bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of the reduced expression of NR4A1 and NR4A3 with poor survival in patients with aggressive lymphomas.
Authors: Deutsch Alexander Josef , Pichler Martin , Reitter Sonja , Troppan Katharina , Beham-Schmid Christine , Neumeister Peter
Published: March 2020

e18525

Background: NR4A1 and NR4A3 belong to the orphan nuclear receptors. Their function as critical tumour suppressor genes was demonstrated by the rapid development of acute myeloid leukemia (AML) in NR4A1 and NR4A3 double knock-out mice and by their reduced expression in leukemic blasts from human AML patients. The aim of our study is to comprehensively study and functionally characterize NR4A1 and NR4A3 expression in Non-Hodgkin's Lymphomas (NHL). Methods: NR4A1 and NR4A3 expression were determined on mRNA- and protein levels in most lymphoid malignancies of B cell type. Additionally direct sequencing, methylation specific PCR and microRNA analyses of potential interacting NR4A partners were performed. For functional characterization NR4A1was over expressed in a Sc-1 lymphoma cell line by using an inducible lentiviral construct, and treated with Cytosporone-B (Csn-B), a non physiological NR4A1 ligand, followed by apoptotic assays (cleaved caspase 3, Sub-G1 peak determination, and the Annexin V staining). Results: We found a more than 50% reduction of both, NR4A1 and NR4A3, in B-CLL (71%) and Follicular Lymphoma (70%), and more pronounced in diffuse large B cell lymphoma (DLBCL) (74%) compared to normal controls. Mutational analyses in selected cases revealed four of 16 aggressive lymphoma samples mutated (one misssense- and three silent mutations (=25%)). Induction of NR4A1 expression in the transduced Sc-1 lymphoma cell line led to apoptosis in a significantly higher proportion of induced cells compared to their uninduced controls. Additionally, Csn-B treatment of an immortalized B cell line and three lymphoma cell lines caused NR4A1 mediated apoptosis. In a patient cohort of 83 DLBCL, NR4A1 and NR4A3 were more than 50% down-regulated in 88% and 74% of patients, respectively. A low expression of NR4A1 was significantly associated with non-germinal center B-cell like subtype (p<0.001) and with poor overall survival (p=0.042, HR=2.2, CI=1.01-4.9). Conclusions: Our data indicates that NR4A1 has pro-apoptotic functions and that Csn-B induces NR4A1 mediated apoptosis in lymphoma cells. Hence, regulation of NR4A1 by Csn-B is a promising target for the development of new therapeutic drugs.
Adolescents and young adults versus adults’ patients with large B-cell lymphoma: A matched-control analysis on 55 patients.
Authors: Bouabdallah Reda , Coso Diane , Esterni Benjamin , Vey Norbert , Chetaille Bruno , Blaise Didier
Published: March 2020

e18526

Background: Among non-Hodgkin’s lymphomas, large B-cell lymphoma (LBCL) accounts for 60% in adolescents and young adults (AYA). There are no so many reports in the literature on LBCL in AYA patients. Moreover, there are no data available to suggest whether AYA patients with LBCL would benefit more from pediatric-chemotherapy regimen or from adult rituximab-chemotherapy treatment. In order to clarify this point, we conducted a matched-control analysis comparing AYA patients and adult’s patients with LBCL. Methods: We performed a clinical and pathological review of LBCL cases referred to our institution over a 15-year period from 1996 to 2010. Fifty-five AYA (16-30 years) were fully matched to 165 adult’s patients aged between 31 years and 65 years (ratio 1/3) for each of the following factors: international prognostic index (IPI), chemotherapy regimen, and rituximab delivery. Results: When compared to LBCL adults’ patients, pathological features in AYA showed a high incidence of primary mediastinal thymic LBCL subtype (33% vs. 5%, P= 0, 0001), while histological transformation was rare (2% vs. 14%, P= 0, 01). LBCL in AYA also presented with a bulky mediastinal mass (51% vs. 21%, P= 0, 0001), gastrointestinal tract involvement was less frequent (2% vs. 13%, P=0, 03), and LDH value was significantly higher (73% vs. 54%, P= 0, 01). The complete response rate to chemotherapy combination regimen was at 82% in AYA, with no difference with that observed in adult patients (82%, P=0, 8). With a median follow-up of 80 months, the 5-year overall survival (OS) and event-free survival (EFS) of AYA patients were at 73% ± 12% and 68% ± 12%, respectively. The matched-control analysis showed no difference either for OS (P = 0.8) or EFS (P = 0.9). Conclusions: LBCL in AYA should be considered as a true clinical and pathological entity. However, age does not confer a prognostic value different from that observed in LBCL in patients older than 30 years.
Outcomes of advanced HL with ABVD: The University of Pennsylvania experience.
Authors: Trivedi Meghna S. , Bajor David , Ahmadi Tahamtan , Svoboda Jakub , Loren Alison W. , Schuster Stephen J. , Nasta Sunita
Published: March 2020

e18529

Background: Hodgkin Lymphoma (HL) is considered a curable malignancy with standard therapy using the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen. Even with standard therapy, the relapse rate for patients with advanced HL (stage IIB and higher) remains significant. The International Prognostic Score (IPS) uses 7 adverse prognostic factors (serum albumin, hemoglobin, male sex, age, stage IV disease, leukocytosis, and lymphopenia) to predict outcomes in advanced HL. Methods: We performed a retrospective chart review of all patients evaluated at the University of Pennsylvania for primary HL from July 2006 to June 2011. Of 257 patients, 26 were identified as those with advanced HL who initiated ABVD treatment at the University of Pennsylvania. The study outcomes were defined by RECIST criteria. The 26 patients were stratified by IPS and outcomes were evaluated. Results: 22 of 26 patients (85%) achieved lasting complete response (CR) after receiving treatment with ABVD with a median length of follow-up of 2.93 years. Three patients had primary refractory disease. Of these patients, two (IPS 1-2) achieved CR with salvage therapy. The third patient (IPS 5) had initial partial response (PR) to ABVD then continued to have relapsed disease after 4.50 years of follow-up. One patient (IPS 5) relapsed 2.74 years after receiving ABVD and at best had PR with salvage chemotherapy. Conclusions: ABVD was effective in achieving CR; however, 4 patients were unable to achieve lasting CR from ABVD alone. Two patients with IPS of 1 and 2 eventually achieved CR from salvage therapy. Two patients with IPS of 5 were unable to achieve lasting CR. Based on this data, IPS of 5 was associated with worse outcome. Use of IPS may be helpful to identify patients needing more intensive initial therapies. [Table: see text]
Preclinical activity of ofatumumab (OFA) in mantle cell lymphoma (MCL) in vitro, ex vivo, and in vivo models.
Authors: Barth Matthew John , Pendurti Gopichand , Mavis Cory , Czuczman Natalie , Skitzki Jospeh J. , Hernandez-Ilizaliturri Francisco J. , Czuczman Myron Stefan
Published: March 2020

e18537

Background: MCL is characterized by an aggressive clinical course and inevitable development of refractory disease despite early intervention that often includes: immunotherapy (e.g., rituximab), multi-agent induction chemotherapy and consolidation with high dose chemotherapy and autologous stem cell transplant in first remission. OFA is a fully human anti-CD20 mAb targeting a novel membrane-proximal epitope on CD20. To characterize the activity of ofatumumab in MCL, we conducted pre-clinical studies in cell lines, primary tumor cells derived from MCL patients and a MCL bearing severe combined immunodeficiency (SCID) mouse model. Methods: Antibody-dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) assays were performed in 51Cr labeled Mino, Jeko, Rec-1 and Z-138 cells comparing RTX or OFA. Primary tumor cells were exposed ex vivo to OFA or RTX with human serum, differences in cell viability were determined by Cell Titer Glo assay. Expression of CD20 and complement inhibitory proteins (CIPs) CD55 and CD59 was determined by Imagestream analysis and Western blot. SCID mice were inoculated SQ with 10x106 Z-138 cells. Once tumors were established, mice were assigned to observation versus 4 doses of either OFA or RTX, and anti-tumor activity was measured by changes in tumor volume. Results: OFA induced higher CDC than RTX in all MCL cell lines tested (Mino: 65.9% vs. 0.5% ; Jeko 43.9% vs. 13.3% ; Rec-1 25.4% vs. 4.7% ; Z-138: 56.4% vs. 0.65%). No differences in ADCC were noted between OFA and RTX. In primary tumor cells, OFA and RTX demonstrated similar activity. CD20 levels were similar in all MCL cell lines tested. Of interest, CIP expression in MCL cell lines was higher when compared to other NHL cell lines, explaining differences observed between OFA and RTX. In vivo OFA was more effective in slowing tumor progression than RTX. Conclusions: Our data suggest OFA is more potent than RTX against MCL pre-clinical models. In addition and as expected, OFA exhibits potent CDC despite high expression of CIP. Our results support the evaluation of ofatumumab in future prospective clinical trials for patients with MCL.
Evaluation of MLN4924, an investigational NEDD8-activating enzyme (NAE) inhibitor, as a novel targeted agent with single-agent antitumor activity in mantle cell lymphoma (MCL) and Hodgkin lymphoma preclinical models.
Authors: Dawar Richa , Barth Matthew John , Mavis Cory , Skitzki Jospeh J. , Czuczman Myron Stefan , Klener Pavel , Hernandez-Ilizaliturri Francisco J.
Published: March 2020

e18539

Background: MLN4924 is a novel, potent, and selective inhibitor of NAE, an essential component of the ubiquitin-proteosome system (UPS). We have previously demonstrated that the UPS plays a pivotal role in the development of rituximab and chemotherapy resistance in B-cell lymphomas. There is a scientific need to target the UPS more efficiently in an attempt to reverse acquired resistance to biological and chemotherapeutic agents in relapsed/refractory aggressive lymphoma. To this end, we studied the anti-tumor activity of MLN4924 in rituximab-chemotherapy sensitive and resistant pre-clinical models. Methods: A panel of Burkitt (BL), diffuse large B-cell (DLBCL), MCL and HL lymphoma cell lines and primary tumor cells isolated from patients with non-Hodgkin lymphoma (NHL) (N=10) were exposed to escalating doses of MLN4924 alone or in combination with a panel of chemotherapeutic agents for up to 72 hrs. Cell viability was determined by alamar Blue reduction or CellTiter-glo assay. Apoptosis was determined by Western blotting. Cell cycle analysis was performed by flow cytometry. Results: MLN4924 demonstrated activity in all cell lines in a time-and dose-dependent manner, including the rituximab/chemotherapy-resistant cell lines. The most potent activity was noted in MCL and HL cell lines (IC50 doses were tenfold lower as compared to DLBCL or BL cell lines). A variable degree of anti-tumor activity was observed in primary tumor cells isolated from NHL patients. Induction of apoptosis was observed in rituximab-resistant cell lines. MLN4924 exhibited synergistic anti-tumor activity when combined with bortezomib, bendamustine, and cytarabine in MCL cell lines. Conclusions: MLN4924 exhibits potent in vitro cytotoxic activity against a variety of human B-cell lymphoma cell lines and primary tumor cells isolated from NHL patients. Significant activity was observed in MCL cell lines. Experiments investigating the in vivo activity of MLN4924 are ongoing. MLN4924 is a highly promising agent for the treatment of relapsed/refractory MCL or HL.
AIDS-related lymphoma (ARL) in Asians in the era of HAART and rituximab.
Authors: Tan Wu Meng , Tan Soo Yong , Ng Tat Ming , Pan Summer , Quek Richard Hong Hui , Tao Miriam , Tai Wai Meng David , Koh Yin Ling , Tan Thuan Tong , Tan Daryl C.L. , Ha Tam Cam , Chan Alexandre , Tay Kevin , Lim Soon Thye
Published: March 2020

e18546

Background: We described EBV & HHV8 co-infection rates, histology subtypes (particularly T-cell), prognosticators and outcomes of Asian ARL and compared them to Western series. Methods: We studied clinicopathologic features of 46 HAART-era ARL diagnosed from 1998-2011 in an Asian Tertiary Cancer Centre. To study HIV effect on survival, we applied multivariate analysis to HIV-DLBCL matched against 453 de novo DLBCL from 2000-2008. Results: The 46 patients’ characteristics are presented in the table below. Of note, germinal centre B-cell (GCB) subtype predominated in HIV-DLBCL with evaluable tissue. In multivariate analysis of HIV-DLBCL and matched de novo DLBCL, HIV status did not predict survival (HR1.33, p=0.63); CR was the only significant prognosticator (HR0.30, p=0.048). Conclusions: 1. EBV+ rates appeared to surpass prior Western ARL series. Although concomitant EBV infection appeared to correlate with inferior survival (HR34.5), it was not statistically significant. 2. Alb<30 (p=0.02) & Hb<10 (p=0.003) significantly predicted worse OS, but not CD4 or concurrent HIV&ARL diagnosis. 3. In this predominantly EPOCH-treated population, BL (HR 2.27) non-significantly trended to worse OS than DLBCL. 4. T-cell ARL (2/46, 4%) was rarer than the expected Asian de novo rate. 5. In multivariate analysis, HIV-DLBCL OS was similar to matched de novo DLBCL, suggesting they should be similarly treated with curative intent. CR rates and 5yr OS were comparable to de novo DLBCL. [Table: see text]
Evaluation of serum B-cell maturation antigen in multiple myeloma.
Authors: Sanchez Eric , Li Mingjie , Kitto Alex , Li Jennifer , Wang Cathy , Kirk Dylan T , Robinson Austin , Madden Erik , Okhovat Jean-Phillip , Waterman Gabriel N. , Swift Regina A. , Bonavida Benjamin , Chen Haiming , Berenson James R.
Published: March 2020

e18549

Background: B cell maturation antigen (BCMA) is a receptor whose expression increases during B-cell development and is found on malignant cells from multiple myeloma (MM) patients; however, it has not been identified in human serum. Methods: Bone marrow (BM) aspirates and peripheral blood were obtained from patients with MM, monoclonal gammopathy of undetermined significance (MGUS) and healthy control subjects following informed consent (Western IRB BIO 001). Serum was isolated and analyzed with a BCMA enzyme‑linked immunosorbent assay. Values represent the mean of triplicate experiments. BM mononuclear cells (MCs) were isolated using density‑gradient centrifugation and cultured for 72 h in RPMI1640 supplemented with 10% fetal bovine serum. Our human MM xenograft (LAGκ-2)was grown in SCID mice and treated with bortezomib (BORT) with cyclophosphamide (CY); tumor volume and BCMA levels were determined. Statistical significance of differences observed was determined using a Student’s t test and analysis was determined using GraphPad prism software. Results: We showed that the supernatants of cultured BMMCs from MM patients had high concentrations of BCMA (median = 2,250 pg/ml) whereas normal subjects showed minimal amounts (56 ng/ml; P < 0.0001). The serum BCMA levels from newly diagnosed MM patients (n = 51) had much higher levels (13.74 ng/ml) than among controls (n = 40; median 2.58 ng/ml; P < 0.0001) and MGUS subjects (n = 26; median 5.40 ng/ml; P = 0.005). Notably, protein levels were much higher among patients with relapsed or refractory (R/R) disease (n = 79; median 20.02 ng/ml) compared to those with responsive (> partial response) disease (n = 80; median 4.14 ng/ml; P = 0.0038). Following treatment, patients with responsive disease showed decreases in BCMA levels whereas those with R/R disease showed increases. Following treatment with BORT and CY, we also showed a marked decrease in tumor volume and serum human BCMA levels in mice bearing the LAGκ-2 xenograft whereas untreated animals showed marked increases in tumor size and serum BCMA. Conclusions: This is the first report identifying serum BCMA in any human disease and suggests that these levels may be a novel biomarker for monitoring disease status and therapeutic response of MM patients.
An evaluation of efficiency, safety, tolerability, patient satisfaction, and preference of subcutaneous (SQ) versus intravenous (IV) bortezomib (BTZ) administration in patients with multiple myeloma (MM).
Authors: Barbee Meagan Spencer , Wilson Nicole Maire , Harvey R. Donald , McKibbin Trevor , Lonial Sagar , Kaufman Jonathan L. , Shah Katherine Sanvidge
Published: March 2020

e18553

Background: SQ BTZ is approved for use in patients (pts) with MM; however, there is no data assessing the effect of SQ BTZ administration on practice variables (e.g., chair time, total time in clinic) or patient preferences. Furthermore, few studies have evaluated the incidence of PN with SQ BTZ, especially in treatment naïve patients. Methods: This study is divided into three components. Eligible pts for the retrospective efficiency study received ≥ 6 doses of either IV or SQ BTZ in the clinic in 2011 with no concurrent infusions/transfusions other than IV fluids, premedications, or concurrent chemotherapy during their visit. Individual clinic encounters of eligible pts were assessed for chair time and overall clinic visit time, and the average times were compared between the IV and SQ groups. Eligible pts for the preference/satisfaction survey study received ≥ 1 dose of each IV and SQ BTZ in 2011 and spoke English. Percent response to answer choices are reported. De novo SQ BTZ pts who received ≥ 6 doses were eligible for the retrospective safety/tolerability study. Patient chart notes were reviewed to identify the incidence and grade of PN. Results: 92 pts representing 1458 encounters were included in the efficiency study. Average chair time was 54 min less with SQ BTZ than IV BTZ (95% CI, 48 to 59 min; n = 1077 encounters; 89 vs 143 min). Average overall clinic visit time was 46 min less with SQ BTZ than IV BTZ (95% CI, 40 to 52 min; n = 1102 encounters; 123 vs 169 min). 28 of 47 eligible pts completed the survey. 19/28 (67.8%) preferred and 19/28 (67.8%) were more satisfied with SQ BTZ than IV BTZ. 11/28 (39%) experienced an injection site reaction, and 14/28 (50%) agreed they would feel comfortable with self-administration at home. Of the 14 pts receiving SQ BTZ who were BTZ naïve, 11 were newly diagnosed. One of these pts had new PN and 3 had worsened PN from baseline. SQ BTZ was dose reduced in 2 patients and discontinued in 2 pts due to PN. Conclusions: A complete transition in the practice of administration of BTZ from IV to SQ could improve clinic efficiency and provide a more preferable/satisfactory experience for pts.
Race- and health-related quality of life among patients newly diagnosed with multiple myeloma.
Authors: Pashos Chris L , Durie Brian G. , Rifkin Robert M. , Abonour Rafat , Fonseca Rafael , Gasparetto Cristina , Mehta Jayesh , Narang Mohit , Shah Jatin J. , Terebelo Howard R. , Thomas Sachdev P. , Toomey Kathleen , Swern Arlene S , Harding Gale , Sullivan Kristen , Street Thomas , Khan Zeba M.
Published: March 2020

e18556

Background: Studies in the United States (US) have identified variation in incidence and survival of multiple myeloma (MM) patients of different races, and noted that MM is the most common hematologic cancer among African Americans. This analysis evaluated whether health-related quality of life (HRQOL) of patients in the US varies by race as they initiate treatment having been newly diagnosed with active, symptomatic MM. Methods: Data were collected in Connect MM, a prospective US observational registry begun in September 2009. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was reported by patients at enrollment within 2 months of diagnosis. Patients completed the Brief Pain Inventory (BPI), EQ-5D, and Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM). Mean reported scores for BPI, EQ-5D and FACT-MM were analyzed by patient race. Statistical significance was ascertained by ANOVA using SAS 9.1. Results: Baseline HRQOL data were reported by 1144 patients (enrolled in 228 centers) of whom 82% were White, 13% Black, and 6% Other race. The cohorts did not differ statistically by ECOG status or by multiple myeloma stage (assessed by either the International Staging System or the Durie and Salmon system). Compared to non-Blacks, Black patients reported less anxiety/depression on the EQ-5D (p=0.030) and better emotional well-being on the FACT-MM (p=0.003). No other statistically significant differences were noted between cohorts on the BPI, other EQ-5D domains (mobility, self care, usual activities, pain/discomfort), or other FACT-MM domains (physical, social/family, functional, and MM-specific considerations). Conclusions: Initial results from the Connect MM Registry indicate that baseline HRQOL prior to initiation of treatment may vary by patient race with respect to emotional well-being, and specifically anxiety/depression. These results serve as a baseline reference for future analyses. As patients in the Connect MM Registry proceed through therapy, analyses should be conducted of patients by race, among other characteristics and factors, to determine whether it may be associated with subsequent clinical outcomes and HRQOL over time.
Incidence of venous thromboembolic events (VTE) in multiple myeloma patients receiving lenalidomide (LEN) with and without dexamethasone (DEX).
Authors: Brandenburg Nancy A. , Knight Tyler , Anastassopoulos Kathryn P. , Minton Neil , Knight Robert D.
Published: March 2020

e18559

Background: LEN showed significant efficacy and was generally well tolerated when combined with DEX in two randomized, double-blind, pivotal phase 3 registration trials in relapsed or refractory multiple myeloma (MM). VTEs have been associated with LEN and DEX combination (LEN+DEX) regimens in patients (pts) who may have other risk factors for VTE. Fewer VTEs have been reported among pts receiving low dose DEX. This study examined the incidence of first VTE and associated risk factors among MM pts receiving LEN and LEN+DEX. Methods: An exploratory, retrospective, claims-based study of pts diagnosed with MM and receiving LEN from Jan 2006 – June 2008 was performed using OptumInsight’s Invision Data Mart Multiplan database. Pts receiving additional MM chemotherapies were excluded. DEX dose level was defined over the first four 28-day cycles of LEN as: low (≤160 mg), medium (>160 mg to <480 mg), or high (≥ 480 mg). Cumulative incidence of first VTE (deep vein thrombosis or pulmonary embolism) within 120 days of initiating LEN treatment was calculated from Kaplan-Meier curves. Risk factors for VTE were examined using hazard ratios (HRs) from a Cox model that included demographics, prior MM therapy, comorbid conditions, DEX dose, and prophylactic use of anti-thrombotics. Results: 643 LEN-treated MM pts were identified (mean age 60 years, 60% male, 13.5% with prior VTE). Cumulative incidence of first VTE at 120 days from first LEN dose was 6.1% overall (95% CI 4.4-8.3%) and 7.2% (5.1-10.2%) in LEN+DEX. VTE risk for LEN without DEX (n=190; 66 with other steroids) was 3.4% (1.5-7.5%). VTE risk by DEX dose level was 5.9% (3.6-9.7%) for low DEX (n=286), 7.5% (3.6-15.1%) for medium DEX (n=99), and 12.3% (6.3-23.1%) for high DEX (n=66). Significant risk factors for VTE were prior VTE (HR=3.9; p<0.001), recent surgery (HR=2.1; p=0.047), renal failure (HR=2.2; p=0.023), and high dose DEX (HR=2.3; p=0.045). Conclusions: Incommunity-based MM pts treated with LEN+DEX, VTE risk increases with the dose of DEX. The exact mechanism by which DEX intensity impacts VTE is not clear. In addition to high dose DEX, other known VTE risk factors were observed.
Summary of treatment-emergent renal events from patients treated with single-agent carfilzomib from four phase II studies in relapsed and/or refractory multiple myeloma.
Authors: Harvey R Donald , Lonial Sagar , Patel Priti , McCulloch Leanne , Niesvizky Ruben , Kaufman Jonathan L.
Published: March 2020

e18569

Background: Patients (pts) with multiple myeloma (MM) are vulnerable to renal injury and impairment both from their disease and treatment-related adverse events (AEs). Carfilzomib (CFZ) is a selective proteasome inhibitor with proven efficacy in MM. Safety data have been compiled from over 700 pts who have received single-agent CFZ. All were pretreated and included individuals with varying degrees of renal function, including hemodialysis pts. Herein we present an analysis of the incidence and severity of CFZ treatment-emergent renal events from 526 pts in four phase 2 trials. Methods: Pts from the 003-A0, 003-A1, 004, and 005 trials were included in this analysis. In all studies, CFZ was dosed on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C). Doses were 20 mg/m2 in C1 for all studies escalating to 27 mg/m2 in C2 per individual protocol, except 005 (15 mg/m2 in C1, 20 mg/m2 in C2, and 27 mg/m2 in C3). Renal AEs—the incidence, frequency, and resolution of episodes of worsening renal function, defined minimally as a doubling of serum creatinine from baseline—and shifts in other laboratory parameters were tabulated and summarized based on NCI CTCAE v.3 criteria. Results: The majority of pts (71%) had renal dysfunction (CrCl <50 mL/min) at baseline. Overall, 87% experienced no significant worsening of renal function during the course of treatment. Transient worsening was reported in 31 pts (6%) with a median duration of 1.4 weeks and a median of 1.0 episode per patient; non-transient worsening was reported in 37 pts (7%) with 8 (2%) of those permanently discontinuing treatment due to a renal dysfunction AE. 38 patients (7.2%) experienced Grade 3/4 acute renal failure, of which 31 were Grade 3. The percentage of patients in 003-A0, 003-A1, and 004 whose creatinine levels shifted to Grade 3 or 4 from any lower grade was <5%. Results from 005 showed no major PK differences in pts with a wide range of renal function. Conclusions: Treatment-emergent renal events resulting in CFZ discontinuation were uncommon. Based on the findings from this cross trial analysis, CFZ dose and schedule need not be adjusted in pts with baseline renal dysfunction, including pts on hemodialysis.
Clinical implication of PET/CT and skeletal bone survey in evaluation of multiple myeloma and related monoclonal disorders.
Authors: Popalzai Muhammad Jawad , Alkaied Homam , Mansoor Maryah , Brenner Arnold , Dai Qun
Published: March 2020

e18574

Background: Whole body skeletal x-ray is considered a gold standard for detecting bone lesions in patients with plasma cell disorders. PET/CT has been increasingly used but its role is yet to be defined. We conducted this study to compare the role of these two imaging modalities in evaluation of plasma cell disorders. Methods: This is single institution, retrospective study to evaluate the role of skeletal survey and PET/CT in patients with multiple myeloma, smoldering myeloma and MGUS. Patients’ records, imaging reports and subsequent management plan were reviewed and compared. Results: A total of 16 patients were reviewed. Among them, 11 patients had multiple myeloma, 2 had smoldering myeloma, and 3 had MGUS. 7/11 patients with multiple myeloma had concordant findings on skeletal survey and PET. 3 of these patients had negative skeletal surveys but had positive finding on PET/CT. PET/CT also identified plasmacytomas in 2 patients. In 2 patients with smoldering myeloma, both skeletal survey and PET/CT were negative. 2/3 patients with MGUS had lytic lesions on skeletal surveys which were not revealed by subsequent PET/CT’s. Both patients were observed without treatment and at 2 years follow up did not show disease progression. Conclusions: Our retrospective analysis showed that skeletal survey is still important for base-line evaluation of bone lesions in multiple myeloma and related monoclonal disorders. PET/CT is more sensitive for detection of bone lesions and can also detect extraosseous lesions such as plasmacytomas. Using tumor metabolic activity, PET/CT may improve diagnostic accuracy and is complementary to conventional skeletal survey. [Table: see text]
Sentinel lymph node evaluation among elderly melanoma patients: Missed opportunities?
Authors: Shah Dhruvil R , Yang Anthony D , Maverakis Emanual , Martinez Steve R.
Published: March 2020

e19001

Background: Elderly patients may not receive indicated therapies offered to younger patients. We hypothesized that elderly patients with intermediate thickness cutaneous melanoma would be less likely to receive a sentinel lymph node biopsy than their younger counterparts. Methods: The Surveillance, Epidemiology, and End Results database was queried for patients who underwent surgery for intermediate thickness cutaneous melanoma (Breslow thickness 0.75 to 4.00 mm) from 2004 to 2008. We excluded patients with mucosal melanoma, those without a biopsy-proven diagnosis, and those diagnosed at autopsy. Patients were categorized according to age by decade. We used multivariate logistic regression models to predict use of sentinel lymph node biopsy. Additional covariates other than age included sex, race/ethnicity, T stage, tumor histology, tumor location, ulceration, and LDH status. Likelihood of undergoing sentinel lymph node biopsy was reported as odds ratios (OR) with 95% confidence intervals (CI); significance was set at p ≤ 0.05. Results: Among 12,283 patients with intermediate thickness cutaneous melanoma, 12,206 had complete information regarding the use of sentinel lymph node biopsy. Of these, 6,642 (54.4%) underwent sentinel node biopsy. On multivariate analysis, patients in the two oldest age categories were less likely to receive sentinel node biopsies (age 70 to 79 years OR 0.65, CI 0.55-0.76 and age 80 years or more OR 0.29, CI 0.24-0.35). Additional factors associated with a decreased likelihood of receiving a sentinel node biopsy included head and neck primary tumor site (OR 0.57, CI 0.51-0.64), high (OR 0.45, CI 0.31-0.65) or unknown (OR 0.32, CI 0.28-0.36) serum LDH, Asian (OR 0.58, CI 0.36-0.94) or unknown (OR 0.51, CI 0.36-0.72) race, and lentigo histology (OR 0.79, CI 0.66-0.95). Conclusions: Elderly patients with intermediate thickness melanoma are less likely to receive sentinel node biopsy than their younger counterparts. The elderly may benefit from sentinel node biopsy, and efforts should be made to increase performance of this procedure in this population. Further research to assess reasons why the elderly are less likely to receive sentinel node biopsy are needed.
Sentinel node biopsy in melanoma patients: The role of day surgery and local anaesthetic approach for quality-of-life and effective cost reduction.
Authors: Ricci Fabio , Saralli Erminio , Capuano Loreto Giovanni , Dorkin Maurizio , Valleriani Mario , D'Achille Anna Maria , Di Emma Veronica , Greco Luigi , Violante Assunta , Filippi Luca , Natali Maurilio , Pacchiarotti Alberto , Annetta Alessandro
Published: March 2020

e19002

Background: Sentinel node biopsy (SNB) is used in the management of melanoma patients without nodal metastases. Methods: From January 1, 1998 to December 31, 2011 we performed 182 SNBs at St. M. Goretti Hospital. Patients presented a primary melanoma, Breslow thickness equal to or higher than 1 mm, lower than 1 mm with regression and/or ulceration, and/or IV-V Clark level, and/or mitotic rate ≥ 1/mm2, according to the 7th edition melanoma staging system. All patients underwent pre-operative lymphoscintigraphy with intradermal injection of 50-70 MBq 99 mTc colloidal albumina particles, 50-80 nm size range, in 0.1-0.2 ml saline solution. We never used blue dye. All patients underwent surgical treatment 4-12 h. later. We performed SNB in day-surgery (DS) under local anaesthesia (LA). Surgery incision was 3-4 cm. This study was approved by an ethics committee, discussed with all patients and informed consent was obtained. Purpose of the study is to investigate the validity of this approach for quality of life and cost reduction. Results: 165 patients underwent SNB, 64 (38.7%) in the inguinal region, 83 (50.3%) in axilla, 1 (0.6%) in the popliteal region, 4 (2.4%) patients showed inguinal bilateral sentinel lymph-node (SLN), 6 (3.6%) axillary bilateral SLN, 4 (2.4%) axillary and 3 (1.8%) inguinal double SLN. The SLN identification rate was 100%. After surgery we distributed a questionnaire to the patients about the acceptability of this approach. In 32 patients SLN was positive. In these patients we performed radical lymphoadenectomy, 12 (37.5%) inguinal and 20 (62.5%) axillary. Conclusions: The results achieved are extremely accurate. This procedure is safe, well accepted by patients (98%), reported better quality of life. The oncological results are absolutely reliable. As regards hospital logistics, operations in DS and LA can be easily managed, leading to a significant cost reduction, 42.15% less expensive than the same operation performed under general anaesthesia.
Prospective pilot study of Merkel cell carcinoma.
Authors: Orlova Kristina Vyacheslavovna , Markovich Alla Anatolievna , Selchuk Vladimir Yur'evich , Demidov Lev V. , Orel Nadezhda Fedorovna , Subramanian Somasundaram
Published: March 2020

e19005

Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. The annual incidence for MCC, based on SEER database, was 0.6 cases per 100,000 in 2006 (0.15 cases per 100,000 in 1986), with slightly more males affected (60%). Due to its rarity, data on its clinico-pathological features and impact of therapy are limited. Aim: To characterize MCC based on immunohistochemical (IHC) features and serum levels of biochemical markers such as chromogranin A (CgA) and serotonin and select treatment options. Methods: This prospective pilot study included 7 patients (pts) since 2009 and their age, sex, primary site, IHC features and serum levels of biochemical markers, progression-free-survival (PFS) were recorded. Median of overall survival was not achieved. Results: Pts characteristics were: age 44–67 years (mean 57), male–female ratio = 4:3. Most common primary sites were extremities (5pts), lymphnode metastases from unknown primary (1pt) and genitals (1pt). IHC showed diffuse positivity for CgA (6pts), dot-like staining for cytokeratin 20 (7pts), synaptophysin (6pts), Ki-67 (40%-1pt, 50%-1pt, 60–70%-5pts). The tumors did not express vimentin, TTF1. Serum levels of Cg A (2pts) and serotonin (1pt) were above normal. Treatment: Local disease – surgery, either alone (1pt) or as part of multimodality plan (2pts); Locoregional disease – surgery plus chemotherapy (2pts) and chemotherapy alone (1pt); Distant disease – chemotherapy plus surgery (1pt). Median of PFS was 16 months.Two patients with improvement of biochemical markers continue to receive maintenance therapy with somatostatin (SST) analogues for 16 and 24 months with complete remission. Conclusions: SST analogues facilitates treatment of MCC without reducing quality of life and increase PFS in patients with high CgA serum level. In spite of recent advances in understanding the biology of MCC, many molecular mechanisms that influence behavior stills are unknown.
Final results of a phase II immunotherapy trial for stage III and IV melanoma patients.
Authors: Riker Adam Irwin , Rossi Gabriela R. , Alsfeld Leonard C , Denham Fiona , Tennant Lucinda , Ramsey William Jay , Link Charles J. , Harrison Marilynn , Vahanian Nicholas N.
Published: March 2020

e19008

Background: Patients with metastatic melanoma have a poor outcome. We hypothesize that combination immunotherapy can synergistically activate host immunity to generate an effective treatment option for high risk, resected stage III, recurrent, refractory or stage IV melanoma patients. Methods: We completed a phase II clinical trial of HyperAcute-Melanoma vaccine (HAM, NLG12036, NewLink Genetics) combined with pegylated interferon (Sylatron, Merck). Trial design was a 12-week regimen with the initial 4 weekly treatments consisting of HAM alone (intradermally) followed by 8 additional treatments of HAM + Sylatron (subcutaneously, 6 µg/kg). Trial endpoints include clinical response, overall safety and correlative findings for observed anti-tumor effect. Results: N=25, median age 60, 68% male with 21 patients completing the trial, 4 stopped due to progressive disease (PD). HAM-related common side effects include erythema and induration at the injection site, without significant grade 3 or 4 toxicities associated with the vaccine. By RECIST criteria, of 16 stage IV patients, there were 2 complete responders (CR), 2 with stable disease (SD) and 3 with no evidence of disease (NED) after resection. For stage III patients, 3/9 remain NED, 1 patient with slowly progressive disease remaining alive for over 30 months. The median overall survival is 29 months, with 50% of the patients surviving for 2 years and 12/25 (48%) still alive. The anti-αGal Ab values increased after vaccination in 24/25 patients by up to 100-fold (median 15, range 3-127). All evaluable patients (21/21) seroconverted, developing autoimmune antibodies. Anti-tyrosinase Ab’s developed in 7/23 correlating with 1 CR and 1 patient NED. Vitiligo developed in 4/25 patients, correlating with 2 CR and 2 NED. Conclusions: Combinatorial immunotherapy with HAM plus Sylatron shows clinical efficacy with tumor regression and concomitant immune activation. Optimization of dosing schedules and addition of other potentially synergistic agents should be explored to further enhance the benefit of this immunotherapeutic approach.
Prevalence of sentinel lymph node evaluation in patients with thick primary cutaneous melanoma.
Authors: Olusanya Abimbola O , Shah Dhruvil R , Yang Anthony D , Maverakis Emanual , Canter Robert J. , Martinez Steve R.
Published: March 2020

e19013

Background: Sentinel lymph node biopsy (SLNB) was developed for intermediate thickness melanoma. Its use for thick cutaneous melanoma is controversial. We aimed to report on clinical and pathologic factors associated with the overuse of SLNB for thick primary cutaneous melanoma. Methods: The Surveillance, Epidemiology, and End Results database was queried for patients who underwent surgery for thick primary cutaneous melanoma (known Breslow thickness > 4.00 mm) from 2004 to 2008. We excluded patients with mucosal melanoma, those without a biopsy-proven diagnosis, those diagnosed at autopsy, patients whose lymph node evaluation was unknown or other than SLNB “yes” or SLNB “no”. We used multivariate logistic regression models to predict use of SLNB. Covariates examined included: age sex, race/ethnicity, Breslow depth, tumor histology, tumor location, and ulceration status. Likelihood of undergoing sentinel lymph node biopsy was reported as odds ratios (OR) with 95% confidence intervals (CI); significance was set at p ≤ 0.05. Results: Among 1,981 patients with thick cutaneous melanoma, 1,158 (58.2%) received a SLNB. On multivariate analysis, patients with primary melanomas of the arm (OR 2.07, CI 1.56-2.75; p<0.001), leg (OR 2.40, CI 1.70-3.40; p<0.001) and trunk (OR 1.82, CI 1.38-2.40; p<0.001) had an increased likelihood of receiving a SLNB, as did those with desmoplastic histology (OR 1.47, CI 1.11-1.96; p=0.008). Conclusions: A significant number of patients with thick melanomas receive a SLNB, even though this procedure was not developed for this patient population. We have identified predictors associated with the use of SLNB. These include: arm, leg and trunk primary sites and desmoplastic histology. Further research to assess whether use of SLNB in this population is detrimental or beneficial is needed.
The prognostic utility of LDH and CRP for survival after melanoma metastasectomy in the urogenital tract.
Authors: Gakis Georgios , Abdelhafez Mohamed F , Todenhoefer Tilman , Renninger Markus , Schwentner Christian , Stenzl Arnulf
Published: March 2020

e19021

Background: Recent studies suggest that serum lactate dehydrogenase (LDH) and serum C-reactive protein (CRP) are risk factors for survival in patients with metastatic melanoma. However, due to the relatively low tropism of metastatic melanoma lesions in the urogenital tract the clinical benefit of metastasectomy in this highly selective group of patients remains uncertain. The objective of this study was to address the role of LDH and CRP as preoperative serological risk factors for survival in patients with solitary or concomitant metastatic melanoma lesions in the urogenital tract. Methods: All patients who were referred for metastasectomy in the urogenital tract in a tertiary center within 1999-2008 were considered for this analysis. Demographic, disease and survival data were collected. Elevated LDH activity was defined as >250U/l and elevated serum CRP>0.5mg/dl. The primary endpoint was overall survival (OS), calculated using Kaplan-Meier method with log-rank test and multivariate Cox-regression analysis. Results: Of a total of 21 patients,16 (76%) had solitary urogenital metastases and 5 patients (24%) concomittant non-urogenital metastases.Median OS after metastasectomy was 23 months (range: 3-59 months). LDH>250U/l was significantly associated with decreased OS (27.6 vs. 6.0 months; p=0.001), but elevated CRP did not (24.1 vs. 20.7 months; p=0.93). No further significant differences in survival were found for age (p=0.76), gender (p=0.83), number of urogenital metastatic sites (0.97) and preoperative solitary vs. concomitant distant metastases (p=0.48). In multivariate analysis, adjusted for the TNM-stage grouping (M1a-c) and CRP level, elevated LDH maintained significance as negative prognostic factor for overall survival (p=0.0015). Conclusions: To our knowledge, this is the first study addressing the prognostic role of LDH and CRP in patients with melanoma urogenital metastases. If confirmed in large prospective studies, LDH level may be used for preoperative risk stratification in patients scheduled for melanoma metastasectomy in the urogenital tract to identify those patients who profit most from the surgical approach.
The impact of sun protective behavior and vitamin D supplementation on vitamin D level in melanoma patients.
Authors: Kumar Rachit , Khanna Sarika , Reutemann Patricia , Wenk Kurt S , Venna Suraj S. , Jang Sekwon
Published: March 2020

e19025

Background: Vitamin D (VitD) is synthesized in the skin as a result of exposure to sunlight and its deficiency is common in the general population as well as in cancer patients. Sun protection is strongly recommended for patients after a melanoma diagnosis. We conducted a pilot study to assess the prevalence of VitD deficiency and the impact of both sun protective behavior and VitD supplementation on VitD levels in melanoma patients Methods: Adult patients with AJCC Stage 0-III melanoma were recruited from the Washington Cancer Institute between July 2011 and January 2012. Subjects completed a questionnaire asking about oral VitD supplementation and sun protective behaviors. VitD deficiency was defined by a 25-hydroxyvitamin D (25(OH)D) level less than 30ng/mL. Pearson Chi-square test and multivariate logistic regression were used to determine predictors of VitD deficiency. Results: A total of 49 participants (20 males, 29 females) completed the questionnaire and provided a blood sample for 25(OH)D determinations. Median age was 52 years (23-82), and most (n=48, 98%) were Caucasian. The majority had either stage 0 (n= 13, 27%) or 1 (n=29, 59%) melanoma. Twenty-six (53%) reported regular use of VitD supplements, and the majority reported sun protective behaviors (n=36, 73%). The prevalence of VitD deficiency was 46% (n=23). VitD deficiency was more common in patients who were not taking VitD supplementation (73% vs. 26%, p<0.01). Other associations include: (1) BMI>25 vs. BMI ≤25 (57% vs. 33%, p=0.10); (2) winter vs. summer months(54% vs. 40%, p=0.34); (3) those who practiced sun protective behavior vs. not (50% vs. 38%, p=0.48). On multivariate analysis, the use or non-use of VitD supplementation remained the only significant predictor of VitD deficiency (OR=0.11, p<0.01). Conclusions: VitD deficiency is common in melanoma patients especially in those who are not on VitD supplementation.
Single-center experience with ipilimumab in patients with pretreated advanced melanoma.
Authors: Wilgenhof Sofie , Seghers Amelie Clementine , Du Four Stephanie , Lienard Danielle , Salmon Isabelle , Del Marmol Veronique , Neyns Bart
Published: March 2020

e19026

Background: Ipilimumab (IPI) is a CTLA-4 blocking mAb with established activity in patients (pts) with advanced melanoma. Methods: Observational study on the outcome of advanced melanoma pts treated with IPI in an expanded access program (EAP) at a single-center. Results: Fifty pts initiated IPI (3 mg/kg q3wks x4, allowing for reinduction after a PFS of >24 wks). Baseline characteristics: 28M/22F, m50y, Stage: 1x IV-M1a, 2x -M1b, 47x -M1c; 44 pts skin-, 2x mucosal-, and 4x unknown primary melanoma; WHO-PS 0/1/2: 17-, 25-, 8 pts; LDH >ULN 33 pts; CRP >ULN 29 pts; ALC<1000/mm³ 15 pts; all pts were pretreated with dacarbazine and 16 pts for brain metastases. Thirty-one pts completed IPI-induction; 8/11 pts offered reinduction completed the planned 4 administrations (treatment ongoing in 1pt). Most immune-related adverse events (irAE) were generally mild/reversible; CTCAE gr3 irAE: diarrhea/colitis (3), hepatitis (1), hypophysitis (1), pancreatitis (1) and Guillain-Barré syndrome (1); no grade 4/5 irAE. BORR by mWHO-criteria: 1 CR, 3 PR and 4 SD (disease control rate [DCR]: 16%). BORR by immune-related response criteria (irRC): additional 2 PR and 3 SD (DCR: 26%). In 5/10 evaluable pts a similar or lower total tumor burden was obtained following reinduction. Two pts who experienced gr3 irAE during induction did not experience the same irAE at reinduction. After a median follow-up of 18 mths (range 7.5-19.3), 32 pts have died. Six- and 12-mths OS were 53% (95% CI 40-67) and 45% (95%CI 31-59) respectively. Disease control with IPI has been maintained in 8 pts (of which 4 received reinduction) after a median follow-up of 17 mths (range 12-17). Elevated CRP (>5x the upper limit of normal [ULN]) was the only independent baseline co-variable (HR 0,10; 95% CI 0,04-0,25; p 0.001). An ALC of <800/mm³ at week 7 and disease-control by irRC post-induction significantly correlated with OS. Conclusions: This single-center experience with IPI in an EAP for pts with advanced pretreated melanoma is comparable with that of prospective studies. Reinduction therapy seems important for long-term disease control in responding pts. Baseline CRP and ALC at week 7 deserve further evaluation as a prognostic and/or predictive (surrogate) markers.