Soluble adenylyl cyclase contributes to imiquimod-mediated inflammation and is a potential therapeutic target in psoriasis.

Cyclic AMP (cAMP) has a key role in psoriasis pathogenesis, as indicated by the therapeutic efficacy of phosphodiesterase inhibitors that prevent the degradation of cAMP. However, whether soluble adenylate cyclase (sAC) (encoded by the ADCY10 gene), which is an important source for cAMP, is involved in Th17 cell-mediated inflammation or could be an alternative therapeutic target in psoriasis is unknown. We have utilized the imiquimod model of murine psoriasiform dermatitis to address this question. Adcy10-/- mice had reduced erythema, scaling and swelling in the skin and reduced CD4+ IL17+ cell numbers in the draining lymph nodes, compared with wild-type mice after induction of psoriasiform dermatitis with imiquimod. Keratinocyte-specific knock out of Adcy10 had no effect on imiquimod-induced ear swelling suggesting keratinocyte sAC has no role in imiquimod-induced inflammation. During Th17 polarization in vitro, naive T cells from Adcy10-/- mice exhibited reduced IL17 secretion and IL-17+ T-cell proliferation suggesting that differentiation into Th17 cells is suppressed without sAC activity. Interestingly, loss of sAC did not impact the expression of Th17 lineage-defining transcription factors (such as Rorc and cMaf) but rather was required for CREB-dependent gene expression, which is known to support Th17 cell gene expression. Finally, topical application of small molecule sAC inhibitors (sACi) reduced imiquimod-induced psoriasiform dermatitis and Il17 gene expression in the skin. Collectively, these findings demonstrate that sAC is important for psoriasiform dermatitis in mouse skin. sACi may provide an alternative class of topical therapeutics for Th17-mediated skin diseases.

Brown adipose tissue is not associated with cachexia or increased mortality in a retrospective study of patients with cancer.

Although brown fat is strongly associated with a constellation of cardiometabolic benefits in animal models and humans, it has also been tied to cancer cachexia. In humans, cancer-associated cachexia increases mortality, raising the possibility that brown fat in this context may be associated with increased cancer death. However, the effect of brown fat on cancer-associated cachexia and survival in humans remains unclear. Here, we retrospectively identify patients with and without brown fat on fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET) scans obtained as part of routine cancer care and assemble a cohort to address these questions. We did not find an association between brown fat status and cachexia. Furthermore, we did not observe an association between brown fat and increased mortality in patients with cachexia. Our analyses controlled for confounding factors including age at cancer diagnosis, sex, body mass index, cancer site, cancer stage, outdoor temperature, comorbid conditions (heart failure, type 2 diabetes mellitus, coronary artery disease, hypertension, dyslipidemia, cerebrovascular disease), and ß-blocker use. Taken together, our results suggest that brown fat is not linked to cancer-associated cachexia and does not worsen overall survival in patients with cachexia.NEW & NOTEWORTHY This study finds that brown fat is not linked to cancer-associated cachexia. Moreover, this work shows that brown fat does not worsen overall survival in patients with cachexia.

Cardiovascular disease and chimeric antigen receptor cellular therapy.

Chimeric antigen receptor T-cell (CAR T) therapy is a revolutionary personalized therapy that has significantly impacted the treatment of patients with hematologic malignancies refractory to other therapies. Cytokine release syndrome (CRS) is a major side effect of CAR T therapy that can occur in 70-90% of patients, with roughly 40% of patients at grade 2 or higher. CRS can cause an intense inflammatory state leading to cardiovascular complications, including troponin elevation, arrhythmias, hemodynamic instability, and depressed left ventricular systolic function. There are currently no standardized guidelines for the management of cardiovascular complications due to CAR T therapy, but systematic practice patterns are emerging. In this review, we contextualize the history and indications of CAR T cell therapy, side effects related to this treatment, strategies to optimize the cardiovascular health prior to CAR T and the management of cardiovascular complications related to CRS. We analyze the existing data and discuss potential future approaches.

Interpreting Absolute and Relative Risk Reduction in the Context of Recent Cardiovascular Outcome Trials in Patients with Type 2 Diabetes.

PURPOSE OF REVIEW: The cardiovascular benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) have increased the focus of type 2 diabetes mellitus (T2DM) care on comprehensive cardiovascular risk reduction. Herein, we review the results of the cardiovascular outcomes trials of SGLT2i and GLP-1 RA, discuss the concepts of relative vs. absolute risk reduction in the context of these trials, and highlight the importance of individualized risk assessment when applying trial results to clinical practice. RECENT FINDINGS: To enable personalized treatment approaches, multiple clinical risk scores have been developed to assess risk of atherosclerotic cardiovascular disease (ASCVD) outcomes and hospitalization for heart failure (HHF) in patients with T2DM. In addition, circulating biomarkers of myocardial injury (cardiac troponin) and hemodynamic stress (natriuretic peptides) have been shown to further refine risk prediction of these clinically important cardiovascular complications. When making decisions about whether to initiate SGLT2i and GLP-1 RA, clinicians should consider the anticipated relative and absolute treatment benefits from these antihyperglycemic therapies. Clinicians can use available clinical and biomarker-based risk tools when counseling patients about their individual cardiovascular risk profiles and when estimating absolute treatment benefits from SGLT2i and GLP-1 RA.

Brown adipose tissue is associated with healthier body fat distribution and metabolic benefits independent of regional adiposity.

The association of brown adipose tissue (BAT) and body fat distribution and their combined effects on metabolic health in humans remains unknown. Here, we retrospectively identify individuals with and without BAT on 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and assemble a propensity score-matched study cohort to compare body fat distribution and determine its role in mediating the benefits of brown fat. We find that BAT is associated with lower amounts of visceral adipose tissue and higher amounts of subcutaneous adipose tissue, resulting in less central obesity. In addition, BAT is independently associated with lower blood glucose and white blood cell count, improved lipids, lower prevalence of type 2 diabetes mellitus, and decreased liver fat accumulation. These observations are most prominent in individuals with central obesity. Our results support a role of BAT in protection from visceral adiposity and improved metabolic health.

Oligometastases After Curative Esophagectomy Are Not One Size Fits All.

BACKGROUND: More than one-half of patients treated with esophagectomy for esophageal cancer experience recurrence. Oligometastasis, a proposed intermediate state of isolated local or solid organ recurrence that occurs before widespread systemic disease, is a potential target for aggressive local intervention. This study investigated presentation and prognosis among solid organ recurrence sites. METHODS: Patients with isolated solid organ recurrence at the liver, lung, or brain who underwent R0 esophagectomy from 1995 to 2016 were identified. Clinicopathologic characteristics and outcomes were compared among sites of recurrence. Overall survival was quantified using the Kaplan-Meier approach and Cox proportional hazards models. RESULTS: In total, 104 patients were included (site: brain, 37; lung, 27; liver, 40). Eighty percent of liver, 51% of brain, and 44% of lung oligometastases occurred in the first 12 months after esophagectomy. Despite the limited use of aggressive therapy, patients with lung oligometastasis had significantly longer median overall survival (2.41 years; 95% confidence interval [CI], 1.58 to 3.31) than did patients with brain (0.95 years; 95% CI, 0.62 to 1.49) or liver (0.95 years; 95% CI, 0.82 to 1.41) oligometastasis (P < .001). This difference remained after patient and tumor characteristics were adjusted for (brain: hazard ratio, 4.48; 95% CI, 2.24 to 8.99; liver: hazard ratio, 2.94; 95% CI, 1.48 to 5.82). CONCLUSIONS: Presentations and prognoses differ by site of esophageal cancer recurrence. Lung oligometastases are associated with a more indolent course, and patients with these lesions may benefit from more aggressive treatment to improve their more favorable outcomes further. These differences by site of recurrence advocate for moving beyond a standardized palliative approach to all esophageal cancer recurrences.

A Deep Learning Approach to Diagnostic Classification of Prostate Cancer Using Pathology-Radiology Fusion.

BACKGROUND: A definitive diagnosis of prostate cancer requires a biopsy to obtain tissue for pathologic analysis, but this is an invasive procedure and is associated with complications. PURPOSE: To develop an artificial intelligence (AI)-based model (named AI-biopsy) for the early diagnosis of prostate cancer using magnetic resonance (MR) images labeled with histopathology information. STUDY TYPE: Retrospective. POPULATION: Magnetic resonance imaging (MRI) data sets from 400 patients with suspected prostate cancer and with histological data (228 acquired in-house and 172 from external publicly available databases). FIELD STRENGTH/SEQUENCE: 1.5 to 3.0 Tesla, T2-weighted image pulse sequences. ASSESSMENT: MR images reviewed and selected by two radiologists (with 6 and 17 years of experience). The patient images were labeled with prostate biopsy including Gleason Score (6 to 10) or Grade Group (1 to 5) and reviewed by one pathologist (with 15 years of experience). Deep learning models were developed to distinguish 1) benign from cancerous tumor and 2) high-risk tumor from low-risk tumor. STATISTICAL TESTS: To evaluate our models, we calculated negative predictive value, positive predictive value, specificity, sensitivity, and accuracy. We also calculated areas under the receiver operating characteristic (ROC) curves (AUCs) and Cohen's kappa. RESULTS: Our computational method (https://github.com/ih-lab/AI-biopsy) achieved AUCs of 0.89 (95% confidence interval [CI]: [0.86-0.92]) and 0.78 (95% CI: [0.74-0.82]) to classify cancer vs. benign and high- vs. low-risk of prostate disease, respectively. DATA CONCLUSION: AI-biopsy provided a data-driven and reproducible way to assess cancer risk from MR images and a personalized strategy to potentially reduce the number of unnecessary biopsies. AI-biopsy highlighted the regions of MR images that contained the predictive features the algorithm used for diagnosis using the class activation map method. It is a fully automatic method with a drag-and-drop web interface (https://ai-biopsy.eipm-research.org) that allows radiologists to review AI-assessed MR images in real time. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Brown adipose tissue is associated with cardiometabolic health.

White fat stores excess energy, whereas brown and beige fat are thermogenic and dissipate energy as heat. Thermogenic adipose tissues markedly improve glucose and lipid homeostasis in mouse models, although the extent to which brown adipose tissue (BAT) influences metabolic and cardiovascular disease in humans is unclear1,2. Here we retrospectively categorized 134,529 18F-fluorodeoxyglucose positron emission tomography-computed tomography scans from 52,487 patients, by presence or absence of BAT, and used propensity score matching to assemble a study cohort. Scans in the study population were initially conducted for indications related to cancer diagnosis, treatment or surveillance, without previous stimulation. We report that individuals with BAT had lower prevalences of cardiometabolic diseases, and the presence of BAT was independently correlated with lower odds of type 2 diabetes, dyslipidemia, coronary artery disease, cerebrovascular disease, congestive heart failure and hypertension. These findings were supported by improved blood glucose, triglyceride and high-density lipoprotein values. The beneficial effects of BAT were more pronounced in individuals with overweight or obesity, indicating that BAT might play a role in mitigating the deleterious effects of obesity. Taken together, our findings highlight a potential role for BAT in promoting cardiometabolic health.

Cosmc controls B cell homing.

The molecular mechanisms regulating lymphocyte homing into lymph nodes are only partly understood. Here, we report that B cell-specific deletion of the X-linked gene, Cosmc, and the consequent decrease of protein O-glycosylation, induces developmental blocks of mouse B cells. After transfer into wild-type recipient, Cosmc-null B cells fail to home to lymph nodes as well as non-lymphoid organs. Enzymatic desialylation of wild-type B cells blocks their migration into lymph nodes, indicating a requirement of sialylated O-glycans for proper trafficking. Mechanistically, Cosmc-deficient B cells have normal rolling and firm arrest on high endothelium venules (HEV), thereby attributing their inefficient trafficking to alterations in the subsequent transendothelial migration step. Finally, Cosmc-null B cells have defective chemokine signaling responses. Our results thus demonstrate that Cosmc and its effects on O-glycosylation are important for controlling B cell homing.

Medical Students' Perceived Interests and Concerns for a Career in Neurosurgery.

OBJECTIVE: The factors that attract and concern medical students about a career in neurosurgery have never been clearly characterized or delineated in a large nationwide cohort of medical students intending to pursue a career in neurosurgery. The objective of the present study was to characterize the factors that influence medical student interest in neurosurgery and assess the effects of a formal neurosurgery training course on participants' perceptions of a career in neurosurgery. METHODS: Before the Medical Student Neurosurgery Training Camp for subinternship preparation, registered students were surveyed about their interest level in neurosurgery, factors that attracted or concerned them about a career in neurosurgery, attendance at a national neurosurgery conference or course, formal clinical neurosurgery exposure in medical school, and whether they had a resident or attending mentor in neurosurgery. At the end of the course, all the participants completed the surveyed again. P < 0.05 was considered significant on Pearson's χ2 and Fisher's exact tests for categorical variables and 2-tailed paired Student's t tests for continuous variables. RESULTS: Of the training camp attendees, >95% completed both pre- and postcourse surveys, including 41 first-year, 19 second-year, 30 third-year, and 5 fourth-year medical school students. The most common factors that concerned students about a career in neurosurgery were work-life balance (76%) and competitiveness (56%). All factors of concern were decreased in the postcourse survey, except for competitiveness. A small cohort (8.4%) of students had no concerns about a career in neurosurgery; this cohort had doubled to 17% after the course (P < 0.05). The students that indicated no concern had a greater postcourse interest level in neurosurgery (95.8 ± 8.7 vs. 86.7 ± 20.5; P < 0.05). Student reasons for an interest in neurosurgery included intellectually stimulating work (94%), interest in neurosciences (93%), effect on patients (84%), innovation and new technology (80%), research opportunities (77%), and prestige (24%). All reasons increased after the course, with the exception of prestige, which decreased to 22%. CONCLUSION: A training camp for students pursuing a neurosurgery subinternship was effective in providing transparency and positively influencing the factors that attract and concern students about a career in neurosurgery. Characterization of medical student perceptions of neurosurgery from a large, nationwide cohort of students pursuing a subinternship has provided novel data and could help identify factors protecting against burnout later in life.

How long is the tail end of the learning curve? Results from 1000 consecutive endoscopic endonasal skull base cases following the initial 200 cases.

OBJECTIVE: Endoscopic endonasal approaches (EEAs) to the skull base have evolved over the last 20 years to become an essential component of a comprehensive skull base practice. Many case series show a learning curve from the earliest cases, in which the authors were inexperienced or were not using advanced closure techniques. It is generally accepted that once this learning curve is achieved, a plateau is reached with little incremental improvement. Cases performed during the early steep learning curve were eliminated to examine whether the continued improvement exists over the "tail end" of the curve. METHODS: A prospectively acquired database of all EEA cases performed by the senior authors at Weill Cornell Medicine/NewYork-Presbyterian Hospital was reviewed. The first 200 cases were eliminated and the next 1000 consecutive cases were examined to avoid the bias created by the early learning curve. RESULTS: Of the 1000 cases, the most common pathologies included pituitary adenoma (51%), meningoencephalocele or CSF leak repair (8.6%), meningioma (8.4%), craniopharyngioma (7.3%), basilar invagination (3.1%), Rathke's cleft cyst (2.8%), and chordoma (2.4%). Use of lumbar drains decreased from the first half to the second half of our series (p <0.05) as did the authors' use of fat alone (p <0.005) or gasket alone (p <0.005) for dural closure, while the use of a nasoseptal flap increased (p <0.005). Although mean tumor diameter was constant (on average), gross-total resection (GTR) increased from 60% in the first half to 73% in the second half (p <0.005). GTR increased for all pathologies but most significantly for chordoma (56% vs 100%, p <0.05), craniopharyngioma (47% vs 0.71%, p <0.05) and pituitary adenoma (67% vs 75%, p <0.05). Hormonal cure for secreting adenomas also increased from 83% in the first half to 89% in the second half (p <0.05). The rate of any complication was unchanged at 6.4% in the first half and 6.2% in the latter half of cases, and vascular injury occurred in only 0.6% of cases. Postoperative CSF leak occurred in 2% of cases and was unchanged between the first and second half of the series. CONCLUSIONS: This study demonstrates that contrary to popular belief, the surgical learning curve does not plateau but can continue for several years depending on the complexity of the endpoints considered. These findings may have implications for clinical trial design, surgical education, and patient safety measures.

Unique Considerations for Females Undergoing Esophagectomy.

OBJECTIVE: To improve understanding of sex differences in clinicopathologic characteristics, treatment and outcomes between male and female patients undergoing esophagectomy for esophageal cancer. SUMMARY BACKGROUND DATA: Esophageal cancer is a male predominant disease, and sex has not been considered in previous studies as an important factor in diagnosis or management. Sex differences in demographics, clinicopathologic characteristics, and postoperative outcomes remain largely undefined. METHODS: Retrospective review of 1958 patients (21% female) with esophageal cancer who underwent esophagectomy at a single institution between 1995 and 2017. RESULTS: Most patients had adenocarcinoma (83%); however, the rate of squamous cell carcinoma was significantly higher in females (35% vs 11%, respectively; P < .0001). Females had a lower rate of smoking (62 vs 73%) and heavy alcohol use (12 vs 19%) but a higher rate of previous mediastinal radiation (8.4 vs 1.8%) (P < 0.001). Postoperative mortality and overall survival (OS) were similar between sexes. However, subanalysis of patients with locoregional disease (clinical stage II/III) demonstrated that females received neoadjuvant therapy less frequently than males and had worse OS (median OS 2.56 yrs vs 2.08; P = 0.034). This difference remained significant on adjusted analysis (HR 1.24, 95% CI 1.06-1.46). CONCLUSIONS: Female patients had higher incidence of squamous cell carcinoma despite lower prevalence of behavioral risk factors. Among patients with locoregional disease, undertreatment in females may reflect treatment bias and history of previous mediastinal radiation. Esophageal cancer in females should be considered a unique entity as compared with the presentation and treatment of males.

Incidence and Risk Factors for Isolated Esophageal Cancer Recurrence to the Brain.

BACKGROUND: Recurrence of esophageal cancer in the brain is rare but associated with a poor prognosis. Identification of risk factors for isolated brain metastasis of esophageal cancer (iBMEC) after surgical treatment may guide surveillance recommendations to enable early identification and intervention before widespread metastasis. METHODS: Patients with iBMEC (n = 38) were identified from a prospective database of patients with esophageal cancer who underwent esophagectomy. Risk factors for iBMEC were identified using competing risk regression analysis. RESULTS: In a cohort of 1760 patients, 39% recurred and iBMEC developed in 2% by the end of the study. Survival in patients with iBMEC was similar to survival in patients with distant recurrence (median overall survival, 0.95 years; 95% confidence interval, 0.6-1.5 years). More than half of patients with iBMEC were diagnosed within 1 year postoperatively. All 38 patients with iBMEC had received neoadjuvant therapy before surgery. Pathologic complete response (PCR) to neoadjuvant therapy was associated with improved survival after brain recurrence (median overall survival, 1.56 vs 0.66 years; P = .019). CONCLUSIONS: In patients with PCR, iBMEC may represent true isolated recurrence, whereas in those with residual nodal disease, iBMEC may actually be the first observed site of widespread metastasis. Patients who receive neoadjuvant therapy, especially with PCR, may benefit from brain imaging, both preoperatively and with routine surveillance.

Compartmentalized gut lymph node drainage dictates adaptive immune responses.

The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure of this balance leads to conditions such as inflammatory bowel diseases, food allergies and invasive gastrointestinal infections1. Multiple immune mechanisms are therefore in place to maintain tissue integrity, including balanced generation of effector T (TH) cells and FOXP3+ regulatory T (pTreg) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively1-4. The gut-draining lymph nodes (gLNs) are key sites for orchestrating adaptive immunity to luminal perturbations5-7. However, it is unclear how they simultaneously support tolerogenic and inflammatory reactions. Here we show that gLNs are immunologically specific to the functional gut segment that they drain. Stromal and dendritic cell gene signatures and polarization of T cells against the same luminal antigen differ between gLNs, with the proximal small intestine-draining gLNs preferentially giving rise to tolerogenic responses and the distal gLNs to pro-inflammatory T cell responses. This segregation permitted the targeting of distal gLNs for vaccination and the maintenance of duodenal pTreg cell induction during colonic infection. Conversely, the compartmentalized dichotomy was perturbed by surgical removal of select distal gLNs and duodenal infection, with effects on both lymphoid organ and tissue immune responses. Our findings reveal that the conflict between tolerogenic and inflammatory intestinal responses is in part resolved by discrete gLN drainage, and encourage antigen targeting to specific gut segments for therapeutic immune modulation.

Neurosurgery Training Camp for Sub-Internship Preparation: Lessons From the Inaugural Course.

OBJECTIVE: Historically, medical student education in neurological surgery has generally limited student involvement to assisting in research projects with minimal formal clinical exposure before starting sub-internships and application for the neurosurgery match. Consequently, students have generally had little opportunity to acquire exposure to clinical neurosurgery and attain minimal proficiency. A medical student training camp was created to improve the preparation of medical students for the involvement in neurological surgery activities and sub-internships. METHODS: A 1-day course was held at Weill Cornell Medicine, which consisted of a series of morning lectures, an interactive resident lunch panel, and afternoon hands-on laboratory sessions. Students completed self-assessment questionnaires regarding their confidence in several areas of clinical neurosurgery before the start of the course and again at its end. RESULTS: A significant increase in self-assessed confidence was observed in all skill areas surveyed. Overall, rising fourth year students who were starting sub-internships in the subsequent weeks reported a substantial increase in their preparedness for the elective rotations in neurosurgery. CONCLUSIONS: The preparation of medical students for clinical neurosurgery can be improved. Single-day courses such as the described training camp are an effective method for improving knowledge and skill gaps in medical students entering neurosurgical careers. Initiatives should be developed, in addition to this annual program, to increase the clinical and research skills throughout medical student education.

Optimal Timing and Sequence of Immunotherapy When Combined with Stereotactic Radiosurgery in the Treatment of Brain Metastases.

Checkpoint immunotherapy (CIT) is an emerging and exciting treatment modality for the treatment of cancer. Much excitement has ensued in the potential of CIT to revolutionize the treatment and prognosis of brain metastases. The combination of stereotactic radiosurgery (SRS) and CIT has also been studied and showed promise compared with either treatment modality alone. However, several questions have arisen, in particular, the timing at which SRS and CIT should be administered relative to each other. We reviewed the reported data and attempted to offer a potential answer to this question.

The effect of diet on BPH, LUTS and ED.

OBJECTIVE: Benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are common conditions that increase in the aging population. Several environmental factors have been linked to the development and progression of BPH and ED. Several studies have shown potential direct and indirect influences of several micronutrients and macronutrients on the risk of developing these conditions. We reviewed the available published literature of the effect of diet on BPH and ED. METHODS: A comprehensive search was performed to identify studies that evaluated how diet affected males with BPH and ED. Searches were run on July 5th, 2018 in the following databases: Ovid MEDLINE®; Ovid EMBASE; and The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL). There were no language restrictions, publication date restrictions, or article type restrictions on the search strategy. RESULTS: We retrieved a total of 1670 results across all databases. After removing any duplicated results, 2 independent reviewers screened a total of 1325 citations. A total of 35 articles were selected for inclusion in this review. Diet is an important factor affecting the risk of development of BPH and ED. Several studies have shown the effect of dietary interventions for BPH and ED. DISCUSSION: A better understanding diet and its relative effects on the development, treatment and prevention of these diseases are an important area of further research for the given aging male population.