Faculty Bibliography

The left ventricular outflow tract (LVOT) velocity time integral (VTI) is an easily measured echocardiographic stroke volume index analog. Low values predict adverse outcomes in left ventricular failure. We postulate the left ventricular VTI may be a signal of right ventricular dysfunction in acute pulmonary embolism, and therefore a predictor of poor outcomes. We retrospectively reviewed echocardiograms on all Pulmonary Embolism Response Team activations at our institution at the time of pulmonary embolism diagnosis. Low LVOT VTI was defined as ⩽ 15 cm. We examined two composite outcomes: (1) in-hospital death or cardiac arrest; and (2) shock or need for primary reperfusion therapies. Sixty-one of 188 patients (32%) had a LVOT VTI of ⩽ 15 cm. Low VTI was associated with in-hospital death or cardiac arrest (odds ratio (OR) 6, 95% CI 2, 17.9; p = 0.0014) and shock or need for reperfusion (OR 23.3, 95% CI 6.6, 82.1; p < 0.0001). In a multivariable model, LVOT VTI ⩽ 15 remained significant for death or cardiac arrest (OR 3.48, 95% CI 1.02, 11.9; p = 0.047) and for shock or need for reperfusion (OR 8.12, 95% CI 1.62, 40.66; p = 0.011). Among intermediate-high-risk patients, low VTI was the only variable associated with the composite outcome of death, cardiac arrest, shock, or need for reperfusion (OR 14, 95% CI 1.7, 118.4; p = 0.015). LVOT VTI is associated with adverse short-term outcomes in acute pulmonary embolism. The VTI may help risk stratify patients with intermediate-high-risk pulmonary embolism.

BACKGROUND AND AIMS/OBJECTIVE:An independent association of body mass index (BMI) with atherosclerotic cardiovascular disease is somewhat controversial and may differ by vascular bed. Sex-specific risk factors for atherosclerosis may further modify these associations. Obesity and peripheral artery disease (PAD) are both more prevalent in women. We sought to determine the association between PAD and BMI using a very large population-based study. METHODS:Self-referred individuals at >20,000 US sites completed medical questionnaires including height and weight, and were evaluated by screening ankle brachial indices (ABI) for PAD (ABI<0.9). RESULTS:). CONCLUSIONS:Our study suggests that increasing BMI is a robust independent risk factor for PAD only in women. This observation requires validation, but highlights the need for further research on sex-specific risk and mechanisms of atherosclerosis.

Introduction: TBS diagnostic category rates, ASCUS/(+)hrHPV (high risk HPV) ratio, and cytotechnologist's (CT'S) concordance with the CP's final diagnosis are used as common quality monitors in gyn cytology. Additionally, extending monitoring of the hrHPV (+) rate to NILM and SIL cases has been proposed as quality indicators for cytopathologist's (CP's) performance. At our institution, Pap tests are finalized without the knowledge of hrHPV status. We investigated the impact of known hrHPV status on CPs' interpretation of cases previously screened as NILM, and stipulated its potential consequence on quality metrics. Material(s) and Method(s): 60 Pap tests previously resulted as NILM, half hrHPV (+) and half hrHPV (-), were reviewed blindly by 5 CPs in two rounds at 4 months interval. At first round, correct hrHPV results were provided to the CPs. At second round, incorrect (reversed) hrHPV results were given. McNemar chi-squared test was used to analyze the impact of knowing the hrHPV test result on Pap test interpretation. Kappa coefficient was calculated to test intra-observer agreement between the first and second review of the same slides for each CP. Result(s): ASCUS (13%) was the most upgraded diagnosis followed by 12 LSILs (2%) and 2 HSILs (0.3%). There were no significant differences in Pap test interpretation based on hrHPV status for 3 CPs and marked differences for 2 CPs (Table 1). Intra-observer agreement between round 1 and round 2 diagnoses varied from moderate to poor (Table 2). Conclusion(s): Knowledge of hrHPV status significantly biases some but not all CPs. hrHPV (+) to NILM, ASCUS and SIL ratios may not be the most objective parameters for evaluation of CP performance under these circumstances. This bias has further implications for CT performance evaluation because it impacts CT discordance rate measured against CPs final diagnosis. [Figure presented] [Figure presented]

Despite major improvements in combatting metastatic melanoma since the advent of immunotherapy, the overall survival for patients with advanced disease remains low. Recently, there is a growing number of reports supporting an "obesity paradox," in which patients who are overweight or mildly obese may exhibit a survival benefit in patients who received immune checkpoint inhibitors. We studied the relationship between body mass index and progression-free survival and overall survival in a cohort of 423 metastatic melanoma patients receiving immunotherapy, enrolled and prospectively followed up in the NYU Interdisciplinary Melanoma Cooperative Group database. We analyzed this association stratified by first vs. second or greater-line of treatment and treatment type adjusting for age, gender, stage, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, number of metastatic sites, and body mass index classification changes. In our cohort, the patients who were overweight or obese did not have different progression-free survival than patients with normal body mass index. Stratifying this cohort by first vs. non-first line immunotherapy revealed a moderate but insignificant association between being overweight or obese and better progression-free survival in patients who received first line. Conversely, an association with worse progression-free survival was observed in patients who received non-first line immune checkpoint inhibitors. Specifically, overweight and obese patients receiving combination immunotherapy had a statistically significant survival benefit, whereas patients receiving the other treatment types showed heterogeneous trends. We caution the scientific community to consider several important points prior to drawing conclusions that could potentially influence patient care, including preclinical data associating obesity with aggressive tumor biology, the lack of congruence amongst several investigations, and the limited reproduced comprehensiveness of these studies.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Inflammatory breast cancer (IBC) is a highly aggressive form of breast cancer that displays profound cancer stem cell (CSC) and mesenchymal features that promote rapid metastasis. Another hallmark of IBC is high infiltration of M2 tumor-associated (immune-suppressing) macrophages (TAM). The molecular mechanism that drives these IBC phenotypes is not well understood. Using patient breast tumor specimens, breast cancer cell lines, and a patient-derived xenograft (PDX) model of IBC, we demonstrate that IBC strongly expresses IL-8 and GRO chemokines that activate STAT3, which promotes development of high levels of CSC-like cells and a mesenchymal phenotype. We also show that IBC expresses high levels of many monocyte recruitment and macrophage polarization factors that attract and differentiate monocytes into tumor-promoting, immune-suppressing M2-like macrophages. The M2 macrophages in turn were found to secrete high levels of IL-8 and GRO chemokines, thereby creating a feed-forward chemokine loop that further drives an IBC epithelial-to-mesenchymal transition. Our study uncovers an intricate IBC-initiated autocrine-paracrine signaling network between IBC cells and monocytes that facilitates development of this highly aggressive form of breast cancer.

Patients diagnosed with metastatic melanoma have varied clinical courses, even in patients with similar disease characteristics. We examine the impact of initial stage of melanoma diagnosis, BRAF status of primary melanoma, and receiving adjuvant therapy on postmetastatic overall survival (pmOS). We studied melanoma patients presenting to Perlmutter Cancer Center at New York University and prospectively enrolled in New York University melanoma biospecimen database and followed up on protocol-driven schedule. Patients were stratified by stage at initial melanoma diagnosis as per AJCC 7th ed. guidelines. pmOS was determined using the Kaplan-Meier method and Cox's proportional hazards models were used to assess hazard ratios (HRs). Three hundred and four out of 3204 patients developed metastatic disease over the time of follow-up (median follow-up 2.2 years, range: 0.08-35.2 years). Patients diagnosed with stage I (n=96) melanoma had longer pmOS (29.5 months) than those diagnosed with stage II (n=99, pmOS 14.9 months) or stage III (n=109, pmOS 15.1 months) melanoma (P=0.036). Initial stage of diagnosis remained significant in multivariate analysis when controlling for lactate dehydrogenase and site of metastases [primary diagnosis stage II (HR 1.44, P=0.046), stage III (HR 1.5, P=0.019)]. Adjuvant treatment was associated with better survival but BRAF mutation status did not show an association. Our data challenge the general assumption that primary melanomas converge upon diagnosis of metastatic disease and behave uniformly. Primary stage of melanoma at the time of diagnosis may be prognostic of outcome, similar to lactate dehydrogenase and metastatic disease sites.

Purpose: Quantification of local metabolic tumor volume changes (DELTAMTV) after chemo-radiotherapy (CRT) would allow accurate tumor response evaluation. The purpose of this study is to measure local DELTAMTVusing blended PET/ CT registration and to provide an early prediction of pathologic tumor response. Method(s): 61 patients with locally advanced esophageal cancer underwent baseline, postinduction chemotherapy (follow-up) and post-CRT PET/CT. A grayscale blended PET/CT image was generated and follow-up blended PET/CT image was registered to the baseline blended PET/CT image with tumor motion correction. Jacobian map (J) was computed from the transformation which measured local MTV shrinkage (J < 1) or expansion (J > 1). Registration accuracy was evaluated by comparing the net DELTAMTV calculated by Jacobian integral [(mean J - 1) x baseline MTV] vs. semi-automatic segmentation. Radiomic features were then extracted from the Jacobian maps and PET/CT images and distinctive features were identified using a hierarchical clustering method. A logistic regression model was constructed using two distinctive features preidentified from PET/CT images (PET Kurtosis) and Jacobian map (Mean of Cluster Shade) to predict pathologic complete response (pCR). The model was evaluated using 10x5-fold cross-validation. Result(s): Qualitatively, Jacobian map by blended PET/CT registration showed smoother local DELTAMTV than PET-PET and CT-CT registrations. Quantitatively, DELTAMTV calculated by Jacobian integral of blended PET/CT registration (-42.0%) was closer to DELTAMTV measured by the semi-automatic segmentation (-50.0%) than by PET-PET (-29.4%) and CT-CT (-8.0%) registrations. Kurtosis in follow-up PET and Jacobian Mean of Cluster Shade represented uniformity of FDG uptake and asymmetry of DELTAMTV, respectively and the logistic model built with these two features achieved a high accuracy (AUC = 0.82) in predicting pCR. Conclusion(s): The novel Blended PET/CT registration led to more accurate quantification of DELTAMTV than PETPET and CT-CT registrations. The model with combination of PET/CT and Jacobian features showed high accuracy in predicting pCR

Purpose: Quantification of local metabolic tumor volume changes (DELTAMTV) after chemo-radiotherapy (CRT) would allow accurate tumor response evaluation. The purpose of this study is to measure local DELTAMTV using blended PET/CT registration and to provide an early prediction of pathologic tumor response. Method(s): 61 patients with locally advanced esophageal cancer underwent baseline, postinduction chemotherapy (follow-up) and post-CRT PET/CT. A grayscale blended PET/CT image was generated and follow-up blended PET/CT image was registered to the baseline blended PET/CT image with tumor motion correction. Jacobian map (J) was computed from the transformation which measured local MTV shrinkage (J < 1) or expansion (J > 1). Registration accuracy was evaluated by comparing the net DELTAMTV calculated by Jacobian integral [(mean J - 1) x baseline MTV] vs. semi-automatic segmentation. Radiomic features were then extracted from the Jacobian maps and PET/CT images and distinctive features were identified using a hierarchical clustering method. A logistic regression model was constructed using two distinctive features preidentified from PET/CT images (PET Kurtosis) and Jacobian map (Mean of Cluster Shade) to predict pathologic complete response (pCR). The model was evaluated using 10x5-fold crossvalidation. Result(s): Qualitatively, Jacobian map by blended PET/CT registration showed smoother local DELTAMTV than PET-PET and CT-CT registrations. Quantitatively, DELTAMTV calculated by Jacobian integral of blended PET/CT registration (-42.0%) was closer to DELTAMTV measured by the semi-automatic segmentation (-50.0%) than by PET-PET (-29.4%) and CT-CT (-8.0%) registrations. Kurtosis in follow-up PET and Jacobian Mean of Cluster Shade represented uniformity of FDG uptake and asymmetry of DELTAMTV, respectively and the logistic model built with these two features achieved a high accuracy (AUC = 0.82) in predicting pCR. Conclusion(s): The novel Blended PET/CT registration led to more accurate quantification of DELTAMTV than PET-PET and CT-CT registrations. The model with combination of PET/CT and Jacobian features showed high accuracy in predicting pCR

The bone marrow microenvironment has a key role in regulating haematopoiesis, but its molecular complexity and response to stress are incompletely understood. Here we map the transcriptional landscape of mouse bone marrow vascular, perivascular and osteoblast cell populations at single-cell resolution, both at homeostasis and under conditions of stress-induced haematopoiesis. This analysis revealed previously unappreciated levels of cellular heterogeneity within the bone marrow niche and resolved cellular sources of pro-haematopoietic growth factors, chemokines and membrane-bound ligands. Our studies demonstrate a considerable transcriptional remodelling of niche elements under stress conditions, including an adipocytic skewing of perivascular cells. Among the stress-induced changes, we observed that vascular Notch delta-like ligands (encoded by Dll1 and Dll4) were downregulated. In the absence of vascular Dll4, haematopoietic stem cells prematurely induced a myeloid transcriptional program. These findings refine our understanding of the cellular architecture of the bone marrow niche, reveal a dynamic and heterogeneous molecular landscape that is highly sensitive to stress and illustrate the utility of single-cell transcriptomic data in evaluating the regulation of haematopoiesis by discrete niche populations.