Faculty Bibliography

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 (FOXP3+Helios+) 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 Naive Tregs [greater than 2.5 (the median of the naive 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 Naive 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 + Naive 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 naive Tregs were associated with 3-month PFS. Exemestane/cyclophosphamide combination had favorable safety profile with evidence of clinical activity in heavily pretreated patients.

PURPOSE/OBJECTIVE: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.

Objectives/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.

Background: Case reports suggest that NS is responsive to dietary modifications including a gluten-free diet (GFD). In celiac disease, zonulin is released from enterocytes after exposure to gliadin, activates protease activated receptor 2 (PAR2), and perturbs the actin cytoskeleton and cell-cell junctions in the gut. PAR2 is present on podocytes and, therefore, zonulin may increase glomerular permeability in NS. We conducted this study to test the hypothesis that plasma zonulin levels are elevated in pediatric patients with NS.
Method(s): Plasma specimens collected from patients <=18 yr old with minimal change disease or FSGS enrolled in the NEPTUNE study, were tested. Clinical and laboratory data were retrieved coincident with the visit when the zonulin level was measured. Samples were available for testing from the 4 or 8 month visit. Plasma zonulin levels were measured by ELISA. Results (mean+/-SD or median (IQR)) were analyzed by t-test, Wilcoxon, Kruskal-Wallis, or linear regression and considered significant if P<0.05 Results: There were 113 patients, 9.5+/-4.9 yr, 53% male, 42% white, 40% black and 18% other. Disease classification was infrequent relapser in 27%, frequent relapser/steroid dependent 42% and steroid resistant 30%. The mean BP, eGFR, and serum albumin were normal. Urine protein:creatinine (UPC) ratio was 3.9+/-6.9 (g:g). The plasma zonulin level in NS children was 14.2+/-6.0 vs 10+/-2.5 ng/ml in healthy adults (P<0.01) and was >3 standard deviations above the mean in 27%. There was a trend toward lower zonulin levels in children with UPC >=2 vs <2, 12.9(7.4) vs 16.7(8.0) (P=0.051). Plasma zonulin levels did not differ by eGFR, disease classification, or BP. Plasma zonulin and serum albumin concentrations were directly correlated, r=0.24, P=0.04.
Conclusion(s): The plasma zonulin level was significantly elevated in more than a quarter of children with NS and was unrelated to BP or eGFR. We observed a significant relationship between zonulin values and serum albumin but not proteinuria. There was a trend to lower zonulin levels in children with nephrotic-range proteinuria. Further study is needed to determine the relationship between plasma zonulin levels and proteinuria and to test whether the plasma zonulin level can be used to predict response to a GFD in children with NS

Background: Although the optimal timing of adjuvant chemotherapy (AC) for stage III colon cancer patients has been debated, most studies recommend initiating AC within approximately 60 days of surgery. Significant disparities in timeliness of AC initiation in colon cancer have been reported in public versus private hospitals, with longer time to AC at public hospitals. We evaluated whether timeliness of AC differed between a public and a private hospital, both affiliated with the same major academic institution in New York City. Methods: We conducted a retrospective cohort study of Stage III colon cancer patients who underwent surgery and received AC at the same institution from 2008-2015 at NYU Langone Medical Center's affiliated public hospital (Bellevue) or its private hospital (Tisch). Patient data were obtained through review of hospital tumor registry and electronic medical records. Patient characteristics were compared by hospital. We defined timeliness as receipt of AC within 60 days postoperatively. Univariate and stepwise multivariable logistic regressions were used to identify factors associated with timely AC. Results: Forty three patients at Bellevue Hospital and 79 patients at Tisch Hospital who underwent surgery and received AC at the same institution were included. Median number of days to AC was significantly greater among patients receiving care at Bellevue (53, range 31-231) compared to Tisch (43, range 25-105; p=0.002). However, the percentage of patients who received timely AC did not differ substantially at Bellevue and Tisch (74% vs 81%, p=0.40). Individual characteristics significantly associated with timely initiation of AC were non-Hispanic ethnicity (OR: 2.71, 95% CI: 1.06-6.95), married (OR: 2.89, 95%CI: 1.15-7.30), and laparoscopic (vs open) surgery (OR: 4.30, 95%CI: 1.64-11.25). The odds of receiving timely AC at Bellevue compared to Tisch was not significant (OR: 0.68, 95% CI: 0.28-1.65). When hospital and other factors were examined jointly, only age (OR: 0.95/year, 95% CI: 0.91-0.99) and laparoscopic (vs open) surgery (OR: 5.65, 95% CI: 1.92-16.62) remained as important factors associated with receiving timely AC (Likelihood Ratio Chi-Square=14.95, p=0.0019). When hospital was omitted from multivariable analysis, age and surgery type still remained the only significant factors associated with timely AC (OR's unchanged, Likelihood Ratio Chi-Square=14.81, p-value=0.0006). Conclusions: The proportion of patients receiving timely AC within 60 days of surgery was similar at both an affiliated public and private hospital at NYU Langone Medical Center. Age and type of surgery were significant predictors of timeliness in our population. Further research should be conducted to understand how system-level factors may promote timely receipt of care

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.