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Peripheral T-Cell Lymphoma Involvement of the Central Nervous System: Impact of Novel Therapeutics on Clinical Outcomes [Meeting Abstract]

Lue, J K; Ma, H; Marchi, E; Spivack, J H; O'Connor, O A
Primary Central Nervous System (CNS) involvement of peripheral T-cell lymphoma (PTCL) is a rare phenomenon, with a reported incidence ranging from 2% to 16.7%. Similarly, secondary CNS lymphoma with PTCL phenotype is rare, with an approximately 2-6% incidence. Both clinical situations lead to dismal outcomes. Given the rarity of CNS involvement with PTCL, our understanding of this clinical manifestation is limited to retrospective studies, which have identified risk factors for CNS involvement such as extranodal involvement, stage III-IV disease, bone marrow involvement as well as ATLL subtype. Herein, we characterize CNS involvement of PTCL over a 26-year time period at a single institution, identify if there are any factors that have a positive impact on survival, and extrapolate risk factors for CNS involvement from this dataset. From the years 1996-2020, 222 patients were diagnosed with PTCL, of those, 25 patients developed CNS involvement. All patients had secondary CNS involvement. Baseline characteristics including first-line therapy are noted in Table 1. Four patients received intrathecal methotrexate for CNS prophylaxis, all of which were patients with an ATLL diagnosis. The median time from initial diagnosis to CNS involvement was 4.77 months (0-64 months). Upon CNS diagnosis, the median time to death was 1.13 months. With a median of 2 lines of treatment (range 1-5), 12 patients were exposed to novel therapeutic agents (HDAC inhibitors [HDACis], brentuximab vedotin, pralatrexate) and/or clinical trials investigating epigenetic combinations. Of these patients, 10 patients were exposed to novel therapeutics and/or epigenetic based clinical trials in the 2 nd line setting. There was a trend towards improved overall survival with exposure to novel therapeutics and/or treatment on epigenetic based clinical trials (p=0.1) (Figure 1). With the majority of patients surviving <6 months from CNS diagnosis, there were three excellent responders that survived >12 months, all of which were exposed to novel therapeutics. Two of the three excellent responders were diagnosed with CNS involvement upon initial diagnosis, while 1 patient relapsed in the fourth-line setting with CNS involvement. All three of the excellent responders were exposed to novel therapeutics, particularly pralatrexate as a commonality in the second line setting. Using logistic regression, an ATLL diagnosis, extranodal involvement, and a high ECOG score were associated with a higher risk of CNS involvement. Unlike other studies, a high IPI score was not associated with a predilection for CNS involvement. In conclusion, we describe one of the largest single-center collection of CNS PTCL involvement. CNS involvement of PTCL is rare, with a reported cumulative incidence in this cohort of 11.3% over a 26-year time period. Risk factors that were identified include an ATLL diagnosis, extranodal involvement, and poor performance status. Exposure to novel therapeutics leads to a trend towards improved outcomes possibly secondary to improved disease control, but overall, the majority of patients had dismal outcomes. Notably, of the novel therapeutics interrogated, romidepsin and pralatrexate have low penetrance into the CNS, while there is no current evidence to suggest brentuximab vedotin is able to cross the blood-brain barrier. The possibility of a disturbed blood-brain barrier to permit improved penetrance of these drugs is plausible, but further studies are warranted to support this. Although a small percentage of patients will suffer from CNS PTCL, there is a dire need to improve therapy for this patient population and to establish universal metrics to identify patients that are at risk of CNS involvement. Moreover, given the rarity of CNS PTCL involvement, a future endeavor would be to validate these findings in larger, multicenter initiative. [Formula presented] Disclosures: Lue: AstraZeneca: Speakers Bureau; Kymera Therapeutics: Research Funding; TG Therapeutics: Consultancy; Epizyme: Consultancy; Kura Oncology: Consultancy. Marchi: Astex: Research Funding; Kyowa Kirin: Honoraria; Merck: Research Funding; BMS: Research Funding; Myeloid Therapeutics: Honoraria; Kymera Therapeutics: Other: Scientific Advisor. O'Connor: Myeloid Therapeutics: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Servier: Research Funding; Kymera: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; BMS: Research Funding; Merck: Research Funding; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company.
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EMBASE:2016087211
ISSN: 0006-4971
CID: 5098602

Association between stromal/TGF-p/EMT gene expression signature and response to pembrolizumab monotherapy in cisplatin-ineligible patients with locally advanced (unresectable) or metastatic urothelial carcinoma [Meeting Abstract]

Grivas, P; Castellano, D E; O'Donnell, P H; Cristescu, R; Frenkl, T L; Keefe, S M; Loboda, A; Souza, S C; Ma, H; Snyder, A; Zhang, C; Albright, A; Lunceford, J; Vasant, Balar A
Background: PD-L1 immunohistochemistry and an 18-gene T cell-inflamed gene expression profile (GEP) are associated with response to anti-PD-1/PD-L1 therapy across tumor types, including urothelial carcinoma. A gene expression signature representing convergent biology related to stromal/EMT/TGF-beta pathways was developed and prespecified for testing for association with pembrolizumab response in urothelial carcinoma patients treated on the KEYNOTE-052 trial (NCT02335424).
Method(s): KEYNOTE-052 was a single-arm phase 2 trial of pembrolizumab in cisplatin-ineligible patients with previously untreated, advanced urothelial carcinoma. Primary objective of this analysis was to assess the association between the Stromal/EMT/TGF-beta signature and outcomes (best overall response [BOR], PFS, OS) as an independent biomarker and to understand its potential prognostic/predictive role beyond the T cell-inflamed GEP score or PD-L1 assessed using combined positive score (CPS). Cox regression models for PFS and OS and a logistic regression model for BOR evaluated associations between Stromal/EMT/TGF-beta signature and outcomes adjusting for ECOG performance status (PS) and level of the GEP or CPS (1-sided P value).
Result(s): RNA-Seq data from baseline tumor specimens were available for 187/370 patients on KEYNOTE-052. Lower Stromal/EMT/TGF-beta score was associated with favorable BOR rate (P < 0.001), PFS (P < 0.001), and OS (P = 0.002) after adjustment for ECOG PS and GEP (which remained significant at the 0.05 level in all cases). The patterns indicated a very consistent downward trend in the distribution of the Stromal/EMT/TGF-beta score for responders versus nonresponders, regardless of GEP. In models that adjusted for both ECOG PS and PD-L1 CPS, the Stromal/EMT/TGF-beta score remained significant (BOR rate, P = 0.002; PFS, P = 0.013; OS, P = 0.029).
Conclusion(s): Higher Stromal/EMT/TGF-beta signature was associated with resistance to pembrolizumab independently of GEP or PD-L1 in urothelial carcinoma patients on the KEYNOTE-052 trial
EMBASE:627164405
ISSN: 1527-7755
CID: 3811652

Polypharmacy and potentially inappropriate medication use in older patients with aggressive non-Hodgkin lymphoma (NHL) leads to inferior survival and increased treatment-related toxicities [Meeting Abstract]

Lin, R J; Ma, H; Guo, R; Grossbard, M L; Troxel, A B; Diefenbach, C S M
Background: Survival outcomes for older patients with aggressive NHL are disproportionally inferior to those of younger patients. While differences in tumor biology may play a role, older patients are often frail with comorbidities, polypharmacy, and use potentially inappropriate medications (PIM) such as anticholinergics and benzodiazepines. Methods: Using Cox proportional hazard and logistic regression models, we analyzed all aggressive NHL patients age >= 60 treated at our two affiliated hospitals from 2009-2014 to examine the association of polypharmacy and PIM use with progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Results: In this updated and final analysis, we included 171 patients with complete records from these two hospitals. They share similar demographic, clinical, and laboratory characteristics except for higher International Prognostic Index (IPI) in patients from one hospital. The median age was 70 years (range 65-77). At the time of diagnosis, 46% of patients used more than 4 medications (polypharmacy) and 47% used at least one PIM. Only 43% of patients received first-line chemotherapy of adequate relative dose intensity (>85% dosage), and 65% experienced >= grade 3 toxicities. Polypharmacy and PIM use were associated with shortened PFS and OS by log-rank test. Most importantly, PIM use remained an independent predictor of PFS, OS, and >= grade 3 toxicities in multivariable analyses (Table). Conclusions: This is the first report of significantly adverse survival impacts of polypharmacy and PIM use in older patients with aggressive NHL, presumably from drug-drug interactions that increase toxicities and impair the delivery of adequate chemotherapy dosage. Our findings support the use of evidence-based geriatric principles to guide meticulous medication management to improve outcome disparity for these patients. (Table presented)
EMBASE:617435400
ISSN: 0732-183x
CID: 2651112

Mental health and acculturation in first generation chinese american immigrants in New York City: A contemporary cross-sectional analysis [Meeting Abstract]

Ma, H; Fried, M C; Hase, J; Hayes, R; Zhang, A; Gillespie, C C
BACKGROUND: Chinese Americans represent the fastest growing immigrant population in the United States, and they face unique mental health challenges. To best care for this population internists should understand the effects of acculturation, defined as the change that occurs when an ethnic minority encounters a dissimilar dominant culture. The relationship between acculturation and mental health is complex. We sought to describe this relationship in Chinese immigrants currently living in New York City. METHODS: We analyzed data from the Chinese American Cardiovascular Health Assessment, a cross-sectional survey of foreign-born Chinese adults living in New York City (n = 2071). Primary outcomes included depression, stress and physical symptoms, and the primary exposure was acculturation. Rates of depression, stress, and physical symptoms were surveyed using validated tools. Acculturation was evaluated using the Stephenson Multigroup Acculturation Scale, which is an assessment of both ethnic and dominant society immersion (ESI and DSI). Mean acculturation, depression and stress scores were stratified by demographics. Differences were assessed using one-way ANOVA analysis. RESULTS: Our population was generally middle-aged, well-educated, and employed. Younger age, female gender, shorter duration of residence in the US, single marital status and poor perceived health were associated with higher rates of depression and stress. Overall the cohort was more acculturated to China (average ESI 3.67 out of 4) than America (DSI 2.11 out of 4). Participants who were depressed had lower acculturation to ethnic society compared to those without depression (ESI 3.59 vs ESI 3.67, p = 7.13e-5). This difference was not seen when comparing acculturation to dominant society in depressed vs not depressed participants (DSI 2.08 vs DSI 2.11, p = 0.53). Higher levels of stress were associated with lower acculturation to both ethnic (ESI 3.62 vs 3.67, p = 0.003) and dominant cultures (DSI 2.0 vs 2.12, p = 0.002). Participants with depression and stress were more likely to have physical symptoms and lower self-rated health. CONCLUSIONS: We performed a descriptive analysis of Chinese immigrants living in NYC to characterize the interaction between acculturation, depression and stress. We observed that depressed participants had lower acculturation to their ethnic society, but not dominant society, perhaps suggesting a protective effect of connection to one's home society. Future mental health interventions may target patients with low acculturation by increasing access to community events, employing Chinese community health workers, or leading group visits to targeted groups. This study is consistent with prior research demonstrating a relationship between physical symptoms and mood in Chinese immigrants. Internists should consider physical symptoms as potential indicators of underlying mood disorders in this underserved population, as early identification may lead to improved diagnosis and treatment
EMBASE:615581485
ISSN: 0884-8734
CID: 2554002

Anti-Glycan Antibody Profiling in De-Novo Stage IV Non-Small Cell Lung Cancer: A Pilot Study [Meeting Abstract]

Seetharamu, Nagashree; Vuskovic, Marko; Chachoua, Abraham; Brusca-Augello, Geraldine; Barbuti, Anna-Maria; Thomson, Jennifer E; Gills, Ingrid; Preiss, Jordan; Joseph, Sasha; Ma, Hilary; Rom, William N; Huflejt, Margaret E
ISI:000370365103401
ISSN: 1556-1380
CID: 2064362

Medical repatriation at end of life: Barriers, facilitation, and fulfillment-A case-series study at a New York public hospital

Seetharamu, Nagashree; Ma, Hilary Y; Smeltz, Robert; Schindewolf, Jessica; Empalmado, Mariam; Cohen, Susan E
141 Background: Foreign-born cancer patients frequently desire to return to their home country at the end of life. However, many barriers can make this process challenging. We herein present our recent experience with such patients. METHODS: We reviewed charts of terminal cancer patients (pts) who traveled to their homeland at the end of life. Pts' age, diagnoses, co-morbidities, prior cancer-directed treatment, predicted survival, symptoms, code status, admissions within 4 weeks of travel, oxygen need were noted. Interval between decision to travel and travel date, events during travel, and feedback from families, if available were collected. RESULTS: 17 charts (11 female, 6 male) were analyzed. Mean age was 60 years and the most common diagnosis was thoracic malignancy (70%, 12 pts). All pts had disseminated cancer and had received an average of 2 lines of cancer-directed therapy. All had progressive cancers with expected survival <6 months. All were under the care of medical oncologists, palliative care and social work. The mean interval between decision to travel and travel date was 9 days. 8 were hospitalized at least once in the 4 weeks prior to the day of travel and 6 were cared for as inpatients immediately prior to travel. 11 pts were receiving opioids for pain and 3 were oxygen-dependent. 10 had documented discussions regarding resuscitation and 9 were discharged with New York State out-of -hospital DNR forms. All were discharged with medical records, medication supply and provider contact information. Mean travel distance was 4,099 miles. Provider concerns for decompensation during travel included brain herniation (2), spinal cord compression (3), bleeding (1), and sepsis (2). 16 pts successfully completed their journey. 1 pt died en-route prior to boarding the aircraft. 12 pts/families provided positive feedback about the experience. CONCLUSIONS: Return to homeland is an important goal for many terminally ill cancer pts and should be a routine part of end-of-life discussions. Medical repatriation can be accomplished when conducted in a planned, well-coordinated manner. Insights from this review can help us create guidelines that can be readily applied to specific scenarios.
ORIGINAL:0013187
ISSN: 1527-7755
CID: 3590052

Regulation of alveolar fluid clearance and ENaC expression in lung by exogenous angiotensin II

Deng, J; Wang, DX; Deng, W; Li, CY; Tong, J; Ma, H
Angiotensin II (Ang II) has been demonstrated as a pro-inflammatory effect in acute lung injury, but studies of the effect of Ang II on the formation of pulmonary edema and alveolar filling remains unclear. Therefore, in this study the regulation of alveolar fluid clearance (AFC) and the expression of epithelial sodium channel (ENaC) by exogenous Ang II was verified. SD rats were anesthetized and were given Ang II with increasing doses (1, 10 and 100mug/kg per min) via osmotic minipumps, whereas control rats received only saline vehicle. AT(1) receptor antagonist ZD7155 (10mg/kg) and inhibitor of cAMP degeneration rolipram (1mg/kg) were injected intraperitoneally 30min before administration of Ang II. The lungs were isolated for measurement of alveolar fluid clearance. The mRNA and protein expression of ENaC were detected by RT-PCR and Western blot. Exposure to higher doses of Ang II reduced AFC in a dose-dependent manner and resulted in a non-coordinate regulation of alpha-ENaC vs the regulation of beta- and gamma-ENaC, however Ang II type 1 (AT1) receptor antagonist ZD7155 prevented the Ang II-induced inhibition of fluid clearance and dysregulation of ENaC expression. In addition, exposure to inhibitor of cAMP degradation rolipram blunted the Ang II-induced inhibition of fluid clearance. These results indicate that through activation of AT(1) receptor, exogenous Ang II promotes pulmonary edema and alveolar filling by inhibition of alveolar fluid clearance via downregulation of cAMP level and dysregulation of ENaC expression.
PMID: 22138610
ISSN: 1569-9048
CID: 159070

Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells

Lee, Jeongwu; Son, Myung Jin; Woolard, Kevin; Donin, Nicholas M; Li, Aiguo; Cheng, Chui H; Kotliarova, Svetlana; Kotliarov, Yuri; Walling, Jennifer; Ahn, Susie; Kim, Misuk; Totonchy, Mariam; Cusack, Thomas; Ene, Chibawanye; Ma, Hilary; Su, Qin; Zenklusen, Jean Claude; Zhang, Wei; Maric, Dragan; Fine, Howard A
Despite similarities between tumor-initiating cells with stem-like properties (TICs) and normal neural stem cells, we hypothesized that there may be differences in their differentiation potentials. We now demonstrate that both bone morphogenetic protein (BMP)-mediated and ciliary neurotrophic factor (CNTF)-mediated Jak/STAT-dependent astroglial differentiation is impaired due to EZH2-dependent epigenetic silencing of BMP receptor 1B (BMPR1B) in a subset of glioblastoma TICs. Forced expression of BMPR1B either by transgene expression or demethylation of the promoter restores their differentiation capabilities and induces loss of their tumorigenicity. We propose that deregulation of the BMP developmental pathway in a subset of glioblastoma TICs contributes to their tumorigenicity both by desensitizing TICs to normal differentiation cues and by converting otherwise cytostatic signals to proproliferative signals.
PMCID:2835498
PMID: 18167341
ISSN: 1535-6108
CID: 159053

A phase I trial of lenalidomide in patients with recurrent primary central nervous system tumors

Fine, Howard A; Kim, Lyndon; Albert, Paul S; Duic, J Paul; Ma, Hilary; Zhang, Wei; Tohnya, Tanyifor; Figg, William D; Royce, Cheryl
PURPOSE: Inhibition of angiogenesis represents a promising new therapeutic strategy for treating primary malignant brain tumors. Lenalidomide, a potent analogue of the antiangiogenic agent thalidomide, has shown significant activity in several hematologic malignancies, and therefore we chose to explore its tolerability and activity in patients with primary central nervous system tumors. EXPERIMENTAL DESIGN: A phase I interpatient dose escalation trial of lenalidomide in patients with recurrent primary central nervous system tumors was conducted. RESULTS: Thirty-six patients were accrued to the study, of which 28 were evaluable for toxicity, the primary end point of the trial. We show that lenalidomide can be given safely up to doses of 20 mg/m(2), with the only toxicity being a probable increased risk of thromboembolic disease. Pharmacokinetic studies reveal good bioavailability, linear kinetics, and no effects of enzyme-inducing antiepileptic drugs on the metabolism of lenalidomide. No objective radiographic responses were seen in any of the treated patients. In the group of 24 patients with recurrent glioblastoma, the median time to tumor progression was <2 months and only 12.5% of patients were progression-free at 6 months. CONCLUSION: Lenalidomide is well tolerated in patients with recurrent glioma in doses up to 20 mg/m(2). Treatment may be associated with an increased risk of thromboembolic disease. Preliminary data suggest that single agent activity may be limited in patients with recurrent glioblastoma at the doses evaluated although larger studies will be needed to confirm these observations.
PMID: 18056189
ISSN: 1078-0432
CID: 159052