Venous malformation may be a feature of EXT1-related hereditary multiple exostoses: A report of two unrelated probands.

Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondroma (HMO), is an autosomal dominant disorder caused by pathogenic variants in exostosin-1 or -2 (EXT1 or EXT2). It is characterized by the formation of multiple benign growing osteochondromas (exostoses) that most commonly affect the long bones; however, it may also occur throughout the body. Although many of these lesions are clinically asymptomatic, some can lead to chronic pain and skeletal deformities and interfere with adjacent neurovascular structures. Here, we report two unrelated probands that presented with a clinical and molecular diagnosis of HME with venous malformation, a clinical feature not previously reported in individuals with HME.

Postembolization Persistence of Pulmonary Arteriovenous Malformations: A Retrospective Comparison of Coils and Amplatzer and Micro Vascular Plugs Using Propensity Score Weighting.

BACKGROUND. Endovascular embolization of pulmonary arteriovenous malformations (PAVMs) was historically performed with embolic coils. The Amplatzer Vascular Plug device (AVP) was introduced for this purpose in 2007 and the Micro Vascular Plug device (MVP) in 2013. OBJECTIVE. The purpose of this study was to compare coils, AVPs, and MVPs in terms of risk of persistence after PAVM embolization by use of propensity score weighting to account for biases in device selection. METHODS. This retrospective study included 112 patients (78 women and girls, 34 men and boys; mean age, 45 years) who underwent embolization of 393 PAVMs with a single device type (coil, MVP, or AVP) from January 2003 to January 2020. Persistence was defined as less than 70% reduction in PAVM sac size or contrast enhancement of the sac on follow-up pulmonary CTA. A Cox proportional hazards regression model was used to assess associations between embolic device selection and PAVM persistence. Inverse propensity score weighting was used to account for differences in embolic device selection based on patient and PAVM characteristics. RESULTS. The median postembolization follow-up period was 1.5 years (IQR, 0.3-5.6 years). Persistence was found in 10% (41/393) of PAVMs, including 16% (34/207) of those treated with coils, 8% (7/88) of those treated with AVPs, and 0% (0/98) of those treated with MVPs. Variables associated with embolization device (p < .25) were age, sex, pediatric versus adult status, smoking status, PAVM complexity, PAVM laterality, number of feeding arteries, and feeding artery diameter. The Cox regression model incorporated inverse propensity score weighting to account for the differences between treatment groups in these variables and incorporated feeding artery diameter because of imbalance remaining after weighting. With coils as the referent, MVPs had a hazard ratio for persistence of less than 0.01 (95% CI, < 0.01 to < 0.01; p < .001), and AVPs had a hazard ratio of 0.37 (95% CI, 0.16-0.90; p = .03). CONCLUSION. The risk of persistence after PAVM embolization was significantly lower for MVPs alone than for coils or AVPs alone. In addition, the risk of persistence was lower for AVPs than for coils. CLINICAL IMPACT. The findings support the clinical use of MVPs as the preferred device for PAVM embolization over coils and polytetrafluoroethylene-covered plugs.

Characteristics and Outcomes of Percutaneous Biliary Interventions in the United States.

OBJECTIVE: To explore baseline characteristics, comorbidities, and clinical diagnoses in the prediction of outcomes for inpatient percutaneous biliary interventions in the United States. METHODS: Hospitalizations for percutaneous transhepatic cholangiography and percutaneous biliary drainage were studied using the National Inpatient Sample 2012 to 2015. Associations between baseline characteristics, comorbidities, clinical diagnoses, and outcomes were analyzed using multivariable regression modeling. Regional variations were studied in an exploratory analysis. RESULTS: Hospitalizations for percutaneous biliary interventions had average inpatient mortality of 3.8% ± 0.8% and length of stay of 7.6 ± 0.3 days. Hypertension was the most common comorbidity (50.5% ± 0.8%), and paralysis was associated with the highest inpatient mortality (19.1% ± 5.7%) and length of stay (11.4 ± 1.3 days). Compared with nonmalignant biliary-pancreatic disorders, sepsis was associated with the highest inpatient mortality (6.5% ± 1.1%; adjusted odds ratio [aOR]: 5.2 [3.9-7.0]) and length of stay (9.0 ± 3.0 days; aOR: 2.2 [1.9-2.5]), followed by underlying malignancy (mortality of 5.5% ± 0.6%; aOR: 2.3 [1.7-3.0]; length of stay of 8.3 ± 0.2 days; aOR: 1.6 [1.4-1.8]). The observed associations were independent of baseline characteristics and comorbidities. With regard to regional variations, the Middle Atlantic states had the lengthiest hospital stays (38.8% ± 2.0% >8 days) and the East South Central states had the highest inpatient mortality (6.6% ± 1.6%) while having the highest frequency of malignancy (37.9% ± 3.7%) and the lowest frequency of postoperative cases (15.2% ± 2.4%). CONCLUSION: In addition to baseline characteristics and comorbidities, sepsis and malignancy were determinants of higher mortality and increased length of stay in hospitalizations for percutaneous biliary interventions. We observed significant regional variations in clinical diagnoses and outcomes across the United States.

Vertebroplasty and kyphoplasty in the USA from 2004 to 2017: national inpatient trends, regional variations, associated diagnoses, and outcomes.

BACKGROUND: To explore the national inpatient trends, regional variations, associated diagnoses, and outcomes of vertebral augmentation (vertebroplasty and kyphoplasty) in the USA from 2004 to 2017. METHODS: Data from the National Inpatient Sample were used to study hospitalization records for percutaneous vertebroplasty and kyphoplasty. Longitudinal projections of trends and outcomes, including mortality, post-procedural complications, length of stay, disposition, and total hospital charges were analyzed. RESULTS: Following a period of decreased utilization from 2008 to 2012, hospitalizations for vertebroplasty and kyphoplasty plateaued after 2013. Total hospital charges and overall financial burden of hospitalizations for vertebroplasty and kyphoplasty increased to a peak of $1.9 billion (range $1.7-$2.2 billion) in 2017. Overall, 8% of procedures were performed in patients with a history of malignancy. In multivariable modeling, lung cancer (adjusted OR (aOR) 2.6 (range 1.4-5.1)) and prostate cancer (aOR 3.4 (range 1.2-9.4)) were associated with a higher risk of mortality. The New England region had the lowest frequency of routine disposition (14.1±1.1%) and the lowest average hospital charges ($47 885±$1351). In contrast, 34.0±0.8% had routine disposition in the West Central South region, and average hospital charges were as high as $99 836±$2259 in the Pacific region. The Mountain region had the lowest number of procedures (5365±272) and the highest mortality rate (1.2±0.3%). CONCLUSION: National inpatient trends of vertebroplasty and kyphoplasty utilization remained stable after a period of decline from 2008 to 2012, while the financial burden of hospitalizations increased. Despite recent improvements in outcomes, significant regional variations persisted across the USA.

Transcatheter and Endoscopic Treatment of Gastric and Duodenal Bleeding: Population-Based Analysis of National Inpatient Trends and Outcomes in the United States.

BACKGROUND: Upper gastrointestinal (GI) bleeding is a common cause of hospital admission in the United States and is frequently treated by endoscopy. Recent studies have shown an increasing role for treatment using transcatheter embolization. METHODS: Data from the national inpatient sample (1993-2015) were used for trend analysis and to compare patient characteristics, comorbidities, and outcomes for endoscopic and transcatheter treatments of gastric and duodenal bleeding. RESULTS: Despite the continued decline in the rate of hospitalization for upper GI bleeding (-43% since 1993, P < .01), admissions for embolization (21.1% per year since 2005, P < .01) and endoscopic treatments (1.2%-6.1% per year since 1993, P < .01) have increased in the past decade. Patients with multiple comorbidities that include coagulopathy (25.6% versus 11.9%, P < .05), liver disease (16.0% versus 10.7%, P < .05), fluid and electrolyte disorder (51.0% versus 35.4%, P < .05), and metastatic cancer (6.9% versus 2.4%, P < .05) were more likely to receive embolization. Embolization was associated with higher crude risk of death (9.2% versus 2.1%, P < .01), lengthier hospital stays (9.1 days versus 5.1 days, P < .01), and greater average total hospital charges (US$135,000 versus US$46,000). The association between embolization (versus endoscopy) and mortality and length of stay diminished after controlling for disease severity and other procedures in propensity score-matched groups and by covariate adjustment. DISCUSSION: Though endoscopy remains the main treatment of upper GI bleeding, embolization is associated with comparable mortality and length of stay after accounting for disease severity and the need for additional procedures.

Theranostics: Leveraging Molecular Imaging and Therapy to Impact Patient Management and Secure the Future of Nuclear Medicine.

Nuclear medicine is experiencing a renaissance, with U.S. Food and Drug Administration approval recently being obtained for theranostic agents and a wide variety of such agents soon to impact patient care significantly in the era of precision medicine. The NETTER-1 trial demonstrated the therapeutic effect of a theranostic agent in markedly improving progression-free survival in patients with metastatic gastroenteropancreatic neuroendocrine tumors. Predominantly retrospective studies have demonstrated a significant response to 177Lu-labeled agents targeting prostate-specific membrane antigen (PSMA) in patients with prostate cancer. At least 2 prospective clinical trials involving 177Lu-PSMA agents are under way that will likely pave the way for Food and Drug Administration approval in the United States. A significant upside to theranostics is that patients tend to tolerate these agents better than chemotherapy. Theranostic compounds are likely to impact many cancers in the near future, not only through improvements in quality of life but also in terms of survival. This article provides an overview of already approved agents as well as those on the horizon. It is important that as these agents are clinically onboarded, nuclear medicine physicians have the expertise to deploy theranostics safely and efficiently, ensuring that these agents attain and maintain their position as leading lines of therapy in managing patients with cancer as well as becoming an important aspect of nuclear medicine practice in the future.

MVP™ Micro Vascular Plug Systems for the Treatment of Pulmonary Arteriovenous Malformations.

PURPOSE: To describe our institutional experience with MVP™ micro vascular plug systems for the treatment of pulmonary arteriovenous malformations (PAVMs). MATERIALS AND METHODS: We performed a retrospective medical record review of 52 patients with 119 PAVMs treated exclusively with MVP™ systems (69 procedures/153 MVP™ systems) between July 2014 and July 2018. All patients had PAVMs with feeding artery diameters ≥ 2 mm. MVP™ systems were deployed according to physician preference. We collected patient demographic information; procedural data (including size of feeding artery, size and number of embolics used per PAVM, fluoroscopy time, contrast administration), technical success rates, complications, and persistence. Persistence was assessed using computed tomography angiography (CTA) performed 1-3 months and 3-5 years after embolization per clinical protocol. RESULTS: All procedures were technically successful without major complications. Mean feeding artery diameter was 3.3 ± 1.2 mm. Mean fluoroscopy time per procedure and contrast volume administered per procedure were 35 ± 16 min and 217 ± 101 mL, respectively. A mean of 1.3 ± 0.8 MVP™ systems was used per PAVM. There were no instances of persistence during a mean follow-up time of 328 ± 258 days (range 26 to 914 days). CONCLUSIONS: For PAVMs with feeding artery diameters of 2 to 7.9 mm (mean 3.3 ± 1.2 mm), MVP™ systems are safe and effective given their high technical success rates and lack of persistence. Further prospective work will be required to elucidate the advantages and disadvantages of these MVP™ systems for PAVM embolization. LEVEL OF EVIDENCE: Level III.

Quality-of-Life Outcomes Improve with Nipple-Sparing Mastectomy and Breast Reconstruction.

BACKGROUND: Loss of the nipple-areola complex can be psychologically and sexually devastating. Nipple-sparing mastectomy provides robust cosmetic results, but few studies have investigated the quality-of-life outcomes associated with it. METHODS: The authors performed an institutional review board-approved retrospective study of 32 patients who underwent nipple-sparing mastectomy with implant-based or autologous reconstruction and 32 control patients who underwent non-nipple-sparing mastectomy with reconstruction matched by reconstruction type and operative period. They then compared premastectomy and postreconstruction responses to the BREAST-Q, a validated and breast reconstruction-specific quality-of-life questionnaire, within and between their study and control populations. RESULTS: The nipple-sparing and non-nipple-sparing mastectomy groups were statistically similar in terms of mean age [49.9 ± 8.5 years (range, 36 to 69 years) and 47.7 ± 10.3 years (range, 26 to 68 years) (p = 0.29), respectively] and mean body mass index [24.3 ± 3.5 kg/m (range, 17.9 to 33.7 kg/m) and 25.5 ± 5.4 kg/m (range, 19.2 to 39.2 kg/m) (p = 0.29), respectively]. There were no significant between-group differences in occurrence of postreconstruction complications. The authors found significantly higher mean postreconstruction scores in the nipple-sparing mastectomy group within the Satisfaction with Breasts (p = 0.039) and the Satisfaction with Outcome (p = 0.017) domains. Finally, they noted higher median postreconstruction scores in the nipple-sparing mastectomy group within the Psychosocial Well-being (p = 0.043) and Satisfaction with Breasts (p = 0.004) domains. CONCLUSIONS: Psychological concerns regarding malignancy may negatively impact premastectomy patient quality of life. Reconstructive surgery improves patients' postmastectomy quality of life. Nipple-sparing mastectomy appears to provide significantly better improvement in postreconstruction quality of life, specifically in the Satisfaction with Breasts and Satisfaction with Outcome domains of the BREAST-Q, compared with non-nipple-sparing mastectomies. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Heat shock proteins: stimulators of innate and acquired immunity.

Adjuvants were reintroduced into modern immunology as the dirty little secret of immunologists by Janeway and thus began the molecular definition of innate immunity. It is now clear that the binding of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) on antigen presenting cells (APCs) activates the innate immune response and provides the host with a rapid mechanism for detecting infection by pathogens and initiates adaptive immunity. Ironically, in addition to advancing the basic science of immunology, Janeway's revelation on induction of the adaptive system has also spurred an era of rational vaccine design that exploits PRRs. Thus, defined PAMPs that bind to known PRRs are being specifically coupled to antigens to improve their immunogenicity. However, while PAMPs efficiently activate the innate immune response, they do not mediate the capture of antigen that is required to elicit the specific responses of the acquired immune system. Heat shock proteins (HSPs) are molecular chaperones that are found complexed to client polypeptides and have been studied as potential cancer vaccines. In addition to binding PRRs and activating the innate immune response, HSPs have been shown to both induce the maturation of APCs and provide chaperoned polypeptides for specific triggering of the acquired immune response.

Heat-shock proteins as dendritic cell-targeting vaccines--getting warmer.

Heat-shock proteins (hsp) provide a natural link between innate and adaptive immune responses by combining the ideal properties of antigen carriage (chaperoning), targeting and activation of antigen-presenting cells (APC), including dendritic cells (DC). Targeting is achieved through binding of hsp to distinct cell surface receptors and is followed by antigen internalization, processing and presentation. An improved understanding of the interaction of hsp with DC has driven the development of numerous hsp-containing vaccines, designed to deliver antigens directly to DC. Studies in mice have shown that for cancers, such vaccines generate impressive immune responses and protection from tumour challenge. However, translation to human use, as for many experimental immunotherapies, has been slow partly because of the need to perform trials in patients with advanced cancers, where demonstration of efficacy is challenging. Recently, the properties of hsp have been used for development of prophylactic vaccines against infectious diseases including tuberculosis and meningitis. These hsp-based vaccines, in the form of pathogen-derived hsp-antigen complexes, or recombinant hsp combined with selected antigens in vitro, offer an innovative approach against challenging diseases where broad antigen coverage is critical.

The Positive Effect of Neurolysis on Diabetic Patients with Compressed Nerves of the Lower Extremities: A Systematic Review and Meta-analysis.

BACKGROUND: Despite proven benefits of upper extremity nerve decompression in diabetics, neurolysis for diabetic patients with lower extremity (LE) nerve compression remains controversial. METHODS: A search of ClinicalTrials.gov and Cochrane clinical trials registries, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, LILACS, CINAHL, SCOPUS, and Google Scholar from 1962 to 2012, yielded 1956 citations. Any potential randomized or quasi-randomized controlled trials and observational cohort studies of diabetics with neurolysis of the common peroneal nerve, deep peroneal nerve, or tibial nerve were assessed. We included articles in any language that 1) provided information about diabetic patients who had neurolysis for symptomatic nerve compression diagnosed by (+) Tinel sign or electrodiagnostic study, and 2) quantified outcomes for pain, sensibility, or ulcerations/amputations. Case reports, review articles, animal or cadaver studies, and studies with <10 patients were excluded. We assessed pain relief, recovery of sensibility, and postoperative incidence of ulcerations/amputations at follow-up >3 months. A meta-analysis of descriptive statistics was performed. RESULTS: Ten clinical series with a mean clinical relevance score of 70% and a mean methodologic quality score of 50% met inclusion criteria. We included 875 diabetic patients and 1053 LEs. Pain relief >3 points on visual analog scale occurred in 91% of patients; sensibility improved in 69%. Postoperative ulceration/amputation incidence was significantly reduced compared to preoperative incidence (odds ratio = 0.066, 95% confidence interval = 0.026-0.164, P < 0.0001). CONCLUSIONS: Observational data suggest that neurolysis significantly improves outcomes for diabetic patients with compressed nerves of the LE. No randomized controlled trials have been published.

Positron emission tomography shows elevated cannabinoid CB1 receptor binding in men with alcohol dependence.

BACKGROUND: Several lines of evidence link cannabinoid (CB) type 1 (CB (1) ) receptor-mediated endogenous CB (eCB) signaling to the etiology of alcohol dependence (AD). However, to date, only peripheral measures of eCB function have been collected in living humans with AD and no human in vivo data on the potentially critical role of the brain CB (1) receptor in AD have been published. This is an important gap in the literature, because recent therapeutic developments suggest that these receptors could be targeted for the treatment for AD. METHODS: Medication-free participants were scanned during early abstinence 4 weeks after their last drink. Using positron emission tomography (PET) with a high-resolution research tomograph and the CB (1) receptor selective radiotracer [(11) C]OMAR, we determined [(11) C]OMAR volume of distribution ( V (T) ) values, a measure of CB (1) receptor density, in a priori selected brain regions in men with AD (n = 8, age 37.4 ± 7.9 years; 5 smokers) and healthy control (HC) men (n = 8, age 32.5 ± 6.9 years; all nonsmokers). PET images reconstructed using the MOLAR algorithm with hardware motion correction were rigidly aligned to the subject-specific magnetic resonance (MR) image, which in turn was warped to an MR template. Time-activity curves (TACs) were extracted from the dynamic PET data using a priori selected regions of interest delineated in the MR template space. RESULTS: In AD relative to HC, [(11) C]OMAR V (T) values were elevated by approximately 20% (p = 0.023) in a circuit, including the amygdala, hippocampus, putamen, insula, anterior and posterior cingulate cortices, and orbitofrontal cortex. Age, body mass index, or smoking status did not influence the outcome. CONCLUSIONS: These findings agree with preclinical evidence and provide the first, albeit still preliminary in vivo evidence suggesting a role for brain CB (1) receptors in AD. The current study design does not answer the important question of whether elevated CB (1) receptors are a preexisting vulnerability factor for AD or whether elevations develop as a consequence of AD.