Radiomic Analysis to Predict Histopathologically Confirmed Pseudoprogression in Glioblastoma Patients.

Purpose: Pseudoprogression mimicking recurrent glioblastoma remains a diagnostic challenge that may adversely confound or delay appropriate treatment or clinical trial enrollment. We sought to build a radiomic classifier to predict pseudoprogression in patients with primary isocitrate dehydrogenase wild type glioblastoma. Methods and Materials: We retrospectively examined a training cohort of 74 patients with isocitrate dehydrogenase wild type glioblastomas with brain magnetic resonance imaging including dynamic contrast enhanced T1 perfusion before resection of an enhancing lesion indeterminate for recurrent tumor or pseudoprogression. A recursive feature elimination random forest classifier was built using nested cross-validation without and with O6-methylguanine-DNA methyltransferase status to predict pseudoprogression. Results: A classifier constructed with cross-validation on the training cohort achieved an area under the receiver operating curve of 81% for predicting pseudoprogression. This was further improved to 89% with the addition of O6-methylguanine-DNA methyltransferase status into the classifier. Conclusions: Our results suggest that radiomic analysis of contrast T1-weighted images and magnetic resonance imaging perfusion images can assist the prompt diagnosis of pseudoprogression. Validation on external and independent data sets is necessary to verify these advanced analyses, which can be performed on routinely acquired clinical images and may help inform clinical treatment decisions.

Effective Low-Cost Ophthalmological Screening With a Novel iPhone Fundus Camera at Community Centers.

Ophthalmologic care is inaccessible to many people due to a variety of factors, including the availability of providers, cost of equipment for ophthalmologic care, and transportation to clinics and appointments. Because many causes of blindness are both highly prevalent and preventable once identified, it is essential to address gaps in care for underserved populations. We developed a novel 3D-printed mobile retinal camera. In this study, we organized recurring student-run screening events around New York City that took place in community centers and churches, at which we utilized our device to take retinal images. Our screening events reached a diverse population of New Yorkers, disproportionately those with lower household income, many of whom had not had recent eye exams. To validate the device for use in telehealth ophthalmologic visits, we transmitted the images to a remote ophthalmologist for evaluation and compared the result with an on-site attending physician's dilated eye exam. The subjective assessment indicated that 97% of images captured with the mobile retinal camera were acceptable for telehealth analysis. Remote image assessment by achieved 92% sensitivity and 83% specificity in detecting optic disc cupping, compared to the gold-standard on-site dilated eye exam. In addition, the device was portable, affordable, and able to be used by those with relatively little ophthalmologic training. We have demonstrated the utility of this affordable mobile retinal camera for telehealth ophthalmologic evaluation during community screening events that reached an underserved population to detect disease and connect with long-term care.

COVID-19 in patients with cancer: can baseline radiologic severity and early evolution predict clinical outcomes?

OBJECTIVE: To determine whether the degree of parenchymal involvement on chest radiograph (CXR) at the time of COVID-19 diagnosis and its early radiologic evolution can predict adverse events including hospitalization, intubation, and death in patients with cancer. METHODS: Retrospective study of 627 COVID-19-positive patients between March and April 2020, of which 248 had baseline CXR within 72 h of diagnosis and 64 patients had follow-up wihtin72 h. CXRs were classified as abnormal (i.e., radiologic findings suggestive of COVID-19 infection were noted), normal, or indeterminate. Baseline and follow-up severity scores were calculated based on lung regions in abnormal CXRs. Statistical analysis was performed to determine associations between abnormal CXR or severity score with adverse events. RESULTS: Of 248 patients (median age = 65) with a baseline CXR, 172/248 (69%) had an abnormal baseline study, which was associated with hospitalization (p < 0.001), intubation (p = 0.001), and death (p = 0.005). For patients with solid neoplasms, when adjusted for stage, it was associated with hospitalization (p = 0.0002), intubation (p = 0.019), and death (p = 0.03). The median baseline severity score was 3 (range = 1-10); the greater the score, the higher the likelihood of adverse outcome (p < 0.003 for all). A baseline severity score > 9 predicted > 50% probability of intubation and a score of ≥ 10 predicted > 50% of probability of death. The baseline severity score was not correlated with cancer-related treatment. Early radiologic progression was not correlated with hospitalization, intubation, or death. CONCLUSION: The degree of parenchymal involvement on CXR within 72 h of COVID-19 diagnosis is associated with adverse outcomes in patients with cancer. KEY POINTS: • In patients with cancer, the presence and severity of radiologic manifestation of COVID-19 on chest radiographs within 72 h of COVID-19 diagnosis are associated with hospitalization, intubation, and death. • Early radiologic progression on chest radiographs is not correlated with adverse outcomes.

Risk of Adverse Outcomes in Hospitalized Patients With Autoimmune Disease and COVID-19: A Matched Cohort Study From New York City.

OBJECTIVE: To examine the effect of autoimmune (AI) disease on the composite outcome of intensive care unit (ICU) admission, intubation, or death from COVID-19 in hospitalized patients. METHODS: Retrospective cohort study of 186 patients hospitalized with COVID-19 between March 1, 2020, and April 15, 2020 at NewYork-Presbyterian Hospital/Columbia University Irving Medical Center. The cohort included 62 patients with AI disease and 124 age- and sex-matched controls. The primary outcome was a composite of ICU admission, intubation, and death, with secondary outcome as time to in-hospital death. Baseline demographics, comorbidities, medications, vital signs, and laboratory values were collected. Conditional logistic regression and Cox proportional hazards regression were used to assess the association between AI disease and clinical outcomes. RESULTS: Patients with AI disease were more likely to have at least one comorbidity (87.1% vs 74.2%, P = 0.04), take chronic immunosuppressive medications (66.1% vs 4.0%, P < 0.01), and have had a solid organ transplant (16.1% vs 1.6%, P < 0.01). There were no significant differences in ICU admission (13.7% vs 19.4%, P = 0.32), intubation (13.7% vs 17.7%, P = 0.47), or death (16.1% vs 14.5%, P = 0.78). On multivariable analysis, patients with AI disease were not at an increased risk for a composite outcome of ICU admission, intubation, or death (ORadj 0.79, 95% CI 0.37-1.67). On Cox regression, AI disease was not associated with in-hospital mortality (HRadj 0.73, 95% CI 0.33-1.63). CONCLUSION: Among patients hospitalized with COVID-19, individuals with AI disease did not have an increased risk of a composite outcome of ICU admission, intubation, or death.

Life in a harsh environment: the effects of age, sex, reproductive condition, and season on hair cortisol concentration in a wild non-human primate.

Hair cortisol concentration (HCC) provides a long-term retrospective measure of hypothalamic-pituitary-adrenal axis activity, and is increasingly used to assess the life history, health and ecology of wild mammals. Given that sex, age, season and pregnancy influence HCC, and that it may indicate ongoing stress, we examined HCC in common marmosets (Callithrix jacchus) naturally inhabiting a hot and dry semi-desert like habitat, Caatinga, in northeastern Brazil. We trapped, measured, weighed, marked and collected shaved hair from the back of the neck of 61 wild marmosets during the wet and dry seasons. Using enzyme immunoassay, we found that HCC was higher in the dry season compared with the wet season among all age/sex classes. Females had significantly higher HCC than males, juveniles had higher HCC than adults, and reproductively active adult females and non-pregnant/non lactating adult females did not differ in HCC. There were no interaction effects of sex, age, group, or season on HCC. The magnitude of the effect of this extremely hot and dry environment (average yearly rainfall was only 271 mm) on HCC in common marmosets is difficult to ascertain as these animals are also experiencing a variety of other stressors. However, the elevated HCC seen in common marmosets during the 5-8 month dry season, suggests these primates face an extended period of heat, water and possibly nutritional stress, which appears to result in a high rate of juvenile mortality.

Imaging Utilization and Outcomes in Vulnerable Populations during COVID-19 in New York City.

BACKGROUND: Coronavirus disease 2019 (COVID-19) affects vulnerable populations (VP) adversely. PURPOSE: To evaluate overall imaging utilization in vulnerable subgroups (elderly, racial/ethnic minorities, socioeconomic status [SES] disadvantage) and determine if a particular subgroup has worse outcomes from COVID-19. MATERIALS/METHODS: Of 4110 patients who underwent COVID-19 testing from March 3-April 4, 2020 at NewYork-Presbyterian Hospital (NYP) health system, we included 1121 COVID-19 positive adults (mean age 59±18 years, 59% male) from two academic hospitals and evaluated imaging utilization rates and outcomes, including mortality. RESULTS: Of 897 (80%) VP, there were 465 (41%) elderly, 380 (34%) racial/ethnic minorities, and 479 (43%) SES disadvantage patients. Imaging was performed in 88% of patients and mostly portable/bedside studies, with 87% of patients receiving chest radiographs. There were 83% hospital admissions, 25% ICU admissions, 23% intubations, and 13% deaths. Elderly patients had greater imaging utilization, hospitalizations, ICU/intubation requirement, longer hospital stays, and >4-fold increase in mortality compared to non-elderlies (adjusted hazard ratio[aHR] 4.79, p<0.001). Self-reported minorities had fewer ICU admissions (p=0.03) and reduced hazard for mortality (aHR 0.53, p=0.004; complete case analysis: aHR 0.39, p<0.001 excluding "not reported"; sensitivity analysis: aHR 0.61, p=0.005 "not reported" classified as minorities) with similar imaging utilization, compared to non-minorities. SES disadvantage patients had similar imaging utilization and outcomes as compared to their counterparts. CONCLUSIONS: In a predominantly hospitalized New York City cohort, elderly patients are at highest mortality risk. Racial/ethnic minorities and SES disadvantage patients fare better or similarly to their counterparts, highlighting the critical role of access to inpatient medical care during the COVID-19 pandemic.

Minor Hematochezia Decreases Use of Venous Thromboembolism Prophylaxis in Patients with Inflammatory Bowel Disease.

BACKGROUND: Despite increased risk of venous thromboembolism (VTE) among hospitalized patients with inflammatory bowel disease (IBD), pharmacologic prophylaxis rates remain low. We sought to understand the reasons for this by assessing factors associated with VTE prophylaxis in patients with IBD and the safety of its use. METHODS: This was a retrospective cohort study conducted among patients hospitalized between January 2013 and August 2018. The primary outcome was VTE prophylaxis, and exposures of interest included acute and chronic bleeding. Medical records were parsed electronically for covariables, and logistic regression was used to assess factors associated with VTE prophylaxis. RESULTS: There were 22,499 patients studied, including 474 (2%) with IBD. Patients with IBD were less likely to be placed on VTE prophylaxis (79% with IBD, 87% without IBD), particularly if hematochezia was present (57% with hematochezia, 86% without hematochezia). Among patients with IBD, admission to a medical service and hematochezia (adjusted odds ratio 0.27; 95% CI, 0.16-0.46) were among the strongest independent predictors of decreased VTE prophylaxis use. Neither hematochezia nor VTE prophylaxis was associated with increased blood transfusion rates or with a clinically significant decline in hemoglobin level during hospitalization. CONCLUSION: Hospitalized patients are less likely to be placed on VTE prophylaxis if they have IBD, and hematochezia may drive this. Hematochezia appeared to be minor and was unaffected by VTE prophylaxis. Education related to the safety of VTE prophylaxis in the setting of minor hematochezia may be a high-yield way to increase VTE prophylaxis rates in patients with IBD.

MRI radiomic features are associated with survival in melanoma brain metastases treated with immune checkpoint inhibitors.

BACKGROUND: Melanoma brain metastases historically portend a dismal prognosis, but recent advances in immune checkpoint inhibitors (ICIs) have been associated with durable responses in some patients. There are no validated imaging biomarkers associated with outcomes in patients with melanoma brain metastases receiving ICIs. We hypothesized that radiomic analysis of magnetic resonance images (MRIs) could identify higher-order features associated with survival. METHODS: Between 2010 and 2019, we retrospectively reviewed patients with melanoma brain metastases who received ICI. After volumes of interest were drawn, several texture and edge descriptors, including first-order, Haralick, Gabor, Sobel, and Laplacian of Gaussian (LoG) features were extracted. Progression was determined using Response Assessment in Neuro-Oncology Brain Metastases. Univariate Cox regression was performed for each radiomic feature with adjustment for multiple comparisons followed by Lasso regression and multivariate analysis. RESULTS: Eighty-eight patients with 196 total brain metastases were identified. Median age was 63.5 years (range, 19-91 y). Ninety percent of patients had Eastern Cooperative Oncology Group performance status of 0 or 1 and 35% had elevated lactate dehydrogenase. Sixty-three patients (72%) received ipilimumab, 11 patients (13%) received programmed cell death protein 1 blockade, and 14 patients (16%) received nivolumab plus ipilimumab. Multiple features were associated with increased overall survival (OS), and LoG edge features best explained the variation in outcome (hazard ratio: 0.68, P = 0.001). In multivariate analysis, a similar trend with LoG was seen, but no longer significant with OS. Findings were confirmed in an independent cohort. CONCLUSION: Higher-order MRI radiomic features in patients with melanoma brain metastases receiving ICI were associated with a trend toward improved OS.

Trait variation and trait stability in common marmosets (Callithrix jacchus) inhabiting ecologically distinct habitats in northeastern Brazil.

Understanding the set of factors that promote and constrain a species' ability to exploit ecologically distinct habitats is central for addressing questions of intraspecific variability in behavior and morphology. In this study, we compared newly collected data with published data on body measurements, group size and composition, daily path length, home range, and reproductive output in wild common marmosets naturally inhabiting two contrasting environments in northeastern Brazil: the Atlantic Forest (AF), which is characterized by high biodiversity and reduced seasonality in food availability and the Caatinga (CAT), which is characterized by a severe hot and dry season lasting from 5 to 11 months, drought-resistant plant species, and reduced primary productivity. Despite marked differences in ecological conditions, CAT marmosets and AF marmosets differed minimally in daily path length, home range, reproductive output, and infant survivorship. CAT marmosets were found to live in smaller groups containing fewer adult females than AF marmosets, and also were characterized by a greater surface area to body mass ratio, a trait that may represent an adaptation to the hot and dry conditions of the Caatinga. We propose that in conjunction with body mass reduction, minor adjustments in behavior, the exploitation of cacti as a source of water and nutrients, and access to exudates as a dependable year-round food resource, common marmosets successfully used the same adaptive pattern to maintain high reproductive output and infant survivorship in exploiting these two ecologically distinct environments.

JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition.

Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617F and mutant IDH1R132H or Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617F Idh2R140Q-mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mut and IDH2mut mutations. Taken together, these data suggest that combined JAK and IDH inhibition may offer a therapeutic advantage in this high-risk MPN subtype.

Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells.

Recent studies have reported that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies, and hematopoietic-specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating TET2 as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of AID loss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing of AID in human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast to Tet2 loss, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD to induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation.

DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling.

Although the majority of patients with acute myeloid leukemia (AML) initially respond to chemotherapy, many of them subsequently relapse, and the mechanistic basis for AML persistence following chemotherapy has not been determined. Recurrent somatic mutations in DNA methyltransferase 3A (DNMT3A), most frequently at arginine 882 (DNMT3AR882), have been observed in AML and in individuals with clonal hematopoiesis in the absence of leukemic transformation. Patients with DNMT3AR882 AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy, suggesting that DNMT3AR882 cells persist and drive relapse. We found that Dnmt3a mutations induced hematopoietic stem cell expansion, cooperated with mutations in the FMS-like tyrosine kinase 3 gene (Flt3ITD) and the nucleophosmin gene (Npm1c) to induce AML in vivo, and promoted resistance to anthracycline chemotherapy. In patients with AML, the presence of DNMT3AR882 mutations predicts minimal residual disease, underscoring their role in AML chemoresistance. DNMT3AR882 cells showed impaired nucleosome eviction and chromatin remodeling in response to anthracycline treatment, which resulted from attenuated recruitment of histone chaperone SPT-16 following anthracycline exposure. This defect led to an inability to sense and repair DNA torsional stress, which resulted in increased mutagenesis. Our findings identify a crucial role for DNMT3AR882 mutations in driving AML chemoresistance and highlight the importance of chromatin remodeling in response to cytotoxic chemotherapy.