Phase II Trial of Five-Fraction Accelerated Partial Breast Irradiation Using Noninvasive Image-Guided Breast Brachytherapy.

PURPOSE/OBJECTIVE(S): NIBB has potential advantages over other APBI techniques by delivering highly conformal radiation with minimal collateral dose to the heart and lung compared with external beam techniques, but unlike other brachytherapy techniques NIBB is non-invasive. Previous data has shown encouraging outcomes using a 10-fraction regimen. To improve efficiency, convenience, and cost, reduction in the fraction number is desirable. Final results of a prospective phase II trial are reported. MATERIALS/METHODS: NIBB APBI was delivered using 28.5Gy in 5 fractions daily over 1 week. Patient eligibility criteria required: invasive carcinoma ≤2.0 cm or DCIS ≤3.0 cm, ER positive (if invasive), lymph node negative, LVI absent, and lumpectomy with margins negative by 2mm. The primary endpoint was grade ≥ 2 subcutaneous fibrosis/induration <30%. Secondary endpoints included any late toxicity, cosmetic outcome, and local control. RESULTS: 40 patients were treated with a median follow-up of 59.7 months. The mean age was 67 years (50-89 years) and tumor size was 1.0cm (0.3-2.0cm). 80% had invasive carcinoma. The mean breast separation with compression was 6.7cm (3.5-8.9cm). The 5-year actuarial local control was 96.6% and overall survival was 96.9%. Grade 2 and 3 late toxicities were 15% and 0%, respectively. The rate of grade 2 subcutaneous fibrosis/induration was 2.5% (+/-2.5%) meeting the study's primary endpoint. The most common late toxicity of any grade was skin telangiectasia; 22.5% grade 1 and 15% grade 2. Only breast separation was associated with telangiectasia risk, p=0.002. Overall cosmetic outcome was excellent, good, and fair/poor in 75%, 25%, and 0%, respectively. CONCLUSIONS: NIBB APBI delivered in 5 fractions results in a low rate of late toxicity and a high rate of good/excellent cosmetic outcomes. Telangiectasia risk can be minimized by keeping breast separation ≤7.0cm. The local failure rate was appropriately low. Further investigation of this technique is warranted.

Bloody nipple discharge due to intraductal papilloma in an adolescent girl.

An early adolescent girl was referred to our breast surgery clinic with multiple right-sided breast masses and several months of unilateral bloody nipple discharge. MRI demonstrated multiple enhancing masses in the right breast with intrinsic hypertensive T1 signal of the ducts extending to the nipple. A biopsy showed partially sclerosed intraductal papillomas without atypia or malignancy. Following extensive counselling with the patient and her family, two palpable breast masses and a single central breast duct responsible for bloody nipple discharge were fully excised. Histopathological analysis showed unique overlapping features of resembling intraductal papilloma, nipple adenoma and fibroadenomas. The patient has had resolution of her bloody nipple discharge and excellent cosmetic outcomes post-surgery. Intraductal papilloma is rare in the adolescent population and the risk of concurrent and future malignancy is not well established. Thus, a tailored approach to the work-up and management of paediatric breast masses is essential.

College Undergraduates in the Operating Room: an Educational Model for Early Surgical Education.

Undergraduate pre-medical education in the USA has not traditionally offered opportunities for hands-on surgical education to college-level students. The absence of exposure has been studied, but an educational model to remedy this has not been shared. This course was designed to share a replicable model for college surgical education. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-022-01577-y.

Determinants of Postpartum Contraception Use Among Teenage Mothers in Eastern Uganda: A Cross-Sectional Study.

INTRODUCTION: In Uganda, the proportion of women having another live birth before age 20 years (repeat adolescent birth) has not declined in 30 years. More women want to delay the next birth. We determined the prevalence and factors associated with postpartum contraceptive use among teenage mothers in Mbale City. PATIENTS AND METHODS: We conducted a cross-sectional study in all the six government-supported health facilities within Mbale City. Over a period of 3 months, 511 teenage mothers in the postpartum period were consecutively enrolled by midwives/nurses. Data were collected using a pretested interviewer-administered questionnaire. We used logistic regression in STATA version 14, to determine the association between various sociodemographic characteristics and utilization of contraception. We set the level of significance at 5% and report odds ratios and the corresponding 95% confidence intervals. RESULTS: Most of the respondents - 314/511 [61.5%, 95% CI= 57.1-65.6%] - were using contraceptives. More than three-fourth (238/314) of the respondents opted for short-term methods of contraception. In the adjusted analyses, intention to resume school [AOR 1.79 (1.16-2.74)], and utilization of maternal Child Heath services such as postnatal care services [AOR 0.40 (0.25-0.63)] were significantly associated with utilisation of postpartum contraception. CONCLUSION: We found a high prevalence of postpartum contraceptives use - over 6 in 10 women - although they were using mainly short-term methods. Those with intentions of resuming schooling and utilised postnatal care services were most likely to use contraceptives. This is encouraging and calls for inquiry into why their use is higher than the national averages. Further, the results call for renewed efforts to maintain adolescent mothers in school.

Phase 2 Trial of Accelerated Partial Breast Irradiation (APBI) Using Noninvasive Image Guided Breast Brachytherapy (NIBB).

PURPOSE: Noninvasive image guided breast brachytherapy (NIBB) is a novel approach to delivery of accelerated partial breast irradiation (APBI) that may hold advantages over established techniques. NIBB is not invasive but maintains a high level of precision by using breast immobilization via breast compression and image guidance; it therefore does not require large planning tumor volume margins. We present the primary outcomes of this prospective phase 2 study (BrUOG Br-251). METHODS AND MATERIALS: Eligible patients with early-stage breast cancer underwent NIBB APBI using a dose 34 Gy in 10 fractions delivered daily or twice a day. Treatment was delivered using an Ir-192 high-dose-rate source via specialized applicators. Two orthogonal treatment axes were used for each fraction. The primary endpoints were late toxicity and cosmesis assessed at 2 and 5 years. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Cosmesis was assessed using the NRG/Radiation Therapy Oncology Group scale. Ipsilateral breast tumor recurrence was defined as any recurrence or new primary in the treated breast. RESULTS: Forty patients underwent protocol treatment. Median patient age was 68 years (50-92 years). Mean tumor size was 1.1 cm (0.3-3.0 cm). Among the cohort, 62.5% had invasive carcinoma and 37.5% had ductal carcinoma in situ. Thirty-nine percent elected to receive hormone therapy. No grade ≥3 late toxicities were observed at any time point. Grade 2 toxicity was 5% and 10% at 2 and 5 years, respectively. Telangiectasia grade 1 and 2 occurred in 27.5% and 5%, respectively. Breast separation of >7 cm was associated with telangiectasia (P < .01). The rate of good to excellent cosmetic outcome was 95% at 2 years and 100% at 5 years. With a median follow-up of 68 months, the actuarial 5-year freedom from ipsilateral breast tumor recurrence was 93.3% (±4.8%), and overall survival was 93.7% (±4.4%). CONCLUSIONS: NIBB to deliver APBI is well tolerated with a low incidence of significant late toxicity and has favorable cosmetic outcomes. Continued evaluation of the NIBB APBI technique in a larger cohort is warranted.

Leveraging Partnerships to Maximize Global Health Security Improvements in Guinea, 2015-2019.

In response to the 2014-2016 West Africa Ebola virus disease (EVD) outbreak, a US congressional appropriation provided funds to the US Centers for Disease Control and Prevention (CDC) to support global health security capacity building in 17 partner countries, including Guinea. The 2014 funding enabled CDC to provide more than 300 deployments of personnel to Guinea during the Ebola response, establish a country office, and fund 11 implementing partners through cooperative agreements to support global health security engagement efforts in 4 core technical areas: workforce development, surveillance systems, laboratory systems, and emergency management. This article reflects on almost 4 years of collaboration between CDC and its implementing partners in Guinea during the Ebola outbreak response and the recovery period. We highlight examples of collaborative synergies between cooperative agreement partners and local Guinean partners and discuss the impact of these collaborations in strengthening the above 4 core capacities. Finally, we identify the key elements of the successful collaborations, including communication and information sharing as a core cooperative agreement activity, a flexible funding mechanism, and willingness to adapt to local needs. We hope these observations can serve as guidance for future endeavors seeking to establish strong and effective partnerships between government and nongovernment organizations providing technical and operational assistance.

Utilization of electronic health records for the assessment of adiponectin receptor autoantibodies during the progression of cardio-metabolic comorbidities.

BACKGROUND: Diabetes is a complex, multi-symptomatic disease whose complications drives increases in healthcare costs as the diabetes prevalence grows rapidly world-wide. Real-world electronic health records (EHRs) coupled with patient biospecimens, biological understanding, and technologies can characterize emerging diagnostic autoimmune markers resulting from proteomic discoveries. METHODS: Circulating autoantibodies for C-terminal fragments of adiponectin receptor 1 (IgG-CTF) were measured by immunoassay to establish the reference range using midpoint samples from 1862 participants in a 20-year observational study of type 2 diabetes and cardiovascular arterial disease (CVAD) conducted by the Fairbanks Institute. The White Blood Cell elastase activity in these patients was assessed using immunoassays for Bikunin and Uristatin. Participants were assigned to four cohorts (healthy, T2D, CV, CV+T2D) based on analysis of their EHRs and the diagnostic biomarkers values and patient status were assessed ten-years post-sample. RESULTS: The IgG-CTF reference range was determined to be 75-821 ng/mL and IgG-CTF out-of-range values did not predict cohort or comorbidity as determined from the EHRs at 10 years after sample collection nor did IgG-CTF demonstrate a significant risk for comorbidity or death. Many patients at sample collection time had other conditions (hypertension, hyperlipidemia, or other risk factors) of which only hypertension, Uristatin and Bikunin values correlated with increased risk of developing additional comorbidities (odds ratio 2.58-13.11, P<0.05). CONCLUSIONS: This study confirms that retrospective analysis of biorepositories coupled with EHRs can establish reference ranges for novel autoimmune diagnostic markers and provide insights into prediction of specific health outcomes and correlations to other markers.

Volatile metabolomic signatures of rabies immunization in two mesocarnivore species.

Rabies is a zoonotic disease caused by infection with rabies virus, which circulates naturally in several wild carnivore and bat reservoirs in the United States (US). The most important reservoir in the US from an animal and public health perspective is the raccoon (Procyon lotor). To prevent the westward expansion of a significant raccoon rabies epizootic along the eastern seaboard, an operational control program implementing oral rabies vaccination (ORV) has existed in the US since the 1990s. Recently, two vaccine efficacy studies conducted with raccoons and striped skunks (Mephitis mephitis) provided the opportunity to determine if volatile fecal metabolites might be used to non-invasively monitor ORV programs and/or predict virus protection for these species. The volatile metabolome is a rich source of information that may significantly contribute to our understanding of disease and infection. Fecal samples were collected at multiple time points from raccoons and striped skunks subjected to oral treatment with rabies vaccine (or sham). Intramuscular challenge with a lethal dose of rabies virus was used to determine protection status at six (raccoons) and 11 (skunks) months post-vaccination. In addition to fecal samples, blood was collected at various time points to permit quantitative assessment of rabies antibody responses arising from immunization. Feces were analyzed by headspace gas chromatography with mass spectrometric detection and the chromatographic responses were grouped according to cluster analysis. Cluster scores were subjected to multivariate analyses of variance (MANOVA) to determine if fecal volatiles may hold a signal of immunization status. Multiple regression was then used to build models of the measured immune responses based on the metabolomic data. MANOVA results identified one cluster associated with protective status of skunks and one cluster associated with protective status of raccoons. Regression models demonstrated considerably greater success in predicting rabies antibody responses in both species. This is the first study to link volatile compounds with measures of adaptive immunity and provides further evidence that the volatile metabolome holds great promise for contributing to our understanding of disease and infections. The volatile metabolome may be an important resource for monitoring rabies immunization in raccoons and striped skunks.

Distress: Characterizing What Causes the Thermometer to Shift in Patients with Newly Diagnosed Breast Cancer Attending a Multidisciplinary Clinic.

BACKGROUND: A diagnosis of breast cancer (BC) can result in multifactorial stress. If not addressed, distress can have a negative impact on outcomes. The experience of patients with newly diagnosed BC has not been sufficiently investigated. This study characterizes distress among new patients in a multidisciplinary care (MDC) clinic. The study aimed to determine the degree of distress at presentation, to characterize the sources, and to evaluate the impact of an MDC visit. METHODS: A retrospective review was performed from January 2015 to November 2017. Charts were accessed for demographics, tumor characteristics, and treatment data. Distress scores (DS) and problems as captured using the National Comprehensive Cancer Network (NCCN) Distress Thermometer were completed before evaluation and in a subgroup after an MDC visit. Predictors of severe distress (DS ≥4) were investigated using multivariable logistic regression. The paired t test was used to determine the impact of an MDC visit. RESULTS: The mean initial DS (n = 474) was 4.98. The top four sources of distress were worry, anxiety, fears, and sadness. Age younger than 65 years was significantly associated with a higher DS at presentation (p < 0.003). Among the patients queried before and after MDC (n = 137), a significant reduction in distress was identified (5.58-2.94; p < 0.0005). CONCLUSIONS: Severe distress was found in 66 % of the patients with a recent diagnosis of BC, with younger age related to higher distress scores at presentation. Emotional stressors were the predominant factors accounting for distress. A same-day MDC visit was associated with a significant reduction in DS. These data indicate the importance and feasibility of proactively screening patients. Our research lends support to the value of multidisciplinary evaluation in this setting.

Use of faecal volatile organic compound analysis for ante-mortem discrimination between CWD-positive, -negative exposed, and -known negative white-tailed deer (Odocoileus virginianus).

Chronic wasting disease (CWD) is a naturally occurring infectious, fatal, transmissible spongiform encephalopathy of cervids. Currently, disease confirmation relies on post-mortem detection of infectious prions in the medial retropharyngeal lymph nodes or obex in the brain via immunohistochemistry (IHC). Detection of CWD in living animals using this method is impractical, and IHC and other experimental assays are not reliable in detecting low concentrations of prion present in biofluids or faeces. Here, we evaluate the capability of faecal volatile organic compound analysis to discriminate between CWD-positive and -exposed white-tailed deer located at two positive cervid farms, and two groups of CWD-negative deer from two separate disease-free farms.

Malignant phyllodes tumors of the breast: A single institution experience.

BACKGROUND: Malignant phyllodes tumors of the breast are uncommon fibroepithelial breast tumors with diverse biological behavior. Our study aim is to share our experience in treating patients with malignant phyllodes presenting to our center. PATIENTS AND METHODS: A total of 11 cases of malignant phyllodes were retrospectively reviewed between Nov 2014 and Oct 2017. RESULTS: The median age was 45 years old (31- 61 years). The median pathological tumor size was 10.5cm (2-28cm). 6 patients (55%) were premenopausal. 7 patients (64%) were treated eventually with mastectomy and 4 (36%) were treated with breast conserving surgery. 4 (36%) patients had Axillary Clearance done while axillary sampling was done in 2 patient. The remainder 5 (45%) required axillary clearance at a later op. 6 (55%) patients received postoperative radiotherapy. After a median follow up period of 11 months (range 4-33 months), 8 developed local recurrence. The overall 2 year survival rate was 18%. CONCLUSION: Malignant Phyllodes tumors are rare tumors that occur in fairly young women, when compared with the adenocarcinoma of the breast. They tend to grow to reach large with absence of nodal metastasis. Ultimately surgery is the mainstay of management but with postoperative radiotherapy it can decrease the local recurrence rates in certain presentations however recurrence rate is high and overall survival rates are poor.

A Bead-Based Flow Cytometric Assay for Monitoring Yersinia pestis Exposure in Wildlife.

Yersinia pestis is the causative agent of plague and is considered a category A priority pathogen due to its potential for high transmissibility and the significant morbidity and mortality it causes in humans. Y. pestis is endemic to the western United States and much of the world, necessitating programs to monitor for this pathogen on the landscape. Elevated human risk of plague infection has been spatially correlated with spikes in seropositive wildlife numbers, particularly rodent-eating carnivores, which are frequently in contact with the enzootic hosts and the associated arthropod vectors of Y. pestis In this study, we describe a semiautomated bead-based flow cytometric assay developed for plague monitoring in wildlife called the F1 Luminex plague assay (F1-LPA). Based upon Luminex/Bio-Plex technology, the F1-LPA targets serological responses to the F1 capsular antigen of Y. pestis and was optimized to analyze antibodies eluted from wildlife blood samples preserved on Nobuto filter paper strips. In comparative evaluations with passive hemagglutination, the gold standard tool for wildlife plague serodiagnosis, the F1-LPA demonstrated as much as 64× improvement in analytical sensitivity for F1-specific IgG detection and allowed for unambiguous classification of IgG status. The functionality of the F1-LPA was demonstrated for coyotes and other canids, which are the primary sentinels in wildlife plague monitoring, as well as felids and raccoons. Additionally, assay formats that do not require species-specific immunological reagents, which are not routinely available for several wildlife species used in plague monitoring, were determined to be functional in the F1-LPA.

Diffuse dermal angiomatosis mimicking inflammatory breast carcinoma.

Diffuse dermal angiomatosis (DDA) is a rare pathologically distinct subtype of reactive angioendotheliomatosis. In the literature, few biopsy-proven cases involving breast skin have been reported. We present a case of a 49-year-old female who presented with an indurated, erythematous, weeping, puckered and tender lesion with focal ulceration. Mammography demonstrated diffuse cutaneous and trabecular thickening concerning for inflammatory breast carcinoma. A punch biopsy demonstrated findings consistent with DDA. To our knowledge, this is the first reported case of DDA mimicking inflammatory carcinoma of the breast by clinical and radiologic examination.

Advanced Human Immunodeficiency Virus Disease in Botswana Following Successful Antiretroviral Therapy Rollout: Incidence of and Temporal Trends in Cryptococcal Meningitis.

Background: Botswana has a well-developed antiretroviral therapy (ART) program that serves as a regional model. With wide ART availability, the burden of advanced human immunodeficiency virus (HIV) and associated opportunistic infections would be expected to decline. We performed a nationwide surveillance study to determine the national incidence of cryptococcal meningitis (CM), and describe characteristics of cases during 2000-2014 and temporal trends at 2 national referral hospitals. Methods: Cerebrospinal fluid data from all 37 laboratories performing meningitis diagnostics in Botswana were collected from the period 2000-2014 to identify cases of CM. Basic demographic and laboratory data were recorded. Complete national data from 2013-2014 were used to calculate national incidence using UNAIDS population estimates. Temporal trends in cases were derived from national referral centers in the period 2004-2014. Results: A total of 5296 episodes of CM were observed in 4702 individuals; 60.6% were male, and median age was 36 years. Overall 2013-2014 incidence was 17.8 (95% confidence interval [CI], 16.6-19.2) cases per 100000 person-years. In the HIV-infected population, incidence was 96.8 (95% CI, 90.0-104.0) cases per 100000 person-years; male predominance was seen across CD4 strata. At national referral hospitals, cases decreased during 2007-2009 but stabilized during 2010-2014. Conclusions: Despite excellent ART coverage in Botswana, there is still a substantial burden of advanced HIV, with 2013-2014 incidence of CM comparable to pre-ART era rates in South Africa. Our findings suggest that a key population of individuals, often men, is developing advanced disease and associated opportunistic infections due to a failure to effectively engage in care, highlighting the need for differentiated care models.

Chylous mesenteric cyst: A diagnostic dilemma.

A mesenteric cyst is defined as a cyst that is located in the mesentery of the gastrointestinal tract and may extend from the base of the mesentery into the retroperitoneum. A case report of a patient with mesenteric cyst is presented. In addition, a systematic review was performed of English language literature on chylous mesenteric cysts in adult humans. Of the 18 articles included in the review, there were 19 cases of chylous mesenteric cysts reported. Male to female ratio was 1.4:1 with a median age of 46 years. A preoperative diagnosis of mesenteric cyst was made in four patients based on computed tomography. All patients underwent surgery and there were no reports of recurrence on follow up. Chylous mesenteric cyst is a rare entity that needs to be recognized whenever a preliminary diagnosis of intra-abdominal cystic mass is made.

The rationale, technique, and feasibility of partial breast irradiation using noninvasive image-guided breast brachytherapy.

PURPOSE: Noninvasive image-guided breast brachytherapy (NIBB) is a novel approach to deliver accelerated partial breast irradiation (APBI). NIBB is noninvasive, yet maintains a high degree of precision by using breast immobilization and image guidance. This makes NIBB an attractive alternative to existing APBI techniques. METHODS AND MATERIALS: Forty patients were enrolled to an institutional review board-approved prospective clinical trial evaluating APBI using NIBB. The NIBB technique is described in detail. Briefly, patients were treated with the breast compressed and immobilized sequentially in two orthogonal axes for each fraction. Radiation was delivered using collimated emissions from a high-dose-rate iridium-192 source via specialized applicators. The prescribed dose was 34.0 Gy in 10 fractions. Feasibility and tolerability of treatment were assessed. RESULTS: All patients completed protocol treatment. The median age was 68 years. Sixty-three percent of patients had invasive carcinoma, and 37% had ductal carcinoma in situ. All were node negative. Ninety-three percent of patients were postmenopausal. Mean tumor size, tumor bed volume, and breast volume were 1.1 cm, 22.4 cc, and 1591 cc, respectively. NIBB treatment was well tolerated. Median patient-reported discomfort was 1 on a 10-point pain scale. Treatment delivery times were reasonable. The average treatment time per axis was 14 min (5-20 min), and the average time from start of first treatment axis to completion of orthogonal axis was 43 min (30-63 min). Acute skin toxicity was Grade 0, 1, and 2 in 20%, 53%, and 28% of patients, respectively. There were no Grade 3 or greater acute toxicities observed. CONCLUSIONS: NIBB holds promise as an alternative method to deliver APBI. NIBB is feasible and well tolerated by patients. Further investigation of NIBB to deliver APBI is warranted.

Precision across the analytical measuring range of a quantitative real-time PCR assay for cytomegalovirus detection among three clinical laboratories.

This study measured the precision of a quantitative laboratory-developed real-time PCR test for cytomegalovirus performed at three different clinical laboratories that use the same methodology. The overall standard deviation (adjusted for analyte level) was 0.18 log(10) copies/ml, and there was no significant relationship between standard deviation and analytical measuring range.

Chemical and mechanistic toxicology evaluation of exon skipping phosphorodiamidate morpholino oligomers in mdx mice.

AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) designed to induce skipping of dystrophin exon 51 and restore its expression in patients with Duchenne muscular dystrophy (DMD). Preclinically, restoration of dystrophin in the dystrophic mdx mouse model requires skipping of exon 23, achieved with the mouse-specific PMO, AVI-4225. Herein, we report the potential toxicological consequences of exon skipping and dystrophin restoration in mdx mice using AVI-4225. We also evaluated the toxicological effects of AVI-4658 in both mdx and wild-type mice. In both studies, animals were dosed once weekly for 12 weeks up to the maximum feasible dose of 960 mg/kg per injection. Both AVI-4658 and AVI-4225 were well-tolerated at all doses. Findings in AVI-4225-treated animals were generally limited to mild renal tubular basophilia/vacuolation, without any significant changes in renal function and with evidence of reversing. No toxicity associated with the mechanism of action of AVI-4225 in a dystrophic animal was observed.

Repeat-dose toxicology evaluation in cynomolgus monkeys of AVI-4658, a phosphorodiamidate morpholino oligomer (PMO) drug for the treatment of duchenne muscular dystrophy.

AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) drug designed to restore dystrophin expression in a subset of patients with Duchenne muscular dystrophy (DMD). Previous reports demonstrated this clinical proof-of-principle in patients with DMD following intramuscular injection of AVI-4658. This preclinical study evaluated the toxicity and toxicokinetic profile of AVI-4658 when administered either intravenously (IV) or subcutaneously (SC) to cynomolgus monkeys once weekly over 12 weeks, at doses up to the maximum feasible dose of 320 mg/kg per injection. No drug-related effects were noted on survival, clinical observations, body weight, food consumption, opthalmoscopic or electrocardiographic evaluations, hematology, clinical chemistry, urinalysis, organ weights, and macroscopic evaluations. Drug-related microscopic renal effects were dose-dependent, apparently reversible, and included basophilic granules (minimal), basophilic tubules (minimal to moderate), and tubular vacuolation (minimal to mild). These data establish the tolerability of AVI-4658 at doses up to and including the maximum feasible dose of 320 mg/kg by IV bolus or SC injection.