Central nervous system metastases in breast cancer patients with germline BRCA pathogenic variants compared to non-carriers: a matched-pair analysis.

BACKGROUND: Breast cancer is a common cause for central nervous system (CNS) metastasis, resulting in a significant reduction in overall survival. Germline pathogenic variants (PVs) in BRCA1/2 are the most common genetic risk factor for breast cancer, associated with poor prognostic factors. This study sought to explore the patterns and outcome of CNS metastases in breast cancer patients with germline PVs in BRCA1/2 genes. METHODS: A retrospective cohort of 75 breast cancer patients with known BRCA1/2 mutation status, who were diagnosed with CNS metastases in 2006-2021. Histopathology, characteristics of CNS disease, treatments, and survival were compared between BRCA1/2 carriers (n = 25) and non-carriers (n = 50), using propensity score matching (1:2 ratio) to control for the possible influence of tumor receptor status (ER, PR, HER2) and patient age. Pearson chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses. RESULTS: Patients with PVs in BRCA1/2 had more high-grade tumors (88% vs. 68%, P = 0.060), were younger at CNS disease diagnosis (median 46.69 vs. 55.02 years, P = 0.003) and had better ECOG performance status (ECOG PS 0 in 20% vs. 2%, P = 0.033), but without significant differences in systemic or CNS-directed treatment approaches. BRCA1/2 mutation was associated with a higher rate of temporal lobe involvement (52% vs. 26%, P = 0.026) and leptomeningeal spread (40% vs. 20%, P = 0.020). Survival after diagnosis of CNS disease was shorter (median 8.03 vs. 28.36 months, P < 0.0001), with no significant differences in time to development of CNS metastases or overall-survival. CONCLUSION: Patients with CNS metastatic breast cancer and PVs in BRCA1/2 showed a higher rate of leptomeningeal and temporal lobe involvement, and a shorter survival with CNS disease. To the best of our knowledge, this is the first study suggesting an exclusive impact of germline BRCA1/2 mutations in CNS metastatic breast cancer.

Are LRRK2 p.G2019S or GBA1 variants associated with long-term outcomes of deep brain stimulation for Parkinson's disease?

BACKGROUND: Deep brain stimulation (DBS) is a well-established treatment option for individuals with advanced Parkinson's disease (PD). The potential influence of the LRRK2 p.G2019S or GBA1 variants on its lasting efficacy and adverse effects should be better characterized. METHODS: We conducted a retrospective single-center case-control study involving PD patients who were carriers of a GBA1 variant (GBA1-PD), the LRRK2 p.G2019S variant (LRRK2-PD), and non-carriers (Nc-PD). All participants underwent DBS and were followed up for at least a year. Assessments before surgery and at 1, 2, 3, 5, and 10 years post-DBS included the following: the Movement Disorder Society's Unified PD Rating Scale (MDS-UPDRS) Part III, Hoehn and Yahr scale, Levodopa Equivalent Daily Dose (LEDD) and non-motor symptoms (psychotic episodes, depressive symptoms, and cognitive decline). RESULTS: The sample was composed of 103 patients (72 males, mean age at DBS surgery 61.5 ± 8.7 years, mean postoperative follow-up 7.0 ± 4.1 years). Of these, 19 were LRRK2-PD, 20 GBA1-PD, and 64 were Nc-PD. No significant differences in motor outcomes were observed between the groups. Compared to the Nc-PD patients, the GBA1-PD patients were at increased risk of both psychotic episodes [hazard ratio (HR) 2.76 (95 % CI: 1.12-6.80), p = 0.027], and cognitive decline [HR 2.28 (95 % CI: 1.04-5.00), p = 0.04]. CONCLUSION: LRRK2 and GBA1 variant status did not affect the motor outcomes of DBS in PD patients. However, GBA1-PD patients were at increased risk for psychosis and cognitive decline. Further studies are required to determine the role of genetic stratification in referral to DBS.

Impact of COVID-19 Pandemic on Human Papillomavirus Vaccine Uptake in Israel.

OBJECTIVE: Isolation and school closure during the COVID-19 pandemic could decrease human papillomavirus (HPV) vaccination uptake and potentially increase future HPV-related morbidity among unvaccinated populations. The aim of our study was to investigate HPV vaccination rates in Israel during the pandemic. METHODS: The HPV vaccination rates were compared before and during the COVID-19 pandemic years (2020-2021). Data regarding HPV vaccination between 2015 and 2021 were extracted from the Israeli Ministry of Health online reports. Vaccination rates were compared with other childhood vaccines, given at similar ages. Israeli HPV vaccination rates were further compared with England and Australia, which have an established vaccination infrastructure. RESULTS: The average Israeli coverage of first-dose HPV vaccine was 60.2%, with significant variations from 2015 to 2021. During the pandemic years, first-dose vaccine coverage increased compared with the 3 previous years. The pandemic had also no apparent influence on other childhood vaccine uptake, even though adolescents in Israel missed many school days during this time. Average vaccine uptake in England and Australia was significantly higher than Israel ( p = .009); however, first-dose vaccination rates decreased considerably in England during 2020, to a nadir of 59%. The pandemic had little effect on HPV vaccination rates in Australia. CONCLUSIONS: Despite many school days missed, the COVID-19 pandemic did not result in a decrease in HPV vaccine uptake in Israel. The pandemic could prove a good opportunity to further educate the public regarding the importance of whole-population vaccination programs. Implementing catch-up vaccination programs may bridge "vaccination gaps" that may be caused by future pandemics.

Cefazolin prophylaxis in minimally invasive gynecologic surgery - are dosage and timing appropriate? Prospective study using resampling simulation.

OBJECTIVE: Cefazolin is a widely used antimicrobial prophylactic agent, however the appropriate dosage, timing, pharmacology and microbial coverage have not been well-established for gynecologic procedures. We aimed to describe serum concentrations and pharmacokinetics of Intravenous cefazolin given to women prior to scheduled minimally invasive gynecologic surgeries, and to determine whether appropriate antimicrobial coverage had been achieved in short time from prophylactic administration to surgical start time. METHODS: A prospective cohort analysis study, using a resampled dataset, of women undergoing scheduled gynecological surgeries in a university affiliated tertiary medical center. IV cefazolin (1 or 2 gr) was administered prior to incision to women weighing <80 kg (Group A) and ≥80 kg (Group B), respectively. Cefazolin serum levels were obtained at the time of skin incision (Time 0) and 30 min later (Time 30), measured by high-pressure liquid chromatography (HPLC). Appropriate antimicrobial coverage was defined when cefazolin serum levels were above minimal inhibitory concentrations (MIC) for Enterobacteriaceae. RESULTS: Overall, 21 women were included. The mean time interval between drug administration and incision did not differ between the two groups (18 ± 10 min vs. 11 ± 10 min, respectively, p = .0.25). A hierarchical mixed linear regression model, using a simulation of multiple random bootstrap resampling (n = 1,000), revealed that cefazolin serum levels exceeded MIC, regardless of the timing of administration in the sampling intervals. Mean cefazolin serum levels in time 0 and time 30 min were not affected by BMI in patients receiving 1 gr. CONCLUSION: A single dose of IV cefazolin given shortly prior to skin incision provides serum concentrations above minimal inhibitory concentrations for susceptible pathogens in most women undergoing scheduled minimally invasive gynecologic surgery.

Central nervous system metastases in breast cancer: the impact of age on patterns of development and outcome.

PURPOSE: The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis. METHODS: A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006-2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45 years. Pearson Chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses. RESULTS: Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45 years old and 109 patients > 45 years old. The younger group was characterized by longer median overall survival (117.1 months vs 88 months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4 months vs 75.9 months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7 months vs 11.1 months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9 months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches. CONCLUSION: While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

Early Indolent Course of Crohn's Disease in Newly Diagnosed Patients Is Not Rare and Possibly Predictable.

BACKGROUND & AIMS: The early stages of Crohn's disease (CD) course are heterogeneous, and it is a challenge to predict the course of disease in patients with new diagnosis. METHODS: We performed an observational longitudinal study of 156 adults (79 male; median age, 27.7 years; 57 treatment naïve) with newly diagnosed CD (within 6 months of enrollment), referred from medical centers and community clinics in Israel from 2013 through 2017. Study participants each received semi-annual scheduled evaluations. Indolent disease was defined as a disease course without need for strict interventions to control complicated course of CD (hospitalization or surgery, or decision to start steroid, immunomodulator, or biologic therapy). Cox regression and receiver operating characteristic analyses were used to identify factors associated with early indolent or complicated course of CD. We validated our findings in an independent cohort of patients with CD from a separate medical center in Israel in 2018. RESULTS: Over a median follow-up period of 17.2 months (interquartile range, 8.8-23.8 months), 52 patients (33.3%) had an indolent course of CD, 29 (18.5%) required hospitalizations, and 75 (48%) were recommended to start steroid, immunomodulator, or biologic therapies. The median time to first intervention was 3.4 months (95% CI, 2.4-4.4). We developed a model based on clinical factors that identified 4 factors associated with complicated course in treatment-naïve patients: body mass index <25 kg/m2 (hazard ratio [HR], 2.45; 95% CI, 1.07-5.43; P = .033), serum level of vitamin B12 <350 pg/mL (HR, 2.78; 95% CI, 1.21-6.41; P = .016), white blood cells ≥7 × 103/µL (HR, 2.419; 95% CI, 1.026-5.703; P = .044), and serum level of ALT ≥25 IU/L (HR, 2.680; 95% CI, 1.186-6.058; P = .018). This model discriminated between patients with vs without a complicated course of disease with 90% and 89% accuracy at 6 and 12 months after diagnosis, respectively. A validation cohort demonstrated a discriminatory ability of 79% at 3 months after diagnosis, and a nomogram was constructed. CONCLUSIONS: In an observational longitudinal study of 156 patients with newly diagnosed CD, we found that one third have an early indolent course of disease. We identified factors that can be measured at diagnosis to identify patients at risk for an early complicated course-these might be used in patient management and selection of treatment.

Pregnancy outcomes in women with inflammatory bowel disease who successfully conceived via assisted reproduction technique.

OBJECTIVE: Women with inflammatory bowel disease (IBD) have an increased risk for adverse pregnancy outcome, so as women using assisted reproduction technology (ART). However, data are scarce regarding the risk imposed by the combination of both. Thus, we aimed to assess pregnancy outcome in these women. METHODS: A retrospective case-control study, of women with IBD who conceived using ART due to female infertility. The study group (IBD-ART) was matched using propensity score and compared in a 1:1 ratio with three control groups, IBD patients who conceived spontaneously (IBD-SP), women using ART (H-ART) and women who conceived spontaneously (H-SP). RESULTS: The study group comprised of 49 women with IBD conceived via ART that gave birth at our center during the study period. All studied groups did not differ in demographics and obstetric characteristics. IBD groups (both ART and spontaneous) were comparable in disease status prior and throughout pregnancy. Maternal outcome showed no difference regarding preterm birth and pregnancy complications among all studied groups. Women in the IBD-ART group had decreased rates of vaginal delivery (34.7% vs 57.1%, p = 0.032) and higher rates of elective CS (32.7% vs 14.3%, p = 0.048) in comparison to H-SP group, but comparable rates to both IBD-SP and H-ART groups. Neonatal outcomes were comparable among all studied groups. In a sub-analysis by disease type, a higher rate of gestational diabetes was found among ulcerative colitis patients using ART (29.4% Crohn's vs 6.1% UC, p = 0.025). CONCLUSION: Patients with IBD undergoing ART have comparable pregnancy outcome to women using ART and to patients with IBD with spontaneous pregnancy.

Outcomes of ultrasound and physical-exam based cerclage: assessment of risk factors and the role of adjunctive progesterone in preventing preterm birth-a retrospective cohort study.

OBJECTIVE: To assess outcomes of ultrasound and physical examination-based cerclage performed at mid to late second trimester and to assess the potential added value of progesterone treatment combined with cerclage for preventing preterm birth. STUDY DESIGN: A retrospective cohort study of women who underwent cerclage in a university-affiliated tertiary medical center (2012-2018). Inclusion criteria included only ultrasound-based cerclage and physical examination-based cerclage. Women who underwent history-based cerclage or multiple gestations were excluded. Study groups were stratified by previous PTB < 37 weeks and other risk factors for PTB. Primary outcome was the incidence of preterm birth < 35 weeks of gestation. Secondary outcomes included the potential added value of progesterone treatment and neonatal outcome. RESULTS: Sixty-nine women underwent cervical cerclage placement between 16-23 weeks of gestation. All women had short cervix (cervical length of < 25 mm) at presentation. Indications for cerclage placement included: 29% previous PTB, 32% prior cervical interventions (history of at least one D&C, hysteroscopy or cold-knife conization in the past), 22% had cervical dilatation > 1 cm at presentation, 12% due to failure of progesterone treatment defined as continued cervical shortening after 14 days of progesterone treatment, and 5% had other indications. Overall, 42 women (61%) gave birth at term. 27 women (39%) delivered prior to 37 weeks of gestation, of them, 20 women (29%) gave birth prior to 35 weeks. Overall median gestational age at delivery was 35 + 5 ± 4.7 weeks. Cervical dilatation at presentation of > 1 cm was associated with an increased risk for PTB < 35 weeks (OR 3.57, CI 1.43-30.81, p = 0.036). Previous PTB, prior cervical interventions and extent of cervical shortening at presentation did not increase the risk of PTB. Progesterone treatment in addition to cerclage did not result in a decreased risk for PTB < 35 weeks of gestation (OR 2.83, CI 0.58-13.89, p = 0.199). CONCLUSION: Late second trimester cerclage is a practical measure for preventing PTB in cases of asymptomatic cervical shortening. Our study did not find adjunctive benefit for progesterone treatment with physical or ultrasound-based cerclage in reducing the rate PTB.