proteins pRb2/p130, p107, p27(kip1), p53, mdm-2, and Ki-67 (MIB-1) in prostatic gland adenocarcinoma.

PURPOSE: The quest for prognostic molecular markers in prostatic carcinoma is still in progress. Many proteins have already been screened by immunohistochemistry with the aim to find the most reliable indicator of progressive disease. In this study, we evaluated the expression of pRb2/p130, p107, p27(kip1), p53, mdm-2, and Ki-67 (MIB-1) by immunohistochemistry in 24 prostate carcinomas compared with the paired expression of normal prostates. EXPERIMENTAL DESIGN: Expression of the different proteins in normal and pathological specimens was evaluated by the Wilcoxon test. A matrix of correlation (Spearman coefficient) was used to evaluate the possible association in expression among the different proteins. Logistic regression analysis was used to test the multivariable prognostic value of the levels of protein expression for the probability of disease development. RESULTS: p53 and Ki-67 (MIB-1) showed a higher expression in cancer than in normal tissue (P = 0.006 and <0.001, respectively). pRb2/p130, p107, and p27(kip1) showed an overall lower expression in cancer, but the difference between cytoplasmic and nuclear expression was always higher for cancer (Ps, from <0.001 to 0.016). mdm-2 expression was lower in cancer, but the difference between cytoplasmic and nuclear expression was not significant (P = 0.571) when compared with that in normal tissue. A positive correlation between p27 and pRb2/p130 levels expressed, in normal and cancer counterparts in the same sample, as the difference between cytoplasmic and nuclear protein concentrations (P = 0.045) was found. Additionally, p107 expression showed an inverse correlation with Ki-67 (MIB-1) expression in the most aggressive tumors (P = 0.046). Logistic regression output showed that Ki-67 (MIB-1) and pRb2/p130 (expressed as differences between cytoplasmic and nuclear concentrations) were the variables associated with a higher risk of cancer. The highest value was reported for Ki-67 (MIB-1) (odds ratio, 2.11), followed by pRb2/p130 (odds ratio, 1.01). pRb2/p130 alone was associated with a sensitivity (rate of cases having a posterior probability of disease >/=0.5) of 61% with a false positive rate of 22%. Ki-67 (MIB-1) alone yielded a sensitivity of 69% and a false positive rate of 14%. The combined model (Ki-67 + pRb2/p130) yielded a sensitivity of 83% with a false positive rate of 17%. Interestingly, one specimen in which we also found a high-grade prostatic intraepithelial neoplasia showed the progressive loss of pRb2/p130 from normal prostatic cells to prostatic intraepithelial neoplasia cells, suggesting that in prostatic cancer, lack of expression of the tumor suppressor gene pRb2/p130 could be involved in the progression of the disease, from an early stage. CONCLUSIONS: This study showed that all of the proteins but mdm-2 were expressed at a different rate in normal and pathological prostate specimens. Multivariate analysis showed that pRb2/p130 and p107 may be involved in the pathogenesis and progression of prostate cancers, and that the expression of the retinoblastoma-related protein pRb2/p130 along with Ki-67 (MIB-1), expressed as differences between cytoplasmic and nuclear concentrations, could be considered new parameters to be evaluated in discriminating patients at a higher risk for prostate cancer.

Frequent loss of expression of the cyclin-dependent kinase inhibitor p27(Kip1) in estrogen-related Endometrial adenocarcinomas.

PURPOSE: p27(Kip1) is a member of the Cip1/Kip1 family of cyclin-dependent kinase inhibitors and is a potential tumor suppressor gene. Low levels of p27 are associated with poor prognosis in a variety of gynecological tumors, including breast, ovarian, and cervical carcinomas. The role of p27 in endometrial cancer remains controversial. EXPERIMENTAL DESIGN: In the present study, p27 protein expression was investigated by immunohistochemistry in a series of 217 endometrial adenocarcinomas and, where present, in synchronous normal endometrium, simple and complex hyperplasia (with or without atypia), and cystic atrophy. The relationship between p27 expression and clinical outcome was also evaluated. RESULTS: Immunohistochemical analysis revealed a significant loss of p27 expression from normal (33%) through hyperplastic endometrium (50%) to endometrial adenocarcinomas (71%; P

Decreased incidence of cervical cancer in medicare-eligible California women.

OBJECTIVE: To determine if the incidence of invasive cervical cancer relative to carcinoma in situ decreased in Medicare-eligible women. METHODS: A retrospective cohort was amassed from the California Cancer Registry database. The hypothesis was prospectively specified. Mean ratio of invasive (International Federation of Gynecology and Obstetrics Stages I-IV) to in situ cervical carcinoma in 1988-1990 versus 1991-1995 was stratified by age (24 or younger, 25-44, 45-64, 65 or older) and race (all races, whites, blacks, Hispanics, Asian/Pacific Islanders). RESULTS: The mean ratio of invasive to in situ cervical cancer incidence for women at least 65 years old was lower in 1991-1995 compared with 1988-1990 (P <.001, 95% confidence interval 0.893, 0.954); and had decreased more than observed for women aged 45-64 and 25-44, for all races combined, and for white women. The decreased ratio of invasive to in situ cancer for blacks, Hispanics, and Asian/Pacific Islanders at least 65 years old was no different than the decreased ratio in younger women. CONCLUSION: In California, in the 5 years after the 1990 change in Medicare funding statutes for cervical cytology screening, the ratio of invasive cervical cancer to in situ disease decreased more in Medicare-eligible patients than in younger women.

Prognostic value of pelvic lymphadenectomy in surgical treatment of apparent stage I endometrial cancer.

BACKGROUND: The role of pelvic lymphadenectomy in early endometrial carcinoma is still being debated. MATERIALS AND METHODS: We retrospectively analyzed a total of 131 patients with FIGO stage I endometrial cancer undergoing surgery without (Group 1) or with (Group 2) pelvic lymphadenectomy. Kaplan-Meier and Cox analyses were used to calculate crude and adjusted survival rates. Moreover, the overlap of pre- and post-surgical staging was analyzed. RESULTS: Overall survival rate at 5 years was 90.1%. The difference in crude survival rates of the two groups is not statistically significant (p-value= 0.3777, log rank test). Five patients of Group 2 presented positive pelvic nodes. Therefore our results showed a pre-surgical understaging, referring to nodal involvement, in 9.1% of cases (5/55). CONCLUSION: Pelvic lymphadenectomy is a useful procedure for prognostic and staging purposes, but does not improve survival in FIGO stage I endometrial carcinoma.

Epithelial ovarian cancer: the role of cell cycle genes in the different histotypes.

Cancer is frequently considered to be a disease of the cell cycle; alterations in different families of cell cycle regulators cooperate in tumor development. Molecular analysis of human tumors has shown that cell cycle regulators are frequently mutated in human neoplasms, which underscores how important the maintenance of cell cycle commitment is in the prevention of human cancer. The regulatory pathways controlling cell cycle phases include several oncogenes and tumor suppressor genes which display a range of abnormalities with potential usefulness as markers of evolution or treatment response in epithelial ovarian cancer. This review summarizes the current knowledge about these aberrations in malignant tumors of the ovary. We sought to focus our attention on the genes involved in the development of tumors arising from the ovarian epithelium, which are the most common types of ovarian malignancies.

Multidisciplinary International Conference on Gynecologic Cancer, Bologna, Italy, June 8-12, 2005.

The first "Multidisciplinary International Conference on Gynecologic Cancer" which was held in Bologna on June 8-12, 2005, addressed some of the most crucial topics in gynecologic oncology, presented the latest achievements and, at the same time, designed the guidelines for future developments in the field. The scientific program was intended not only to share and compare views and ideas among gynecologists but also with oncologists and researchers in basic science. The scientific committee strongly believed in the "multidisciplinary approach" towards medicine and particularly towards patients.

Intrauterine progesterone treatment of early endometrial cancer.

OBJECTIVE: Our purpose was to assess the feasibility of using a progesterone-containing intrauterine device (IUD) to treat presumed Federation Internationale Gynecologie et d'Obstetrique (FIGO) stage IA, grade 1 endometrioid cancer in women at high risk for perioperative complications. STUDY DESIGN: Candidates were women with American Society of Anesthesiologists class III or IV grade 1 endometrioid cancer and no imaging evidence of myometrial invasion. Subjects underwent hysteroscopy, curettage, and IUD placement, followed by endometrial biopsy every 3 months for 1 year. The records of similar patients treated surgically during the 3 years before protocol initiation were reviewed for comparison. RESULTS: Sixteen patients fulfilled study criteria. Fourteen consented to participation; one was excluded at the time of IUD placement (grade 2 disease identified) and one was lost to follow-up. Twelve subjects have been followed up to 36 months; results of biopsies were negative in 7 of 11 at 6 months and 6 of 8 at 12 months. No IUD-related complications, except for expulsion, occurred. Sixteen complications (one fatal) occurred in 9 of the 15 control patients. CONCLUSION: Intrauterine progesterone appears to eradicate some cases of presumed stage IA, grade 1 endometrioid cancer in women at high risk for perioperative morbidity.

Does microcolposcopy protect patients with CIN and unsatisfactory colposcopy from the risk of incomplete excision of disease at the time of conization?

OBJECTIVE: To evaluate the effectiveness of microcolposcopy in preventing incomplete electrosurgical excision at the endocervical cone margin in patients with CIN and unsatisfactory colposcopy. MATERIALS AND METHODS: Four-hundred and twenty-one patients were studied. Complete excision of disease at the endocervical margin was evaluated using multiple logistic regression analysis. RESULTS: One-hundred and eighty-three patients underwent microcolposcopy. In 160 patients, the cone depth exceeded the endocervical extension of the squamocolumnar junction as predicted by microcolposcopy. In 23 patients, the opposite was observed. Microcolposcopy was not performed in 238 patients. For the three groups, the frequency of endocervical cone margin involvement was 22%, 22%, and 13%, respectively. Multiple logistic regression analysis showed that patients with a cone depth exceeding the endocervical margin of the squamocolumnar junction as predicted by microcolposcopy had no reduction in the risk of incomplete conization. CONCLUSION: The use of microcolposcopy awaits validation for assessment of the transformation zone to predict negative conization margins.