Ovarian Cancer Risk-Reduction and Screening in BRCA1/2 Mutation Carriers.

Objective: To determine the utilization of risk-reducing strategies and screening protocols for ovarian cancer in female BRCA1/2 carriers. Methods: This study was a sub-analysis of female participants from a larger multicenter, cross-sectional survey of BRCA1/2 mutation carriers unaffected by cancer. The questionnaire was administered electronically via email at four institutions located in the northeast United States. Data were analyzed with Fisher's exact test. Results: The survey was completed by 104 female BRCA mutation carriers. BRCA subtypes included 54.3% BRCA2, 41.0% BRCA1, and 2.9% both. The age at which patients underwent genetic testing varied 21.2% were 18-24 years, 25.0% were 25-34 years, 29.8% were 35-44 years, and 24.0% were 45 years or older. Nearly, all respondents (97.1%) reported that a provider had discussed risk-reducing surgeries. Of the 79 females who underwent genetic testing before 45 years of age, 53.2% reported that a health care provider recommended taking combined oral contraceptive pills (COCs) to reduce their risk of ovarian cancer, and, of these women, 88.1% chose to use them. COCs were offered at higher rates among women who were younger at the age of genetic testing (18-24: 86%, 25-34: 62%, 35-44: 23%; p < 0.0001). Approximately half (55.8%) of the respondents reported having been offered increased screening for possible early detection of ovarian cancer, of which 81.0% chose to undergo screening. The majority utilized a combination of transvaginal ultrasound and serum CA125 measurements. There were no differences observed in screening utilization based on BRCA mutation type. Conclusion: In our cohort of female BRCA mutation carriers, risk-reducing surgery was offered to almost all women, whereas only half were offered risk-reducing medication and/or increased screening. Further investigation is needed to identify barriers to the utilization of risk-reducing strategies among this high-risk population.

Barriers to hormone therapy following prophylactic bilateral salpingo-oophorectomy in BRCA1/2 mutation carriers.

OBJECTIVE: This study aimed to identify barriers to hormone therapy (HT) use among women with BRCA1/2 mutations after prophylactic bilateral salpingo-oophorectomy (BSO). METHODS: A cross-sectional, electronic survey was conducted of BRCA1/2 mutation carriers at Women and Infants Hospital, Yale Medical Center, Hartford Healthcare, and Maine Medical Center. This study was a subanalysis of a subset of female BRCA1/2 mutation carriers who had undergone a prophylactic BSO. Data were analyzed using the Fisher's exact test or t test. RESULTS: We performed a subanalysis of 60 BRCA mutation carriers who underwent a prophylactic BSO. Only 24 women (40%) reported ever using HT. HT use was higher in women who underwent their prophylactic BSO at age younger than 45 years (51% vs. 25%, P = 0.06). Among all women who had a prophylactic BSO, the majority (73%) reported that a provider talked to them about using HT. Two thirds reported having seen contradictory information in the media about long-term consequences of HT. Seventy percent listed their provider as the primary influence in their decision to start HT. The most common reasons for not starting HT included it not being recommended by their physician (46%) and that it was not necessary (37%). CONCLUSIONS: BRCA mutation carriers frequently undergo prophylactic BSO at young ages, and less than half report using HT. This study highlights barriers to HT use, such as patient fears and physician discouragement, and identifies potential areas to improve educational efforts.

Evidence of accelerated epigenetic aging of breast tissues in patients with breast cancer is driven by CpGs associated with polycomb-related genes.

PURPOSE: Age is one of the strongest risk factors for the development of breast cancer, however, the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression. METHODS: Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls). RESULTS: The Levine (p = 0.0037) and Yang clocks (p = 0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb-related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb-related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p = 0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration. CONCLUSIONS: Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb-related genes can be used to assess the risk of developing breast cancer among unaffected individuals.

Niche-directed therapy in acute myeloid leukemia: optimization of stem cell competition for niche occupancy.

Acute myeloid leukemia (AML) is an aggressive malignancy of stem cell origin that contributes to significant morbidity and mortality. The long-term prognosis remains dismal given the high likelihood for primary refractory or relapsed disease. An essential component of relapse is resurgence from the bone marrow. To date, the murine hematopoietic stem cell (HSC) niche has been clearly defined, but the human HSC niche is less well understood. The design of niche-based targeted therapies for AML must account for which cellular subsets compete for stem cell occupancy within respective bone marrow microenvironments. In this review, we highlight the principles of stem cell niche biology and discuss translational insights into the AML microenvironment as of 2021. Optimization of competition for niche occupancy is important for the elimination of measurable residual disease (MRD). Some of these novel therapeutics are in the pharmacologic pipeline for AML and may be especially useful in the setting of MRD.

Family planning in carriers of BRCA1 and BRCA2 pathogenic variants.

BRCA1 and BRCA2 pathogenic variant carriers have a high lifetime risk of developing breast and ovarian malignancies. Given the risks and significant ramifications of undergoing risk-reducing surgeries, many pathogenic variant carriers unaffected by cancer (previvors) struggle with family planning and reproductive decision making. The objective of this study was to determine the attitudes and practices of BRCA1 and BRCA2 pathogenic variant carriers with respect to family planning decision making. A cross-sectional survey was conducted of BRCA1 and BRCA2 previvors at four Northeastern medical centers. The survey was administered electronically via email using REDCap. The survey included demographic information as well as questions about genetic testing, prophylactic surgeries, family planning, and partnering. Data were analyzed with Fisher's exact tests and t tests. The survey was completed by 139 of 422 BRCA1 and BRCA2 pathogenic variant carriers (response rate 33%). Thirteen were excluded from analysis due to self-reported cancer history. Of the remaining 126, 21 (16.7%) were male and 105 (83.3%) were female. Female participants <35 years old at the time of genetic testing were significantly more likely than those 35 or greater to report feeling urgency to have a family after finding out about their BRCA1 and BRCA2 pathogenic variant (p < 0.0001). Younger women also reported their genetic status had a stronger impact on their romantic relationships (p = 0.029). Men were significantly more likely to report that they felt no urgency to have a family compared to women (p < 0.0001). Our study reflects the complex decision making for previvors and the intricacies of family planning in this population. Providers can use this knowledge as a guide to counsel patients about reproductive options.

Increased epigenetic age in normal breast tissue from luminal breast cancer patients.

BACKGROUND: Age is one of the most important risk factors for developing breast cancer. However, age-related changes in normal breast tissue that potentially lead to breast cancer are incompletely understood. Quantifying tissue-level DNA methylation can contribute to understanding these processes. We hypothesized that occurrence of breast cancer should be associated with an acceleration of epigenetic aging in normal breast tissue. RESULTS: Ninety-six normal breast tissue samples were obtained from 88 subjects (breast cancer = 35 subjects/40 samples, unaffected = 53 subjects/53 samples). Normal tissue samples from breast cancer patients were obtained from distant non-tumor sites of primary mastectomy specimens, while samples from unaffected women were obtained from the Komen Tissue Bank (n = 25) and from non-cancer-related breast surgery specimens (n = 28). Patients were further stratified into four cohorts: age < 50 years with and without breast cancer and age ≥ 50 with and without breast cancer. The Illumina HumanMethylation450k BeadChip microarray was used to generate methylation profiles from extracted DNA samples. Data was analyzed using the "Epigenetic Clock," a published biomarker of aging based on a defined set of 353 CpGs in the human genome. The resulting age estimate, DNA methylation age, was related to chronological age and to breast cancer status. The DNAmAge of normal breast tissue was strongly correlated with chronological age (r = 0.712, p < 0.001). Compared to unaffected peers, breast cancer patients exhibited significant age acceleration in their normal breast tissue (p = 0.002). Multivariate analysis revealed that epigenetic age acceleration in the normal breast tissue of subjects with cancer remained significant after adjusting for clinical and demographic variables. Additionally, smoking was found to be positively correlated with epigenetic aging in normal breast tissue (p = 0.012). CONCLUSIONS: Women with luminal breast cancer exhibit significant epigenetic age acceleration in normal adjacent breast tissue, which is consistent with an analogous finding in malignant breast tissue. Smoking is also associated with epigenetic age acceleration in normal breast tissue. Further studies are needed to determine whether epigenetic age acceleration in normal breast tissue is predictive of incident breast cancer and whether this mediates the risk of chronological age on breast cancer risk.

Distal Duodenal Obstruction: a Surgical Enigma.

The postbulbar segment also known as the distal duodenum is a separate clinical entity in terms of the intrinsic pathologies of this region and its varied anatomical relations. The common bile duct and the pancreatic duct open through the major papilla, which marks the beginning of this segment. Distal duodenal obstruction can be defined as a clinicoradiological entity that is characterized by features of gastric outlet obstruction with recurrent bilious vomiting and a radiological evidence of postbulbar obstruction. A Medline search for distal duodenal obstruction revealed 1409 entries, mostly in the form of case reports. In the last 10 years, 310 cases are reported. Clinical features like abdominal pain, nausea, and vomiting are non-specific and quite similar to gastric outlet obstruction. Clinical findings are also non-specific and do not aid in diagnosis. Laboratory findings also do not add much. Contrast-enhanced CT scan and MR enterography are diagnostic modalities of choice. Distal duodenal obstruction is a clinical entity that has a wide list of differential diagnosis which requires due consideration in terms of its management and follow-up. Most of these lesions require adequate workup with the help of a multidisciplinary team consisting of radiologists, gastroenterologists, and pathologists to adequately diagnose and stage the disease before a treatment plan is formulated. A thorough knowledge is a must regarding the treatment options available for each of the conditions so that the management can be personalized leading to better results.

W-V flap: a new technique for reconstruction of female distal urethral stricture using vestibular mucosa.

A premenopausal woman having a totally occlusive distal urethral stricture, with suprapubic catheter (SPC) in situ, was referred to us for a definitive procedure. On discussion of the treatment options, the patient refused for a buccal or vaginal flap procedure. Thus, a local W-V flap was fashioned from the periurethral vestibular mucosa with seemingly excellent results, both in terms of resolution of her symptoms and a forwardly directed stream of urine without incontinence.

Meatal Occlusive Disease in Adult Males: Are There Any Clinical Variations?

OBJECTIVE: The study aimed to document the types of meatal occlusive disease (MOD) in adult males in terms of its clinical presentation, management and prognosis. MATERIAL AND METHODS: Eighty-six adult males with MOD were assessed during the study period. The patients were divided into Group 1, having meatal opening that was occluded by flimsy adhesions (meatal synechia/adhesive type MOD), and Group 2 that included patients who had circumferential constriction of the meatus (meatal stenosis/constrictive type MOD). All patients underwent meatal dilatation up to 18 Fr followed by self-dilatation for 3 months with topical clobetasol for 4 weeks. Degree of discomfort during self-dilation, improvement in flow rate, International Prostate Symptom Score (IPSS score) and recurrences were recorded at pre-determined intervals. RESULTS: Twenty-eight patients had meatal synechia (Group 1) and 48 had meatal stenosis (Group 2). Discomfort during self-dilatation in Group 1 patients was significantly less; there was improvement in IPSS and peak flow rate (mean follow-up 26.8 months) as compared to Group 2. With dilation alone, no recurrence was noted in Group 1; however, Group 2 showed 62.8% recurrence indicating poor outcome in this subset of patients. CONCLUSION: MOD in adult males consists of 2 separate clinical entities with different therapeutic outcomes.

Transurethral Bougie-guided Placement of Suprapubic Catheter Over Guide Wire Monorail in Females: A Novel Technique.

OBJECTIVE: To assess the safety and effectiveness of a novel transurethral bougie-guided monorail technique for suprapubic catheterization in females with vesicovaginal fistula. METHODS: Patients undergoing transvaginal vesicovaginal fistula repair from February 2013 to December 2013 were selected. Suprapubic catheter was placed using this technique and assessment was done in terms of time taken, intraprocedural dislodgement or entanglement of catheter during the procedure, bleeding from the anterior abdominal wall or urethra, or any other intraoperative difficulty. RESULTS: All patients were catheterized smoothly without any intraoperative difficulty, with a mean time of 6 minutes. CONCLUSION: We describe a new technique of performing suprapubic cystostomy in patients, especially where the bladder cannot be distended. It is safe and easy to perform.

Preventing intra-urethral migration of a guidewire during antegrade placement of a JJ stent: a technical modification.

A JJ stent is usually inserted in antegrade fashion after percutaneous renal surgery. We describe a new technical modification for antegrade stent insertion that prevents intraoperative intra-urethral migration of the guidewire and saves operative time and cost.