bluuebunny/crossref_metadata_2025 huggingface dataset:
Absolute lymphocyte count (ALC), absolute monocyte count (AMC), and ALC/AMC ratio to predict outcome in aggressive non-Hodgkin lymphoma (aNHL).
Authors: Rivera-Rodriguez Noridza , Cabanillas Fernando , Pardo Wandaly Ibis , Santiago Karen J. , Pavia Orestes Antonio , Bruno Margarita
Published: March 2020

e18547

Background: Prognostic factors in NHL have been well studied in the pre-rituximab era. More recently, tumor infiltrating macrophages were found to confer an adverse prognosis. Porrata et al. at Mayo Clinic have described the ALC, AMC, and ALC/AMC ratio as important prognostic factors. We have evaluated pts with aNHL treated in the rituximab era to identify prognostic factors Methods: From January 2006 and April 2011, 89 pts with aNHL treated at our center were accrued. Initial treatment was R-CHOP based. 59 were entered on R-CHOP + GM-CSF protocol and the remainder were identified from our database. Results: Median age was 59 (25-89), 44% were male; histologies included DLBCL (n=75), high grade follicular lymphoma (n=11), and other (n=5). Median follow up = 27 mo. 3 year FFS and OS for the entire group: 78% and 83% respectively. On univariate analysis, FFS was superior for low IPI (0-2, p=0.01), normal B2 microglobulin (p=0.008), females (p=0.04), ALC > 865 (p=0.001), ALC/AMC ratio of >1.43 (p=0.02) but contrary to Porrata’s findings, there was no difference by AMC. In pts with low IPI, there was a significant difference in FFS and OS for those with an ALC >865 (93% vs 56%, p=0.0008;96% vs 60%, p=0.0004). In females ALC had no prognostic value, but males with low ALC had a significantly worse FFS and OS (85 vs 34%, p=0.007; 91% vs 53%, p=0.006). Females with high AMC had superior FFS (p=.02) but the opposite trend was seen in males. On multivariate analysis, gender, B2-microglobulin, and combined IPI with ALC/AMC ratio >1.43 remained as independent prognostic factors with gender being the most significant factor in the model. Conclusions: Prior to Rituximab, gender was not prognostic. Our findings suggest that: 1- favorable impact of Rituximab occurs mostly in females; this could be related to their immune system. 2- Both ALC and ALC/AMC ratio have prognostic significance, and can identify patients with favorable IPI who have poor outcome. This effect is particularly striking for males. To the best of our knowledge this is the first study to find an interaction between gender and ALC, and ALC/AMC as well as a divergent effect of gender and AMC on prognosis
A single-center analysis of initial imaging in multiple myeloma (MM).
Authors: Markow Justin M. , Desai Amishi , Staszewski Harry
Published: March 2020

e18554

Background: Current recommendations for the evaluation of MM include a skeletal survey (SS) and possibly an MRI. The literature documents a discrepancy in the detection of important skeletal lesions between these two techniques. There is limited data on the relationship between symptoms and spinal MRI findings. We analyzed the correlation of symptoms with an abnormal MRI in our patients. Methods: We analyzed 66 unselected,retrospectively identified patients with MM using lab values, ISS scores, the initial SS, and MRI. Skeletal symptoms, interval between studies, discordance between imaging by modality, and interventions were also tabulated. Risk ratios (RR) were calculated for the probability of radiologic abnormalities based on symptoms. Fischer's exact test was applied. Results: The baseline characteristics by age, gender, race, ISS score, and other lab values were similar between groups. 53% (35/66) of patients had an MRI at diagnosis. 51.4% (18/35) of these had different findings from the SS (95% CI, 35.6% - 67.0%). 30.8% (8/26) of patients with an MRI abnormality were asymptomatic or had symptoms in a different location than seen on MRI (95% CI, 16.3% - 50.1%). 15.4% (4/26) of these patients were asymptomatic at presentation (95% CI, 5.5% - 34.2%). (RR) for patients with any reported symptom and abnormal MRI finding is 2.6 (95% CI, 1.1 - 5.6, p< 0.01), while the RR for a symptom corresponding to its anatomic area on MRI is 1.3 (95%CI .8 - 2.1, p = 0.23). Conclusions: 30% of our patients with an abnormal MRI were asymptomatic or reported symptoms in a different area. The RR for an abnormal MRI result in patients with any symptom was significant, but the symptomatic area did not correlate with the anatomic MRI abnormality. This suggests that a significant amount of disease is missed because imaging may be confined to the symptomatic area and asymptomatic patients are less likely to have an MRI. Within this limited data set, there appears to be an advantage to performing routine initial MRI
Drug resource use and costs for novel agents in multiple myeloma.
Authors: Binder Gary , Harwin William N. , Stemkowski Stephen , Zhou Yunping , Khan Zeba M. , Nourbakhsh Ali
Published: March 2020

e18560

Background: Lenalidomide plus dexamethasone and bortezomib are NCCN guideline-recommended treatments for multiple myeloma (MM). While several economic models have assessed these regimens (Fullerton AMCP 2007, Durie IMW 2011), there is a lack of published real-world evidence on payer drug costs, particularly regarding billed unit quantities. This analysis evaluated utilization quantities per claim and incurred payer costs for a common time period for lenalidomide and bortezomib in MM. Methods: A retrospective claims analysis was conducted using pharmacy and medical claims data from a large US payer. Claims for 5 million Medicare Advantage (MA) and commercial plan members continuously and non-continuously enrolled within the period 07/01/2009 to 06/30/2011 were evaluated to select patients having at least 2 medical claims for MM (ICD9 203.0x), and at least 1 claim for units of these drugs, to identify billed unit quantity and allowed charges per claim. Results: 1,249 patients had MM diagnoses and use of these drugs. The MA and commercial populations had similar utilization and costs. For bortezomib, average quantity billed per claim was 3.3 mg (94% of a full 3.5 mg/10 mL single-use vial); 78% of claims billed 3.5mg. For lenalidomide, average and most common quantity billed per claim was 21 capsules at an average strength of 17.1 mg; the most common strength was 25 mg (43%). Average allowed charges for a common 28-day month were $7,031 for bortezomib (applied over 28 days at $1,318 per each of 4 administrations per 21-day cycle) vs. $6,911 for lenalidomide. Conclusions: Billed and paid utilization for commercial and Medicare Advantage MM patients was generally 1 full vial of bortezomib and 21 capsules of lenalidomide per date of service. Drug costs per month of lenalidomide and bortezomib treatment were very similar, differing by less than $10/day, prior to physician administration charges. Future cost analyses should consider these rates and focus on total drug and medical costs of care, factoring in actual treatment episodes and evaluating common time periods.
Efficacy and safety of lenalidomide and dexamethasone in overtreated multiple myeloma patients.
Authors: Moscetti Alessandro , Resci Federica , Antolino Giusy , Saltarelli Francesca , Monarca Bruno , Bianchi Maria Paola , Naso Virginia , De Benedittis Daniela , La Verde Giacinto
Published: March 2020

e18566

Background: Lenalidomide is a therapeutic option for pretreated patients with multiple myeloma, especially in association with steroids. Methods: Oraldaily lenalidomide (10-25 mg) for 21 days every month (median courses 8.6) and weekly dexamethasone (Dex) were administered until progression in 33 pretreated patients (median age 68.1 yrs) observed between June 2008 and January 2012 at Hematology Department of Sant’Andrea Hospital in Rome. Previous treatment included alkylants, anthracyclines, IFN-α, thalidomide, bortezomib and single or double autograft. Fifteen patients were evaluated after 6 courses of therapy, administered as second to fifth line, and prospectively followed-up; two patients weren’t considered because of early death. Treatment response was assessed according to IMWG uniform response criteria. Results: The overall response rate was 53.3% (8/15 pts) with a median duration of response of 12 months: 8 patients reached a partial response (PR), 6 showed a stable disease (SD) and 1 progressive disease (PD). The median progression free survival was 14 months. Among patients in PR, 5 are alive in continous treatment, 2 died due to PD after 17 courses administered as fifth line therapy and 1 died for unrelated surgical complicancies. The whole responses were achieved indifferently if lenalidomide was administered as second, third or fifth line of therapy (2, 3 and 3 patients respectively). Out of patients in SD, all experienced progressive disease after a median of 12 courses: 3 are still alive in salvage therapy, 3 died during treatment. The only patient in PD died 9 months after the end of Len-Dex treatment during salvage chemotherapy. The reported side effects included pneumonia, neutropenia, diarrhea, peripheral sensitive polyneuropathy, transient liver failure, lower urinary tract infection, skin rash, transient aphasia, conjunctival hemorrhage and deep vein thrombosis, all resolved with brief discontinuance and specific support therapy without hospitalization. Conclusions: Len-Dex association is a completely oral effective salvage therapy with good response rate and manageable side effects also for overtreated relapsed and refractory multiple myeloma patients.
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.
Lines of systemic therapy in patients with metastatic melanoma in the United States.
Authors: Zhao Zhongyun , Wang Song , Barber Beth , Wagner Volker Jean
Published: March 2020

e19043

Background: To describe treatment patterns by lines of systemic (drug) therapy in patients with metastatic melanoma in the U.S. Methods: Using a large U.S. medical claims database, patients were identified between 2005 and 2010 using ≥2 melanoma diagnoses (ICD-9-CM: 172.xx, V10.82) and ≥2 diagnoses for metastasis (ICD-9-CM: 197.xx, 198.xx). Patients were followed from the metastatic diagnosis date to death, disenrollment, or end of study period (6/30/2010), whichever occurred first. Lines of systemic therapy were identified based on the temporal order, gaps, and changes in the drug regimens. Systemic therapies and the duration of therapy in each line were examined. Results: A total of 2,546 patients with metastatic melanoma were included and 985 (38.7%) received systemic therapy. As the first documented therapy after diagnosis, 82.4% of patients received mono-therapy (38.5% temozolomide, 14.3% interleukin-2, 11.4% interferon alfa-2b, 8.2% dacarbazine, 2.9% paclitaxel, 2.5% GM-CSF) and 9.4% received carboplatin plus paclitaxel. Mean duration of mono-therapy was 60 days, ranging from 32 days on interleukin-2 to 124 days on GM-CSF. Of 287 patients (29.1% of previously treated) received subsequent therapy, 68.0% received mono-therapy (26.8% temozolomide, 11.9% interleukin-2, 10.5% dacarbazine, 8.4% paclitaxel, 3.1% interferon alfa-2b, 1.7% GM-CSF), 16.7% carboplatin plus paclitaxel, and 7.3% dacarbazine-containing therapies. Mean duration of mono-therapy was 67 days, ranging from 30 days on interleukin-2 to 238 days on GM-CSF. Among 71 patients who further received additional therapy, mono-therapy was still the dominant regimen (63.4%) with 21.1% temozolomide, 18.3% paclitaxel, 8.5% interleukin-2, 5.6% dacarbazine, 4.2% GM-CSF, and 1.4% interferon alfa-2b. Carboplatin plus paclitaxel was given to 19.7% of patients. Mean duration of mono-therapy was 63 days, ranging from 7 days on interferon alfa-2b to 90 days on temozolomide. Conclusions: The majority of patients with advanced melanoma didn’t receive systemic therapy as captured in the claims database; among those who received systemic therapy, mono-therapy was most common.
Acral melanoma among the minority population in Hawaii and the Pacific basin: Analysis of downstream effectors within the PI3K pathway.
Authors: Morita Shane Young , Lum Christopher A. , Davis James W.
Published: March 2020

e19051

Background: Acral melanoma (AM) has been described as a distinct entity in the molecular classification of melanoma. The minority population tends to be more commonly afflicted by AM. Recent studies have profiled the importance of the PI3K (phosphatidylinositol 3-kinase) cascade in melanoma biology and therapy. Both mTOR (mammalian target of rapamycin) and S6K (S6 kinase) are involved in translational control and protein synthesis. However, characterization of this pathway focusing on these pivotal components in a multi-ethnic AM population has not been reported. We elected to determine the frequency of PI3K involvement of the critical downstream effectors, mTOR and S6K. Methods: IRB approval was obtained. From 1992 to 2011, 24 non-Caucasian patients histologically confirmed to have AM were evaluated at a tertiary institution. Data including age, gender, tumor location, Breslow thickness, Clark level, ulceration and mitoses per mm squared were compiled. Immunohistochemical expression for both phosphorylated mTOR and S6K was performed on archived biospecimens (primary lesions). Both mTOR and S6K expression were graded on a scale from 0 (absent) to 2 (high). Results: Our findings demonstrated that mTOR 12/24 (50%) and S6K 20/24 (84%) were highly expressed. Demographics of the non-Caucasian cohort (17 Filipino and 7 Pacific Islanders) included mean age of 67.2 years old (range 44-89) and male gender 12/24 (50%). Tumor location principally involved the foot 20/24 (83%); mean Breslow thickness was 5.0 mm (range 1.6-11.0), Clark IV or higher 18/24 (75%), ulceration 18/24 (75%) and mean mitoses per mm squared was 8.9 (range 1-30). Conclusions: A high proportion of minority patients with AM displayed evidence of an activated PI3K pathway. Over half of our cohort had thick primary lesions with a high propensity for ulceration. This is the first study to our knowledge that has examined the downstream effectors, mTOR and S6K within the PI3K pathway in a minority population of AM patients. This is compelling data that may be applied to the metastatic phenotype in future trials and help stratify which patients will benefit from rapalogs.
Clinical and dermoscopic features of keratinizing skin tumors in BRAFi-treated patients.
Authors: Rosen Alyx C. , Jaimes Natalia , Marghoob Ashfaq A. , Halpern Allan C. , Myskowski Patricia L. , Lacouture Mario E.
Published: March 2020

e19052

Background: Development of keratinizing skin tumors (KST), including squamous cell carcinomas (SCC), keratoacanthomas (KA) and verrucae (warts), are common in patients receiving BRAF inhibitors (BRAFi), including vemurafenib (V), XL281 (X) and GSK211846 (G). Dermoscopy is a specialized technique for examining skin lesions. While the clinical characteristics of these lesions are well known, the dermoscopic morphology remains to be elucidated. Methods: Patients on V, X or G who developed biopsy-proven KSTs were included in the study. Clinical and dermoscopic images of the KSTs were evaluated to determine the clinical and dermoscopic features. Frequent and reproducible structures were identified. P values were calculated based on Fisher's exact test. Results: 44 lesions (8 SCC/KAs, 36 verrucae) were identified in 21 patients. Clinically, SCC/KAs presented as scaly papules (75%) or plaques (25%) with a central scale/crust (63%), erythematous halo (63%) and/or scaly rim (63%). Verrucae presented as papules (97%) with an erythematous halo (50%). Dermoscopically, keratinizing pearls were exclusive to the SCC/KAs and keratin “petals”, “domes” or horns were seen exclusively in verrucae (Table). In the verrucae, thrombosed vessels were often observed within keratin structures; vs. vessels seen in the SCC/KAs, which were mainly located outside the keratin, around the center or in the base of the tumor. Conclusions: Although KSTs secondary to BRAFi do not result in drug discontinuation, they can affect dosing and quality of life. The dermoscopic features described herein may aid in the differentiation of benign vs. malignant lesions, with keratinizing pearls appearing to be unique to SCC/KAs. Management strategies for BRAFi KSTs may be tailored based on dermoscopic findings, with more conservative treatment for verrucae vs. SCC/KAs, which may decrease morbidity and cost. [Table: see text]
Conditional survival (CS) in patients with stage II melanoma.
Authors: Gamerman Victoria , Karakousis Giorgos Constantine , Guerry DuPont , Gimotty Phyllis A.
Published: March 2020

e19054

Background: While sentinel lymph node biopsy is recommended for those presenting with clinical stage II melanoma, it is not always performed. Future survival beyond the time already survived is captured by CS and is relevant to patient counseling and guiding follow up. We sought to investigate patterns of CS in patients with clinical (no nodal biopsy) or pathological stage II melanomas controlling for ulceration. Methods: The study included 5,370 patients diagnosed with primary cutaneous melanoma in 2004-2008 from the Surveillance, Epidemiology, and End Results (SEER) data. Three-year CS probabilities were estimated from the Kaplan-Meier survival curves (time to melanoma-specific death) at 6, 12, and 18 months from diagnosis. Newly developed biostatistical methods were used to evaluate the statistical significance of changes in CS as the time survived increased for four groups of patients: those clinically and pathologically staged with and without ulceration. Results: With increasing time survived up to 18 months, there was no significant change in the 3-year CS estimates for the cohort of pathologically-staged patients with non-ulcerated lesions (n=1702). For pathologically-staged patients with ulcerated lesions (n=1915), 3-year CS increased significantly only after having survived 1 year (86% to 87% p=0.001). A similar pattern was seen for the cohort of clinically-staged patients with non-ulcerated lesions (n=801), (85% to 87% p<0.001). For clinically-staged patients with ulcerated lesions (n=952), the 3-year CS estimates for those who had survived 6, 12, or 18 months were 74%, 78%, and 82%. After the initial 6 months of survival, there was a significant change in 3-year CS having survived 6 versus 12 months (p=0.002), as well as having survived 12 versus 18 months (p<0.001). Among patients with ulcerated lesions, CS for those clinically staged begins to change after 6 months whereas for those pathologically staged change occurs only after a year. Conclusions: CS provides up-to-date prognostic information to patients, their physicians and clinical trialists. Formal statistical methods, as illustrated here, identify when clinically meaningful CS estimates change in statistically significant ways.
Biomarkers of treatment effect in a phase II trial of velimogene aliplasmid in patients with metastatic melanoma.
Authors: Wloch Mary K , Kharkevitch Dmitri D. , Chu Alice , Schulte John , Smith Larry R , Kenney Richard T. , Rolland Alain
Published: March 2020

e19058

Background: Velimogene aliplasmid (Allovectin, A) is a plasmid-based immunotherapeutic that encodes human leukocyte antigen-B7 and β-2 microglobulin. A is designed to induce allogeneic and tumor-antigen-specific T-cell responses against tumor cells. In a phase II trial, 127 patients with stage III or IV recurrent metastatic melanoma were treated in cycles of 6 weekly intralesional injections of 2 mg/dose. Complete (CR) or partial responses (PR) were observed in 15 patients (11.9%, 95% CI: 6.2-17.4), stable disease (SD) in 32 (25.2%), and progressive disease (PD) in 80 (63.0%). Methods: Serum collected before treatment and 3 weeks after each cycle from 29 patients who showed clinical benefit (CB: 15 CR or PR patients and 14 patients with SD for >4 months) and 62 with PD (progressed by the end of the first cycle) were evaluated for 45 inflammation biomarkers in a quantitative multiplex immunoassay. Changes in analyte concentrations relative to baseline were evaluated by paired t-test or Wilcoxon signed-rank test. Results: Overall, 52% of patients had decreases in serum IL-10 after treatment; however, decreases were more prevalent in CB patients (71.4% for CB, 44.4% for PD; p=0.036; Chi-square test). At week 8, mean serum IL-10 concentration within a group was reduced relative to baseline in CB (p=0.008) but not PD patients suggesting greater treatment effect in CB patients. In CB patients, IL-10 remained at lower levels relative to baseline through week 26. CCL-3 decreased in CB patients by week 26 (p=0.021) and von Willebrand factor (a biomarker of vascular endothelium dysfunction) was increased at week 26 (p=0.007). In PD patients, by week 8, several biomarkers associated with metastatic melanoma (TIMP-1, VCAM-1, and TNF-R2) or inflammation (haptoglobin) increased (p=0.001, 0.022, <0.001, 0.004, respectively) consistent with tumor progression, whereas others (IL-8 and stem cell factor) decreased (p=0.007, 0.013, respectively). Conclusions: Consistent with A’s proposed mechanism of action, treatment was associated with a decrease in the production of the T-cell suppressive cytokine, IL-10. Furthermore, biomarker profiles in the two groups were markedly different and analogous with treatment outcomes.
Do patients with thin melanomas benefit from sentinel lymph node biopsy with selective lymph node dissection?
Authors: Krishnamurthy Vikram , Hieken Tina J.
Published: March 2020

e19061

Background: Sentinel lymph node (SLN) biopsy for thin melanoma remains controversial. While most patients diagnosed with thin melanoma have an excellent prognosis, ~5% will die of their disease. With the growing number of thin melanomas, nearly 25% of all melanoma-related deaths now result from thin primary tumors. Yet these patients are unlikely to have LN disease at presentation and when SLN disease is identified, it is often minimal. It remains unclear whether SLN biopsy with selective LN dissection (LND) represents an opportunity to cure patients with high-risk thin melanoma or whether they are a subgroup with disease likely confined to the SLN(s) or of unclear clinical significance. We undertook this study to examine outcomes in patients with thin melanomas (<1.0mm on biopsy) who underwent SLN biopsy. Methods: From our Melanoma Registry, we identified 338 consecutive thin melanoma cases in 300 patients. Data were verified by pathology and record review. Median patient follow up was 61 months. SAS software was used for statistical analysis. Results: 36 of 300 patients (12%) underwent SLN biopsy. Patients selected for SLN biopsy were younger (median 58 v 69 yrs, p=0.03), their melanomas were thicker (median 0.9 v 0.25 mm), more often level IV/V (44 v 5%), ulcerated (11 v 0.3%) and 53 v 22% had ≥1 mitoses/mm2, all p<0.001. Two (5.5%) were SLN+, one with isolated tumor cells in a solitary SLN, the other with 2.0 and 0.2 mm foci in 2 of 2 SLNs. Neither had additional disease identified after LND. Recurrent disease developed in 6/36 SLN patients (16.7%) and in 20/264 non-SLN patients (6.6%), after a median 32 of months. Isolated regional recurrence as site of first relapse occurred in 9/264 non-SLN patients (3.4%) and in no patients after SLN biopsy, p<0.001. Disease-free and overall survival were governed by tumor thickness. Conclusions: SLN biopsy with selective LND provides excellent regional control and prognostic information for selected patients with thin cutaneous melanoma, and may alter treatment and improve outcome for patients who harbor LN disease. Pending ongoing randomized controlled trial results, selective completion LND for patients with thin melanoma and evidence of SLN metastases appears warranted.
Cancer survivors’ perspectives on the U.S. generic drug shortage.
Authors: Nutt Stephanie , Rechis Ruth , Shulman Lawrence N. , Hayes-Lattin Brandon M.
Published: March 2020

e19503

Background: Approximately 1.6 million new cancer cases are expected to be diagnosed in 2012 in the United States, making the need for generic cancer treatment drugs widespread. Methods: In late 2011, LIVESTRONG fielded the Drug Shortage Survey, which mirrored the questions from the American Hospital Association drug shortage survey for providers reworded for a patient audience. The primary goals of the brief survey were to 1) assess if survivors were aware of a generic drug shortage in the U.S. and 2) gauge the impact that the drug shortage has had on people affected by cancer. Individuals were asked to participate in this online survey through a number of means (including the LIVESTRONG Blog). Results: Between October 31, 2011 and January 30, 2012, 114 individuals completed the drug shortage survey, including 54 individuals who have been personally diagnosed with cancer. A little under half of the respondents (47%) felt they or a loved one had been impacted by the drug shortage, while an additional 30% were not sure if they had been impacted. Of the individuals impacted, the most commonly reported adverse effects of the drug shortage were not receiving medications needed for cancer treatment (40%) and receiving different medications (36%). The table highlights the reported effects. Conclusions: Results from this survey indicate that for cancer survivors who chose to participate in this survey who had been impacted by the drug shortage, the impact has been very significant. Additionally, results indicate that more information may need to be disseminated to the patient population about the drug shortage. [Table: see text]