INTRODUCTION: R-CHOP is effective for diffuse large B-cell Lymphoma (DLBCL), but many patients (Pts) relapse or have refractory disease, likely due to inherent biologic differences in DLBCL subtype. Activated B-Cell (ABC) subtype DLBCL signals through Nuclear Factor-κ-B (NF-κB) and is more likely to display treatment failure than DLBCL arising from the germinal center (GC). Proteasome inhibitors disrupt NF-κB signaling, but randomized trials have failed to demonstrate clinical benefit of adding bortezomib to R-CHOP for the treatment of non-GC DLBCL. Carfilzomib (Car) displays superior clinical activity relative to bortezomib in plasma cell neoplasms and, while occasionally associated with cardiac events, does not have dose-limiting neuropathy. To explore the safety and efficacy of Car in upfront treatment of DLBCL, we initiated a phase I/II clinical trial of Car + R-CHOP and report the phase I results. METHODS: 24 adult (age ≥ 18) Pts with untreated de novo or transformed DLBCL, adequate organ function and performance status were enrolled. During 3 x 3 dose escalation, Car was given at 20 mg/m2 on days 1 and 2, with R-CHOP on day 2 for 6 cycles (n = 6). Due to grade 4 thrombocytopenia, the protocol was amended to administer Car at a dose (in mg/m2) of 20 on days 1 and 2 of cycle 1 with rituximab (R) on day 2 and CHOP on day 3, followed by a Car dose of 20 (n=3), 27 (n=3), 36 (n=3), 45 (n=3) and 54 (n = 6) on days 1 and 2 of cycles 2-6. All Pts received pegfilgrastim the day after CHOP and zoster prophylaxis with acyclovir x 6 months post treatment. Echocardiograms were obtained at baseline and at conclusion of therapy to assess the cardiac safety of combining Car with anthracycline. Interim response assessments with CT +/- PET were performed after cycle 3 and end-of-treatment response assessments were uniformly captured with PET. RESULTS: The median age was 57 (range 24-77) years old. 63% of patients were female. Stage at diagnosis was I-II (58%) or III-IV (32%). The majority of Pts had ECOG performance status of 0-1 (88%). B symptoms were present in 21% of Pts and 54% had an increased LDH at diagnosis. 29% had >1 extranodal site. IPI score was 0-1 (50%), 2 (21%) or 3-4 (39%). For this phase I dose escalation study, eligible Pts included primary mediastinal lymphoma (n = 1) and DLBCL of GC (n = 9), non-GC (n = 13) and unknown (n = 1) Hans algorithm subtypes. Hematologic adverse events (AEs) included 60 grade 1/2, 27 grade 3 and 16 grade 4 AEs. Grade 3/4 hematologic toxicities included neutropenia (n=14), thrombocytopenia (n = 6) anemia (n = 6), with only 4 cases of grade 3 febrile neutropenia. Grade 3/4 non-hematologic AEs were generally consistent with known R-CHOP toxicity were notable for: hypertension (n = 2), decreased ejection fraction (n =2), GI hemorrhage (n = 2) dizziness, headache, and syncope (n = 1 each), thromboembolic event (n=1), hyperglycemia (n=2), increased ALT (n=1) and nausea/vomiting (n=2). Compared to age-matched controls, end-of-treatment echocardiograms of CarR-CHOP treated Pts showed no statistically significant additional effect on ejection fraction (EF) [94.8% vs. 90.0% of pre-treatment value, respectively (P = 0.19)] after 6 cycles of treatment and there was no association of change in EF with Car dose (P = 0.61). There were no dose limiting toxicities. As of June 2018, median follow-up among surviving Pts was 16 months. There were 3 deaths during the study period, 2 from lymphoma and 1 from lung cancer. The overall response rate was 92% [75% complete remission (CR), 17% partial remission]. 18-month Kaplan Meier estimates of PFS and overall survival were 77% and 88%, respectively (Figure). There was no significant difference in CR rates or PFS for patients with GC vs. non-GC subtype (P = 0.65 and 0.61, respectively). CONCLUSION: CarR-CHOP is safe at a recommended phase II dose of 20 mg/m2 on day 1 & 2 for cycle 1 followed by 56 mg/m2 for cycles 2-6, without significant excess cardiac effects. Within the limitations of a prospective phase I clinical trial with potential patient selection bias, preliminary efficacy data suggest a high complete metabolic response rate and equivalent outcomes for patients with GC and non-GC subtype. Phase II accrual is ongoing for non-GC DLBCL only and additional correlative studies of the molecular subtype of DLBCL will be incorporated into future analysis. Disclosures Hill: Amgen: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tomlinson:Foundation Medicine: Consultancy. Caimi:Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees.
Background: Patients who have undergone orthotopic heart transplant (OHT) undergo frequent endomyocardial biopsies (EMBx) to assess for rejection. Difficulty crossing the superior venous caval anastomosis and tricuspid valve often complicates these procedures. We studied a new approach in which a peel-away sheath is placed in the right internal jugular vein through which a Swan-Ganz catheter is then inserted and advanced. Following right heart catheterization, the peel-away sheath is removed and a long biopsy sheath is advanced over the Swan-Ganz catheter, which is then removed, leaving the long sheath behind for advancement of the bioptome into the right ventricle. Objective: To compare fluoroscopy (fluoro) time, procedure time, and complications between a modified and standard approach to EMBx. Methods: We included patients who underwent OHT and had EMBx data available for review at two University-affiliated institutions. We excluded EMBx cases that combined a left heart catheterization. We compared fluoro time and procedure time between modalities using mixed effects gamma regression with operators and patients both included as random effects. Results: We analyzed 964 (198 modified, 766 standard) EMBx cases in 71 patients who underwent OHT from 2017 to 2022. The mean patient age was 53.9 at time of OHT; 14% (n=10) were female. Median fluoro time was 2.8 and 4.9 minutes, and median procedure time was 27 and 29 minutes, for the modified and standard approach, respectively. Cases performed using the modified approach had a shorter fluoro time by 28%, and a shorter procedure time by 7% as compared to the standard approach (Ratio=0.72, 95% CI: 0.62 ~ 0.84, p<0.001 for fluoro time; Ratio=0.93, 95% CI: 0.87 ~ 0.98, p=0.014 for total procedure time). Only one complication was identified. Conclusion: In this cohort, a modified approach to EMBx was associated with reduced fluoroscopy and procedure time as compared to the standard approach with no difference in complications.
Exposure to ultraviolet radiation (UVR) in sunlight activates both defensive and repair pathways in the skin. As the major cell type affected by UVR, keratinocytes coordinate critical aspects of the skin response. Molecularly, the transcription factor p53 is induced by UVR in keratinocytes leading to their cell death by apoptosis (peeling). p53 also stimulates the expression of paracrine melanocyte growth factors involved in tanning defined as increase in melanocyte proliferation and melanin synthesis. Here, we investigate the less defined role of p53 in tanning. For this, we use a mouse model that has high p53 levels in keratinocytes and presents with elevated melanocyte number and melanin production. Interestingly, loss of p53 in keratinocytes completely abrogates the hyperpigmentation phenotype. These data demonstrate in a powerful way the paracrine role of p53 expressed in keratinocytes on melanocyte behavior and function. Moreover, it provides an excellent tool to examine molecular and cellular changes that accompany the melanocyte response to sunburn. Sunburn increases melanoma risk in epidemiological studies. To elucidate the role of the p53 response in melanoma, we treated mice with “sunburning” doses of UVB and followed melanocyte proliferation and the expression of keratinocyte-induced melanocyte growth factors. We present our latest findings reinforcing the signs of cross-talk between keratinocytes and melanocytes which support a paracrine role for p53 expressed in keratinocyte on promoting melanocyte proliferation through the release of paracrine factors. Citation Format: Tamara Terzian, Nema Sobhani, Rohan Mylavarapu, Manale El Kharbili, Andrew Parker, Colleen Little, Ethan Krauspe, Neil Box. The paracrine role of p53 in skin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4503.
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