Use of Vacuum-Assisted Closure to Reduce the Likelihood of Wound Complications After Limb-Sparing Resection of Pediatric Primary Bone Sarcomas of the Femur.

BACKGROUND: Limb-sparing surgery is the standard of care for primary bone tumors. However, such procedures are associated with high rates of wound complications, specifically in lower-extremity surgeries. Therefore, identifying and implementing interventions to minimize the likelihood of wound complications after limb-sparing resection of the lower extremity is crucial. METHODS: Patients who underwent limb-sparing osteosarcoma or Ewing sarcoma resection during a 7-year period at a single institution were retrospectively reviewed. Data were collected on 39 patients who underwent limb-sparing resection of the femur. Patient demographics, tumor characteristics, and perioperative and postoperative data were extracted and analyzed. Patients who underwent resection before April 2017 received conventional postoperative incision dressings. Starting in April 2017, patients received vacuum-assisted closure (VAC) with the 3 M™ Prevena VAC system after surgical closure. Eighteen patients received conventional postoperative incision dressing, and 21 received incisional wound VAC. A wound complication was defined as any Clavien-Dindo classification greater than 0 within a 28-day postoperative period. RESULTS: Patients who received postoperative incisional wound VAC had lower rates of wound complications than those who received conventional incision dressings (14% vs. 50%; p = 0.035). Additionally, patients in whom wound complications developed had a longer average hospital stay than those without wound complications (5 days vs. 4 days; p = 0.029). CONCLUSIONS: Wound complications prolong the hospital stay and can delay adjuvant chemotherapy for bone tumors. The use of postoperative incisional wound VAC is associated with less likelihood of wound complications and should be considered in any high-risk surgical closure. LEVEL OF EVIDENCE: Level III Treatment Study.

Longitudinal clinical data improve survival prediction after hematopoietic cell transplantation using machine learning.

ABSTRACT: Serial prognostic evaluation after allogeneic hematopoietic cell transplantation (allo-HCT) might help identify patients at high risk of lethal organ dysfunction. Current prediction algorithms based on models that do not incorporate changes to patients' clinical condition after allo-HCT have limited predictive ability. We developed and validated a robust risk-prediction algorithm to predict short- and long-term survival after allo-HCT in pediatric patients that includes baseline biological variables and changes in the patients' clinical status after allo-HCT. The model was developed using clinical data from children and young adults treated at a single academic quaternary-care referral center. The model was created using a randomly split training data set (70% of the cohort), internally validated (remaining 30% of the cohort) and then externally validated on patient data from another tertiary-care referral center. Repeated clinical measurements performed from 30 days before allo-HCT to 30 days afterwards were extracted from the electronic medical record and incorporated into the model to predict survival at 100 days, 1 year, and 2 years after allo-HCT. Naïve-Bayes machine learning models incorporating longitudinal data were significantly better than models constructed from baseline variables alone at predicting whether patients would be alive or deceased at the given time points. This proof-of-concept study demonstrates that unlike traditional prognostic tools that use fixed variables for risk assessment, incorporating dynamic variability using clinical and laboratory data improves the prediction of mortality in patients undergoing allo-HCT.

Retroperitoneoscopic or Transperitoneal Approach for Neurogenic and Adrenal Tumors in Children? A Comparison on the Way to Enhanced Recovery in Pediatric Surgical Oncology.

BACKGROUND: Minimally invasive surgery is increasingly utilized for resection of neurogenic tumors in children. The minimally invasive retroperitoneoscopic approach was recently reported in children, but transperitoneal laparoscopy still remains the most common technique. The aim of this study is to compare a novel single-port retroperitoneoscopy (SPR) approach for pediatric neurogenic tumor resection with transperitoneal laparoscopic (TPL). METHODS: Patients undergoing minimally invasive resection of abdominal neurogenic tumors over 5 years at a single institution (from 2018 to 2022) were retrospectively reviewed. Tumor volume, stage, presence of image-defined risk factors (IDRFs), neoadjuvant chemotherapy, operative time, estimated blood loss (EBL), length of stay (LOS), complications, oral morphine equivalents per kilogram (OME/Kg), and time to chemotherapy were assessed and compared with SPR and TPL approaches. RESULTS: Eighteen and fifteen patients underwent TPL and SPR, respectively. No significant differences were found between the TPL and SPR approaches in terms of tumor characteristics and IDRFs. Patients who underwent SPR had a significantly faster recovery (p = 0.008) and less postoperative opioid use compared to those in TPL (p = 0.02), thus allowing an enhanced recovery after surgery (ERAS) protocol application. TPL and SPR approaches were performed in presence of IDRFs, respectively in 2 (11%) and 4 patients (27%), with a IDRFs-related conversion in one TPL procedure. Both approaches had one < Grade 3 Clavien Dindo complication, but not requiring further surgery. DISCUSSION: SPR approach can be considered as a safe and feasible minimally invasive approach for the resection of pediatric primary adrenal and neurogenic tumors. The retroperitoneoscopic approach performed using a single port technique represents a promising new frontier of ERAS application in pediatric surgical oncology. CONCLUSION: SPR is a viable surgical alternative in selected neurogenic abdominal tumors with limited IDRFs, thus allowing for the application of ERAS protocols in these patients. LEVEL OF EVIDENCE: Level III.

Feasibility of indocyanine green-guided localization of pulmonary nodules in children with solid tumors.

BACKGROUND: Clearing all pulmonary metastases is essential for curing pediatric solid tumors. However, intraoperative localization of such pulmonary nodules can be challenging. Therefore, an intraoperative tool that localizes pulmonary metastases is needed to improve diagnostic and therapeutic resections. Indocyanine green (ICG) real-time fluorescence imaging is used for this purpose in adult solid tumors, but its utility in pediatric solid tumors has not been determined. METHODS: A single-center, open-label, nonrandomized, prospective clinical trial (NCT04084067) was conducted to assess the ability of ICG to localize pulmonary metastases of pediatric solid tumors. Patients with pulmonary lesions who required resection, either for therapeutic or diagnostic intent, were included. Patients received a 15-minute intravenous infusion of ICG (1.5 mg/kg), and pulmonary metastasectomy was performed the following day. A near-infrared spectroscopy iridium system was optimized to detect ICG, and all procedures were photo-documented and recorded. RESULTS: ICG-guided pulmonary metastasectomies were performed in 12 patients (median age: 10.5 years). A total of 79 nodules were visualized, 13 of which were not detected by preoperative imaging. Histologic examination confirmed the following histologies: hepatoblastoma (n = 3), osteosarcoma (n = 2), and one each of rhabdomyosarcoma, Ewing sarcoma, inflammatory myofibroblastic tumor, atypical cartilaginous tumor, neuroblastoma, adrenocortical carcinoma, and papillary thyroid carcinoma. ICG guidance failed to localize pulmonary metastases in five (42%) patients who had inflammatory myofibroblastic tumor, atypical cartilaginous tumor, neuroblastoma, adrenocortical carcinoma, or papillary thyroid carcinoma. CONCLUSIONS: ICG-guided identification of pulmonary nodules is not feasible for all pediatric solid tumors. However, it may localize most metastatic hepatic tumors and high-grade sarcomas in children.

Associations of Iron Sucrose and Intradialytic Blood Pressure.

RATIONALE & OBJECTIVE: Intradialytic hypotension and intradialytic hypertension are associated with morbidity and mortality in hemodialysis (HD). Many factors can contribute to intra-HD blood pressure (BP) changes, such as drugs with vasoactive properties that can destabilize an already tenuous BP. Intravenous iron sucrose is commonly administered to correct iron deficiency; however, its reported associations with altered hemodynamics have not been consistent. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 950 outpatients receiving maintenance HD. EXPOSURE: Iron sucrose administered during HD. OUTCOME: Intradialytic hypotension, intradialytic hypertension, systolic blood pressure parameters. ANALYTICAL APPROACH: Unadjusted and adjusted Poisson and linear repeated measures regression models. RESULTS: The mean age of patients included in the study was 53±22 years, 43% were female, and 38% were Black. Mean pre-HD SBP was 152±26 (SD) mm Hg. At baseline, the patients who received higher doses of iron sucrose tended to have diabetes, have longer HD sessions, and have a higher frequency of erythropoiesis-stimulating agent use, compared with those who did not receive iron sucrose. In adjusted models, higher doses of iron sucrose were associated with an 11% lower rate of intradialytic hypotension (incidence rate ratio [IRR] for iron sucrose≥100mg vs 0 mg, 0.89 [95% CI, 0.85-0.94]). In adjusted analyses, the administration of higher doses of iron sucrose during HD was associated with intradialytic hypertension (IRR for iron sucrose≥100mg vs 0 mg, 1.07 [95% CI, 1.04-1.10]). LIMITATIONS: Nonavailability of the precise iron sucrose formulation (volume), laboratory data for each HD session, and outpatient medications. Objective measures of volume status, home medications, and symptom data were not recorded in this study. CONCLUSIONS: We observed an independent association of intravenous iron sucrose administration during HD with a lower risk of intradialytic hypotension and higher risk of intradialytic hypertension. Future studies to better understand the mechanisms underlying these associations are warranted. PLAIN-LANGUAGE SUMMARY: Intradialytic hypotension and intradialytic hypertension are common among patients on hemodialysis, and they are associated with morbidity and mortality. Although many factors may contribute to these risks, medications administered during hemodialysis play an important role. We studied the significance of the intravenous iron sucrose used to treat iron deficiency and the impact it may have on blood pressure during dialysis. In our study of 950 outpatient hemodialysis patients, we observed that administration of iron sucrose was associated with higher systolic blood pressure (during and after hemodialysis sessions) as well as a lower risk of intradialytic hypotension. We also observed that higher doses of iron sucrose are associated with the development of intradialytic hypertension.

The Kidney Failure Risk Equation Score and CKD Care Delivery Measures: A Cross-sectional Study.

RATIONALE & OBJECTIVE: The 4-variable kidney failure risk equation (KFRE) allows for the prediction of chronic kidney disease (CKD) progression using age, sex, estimated glomerular filtration rate, and urine albumin/creatinine ratio. Electronic health records enable KFRE auto-calculation, and registries allow population-level application. We assessed whether 2-year KFRE score categories are associated with CKD care metrics. STUDY DESIGN: Cross-sectional cohort. SETTING & PARTICIPANTS: This study included individuals with CKD in March 2020 who were receiving care within the Partners HealthCare system in Massachusetts. OUTCOMES: The presence of sufficient data to calculate the KFRE and, among those with a KFRE score, performance on CKD clinical care metrics, including (1) prescription of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; (2) blood pressure at goal (<140/90 mm Hg) based on clinic measurements; (3) composite metric of hepatitis B virus immunity; (4) composite metric of referral, evaluation, or waitlist status for kidney transplantation; (5) advance directive documentation; (6) yearly influenza vaccination; and (7) pneumonia vaccination. ANALYTICAL APPROACH: Multivariable logistic regression analysis was used to analyze the association of KFRE score category with CKD care metrics. RESULTS: Of 61,546 patients, 18,272 (30%) had auto-calculated 2-year KFRE scores; the remaining patients lacked KFRE scores because of absent albuminuria assessment. Individuals with a KFRE score were more likely to have a primary care provider or nephrologist. Among patients with 2-year KFRE scores, high-risk patients had increased odds of completing advance directives (OR, 1.52; 95% CI, 1.07-2.17), while low-risk patients had decreased odds of influenza vaccination (OR, 0.85; 95% CI, 0.75-0.97). Patients with moderate- and high-risk KFRE scores had lower odds of having blood pressure at goal (OR, 0.77; 95% CI, 0.61-0.96 and OR, 0.63; 95% CI, 0.44-0.88, respectively). LIMITATIONS: Albuminuria data may have been assessed outside of the Partners system. CONCLUSIONS: A higher-risk KFRE score is associated with the delivery of some but not all CKD care measures. An opportunity exists to improve albuminuria measurement.

Endothelin-1 and Parameters of Systolic Blood Pressure in Hemodialysis.

BACKGROUND: Hypertension is common in hemodialysis (HD) patients. Increased blood pressure (BP) variability, particularly higher and lower extremes, is associated with adverse outcomes. We explored the association of endothelin-1 (ET-1), a potent vasoconstrictor, with different BP parameters (pre-HD, intra-HD, and post-HD) during HD in a contemporary patient cohort. METHODS: This study uses the DaVita Biorepository, a longitudinal prospective cohort study with quarterly collection of clinical data and biospecimens. Unadjusted and adjusted linear mixed effects regression models were fit to determine association of pre-HD ET-1 (log-transformed and quartiles) with HD-related systolic BP (SBP) parameters (pre-HD, nadir intra-HD, and post-HD). As ET-1 was measured at baseline, analyses were restricted to 1 year of follow-up. RESULTS: Among 769 participants, mean age was 52 years, 42% were females, and 41% were Black. Mean pre-HD SBP was 152 (±28) mm Hg and mean ET-1 concentration was 2.3 (±1.2) ng/ml. In fully adjusted models, each unit increase in SD of log-transformed ET-1 was associated with a 2.7 (95% confidence interval [CI] 1.5, 4.0) mm Hg higher pre-SBP; 1.6 (95% CI 0.9, 2.3) mm Hg higher nadir SBP; and 2.0 (95% CI 1.1, 2.9) mm Hg higher post-SBP. Each SD increase in log-transformed ET-1 was associated with 21% higher odds of experiencing intradialytic hypertension (odds ratio 1.21; 95% CI 1.10-1.34). CONCLUSIONS: Higher baseline ET-1 levels are independently associated with higher SBP and higher odds of intradialytic hypertension. These results highlight a potential role for ET-1 in BP control in HD patients and raise the possibility of ET-1 antagonism as a therapeutic target.

Acute kidney injury after cytoreductive surgery and hyperthermic intraoperative cisplatin chemotherapy for malignant pleural mesothelioma.

OBJECTIVES: Cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin has been used successfully to treat malignant pleural mesothelioma, a highly aggressive malignancy that is rapidly fatal in most cases. We hypothesized that the combination of ischemic injury with nephrotoxic injury from cisplatin would result in high rates of acute kidney injury. METHODS: We conducted an observational study in 503 patients to study the risks and outcomes of acute kidney injury after surgical resection of malignant pleural mesothelioma. Eligible subjects underwent extrapleural pneumonectomy or pleurectomy/decortication with or without hyperthermic intraoperative chemotherapy. Acute kidney injury was defined as an increase in creatinine of 26.5 µmol/L or greater within 48 hours of surgery or a 50% or greater increase over 7 days. RESULTS: Acute kidney injury developed in 243 patients (48.3%). Severe acute kidney injury requiring renal replacement therapy developed in 16 patients (3.2%). Major significant predictors for acute kidney injury included male sex (odds ratio, 2.98; P < .001), intraoperative cisplatin administration (odds ratio, 3.12; P < .001), previous cisplatin exposure (odds ratio, 1.96; P = .02), hypertension (odds ratio, 1.57; P = .02), and longer surgical time (odds ratio, 1.15 per hour; P = .02). Compared with patients without acute kidney injury, those with severe acute kidney injury had longer length of stay (26 vs 13 days) and a 2.71-fold increased risk of death in multivariable-adjusted models. CONCLUSIONS: Acute kidney injury is common after cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin and is associated with poor long-term outcomes. Strategies to prevent postoperative acute kidney injury are needed to improve multimodal treatment of malignant pleural mesothelioma.

Do neurobiological differences exist between paranoid and non-paranoid schizophrenia? Findings from the bipolar schizophrenia network on intermediate phenotypes study.

Subtypes of schizophrenia, constructed using clinical phenomenology to resolve illness heterogeneity, have faced criticism due to overlapping symptomatology and longitudinal instability; they were therefore dropped from the Diagnostic Statistical Manual-5. Cognitive and imaging findings comparing paranoid (P-SZ) and non-paranoid (disorganized, residual and undifferentiated; NP-SZ) schizophrenia have been limited due to small sample sizes. We assessed P-SZ and NP-SZ using symptomatology, cognition and brain structure and predicted that there would be few neurobiological differences. P-SZ (n = 237), NP-SZ (n = 127) and controls (n = 430) were included from a multi-site study. In a subset of this sample, structural imaging measures (P-SZ, n = 133; NP-SZ, n = 67; controls, n = 310) were calculated using Freesurfer 6.0. Group contrasts were run using analysis of covariance, controlling for age, sex, race and site, p-values were corrected using False Discovery Rate (FDR) and were repeated excluding the residual subtype. Compared to NP-SZ (with and without the residual subtype), P-SZ displayed fewer negative symptoms, faster speed of processing, larger bilateral hippocampus, right amygdala and their subfield volumes. Additionally, NP-SZ (with residual subtype) displayed fewer depressive symptoms and higher left transverse temporal cortical thickness (CT) but NP-SZ without residual subtype showed lower GAF scores and worse digit sequencing compared to P-SZ. No differences in positive symptoms and functioning (global or social) were detected. Subtle but significant differences were seen in cognition, symptoms, CT and subcortical volumes between P-SZ and NP-SZ. While the magnitude of these differences is not large enough to justify them as distinct categories, the paranoid- nonparanoid distinction in schizophrenia merits further investigation.

High Prevalence and Low Awareness of Albuminuria in the Community Setting in the KDSAP.

INTRODUCTION: Albuminuria is a sign of kidney disease and associated with adverse outcomes. However, most individuals with albuminuria are unaware of it. The Kidney Disease Screening and Awareness Program (KDSAP) aims for early detection and raising awareness of albuminuria, targeting underserved populations in communities. This study will assess the prevalence and awareness of albuminuria and identify associated risk factors among KDSAP participants. METHODS: KDSAP participants ≥18 years old without a history of dialysis or kidney transplant were included. Albuminuria was identified by dipstick urinalysis. Individuals with albuminuria who answered yes to either of the following 2 questions were defined as being aware: (i) Have you ever had protein in the urine? (ii) Do you have kidney disease? RESULTS: Among 2304 participants, 461 (20.0%) had albuminuria: 16.3% with trace or 1+ (low degree) and 3.7% with 2+ or more (high degree). Correlating factors of albuminuria included young age, male sex, African American descent, self-reported diabetes, hypertension, family history of kidney disease, and smoking. Overall albuminuria awareness was 15.8%, but awareness inversely correlated to younger age groups: 7.0% for ages 18-39 years, 13.5% for ages 40-59 years, and 24.0% for ages ≥60 years (P < 0.001). A high degree of albuminuria (vs. low, odds ratio: 5.04, P < 0.001) and concurrent hematuria (odds ratio: 2.12, P=0.024) were both associated with higher awareness; conversely, risk factors for low awareness included African American and better self-assessments of health. CONCLUSIONS: There was a high albuminuria prevalence among KDSAP participants, yet low awareness. KDSAP can potentially be a useful model for detecting albuminuria and raising awareness in communities.

Recurrence of FSGS after Kidney Transplantation in Adults.

BACKGROUND AND OBJECTIVES: FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors. RESULTS: Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m2; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival. CONCLUSIONS: Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases.

Trajectory of neurological examination abnormalities in antipsychotic-naïve first-episode psychosis population: a 1 year follow-up study.

BACKGROUND: Neurological Examination Abnormalities (NES) are quantified by measuring subtle, partially localizable (cerebello-thalamo-prefrontal cortical circuit) and heritable neurological signs comprising sensory integration, motor coordination and complex motor sequencing that are associated with first-episode psychosis (FEP). A few studies have evaluated NES longitudinally and as a predictor for diagnostic and response classification, but these studies have been confounded, underpowered and divergent. We examined (1) baseline and longitudinal NES differences between diagnostic and year 1 response groups; (2) if NES predicts diagnostic and response groups and (3) relationships between clinical variables and NES measures in antipsychotic-naïve FEP. METHODS: NES and clinical measures were obtained for FEP-schizophrenia (FEP-SZ, n = 232), FEP non-schizophrenia (FEP-NSZ, n = 117) and healthy controls (HC, n = 204). Response groups with >25% improvement in average year 1 positive and negative symptomatology scores were classified as responsive (n = 97) and <25% improvement as non-responsive (n = 95). Analysis of covariance, NES trajectory analysis and logistic regression models assessed diagnostic and response group differences. Baseline and longitudinal NES relationships with clinical variables were performed with Spearman correlations. Data were adjusted for age, sex, race, socioeconomic status and handedness. RESULTS: Cognitive perceptual (COGPER) score was better than repetitive motor (REPMOT) at differentiating FEP-SZ from FEP-NSZ and distinguishing responders from non-responders. We identified significant group-specific associations between COGPER and worse GAF, positive and negative symptomatology and some of these findings persisted at 1-year assessment. CONCLUSION: NES are an easy to administer, bedside-elicited, endophenotypic measure and could be a cost-effective clinical tool in antipsychotic-naïve FEP.

Expression of Tumor-mediated CD137 ligand in human colon cancer indicates dual signaling effects.

CD137-targeting immune therapy, which activates anti-tumor T effector cell responses, seems to be an attractive concept in clinical oncology. Recent evidence has demonstrated that tumor cells besides T cells and antigen-presenting cells are able to express CD137 and CD137L. Here we aimed to identify CD137/CD137L expression in established colon cancer cell lines and primary tumors (UICC stages I-IV) from patients with documented long-term follow-up. CD137/CD137L expression was highly upregulated in early to late-stage tumors while the inverse was observed in patient-derived peripheral blood mononuclear cells. High CD137L expression within primary tumors was mediated by tumor cells and significantly correlated with the occurrence of distant metastases and shortened survival in advanced stages of disease (UICC stage IV). Interestingly, induced tumor cell signaling via CD137L on its surface in vitro resulted in dual effects: (i) reduced tumor cell proliferation suggesting inhibitory signaling in all investigated cancers and (ii) increased epithelial-to-mesenchymal transition signaling events. Taken together CD137/CD137L expression was stage-dependently upregulated with shortened survival in patients with highly CD137L-expressing tumors. Our clinical and experimental data suggest that colon cancer cells predominantly express CD137L and thereby have negative impact on overall survival through a process of reverse signaling. Beside agonistic CD137 antibody therapy to foster T effector cell responses, CD137L-mediated intervention strategies may become instrumental to circumvent relapsed tumor growth through induced epithelial-to-mesenchymal transition and consecutive metastases formation.

Hypogyrification and its association with cognitive impairment in children with 22q11.2 deletion Syndrome: A preliminary report.

22q11.2 Deletion Syndrome (22qDS) is a neurogenetic disorder resulting in cognitive deficits and hypogyrification, but relationships between these processes have not been established. 22qDS youth and healthy controls (HC) were administered a battery of cognitive tasks. Gyrification measurements were extracted from structural T1 scans using Freesurfer, contrasted between groups, and correlated to cognition. Data was adjusted for age, sex, socio-economic status and intracranial volume. 22qDS displayed significant hypogyrification which was associated with poorer executive functioning and verbal learning in orbitofrontal and anterior cingulate cortex. Our preliminary findings identified neurodevelopmental deficits in 22qDS shown by hypogyria, which relate to cognitive impairments.

Association of sFlt-1 and worsening psychopathology in relatives at high risk for psychosis: A longitudinal study.

BACKGROUND: Angiogenic dysfunction and abnormalities in psychopathology and brain structure have been reported in schizophrenia, but their relationships are mostly unknown. We recently demonstrated that sFlt-1, anti-angiogenic factor, was significantly elevated in patients at familial high-risk for psychosis (FHR). We hypothesized that elevated sFlt-1 correlates with baseline and longitudinal changes in psychopathology, cognition, and brain structure. METHODS: Plasma sFlt-1 in FHR (n=35) and HC (n=39) was obtained at baseline. Schizotypal, cognitive, soft neurologic signs, and structural brain imaging (1.5T T1-weighted MRI, FreeSurfer software) measures were obtained in both groups. Longitudinal clinical and brain structural measures were obtained in a subgroup of FHR patients. Baseline data analysis used correlations between sFlt-1 and clinical/imaging measures and adjusted for multiple corrections. Linear mixed-effects models described differences in trajectories between high sFlt-1 and low sFlt-1. RESULTS: Baseline sFlt-1 was significantly correlated with soft neurologic signs (r=0.27, p=0.02) and right entorhinal volume (r=0.50, p=0.02), but not other baseline clinical/brain structural measures. Longitudinal examination of the FHR group (sFlt-1 high, n=14; sFlt-1 low, n=14) demonstrated that high sFlt-1 was significantly associated with worsening schizotypal symptoms (t=2.4, p=0.018). Reduced right hippocampal/parahippocampal volume/thickness trajectories were observed in high versus low sFlt-1 groups. CONCLUSIONS: The findings from this FHR study demonstrate that peripheral markers of angiogenic dysfunction can predict longitudinal clinical and brain structural changes. Also, these findings further support the hypothesis of altered microvascular circulation in schizophrenia and those at risk.