Faculty Bibliography

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.

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

In this paper, we discuss adjusted cumulative incidence in multiple treatment groups with unbalanced samples. In a nonrandomized experiment or an observational study, the observed data may be unbalanced in covariates when multiple treatments are administered differently based on patients' characteristics. In the case of multiple survival outcomes, clinical researchers are often interested in estimating the cumulative incidence within a specific treatment group, and this approach is subject to a potential bias with unbalanced samples. Using extensive simulation analyses, we demonstrate that a naïve approach to the estimation of a cumulative incidence curve may yield misleading results, unless patients' characteristics are fully considered. To achieve an unbiased estimation from unbalanced data, we propose an adjusted cumulative incidence based on the inverse probability of a treatment weighting. In a series of simulations, the proposed method shows robust performance when estimating cumulative incidence under various scenarios, including balanced and unbalanced samples. Lastly, we explain how to apply the proposed method using an example based on real data.

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.

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.

BACKGROUND:Full-term pregnancy (FTP) at an early age confers long-term protection against breast cancer. Previously, we reported that a FTP imprints a specific gene expression profile in the breast of postmenopausal women. Herein, we evaluated gene expression changes induced by parity in the breast of premenopausal women. METHODS:Gene expression profiling of normal breast tissue from 30 nulliparous (NP) and 79 parous (P) premenopausal volunteers was performed using Affymetrix microarrays. In addition to a discovery/validation analysis, we conducted an analysis of gene expression differences in P vs. NP women as a function of time since last FTP. Finally, a laser capture microdissection substudy was performed to compare the gene expression profile in the whole breast biopsy with that in the epithelial and stromal tissues. RESULTS:Discovery/validation analysis identified 43 differentially expressed genes in P vs. NP breast. Analysis of expression as a function of time since FTP revealed 286 differentially expressed genes (238 up- and 48 downregulated) comparing all P vs. all NP, and/or P women whose last FTP was less than 5 years before biopsy vs. all NP women. The upregulated genes showed three expression patterns: (1) transient: genes upregulated after FTP but whose expression levels returned to NP levels. These genes were mainly related to immune response, specifically activation of T cells. (2) Long-term changing: genes upregulated following FTP, whose expression levels decreased with increasing time since FTP but did not return to NP levels. These were related to immune response and development. (3) Long-term constant: genes that remained upregulated in parous compared to nulliparous breast, independently of time since FTP. These were mainly involved in development/cell differentiation processes, and also chromatin remodeling. Lastly, we found that the gene expression in whole tissue was a weighted average of the expression in epithelial and stromal tissues. CONCLUSIONS:Genes transiently activated by FTP may have a role in protecting the mammary gland against neoplastically transformed cells through activation of T cells. Furthermore, chromatin remodeling and cell differentiation, represented by the genes that are maintained upregulated long after the FTP, may be responsible for the lasting preventive effect against breast cancer.