Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis.

BACKGROUND: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in BRCA1 mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline BRCA1 mutation in the context of cancer immunosurveillance of CD3- CD56+ natural killer (NK) cells. METHODS: Premenopausal BRCA1 mutation carriers versus age-matched non-carriers were compared. Daily urinary 5ß-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence®) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1α) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner. RESULTS: BRCA1 mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 µM). The fimbrial fallopian tube demonstrated significantly higher HIF-1α staining, particularly in BRCA1 mutation carriers, reflecting a site-specific 'hypoxic niche'. Exposure to hypoxic conditions (1% O2) can further impair tumor cytotoxicity in high-risk carriers. CONCLUSIONS: Phase-specific differential NK cell activity in BRCA1 mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition.

Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer.

Importance: Pathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BRIP1 cancer susceptibility genes (CSGs) confer an increased ovarian cancer (OC) risk, with BRCA1, BRCA2, PALB2, RAD51C, and RAD51D PVs also conferring an elevated breast cancer (BC) risk. Risk-reducing surgery, medical prevention, and BC surveillance offer the opportunity to prevent cancers and deaths, but their cost-effectiveness for individual CSGs remains poorly addressed. Objective: To estimate the cost-effectiveness of prevention strategies for OC and BC among individuals carrying PVs in the previously listed CSGs. Design, Setting, and Participants: In this economic evaluation, a decision-analytic Markov model evaluated the cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) and, where relevant, risk-reducing mastectomy (RRM) compared with nonsurgical interventions (including BC surveillance and medical prevention for increased BC risk) from December 1, 2022, to August 31, 2023. The analysis took a UK payer perspective with a lifetime horizon. The simulated cohort consisted of women aged 30 years who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. Appropriate sensitivity and scenario analyses were performed. Exposures: CSG-specific interventions, including RRSO at age 35 to 50 years with or without BC surveillance and medical prevention (ie, tamoxifen or anastrozole) from age 30 or 40 years, RRM at age 30 to 40 years, both RRSO and RRM, BC surveillance and medical prevention, or no intervention. Main Outcomes and Measures: The incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained. OC and BC cases and deaths were estimated. Results: In the simulated cohort of women aged 30 years with no cancer, undergoing both RRSO and RRM was most cost-effective for individuals carrying BRCA1 (RRM at age 30 years; RRSO at age 35 years), BRCA2 (RRM at age 35 years; RRSO at age 40 years), and PALB2 (RRM at age 40 years; RRSO at age 45 years) PVs. The corresponding ICERs were -£1942/QALY (-$2680/QALY), -£89/QALY (-$123/QALY), and £2381/QALY ($3286/QALY), respectively. RRSO at age 45 years was cost-effective for RAD51C, RAD51D, and BRIP1 PV carriers compared with nonsurgical strategies. The corresponding ICERs were £962/QALY ($1328/QALY), £771/QALY ($1064/QALY), and £2355/QALY ($3250/QALY), respectively. The most cost-effective preventive strategy per 1000 PV carriers could prevent 923 OC and BC cases and 302 deaths among those carrying BRCA1; 686 OC and BC cases and 170 deaths for BRCA2; 464 OC and BC cases and 130 deaths for PALB2; 102 OC cases and 64 deaths for RAD51C; 118 OC cases and 76 deaths for RAD51D; and 55 OC cases and 37 deaths for BRIP1. Probabilistic sensitivity analysis indicated both RRSO and RRM were most cost-effective in 96.5%, 89.2%, and 84.8% of simulations for BRCA1, BRCA2, and PALB2 PVs, respectively, while RRSO was cost-effective in approximately 100% of simulations for RAD51C, RAD51D, and BRIP1 PVs. Conclusions and Relevance: In this cost-effectiveness study, RRSO with or without RRM at varying optimal ages was cost-effective compared with nonsurgical strategies for individuals who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. These findings support personalizing risk-reducing surgery and guideline recommendations for individual CSG-specific OC and BC risk management.

Plasma cell-free DNA methylation analysis for ovarian cancer detection: Analysis of samples from a case-control study and an ovarian cancer screening trial.

Analysis of cell-free DNA methylation (cfDNAme), alone or combined with CA125, could help to detect ovarian cancers earlier and may reduce mortality. We assessed cfDNAme in regions of ZNF154, C2CD4D and WNT6 via targeted bisulfite sequencing in diagnostic and early detection (preceding diagnosis) settings. Diagnostic samples were obtained via prospective blood collection in cell-free DNA tubes in a convenience series of patients with a pelvic mass. Early detection samples were matched case-control samples derived from the UK Familial Ovarian Cancer Screening Study (UKFOCSS). In the diagnostic set (ncases = 27, ncontrols = 41), the specificity of cfDNAme was 97.6% (95% CI: 87.1%-99.9%). High-risk cancers were detected with a sensitivity of 80% (56.3%-94.3%). Combination of cfDNAme and CA125 resulted in a sensitivity of 94.4% (72.7%-99.9%) for high-risk cancers. Despite technical issues in the early detection set (ncases = 29, ncontrols = 29), the specificity of cfDNAme was 100% (88.1%-100.0%). We detected 27.3% (6.0%-61.0%) of high-risk cases with relatively lower genomic DNA (gDNA) contamination. The sensitivity rose to 33.3% (7.5%-70.1%) in samples taken <1 year before diagnosis. We detected ovarian cancer in several patients up to 1 year before diagnosis despite technical limitations associated with archival samples (UKFOCSS). Combined cfDNAme and CA125 assessment may improve ovarian cancer screening in high-risk populations, but future large-scale prospective studies will be required to validate current findings.

Combined Bilateral Salpingo-oophorectomy and Cesarean Delivery in BRCA1/2 Alteration Carriers : A Case Series.

BACKGROUND: The cumulative lifetime risk of ovarian cancer is 16-68% and 11-30% in female BRCA1 and BRCA2 gene alteration carriers, respectively. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only proven way to reduce ovarian cancer mortality. We report a series of patients who underwent risk-reducing surgery at the time of planned obstetric-indicated cesarean delivery. CASES: This is a case series of four women carrying a pathogenic germline BRCA1 or BRCA2 gene alteration who underwent RRSO at the time of cesarean delivery between March 1, 2018, and March 31, 2022. All women were referred during pregnancy to the University College London Hospitals Familial Cancer Clinic for consideration of RRSO at the time of obstetric-indicated cesarean delivery. Women were considered eligible for RRSO if they had a proven pathogenic germline alteration, would have completed childbearing after the cesarean delivery, and were older than age 35 or 40 years with BRCA1 or BRCA2 alterations, respectively. Operating time, blood loss, transfusion requirements, length of hospital stay, complications, and ability to breastfeed were assessed and, where possible, compared with the institutional means for similar patients who underwent cesarean delivery only, to determine whether RRSO was associated with increased morbidity. Women were contacted 11-59 months postprocedure to assess satisfaction. The mean blood loss was 687 mL (range 400-1,000 mL), mean operating time was 68 minutes, mean length of hospital stay was 3 days, and mean change in hemoglobin was -1 g/dL. No patient required a transfusion, had internal organ damage, returned to the operating room, or was readmitted. One of two women with intact breast tissue successfully breastfed, and the other chose to bottle feed. The mean contemporaneous institutional blood loss for cesarean delivery was not significantly different at 681 mL for singleton pregnancies and 872 mL for twin pregnancies. All four women reported a high level of satisfaction with the combined procedure. CONCLUSION: Our results show that RRSO can be performed at the time of cesarean delivery with high patient satisfaction. This approach can be offered to appropriately counseled individuals, with the benefit of avoiding the need for two separate procedures, with potentially reduced patient morbidity and health care costs.

Circulating HPV DNA as a Biomarker for Pre-Invasive and Early Invasive Cervical Cancer: A Feasibility Study.

BACKGROUND: High-risk HPV infection is responsible for >99% of cervix cancers (CC). In persistent infections that lead to cancer, the tumour breaches the basement membrane, releasing HPV-DNA into the bloodstream (cHPV-DNA). A next-generation sequencing assay (NGS) for detection of plasma HPV circulating DNA (cHPV-DNA) has demonstrated high sensitivity and specificity in patients with locally advanced cervix cancers. We hypothesised that cHPV-DNA is detectable in early invasive cervical cancers but not in pre-invasive lesions (CIN). METHODS: Blood samples were collected from patients with CIN (n = 52) and FIGO stage 1A-1B CC (n = 12) prior to treatment and at follow-up. DNA extraction from plasma, followed by NGS, was used for the detection of cHPV-DNA. RESULTS: None of the patients with pre-invasive lesions were positive for CHPV-DNA. In invasive tumours, plasma from one patient (10%) reached the threshold of positivity for cHPV-DNA in plasma. CONCLUSION: Low detection of cHPV-DNA in early CC may be explained by small tumour size, poorer access to lymphatics and circulation, and therefore little shedding of cHPV-DNA in plasma at detectable levels. The detection rate of cHPV-DNA in patients with early invasive cervix cancer using even the most sensitive of currently available technologies lacks adequate sensitivity for clinical utility.

UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2.

Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1, BRCA2, MLH1, MSH2 and MSH6, there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1, PALB2, RAD51D and RAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and RAD51D as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1, PALB2, RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting.

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2.

BACKGROUND: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. RESULTS: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY. CONCLUSION: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery.

A Simple Cervicovaginal Epigenetic Test for Screening and Rapid Triage of Women With Suspected Endometrial Cancer: Validation in Several Cohort and Case/Control Sets.

PURPOSE: Endometrial cancer (EC) incidence has been rising over the past 10 years. Delays in diagnosis reduce survival and necessitate more aggressive treatment. We aimed to develop and validate a simple, noninvasive, and reliable triage test for EC to reduce the number of invasive diagnostic procedures and improve patient survival. METHODS: We developed a test to screen and triage women with suspected EC using 726 cervical smear samples from women with and without EC, and validated the test in 562 cervicovaginal samples using three different collection methods (cervical smear: n = 248; vaginal swab: n = 63; and self-collection: n = 251) and four different settings (case/control: n = 388; cohort of women presenting with postmenopausal bleeding: n = 63; a cohort of high-risk women with Lynch syndrome: n = 25; and a nested case/control setting from a screening cohort and samples taken up to 3 years before EC diagnosis: n = 86). RESULTS: We describe the Women's cancer risk IDentification - quantitative polymerase chain reaction test for Endometrial Cancer (WID-qEC), a three-marker test that evaluates DNA methylation in gene regions of GYPC and ZSCAN12. In cervical, self-collected, and vaginal swab samples derived from symptomatic patients, it detected EC with sensitivities of 97.2% (95% CI, 90.2 to 99.7), 90.1% (83.6 to 94.6), and 100% (63.1 to 100), respectively, and specificities of 75.8% (63.6 to 85.5), 86.7% (79.3 to 92.2), and 89.1% (77.8 to 95.9), respectively. The WID-qEC identified 90.9% (95% CI, 70.8 to 98.9) of EC cases in samples predating diagnosis up to 1 year. Test performance was similar across menopausal status, age, stage, grade, ethnicity, and histology. CONCLUSION: The WID-qEC is a noninvasive reliable test for triage of women with symptoms suggestive of ECs. Because of the potential for self-collection, it could improve early diagnosis and reduce the reliance for in-person visits.

Comparison of Expectant and Excisional/Ablative Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) in the Era of HPV Testing.

Objective: To investigate conservative and excisional/ablative treatment outcomes for cervical intraepithelial neoplasia grade 2 (CIN2) following introduction of virological test of cure. Methods: This was a retrospective study of prospectively collected data at a teaching hospital colposcopy unit. 331 sequential biopsy-proved CIN2 cases were involved. CIN2 cases diagnosed between 01/07/2014 and 31/12/2017 were either conservatively managed or treated with excision/ablation and then were followed up until discharge from colposcopy clinic and then using the national cervical cytology database. Outcomes were defined: cytological/histological regression was absence of high-grade CIN on biopsy and/or high-grade dysplasia; virological regression was cytological/histological regression and negative human papillomavirus testing; persistence was biopsy-proven CIN2 and/or moderate dyskaryosis; progression was biopsy-proven CIN3+ and/or severe dyskaryosis. Results: Median follow-up was 22.6 months (range: 1.9-65.1 months). Among 175 (52.9%) patients initially managed conservatively, 77.3% (133/172) regressed, 13.4% (23/172) persisted, 9.3% (16/172) progressed to CIN3+, and 97 (56.4%) patients achieved virological regression. 156 (47.1%) patients underwent initial excision/ablation, with an 89.4% (110/123) virological cure rate. After discharge, 7 (4.0%) and 3 (1.9%) patients redeveloped CIN in the conservative and treatment groups, respectively, during a median period of 17.2 months. Conclusion: Conservative management is a reasonable and effective management strategy in appropriately selected women with CIN2. High rates of histological and virological regression should be expected. The previously mentioned data provide useful information for deciding management options.

Fibroadenoma in vulval ectopic breast tissue in a patient with PTEN Hamartoma Tumour Syndrome.

PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline variants in PTEN predispose to benign and malignant growths of numerous organs, including of the breast. In the following report, we describe the first documented case of a fibroadenoma developing in ectopic breast tissue of the vulva in a patient with a germline pathogenic variant in PTEN. This highlights the risk of hyperplasia developing in any breast tissue, including rare ectopic sites, particularly in patients with underlying germline variants in cancer susceptibility genes.

Multizonal anogenital neoplasia in women: a cohort analysis.

BACKGROUND: There is currently a lack of information on full anogenital evaluation of women with a previous history of anogenital neoplasia. METHODS: Retrospective analysis of the Homerton Anogenital Neoplasia Service records from January 2012 to March 2017, to identify all new referrals of women with previous anogenital neoplasia, who had had at least one complete examination of all anogenital sites. Multizonal anogenital disease (MZD) was defined as the presence of high-grade squamous intraepithelial lesions (HSIL)/carcinoma concurrently at two or more of the following sites/zones: perianus, anal canal, vulva, vagina or cervix. RESULTS: 253 women were included, mean age was 47 (SD=15) years and median duration of follow-up was 12 (IQR=21) months. Fifty-six women (22%) were diagnosed with MZD at first assessment and/or during follow-up. Current smokers (RR=1.84, 95% CI 1.21-2.79, p=0.004) and women on immunodulators/immunosuppressive drugs (RR=2.57, 95% CI 1.72-3.86, p<0.001) had an increased risk for MZD. The risk was lower for women without a previous history of anogenital high-grade lesions/cancer compared to those with this history (RR=0.06, 95% CI 0.01-0.45, p=0.006). CONCLUSIONS: Multizonal assessment was important to diagnose occult areas of disease and should be especially considered in current smokers, pharmacologically immunocompromised and those with a previous history of anogenital HSIL/cancer.

High-Resolution Anoscopy Surveillance After Anal Squamous Cell Carcinoma: High-Grade Squamous Intraepithelial Lesion Detection and Treatment May Influence Local Recurrence.

BACKGROUND: Local recurrence is a significant risk after anal squamous cell carcinoma. OBJECTIVES: This study aimed to examine the occurrence of high-grade squamous intraepithelial lesions and local recurrence after anal cancer at surveillance with high-resolution anoscopy. DESIGN: This is a retrospective observational study. SETTING: This study was conducted at an anogenital neoplasia referral center. PATIENTS: There were 76 anal/perianal cancers from 1998 to 2018. Sixty-three patients were eligible and 3 were excluded, for a total of 60 patients; 35 of 60 (58%) patients were male. INTERVENTION: High-resolution anoscopy after chemoradiation or excision only for anal squamous cell carcinoma was performed. MAIN OUTCOME MEASURES: The primary outcomes measured were local recurrence and high-grade squamous intraepithelial lesion detection rates. RESULTS: Sixty patients, 27% HIV positive, underwent surveillance over a median 42 (range 7-240) months of follow-up. Seven had had a prior local recurrence at study entry so were analyzed separately. Thirty of 53 underwent chemoradiation (57%) and 23 of 53 underwent excision alone (43%); 33 had perianal cancer and 20 had anal cancer. Ten of 30 of the chemoradiation group had had stage 1 (33%) disease in comparison with 22 of 23 of the excision only group (96%, p < 0.001). OUTCOMES: High-grade squamous intraepithelial lesions were detected in 4 of 30 (13%) patients after chemoradiation and in 17 of 23 (74%) patients after excision only (p < 0.001). Twenty of 21 (95%) high-grade lesions were treated with ablation. Six of 7 (86%) patients with prior local recurrence had high-grade squamous intraepithelial lesions over a median of 21 months follow-up. One local recurrence (T1N0M0) occurred during surveillance after primary chemoradiation (0.56/1000 person-months), none occurred after excision only, and 2 of 7 with prior local recurrence developed further local recurrence (6.86/1000 person-months). All 3 local recurrences occurred after treatment of high-grade squamous intraepithelial lesions. There were no metastases, abdominoperineal excisions, or deaths from anal squamous cell carcinoma. LIMITATIONS: Retrospective data were used for this study. CONCLUSIONS: High-grade squamous intraepithelial lesions after anal squamous cell carcinoma are more common after excision only than after chemoradiation. Local recurrence is low in this high-resolution anoscopy surveillance group in which high-grade squamous intraepithelial disease was ablated. Excision of small perianal cancers appears safe; however, a subset of patients is at excess risk. See Video Abstract at http://links.lww.com/DCR/B285. VIGILANCIA POR ANOSCOPÍA DE ALTA RESOLUCIÓN EN CASOS DE CARCINOMA ANAL A CÉLULAS ESCAMOSAS: LA DETECCIÓN Y TRATAMIENTO DE UNA LESIÓN INTRAEPITELIAL ESCAMOSA DE ALTO GRADO (HSIL) PUEDE INFLUIR EN LA RECURRENCIA LOCAL: La recurrencia local tiene un riesgo significativo después del carcinoma anal a células escamosas.Evaluar la aparición de lesiones intraepiteliales escamosas de alto grado (HSIL) y su recurrencia local durante la vigilancia con anoscopía de alta resolución en casos de cancer anal.Estudio observacional retrospectivo.Centro de referencia de neoplasia anogenital.Se diagnosticaron 76 cánceres anales / perianales entre 1998 y 2018. Un total de 63 pacientes fueron elegidos, 3 excluidos (n = 60), 35/60 (58%) fueron varones.Anoscopía de alta resolución después de la quimio-radioterapia, o solo excisión en casos de carcinoma anal a células escamosas.Recurrencia local primaria y tasas de detección de lesión intraepitelial escamosa de alto grado.Sesenta pacientes, 27% VIH positivos, fueron sometidos a vigilancia durante una mediana de 42 (rango 7-240) meses de seguimiento. Siete habían tenido una recurrencia local antes de ser incluidos en el estudio, por lo que se analizaron por separado. Treinta de 53 se sometieron a quimio-radioterapia (57%) y 23/53 solo a excisión (43%). 33 eran lesiones perianales, 20 de canal anal. 10/30 del grupo de quimio-radioterpia se encontraban en Fase 1 (33%) comparados con 22/23 del grupo de excisión (96%, p <0.001).Se detectaron lesiones intraepiteliales escamosas de alto grado en 4/30 (13%) después de la quimio-radioterapia, y en 17/23 (74%) solo después de la excisión (p < 0.001). 20/21 (95%) lesiones de alto grado fueron tratadas con ablación. Seis de siete (86%) con recurrencia local previa tenían lesiones intraepiteliales escamosas de alto grado durante una mediana de seguimiento de 21 meses. Se produjo una recurrencia local (T1N0M0) durante la vigilancia después de la quimio-radioterapia primaria (0.56/1000 persona-meses), ninguna después de la excisión sola y 2/7 con recurrencia local previa desarrollaron una recurrencia local adicional (6.86/1000 persona-meses). Las 3 recidivas locales ocurrieron después del tratamiento de las lesiones intraepiteliales escamosas de alto grado. No hubieron metástasis, excisiones abdominoperineales o muertes por carcinoma anal a células escamosas.Datos retrospectivos.Las lesiones intraepiteliales escamosas de alto grado en casos de carcinoma escamocelular anal son más comunes después de la excisión sola que después de la quimio-radioterapia. La recurrencia local es baja en este grupo de vigilancia de anoscopía de alta resolución en el que se retiró la enfermedad intraepitelial escamosa de alto grado. La excisión de pequeños cánceres perianales parece segura; sin embargo, un subconjunto de pacientes tiene un riesgo excesivo. Consulte Video Resumen en http://links.lww.com/DCR/B285. (Traducción-Dr. Xavier Delgadillo).

Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D.

BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

Anal High-Grade Squamous Intraepithelial Lesions in Pharmacologically Immunocompromised Patients Followed in a Referral Center.

BACKGROUND: Information is lacking regarding anal/perianal precancerous lesions in referral cohorts of pharmacologically immunocompromised patients. OBJECTIVE: The aim of this study is to evaluate the prevalence of anal/perianal high-grade squamous intraepithelial lesions in a referral cohort of patients on immunomodulator/immunosuppressive medications, who were assessed and followed with high-resolution anoscopy. DESIGN: This is a retrospective study. SETTING: This study was conducted in a single anal neoplasia service from January 2012 to June 2017. PATIENTS: Patients on chronic immunomodulator/immunosuppressive medications were included. Cases of concomitant immunosuppression due to HIV infection were excluded, and immunosuppression due to chemotherapy was not considered for this analysis. INTERVENTION: High-resolution anoscopy was performed. MAIN OUTCOME: The primary outcome measured was the prevalence of anal/perianal high-grade squamous intraepithelial lesions in a referral cohort of pharmacologically immunocompromised patients. RESULTS: Fifty-four patients were included, of whom 40 were women (74%), with a mean age of 48 ± 17 years. A total of 232 high-resolution anoscopy examinations were performed in this cohort. At the first evaluation, 28 patients (52%) were diagnosed with anal and/or perianal high-grade squamous intraepithelial lesions (including 2 cases of perianal squamous cell carcinoma); 11 cases (20%) were new diagnoses. Ten of 46 patients (22%) with follow-up developed a new lesion (high-grade/cancer) during a median follow-up period of 17 (interquartile range, 6-28) months. Overall, 37 patients (69%) in our cohort had anal/perianal high-grade squamous intraepithelial lesions ever diagnosed (including previous history, first visit, and follow-up); 5 patients had perianal squamous cell carcinoma. At our center, 6% of the new referrals were known to be pharmacologically immunocompromised patients. LIMITATIONS: The retrospective nature of this study, the heterogeneity of the cohort, and the absence of human papillomavirus testing were limitations of this study. CONCLUSIONS: The presence of anal and/or perianal high-grade squamous intraepithelial lesions or cancer detected by high-resolution anoscopy in this referral population was high, and the detection of new lesions suggests that long-term follow-up is needed. Patients on immunomodulator/immunosuppressive drugs represented only a small percentage of the new referrals to our center. See Video Abstract at http://links.lww.com/DCR/A748.

Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration.

PURPOSE: Transplantation of human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells offers the potential for benefit in macular degeneration. Previous trials have reported improved visual acuity (VA), but lacked detailed analysis of retinal structure and function in the treated area. DESIGN: Phase 1/2 open-label dose-escalation trial to evaluate safety and potential efficacy (clinicaltrials.gov identifier, NCT01469832). PARTICIPANTS: Twelve participants with advanced Stargardt disease (STGD1), the most common cause of macular degeneration in children and young adults. METHODS: Subretinal transplantation of up to 200 000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks. MAIN OUTCOME MEASURES: The primary end points were the safety and tolerability of hESC-derived RPE cell administration. We also investigated evidence of the survival of transplanted cells and measured retinal structure and function using microperimetry and spectral-domain OCT. RESULTS: Focal areas of subretinal hyperpigmentation developed in all participants in a dose-dependent manner in the recipient retina and persisted after withdrawal of systemic immunosuppression. We found no evidence of uncontrolled proliferation or inflammatory responses. Borderline improvements in best-corrected VA in 4 participants either were unsustained or were matched by a similar improvement in the untreated contralateral eye. Microperimetry demonstrated no evidence of benefit at 12 months in the 12 participants. In one instance at the highest dose, localized retinal thinning and reduced sensitivity in the area of hyperpigmentation suggested the potential for harm. Participant-reported quality of life using the 25-item National Eye Institute Visual Function Questionnaire indicated no significant change. CONCLUSIONS: Subretinal hyperpigmentation is consistent with the survival of viable transplanted hESC-derived RPE cells, but may reflect released pigment in their absence. The findings demonstrate the value of detailed analysis of spatial correlation of retinal structure and function in determining with appropriate sensitivity the impact of cell transplantation and suggest that intervention in early stage of disease should be approached with caution. Given the slow rate of progressive degeneration at this advanced stage of disease, any protection against further deterioration may be evident only after a more extended period of observation.

The acceptability of high resolution anoscopy examination in patients attending a tertiary referral centre.

BACKGROUND: High resolution anoscopy (HRA) examination is regarded as the best method for the management of anal high grade squamous intraepithelial lesions to prevent anal squamous carcinoma. However, little is known about the acceptability of this procedure. This analysis looks at patient experience of HRA examination and ablative treatment under local anaesthetic. METHODS: Patients took part in anonymised feedback of their experience immediately after their HRA examinations and/or treatments. A standard questionnaire was used that included assessment of pain and overall satisfaction scores as well as willingness to undergo future HRA examinations. RESULTS: Four hundred four (89.4%) responses were received and all responses were analysed. The group consisted of 119 females (29.4%) and 261 males (64.6%) with median age of 45 years (IQR = 19) and 45 years (IQR = 21) respectively, and included 58 new cases, 53 treatment cases and 202 surveillance cases. 158 patients (39.1%) had at least one biopsy during their visits. The median pain score was 2 [Inter Quartile Range (IQR) 3] on a visual analogue scale of 0 to 10, where 0 indicated no pain / discomfort and 10 indicated severe pain. The median pain score was 2 (IQR 2) in men and 4 (IQR = 3) in women [Dunn's Test = 4.3, p < 0.0001] and 3 (IQR 4.5) in treatment cases. Problematic pain defined as a pain score of ≥7 occurred more frequently in women (14%) than in men (6%), [Chi square test (chi2) = 5.6, p = 0.02]. Patient satisfaction with the care they received, measured on a scale of 0 (not happy) to 10 (very happy) found the median score to be 10 with 76% reporting a score of 10. Out of 360 responses, 98% of women and 99% of men said that they would be willing to have a future HRA examination. CONCLUSIONS: In this cohort, the overall pain scores were low and similar across appointment types. However, women had a higher pain score, including troublesome pain levels. Despite this, both women and men were equally satisfied with their care and were willing to have a future examination. The results of the analysis show that the procedure is acceptable to patient groups. A small number of women may need general anaesthesia for their examinations/treatment.

Performance of Anal Cytology Compared With High-Resolution Anoscopy and Histology in Women With Lower Anogenital Tract Neoplasia.

Background: Information on the performance of anal cytology in women who are high risk for human papillomavirus-related lesions and the factors that might influence cytology are largely lacking. Methods: Retrospective study including all new referrals of women with a previous history of anogenital neoplasia from January 2012 to July 2017, with concomitant anal cytology and high-resolution anoscopy with or without biopsies. Results: Six hundred and thirty six anal cytology samples and 323 biopsies obtained from 278 women were included. Overall sensitivity and specificity of "any abnormality" on anal cytology to predict any abnormality in histology was 47% (95% confidence interval [CI], 41%-54%) and 84% (95% CI, 73%-91%), respectively. For detecting high-grade squamous intraepithelial lesions (HSIL)/cancer, sensitivity was 71% (95% CI, 61%-79%) and specificity was 73% (95% CI, 66%-79%). There was a poor concordance between cytological and histological grades (κ = 0.147). Cytology had a higher sensitivity to predict HSIL/cancer in immunosuppressed vs nonimmunosuppressed patients (92% vs 60%, P = .002). The sensitivity for HSIL detection was higher when 2 or more quadrants were affected compared with 1 (86% vs 57%, P = .006). A previous history of vulvar HSIL/cancer (odds ratio [OR], 1.71, 1.08-2.73; P = .023), immunosuppression (OR, 1.88, 1.17-3.03; P = .009), and concomitant genital HSIL/cancer (OR, 2.51, 1.47-4.29; P = .001) were risk factors for abnormal cytology. Conclusions: Women characteristics can influence the performance of anal cytology. The sensitivity for detecting anal HSIL/cancer was higher in those immunosuppressed and with more extensive disease.

Evidence of Stage Shift in Women Diagnosed With Ovarian Cancer During Phase II of the United Kingdom Familial Ovarian Cancer Screening Study.

Purpose To establish the performance of screening with serum cancer antigen 125 (CA-125), interpreted using the risk of ovarian cancer algorithm (ROCA), and transvaginal sonography (TVS) for women at high risk of ovarian cancer (OC) or fallopian tube cancer (FTC). Patients and Methods Women whose estimated lifetime risk of OC/FTC was ≥ 10% were recruited at 42 centers in the United Kingdom and underwent ROCA screening every 4 months. TVS occurred annually if ROCA results were normal or within 2 months of an abnormal ROCA result. Risk-reducing salpingo-oophorectomy (RRSO) was encouraged throughout the study. Participants were observed via cancer registries, questionnaires, and notification by centers. Performance was calculated after censoring 365 days after prior screen, with modeling of occult cancers detected at RRSO. Results Between June 14, 2007, and May 15, 2012, 4,348 women underwent 13,728 women-years of screening. The median follow-up time was 4.8 years. Nineteen patients were diagnosed with invasive OC/FTC within 1 year of prior screening (13 diagnoses were screen-detected and six were occult at RRSO). No symptomatic interval cancers occurred. Ten (52.6%) of the total 19 diagnoses were stage I to II OC/FTC (CI, 28.9% to 75.6%). Of the 13 screen-detected cancers, five (38.5%) were stage I to II (CI, 13.9% to 68.4%). Of the six occult cancers, five (83.3%) were stage I to II (CI, 35.9% to 99.6%). Modeled sensitivity, positive predictive value, and negative predictive value for OC/FTC detection within 1 year were 94.7% (CI, 74.0% to 99.9%), 10.8% (6.5% to 16.5%), and 100% (CI, 100% to 100%), respectively. Seven (36.8%) of the 19 cancers diagnosed < 1 year after prior screen were stage IIIb to IV (CI, 16.3% to 61.6%) compared with 17 (94.4%) of 18 cancers diagnosed > 1 year after screening ended (CI, 72.7% to 99.9%; P < .001). Eighteen (94.8%) of 19 cancers diagnosed < 1 year after prior screen had zero residual disease (with lower surgical complexity, P = .16) (CI, 74.0% to 99.9%) compared with 13 (72.2%) of 18 cancers subsequently diagnosed (CI, 46.5% to 90.3%; P = .09). Conclusion ROCA-based screening is an option for women at high risk of OC/FTC who defer or decline RRSO, given its high sensitivity and significant stage shift. However, it remains unknown whether this strategy would improve survival in screened high-risk women.

Osteoprotegerin (OPG), The Endogenous Inhibitor of Receptor Activator of NF-κB Ligand (RANKL), is Dysregulated in BRCA Mutation Carriers.

Breast cancer development in BRCA1/2 mutation carriers is a net consequence of cell-autonomous and cell nonautonomous factors which may serve as excellent targets for cancer prevention. In light of our previous data we sought to investigate the consequences of the BRCA-mutation carrier state on RANKL/osteoprotegerin (OPG) signalling. We analysed serum levels of RANKL, OPG, RANKL/OPG complex, oestradiol (E2), and progesterone (P) during menstrual cycle progression in 391 BRCA1/2-mutation carriers and 782 noncarriers. These studies were complemented by analyses of RANKL and OPG in the serum and mammary tissues of female cynomolgus macaques (n = 88) and serum RANKL and OPG in postmenopausal women (n = 150). BRCA-mutation carriers had lower mean values of free serum OPG in particular in BRCA1-mutation carriers (p = 0.018) compared with controls. Among BRCA1/2 mutation carriers, lower OPG levels were associated with germline mutation locations known to confer an increased breast cancer risk (p = 0.003). P is associated with low OPG levels in serum and tissue, particularly in BRCA-mutation carriers (rho = - 0.216; p = 0.002). Serum OPG levels were inversely correlated (rho = - 0.545, p < 0.001) with mammary epithelial proliferation measured by Ki67 expression and increased (p = 0.01) in postmenopause. The P-RANKL/OPG system is dysregulated in BRCA-mutation carriers. These and previously published data provide a strong rationale for further investigation of antiprogestogens or an anti-RANKL antibody such as denosumab for breast cancer prevention.