Publications by authors named "Judith D Goldberg"

92 Publications

Comparison of Clinical Measures Among Interstitial Lung Disease (ILD) Patients with Usual Interstitial Pneumonia (UIP) Patterns on High-Resolution Computed Tomography.

Lung 2020 10 5;198(5):811-819. Epub 2020 Sep 5.

Division of Pulmonary, Sleep and Critical Care Medicine, Department of Medicine, NYU Langone Health, NYU Grossman School of Medicine, 550 1 Ave, New York, NY, 10016, USA.

Purpose: Idiopathic Pulmonary Fibrosis is a progressive and fatal interstitial lung disease (ILD) characterized by a typical radiographic or histologic usual interstitial pneumonia (UIP) pattern. In 2018, diagnostic categories of UIP based on computed tomography patterns were revised by the Fleischner Society. The study aimed to describe differences in comorbidities and spirometry in ILD patients that were characterized by high-resolution computed tomography (HRCT) images as having a typical, probable, indeterminate, and alternative diagnosis of UIP.

Methods: We retrospectively studied 80 ILD patients from 2017 to 2019. Typical UIP was defined using the Fleischner Society diagnostic criteria for IPF. Atypical UIP was reached by consensus after a multidisciplinary clinical-radiological-pathological review of patient data. Baseline characteristics, comorbidities, and spirometry were compared among the four subgroups.

Results: Among 80 patients, 59% were male, 61% had a history of smoking, and the mean age was 67.7 ± 10 years (SD). A typical UIP pattern was more frequently observed among patients with chronic obstructive pulmonary disease (COPD) (p < 0.001) and pulmonary hypertension (p = 0.03). Of 30 patients with COPD, 14 had emphysema, while 10 had IPF. After adjusting for forced expiratory volume in one second (FEV) in liters, change of FEV% from baseline to 6-12 months, age, and sex, only COPD remained significantly associated with typical UIP (p = 0.018). Tobacco use was not significantly associated with any radiographic type (p = 0.199).

Conclusion: Typical UIP was prevalent among COPD/emphysema patients. Although smoking has a strong association with IPF, we did not find a significant association with smoking and typical UIP in our cohort.
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http://dx.doi.org/10.1007/s00408-020-00387-6DOI Listing
October 2020

Value of metalloproteinases in predicting COPD in heavy urban smokers.

Respir Res 2020 Sep 2;21(1):228. Epub 2020 Sep 2.

William N. Rom Environmental Lung Disease Laboratory, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA.

Background: Emphysema in asymptomatic heavy smokers can be detected during CT-scan screening for lung cancer. Metalloproteinases (MMPs) have been found to play a role in the pathogenesis of chronic obstructive pulmonary disease and to possibly serve as biomarkers for emphysema.

Methods: The NYU Lung Cancer Biomarker Center enrolled study subjects over 50 years of age with lung cancer risk factors from January 1, 2010, to December 31, 2015. These subjects received chest multi-detector computed tomography, spirometry, and provided serum for immunoassays for metalloproteinases (MMP) -1, -2, -7, -9, -10 and tissue inhibitor of metalloproteinases (TIMP) -1 and -2.

Results: Three hundred sixteen study subjects were enrolled. Of the 222 patients who met the inclusion criteria, 46% had emphysema. Smokers with emphysema had increased pack-years of smoking compared to smokers without emphysema (51 ± 24 pack-years (mean ± sd) versus 37 ± 20; p < 0.0001). Smokers with emphysema also had lower FEV/FVC percent compared to smokers without emphysema (68 ± 11 (mean ± sd) versus 75 ± 8; p < 0.0001). Increased age and pack-years of smoking were associated with increased odds of emphysema. None of the metalloproteinases or tissue inhibitors of metalloproteinases were useful to predict the presence of emphysema in smokers.

Conclusion: Emphysema was detected by CT in almost half of heavy urban smokers. Serum MMP levels provided minimal additional information to improve the detection of mild emphysema among smokers given their clinical characteristics (age, pack-years, and FEV/FVC ratio).
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http://dx.doi.org/10.1186/s12931-020-01496-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465798PMC
September 2020

Pharmacodynamics of natalizumab extended interval dosing in MS.

Neurol Neuroimmunol Neuroinflamm 2020 03 4;7(2). Epub 2020 Feb 4.

From NYU Multiple Sclerosis Comprehensive Care Center (L.Z.R., I.K.), New York; Division of Biostatistics (X.L., J.D.G.), New York University School of Medicine; and Rocky Mountain MS Research Group (T.H., A.C., R.R.M., J.F.), Salt Lake City, UT.

Objective: To determine if the concentration and saturation of natalizumab (NTZ) administration at extended interval dosing (EID; every 5-8 weeks) over 18 months is able to be maintained in the range considered adequate to sustain the clinical efficacy of NTZ.

Methods: In a cross-sectional assessment of patients with multiple sclerosis (MS) who received standard interval dosing (every 4 weeks) or EID, serum NTZ concentrations were measured using ELISA, and α-integrin receptor saturations were analyzed via cytometry, in blood samples obtained at trough timepoints.

Results: Trough serum concentration was above the "therapeutic" concentration of 2.0 μg/mL in 72% of EID patients. Trough saturation was above the "therapeutic" 50% threshold in 79% of EID-treated patients. Our model predicted that at least 9 NTZ infusions/year are required to maintain adequate trough saturation and concentration levels. Higher body mass index (BMI) was a predictor of suboptimal trough saturation on EID NTZ.

Conclusions: Trough α4-integrin receptor saturation >50% correlated with high clinical efficacy of NTZ in previous studies. A continual treatment with EID maintains receptor saturation and concentration that are in the "therapeutic range" for most patients. This finding provides biological plausibility for the clinical efficacy of NTZ EID. Patients with higher BMI may require closer clinical and MRI follow-up.
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http://dx.doi.org/10.1212/NXI.0000000000000672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057061PMC
March 2020

A Prospective Trial to Compare Deep Inspiratory Breath Hold With Prone Breast Irradiation.

Pract Radiat Oncol 2020 Sep - Oct;10(5):330-338. Epub 2020 Feb 1.

Division of Biostatistics Department of Population Health, New York University School of Medicine, New York, New York.

Purpose: To compare heart and lung doses for adjuvant whole breast irradiation (WBI) between radiation plans generated supine with deep inspiratory breath hold (S-DIBH) and prone with free-breathing (P-FB) and examine the effect of breast volume (BV) on dosimetric parameters.

Methods And Materials: Patients with left breast ductal carcinoma in situ or invasive cancer receiving adjuvant WBI were enrolled on a single-institutional prospective protocol. Patients were simulated S-DIBH and P-FB; plans were generated using both scans. Wilcoxon signed-rank and rank-sum tests were used to compare intrapatient differences between plans for the entire cohort and within BV groups defined by tertiles.

Results: Forty patients were enrolled. Thirty-four patients are included in the analysis owing to patient withdrawal or inability to hold breath. With WBI dose of 4005 to 4256 cGy, mean heart dose (MHD) was 80 cGy in S-DIBH and 77 cGy in P-FB (P = .08). Mean ipsilateral lung dose (MLD) was 453 cGy in S-DIBH and 45 cGy in P-FB (P < .0001). Mean and max left anterior descending artery doses were 251 cGy and 551 cGy in S-DIBH, respectively (P = .1), and 324 cGy and 993 cGy in P-FB, respectively (P = .3). Hot spot and separation were 109% and 22 cm in S-DIBH, respectively, and 107% and 16 cm in P-FB, respectively (P < .0001). For patients with smallest BV, S-DIBH improved MHD and left anterior descending artery doses; for those with largest BV, P-FB improved cardiac dosimetry. With increasing BV, there was an increasing advantage of P-FB for MHD (P = .05), and max (P = .03) and mean (P = .02) left anterior descending artery doses, and the reduction in MLD, hot spot, and separation with P-FB increased (P < .05).

Conclusions: MHD did not differ between P-FB and S-DIBH, whereas MLD was significantly lower with P-FB. Analysis according to breast volume revealed improved cardiac dosimetry with S-DIBH for women with smallest BV and improved cardiac dosimetry with P-FB for women with larger BV, thereby providing a dosimetric rationale for using breast size to help determine the optimal positioning for WBI.
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http://dx.doi.org/10.1016/j.prro.2020.01.001DOI Listing
February 2020

Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing.

Neurology 2019 10 12;93(15):e1452-e1462. Epub 2019 Sep 12.

From the Department of Neurology (L.Z.R., I.K.), NYU Langone Health, New York University, New York; Rocky Mountain MS Clinic (J.F., R.R.M.), Salt Lake City, UT; Biogen (I.C., E.R., K.S., R.K., Z.R., C.H., P-R.H., N.C.), Cambridge, MA; University of Alabama School of Public Health (G.C.), Birmingham; and Division of Biostatistics (J.D.G., X.L.), New York University School of Medicine, New York.

Objective: To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS).

Methods: This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions.

Results: This study included 35,521 patients (primary analysis: 1,988 EID, 13,132 SID; secondary analysis: 3,331 EID, 15,424 SID; tertiary analysis: 815 EID, 23,168 SID). Mean average dosing intervals were 35.0 to 43.0 and 29.8 to 30.5 days for the EID and SID cohorts, respectively. Hazard ratios (95% confidence intervals) of PML risk for EID vs SID were 0.06 (0.01-0.22, < 0.001) and 0.12 (0.05-0.29, < 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID.

Conclusion: Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID.

Classification Of Evidence: This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.
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http://dx.doi.org/10.1212/WNL.0000000000008243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010325PMC
October 2019

Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea.

Blood 2019 10;134(18):1498-1509

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was -6% (range, -84% to 47%) in patients achieving a CR vs +4% (range, -18% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU. This trial was registered at www.clinicaltrials.gov as #NCT01259856.
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http://dx.doi.org/10.1182/blood.2019000428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839950PMC
October 2019

Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients.

J Immunother Cancer 2019 07 11;7(1):177. Epub 2019 Jul 11.

Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, 10065, USA.

Background: We previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGFβ blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, p = 0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP).

Methods: The original trial randomized metastatic breast cancer patients to either 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5 Gy given in 3 doses of 7.5 Gy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression.

Results: At baseline, a significantly higher level of expression (p < 0.05) of PD-L1 was identified in patient monocytes compared to HD. TCR modulation revealed dysfunction of circulating T-cells in patient baseline samples as compared to HD, and this was more pronounced in PD-1 cells. Treatment with radiotherapy and fresolimumab did not resolve this dyfunctional signaling. However, in vitro PD-1 blockade enhanced TCR signaling in patient PD-1 T cells and not in PD-1 T cells or in PD-1 T cells from HD.

Conclusions: Functional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy.

Trial Registration: NCT01401062 .
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http://dx.doi.org/10.1186/s40425-019-0633-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624899PMC
July 2019

Plasma Zonulin Levels in Childhood Nephrotic Syndrome.

Front Pediatr 2019 16;7:197. Epub 2019 May 16.

Department of Population Health, NYU School of Medicine, New York, NY, United States.

We conducted this study to test the hypothesis that plasma zonulin levels are elevated in pediatric patients with nephrotic syndrome compared to healthy controls. Plasma zonulin levels were measured by ELISA in 114 children enrolled in the NEPTUNE study. Clinical and laboratory data were retrieved from the NEPTUNE database. The median age of the patients was 10 (IQR = 5 to 14) years, 59 were male, 64 had minimal change disease, 47 focal segmental glomerulosclerosis, median eGFR was 96 (IQR = 80 to 114) ml/min/1.73 m, and median urine protein:creatinine ratio was 0.5 (IQR = 0.1 to 3.4) (g:g). The plasma zonulin level was 14.2 ± 5.0 vs. 10.2 ± 2.5 ng/ml in healthy adults in a report using the same assay kit, = 0.0025. These findings were confirmed in an independent cohort of children with nephrotic syndrome compared to healthy age-matched controls, = 0.01. Zonulin concentrations did not differ in children with minimal change disease vs. focal segmental glomerulosclerosis, frequently relapsing vs. steroid-dependent vs. steroid-resistant clinical course, and were not influenced by the immunosuppressive treatment regimen. There was no relationship between plasma zonulin levels and the absolute or percentage change in proteinuria from enrollment until the time of the zonulin assay. Plasma zonulin levels are elevated in childhood nephrotic syndrome regardless of level of proteinuria or specific treatment. The cause of the high plasma zonulin levels and whether zonulin contributes to glomerular injury requires further study.
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http://dx.doi.org/10.3389/fped.2019.00197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532587PMC
May 2019

Safety and efficacy of combined ruxolitinib and decitabine in accelerated and blast-phase myeloproliferative neoplasms.

Blood Adv 2018 12;2(24):3572-3580

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to evolve into accelerated and blast-phase disease (MPN-AP/BP), carrying a dismal prognosis. Conventional antileukemia therapy has limited efficacy in this setting. Thus, MPN-AP/BP is an urgent unmet clinical need. Modest responses to hypomethylating agents and single-agent ruxolitinib have been reported. More recently, combination of ruxolitinib and decitabine has demonstrated synergistic in vitro activity in human and murine systems. These observations led us to conduct a phase 1 study to explore the safety of combined decitabine and dose-escalated ruxolitinib in patients with MPN-AP/BP. A total of 21 patients were accrued to this multicenter study. Ruxolitinib was administered at doses of 10, 15, 25, or 50 mg twice daily in combination with decitabine (20 mg/m per day for 5 days) in 28-day cycles. The maximum tolerated dose was not reached. The most common reasons for study discontinuation were toxicity/adverse events (37%) and disease progression (21%). Fourteen patients died during study treatment period or follow-up. The median overall survival for patients on study was 7.9 months (95% confidence interval, 4.1-not reached). Among evaluable patients, the overall response rate by protocol-defined criteria (complete remission with incomplete count recovery + partial remission) was 9/17 (53%) and by intention-to-treat analysis was 9/21 (42.9%). The combination of decitabine and ruxolitinib was generally well tolerated by patients with MPN-AP/BP and demonstrates potentially promising clinical activity. A phase 2 trial evaluating the efficacy of this combination regimen is ongoing within the Myeloproliferative Disorder Research Consortium.
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http://dx.doi.org/10.1182/bloodadvances.2018019661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306885PMC
December 2018

Serum albumin at 1 year predicts long-term renal outcome in lupus nephritis.

Lupus Sci Med 2018 4;5(1):e000271. Epub 2018 Sep 4.

NYU Division of Rheumatology, NYU Medical Center, New York, USA.

Objectives: The study aimed to determine if serum albumin at 12 months predicts long-term renal outcome at 48 months. Data from the NYU SAMPLE (Specimen and Matched Phenotype Linked Evaluation) Lupus Registry were used to compare the performance of albumin, anti-double-stranded DNA, C3/C4, proteinuria and haematuria.

Methods: 82 patients with SLE with data at time of renal biopsy, at 12 months and at a second visit, and up to 48 months were included. The significance of each biomarker as a predictor of an adverse renal outcome (ARO), defined as doubling of serum creatinine, as creatinine >4 mg/dL if initial >2.5 mg/dL or ESRD, was evaluated in univariate and exploratory multivariable Cox proportional hazards models. Hazard ratios (HRs) for ARO with 95% CIs were generated. The receiver operating characteristic (ROC) curves at 48 months were used to identify the optimal cut-off point for albumin and proteinuria to predict ARO. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for albumin and proteinuria.

Results: Serum albumin and proteinuria had statistically significant HRs for ARO (0.140 and 1.459, respectively). The model with both albumin and proteinuria indicated no additional independent contribution of proteinuria to albumin alone. The ROC curves identified cut-offs of 3.7 g/dL for albumin and 0.964 urine protein to creatinine ratio for proteinuria. Albumin had a sensitivity of 94%, specificity of 87%, PPV of 64% and NPV of 98%.

Conclusions: This study demonstrates serum albumin >3.7 g/dL is a predictor of a favourable long-term renal outcome. These results support the inclusion of albumin as an outcome in lupus nephritis trials and treat-to-target guidelines.
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http://dx.doi.org/10.1136/lupus-2018-000271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135447PMC
September 2018

Hypofractionated Whole-Breast Irradiation in Women Less Than 50 Years Old Treated on 4 Prospective Protocols.

Int J Radiat Oncol Biol Phys 2018 08 19;101(5):1159-1167. Epub 2018 Apr 19.

Department of Radiation Oncology, New York University School of Medicine, New York, New York. Electronic address:

Purpose: Hypofractionated whole-breast radiation therapy (RT) has proved to be equivalent to conventionally fractionated RT in multiple randomized trials. There is controversy regarding its use in younger women because of their underrepresentation in trials and the concern for late toxicity. We evaluated disease control and cosmetic outcomes in patients aged <50 years treated with hypofractionated RT in 4 prospective single-institutional trials.

Methods And Materials: From 2003 to 2015, 1313 patients were enrolled in 4 prospective protocols investigating the use of adjuvant hypofractionated RT after breast-conserving surgery with a daily or weekly concomitant boost. We identified the records of 348 patients aged <50 years at consultation for this analysis. Overall survival, disease-free survival, and local recurrence-free survival were estimated using the Kaplan-Meier method by study and across studies using meta-analytic methods. The late effects of RT, clinician-rated cosmesis, and patient-rated cosmesis were also evaluated.

Results: With a median follow-up period of 66.9 months, the overall survival rate was 99.6%, the disease-free survival rate was 96.3%, and the local recurrence-free survival rate was 97.7% at 3 years. Clinician-rated cosmesis (n = 242) was excellent or good in 93.4% of cases and fair or poor in 6.6%. Patient-rated cosmesis (n = 259) was excellent or good in 86.1% and fair or poor in 13.9%. When patients rated themselves differently than their physicians, patients more often rated themselves poorly compared with their physicians (P = .0044, Cochran-Mantel-Haenszel test).

Conclusions: At a median follow-up of 5 years, an analysis of patients aged <50 years demonstrated that hypofractionated RT was safe and effective, with good to excellent cosmesis as assessed by both clinicians and patients.
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http://dx.doi.org/10.1016/j.ijrobp.2018.04.034DOI Listing
August 2018

Focal Irradiation and Systemic TGFβ Blockade in Metastatic Breast Cancer.

Clin Cancer Res 2018 06 23;24(11):2493-2504. Epub 2018 Feb 23.

Department of Radiation Oncology, University of California, Los Angeles, California.

This study examined the feasibility, efficacy (abscopal effect), and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients. Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for five cycles, with focal radiotherapy to a metastatic site at week 1 (three doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5, and 15 to isolate PBMCs, plasma, and serum. Twenty-three patients were randomized, median age 57 (range 35-77). Seven grade 3/4 adverse events occurred in 5 of 11 patients in the 1 mg/kg arm and in 2 of 12 patients in the 10 mg/kg arm, respectively. Response was limited to three stable disease. At a median follow up of 12 months, 20 of 23 patients are deceased. Patients receiving the 10 mg/kg had a significantly higher median overall survival than those receiving 1 mg/kg fresolimumab dose [hazard ratio: 2.73 with 95% confidence interval (CI), 1.02-7.30; = 0.039]. The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool. TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999326PMC
June 2018

Delivery of adjuvant chemotherapy among stage III colon cancer patients at a public versus private hospital in New York City.

Cancer Causes Control 2018 02 18;29(2):253-260. Epub 2017 Dec 18.

Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.

Purpose: Prior studies of timeliness of adjuvant chemotherapy (AC) initiation in stage III colon cancer have suggested longer time to AC at public compared with private hospitals. Few studies have explored differences in AC completion. We investigated whether timely initiation and completion of AC differed between a public and private hospital, affiliated with the same academic institution in a large, urban setting.

Methods: We conducted a retrospective cohort study of stage III colon cancer patients who had surgery and AC at the same medical center between 2008 and 2015, either at its affiliated public hospital (n = 43) or private hospital (n = 79). We defined timely initiation as receiving AC within 60 days postoperatively, and completion as receiving ≥ 75% of planned AC. Univariate and stepwise multivariable logistic regressions were used to identify factors associated with AC delivery.

Results: Median number of days to AC was significantly greater among patients at the public (53, range 31-231) compared with the private hospital (43, range 25-105; p = 0.002). However, the percentage of patients with timely AC initiation did not differ substantially by hospital (74 vs 81%, p = 0.40). In multivariable analysis, age (OR 0.95/year, 95% CI 0.91-0.99) and laparoscopic versus open surgery (OR 5.65, 95% CI 1.92-16.62) were significant factors associated with timely AC initiation. Moreover, AC completion did not differ significantly between public (83.7%) and private (89.9%) hospital patients (p = 0.32).

Conclusions: The proportions of patients with timely initiation and completion of AC were similar at a public and private hospital affiliated with a large, urban medical center. Future research should investigate how specific system-level factors help alleviate this expected difference in timely care delivery.
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http://dx.doi.org/10.1007/s10552-017-0996-6DOI Listing
February 2018

Serial immunological parameters in a phase II trial of exemestane and low-dose oral cyclophosphamide in advanced hormone receptor-positive breast cancer.

Breast Cancer Res Treat 2018 Feb 9;168(1):57-67. Epub 2017 Nov 9.

Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, 160 East 34th Street, New York, NY, 10016, USA.

Background And Purpose: Resistance to endocrine therapies in hormone receptor (HR)-positive breast cancer is a significant challenge. Prior studies have shown that low-dose oral cyclophosphamide can transiently deplete regulatory T cells (Tregs) and improve anti-tumor immunity. We investigated the combination of exemestane with cyclophosphamide in patients with advanced HR-positive breast cancer and assessed changes in circulating immune cell subsets.

Methods: This was a single-arm phase II trial of exemestane with cyclophosphamide in patients with metastatic HR-positive/HER2-negative breast cancer who had progressed on prior endocrine therapy (ClinicalTrials.gov: NCT01963481). Primary endpoint was progression-free survival (PFS) at 3 months (RECIST 1.1). Secondary objectives included median PFS, objective response rate, duration of response, and safety. Circulating Tregs (FOXP3Helios) and other immune cell subsets were monitored during treatment and compared with healthy controls.

Results: Twenty-three patients were enrolled. Treatment was well tolerated, without grade 4/5 toxicities. Objective responses were seen in 6/23 patients (26.1%; 95% CI 10.2-48.4%) and were durable (median 11.6 months). Three-month PFS rate was 50.1% (95% CI 33.0-76.0%); median PFS was 4.23 months (95% CI 2.8-11.7). No treatment-related decrease in Tregs was observed. However, elevated baseline levels of Naïve Tregs [greater than 2.5 (the median of the naïve Tregs)] were associated with relative risk of disease progression or death [hazard ratio 11.46 (95% CI 2.32-56.5)]. In addition, the baseline levels of Naïve Tregs (adj-p = 0.04), Memory Tregs (adj-p = 0.003), CD4 + Central Memory T cells (adj-p = 0.0004), PD-1 + CD4 + Central Memory T cells (adj-p = 0.008), and PD-1 + CD4 + Effector Memory T cells (adj-p = 0.009) were significantly greater in the patients than in the healthy controls; the baseline levels of  %CD4 + Naïve T cells (adj-p = 0.0004) were significantly lower in patients compared with healthy controls (n = 40).

Conclusion: Treg depletion was not observed with low-dose cyclophosphamide when assessed by the specific marker FOXP3 + Helios +; however, baseline naïve Tregs were associated with 3-month PFS. Exemestane/cyclophosphamide combination had favorable safety profile with evidence of clinical activity in heavily pretreated patients.
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http://dx.doi.org/10.1007/s10549-017-4570-4DOI Listing
February 2018

Rapid Number Naming and Quantitative Eye Movements May Reflect Contact Sport Exposure in a Collegiate Ice Hockey Cohort.

J Neuroophthalmol 2018 03;38(1):24-29

Departments of Neurology (LH, SPT, LS, RCN, JR, TEH, J-RR, WD, JCR, SLG, LJB), Population Health (LJB, BM, JDG), Ophthalmology (JCR, SLG, LJB), and Physical Medicine and Rehabilitation (JDD, TEH, J-RR), New York University School of Medicine, New York, New York; and Department of Athletics (NW), New York University, New York, New York.

Background: The King-Devick (K-D) test of rapid number naming is a reliable visual performance measure that is a sensitive sideline indicator of concussion when time scores worsen (lengthen) from preseason baseline. Within cohorts of youth athletes <18 years old, baseline K-D times become faster with increasing age. We determined the relation of rapid number-naming time scores on the K-D test to electronic measurements of saccade performance during preseason baseline assessments in a collegiate ice hockey team cohort. Within this group of young adult athletes, we also sought to examine the potential role for player age in determining baseline scores.

Methods: Athletes from a collegiate ice hockey team received preseason baseline testing as part of an ongoing study of rapid rink-side performance measures for concussion. These included the K-D test (spiral-bound cards and tablet computer versions). Participants also performed a laboratory-based version of the K-D test with simultaneous infrared-based video-oculographic recordings using an EyeLink 1000+. This allowed measurement of the temporal and spatial characteristics of eye movements, including saccadic velocity, duration, and intersaccadic interval (ISI).

Results: Among 13 male athletes, aged 18-23 years (mean 20.5 ± 1.6 years), prolongation of the ISI (a combined measure of saccade latency and fixation duration) was the measure most associated with slower baseline time scores for the EyeLink-paired K-D (mean 38.2 ± 6.2 seconds, r = 0.88 [95% CI 0.63-0.96], P = 0.0001), the K-D spiral-bound cards (36.6 ± 5.9 seconds, r = 0.60 [95% CI 0.08-0.87], P = 0.03), and K-D computerized tablet version (39.1 ± 5.4 seconds, r = 0.79 [95% CI 0.42-0.93], P = 0.001). In this cohort, older age was a predictor of longer (worse) K-D baseline time performance (age vs EyeLink-paired K-D: r = 0.70 [95% CI 0.24-0.90], P = 0.008; age vs K-D spiral-bound cards: r = 0.57 [95% CI 0.03-0.85], P = 0.04; age vs K-D tablet version: r = 0.59 [95% CI 0.06-0.86], P = 0.03) as well as prolonged ISI (r = 0.62 [95% CI 0.11-0.87], P = 0.02). Slower baseline K-D times were not associated with greater numbers of reported prior concussions.

Conclusions: Rapid number-naming performance using the K-D at preseason baseline in this small cohort of collegiate ice hockey players is best correlated with ISI among eye movement-recording measures. Baseline K-D scores notably worsened with increasing age, but not with numbers of prior concussions in this small cohort. While these findings require further investigation by larger studies of contact and noncontact sports athletes, they suggest that duration of contact sports exposure may influence preseason test performance.
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http://dx.doi.org/10.1097/WNO.0000000000000533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022287PMC
March 2018

Preplanning prediction of the left anterior descending artery maximum dose based on patient, dosimetric, and treatment planning parameters.

Adv Radiat Oncol 2016 Oct-Dec;1(4):373-381. Epub 2016 Aug 9.

Department of Radiation Oncology, New York University School of Medicine and Langone Medical Center, New York, New York.

Purpose: Maximum dose to the left anterior descending artery (LADmax) is an important physical constraint to reduce the risk of cardiovascular toxicity. We generated a simple algorithm to guide the positioning of the tangent fields to reliably maintain LADmax <10 Gy.

Methods And Materials: Dosimetric plans from 146 consecutive women treated prone to the left breast enrolled in prospective protocols of accelerated whole breast radiation therapy, with a concomitant daily boost to the tumor bed (40.5 Gy/15 fraction to the whole breast and 48 Gy to the tumor bed), provided the training set for algorithm development. Scatter plots and correlation coefficients were used to describe the bivariate relationships between LADmax and several parameters: distance from the tumor cavity to the tangent field edge, cavity size, breast separation, field size, and distance from the tangent field. A logistic sigmoid curve was used to model the relationship of LADmax and the distance from the tangent field. Furthermore, we tested this prediction model on a validation data set of 53 consecutive similar patients.

Results: A lack of linear relationships between LADmax and distance from cavity to LAD (-0.47), cavity size (-0.18), breast separation (-0.02), or field size (-0.28) was observed. In contrast, distance from the tangent field was highly negatively correlated to LADmax (-0.84) and was used in the models to predict LADmax. From a logistic sigmoid model we selected a cut-point of 2.46 mm (95% confidence interval, 2.19-2.74 mm) greater than which LADmax is <10 Gy (95% confidence interval, 9.30-10.72 Gy) and LADmean is <3.3 Gy.

Conclusions: Placing the edge of the tangents at least 2.5 mm from the closest point of the contoured LAD is likely to assure LADmax is <10 Gy and LADmean is <3.3 Gy in patients treated with prone accelerated breast radiation therapy.
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http://dx.doi.org/10.1016/j.adro.2016.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514165PMC
August 2016

Results of a phase I-II study of adjuvant concurrent carboplatin and accelerated radiotherapy for triple negative breast cancer.

Oncoimmunology 2017;6(3):e1274479. Epub 2016 Dec 27.

Department of Medicine, New York University School of Medicine , New York, NY, USA.

: To determine feasibility and explore the clinical efficacy of concurrent radiotherapy and carboplatin as adjuvant treatment of triple negative breast cancer (TNBC). : Women with Stage I-II TNBC were treated after surgery in a phase I-II prospective trial [NCT01289353]. Weekly carboplatin (AUC = 2.0) was delivered for 6 weeks. Concurrent radiotherapy was delivered in the prone position during weeks 2-4, for a total dose of 40.5 Gy in 15 fractions to the breast, and 46.5 Gy in 17 fractions to the tumor bed. Adverse events (AE) were assessed weekly during treatment, once at 45-60 d, and every 6 mo thereafter, using the Common Terminology Criteria for AE (CTCAE) v3.0. : A total of 39 patients accrued and 36 received treatment. Eight patients (22%, exact 95% CI: 10%, 39%) developed grade 2 or greater acute radiation dermatitis. Overall, grade 2 AE were seen in nine and grade 3 in two patients. Twenty-three patients (64%) received additional adjuvant chemotherapy. With a median follow-up of 48 mo, 34/36 (94%) are alive and disease free. One patient died of pulmonary failure with possible but unproven breast cancer recurrence, and one patient died of pelvic malignancy. One patient recurred locally and is alive and disease free after surgical management. Brisk lymphocytic infiltrate was present pre-treatment in 39% of 18 patients with evaluable tumor. : Adjuvant concurrent carboplatin and prone accelerated radiotherapy is a well-tolerated and promising treatment of early stage TNBC. The observed 3% compares favorably with the expected 30% recurrence rate within 1-4 y from treatment, warranting further studies.
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http://dx.doi.org/10.1080/2162402X.2016.1274479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384379PMC
December 2016

Phase II study of irinotecan in combination with bevacizumab in recurrent ovarian cancer.

Gynecol Oncol 2017 Feb 5;144(2):279-284. Epub 2016 Dec 5.

Medical Oncology, Perlmutter Cancer Center at the New York University Langone Medical Center, United States. Electronic address:

Objectives: To evaluate the efficacy and safety of irinotecan and bevacizumab in recurrent ovarian cancer. The primary objective was to estimate the progression free survival (PFS) rate at 6months. Secondary objectives included estimation of overall survival (OS), objective response rate (ORR), duration of response, and an evaluation of toxicity.

Methods: Recurrent ovarian cancer patients with no limit on prior treatments were eligible. Irinotecan 250mg/m2 (amended to 175mg/m2 after toxicity assessment in first 6 patients) and bevacizumab 15mg/kg were administered every 3weeks until progression or toxicity. Response was assessed by RECIST or CA-125 criteria every 2cycles.

Results: Twenty nine patients enrolled (10 were platinum-sensitive and 19 were platinum-resistant). The median number of prior regimens was 5 (range 1-12); 13 patients had prior bevacizumab and 11 prior topotecan. The PFS rate at 6months was 55.2% (95% CI: 40%-77%). The median number of study cycles given was 7 (range 1-34). Median PFS was 6.8months (95% CI: 5.1-12.1months); median OS was 15.4months (95% CI: 11.9-20.4months). In this study, no complete response (CR) was observed. The objective response rate (ORR; PR or CR) for all patients entered was 27.6% (95% CI: 12.7%-47.2%) and the clinical benefit rate (CR+PR+SD) was 72.4% (95% CI: 52.8%-87.3%); twelve patients experienced duration of response longer than 6months. In the 24 patients with measurable disease, a partial response (PR) was documented in 8 (30%) patients; 13 patients maintained stable disease (SD) at first assessment. The most common grade 3/4 toxicity was diarrhea. No treatment-related deaths were observed.

Conclusions: Irinotecan and bevacizumab has activity in heavily pre-treated patients with recurrent ovarian cancer, including those with prior bevacizumab and topoisomerase inhibitor use.
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http://dx.doi.org/10.1016/j.ygyno.2016.11.043DOI Listing
February 2017

A phase II study of panobinostat in patients with primary myelofibrosis (PMF) and post-polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET MF).

Leuk Res 2017 02 30;53:13-19. Epub 2016 Nov 30.

Tisch Cancer Institute, Division of Hemato and Oncologylogy, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Myelofibrosis is a chronic and progressive myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating symptoms and leukemic transformation. Ruxolitinib, an oral JAK1/2 inhibitor, is highly effective in ameliorating systemic symptoms and reducing splenomegaly. Current clinical research is focused on the evaluation of agents based on pre-clinical rationale that can result in disease course modification. Panobinostat is a pan-histone deacetylase inhibitor that has demonstrated clinical activity as a single agent in early phase trials of myelofibrosis. We previously conducted a phase I trial of panobinostat monotherapy in patients with myelofibrosis and determined 25mg thrice weekly as the recommended phase II dose. We then completed an investigator initiated, Simon 2-stage, phase II trial of 22 myelofibrosis patients at our single institution. After 6 cycles of therapy, the overall response rate by IWG-MRT criteria was 36% (8/22; 95% CI: 16-56%). The median percent reduction in spleen volume was 34% (range, 1.6%-73%) in eight evaluable patients. The average reduction in JAK2V617F allele burden was 6.8% (Range; -4.0% to 20.2%) and one patient obtained a complete molecular response. Six patients remained on therapy in the extension phase for a median of 18 months (range, 7-44). Treatment discontinuation was frequent due to patient/physician perception of therapy ineffectiveness. The optimal dosing of panobinostat for the treatment of MF remains somewhat ill-defined but appears to be most effective and better tolerated when administered at lower doses over a prolonged duration of therapy.
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http://dx.doi.org/10.1016/j.leukres.2016.11.015DOI Listing
February 2017

Multifocal Invasive Ductal Cancer: Distinguishing Independent Tumor Foci From Multiple Satellites.

Int J Surg Pathol 2017 Jun 10;25(4):298-303. Epub 2016 Nov 10.

1 NYU Langone Medical Center, New York, NY, USA.

Patients with multifocal breast cancers (MBCs) have a poorer prognosis than patients with unifocal breast cancers. Studies have attributed this to tumor size underestimation in MBC. An alternative hypothesis is that some MBCs behave in a fashion analogous to the "satellite" and "in-transit metastasis" observed in melanoma and, thereby, are more clinically aggressive. We identified 79 cases of MBC, which we classified into 2 groups: study cases defined as ≥2 morphologically similar tumor foci with ≥1 focus without in situ carcinoma (n = 21); and a control group defined as ≥2 morphologically similar or dissimilar foci with associated in situ carcinoma in all foci (n = 58). The odds of being a study case is 1.86 (95% confidence interval [CI] 1.26-2.74) times greater per unit increase in number of tumor foci (median of 4 tumor foci; P = .002). Study cases were 73.33 (95% CI = 8.91-603.16) times more likely to have lymphovascular invasion (LVI) and 14.72 (95% CI = 4.37-49.61) times more likely to have nodal metastases. Grade I/II tumors were 0.20 (95% CI = 0.07-0.59) times less likely to be study cases. There was a significant positive interaction ( P < 0.001) indicated by the relationship of LVI status and nodal status with the study case and control group. We conclude that there is a subset of MBC that presents with more numerous tumor foci and a higher rate of nodal metastasis. The aggressive behavior of these cases may be attributed to their proclivity for LVI.
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http://dx.doi.org/10.1177/1066896916676586DOI Listing
June 2017

Prospective Randomized Trial of Prone Accelerated Intensity Modulated Breast Radiation Therapy With a Daily Versus Weekly Boost to the Tumor Bed.

Int J Radiat Oncol Biol Phys 2016 06 29;95(2):571-8. Epub 2015 Dec 29.

Department of Radiation Oncology, New York University School of Medicine and Langone Medical Center, New York, New York. Electronic address:

Purpose: To report the results of a prospective randomized trial comparing a daily versus weekly boost to the tumor cavity during the course of accelerated radiation to the breast with patients in the prone position.

Methods And Materials: From 2009 to 2012, 400 patients with stage 0 to II breast cancer who had undergone segmental mastectomy participated in an institutional review board-approved trial testing prone breast radiation therapy to 40.5 Gy in 15 fractions 5 d/wk to the whole breast, after randomization to a concomitant daily boost to the tumor bed of 0.5 Gy, or a weekly boost of 2 Gy, on Friday. The present noninferiority trial tested the primary hypothesis that a weekly boost produced no more acute toxicity than did a daily boost. The recurrence-free survival was estimated for both treatment arms using the Kaplan-Meier method; the relative risk of recurrence or death was estimated, and the 2 arms were compared using the log-rank test.

Results: At a median follow-up period of 45 months, no deaths related to breast cancer had occurred. The weekly boost regimen produced no more grade ≥2 acute toxicity than did the daily boost regimen (8.1% vs 10.4%; noninferiority Z = -2.52; P=.006). No statistically significant difference was found in the cumulative incidence of long-term fibrosis or telangiectasia of grade ≥2 between the 2 arms (log-rank P=.923). Two local and two distant recurrences developed in the daily treatment arm and three local and one distant developed in the weekly arm. The 4-year recurrence-free survival rate was not different between the 2 treatment arms (98% for both arms).

Conclusions: A tumor bed boost delivered either daily or weekly was tolerated similarly during accelerated prone breast radiation therapy, with excellent control of disease and comparable cosmetic results.
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http://dx.doi.org/10.1016/j.ijrobp.2015.12.373DOI Listing
June 2016

Likelihood ratio and score tests to test the non-inferiority (or equivalence) of the odds ratio in a crossover study with binary outcomes.

Stat Med 2016 09 19;35(20):3471-81. Epub 2016 Apr 19.

Division of Biostatistics, Department of Population Health, New York University School of Medicine, New York, U.S.A.

We consider the non-inferiority (or equivalence) test of the odds ratio (OR) in a crossover study with binary outcomes to evaluate the treatment effects of two drugs. To solve this problem, Lui and Chang (2011) proposed both an asymptotic method and a conditional method based on a random effects logit model. Kenward and Jones (1987) proposed a likelihood ratio test (LRTM ) based on a log linear model. These existing methods are all subject to model misspecification. In this paper, we propose a likelihood ratio test (LRT) and a score test that are independent of model specification. Monte Carlo simulation studies show that, in scenarios considered in this paper, both the LRT and the score test have higher power than the asymptotic and conditional methods for the non-inferiority test; the LRT, score, and asymptotic methods have similar power, and they all have higher power than the conditional method for the equivalence test. When data can be well described by a log linear model, the LRTM has the highest power among all the five methods (LRTM , LRT, score, asymptotic, and conditional) for both non-inferiority and equivalence tests. However, in scenarios for which a log linear model does not describe the data well, the LRTM has the lowest power for the non-inferiority test and has inflated type I error rates for the equivalence test. We provide an example from a clinical trial that illustrates our methods. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/sim.6970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961621PMC
September 2016

Quality of Life in Women Undergoing Breast Irradiation in a Randomized, Controlled Clinical Trial Evaluating Different Tumor Bed Boost Fractionations.

Int J Radiat Oncol Biol Phys 2016 06 6;95(2):579-89. Epub 2016 Feb 6.

Department of Radiation Oncology, New York University School of Medicine, New York, New York. Electronic address:

Purpose: To identify differences in breast cancer patient-reported quality of life (QOL) between 2 radiation tumor bed boost dose regimens.

Methods And Materials: Four hundred patients with stage 0, I, or II breast cancer who underwent segmental mastectomy with sentinel node biopsy and/or axillary node dissection were treated with either a daily or weekly boost. Patients were treated prone to 40.5 Gy/15 fractions to the whole breast, 5 days per week. Patients were randomized to a concomitant daily boost to the tumor bed of 0.5 Gy, or a weekly boost of 2 Gy on Friday. Patients completed 6 validated QOL survey instruments at baseline, last week of treatment (3 weeks), 45-60 days from the completion of radiation treatment, and at 2-year follow-up.

Results: There were no statistically significance differences in responses to the 6 QOL instruments between the daily and weekly radiation boost regimens, even after adjustment for important covariates. However, several changes in responses over time occurred in both arms, including worsening functional status, cosmetic status, and breast-specific pain at the end of treatment as compared with before and 45 to 60 days after the conclusion of treatment.

Conclusions: Whole-breast, prone intensity modulated radiation has similar outcomes in QOL measures whether given with a daily or weekly boost. This trial has generated the foundation for a current study of weekly versus daily radiation boost in women with early breast cancer in which 3-dimensional conformal radiation is allowed as a prospective stratification factor.
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http://dx.doi.org/10.1016/j.ijrobp.2016.02.004DOI Listing
June 2016

Hyperactivated mTOR and JAK2/STAT3 Pathways: Molecular Drivers and Potential Therapeutic Targets of Inflammatory and Invasive Ductal Breast Cancers After Neoadjuvant Chemotherapy.

Clin Breast Cancer 2016 Apr 1;16(2):113-22.e1. Epub 2015 Dec 1.

Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY; Department of Microbiology, New York University School of Medicine, New York, NY.

Introduction: Inflammatory breast cancer (IBC) is an aggressive and rare cancer with a poor prognosis and a need for novel targeted therapeutic strategies. Preclinical IBC data showed strong activation of the phosphatidylinositide-3-kinase/mammalian target of rapamycin (mTOR) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, and expression of inflammatory cytokines and tumor-associated macrophages (TAMs).

Patients And Methods: Archival tumor tissue from 3 disease types (IBC treated with neoadjuvant chemotherapy [NAC], n = 45; invasive ductal carcinoma [IDC] treated with NAC [n = 24; 'treated IDC'; and untreated IDC [n = 27; 'untreated IDC']) was analyzed for the expression of biomarkers phospho-S6 (pS6) (mTOR), phospho-JAK2 (pJAK2), pSTAT3, interleukin (IL)-6, CD68 (monocytes, macrophages), and CD163 (TAMs). Surrounding nontumor tissue was also analyzed.

Results: Biomarker levels and surrogate activity according to site-specific phosphorylation were shown in the tumor tissue of all 3 disease types but were greatest in IBC and treated IDC and least in untreated IDC for pS6, pJAK2, pSTAT3, and IL-6. Of 37 IBC patients with complete biomarker data available, 100% were pS6-positive and 95% were pJAK2-positive. In nontumor tissue, biomarker levels were observed in all groups but were generally greatest in untreated IDC and least in IBC, except for JAK2.

Conclusion: IBC and treated IDC display similar levels of mTOR and JAK2 biomarker activation, which suggests a potential mechanism of resistance after NAC. Biomarker levels in surrounding nontumor tissue suggested that the stroma might be activated by chemotherapy and resembles the oncogenic tumor-promoting environment. Activation of pS6 and pJAK2 in IBC might support dual targeting of the mTOR and JAK/STAT pathways, and the need for prospective studies to investigate combined targeted therapies in IBC.
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http://dx.doi.org/10.1016/j.clbc.2015.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794410PMC
April 2016

Inflammatory cytokines and non-small cell lung cancer in a CT-scan screening cohort: Background review of the literature.

Cancer Biomark 2016 ;16(2):219-33

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University School of Medicine, New York, NY, USA.

Background: Inflammatory cytokines are at the intersection of tumor cell biology and host immune response. Peripheral cytokine expression levels may reflect the microscopic tumor milieu, and specific cytokines play an integral role in tumor initiation, growth, and metastasis. High-throughput cytokine analysis may identify panels for early-stage non-small cell lung cancer (NSCLC) diagnosis and identify individuals at high-risk for lung cancer with indeterminate lung nodules 8-20 mm in size.

Methods: Thirteen serum cytokines from the NYU Lung Cancer Biomarker Center cohort with early-stage NSCLC were analyzed using bead-based immunoassay technology.

Results: In the NYU cohort, a one unit increase in interferon-γ increased risk of lung cancer by 3% (OR = 1.03, 95% CI, 1.02-1.05) and a one unit increase in TNF-α decreased the risk of lung cancer by 53% (OR = 0.47, 95% Cl, 0.31-0.71) when both cytokines were included in a logistic regression model with adjustments for age and pack-years of smoking. The resulting AUC for the Receiver Operating Characteristic (ROC) curve was 0.88; the sensitivity and specificity at the optimal cutpoint were 78.9% and 90.3%, respectively.

Conclusions: Cytokines have limited value in the early diagnosis of early-stage NSCLC. Our review of the literature suggests that although inflammation is important for the development of NSCLC, that cytokines are increased in more advanced lung cancer than when the diagnosis occurs at presentation.
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http://dx.doi.org/10.3233/CBM-150559DOI Listing
December 2016

Cell cycle features of C. elegans germline stem/progenitor cells vary temporally and spatially.

Dev Biol 2016 Jan 11;409(1):261-271. Epub 2015 Nov 11.

Skirball Institute of Biomolecular Medicine, Helen L. and Martin S. Kimmel Center for Stem Cell Biology, Departments of Cell Biology and Pathology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA. Electronic address:

Many organisms accumulate a pool of germline stem cells during development that is maintained in later life. The dynamics of establishment, expansion and homeostatic maintenance of this pool are subject to both developmental and physiological influences including the availability of a suitable niche microenvironment, nutritional status, and age. Here, we investigated the dynamics of germline proliferation during stages of expansion and homeostasis, using the C. elegans germ line as a model. The vast majority of germ cells in the proliferative zone are in interphase stages of mitosis (G1, S, G2) rather than in the active mitotic (M) phase. We examined mitotic index and DNA content, comparing different life stages, mutants, and physiological conditions. We found that germ cells in larval stages cycle faster than in adult stages, but that this difference could not be attributed to sexual fate of the germ cells. We also found that larval germ cells exhibit a lower average DNA content compared to adult germ cells. We extended our analysis to consider the effects of distance from the niche and further found that the spatial pattern of DNA content differs between larval and adult stages in the wild type and among mutants in pathways that interfere with cell cycle progression, cell fate, or both. Finally, we characterized expansion of the proliferative pool of germ cells during adulthood, using a regeneration paradigm (ARD recovery) in which animals are starved and re-fed. We compared adult stage regeneration and larval stage expansion, and found that the adult germ line is capable of rapid accumulation but does not sustain a larval-level mitotic index nor does it recapitulate the larval pattern of DNA content. The regenerated germ line does not reach the number of proliferative zone nuclei seen in the continuously fed adult. Taken together, our results suggest that cell cycle dynamics are under multiple influences including distance from the niche, age and/or maturation of the germ line, nutrition and, possibly, latitude for physical expansion.
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http://dx.doi.org/10.1016/j.ydbio.2015.10.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827254PMC
January 2016

Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells.

Blood 2015 Aug 28;126(8):972-82. Epub 2015 May 28.

Division of Hematology/Oncology, Department of Medicine and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;

Myelofibrosis (MF) is characterized by cytopenias, constitutional symptoms, splenomegaly, and marrow histopathological abnormalities (fibrosis, increased microvessel density, and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2), were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > polycythemia vera or essential thrombocythemia) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species, leading to increased DNA strand breaks and apoptosis of normal, but not MF, CD34(+) cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts, but not adipocytes. LCN2 priming of mesenchymal stem cells resulted in the upregulation of RUNX2 gene as well as other genes that are capable of further affecting osteoblastogenesis, angiogenesis, and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine that likely contributes to the creation of a cascade of events that results in not only a predominance of the MF clone but also a dysfunctional microenvironment.
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http://dx.doi.org/10.1182/blood-2014-12-618595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543230PMC
August 2015

Evaluating Academic Scientists Collaborating in Team-Based Research: A Proposed Framework.

Acad Med 2015 Oct;90(10):1302-8

M. Mazumdar was professor and chief, Division of Biostatistics and Epidemiology, Department of Public Health, Weill Cornell Medical College, and director, Research Design and Biostatistics Core, Clinical and Translational Sciences Center, New York, New York, at the time this article was written. She is currently director, Institute of Healthcare Delivery Science, Mount Sinai Health System, New York, New York.S. Messinger is associate professor, Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, and director, Research Design and Biostatistics Core, Miami Clinical and Translational Sciences Institute, Miami, Florida.D.M. Finkelstein is professor of medicine (biostatistics), Harvard Medical School, and Department of Biostatistics, Harvard School of Public Health, and chief, Biostatistics Unit, Massachusetts General Hospital, Boston, Massachusetts.J.D. Goldberg is professor of biostatistics, Departments of Population Health and Environmental Medicine, New York University School of Medicine, and director, Study Design, Biostatistics, and Clinical Research Ethics Program, NYU-HHC Clinical and Translational Science Institute, New York, New York.C.J. Lindsell is professor and vice chair, Department of Emergency Medicine, associate dean for clinical research, College of Medicine, and codirector, Biostatistics, Epidemiology, and Research Design, Center for Clinical and Translational Science and Training, University of Cincinnati, Cincinnati, Ohio.S.C. Morton is professor and chair, Department of Biostatistics, Graduate School of Public Health, and director, Comparative Effectiveness Research Core, Clinical and Translational Sciences Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.B.H. Pollock was professor and director, Division of Clinical and Translational Sciences, Department of Internal Medicine, professor, Biostatistics, Epidemiology, and Research Design, and director, Informatics, Institute for t

Criteria for evaluating faculty are traditionally based on a triad of scholarship, teaching, and service. Research scholarship is often measured by first or senior authorship on peer-reviewed scientific publications and being principal investigator on extramural grants. Yet scientific innovation increasingly requires collective rather than individual creativity, which traditional measures of achievement were not designed to capture and, thus, devalue. The authors propose a simple, flexible framework for evaluating team scientists that includes both quantitative and qualitative assessments. An approach for documenting contributions of team scientists in team-based scholarship, nontraditional education, and specialized service activities is also outlined. Although biostatisticians are used for illustration, the approach is generalizable to team scientists in other disciplines.The authors offer three key recommendations to members of institutional promotion committees, department chairs, and others evaluating team scientists. First, contributions to team-based scholarship and specialized contributions to education and service need to be assessed and given appropriate and substantial weight. Second, evaluations must be founded on well-articulated criteria for assessing the stature and accomplishments of team scientists. Finally, mechanisms for collecting evaluative data must be developed and implemented at the institutional level. Without these three essentials, contributions of team scientists will continue to be undervalued in the academic environment.
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http://dx.doi.org/10.1097/ACM.0000000000000759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653084PMC
October 2015

Surveillance epidemiology and end results analysis demonstrates improvement in overall survival for cervical cancer patients treated in the era of concurrent chemoradiotherapy.

Front Oncol 2015 13;5:81. Epub 2015 Apr 13.

Department of Radiation Oncology, New York University School of Medicine , New York, NY , USA.

Background: In February 1999, the National Cancer Institute (NCI) issued a clinical alert based on five randomized trials that reported better overall survival (OS) with concurrent chemoradiotherapy (CCRT) than with surgery or radiation alone for locoregional cervical cancer. This study analyzes data from the surveillance epidemiology and end results (SEER) program to evaluate the improvement in survival in the era of CCRT.

Methods: The SEER database was queried for FIGO stages IB2-IVA cervical cancer patients treated with radiotherapy between 1995 and 2002. Patients diagnosed between 1999 and 2002 (CCRT era) were assumed to have received CCRT more frequently than patients diagnosed between 1995 and 1998 (RT era). Cases were stratified by period of diagnosis, age, and SEER region. OS and cause specific survival (CSS) were compared between the two time periods with chi-square log-rank tests. Multivariable Cox models were also used to compare OS and CSS between the two time periods, with adjustment for stratification variables and other covariates.

Results: The study included 3517 patients. Unadjusted OS and CSS were significantly improved in 1999-2002 compared with 1995-1998 (OS: p < 0.001, hazard ratio (HR): 0.81; CSS: p < 0.001, HR: 0.79). Significant improvements in OS and CSS were retained after adjustment for multiple variables (multivariable OS HR 0.78; CSS HR 0.76).

Conclusion: Cervical cancer patients treated with radiotherapy after 1999 had improved OS and CSS compared with patients treated before 1999, likely reflecting increased usage of CCRT. This study adds to the population-level evidence supporting the adoption of CCRT as the standard of care for locoregional cervical cancer.
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http://dx.doi.org/10.3389/fonc.2015.00081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394706PMC
April 2015