Delivery of hereditary cancer genetics services to patients newly diagnosed with ovarian and endometrial cancers at three gynecologic oncology clinics in the USA, Brazil, and Mexico.

OBJECTIVE: Three gynecologic oncology clinics located in the USA, Brazil, and Mexico collaborated to evaluate their delivery of hereditary cancer genetics services. This descriptive retrospective review study aimed to establish baseline rates and timeliness of guideline-recommended genetics service delivery to patients with ovarian, fallopian tube, primary peritoneal (ovarian), and endometrial cancers at each clinic. METHODS: Patients who were newly diagnosed with ovarian and endometrial cancers between September 1, 2018 and December 31, 2020 were identified from the medical records of the clinics. Genetics service delivery metrics included the rates of mismatch repair deficiency tumor testing for patients with endometrial cancer (microsatellite instability/immunohistochemistry, MSI/IHC), referral to genetics services for patients with ovarian cancer, completed genetics consultations, and germline genetic testing for patients with ovarian and endometrial cancers. Timeliness was calculated as the average number of days between diagnosis and the relevant delivery metric. Descriptive statistics were used to analyze data. RESULTS: In total, 1195 patients (596 with ovarian cancer, 599 with endometrial cancer) were included in the analysis, and rates of genetics service delivery varied by clinic. For patients with ovarian cancer, referral rates ranged by clinic from 32.6% to 89.5%; 30.4-65.1% of patients completed genetics consultation and 32.6-68.7% completed genetic testing. The timeliness to genetic testing for patients with ovarian cancer ranged by clinic from 107 to 595 days. A smaller proportion of patients with endometrial cancer completed MSI/IHC testing (10.0-69.2%), with the average time to MSI/IHC ranging from 15 to 282 days. Rates of genetics consultation among patients with endometrial cancer ranged by clinic from 10.8% to 26.0% and 12.5-16.6% completed genetic testing. CONCLUSIONS: All clinics successfully established baseline rates and timeliness of delivering hereditary cancer genetics services to patients with ovarian and endometrial cancers. Lower rates of delivering genetics services to patients with endometrial cancer warrant additional research and quality improvement efforts.

Cancer risk-reducing surgery: Brazilian Society of Surgical Oncology Guideline Part 2 (Gastrointestinal and thyroid).

BACKGROUND: Risk-reducing operations are an important part of the management of hereditary predisposition to cancer. In selected cases, they can considerably reduce the morbidity and mortality associated with cancer in this population. OBJECTIVES: The Brazilian Society of Surgical Oncology (BSSO) developed this guideline to establish national benchmarks for cancer risk-reducing operations. METHODS: The guideline was prepared from May to December 2021 by a multidisciplinary team of experts to discuss the surgical management of cancer predisposition syndromes. Eleven questions were defined and assigned to expert groups that reviewed the literature and drafted preliminary recommendations. Following a review by the coordinators and a second review by all participants, the groups made final adjustments, classified the level of evidence, and voted on the recommendations. RESULTS: For all questions including risk-reducing colectomy, gastrectomy, and thyroidectomy, a major agreement was achieved by the participants, always using accessible alternatives. CONCLUSION: This and its accompanying article represent the first guideline in cancer risk reduction surgery developed by the BSSO and it should serve as an important reference for the management of families with cancer predisposition.

Prognostic role of hydronephrosis in the treatment of patients with locally advanced cervical cancer: a retrospective cohort.

BACKGROUND: Obstructive uropathy is present in almost 50% of patients with advanced cervical cancer and is associated with worse outcomes. OBJECTIVE: To estimate the prognostic role of hydronephrosis and the impact of ureteral obstruction resolution in patients with locally advanced cervical cancer undergoing treatment. METHODS: A retrospective cohort study was conducted of patients with International Federation of Gynecology and Obstetrics 2018 stage IIIB to IVA treated in a tertiary oncologic referral center in Brazil between January 2009 and June 2018. Three different groups were evaluated: (I) without hydronephrosis, (II) with hydronephrosis and urinary diversion, and (III) with hydronephrosis but no urinary diversion. Kaplan-Meier curves and log-rank tests estimated overall survival and progression-free survival based on the presence of hydronephrosis and urinary diversion. Clinicopathological variables were evaluated using univariate and multivariate Cox proportional hazard regression model for overall survival and progression-free survival. RESULTS: A total of 151 patients were evaluated: group I - 62 (41.1%); II - 44 (29.1%), and III - 45 (29.8%). Stage, histological type or grade, tumor size, parametrial or lymph node involvement were not statistically different between groups. Group I had more favorable overall survival than groups II (p<0.003) and III (p<0.02); however, no difference was noted between groups II and III. Progression-free survival was similar between groups (log-rank test p=0.95). Univariate analysis revealed hydronephrosis (p=0.002) and concurrent chemoradiotherapy (p<0.001) as a prognostic factor for worse overall survival; while tumor size (p=0.023), pelvic lymphadenopathy (p=0.015), and histological type (p=0.03) were associated with worse progression-free survival. On multivariate analysis, hydronephrosis remained as an independently associated factor with worse overall survival (HR=2.06; 95% CI 1.12 to 3.79, p=0.02). CONCLUSION: Patients with locally advanced cervical cancer with hydronephrosis had lower overall survival even after controlling for potential confounding factors, but no difference in progression-free survival. Urinary diversion showed no impact on overall survival or progression-free survival.

Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer.

The current study aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole-exome sequencing (WES) was performed in the germline DNA of 52 non-BRCA1/BRCA2/TP53 mutation carrier women at high-risk for hereditary breast and ovarian cancer (HBOC). All variants were classified using information from population and disease specific databases, in silico prediction tools and the American College of Medical Genetics and Genomics (ACMG) criteria. Loss of heterozygosity (LOH) of tumor samples and segregation analyses were performed whenever possible. The variants identified were investigated in a second, independent cohort of 17 BC cases. Pathogenic/Likely Pathogenic variants were identified in known cancer genes such as CHEK2, MUTYH, PMS2, and RAD51C. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, and RAD54L) and other cancer-related genes such as DROSHA and SLC34A2. Interestingly, the variant c.149T>G in the FAN1 gene was identified in two unrelated families, and exhibited LOH in the tumor tissue of one of them. In conclusion, this is the largest Brazilian WES study involving families at high-risk for HBOC which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer.

Early removal of indwelling urinary catheter after radical surgery for early-stage cervical cancer-A cohort study.

OBJECTIVE: To evaluate the difference between early and delayed removal of indwelling urinary catheter after radical hysterectomy (RH) or radical trachelectomy (RT). METHODS: An ambispective study was conducted in early-stage cervical cancer patients who underwent RH or RT. Delayed indwelling urinary catheter removal occurred on a postoperative day (POD) 7 in the retrospective group (January 2012-November 2013), and early removal occurred on POD 1 in the prospective group (May 2014-June 2017). The postvoid residual (PVR) test was performed after indwelling catheter removal in both groups. RESULTS: Our sample included 47 patients in the delayed group and 48 in the early one. There was no difference in age, body mass index, tumor size, histology, stage, surgical approach, and intraoperative and postoperative complications. Indwelling urinary catheter reinsertion was needed in 16 (34%) patients in the delayed group and 12 (25%) in the early group (P = .37), with no statistical difference between the median PVR volumes -82.5 and 45 mL (P = .06), respectively. Seven (14.9%) patients in the delayed group presented with 30-day urinary tract infection vs two (4.2%) in the early group (P = .09). CONCLUSIONS: Early indwelling urinary catheter removal, in regard to the rate of catheter reinsertion and PVR volume, does not differ from delayed removal.

Pelvic radiotherapy for cervical cancer affects importantly the reproducibility of cytological alterations evaluation.

BACKGROUND: to evaluate the intraobserver and interobserver reproducibility of cervical cytopathology according to previous knowledge of whether patients received radiotherapy (RT) treatment or not. METHODS: The study analyzed a sample of 95 cervix cytological slides; 24 with cytological abnormalities (CA) and presence of RT; 21 without CA and presence of RT; 25 without CA and without previous RT; 25 with CA and without previous RT. Two cytopathology (CP) evaluations of the slides were carried out. For the first CP re-evaluation, the cytotechnologist was blinded for the information of previous RT. For the second CP re-evaluation, the cytotechnologist was informed about previous RT. The results were analyzed through inter and intraobserver agreement using the unweighted and weighted kappa. RESULTS: Post radiotherapy effects were identified in 44.4% of cases that undergone previous pelvic RT. The agreement for RT status was 66.32% (unweighted K = 0.31, 95%CI: 0.13; 0.49, moderate agreement). The intraobserver agreement, regarding the cytological diagnoses, regardless of radiotherapy status, was 80.32% (weighted K = 0.52, 95%CI: 0.34; 0.68). In no RT group, the intraobserver agreement was 70% (weighted K = 0.47, 95%CI: 0.27;0.65) and in patients that received RT, the intraobserver agreement was 84.09% (unweighted K = 0.37, 95%CI: 0.01;0.74). The interobserver agreement between cytopathology result (abnormal or normal) in the group with RT, considering normal and abnormal CP diagnosis was 14.0% and 12.5%, respectively. There was no association between the cytological alterations and the median time between the end of RT and the cytological diagnosis. CONCLUSION: This study showed that RT has an important impact in CP diagnosis because the agreement, also in interobserver and intraobserver analysis, had high discrepancy in patients that received RT. Also, demonstrated that it is difficult to recognize the presence of RT in cytological slides when this information is not provided.

Radical Hysterectomy and Age: Outcomes Comparison Based on a Minimally Invasive vs an Open Approach.

STUDY OBJECTIVE: To compare outcomes of radical hysterectomy (RH) across age groups based on surgical approach: minimally invasive surgery (MIS) vs laparotomy (LP). DESIGN: Cross-sectional retrospective review (Canadian Task Force classification II-2). SETTING: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center. PATIENTS: Patients with early-stage cervical cancer who underwent RH at a tertiary cancer center between 1990 and 2013. INTERVENTIONS: Patients were stratified by age group (<50, 50-59, and ≥60 years) and by surgical approach (minimally invasive surgery [MIS] vs laparotomy [LP]). MEASUREMENTS AND MAIN RESULTS: Patients with early-stage cervical cancer who underwent RH were retrospectively reviewed to obtain demographic data, surgical data, and clinical outcomes. We used the Fisher exact, Wilcoxon rank-sum, and Cochran-Mantel-Haenszel tests to compare categorical and continuous variables stratified by surgical approach and age group. A total of 548 patients were evaluated, including 427 (77.9%) who underwent LP (age <50, 84.3%; 50-59, 11.2%; ≥60, 4.5%) and 121 (22.1%) who underwent MIS (age <50, 71.9%; 50-59, 17.3%; ≥60, 10.8%). In the MIS group, 71 patients (58.7%) underwent laparoscopy and 50 (41.3%) underwent robotic surgery. Patients in the MIS group were significantly older and heavier than those in the LP group. The operative time was significantly longer in the MIS group. There was no between-group difference in intraoperative complications in any of the 3 age groups. LP patients had more infectious complications (respiratory, systemic, and wound) than MIS patients in the <50-year age group (53.3% vs 21.8%). The difference between the LP and MIS groups with respect to the postoperative noninfectious complication rate was greatest in the ≥60-year age group (p = .0324). CONCLUSION: The between-group difference in postoperative noninfectious complication rate in the oldest age group was twice that in either of the other 2 age groups (p = .0324), even though the MIS patients were older, heavier, and had a longer operative time compared with the LP patients.

Oncogenetics service and the Brazilian public health system: the experience of a reference Cancer Hospital.

The identification of families at-risk for hereditary cancer is extremely important due to the prevention potential in those families. However, the number of Brazilian genetic services providing oncogenetic care is extremely low for the continental dimension of the country and its population. Therefore, at-risk patients do not receive appropriate assistance. This report describes the creation, structure and management of a cancer genetics service in a reference center for cancer prevention and treatment, the Barretos Cancer Hospital (BCH). The Oncogenetics Department (OD) of BCH offers, free of charge, to all patients/relatives with clinical criteria, the possibility to perform i) genetic counseling, ii) preventive examinations and iii) genetic testing with the best quality standards. The OD has a multidisciplinary team and is integrated with all specialties. The genetic counseling process consists (mostly) of two visits. In 2014, 614 individuals (371 families) were seen by the OD. To date, over 800 families were referred by the OD for genetic testing. The support provided by the Oncogenetics team is crucial to identify at-risk individuals and to develop preventive and personalized behaviors for each situation, not only to the upper-middle class population, but also to the people whose only possibility is the public health system.

Prognostic scores after surgical treatment for cervical intraepithelial neoplasia: a proposed model and possible implications for post-operative follow-up.

OBJECTIVE: To develop a prognostic model for women who underwent surgical treatment for cervical intraepithelial neoplasia. DESIGN: Cohort study. Patient inclusion and follow-up occurred retrospectively and prospectively. SETTING: Barretos Cancer Hospital, Barretos, São Paulo, Brazil. POPULATION: Women (n = 242) diagnosed with cervical intraepithelial neoplasia who were submitted to conization. METHODS: Immediately prior to surgical treatment, a cervical cytology sample was collected from each individual included in the study by endocervical brushing and stored in a preservative solution with methanol. A human papilloma virus-DNA test was conducted using an aliquot of the endocervical brushings. The surgical specimens were subjected to immunohistochemical analysis of p16 (immunohistochemical analysis 4a) protein expression. MAIN OUTCOME MEASURES: Two-year disease-free survival rates calculated for each study variable. Identified variables in the multivariate Cox model were used for elaboration of prognostic scores. RESULTS: Variables associated with outcome included age (p = 0.033), tobacco use (p < 0.001), final histopathological diagnosis (p = 0.007), surgical margins (p < 0.001), high-risk human papilloma virus status (p = 0.008), human papilloma virus-16 status (p < 0.001) and immunoexpression of p16 in the cytoplasm (p = 0.049). By the Cox model, independent risk factors for disease recurrence/persistence were: tobacco use (hazard risk = 3.0; 95% confidence interval 1.6-5.6), positive surgical margins (hazard risk = 3.2; 95% confidence interval 1.6-6.1), human papilloma virus-16 (hazard risk = 3.3; 95% confidence interval 1.6-6.9) and age over 45 years (hazard risk = 2.7; 95% confidence interval 1.1-6.6). CONCLUSIONS: Establishment of a prognostic score can represent a valuable tool for determining the risk of cervical intraepithelial neoplasia recurrence after conization. The use of clinical (age and tobacco use), pathological (surgical margins) and molecular (human papilloma virus-16 genotyping) factors can facilitate more appropriate patient follow up according to risk stratification.

The every woman study™ low- and middle-income countries edition protocol: A multi-country observational study to assess opportunities and challenges to improving survival and quality of life for women with ovarian cancer.

BACKGROUND: Ovarian cancer is a challenging disease to diagnose and treat effectively with five-year survival rates below 50%. Previous patient experience research in high-income countries highlighted common challenges and opportunities to improve survival and quality of life for women affected by ovarian cancer. However, no comparable data exist for low-and middle-income countries, where 70% of women with the disease live. This study aims to address this evidence gap. METHODS: This is an observational multi-country study set in low- and middle-income countries. We aim to recruit over 2000 women diagnosed with ovarian cancer across multiple hospitals in 24 countries in Asia, Africa and South America. Country sample sizes have been calculated (n = 70-96 participants /country), taking account of varying national five-year disease prevalence rates. Women within five years of their diagnosis, who are in contact with participating hospitals, are invited to take part in the study. A questionnaire has been adapted from a tool previously used in high-income countries. It comprises 57 multiple choice and two open-ended questions designed to collect information on demographics, women's knowledge of ovarian cancer, route to diagnosis, access to treatments, surgery and genetic testing, support needs, the impact of the disease on women and their families, and their priorities for action. The questionnaire has been designed in English, translated into local languages and tested according to local ethics requirements. Questionnaires will be administered by a trained member of the clinical team. CONCLUSION: This study will inform further research, advocacy, and action in low- and middle-income countries based on tailored approaches to the national, regional and global challenges and opportunities. In addition, participating countries can choose to repeat the study to track progress and the protocol can be adapted for other countries and other diseases.

Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry.

BACKGROUND: There are very few data about the mutational profile of families at-risk for hereditary breast and ovarian cancer (HBOC) from Latin America (LA) and especially from Brazil, the largest and most populated country in LA. RESULTS: Of the 349 probands analyzed, 21.5% were BRCA1/BRCA2 mutated, 65.3% at BRCA1 and 34.7% at BRCA2 gene. The mutation c.5266dupC (former 5382insC) was the most frequent alteration, representing 36.7% of the BRCA1 mutations and 24.0% of all mutations identified. Together with the BRCA1 c.3331_3334delCAAG mutation, these mutations constitutes about 35% of the identified mutations and more than 50% of the BRCA1 pathogenic mutations. Interestingly, six new mutations were identified. Additionally, 39 out of the 44 pathogenic mutations identified were not previously reported in the Brazilian population. Besides, 36 different variants of unknown significance (VUS) were identified. Regarding ancestry, average ancestry proportions were 70.6% European, 14.5% African, 8.0% Native American and 6.8% East Asian. MATERIALS AND METHODS: This study characterized 349 Brazilian families at-risk for HBOC regarding their germline BRCA1/BRCA2 status and genetic ancestry. CONCLUSIONS: This is the largest report of BRCA1/BRCA2 assessment in an at-risk HBOC Brazilian population. We identified 21.5% of patients harboring BRCA1/BRCA2 mutations and characterized the genetic ancestry of a sample group at-risk for hereditary breast cancer showing once again how admixed is the Brazilian population. No association was found between genetic ancestry and mutational status. The knowledge of the mutational profile in a population can contribute to the definition of more cost-effective strategies for the identification of HBOC families.

Clinical and laboratorial study of 19 cases of mucopolysaccharidoses

The mucopolysaccharidoses (MPS) are a heterogeneous group of inborn errors of lysosomal glycosaminoglycan (GAG) metabolism. The importance of this group of disorders among the inborn errors of metabolism led us to report 19 cases. METHOD: We performed clinical, radiological, and biochemical evaluations of the suspected patients, which allowed us to establish a definite diagnosis in 19 cases. RESULTS: Not all patients showed increased GAG levels in urine; enzyme assays should be performed in all cases with strong clinical suspicion. The diagnosis was made on average at the age of 48 months, and the 19 MPS cases, after a full clinical, radiological, and biochemical study, were classified as follows: Hurler -- MPS I (1 case); Hunter -- MPS II (2 cases); Sanfilippo -- MPS III (2 cases); Morquio -- MPS IV (4 cases); Maroteaux-Lamy -- MPS VI (9 cases); and Sly -- MPS VII (1 case). DISCUSSION: The high relative frequency of Maroteaux-Lamy disease contrasts with most reports in the literature and could express a population variability

Sequência da displasia septo-optica: descriçäo de caso / Septo-optic dysplasia: case report

Os autores descrevem um caso da sequência da displasia septo-óptica, que mostra agenesia do septo pelucido e hipopituitarismo, chamando a atençäo para os casos que cursam com deficiência do hormônio de crescimento que, no periodo neonatal, traduzem-se por hipoglicemia sintomática e refrataria a reposiçäo de glicose, necessitando do próprio hormonio para reverte-la

Síndrome unha-patela: estudo de duas famílias e revisäo de literatura / Nail-patella syndroem: study of two families and literature review

A síndrome unha-patela (SUP) é uma condiçao rara com padrao de herança autossômica dominante que se caracteriza pela tétrade: displasia ungueal, hipoplasia ou agenesia de patela, displasia do cotovelo e esporoes ósseos no íliaco. As principais complicaçoes da USP consistem nas deformidades esqueléticas e na nefropatia. Aproximadamente, 45 por cento dos pacientes com hipoplasia da patela necessitarao de cirurgia para o realinhamento desta. A doença renal pode estar associada à SUP, embora a maioria dos pacientes seja assintomática e apresente somente proteinúria. Foram estudadas duas famílias: uma com um caso esporádico e uma com três afetados pela SUP.