bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone (CRd) in newly diagnosed multiple myeloma (MM) patients.
Authors: Korde Neha , Zingone Adriana , Kwok Mary , Manasanch Elisabet E. , Bhutani Manisha , Costello Rene , Yancey Mary Ann , Mulquin Marcia , Calvo Katherine R. , Maric Irina , Tembhare Prashant , Yuan Constance , Stetler-Stevenson Maryalice , Arthur Diane Carol , Choyke Peter L. , Kurdziel Karen A , Steinberg Seth M. , Raffeld Mark , Roschewski Mark J. , Landgren Ola 
Published: March 2020

e18568 Background: Carfilzomib (Cz) is an irreversible proteasome inhibitor with potent anti-MM effects and decreased peripheral neuropathy rates compared to bortezomib. In this two-stage phase II trial of 45 planned patients, we treat newly diagnosed MM patients with Cz, lenalidomide(Ln), and dexamethasone (Dx). Methods: Eight 28-day cycles of induction comprises of Cz IV 20/36 mg/m2 on days 1, 2, 8, 9, 15, 16; Ln oral 25 mg days 1-21; and Dx IV/oral 20/10 mg on days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients undergo stem cell collection after 4 cycles of CRd and continue with induction. After 8 cycles of induction, patients with SD or better receive 12 cycles of Ln maintenance 10 mg days 1-21. Primary endpoint is ≥ grade 3 neuropathy. Bone marrow samples are collected at baseline, C1D2 (single agent Cz exposed), CR/end of cycle 8 (cycles 1-8), and CR/end of cycle 21 (cycles 9-21). Patients are evaluated for clinical biomarkers and MRD studies (flow cytometry, PCR, and FDG PET-CT) at regular time points. Results: Approximate enrollment rate is 1-2 patients/month. Six patients meeting eligibility criteria have been enrolled (2 male, 4 female; median age 58; age 42-74). Thus far, 5/6 patients are evaluable for toxicity and response (1-5 cycles, 2-4 cycles, 1-2 cycles, and 1-1 cycle). No patients have reported ≥ grade 3 neuropathy. Non-hematologic toxicity (≥ grade3) includes: 1 - LFT elevation and 1 - anxiety. One patient had ≥ grade3 hematologic toxicity with lymphopenia. After median 3 cycles of CRd, 3 patients achieved VGPR, 1 patient achieved PR, and 1 remained at SD. Mean decline in serum markers (M-protein or FLCs) was 87% (60-100%) among responders. One patient had 98% decline in FLCs after 1 cycle and a decrease in abnormal plasma cell burden to ≤ 2% by flow cytometry after 3 cycles. Updated results on additional patients and molecular/MRD studies (flow cytometry, PCR, and FDG PET-CT) will be presented at meeting. Conclusions: Combination therapy with CRd is a tolerable and effective regimen against upfront MM, evoking rapid and deep disease control.
Risk of rash associated with lenalidomide in multiple myeloma and myelodisplastic syndrome: A systematic review of the literature and meta-analysis.
Authors: Garden Benjamin C , Nardone Beatrice , Wu Shenhong , West Dennis P. , Emmanuel Romala , Lacouture Mario E. 
Published: March 2020

e18571 Background: Indications of lenalidomide (Len) include treatment of multiple myeloma (MM) in combination with dexamethasone (Dex) and myelodyplastic syndrome (MDS). The reported incidence and risk of rash varies widely and has been inconsistently reported in trials. Therefore, we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing rash. Methods: Relevant studies were identified from PubMed (1998-2011), abstracts presented at ASCO conferences (2004-2011) and the Web of Science database (1998-2011). Eligible studies were limited to prospective Phase II-III clinical trials in which patients received daily Len doses of either 10mg or 25 mg with or without 40mg of Dex. Incidence, relative risk (RR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on heterogeneity of included studies. Results: Data from a total of 1,127 patients in 15 trials were available for analysis. The overall incidence of all-grade and high-grade (grade ≥3) rash was 29.9% (95% CI: 24.8- 35.5) and 3.8% (95% CI: 2.7-5.5), respectively. Len was associated with increased risk of all-grade rash (RR=1.7, 95% CI: 1.3-2.3; P<0.001) when compared to patients treated with a placebo and Dex. Risk of high-grade rash was increased (RR=3.7, 95% CI: 0.8-16.0) with a trend toward statistical significance (P=0.08). No significant difference in incidence of all-grade rash between patients receiving LEN doses of 10mg or 25mg (25.6%, 95% CI: 19.6-32.8% vs. 30.8%, 95% CI: 24.7-37.7%, respectively, p=0.28) was observed. Similarly, no difference was observed between patients receiving LEN monotherapy or in combination with Dex (31.0%, 95% CI: 26.6-43.3% and 23.8%, 95% CI: 14.9-35.8%, respectively, p=0.17). Conclusions: Patients with MM or MDS who are treated with Len are at significant risk for developing rash. The risk appears to be independent of LEN dosage or in combination with Dex. Further studies for prevention and treatment of this untoward toxicity are needed in order to maintain patient’s quality of life and minimize the need for dose modification, all of which may impact clinical outcome.
Hyperbaric oxygen therapy for hematopoietic progenitor cell (HPC) collection in poor mobilizers.
Authors: Nair Bijay , Waheed Sarah , Villines Gary , Van Rhee Frits , Usmani Saad Zafar , Medlin Stephen , Anaissie Elias J. , Singh Zeba , Zhou Daohong , Barlogie Bart , Cottler-Fox Michele 
Published: March 2020

e18576 Background: Currently available agents such as cyclophosphamide or etoposide in combination with G-CSF and plerixafor are effective in mobilizing HPC in most patients with myeloma and refractory lymphoma needing autologous HPC transplant. Unfortunately, there are patients who are unable to mobilize HPC adequately because of prior radiation or stem cell toxic alkylating chemotherapy. As Thom et al. noted an increase in circulating CD34+ cells in patients undergoing hyperbaric oxygen therapy (HBOT) for osteoradionecrosis of the mandible, we examined this modality as a mobilizing agent in those who failed at least one other modality. Methods: A retrospective data review of all patients undergoing HPC mobilization from January 2009 to December 2011 identified 9 patients (7 male, 2 female), (8 multiple myeloma, 1 non-Hodgkin lymphoma) who underwent HBOT for mobilization of HPC after failing to collect at least 2 x 10e6 CD34+ cells/kg CD34 cells/kg body weight following standard mobilization using chemotherapy, G-CSF and/or plerixafor. Mean age was 61 (range 52-82 y). Four had previously undergone autologous transplant. Treatment was in hyperbaric oxygen chambers pressurized with 100% oxygen at 1.5 atmospheres of pressure for 90 minutes per day, with treatment ranging from 3 to 8 days. During this period patients also received growth factors and plerixafor. Results: Total CD34+ cells/kg collected ranged from 0.1 - 20.6 x 10e6 CD34+ cells/kg; 5 patients collected > 2 x 10e6 CD34+ cells/kg, of which 3 collected > 5 x 10e6 CD34+ cells/kg. All patients had failed prior mobilization and collection with G-CSF, and 8 had also previously received plerixafor. One of the patients who had undergone prior tandem transplant collected 8.23 x10e6 CD34+ cells/kg. No patient experienced toxicities known to be associated with use of HBOT such as barotrauma. Conclusions: HBOT appears to be an effective and safe modality to mobilize HPC in patients who are poor mobilizers, when used in conjunction with G-CSF and plerixafor.
Prognostic value of mitosis-specific antibodies and computer image analysis in calculating mitotic rate in melanoma.
Authors: Hale Christopher , Qian Meng , Ma Michelle W. , Shao Yongzhao , Polsky David , Shapiro Richard L. , Berman Russell S. , Pavlick Anna C. , Osman Iman , Darvishian Farbod 
Published: March 2020

e19003 Background: Mitotic rate (MR) is an important part of staging for thin melanomas (≤1 mm) but its value in thick melanomas (>1 mm) has not been determined. Additionally, accurate calculation of MR on hematoxylin and eosin (H&E) stained sections can be challenging. Several mitosis-specific antibodies are commercially available but their role in predicting clinical outcome in melanoma has not been adequately assessed compared to H&E. Methods: Primary tissues from 190 cutaneous melanoma patients [≤1 mm (n = 22); >1 mm (n=168)] prospectively enrolled at New York University Medical Center were stained with MPM-2 and PHH3, two mitosis-specific antibodies. Using light microscopy, MR was quantified manually from corresponding H&E, MPM-2, and PHH3-stained sections. Computer-assisted image analysis was then applied to detect immunolabeled mitoses on the previously examined PHH3 and MPM-2 slides. We then analyzed the association between MR and progression-free survival (PFS) and melanoma-specific survival (MSS). Results: Manual quantification of PHH3-derived MR was associated with shorter PFS in thick melanomas (P=0.042). Computer-assisted quantification of PHH3 showed a significant association with shorter PFS and MSS in thick melanomas (P=0.021, P=0.04, respectively). Relative to manual analysis of corresponding H&E-stained sections, manual analysis of PHH3 and MPM-2 stains increased mean MR (86% and 159% increases, respectively). MPM-2 did not have value as mitosis-specific marker in melanoma of any thickness. Conclusions: PHH3-derived MR might be useful in predicting worse clinical outcome in primary melanoma patients with thicker melanoma.
Overall survival (OS) in treatment (tmt) naive patients with unresectable stage III/IV (USIII/IV) melanoma: A systematic literature review and network meta-analysis (NMA).
Authors: Kotapati Srividya , Lorigan Paul , Verduyn Cora , Lees Michael , Chin Kevin M. , Jansen Jeroen P. 
Published: March 2020

e19010 Background: Tmt with ipilimumab (IPI) & dacarbazine (DTIC) resulted in greater OS than DTIC alone (Robert et al., 2011) in tmt naïve patients with USIII/IV melanoma. Direct comparisons vs. other systemic therapies in first line are lacking. The objective was to compare OS of patients receiving systemic therapies, including IPI, for naïve USIII/IV melanoma based on randomized controlled trials (RCTs). Methods: A systematic literature search was performed to identify RCTs. Kaplan-Meier OS curves for each intervention (ITV) were digitized, survival proportions over time were obtained from these images, and data were combined with a NMA using the best fit survival distribution resulting in pooled survival proportions (SPs) and expected OS (mean OS). Results: 16 studies provided OS curves and allowed for a NMA of the ITV groups listed in the table. Populations were comparable across trials other than in the vemurafenib study that selected patients with a BRAF mutation. IPI with DTIC showed greater mean OS than other ITVs (Table). The short follow-up for vemurafenib (median 3.8 months, max 12 months) did not allow for valid comparisons. Conclusions: Results of this NMA suggests that mean OS is expected to be greater with IPI & DTIC than with other ITVs for the management of tmt naïve patients with USIII/IV melanoma. [Table: see text]
Newmouse models of melanoma metastasis and differences in brain tropism and metastatic growth pattern.
Authors: Morsi Amr M. , Gazial-Sovran Avital , Baig Hana , Kerbel Robert S. , Golfinos John , Wadghiri Youssef Zaim , Hernando Eva 
Published: March 2020

e19015 Background: 75% of patients with metastatic melanoma develop brain metastases (B-mets). Such patients show dismal prognosis with a median survival of < 6 months. Scarcity of clinically relevant in vivo models has hindered melanoma B-met studies. We compared the in vivo dissemination upon ultrasound (u/s) guided intracardiac injection of B16F10 cells to 131/4-5B1 (hereafter 5B1), a WM239A subclone with enhanced brain tropism. We also implemented an ex vivo MRI protocol as a high throughput three dimensional approach for characterizing B-mets penetrance and growth. Methods: B16-F10 or 5B1 melanoma cells were injected in C57BL/6J mice (n=40) or athymic/nude mice (n=40) respectively using u/s-guided intracardiac injection. Upon weight loss, mice were euthanized, and heads prepared for ex vivo imaging. All µMRI experiments were performed with a 7T Bruker Avance II console. The protocol consisted of (110-mm)3 isotropic T1-, T2- and T2*-weighted sequences. Results: Our ex vivo MRI recapitulates the clinical radiological T1 and T2 brightening as well as susceptibility-induced T2* darkening effect of melanoma. The B16F10 model revealed exclusive ventricular and leptomeningeal spread while the 5B1 model showed parenchymal lesions. In addition, 90% of the 5B1 mice with brain tumors showed multiple lesions (3-16) vs. 18% in the B16F10 model (1- 3). Finally, 3D volume studies revealed a higher B-met penetrance (68% vs. 18%), delayed onset of tumor detection (earliest-day 27 vs. day 15) post-injection and a slower growth rate of 5B1 brain metastases compared to B16F10 tumors. Conclusions: Our results suggest that u/s-guided intracardiac injection of melanoma cells is an optimal method to capture the cells’ spontaneous dissemination pattern (or site-specific tropism) and that the 5B1 model is a more clinically relevant model of melanoma B-met for preclinical studies.
Ipilimumab in patients with melanoma brain metastases, a single-center experience in an expanded access program.
Authors: Du Four Stephanie , Wilgenhof Sofie , Seghers Amelie Clementine , Duerinck Johnny , Neyns Bart 
Published: March 2020

e19027 Background: patients (pts) diagnosed with melanoma brain metastases (MBM) have a poor prognosis with conventional treatment options. Ipilimumab (IPI) is a CTLA-4 blocking monoclonal antibody with established activity in patients (pts) with pretreated advanced melanoma. Methods: observational study on the clinical outcome of melanoma pts with a prior diagnosis of MBM among pts treated with IPI (3 mg/kg q3wks x4, allowing for retreatment after a PFS of >24 wks) in an expanded access program at a single center. Results: among the 50 pts who initiated IPI treatment between April 2010 and May 2011, 16 pts had been diagnosed with MBM. Only 1 pt had a solitary MBM, all other pts had > 3 MBM. Baseline characteristics for pts with- and without MBM: M/F 8/8 vs. 20/14; mAge 44- vs. 50y; BRAF V600-mut/wt 10/6 vs 19/15; stage IV-M1c/-a&b 16/0 vs 31/3; WHO-PS 0-1/2 9/7 vs 30/4; LDH >ULN 10/6 vs 23/11; CRP >ULN 10/6 vs 20/14; ALC<1000/mm³ 3/13 vs 11/23. All pts were pretreated with DTIC; 3 pts with stereotactic (stRT), 7 pts with WBRT, and 2 pts with WBRT followed by a stRT boost; 4 pts had no prior therapy for MBM. 7/16 pts with- vs. 24/34 pts without MBM completed IPI-treatment; 3/16 pts with- vs 8/34 pts without MBM had IPI-retreatment. Adverse events were managed following established guidelines and were generally mild/reversible (<20% pts gr3-, none gr4/5) and similar in pts with- or without MBM at the exception of symptomatic radiation necrosis of the brain (RNB) observed in 3 pts (1x gr2, 2x gr3). Following surgery (1pt), and corticotherapy (3pts) all pts recovered their RNB related symptoms. Best objective tumor response (BOR) by RECIST outside the CNS in pts with- vs without MBM was 1PR vs. 1CR/2PR/4SD; according to the immune-related response criteria: 3PR vs. 1CR/2PR/7SD. After a median follow-up of 18 months, 32 pts have died (11/16 with- vs. 21/34 without MBM). The probability for OS was not significantly different for pts with- or without MBM (HR .76 [95%CI 0.36-1.59]; p: .475 by Log-Rank test). Conclusions: in our single-center experience with IPI for pts with advanced melanoma treated in an EAP, the probability for OS for patients with a prior history of MBM was not significantly different from pts without a prior history of MBM.
The impact of a multi-epitope melanoma helper peptide vaccine on Th1 cytokine production by responding lymphocytes.
Authors: Dillon Patrick Michael , Olson Walter C. , Chianese-Bullock Kimberly A. , Czarkowski Andrea , Slingluff Craig L. 
Published: March 2020

e19028 Background: Melanomas produce soluble and cell-associated molecules that can suppress or alter antitumor immunity. Preclinical studies suggest the disease burden may alter the cytokine profile of helper T cell responses to cancer antigens. To describe the vaccine-induced production of Th2 or Th1 responses to helper peptides in the setting of advanced melanoma, we measured cytokine production of helper T cells responding to vaccination by 6 melanoma helper peptides (6MHP). We then analyzed results by measurable disease status. Methods: Thirty-nine patients with stage IIIB-IV melanoma received a 6MHP vaccine as a part of the UVA Mel41 clinical trial. For analysis of this correlative endpoint, antigen-reactive T cells were exposed to antigen, and supernatants (days 2 and 5) were assayed by cytokine bead arrays for Th1 and Th2 cytokines. Results: The dominant Th1 and Th2 cytokines detected were IFN-g and IL-5, respectively, though high levels of IL-2 were also produced early by sentinel lymph node lymphocytes. Th1 cytokine responses predominated both pre and post vaccine. Peripheral blood lymphocytes from patients with clinically measurable disease produced similar levels of total cytokine as patients with no evidence of disease (111pg/ml versus 174pg/ml respectively, p=0.44). For both disease statuses, the cytokine profile was Th1-dominant in most patients. Total cytokine production varied significantly among patients and varied over time but persisted up to nine months post-vaccine. Conclusions: The MHC class II-associated peptides used in this study induced helper T cells with a Th1-biased cytokine response in both PBMC and sentinel immunized nodes. However, both groups of patients can mount a Th1 dominant response to these peptides, which may persist long after the vaccination sequence. Future studies are needed to test newer vaccine adjuvants in combination with these peptides.
Phase I/II study of LOC-paclitaxel (LOC-Pac) in patients (pts) with metastatic melanoma.
Authors: Bedikian Agop Y. , Kim Kevin B. , Papadopoulos Nicholas E. , Hwu Wen-Jen , Patel Sapna Pradyuman , Davies Michael A. , Mahoney Sandy , Hwu Patrick , Woodman Scott 
Published: March 2020

e19039 Background: LOC-Pac is a covalent conjugate of paclitaxel (Pac) and omega-3 fatty acid. In in-vivo animal studies in various tumor models LOC-Pac was found to be superior to Pac in safety as determined by maximum tolerated dose and efficacy as determined by delay in tumor growth and complete response rates. This is the first in human phase I study of LOC-Pac. Methods: Adult patients (pts) with confirmed metastatic melanoma (MM), life expectancy > 3 months, with normal renal and liver profiles, failed prior systemic therapy (Rx) or ineligible for Rxs of higher priority, ECOG performance status 0-2 and with at least one measurable metastasis (met) were eligible to this trial. Pts with known CNS met, neuropathy > grade 1, hypersensitivity to cremophor or Paclitaxel and HIV infection, serious concurrent medical conditions were excluded. LOC-Pac was given intravenously over 1 hour on days 1, 8, 15, 22 and 29 every 42 days. Each dose of LOC-Pac was preceded by a dose of dexamethasone, diphenhydramine and cimetidine. LOC-Pac dose was escalated from 100 to 150, 200, 300, 400, 500 and 600mg/m2 after safety of the prior dose level was confirmed in cohorts of 3 pts each. Responses were assessed by RECIST every 6 weeks. Results: 18 pts were treated. Median age was 61 (range 49-76) years, with 83% male and 100% Caucasian. 16 pts had received prior Rx with cytotoxics/ biologicals. Tumor stages were III/M1a/M1b/M1c in 2/1/3/12 pts. 4 pts had elevated baseline serum LDH levels. 53 cycles have been given. There were 3 responses. A pt with lung met had histologically confirmed complete response. A pt with l. node and spleen mets and another with adrenal mets had partial response. 5 pts had stable disease. The Rx related toxicities were mild and manageable. There were no grade 3/4 toxicities. Grade 2 toxicities included fatigue in 9 (17%) of cycles, Neuropathy and dyspnea each in 7(13%) anemia in 3 (6%), leucopenia and neutropenia, urinary tract infection and seizure occurred in 1(2%) of cycles each. No pt developed alopecia or discolored brittle nails. Currently pts are being accrued at 600mg/m2 dose level. Conclusions: LOC-Pac is effective against MM with an acceptable toxicity profile and may provide a way to deliver higher dose of Pac and improve its clinical efficacy.
Resistance to BRAF inhibition in melanoma: An epigenetic approach.
Authors: Walston Steve , Gordon Nicolaus , Chakravarti Arnab , Palanichamy Kamalakannan 
Published: March 2020

e19040 Background: Melanoma only accounts for 4% of skin cancer while causing 75% of cancer related deaths. Worldwide incidence is increasing faster than any other cancer, and there are few effective treatment options for invasive disease translating to poor survival. The burgeoning understanding of molecular mechanisms driving carcinogenesis creates unique opportunities to develop targeted therapy. This is especially apparent in the case of BRAF in melanoma. BRAF V600E mutations occur in up to 50% of melanomas endowing these tumors with a constitutively activated MAPK pathway. Blockade of BRAF mutated tumors shows impressive initial responses above 80%. However, single-agent targeted therapy is often plagued with an emergence of resistant clones, and these impressive responses were transient. Diverse resistance mechanisms have been reported at the transcriptome level in patients treated with BRAF inhibitors. However, reports elucidating the prominent epigenetic regulators of resistance to BRAF inhibition are lacking. Methods: We sequenced the DNA of 14 melanoma cell lines and determined 9 had BRAF V600E mutation and 5 were wild type. We also sequenced cancer genes such as p53, PTEN, cKit, NRAS, etc. The BRAF mutant cells were exposed to PLX4032 (BRAF V600E inhibitor) and the concentrations were incrementally increased to develop resistant clones. This resistance was corroborated using annexin V / PI assay to display approximately a 50% decrease in apoptosis in drug resistant cells compared with control cells after 5 days of 5 µM PLX4032 exposure. The epigenome was profiled in control and resistance clones. Results: The statistically significant clusters were identified and currently we are validating their relevance using functional models. We are also profiling the epigene expression levels in melanoma patient biopsies to determine their predictive and prognostic value. Conclusions: It is likely the epigenome plays an integral role in the previously demonstrated mechanisms of BRAF resistance. Our study should illuminate connections with pathways conveying drug resistance to increase understanding of these mechanisms. Consequently, it may be possible to develop improved treatments and prognostic biomarkers.