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Obstructive sleep apnea (OSA) is a common, identifiable, and treatable disorder with serious health, safety, and financial implications-including sleepiness- related crashes and incidents-in workers who perform safety-sensitive functions in the transportation industry. Up to one-third of crashes of large trucks are attributable to sleepiness, and large truck crashes result in more than 4,000 deaths annually. For each occupant of a truck who is killed, 6 to 7 occupants of other vehicles are killed. Treatment of OSA is cost-effective, lowers crash rates, and improves health and well-being. A large body of scientific evidence and expert consensus supports the identification and treatment of OSA in transportation operators. An Advanced Notice of Proposed Rulemaking regarding the diagnosis and treatment of OSA in commercial truck and rail operators was issued by the Federal Motor Carrier Safety Administration and Federal Railroad Administration, but it was later withdrawn. This reversal of the agencies' position has caused confusion among some, who have questioned whether efforts to identify and treat the disorder are warranted. In response, we urge key stakeholders, including employers, operators, legislators, payers, clinicians, and patients, to engage in a collaborative, patient-centered approach to address the disorder. At a minimum, stakeholders should follow the guidelines issued by a medical review board commissioned by the Federal Motor Carrier Safety Administration in 2016 alone, or in combination with the 2006 criteria, "Sleep Apnea and Commercial Motor Vehicle Operators," a Statement from the Joint Task Force of the American College of Chest Physicians, the American College of Occupational and Environmental Medicine, and the National Sleep Foundation developed by a joint task force. As research in this area continues to evolve, waiting is no longer an option, and the current standard of care demands action to mitigate the burden of serious health and safety risks due to this common, treatable disorder.Das AM, Chang JL, Berneking M, Hartenbaum NP, Rosekind M, Gurubhagavatula I. Obstructive sleep apnea screening, diagnosis, and treatment in the transportation industry.

BACKGROUND Higher-volume centers for pancreatic cancer surgeries have been shown to have improved outcomes such as length of stay. We examined how centralization of pancreatic cancer care within a regional integrated healthcare system improves overall survival. METHODS We conducted a retrospective study of 1621 patients treated for pancreatic cancer from February 2010 to December 2018. Care was consolidated into 4 Centers of Excellence (COE) in surgery, medical oncology, and other specialties. Descriptive statistics, bivariate analysis, Chi-square tests, and Kaplan-Meier analysis were performed. RESULTS Neoadjuvant chemotherapy use rose from 10% to 31% (p

OBJECTIVE Resection of meningiomas in direct contact with the anterior optic apparatus carries risk of injury to the visual pathway. Stereotactic radiosurgery (SRS) offers a minimally invasive alternative. However, its use is limited owing to the risk of radiation-induced optic neuropathy. Few SRS studies have specifically assessed the risks and benefits of treating meningiomas in direct contact with the optic nerve, chiasm, or optic tract. The authors hypothesized that SRS is safe for select patients with meningiomas in direct contact with the anterior optic apparatus. METHODS The authors performed an international multicenter retrospective analysis of 328 patients across 11 institutions. All patients had meningiomas in direct contract with the optic apparatus. Patients were followed for a median duration of 56 months after SRS. Neurological examinations, including visual function evaluations, were performed at follow-up visits. Clinical and treatment variables were collected at each site according to protocol. Tumor volumes were assessed with serial MR imaging. Variables predictive of visual deficit were identified using univariable and multivariable logistic regression. RESULTS SRS was the initial treatment modality for 64.6% of patients, and 93% of patients received SRS as a single fraction. Visual information was available for 302 patients. Of these patients, visual decline occurred in 29 patients (9.6%), of whom 12 (41.4%) had evidence of tumor progression. Visual decline in the remaining 17 patients (5.6%) was not associated with tumor progression. Pre-SRS Karnofsky Performance Status predicted visual decline in adjusted analysis (adjusted OR 0.9, 95% CI 0.9–1.0, p < 0.01). Follow-up imaging data were available for 322 patients. Of these patients, 294 patients (91.3%) had radiographic evidence of stability or tumor regression at last follow up. Symptom duration was associated with tumor progression in adjusted analysis (adjusted OR 1.01, adjusted 95% CI 1.0–1.02, adjusted p = 0.02). CONCLUSIONS In this international multicenter study, the vast majority of patients exhibited tumor control and preservation of visual function when SRS was used to treat meningioma in direct contact with the anterior optic pathways. SRS is a relatively safe treatment modality for select patients with perioptic meningiomas in direct contact with the optic apparatus.

OBJECTIVE Stereotactic radiosurgery (SRS) provides a safe and effective therapeutic modality for patients with pituitary adenomas. The mechanism of delayed endocrine deficits based on targeted radiation to the hypothalamic-pituitary axis remains unclear. Radiation to normal neuroendocrine structures likely plays a role in delayed hypopituitarism after SRS. In this multicenter study by the International Radiosurgery Research Foundation (IRRF), the authors aimed to evaluate radiation tolerance of structures surrounding pituitary adenomas and identify predictors of delayed hypopituitarism after SRS for these tumors. METHODS This is a retrospective review of patients with pituitary adenomas who underwent single-fraction SRS from 1997 to 2019 at 16 institutions within the IRRF. Dosimetric point measurements of 14 predefined neuroanatomical structures along the hypothalamus, pituitary stalk, and normal pituitary gland were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiographic, and endocrine outcomes. RESULTS The study cohort comprised 521 pituitary adenomas treated with SRS. Tumor control was achieved in 93.9% of patients over a median follow-up period of 60.1 months, and 22.5% of patients developed new loss of pituitary function with a median treatment volume of 3.2 cm3. Median maximal radiosurgical doses to the hypothalamus, pituitary stalk, and normal pituitary gland were 1.4, 7.2, and 11.3 Gy, respectively. Nonfunctioning adenoma status, younger age, higher margin dose, and higher doses to the pituitary stalk and normal pituitary gland were independent predictors of new or worsening hypopituitarism. Neither the dose to the hypothalamus nor the ratio between doses to the pituitary stalk and gland were significant predictors. The threshold of the median dose to the pituitary stalk for new endocrinopathy was 10.7 Gy in a single fraction (OR 1.77, 95% CI 1.17–2.68, p = 0.006). CONCLUSIONS SRS for the treatment of pituitary adenomas affords a high tumor control rate with an acceptable risk of new or worsening endocrinopathy. This evaluation of point dosimetry to adjacent neuroanatomical structures revealed that doses to the pituitary stalk, with a threshold of 10.7 Gy, and doses to the normal gland significantly increased the risk of post-SRS hypopituitarism. In patients with preserved pre-SRS neuroendocrine function, limiting the dose to the pituitary stalk and gland while still delivering an optimal dose to the tumor appears prudent.

Hypoglossal nerve stimulation (HGNS) has evolved as a novel and effective therapy for patients with moderate-to-severe obstructive sleep apnea. Despite positive published outcomes of HGNS, there exist uncertainties regarding proper patient selection, surgical technique, and the reporting of outcomes and individual factors that impact therapy effectiveness. According to current guidelines, this therapy is indicated for select patients, and recommendations are based on the Stimulation Therapy for Apnea Reduction or STAR trial. Ongoing research and physician experiences continuously improve methods to optimize the therapy. An understanding of the way in which airway anatomy, obstructive sleep apnea phenotypes, individual health status, psychological conditions, and comorbid sleep disorders influence the effectiveness of HGNS is essential to improve outcomes and expand therapy indications. This article presents discussions on current evidence, future directions, and research gaps for HGNS therapy from the 10th International Surgical Sleep Society expert research panel. CITATION: Suurna MV, Jacobowitz O, Chang J, et al. Improving outcomes of hypoglossal nerve stimulation therapy: current practice, future directions and research gaps. Proceedings of the 2019 International Sleep Surgery Society Research Forum. J Clin Sleep Med. 2021;17(12):2477–2487.

Purpose The purpose of this study was to describe anterior subcapsular cataract development in patients on long-term topical netarsudil use. Patients and methods This clinical observational study summarizes a similar cataract pattern demonstrated in a series of patients from a single physician practice and a university-based outpatient clinic during their routine clinical follow-up visits from October 2020 to August 2021. All patients have been using topical netarsudil once daily for at least 15 months. No anterior capsular changes have been observed in any patient at the time when netarsudil was initiated. Results Five eyes from 4 patients between the ages of 41 and 61 and 1 eye from a patient aged 84 were found to develop anterior subcapsular opacities 15 to 37 months after beginning netarsudil. These cataracts were overall small, 1 to 3 mm, round, oval or ring-shaped, central or paracentral with mild density. No other risk factors for cataract development apart from age were found in these patients. Conclusion Patients on long-term netarsudil should be monitored for potential development of anterior subcapsular cataracts.

Background Hypertensive disorders of pregnancy and maternal diabetes profoundly affect fetal and newborn growth, yet disturbances in intermediate metabolism and relevant mediators of fetal growth alterations remain poorly defined. We sought to determine whether there are distinct newborn screen metabolic patterns among newborns affected by maternal hypertensive disorders or diabetes in utero. Methods A retrospective observational study investigating distinct newborn screen metabolites in conjunction with data linked to birth and hospitalization records in the state of California between 2005 and 2010. Results A total of 41,333 maternal-infant dyads were included. Infants of diabetic mothers demonstrated associations with short-chain acylcarnitines and free carnitine. Infants born to mothers with preeclampsia with severe features and chronic hypertension with superimposed preeclampsia had alterations in acetylcarnitine, free carnitine, and ornithine levels. These results were further accentuated by size for gestational age designations. Conclusions Infants of diabetic mothers demonstrate metabolic signs of incomplete beta oxidation and altered lipid metabolism. Infants of mothers with hypertensive disorders of pregnancy carry analyte signals that may reflect oxidative stress via altered nitric oxide signaling. The newborn screen analyte composition is influenced by the presence of these maternal conditions and is further associated with the newborn size designation at birth. Impact Substantial differences in newborn screen analyte profiles were present based on the presence or absence of maternal diabetes or hypertensive disorder of pregnancy and this finding was further influenced by the newborn size designation at birth. The metabolic health of the newborn can be examined using the newborn screen and is heavily impacted by the condition of the mother during pregnancy. Utilizing the newborn screen to identify newborns affected by common conditions of pregnancy may help relate an infant's underlying biological disposition with their clinical phenotype allowing for greater risk stratification and intervention.

Previous studies have reported that phosphodiesterase 10A (PDE10) is overexpressed in colon epithelium during early stages of colon tumorigenesis and essential for colon cancer cell growth. Here we describe a novel non-COX inhibitory derivative of the anti-inflammatory drug, sulindac, with selective PDE10 inhibitory activity, ADT 061. ADT 061 potently inhibited the growth of colon cancer cells expressing high levels of PDE10, but not normal colonocytes that do not express PDE10. The concentration range by which ADT 061 inhibited colon cancer cell growth was identical to concentrations that inhibit recombinant PDE10. ADT 061 inhibited PDE10 by a competitive mechanism and did not affect the activity of other PDE isozymes at concentrations that inhibit colon cancer cell growth. Treatment of colon cancer cells with ADT 061 activated cGMP/PKG signaling, induced phosphorylation of oncogenic β-catenin, inhibited Wnt-induced nuclear translocation of β-catenin, and suppressed TCF/LEF transcription at concentrations that inhibit cancer cell growth. Oral administration of ADT 061 resulted in high concentrations in the colon mucosa and significantly suppressed the formation of colon adenomas in the Apc+/min-FCCC mouse model of colorectal cancer without discernable toxicity. These results support the development of ADT 061 for the treatment or prevention of adenomas in individuals at risk of developing colorectal cancer. Prevention Relevance: PDE10 is overexpressed in colon tumors whereby inhibition activates cGMP/PKG signaling and suppresses Wnt/β-catenin transcription to selectively induce apoptosis of colon cancer cells. ADT 061 is a novel PDE10 inhibitor that shows promising cancer chemopreventive activity and tolerance in a mouse model of colon cancer.

OBJECTIVE Radiation-induced meningiomas (RIMs) are associated with aggressive clinical behavior. Stereotactic radiosurgery (SRS) is sometimes considered for selected RIMs. The authors investigated the effectiveness and safety of SRS for the management of RIMs. METHODS From 12 institutions participating in the International Radiosurgery Research Foundation, the authors pooled patients who had prior cranial irradiation and were subsequently clinically diagnosed with WHO grade I meningiomas that were managed with SRS. RESULTS Fifty-two patients underwent 60 SRS procedures for histologically confirmed or radiologically suspected WHO grade I RIMs. The median ages at initial cranial radiation therapy and SRS for RIM were 5.5 years and 39 years, respectively. The most common reasons for cranial radiation therapy were leukemia (21%) and medulloblastoma (17%). There were 39 multiple RIMs (35%), the mean target volume was 8.61 ± 7.80 cm3, and the median prescription dose was 14 Gy. The median imaging follow-up duration was 48 months (range 4–195 months). RIM progressed in 9 patients (17%) at a median duration of 30 months (range 3–45 months) after SRS. Progression-free survival at 5 years post-SRS was 83%. Treatment volume ≥ 5 cm3 predicted progression (HR 8.226, 95% CI 1.028–65.857, p = 0.047). Seven patients (14%) developed new neurological symptoms or experienced SRS-related complications or T2 signal change from 1 to 72 months after SRS. CONCLUSIONS SRS is associated with durable local control of RIMs in the majority of patients and has an acceptable safety profile. SRS can be considered for patients and tumors that are deemed suboptimal, poor surgical candidates, and those whose tumor again progresses after removal.

Resection of clinoid meningiomas can be associated with significant morbidity. Experience with stereotactic radiosurgery (SRS) for clinoid meningiomas remains limited. We studied the safety and effectiveness of SRS for clinoid meningiomas. From twelve institutions participating in the International Radiosurgery Research Foundation, we pooled patients treated with SRS for radiologically suspected or histologically confirmed WHO grade I clinoid meningiomas. Two hundred seven patients (median age: 56 years) underwent SRS for clinoid meningiomas. Median treatment volume was 8.02 cm3, and 87% of tumors were immediately adjacent to the optic apparatus. The median tumor prescription dose was 12 Gy, and the median maximal dose to the anterior optic apparatus was 8.5 Gy. During a median post-SRS imaging follow-up of 51.1 months, 7% of patients experienced tumor progression. Greater margin SRS dose (HR = 0.700, p = 0.007) and pre-SRS radiotherapy (HR = 0.004, p

A healthy pregnancy depends on complex interrelated biological adaptations involving placentation, maternal immune responses, and hormonal homeostasis. Recent advances in high-throughput technologies have provided access to multiomics biological data that, combined with clinical and social data, can provide a deeper understanding of normal and abnormal pregnancies. Integration of these heterogeneous datasets using state-of-the-art machine-learning methods can enable the prediction of short- and long-term health trajectories for a mother and offspring and the development of treatments to prevent or minimize complications. We review advanced machine-learning methods that could: provide deeper biological insights into a pregnancy not yet unveiled by current methodologies; clarify the etiologies and heterogeneity of pathologies that affect a pregnancy; and suggest the best approaches to address disparities in outcomes affecting vulnerable populations.

Purpose This study assesses a large multi-institutional database to present the outcomes of World Health Organization grade 2 meningiomas treated with stereotactic radiosurgery (SRS). We also compare the 3-year progression-free survival (PFS) to that reported in the Radiation Therapy Oncology Group 0539 phase 2 cooperative group meningioma trial. Methods and Materials From an international, multicenter group, data were collected for grade 2 meningioma patients treated with SRS for demonstrable tumor from 1994 to 2019. Statistical methods used included the Kaplan-Meier method, Cox proportional hazards analysis, and recursive partitioning analysis. Results Two hundred thirty-three patients treated at 12 institutions were included. Patients presented at a median age of 60 years (range, 13-90), and many had at least 2 prior resections (30%) or radiation therapy (22%). Forty-eight percent of patients had prior gross total resection. At SRS, the median treatment volume was 6.1 cm3 (0.1-97.6). A median 15 Gy (10-30) was delivered to a median percent isodose of 50 (30-80), most commonly in 1 fraction (95%). A model was developed using recursive partitioning analysis, with one point attributed to age >50 years, treatment volume >11.5 cm3, and prior radiation therapy or multiple surgeries. The good-prognostic group (score, 0-1) had improved PFS (P 50 years (hazard ratio = 1.85 [95% confidence interval, 1.09-3.14]) and multiple prior surgeries (hazard ratio = 1.80 [1.09-2.99]) also portended reduced PFS in patients without prior radiation therapy. Two hundred eighteen of 233 patients in this study qualified for the high-risk group of Radiation Therapy Oncology Group 0539, and they demonstrated similar outcomes (3-year PFS: 53.9% vs 58.8%). The good-prognostic group of SRS patients demonstrated slightly improved outcomes (3-year PFS: 63.1% vs 58.8%). Conclusions SRS should be considered in carefully selected patients with atypical meningiomas. We suggest the use of our good-prognostic group to optimize patient selection, and we strongly encourage the initiation of a clinical trial to prospectively validate these outcomes.

Background Catatonia is an often underdiagnosed diagnosis in the pediatric population that carries substantial morbidity and mortality. Early recognition of catatonia is important, especially whenit presents with autonomic abnormalities to ensure timely initiation of treatment. Treatment of catatonia is well established, especially the use of GABAergic agents such as benzodiazepines. Although the use of high potency cannabis has been associated with multiple neuropsychiatric sequelae, the relationship between vaporized cannabis use and catatonia has not been previously described. Case Presentations We report two cases of malignant catatonia in adolescent males with psychiatric histories significant for trauma and depression, and a recent history of vaporized marijuana use. These adolescents presented to the pediatric emergency room with classic symptoms of catatonia including psychomotor and behavioral disturbances. Both patients had evidence of autonomic dysfunction including hypertension, tachycardia, and mydriasis, and in one case, even evidence of cardiac ischemia. Laboratory and imaging workups for both patients were otherwise unremarkable. Both patients had resolution of symptoms following the administration of lorazepam. Conclusions These cases represent the first reported instances of pediatric malignant catatonia secondary to vaporized cannabis use. Given the increasing popularity of vaporized cannabis use among adolescents, malignant catatonia should be on the differential in a pediatric patient presenting with psychomotor disturbances and autonomic instability. Further research is needed to quantify the risk of catatonia secondary to vaporized cannabis use.

PURPOSE: This multicenter randomized phase 2 trial investigates the impact of intense androgen deprivation on radical prostatectomy (RP) pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368). MATERIALS AND METHODS: Eligible patients had a Gleason score ≥4+3=7, PSA >20 ng/mL or T3 disease and lymph nodes

OBJECTIVES Numerous therapies exist for adult obstructive sleep apnea (OSA), creating potential for patient decisional conflict (DC) that impacts treatment adherence and post-treatment regret. We evaluated the prevalence of elevated DC in OSA patients presenting for positive airway pressure (PAP) alternative therapies and identified gaps in available resources about OSA therapies. STUDY DESIGN Cross-sectional study. METHODS A cross-sectional study was performed based on questionnaires completed by adult OSA patients presenting to an academic sleep surgery clinic from March to October 2020. Surveys examined sleep symptoms, sleep apnea treatment history, goals of therapy, and the SURE checklist, a validated 4-item DC screening scale. Additional qualitative data about OSA decision tool needs were queried with structured interviews in a smaller subset of patients. RESULTS Among 100 respondents, 60 were open to multiple treatment options, whereas 22 were not interested in surgical treatment. Eighty-one respondents (81%) had elevated DC (SURE score

Stomach cancer is one of the most common tumors of the gastrointestinal tract. In Russia, stomach cancer is ranked fourth in incidence among malignancies and gives ground for lung, breast and colon cancers. Although the success of PD-1/PD-L1 inhibitors application in clinical practice has been proven in cases of many forms of malignancies, the advantages of application of these types of drugs in cases of stomach cancer has not yet been determined. The purpose of this review is to analyze modern studies concerning the clinical significance of PD-1 and PD-L1 expression in stomach tumors and to find the prospects of immunotherapy these tumors. The large number of studies are currently being described, concerning the analysis of the expression of PD-1, PD-L1 levels in tumor cells and soluble forms of these proteins sPD-1 and sPD-L1 in the serum in patients with stomach cancer. However, their clinical significance is unclear, and in many cases the predictive role of PD-L1 expression for the efficacy of immunotherapy is not yet clearly defined. Further accumulation of knowledge in this area can help to improve the efficacy of existing immunotherapy methods and to develop new predictive criteria.

Objective To establish if the cessation of testosterone (T) therapy reverses T-induced acyclicity in a transgender mouse model that allows for well-defined T cessation timing. Design Experimental laboratory study using a mouse model. Setting University-based basic science research laboratory. Animals A total of 10 C57BL/6NHsd female mice were used in this study. Intervention(s) Postpubertal C57BL/6NHsd female mice were subcutaneously implanted with T enanthate (n = 5 mice) or placebo (n = 5 mice) pellets. Pellets were surgically removed after 6 weeks to ensure T cessation, after which the mice were followed for four estrous cycles after the resumption of cyclicity. Main Outcome Measure(s) Primary outcomes included daily vaginal cytology and weekly T levels before, during, and after T enanthate or placebo pellet implantation and removal. Secondary outcomes included ovarian follicle distribution and corpora lutea numbers, body metrics, and terminal diestrus hormone levels. Result(s) T-treated mice (100%) resumed cycling within one week of T pellet removal after six weeks of T therapy. T levels were significantly elevated during T therapy and decreased to control levels after surgical pellet removal. No detectable differences were observed in the follicle count, corpora lutea formation, diestrus hormone levels, or body metrics after four estrous cycles, with the exception of persistent increased clitoral area between T-treated mice and controls. One T-treated mouse was sacrificed early due to vaginal prolapse and not included in subsequent analyses. Conclusion(s) Our results demonstrated a close temporal relationship between estrous cycle return and T levels dropping to control levels following T pellet removal. The return of regular cyclic ovulatory function is also supported by the formation of corpora lutea and the lack of detectable differences in key reproductive parameters as compared to controls four cycles after T cessation. These results may be relevant to understanding the reversibility of T-induced amenorrhea and possible anovulation in transgender men interested in pausing T to pursue pregnancy or oocyte donation. Results may be limited by the duration of T treatment, lack of functional testing, and physiological differences between mice and humans.

Context To improve the prognosis of upper tract urothelial carcinoma (UTUC), clinicians have used neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (AC) before or after radical nephroureterectomy (RNU). Despite some new data, the evidence remains mixed on their efficacy. Objective To update the current evidence on the role of NAC and AC for UTUC. Evidence acquisition We searched for all studies investigating NAC or AC for UTUC in Medline, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from the American Society of Clinical Oncology meetings up to February 2020. A systematic review and meta-analysis was performed. Evidence synthesis For NAC, the pooled pathologic complete response rate (≤ypT0N0M0) was 11% (n = 811) and pathologic partial response rate (≤ypT1N0M0) was 43% (n = 869), both across 14 studies. Across six studies, the pooled hazard ratios (HRs) were 0.44 (95% confidence interval [CI]: 0.32–0.59, p Conclusions NAC for UTUC confers a favorable pathologic response and tumor downstaging rate, and an OS and CSS benefit compared with RNU alone. AC confers an OS, CSS, and DFS benefit compared with RNU alone. Currently, the evidence for AC appears stronger (with positive level 1 evidence) than that for NAC (at best level 2 evidence). Limited data are available for chemoimmunotherapy approaches, but preliminary data support an active research investment. Patient summary After a comprehensive search of the latest studies examining the role of neoadjuvant and adjuvant chemotherapy for upper tract urothelial cancer, the pooled evidence shows that perioperative chemotherapy was beneficial for prolonging survival; however, the evidence for adjuvant chemotherapy was stronger than that for neoadjuvant chemotherapy.

Pulmonary infection due to Mycobacterium abscessus occurs in patients with cystic fibrosis, but rarely in immunocompetent children without underlying lung pathology. Treatment is complicated by frequent resistance to many antibiotics. We present a case report of a 4-month-old female infant with 2 months of cough, difficulty feeding, and failure to thrive, with extensive culture-confirmed M. abscessus pulmonary infection without identified immunodeficiency or underlying lung pathology following multidisciplinary evaluation. We describe our complete evaluation including immunodeficiency evaluation incorporating whole-exome sequencing, describe our antibiotic selection and treatment duration given complicated susceptibility pattern of the M. abscessus isolate, and review literature for nontuberculous mycobacterial pulmonary disease in immunocompetent children. A complete multidisciplinary evaluation for underlying lung disease and primary and acquired immunodeficiency should be undertaken in pediatric patients with M. abscessus pneumonia. Confirming macrolide susceptibility through erm(41) gene evaluation is clinically important for isolates with complicated susceptibility pattern.

Identifying valid biomarkers for patient selection impressively promotes the success of anti-PD-1 therapy. However, the unmet need for biomarkers in gastrointestinal (GI) cancers remains significant. We aimed to explore the predictive value of the circulating T-cell receptor (TCR) repertoire for clinical outcomes in GI cancers who received anti-PD-1 therapy. 137 pre- and 79 post-treated peripheral blood samples were included. The TCR repertoire was evaluated by sequencing of complementarity-determining region 3 (CDR3) in the TRB gene. The Shannon index was used to measure the diversity of the TCR repertoire, and Morisita’s overlap index was used to determine TCR repertoire similarities between pre- and post-treated samples. Among all enrolled patients, 76 received anti-PD-1 monotherapy and 61 received anti-PD-1 combination therapy. In the anti-PD-1 monotherapy cohort, patients with higher baseline TCR diversity exhibited a significantly higher disease control rate (77.8% vs. 47.2%; hazard ratio [HR] 3.92; 95% confidence interval [CI] 1.14–13.48; P = 0.030) and a longer progression-free survival (PFS) (median: 6.47 months vs. 2.77 months; HR 2.10; 95% CI 1.16–3.79; P = 0.014) and overall survival (OS) (median: NA vs. 8.97 months; HR 3.53; 95% CI 1.49–8.38; P = 0.004) than those with lower diversity. Moreover, patients with a higher TCR repertoire similarity still showed a superior PFS (4.43 months vs. 1.84 months; HR 13.98; 95% CI 4.37–44.68; P

BACKGROUND: Stereotactic radiosurgery (SRS) is increasingly used for management of perioptic meningiomas. OBJECTIVE: To study the safety and effectiveness of SRS for perioptic meningiomas. METHODS: From 12 institutions participating in the International Radiosurgery Research Foundation (IRRF), we retrospectively assessed treatment parameters and outcomes following SRS for meningiomas located within 3 mm of the optic apparatus. RESULTS: A total of 438 patients (median age 51 yr) underwent SRS for histologically confirmed (29%) or radiologically suspected (71%) perioptic meningiomas. Median treatment volume was 8.01 cm(3). Median prescription dose was 12 Gy, and median dose to the optic apparatus was 8.50 Gy. A total of 405 patients (93%) underwent single-fraction SRS and 33 patients (7%) underwent hypofractionated SRS. During median imaging follow-up of 55.6 mo (range: 3.15-239 mo), 33 (8%) patients experienced tumor progression. Actuarial 5-yr and 10-yr progression-free survival was 96% and 89%, respectively. Prescription dose of ≥12 Gy (HR: 0.310; 95% CI [0.141-0.679], P = .003) and single-fraction SRS (HR: 0.078; 95% CI [0.016-0.395], P = .002) were associated with improved tumor control. A total of 31 (10%) patients experienced visual decline, with actuarial 5-yr and 10-yr post-SRS visual decline rates of 9% and 21%, respectively. Maximum dose to the optic apparatus ≥10 Gy (HR = 2.370; 95% CI [1.086-5.172], P = .03) and tumor progression (HR = 4.340; 95% CI [2.070-9.097], P

BACKGROUND Atypical and anaplastic meningiomas have reduced progression-free/overall survival (PFS/OS) compared to benign meningiomas. Stereotactic radiosurgery (SRS) for atypical meningiomas (AMs) and anaplastic meningiomas (malignant meningiomas, MMs) has not been adequately described. OBJECTIVE To define clinical/radiographic outcomes for patients undergoing SRS for AM/MMs. METHODS An international, multicenter, retrospective cohort study was performed to define clinical/imaging outcomes for patients receiving SRS for AM/MMs. Tumor progression was assessed with response assessment in neuro-oncology (RANO) criteria. Factors associated with PFS/OS were assessed using Kaplan-Meier analysis and a Cox proportional hazards model. RESULTS A total of 271 patients received SRS for AMs (n = 233, 85.9%) or MMs (n = 38, 14.0%). Single-fraction SRS was most commonly employed (n = 264, 97.4%) with a mean target dose of 14.8 Gy. SRS was used as adjuvant treatment (n = 85, 31.4%), salvage therapy (n = 182, 67.2%), or primary therapy (1.5%). The 5-yr PFS/OS rate was 33.6% and 77.0%, respectively. Increasing age (hazard ratio (HR) = 1.01, P 15% (HR = 1.66, P

Tuberculosis (TB) is a global health threat that affects 10 million people worldwide. Human Immunodeficiency Virus (HIV) remains one of the major contributors to the reactivation of asymptomatic latent tuberculosis (LTBI). Over the recent years, there has been a significant focus in developing in-vitro 3D models mimicking early events of Mycobacterium tuberculosis (Mtb) pathogenesis, especially formation of the granuloma. However, these models are low throughput and require extracellular matrix. In this article, we report the generation of a matrix-free 3D model, using THP-1 human monocyte/macrophage cells and mCherry-expressing Mycobacterium bovis BCG (Bacilli Camille Guérin), henceforth referred as 3D spheroids, to study the host cell-bacterial interactions. Using mCherry-intensity-based tracking, we monitored the kinetics of BCG growth in the 3D spheroids. We also demonstrate the application of the 3D spheroids for testing anti-TB compounds such as isoniazid (INH), rifampicin (RIF), as well as a host-directed drug, everolimus (EVR) as single and combinational treatments. We further established a dual infection 3D spheroid model by coinfecting THP-1 macrophages with BCG mCherry and pseudotype HIV. In this HIV-TB co-infection model, we found an increase in BCG mCherry growth within the 3D spheroids infected with HIV pseudotype. The degree of disruption of the granuloma was proportional to the virus titers used for co-infection. In summary, this 3D spheroid assay is an useful tool to screen anti-TB response of potential candidate drugs and can be adopted to model HIV-TB interactions.

Background Although the novel 2019 coronavirus (COVID-19) pandemic delayed elective microsurgical reconstruction cases, traumatic injuries requiring microsurgical reconstruction for limb salvage still presented to our hospital. Recent data suggests a link between COVID-19 and increased venous and arterial thromboembolic events, theoretically increasing the risk of microvascular anastomotic thrombosis and flap failure. Methods We provide a single case report of microsurgical limb salvage in a COVID-19-positive patient with a Gustilo IIIb open tibial-fibular fracture. Results A free latissimus dorsi muscle flap was used to successfully cover a Gustilo IIIb open tibial-fibular fracture with exposed orthopedic hardware and large soft tissue defect, with 5-month follow-up demonstrating a well-healed flap allowing for preserved ambulation. Conclusion Although there is a theoretical increased incidence of venous and arterial thrombotic microvascular failure in COVID-19-positive patients, microsurgical reconstruction is occasionally the lone option for salvage. Microsurgical reconstruction in this population must be carefully considered, meticulously executed, and closely monitored.

Clinical practice guidelines (CPGs) have been associated with improved patient outcomes. We aimed to evaluate institutional CPG adherence and hypothesized that adherence would be associated with fewer complications in pediatric appendicitis.A retrospective review was conducted of pediatric (18 y) appendicitis patients who underwent appendectomy (6/1/2017-5/30/2018). Patients were managed using an institutional pediatric appendicitis CPG. The primary outcome was CPG adherence, defined as receipt of preoperative antibiotics at diagnosis, surgical prophylaxis before incision, and, in perforated/gangrenous appendicitis, continued postoperative antibiotics, and prescription for discharge antibiotics. Univariate and multivariate analyzes were performed.Among 399 patients, the baseline characteristics were similar between CPG-adherent and nonadherent patients. Overall CPG adherence was low at 55% (n = 221). Only 58% of patients received preoperative antibiotics per protocol (n = 233). Patients with simple appendicitis were more likely to proceed to surgery without receiving any preoperative antibiotics (35% vs. 21%, P = 0.004). Surgical prophylaxis compliance was high at 97% (n = 389). CPG violation was associated with reoperation (n = 5 versus 0, P = 0.02). After adjusting for age and admission white blood cell count, the association between CPG adherence and postoperative surgical site infection or intra-abdominal abscess remained nonsignificant (OR: 1.2, 95% CI: 0.5-2.5).Despite a long-standing pediatric appendicitis CPG, adherence with antibiotic components of the CPG was poor. CPG violation was significantly associated with reoperation, but was not associated with other postoperative complications. Regular audits of CPG adherence are necessary to ascertain reasons for noncompliance and identify ways to improve adherence.

Introduction We sought quantify racial disparities in use of analgesia amongst patients seen in Emergency Departments for renal colic. Methods We identified all individuals presenting to the Emergency Department with urolithiasis from 2003 to 2015 in the nationally representative Premier Hospital Database. We included patients discharged in ≤1 day and excluded those with chronic pain or renal insufficiency. We assessed the relationship between race/ethnicity and opioid dosage in morphine milligram equivalents (MME), and ketorolac, through multivariable regression models adjusting for patient and hospital characteristics. Results The cohort was 266,210 patients, comprised of White (84%), Black (6%) and Hispanic (10%) individuals. Median opioid dosage was 20 MME and 55.5% received ketorolac. Our adjusted model showed Whites had highest median MME (20 mg) with Blacks (−3.3 mg [95% CI: −4.6 mg to −2.1 mg]) and Hispanics (−6.0 mg [95% CI: −6.9 mg to −5.1 mg]) receiving less. Blacks were less likely to receive ketorolac (OR: 0.72, 95% CI: 0.62–0.84) while there was no difference between Whites and Hispanics. Conclusions Black and Hispanic patients in American Emergency Departments with acute renal colic receive less opioid medication than White patients; Black patients are also less likely to receive ketorolac.

Introduction Glucocorticoids (GCs) are the primary treatment for nephrotic syndrome (NS), although ∼10% to 20% of children develop steroid-resistant NS (SRNS). Unfortunately, there are no validated biomarkers able to predict SRNS at initial disease presentation. We hypothesized that a plasma cytokine panel could predict SRNS at disease presentation, and identify potential pathways regulating SRNS pathogenesis. Methods Paired plasma samples were collected from 26 children with steroid-sensitive NS (SSNS) and 14 with SRNS at NS presentation and after ∼7 weeks of GC therapy, when SSNS versus SRNS was clinically determined. Plasma cytokine profiling was performed with a panel of 27 cytokines. Results We identified 13 cytokines significantly different in Pretreatment SSNS versus SRNS samples. Statistical modeling identified a cytokine panel (interleukin [IL]-7, IL-9, monocyte chemoattractant protein–1 [MCP-1]) able to discriminate between SSNS and SRNS at disease presentation (receiver operating characteristic [ROC] value = 0.846; sensitivity = 0.643; specificity = 0.846). Furthermore, GC treatment resulted in significant decreases in plasma interferon-γ (IFN-γ), tumor necrosis factor–α (TNF-α), IL-7, IL-13, and IL-5 in both SSNS and SRNS patients. Conclusions These studies suggest that initial GC treatment of NS reduces the plasma cytokines secreted by both CD4+ TH1 cells and TH2 cells, as well as CD8+ T cells. Importantly, a panel of 3 cytokines (IL-7, IL-9, and MCP-1) was able to predict SRNS prior to GC treatment at disease presentation. Although these findings will benefit from validation in a larger cohort, the ability to identify SRNS at disease presentation could greatly benefit patients by enabling both avoidance of unnecessary GC-induced toxicity and earlier transition to more effective alternative treatments., Graphical abstract

BACKGROUND Smoking, the most common risk factor for bladder cancer (BC), is associated with increased complications after radical cystectomy (RC), poorer oncologic outcomes, and higher mortality. The authors hypothesized that the effect of smoking on the probability of major complications increases with increasing age among patients who undergo RC. METHODS The authors analyzed the American College of Surgeons National Surgical Quality Improvement Program database (2011-2017), identified all patients undergoing RC using Current Procedural Terminology codes, and formed two groups according to smoking status (active smoker and nonsmoker [included former and never-smokers]). Patient characteristics and 30-day postoperative complications using the Clavien-Dindo Classification (CDC) were assessed. A multivariable logistic regression model was constructed that included age, sex, race, body mass index, operative time, comorbidities, chemotherapy status, and type of diversion with major complications (CDC ≥III) as the outcome variable, and explored the interaction between age and smoking status. RESULTS A total of 10,528 patients underwent RC, including 22.8% who were active smokers. The authors identified an interaction between age and smoking status (P = .045). Older patients were found to experience a stronger smoking effect than younger patients with regard to the probability of major complications. The risk of a major complication was the same for 50-year-old nonsmokers and smokers, but it increased from 17.8% to 21.7% for 70-year-old nonsmokers and smokers, respectively (P < .001). CONCLUSIONS Up to 20% of patients who undergo RC are active smokers, and these individuals have an increased risk of major complications. The effect of smoking is stronger with increasing age; the difference with regard to complications for smokers versus nonsmokers was found to increase substantially, wherein older smokers are at an especially high risk of complications.

Purpose/Objective(s) The grade of meningioma has significant implications on the selection of treatment regimens ranging from observation to surgical resection with adjuvant radiation. For most patients, meningiomas are diagnosed radiologically and grade is not determined unless a surgical procedure is completed. We hypothesize that the use of a 3D convolutional neural network (CNN) architecture with two encoding paths will provide auto-classification of grade I and II meningioma using T1-contrast enhancing (T1-CE) and T2-Fluid attenuated inversion recovery (FLAIR) magnetic resonance (MR) images. Materials/Methods Ninety-six consecutive treatment naive patients with pre-operative T1-CE and T2-FLAIR MR images from 2010 to 2019 were evaluated. The patients underwent surgical resection resulting in a diagnosis of grade I or II meningioma. Histopathology was confirmed by a neuropathologist and neuropathology fellow based on current classification guidelines described in the 2016 World Health Organization (WHO) Bluebook. The delineation of meningiomas was completed on both T1-CE and T2-FLAIR MR with the inclusion of surrounding T2-FLAIR hyperintensity. A novel asymmetric 3D CNN architecture was constructed with two encoding paths based on T1-CE and T2-FLAIR MR. Each path used the same 3 × 3 × 3 kernel with different filters to weight the spatial features of each sequence separately. Final model performance was assessed by 10-fold cross-validation. Results Of the 96 patients, 55 (57%) were pathologically classified as grade I and 41 (43%) as grade II meningiomas. Optimization of our model led to a filter weighting of 18:2 between the T1-CE and T2-FLAIR MR image paths with alternative weighting shown in Table 1. Eighty-six (90%) patients were classified correctly and 10 (10%) were misclassified based on their pre-operative MRs with a model sensitivity of 0.85 and specificity of 0.93. Among the misclassified, 4 were grade I, and 6 were grade II. The model was robust to tumor locations and sizes. Conclusion A novel asymmetric CNN with two differently weighted encoding paths was developed for successful automated meningioma grade classification. Our model outperforms CNN using a single path for single or multimodal MR-based classification.

8090%. The identification of gene mutation profile of non-small cell cancer allows to make a molecular portrait, which plays the crucial role in choosing the targeted therapy with tyrosine kinase inhibitors. The aimis to study the frequency and spectrum of activating mutations in non-small cell lung cancer in Tambov region. The study of the presence of mutations and the main driver gene mutation profile: EGFR, ALK, BRAF, ROS1 and PDL-1 using sections of paraffin-embedded after the surgery and biopsy in 238 patients with the help of polymerase chain reaction and immunohistochemistry. The age of patients ranged from 28 years to 82 years, with a mean age of 60.3 years. Results.Adenocarcinoma was detected in 80.3% of patients, and squamous cell variant in 19.7% of cases. The frequency of the driver gene activating mutations in non-small cell lung cancer was 29%, this index exceeded the frequency in the European population. Statistically significant predominance of female (63.6%) vs male (36.4%) was achieved. The mutation frequency increases with age. In this case, EGFR mutations were observed more often 22.3%. This index was slightly higher than in the European population. Statistically significant predominance of female was achieved. The highest frequency of mutations was demonstrated in patients 6570 years of age (24%). The deletion of exon 19 and single-nucleotide replacement L858R of exon 21 were observed in 54.5% and 45.5% of cases, respectively. The mutation of exon 19 was more often detected in male, at the same time the mutations of exons 19 and 21 in female were detected in almost the same frequency. Maximum frequency mutation rate (77.7%) in the EGFR gene was detected free from metastases to the regional lymph nodes. ALK mutations were found in 14.6% of patients, this index was slightly higher than the European level. PDL-1 expression is found in 40% male patients. Conclusion.The results of the study revealed some features of the profile of activating mutations in non-small cell lung cancer in the region. This data should be taken into account on planning and applying targeted therapy.

Objective To determine the risk of acquiring perioperative COVID-19 infection in previously COVID-19 negative patients. Summary of background data During the initial peak of the COVID-19 pandemic, there was significant concern of hospital acquired COVID-19 infections. Medical centers rapidly implemented systems to minimize perioperative transmission, including routine preoperative testing, patient isolation, and enhanced cleaning. Methods In this retrospective cohort study, medical records of all adult patients who underwent surgery at our quaternary, acute care hospital between March 15 and May 15, 2020 were reviewed. The risk of preoperatively negative patients developing symptomatic COVID-19 within 2-14 days postoperatively was determined. Surgical characteristics, outcomes, and complications were compared between those with and without acquired perioperative COVID-19 infection. Results Among 501 negative patients undergoing index surgeries, 9 (1.8%) developed symptomatic COVID-19 in the postoperative period; all occurred before implementation of routine preoperative testing [9/243, 3.7% vs 0/258, 0%, odds ratio (OR): 0.048, P = 0.036]. No patient who was polymerase-chain-reaction negative on the day of surgery (n = 170) developed postoperative infection. Perioperative infection was associated with preoperative diabetes (OR: 3.70, P = 0.042), cardiovascular disease (OR: 3.69, P = 0.043), angiotensin receptor blocker use (OR: 6.58, P = 0.004), and transplant surgery (OR: 11.00, P = 0.002), and multiple complications, readmission (OR: 5.50, P = 0.029) and death (OR: 12.81, P = 0.001). Conclusions During the initial peak of the COVID-19 pandemic, there was minimal risk of acquiring symptomatic perioperative COVID-19 infection, especially after the implementation of routine preoperative testing. However, perioperative COVID-19 infection was associated with poor postoperative outcome.

Patients with a renal mass traditionally proceed directly to surgery without a preoperative tissue diagnosis confirming malignancy. Many surgically treated renal masses represent benign tumors or indolent malignancies on final pathology. This has led to a growing body of literature supporting an expanded role for percutaneous renal mass biopsy (RMB). This study aims to characterize national trends in RMB utilization.Patients undergoing renal biopsy during a 12-year period (2006-2017) in the Premier Hospital Database were captured using International Classification of Diseases, Ninth Revision and Tenth Revision codes. We restricted our analysis to patients with a concurrent diagnosis of a renal mass. We determined utilization rate, subsequent interventions within 90 days of biopsy, predictors of RMB, and 30-day RMB complication rates. We applied sampling weights and adjusted for hospital clustering to achieve a nationally representative analysis.Among 115,511 patients who met the inclusion criteria, the annual number of RMB rose from 7,196 in 2006 to 11,528 in 2017; during this period, more than 3 times as many patients proceeded directly to surgery without a prior RMB. After RMB, 85,848 (74.32%) patients were not treated within 90 days. Of those treated, thermal ablation was more common than surgery (17,269 vs. 12,394). Trend analysis showed that patients with metastatic disease represented a decreasing proportion of patients receiving RMB (27.0%-21.8%; P0.001). Compared to patients who proceeded directly to surgery, RMB was more commonly performed in patients in the highest age group (80 years and older, 15.9% vs. 9.2%), unmarried (50% vs. 45.9%), with more medical comorbidities (Charlson comorbidity index ≥4, 30.9% vs. 17.4%), or with metastatic disease (24.5% vs. 10.4%). Multivariable regression analysis determined the primary predictor of RMB was the presence of metastatic disease. Hematuria was the most common complication present in 5.18% of patients followed by pneumothorax in 1.75%. All other complications were rare (0.4%).Although there has been progressive adoption of RMB for the management of renal masses in the United States, utilization remains relatively limited and differentially employed across the population based on both clinical and nonclinical patient factors. More research is needed to understand which factors are considered when determining whether to utilize RMB in the evaluation of a renal mass.

In patients with residual or recurrent nonfunctioning pituitary adenomas (NFPAs) after transsphenoidal resection, both GammaKnife (GKRS) and CyberKnife (CKRS) stereotactic radiosurgery (SRS) are viable treatment options.We report a retrospective single center series comparing assessing the effectiveness and complications from of these 2 commonly used SRS techniques.A total of 53 patients with prior surgical resection and residual or recurrent NFPAs who underwent GKRS or CKRS and minimum 3-month follow-up between January 2002 and February 2017 at a single center were identified.A total of 34 patients underwent GKRS and 19 received CKRS. CKRS patients had a larger maximal tumor diameter (P = 0.005) and tumor volume treated (P = 0.001). Differences between GKRS and CKRS treatment parameters included target volume, target volume treated, prescribed dose, maximum dose, prescription isodose line, and conformity index (P0.05). The mean follow-up time was 53.74 months for GKRS and 41.48 months for CKRS patients. Tumor progression developed in 6% of cases after GKRS versus 5% after CKRS. The mean progression-free survival was 48.44 months after GKRS and 38.57 months after CKRS (P = 0.61). Five-year actuarial tumor control rates were 91% after GKRS versus 89% after CKRS (P0.99). There were no differences in worsened vision or rates of hypopituitarism.In patients undergoing single fraction GKRS versus fractionated CKRS for NFPAs, both modalities had similar rates of tumor control, new hypopituitarism, and visual morbidity despite varying indications. This study validates the versatile use of these 2 SRS modalities for patients meeting their relative criteria, especially based on proximity to the optic apparatus and normal pituitary gland.

BACKGROUND AND OBJECTIVE Non-selective beta-blockers impair the bronchodilator response to beta2 -agonists. Cardio-selective beta1 -blockers are less likely to cause this effect, yet they remain relatively contraindicated in asthma. We investigated whether the response to salbutamol is impaired during cardio-selective beta1 -blocker treatment in people with asthma. METHODS A random-order, double-blind, placebo-controlled, non-inferiority, crossover study was conducted comparing up to 5 mg bisoprolol daily for 2 weeks with matching placebo, with an open-label extension of up to 10 mg bisoprolol daily. After each treatment period, mannitol was inhaled to induce bronchoconstriction with a 15% fall in forced expiratory volume in 1 s (FEV1 ). Immediately after mannitol challenge, salbutamol (100, 100 and 200 μg) was administered via spacer at 5-min intervals with repeated FEV1 measures. The FEV1 recovery with salbutamol was measured as an area under recovery curve (AUC). Based on earlier research, a clinically relevant non-inferiority limit of a 30% reduction in the AUC was set. RESULTS A total of 19 adults with mild asthma and positive inhaled mannitol challenge completed the study. Adjusting for the FEV1 fall induced by mannitol and treatment sequence, the mean AUC response to salbutamol after bisoprolol was 5% lower than after placebo, with a one-sided 95% confidence interval (CI) of 26% lower. Thirteen participants completed the open-label extension up to 10 mg bisoprolol daily with mean AUC 11% higher after bisoprolol with a 95% CI of 5% lower. CONCLUSION The bronchodilator response to rescue salbutamol after mannitol-induced bronchoconstriction is non-inferior during regular treatment with the cardio-selective beta1 -blocker, bisoprolol, compared to placebo. CLINICAL TRIAL REGISTRATION ACTRN12618000306213 at https://www.anzctr.org.au.

To evaluate long-term chronic sialadenitis symptoms in patients without sialolithiasis following sialendoscopy-assisted salivary duct surgery (SASDS) compared to a control group managed conservatively.Prospective cohort study.Tertiary care center.Thirty-six patients (52 glands) with chronic sialadenitis without sialolithiasis completed the Chronic Obstructive Sialadenitis Symptoms (COSS) questionnaire at presentation and at 3-month time intervals thereafter for 1 year. Lower COSS scores represent lower symptom severity. We compared 27 patients who underwent SASDS to 9 control patients who elected conservative management.COSS gland-specific scores from 38 SASDS-treated glands (cases) and 14 control glands were similar at baseline. At 6 to 12 months (mean, 8.4 months), the surgically treated group had significantly lower scores and a greater score reduction from baseline compared to controls (mean score change [95% confidence interval] cases: 20.7 points [15.7-25.8]; controls: 11.7 points [4.9-18.4];Compared to patients electing for conservative management, patients with sialadenitis without sialolithasis treated with SASDS had improved symptom scores and a greater reduction of symptom severity after 6 months. With SASDS, patients had higher rates of significant overall symptom improvement. In evaluating chronic sialadenitis, assessment at multiple time points is necessary to capture the intermittent and cyclical pattern of obstructive symptoms.

Background Percutaneous ablation for cT1 renal cell carcinoma (RCC) remains underused, partially because of heterogeneous and limited long-term outcomes data assessing recent cryoablation methods. Purpose To report intermediate- to long-term outcomes of image-guided percutaneous cryoablation of cT1 RCC and to compare outcomes for CT versus MRI guidance. Materials and Methods This HIPAA-compliant retrospective single-institution study assessed patients who underwent percutaneous cryoablation for solitary pathology-proven cT1 RCC between August 2000 and July 2017. Tumors (cT1a, n = 282; cT1b, n = 25; size range, 0.6-6.5 cm; median size, 2.5 cm) underwent cryoablation with CT (n = 155) or MRI (n = 152) guidance. Primary end points of overall survival (OS), disease-specific survival (DSS), imaging-confirmed disease-free survival (DFS), and local progression-free survival (LPFS) were calculated by using Kaplan-Meier analysis. Secondary end points of technique efficacy and adverse event rate were also calculated. Primary and secondary end points for CT and MRI guidance were compared by using univariable regression analysis. Results A total of 307 patients (mean age, 68 years ± 11 [standard deviation]; 192 men) were evaluated. Median clinical follow-up lasted 95 months (range, 8-219 months), and median imaging follow-up lasted 41 months (range, 0-189 months). Survival metrics at 3, 5, 10, and 15 years, respectively, included OS of 91% (95% confidence interval [CI]: 88%, 94%), 86% (95% CI: 82%, 90%), 78% (95% CI: 73%, 84%), and 76% (95% CI: 69%, 83%); DSS of 99.6% (95% CI: 99%, 100%), 99% (95% CI: 98%, 100%), 99% (95% CI: 98%, 100%), and 99% (95% CI: 98%, 100%); DFS of 94% (95% CI: 92%, 97%), 91% (95% CI: 88%, 96%), 88% (95% CI: 83%, 93%), and 88% (95% CI: 83%, 93%); and LPFS of 97% (95% CI: 94%, 99%), 95% (95% CI: 93%, 98%), 95% (95% CI: 93%, 98%), and 95% (95% CI: 93%, 98%). Survival did not significantly differ between CT and MRI guidance, with univariable Cox regression analysis hazard ratios of 0.97 (95% CI: 0.57, 1.67; P = .92) for OS, 0.63 (95% CI: 0.26, 1.52; P = .30) for DFS, and 0.83 (95% CI: 0.26, 2.74; P = .77) for LPFS. Primary and secondary technique efficacy were 96% and 99%, respectively. Overall adverse event rate was 14% (43 of 307), including 11 grade 3 events and three grade 4 events according to the Common Terminology Criteria for Adverse Events. Conclusion Percutaneous CT- and MRI-guided cryoablation of cT1 renal cell carcinoma had similar excellent intermediate- and long-term outcomes. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Georgiades in this issue.

This review will cover clinical presentations for sialadenosis, radiation-related sialadenitis, and medication-induced salivary disorders. Presentation of metabolic disorder–related sialadenosis or gland enlargement is gradual and progressive without obstructive salivary symptoms. In contrast, radioactive iodine therapy can induce acute and chronic sialadenitis due to salivary gland dysfunction and duct damage with subsequent duct stenosis. Obstructive symptoms associated with fluctuating gland swelling and pain can be treated with sialendoscopy and dilation of the main salivary ducts. Further investigation of radioprotective agents to prevent salivary gland damage from radioactive iodine and external beam radiation to the head and neck is necessary. Iodine contrast–induced sialadenitis and medications that may affect salivary function are also described. Metabolic disorders, medications, radiation, and iodine contrast can cause salivary gland dysfunction. Management of salivary gland swelling and obstruction depends on the cause of chronic sialadenitis.

Objective Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. Identifying mutated causative genes can provide diagnostic and prognostic information. In this study, we describe the clinical application of a next generation sequencing (NGS)-based, targeted multi-gene panel test for the genetic diagnosis of patients with ADPKD. Methods We applied genetic analysis on 26 unrelated known or suspected patients with ADPKD. A total of 10 genes related to cystic change of kidney were targeted. Detected variants were classified according to standard guidelines. Results We identified 19 variants (detection rate: 73.1%), including PKD1 (n = 18) and PKD2 (n = 1). Of the 18 PKD1 variants, 8 were novel. Conclusion Multigene panel test can be a comprehensive tool in a clinical setting for genetic diagnosis of ADPKD. It allows us to identify clinically significant novel variants and confirm the diagnosis, and these objectives are difficult to achieve using conventional diagnostic tools.

Sialadenitis due to salivary obstruction is associated with characteristic intermittent pain and swelling of the affected gland. Common etiologies of adult salivary obstruction include salivary duct stones or duct stenosis. However, various pathologic processes can mimic obstructive salivary gland symptoms. This is a case-based review of pathologies that may present similar to the signs and symptoms of salivary obstruction with gland inflammation. Multiple cases with pathologies mimicking inflammatory salivary gland disease have been reported and described. This review uses a case-based approach to highlight the clinical presentation, exam, and imaging findings of disorders that imitate sialadenitis in order to describe approaches for achieving accurate diagnoses. Cases involving nonobstructive salivary pathology are presented to demonstrate a broad differential diagnosis for facial and salivary gland swelling.

Intra-articular distal humerus fractures with an associated coronal shear capitellar fragment present a challenge for stable internal fixation. Adequate visualization and fixation of the capitellar shear fragment are difficult to achieve with conventional exposures, including the olecranon osteotomy. The capitellar fragment often translates anterior and proximally and is challenging to visualize with intact soft tissue attachments from a posterior approach. We describe a surgical exposure that releases the lateral ulnar collateral ligament in addition to an olecranon osteotomy to allow complete visualization of the entire articular surface. In contrast to an isolated capitellar fracture, the column stability and the posterior cortex are frequently disrupted with distal humerus fractures. Depending on the comminution of the posterior cortex, a supplemental posterolateral plate or headless compression screws can provide fixation to the coronal fracture plane. The lateral ulnar collateral ligament is repaired at the conclusion of fracture stabilization through a bone tunnel or to the plate to restore lateral stability. Despite the release of the ligament and additional soft tissue stripping, there were no cases of elbow instability or avascular necrosis in our case series of 9 patients.

Objective To evaluate the impact of alvimopan in patient undergoing radical cystectomy (RC) for bladder cancer. We hypothesize that alvimopan can decrease cost for RC by reducing length of stay (LOS). Methods We identified patients who underwent elective RC for bladder cancer from 2009 to 2015 in the Premier Healthcare Database, a nationwide, all-payer hospital-based database, and compared patients who received and did not receive alvimopan in the perioperative period. Hospitals that had no record of administering alvimopan for patients undergoing RC were excluded. The primary outcomes were LOS and the direct hospital costs. The secondary outcomes were 90-day readmission for ileus and major complications. Results After applying the inclusion criteria, the study cohort consisted of 1087 patients with 511 patients receiving perioperative alvimopan. Alvimopan was associated with a reduction in hospital costs by −$2709 (95% confidence interval: −$4507 to −$912, P = .003), decreased median LOS (7 vs 8 days, P Conclusion Our data show that alvimopan is associated with a substantial cost-saving in patients undergoing RC, and suggest that routine use of alvimopan may be a potential cost-effective strategy to reduce the overall financial burden of bladder cancer.

Background & Aims Tenofovir disoproxil fumarate (TDF) is the preferred treatment to prevent maternal transmission of HBV, owing to its efficacy and safety. However, data are lacking on the long-term safety outcomes in children following fetal exposure to TDF. Methods Children participating in a prospective, multisite trial of maternal TDF treatment during late pregnancy were recruited for follow-up visits once a year. Growth parameters, serum biochemistry, HBV serology, and bone mineral density (BMD) by dual-energy x-ray absorptiometery scan were measured. Results One hundred and twenty-eight children, 71 in the TDF and 57 in the control group, completed 255 follow-up visits at the age of 2 to 7 (median, 4.08) years. No differences in z-scores for weight-for-age (0.26 ± 0.90 vs. 0.22 ± 0.99, p = 0.481), z-scores for height-for-age (0.20 ± 1.02 vs. 0.25 ± 0.98, p = 0.812), and estimated glomerular filtration rate (169.12 ± 50.48 vs. 169.06 ± 34.46 ml/min/1.73m2, p = 0.479) were detected. After adjustment for age, sex and HBV status by multiple linear regression, children in the TDF and control group had comparable levels of serum calcium, phosphorus, bone-specific alkaline phosphatase, calcidiol and BMD of lumbar spines (0.55 ± 0.01 vs. 0.57 ± 0.01 g/cm2, p = 0.159) and left hip (0.56 ± 0.01 vs. 0.56 ± 0.01 g/cm2, p = 0.926). Conclusions Children of HBV-infected mothers who did or did not receive tenofovir disoproxil fumarate treatment during late pregnancy had comparable long-term growth, renal function, and bone development up to 6–7 years after delivery. Clinical trial number NCT01312012 ( ClinicalTrials.gov ) Lay summary Currently there are insufficient long-term safety data in children born to mothers who took antiviral agents during pregnancy to prevent mother-to-infant transmission of hepatitis B virus (HBV). In this study, we found that children of HBV-infected mothers who did or did not receive tenofovir disoproxil fumarate treatment during late pregnancy had comparable long-term growth, renal function, and bone development up to 6-7 years after delivery.

Results of comparative ELISA investigation of pretreatment sPD-1 and sPD-L1 content in blood plasma of 100 gastric cancer patients at various disease stages aged 25 to 81 years are presented. Control group included 60 practically healthy donors aged 18 - 68 years. Plasma sPD-L1 concentrations did not differ between gastric cancer patients and control group, and sPD-1 levels were statistically significantly lower in patients than in healthy donors (p

Brain metastases are a very common manifestation of cancer that have historically been approached as a single disease entity given the uniform association with poor clinical outcomes. Fortunately, our understanding of the biology and molecular underpinnings of brain metastases has greatly improved, resulting in more sophisticated prognostic models and multiple patient-related and disease-specific treatment paradigms. In addition, the therapeutic armamentarium has expanded from whole-brain radiotherapy and surgery to include stereotactic radiosurgery, targeted therapies and immunotherapies, which are often used sequentially or in combination. Advances in neuroimaging have provided additional opportunities to accurately screen for intracranial disease at initial cancer diagnosis, target intracranial lesions with precision during treatment and help differentiate the effects of treatment from disease progression by incorporating functional imaging. Given the numerous available treatment options for patients with brain metastases, a multidisciplinary approach is strongly recommended to personalize the treatment of each patient in an effort to improve the therapeutic ratio. Given the ongoing controversies regarding the optimal sequencing of the available and expanding treatment options for patients with brain metastases, enrolment in clinical trials is essential to advance our understanding of this complex and common disease. In this Review, we describe the key features of diagnosis, risk stratification and modern paradigms in the treatment and management of patients with brain metastases and provide speculation on future research directions.

Introduction Chordomas are locally destructive neoplasms characterized by appreciable recurrence rates after initial multimodality treatment. We examined the outcome of salvage treatment in recurrent/progressive skull base chordomas. Methods This is a retrospective review of recurrent/progressive skull base chordomas at a tertiary urban academic medical center. The outcomes evaluated were overall survival, progression-free survival (PFS), and incidence of new toxicity. Results Eighteen consecutive patients who underwent ≥1 course of treatment (35.3% salvage surgery, 23.5% salvage radiation, and 41.2% both) were included. The median follow-up was 98.6 months (range 16–215 months). After initial treatment, the median PFS was 17.7 months (95% confidence interval [CI]: 4.9–22.6 months). Following initial therapy, age ≥ 40 had improved PFS on univariate analysis (p = 0.03). All patients had local recurrence, with 15 undergoing salvage surgical resections and 16 undergoing salvage radiation treatments (mostly stereotactic radiosurgery [SRS]). The median PFS was 59.2 months (95% CI: 4.0–99.3 months) after salvage surgery, 58.4 months (95% CI: 25.9–195 months) after salvage radiation, and 58.4 months (95% CI: 25.9.0–98.4 months) combined. Overall survival for the total cohort was 98.7% ± 1.7% at 2 years and 92.8% ± 5.5% at 5 years. Salvage treatments were well-tolerated with two patients (11%) reporting tinnitus and one patient each (6%) reporting headaches, visual field deficits, hearing loss, anosmia, dysphagia, or memory loss. Conclusion Refractory skull base chordomas present a challenging treatment dilemma. Repeat surgical resection or SRS seems to provide adequate salvage therapy that is well-tolerated when treated at a tertiary center offering multimodality care.

Background Novel venous thromboembolism (VTE) prophylaxis programs, including postdischarge pharmacologic prophylaxis, have been associated with decreased VTE rates. Such practices have not been widely adopted in managing radical cystectomy (RC) patients. Objective To evaluate the effect of a perioperative VTE prophylaxis program on VTE rates after RC. Design, setting, and participants Single-institution, nonrandomized, pre- and post-intervention analysis of 319 patients undergoing RC at Brigham and Women’s Hospital between July 2011 and April 2017. Patient and outcome data were prospectively collected as part of the American College of Surgeons National Surgical Quality Improvement Program. Intervention Before June 2015, patients only received postoperative pharmacologic and mechanical VTE prophylaxis in the inpatient setting. Starting June 2015, a perioperative VTE prophylaxis program was implemented as part of an enhanced recovery after surgery (ERAS) protocol, including a 28-d course of postdischarge enoxaparin. Outcome measurements and statistical analysis Primary outcome was 30-d postoperative VTE rate. Secondary outcomes were perioperative bleeding rates, 30-d complication, readmission, and mortality rates, and length of stay. Univariate analysis was performed comparing outcomes between pre- and post-intervention cohorts. Results and limitations Of the 319 patients who underwent RC, 210 (66%) were in the pre- and 109 (34%) in the post-intervention cohort. VTE rate was significantly lower in the post-intervention cohort (n = 1, 0.9% vs n = 13, 6.2%; p = 0.04). Rates of perioperative bleeding (35% vs 33%; p = 0.80) and 30-d readmissions related to bleeding (1% vs 3.7%; p = 0.19) did not differ significantly. Single-institution data limits generalizability, and patient compliance with postdischarge enoxaparin was unknown. Conclusions Implementation of a perioperative VTE prophylaxis program as part of an ERAS protocol that includes extended postdischarge pharmacologic prophylaxis was associated with decreased rate of VTE events after RC. Perioperative bleeding and readmissions related to bleeding did not increase with this intervention. Patient summary This study evaluated whether clotting complication rates after radical cystectomy (RC) for bladder cancer can be reduced by implementing a new postoperative care pathway. This pathway reduced rates of clotting complications without increasing bleeding rates and should be considered for all patients undergoing RC.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the progressive loss of cognitive functions in affected individuals. Brain tissue pathology is associated with the formation of senile plaques which result from the over-production of amyloid β (Aβ), due to the cleavage of a membrane bound glycoprotein. It is unclear what causes AD and its associated pathologies, but age and genetic predisposition play an import role in the likelihood of disease development. Studies have shown that the reactivation of latent herpes simplex virus 1 (HSV-1) infection can lead to the neuropathy of acute herpes simplex encephalitis (HSE), which causes similar symptoms to AD. HSV-1 infection is a known risk factor for the development of AD, but no study has determined a definitive causal relationship. Using the Qiagen Ingenuity Pathway Analysis (IPA) tool, the inhibitory relationship between therapeutics for AD and HSV-1 were explored. Thirteen drugs developed to decrease Aβ buildup in AD and 32 drugs that act as HSV antivirals were retrieved from the data in the Qiagen Knowledge Base. These drugs were analyzed displayed as two separate networks. While many promising Aβ aggregation-targeting drugs have been discontinued due to lack of efficacy, HSV drugs could serve as potential therapeutics for those with AD. This review aims to describe new insights on how HSV-1 relates to the development of AD and highlight the mechanism of action of Aβ-related drugs and HSV drugs in the context of AD. With HSV-1 being a likely candidate for the causation of AD, there is a need to study the effects of HSV antiviral drugs on those who have AD.

To determine the overall survival (OS) in patients who underwent planned trimodality therapy (TMT) and those who underwent definitive concurrent chemoradiation (CRT), but later received salvage resection (SR) for stage IIIA (cN2) (AJCC 7th ed.) non–small cell lung cancer. National Cancer Database data set from 2004 to 2014 was queried. TMT was defined as multiagent CRT with dose >45 Gy, followed by lobectomy or pneumonectomy ≤90 days from end of CRT. SR was defined as multiagent CRT with dose >59 Gy and lobectomy or pneumonectomy performed >90 days from CRT completion. Propensity score weighting and propensity score matching methods were used to balance patient and tumor characteristics and to calculate hazard ratios. A total of 2025 (1899 TMT and 126 SR) patients were analyzed. TMT and SR groups shared similar characteristics. Surgery occurred at a median of 41 days (range 1–90) after CRT in the TMT group and 114 days (91–440) in the SR group. The 90-day mortality after surgery was 6.5% for TMT and 5% for SR (P = 0.43). The 3- and 5-year OS were 55.1% and 35.7% for TMT and 51.6% and 45.0% for SR (P = 0.92, 0.68), with no difference across unadjusted cohort and propensity-adjusted cohort. Patients with cN2 stage IIIA non–small cell lung cancer treated in the United States with definitive CRT followed by SR had similar OS as upfront TMT with similar postoperative mortality despite SR occurring >90 days after >59 Gy CRT. SR remains an option for medically appropriate patients after definitive dose CRT.

Background Upfront cytoreductive nephrectomy (CRN) in renal cell carcinoma (RCC) has come into question in recent prospective clinical trials. Objective We investigated the effect of systemic therapies on primary tumor response in patients with metastatic RCC. Design, setting, and participants A pooled analysis of 12 phase II/III clinical trials of metastatic RCC patients treated with systemic therapy between 2003 and 2013 was performed. Patients with one target lesion in the kidney and no prior nephrectomy were identified as having their primary tumor in place. Outcome measurements and statistical analysis The objective response rate (ORR) of the primary tumor was defined as per the Response Evaluation Criteria in Solid Tumors (RECIST). ORR was assessed in the overall population and patient subsets based on prior treatment and International Metastatic RCC Database Consortium (IMDC) risk group. Cox’s models adjusting for baseline characteristics, treatment, line of therapy, and site of metastases were used for survival analyses. Results and limitations In total, 4736 patients were identified, of whom 565 had their primary tumor in place: 461 (82%) were treatment naive, 283 (50%) received first-line vascular endothelial growth factor (VEGF)-targeted therapy, and 222 (39%) were IMDC poor risk. The ORRs of the primary tumor were 19% (95% confidence interval 16–23) in patients treated with first-line therapy (any type), 28% (22–33) in those treated with first-line VEGF-targeted therapy, and 23% (19–28) in those treated with VEGF-targeted therapy (any line). The ORRs were 9% (5–13) and 20% (15–27) in IMDC poor- and intermediate-risk patients, respectively. Conclusions Systemic therapy reduces primary tumor size in patients with metastatic RCC. Responses in primary tumors treated with VEGF-targeted therapy were observed in upward of 28% of patients. Selection of patients for immediate CRN requires careful consideration of patient and disease characteristics. Patient summary Antiangiogenic therapy meaningfully decreases the size of primary kidney tumor. Hence, for patients with metastatic disease who are not undergoing upfront cytoreductive nephrectomy, systemic therapy can palliate both primary tumor and metastases.