bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective analysis of second malignancies in patients with multiple myeloma.
Authors: Talamo Giampaolo , Ehmann W. Christopher , Dolloff Nathan G , Malysz Jozef , Drabick Joseph J. , Rybka Witold B. 
Published: March 2020

8090 Background: Recent data from patients with multiple myeloma (MM) enrolled in randomized clinical trials have shown an increased incidence of second malignancies after treatment with lenalidomide, but the prevalence of second malignancies in the overall MM population is uncertain. Methods: We retrospectively analyzed the medical records of 320 consecutive MM patients followed at the Penn State Hershey Cancer Institute between 2006 and 2010. We excluded from the analysis basocellular and squamocellular carcinomas of the skin. Results: Forty-three patients (13%) were found to have second malignancies, and 5 of them had a third cancer. One pt had 4 cancers. They included cancers of the prostate (8 pts), breast (8), MDS/leukemia (6), colon/rectum (5), melanoma (5), lung (4), uterus (4), bladder (3), kidneys (2), pancreas (2), testicle (1), myeloproliferative disorders (1), and sarcoma (1). Of 50 cancers, 36 (72%) developed before the diagnosis of MM, at a median of 65 months (range, 1-372), and 14 after that, at a median of 37 months (range, 3-104). Lenalidomide was used in 239 (75%) patients, and in 9 of 14 cases of post-MM second malignancies. Conclusions: Second malignancies usually develop before the diagnosis of MM, i.e., MM is the second malignancy for the majority of patients. The use of lenalidomide could not be indicated as a possible carcinogenic factor for the majority of MM patients with second malignancies.
A phase I/II study of carfilzomib (CFZ) as a replacement for bortezomib (BTZ) for multiple myeloma (MM) patients (Pts) progressing while receiving a BTZ-containing combination regimen.
Authors: Berenson James R. , Yellin Ori , Dichmann Robert , Patel-Donnelly Dipti , Boccia Ralph V. , Hilger James D. , Nassir Youram , Swift Regina A. , Vescio Robert A. 
Published: March 2020

8098 Background: Recent data has shown that single-agent CFZ can produce responses among MM pts refractory to previous treatment regimens including those containing BTZ. We conducted an intrapatient Phase 1/2 trial investigating the safety and efficacy of CFZ as a replacement for BTZ in BTZ‑containing regimens to which pts have progressed. Methods: Eligible pts had to have progressed while receiving their most recent BTZ‑containing regimen after at least 4 doses of BTZ at > 1.0 mg/m² in < 4 weeks per cycle. Combination regimens containing an alkylating agent, anthracycline, or a glucocorticosteroid were eligible. CFZ replaced BTZ in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each cycle. Treatment continued using the same dose(s) and schedule(s) of each drug administered in the BTZ‑containing regimen. CFZ doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m² or until a maximum tolerated dose (MTD) was reached for that regimen. Results: Of 19 enrolled pts 13 are evaluable to date and 6 have recently started treatment. Pts received a median of 7 (range, 1-18) prior treatments and 5 (range, 1-5) different BTZ-containing regimens. Pts were treated with CFZ and the following different combinations: bendamustine (BEND) alone, BEND + methylprednisolone, dexamethasone (DEX) alone, DEX + pegylated liposomal doxorubicin, ascorbic acid + cyclophosphamide, and melphalan alone. Pts have completed a median of 3 cycles. Clinical benefit was seen in 10 (77%) pts (complete response = 8%; very good partial response = 8%; partial response = 31%; minor response = 31%) with another 23% showing stable disease. The median time to progression (range: 2-8 months) has not been reached and only 2 pts have progressed. The most common grade 3/4 adverse events were thrombocytopenia occurring in 5 pts (all = grade 3 except 1 event) and fever occurring in two pts (grade 3). Four pts experienced a serious adverse event but no regimen has reached a MTD. Conclusions: These early results suggest that CFZ is an effective and tolerable replacement for BTZ for pts who are refractory to BTZ-containing combination regimens.
Efscalefect of lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy in transplant-eligible patients (Pts) with newly diagnosed multiple myeloma (MM) on CR rates and survival.
Authors: Gleason Charise , Nooka Ajay K. , Muppidi Samatha , Heffner Leonard T. , Steuer Conor E , Kumar Mukesh , Casbourne Daniela , Langston Amelia A. , Watson Melanie , Boise Lawrence , Kaufman Jonathan L. , Lonial Sagar 
Published: March 2020

8101 Background: Addition of lenalidomide to bortezomib and dexamethasone (RVD) demonstrated to be an effective and well tolerated regimen in phase II trials with overall response rate (ORR) >95% (Richardson P et al). Given the lack of phase III data, we have evaluated our institutional experience of pts treated with RVD induction therapy, to support this triplet combination. Methods: 286 transplant-eligible pts with newly diagnosed MM were treated with RVD induction therapy [R - 25 mg/day (days1–14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 2008 until January 2012. 148 pts underwent ASCT and 138 pts opted for delayed transplant. Post-ASCT 56% pts are on maintenance therapy tailored to their risk (R-40%; RVD-10%; V-6%). Demographic and outcomes data for the pts that underwent ASCT were collected and responses were evaluated per IMWG Uniform Response Criteria. Results: Median age of the pts is 60 years (range 32-77). Other pt characteristics include: M/F 55%/45%; ISS I/II/III 40%/30%/30%; Isotype IgG/IgA/FLC/IgM 61%/20%/18%/1%; high risk/standard risk 13%/87%. Pts received a median of 4 cycles (2-9) of RVD. Median CD34+ stem cell collection was 11.24 x 106/kg. 18% pts required dose reductions (R/V/D-5%/9%/2%) and discontinuation in 2% pts for progressive disease. 49%/8% pts had G1-2/G3-4 PN. Median estimated PFS is 47 months and median OS has not been reached. Response rates are included in the table. Conclusions: RVD is an active induction regimen with superior response rates of > 80% ≥VGPR rates post-ASCT and is well tolerated in newly diagnosed MM pts. Incorporation of lenalidomide did not impact the stem cell collection. Until phase III data are available, our institutional experience could provide a perspective in the choice of RVD as an effective induction regimen in improving ORR and prolonging survival. [Table: see text]
miRNA expression profiling of CD20+ plasma cell myeloma (PCM): Upregulation of miR-155 shedding new insight into disease biology and clinicopathologic behavior.
Authors: Kolhe Ravindra , Jillella Anand P. , Natrajan Kavita , Awan Farrukh Tauseef , Manaloor Elizabeth , Kota Vamsi 
Published: March 2020

8108 Background: Up to15-20% of patients with PCM have expression of CD20, although the significance of this remains unclear. The prognostic significance of CD20 expression in PCM is unclear. Recently, a class of noncoding RNAs, miRNAs, were identified as critical gene regulators in cell growth, disease, and development. Our study investigates importance of miRNAs in cases of CD20+ PCM and correlates them with clinicopathological parameters. Methods: The miRNA expression profile of CD20+ PCM (n=6), diffuse large B cell lymphoma (DLBCL) (n=6), and CD20 negative PCM (n=8) were evaluated using the Affeymertrix miRNA microarray platform on GeneChip miRNA 2.0 array in paraffin-embedded samples. After hybridization and data acquisition, we used Partek Genomics Suite software for RMA normalization and to determine statistically significant differences in miRNA expression between experimental groups by ANOVA and pairwise comparisons (two-sided α=0.05). Results: miRNA expression profiles of CD20+ PCM, show upto >4 times upregulation of 7 miRNAs and downregulation of 8 miRNAs. miR-155, the miRNA upregulated in various B cell lymphomas and plays a key role in the lymphomagenesis, was amongst the highest miRNAs that were upregulated. Conclusions: miR-155 is known to repress SH2-domain containing inositol-5-phosphatase-1 (SHIP-1), which is a critical phosphatase that negatively down modulates AKT pathway and has functions during normal B-cell development. Physiologically, miR-155 is upregulated during B-cell activation upon antigen stimulation and so plays a role in antibody class switching and plasma cell formation. We propose that this overexpression of miR-155 in CD20+ PCM unblocks AKT activity, inducing cell proliferation and may explain some of the immunophenotypic behavior of CD20+ PCM. This work is intriguing for the new information it provides about the role of miR-155 in CD20+ PCM. Furthermore, the phenotype of miR-155+ve CD20+ PCM might ultimately provide new insights into regulation of poorly understood steps in B cell differentiation and maturation into plasma cell and more importantly the clinicopathological behavior of this entity.
Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with high-risk melanoma (SWOG S0008): An intergroup study of CALGB, COG, ECOG, and SWOG.
Authors: Flaherty Lawrence E. , Moon James , Atkins Michael B. , Tuthill Ralph , Thompson John A. , Vetto John T. , Haluska Frank G. , Pappo Alberto S. , Sosman Jeffrey Alan , Redman Bruce G. , Ribas Antoni , Kirkwood John M. , Sondak Vernon K. 
Published: March 2020

8504 Background: High-dose interferon for one year (HDI) is the FDA approved adjuvant therapy for patients (pts) with high-risk melanoma (HRM). Efforts to modify IFN dose or schedule have not improved efficacy. A meta-analysis demonstrated that biochemotherapy (BCT) produced superior response rates compared with chemotherapy in pts with stage IV melanoma (Wheatley et al J Clin Oncol 25:5426, 2007). We sought to determine whether a short course of BCT would be more effective than HDI as adjuvant treatment in pts with HRM. Methods: S-0008 (an Intergroup Phase III trial) enrolled pts who were high risk (Stage III A-N2a thru Stage III C N3) and randomized them to receive either HDI or BCT consisting of dacarbazine 800 mg/m2 day 1, cisplatin 20 mg/m2/ days 1-4, vinblastine 1.2 mg/m2 days 1-4, IL-2 9 MIU/m2/day continuous IV days 1-4, IFN 5 MU/m2/day sc days 1-4, 8,10,12, and G-CSF 5 ug/kg/day sc days 7-16. BCT cycles were given every 21 days x 3 cycles (9 weeks total). Pts were stratified for number of involved nodes (1-3 v ≥4), micro v macro metastasis, and ulceration of the primary. Co-primary endpoints were relapse free survival (RFS) and overall survival (OS) using a one-sided log rank test at p= 0.05. Results: 432 pts were enrolled between 8/2000 and 11/2007: 30 were ineligible or withdrew consent. Grade 3 and 4 adverse events occurred in 57% and 7% respectively of HDI pts and 36% and 40% of BCT pts. At a median f/up of 6 yrs, BCT improved RFS (p = 0.02, HR 0.77 [90% CI: 0.62 – 0.96]) with median RFS for BCT of 4.0 yrs (90% CI:1.9 – 5.9) v 1.9 yrs (90% CI: 1.4 – 2.5) and 5 yr RFS of 47% v 39%. Median OS was not different between the two arms (p = 0.49 HR 1.0 [90% CI: 0.78 – 1.27]) with median OS not yet reached for BCT v 8.4 yrs (90% CI: 4.5 – 9.3) for HDI and 5 yr survival 56% for both arms. Conclusions: In HRM pts, BCT provides a statistically significant improvement in RFS compared to HDI, but no discernable difference in OS and more grade IV toxicity. BCT represents a shorter, alternative treatment for pts with HRM, and a potential control arm and basis for future combinations in the adjuvant setting.
Safety of ipilimumab in patients (pts) with untreated, advanced melanoma alive beyond 2 years: Results from a phase III study.
Authors: Thomas Luc , Wolchok Jedd D. , Garbe Claus , Lebbe Celeste , Bondarenko Igor , Rodrigues Kristen , Konto Cyril , Chin Kevin M. , Francis Stephen , Robert Caroline 
Published: March 2020

8512 Background: Ipilimumab (IPI), a fully human monoclonal antibody, blocks cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor T-cell response. In a phase 3 study (CA184-024) of previously untreated pts with stage III or IV melanoma, IPI + dacarbazine (DTIC) significantly improved overall survival (OS) vs. DTIC alone (Robert et al. NEJM 2011). We now report safety data of IPI in pts from this study alive > 2 yrs from study initiation. Methods: Pts with untreated advanced melanoma, were randomized to IPI (10 mg/kg) + DTIC (850 mg/m2) or placebo + DTIC (850 mg/m2) given at Wks 1, 4, 7, 10 followed by DTIC q 3 wks through Wk 22. Eligible pts (stable disease or better) received IPI or placebo q 12 wks as maintenance. In the population of subjects alive >2 yrs, the appearance of immune-related adverse events (irAEs) occurring after 2 yrs was evaluated. Within this group was a subset of subjects still receiving IPI dosing after 2 yrs; safety for these pts was evaluated to assess the impact of prolonged IPI exposure. Results: In the IPI + DTIC group 68 (28%) pts survived > 2 yrs compared to 44 (18%) in the DTIC alone group; 11 of the 68 continued IPI dosing for ≥ 2 yrs. Safety assessment beyond 2 yrs showed 3 of the 11 pts had any grade irAEs; 1 pt had grade 3/4 rash, pruritus while low grade events included rash, pruritus (n=2) and elevated ALT / AST (n=1). Overall among all 68 pts in the Ipi + DTIC group, there were 5 pts (7.4%) with any grade irAEs including grade 3/4 rash, pruritus (n=1) and low grade rash (n=3), pruritus (n=2), skin hypopigmentation, and elevated ALT / AST (n=1). No gastrointestinal or endocrine events (any grade) were observed. Conclusions: In Study 024, IPI + DTIC treatment improved OS pts with untreated, advanced melanoma with higher survival rates in the IPI + DTIC group at 1 yr (47.3% vs. 36.3%), 2 yrs (28.5% vs. 17.9%), and 3 yrs (20.8% vs. 12.2%) (HR 0.72, p<0.001). The safety profile of pts alive after 2 yrs suggests that treatment with IPI + DTIC is associated with low rates of irAEs in these pts. Furthermore, in pts still receiving active IPI treatment beyond ≥ 2 yrs, the safety profile appears to be consistent and medically manageable using established safety guidelines (Weber, Oncologist 2007).
Phase II multicenter trial of ipilimumab combined with fotemustine in patients with metastatic melanoma: The Italian Network for Tumor Biotherapy (NIBIT)-M1 trial.
Authors: Di Giacomo Anna Maria , Ascierto Paolo Antonio , Pilla Lorenzo , Ridolfi Ruggero , Santinami Mario , Testori Alessandro , Queirolo Paola , Simeone Ester , Guidoboni Massimo , Del Vecchio Michele , Ferrucci Pier Francesco , Marasco Antonella , Fonsatti Ester , Annesi Diego , Giannarelli Diana , Parmiani Giorgio , Maio Michele 
Published: March 2020

8513 Background: Ipilimumab (ipi), an antibody against cytotoxic T-lymphocyte-associated antigen-4, improves survival in patients (pts) with metastatic melanoma (MM); however, objective tumor responses are limited. NIBIT-M1 aims to investigate the efficacy and safety of ipi plus fotemustine (FTM), a cytotoxic alkylating drug, in pts with MM. Methods: Eligible pts, with or without brain metastases, received induction therapy with ipi 10 mg/kg every 3 weeks (Q3W) for four doses and FTM 100 mg/m2 weekly for 3 weeks. Ipi and FTM maintenance therapy was provided Q12W from Week 24 and Q3W from Week 9, respectively. The primary objective was the immune-related (ir) disease control rate (irDCR: pts with complete response [CR], partial response [PR] or stable disease [SD] as determined using the ir response criteria). Secondary objectives included ir objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS); overall survival (OS), and safety. Tumor assessments were performed Q8W from Week 12 to Week 36 and Q12W thereafter. Results: Among 86 pts with unresectable stage III (n=3) or stage IV (n=83) MM treated at 7 NIBIT centers, 42 were previously untreated, 44 had progressed following first-line treatment and 20 had asymptomatic brain metastases. As of December 2011, the irDCR was 46.5% (40/86; 95% CI, 35.7–57.6%); the irORR was 29.1% (95% CI, 19.8–39.8%; 5 CRs and 20 PRs) and with a median 8.3 months follow-up, median irPFS was 5.3 months (95% CI, 3.5–7.1). The 1-year OS rate was 51.8% (95% CI, 37.5–66.1%); median OS was not yet reached. Among all pts, 58.1% and 87% completed ipi or FTM induction, respectively. The most common grade 3/4 drug-related adverse events (AEs) (reported in 54.6% pts overall) were myelotoxicity (43.5%), increased ALT/AST (14.1/10.6%), gastrointestinal (4.7%) and skin-related (2.3%). AEs were generally manageable and reversible per protocol guidance. Conclusions: The study reached its primary objective with 46.5% of pts achieving disease control. The combination of ipi plus FTM is safe; the irDCR, 1-year OS rate and median irPFS warrant its further investigation in MM pts.
SWOG S0826: A phase II trial of SCH 727965 (NSC 747135) in patients with stage IV melanoma.
Authors: Lao Christopher D. , Moon James , Fruehauf John P. , Flaherty Lawrence E. , Bury Martin J. , Ribas Antoni , Sondak Vernon K. 
Published: March 2020

8521 Background: Cyclin-dependent kinases (cdks) function to regulate cell cycle control and agents that can target cdks in malignant progression remain viable therapeutic strategies. Selective inhibition of cdk2, in particular, may be of therapeutic value in a subset of patients with melanoma. Methods: 60 patients with metastatic melanoma of cutaneous or mucosal origin were planned to be recruited to a multicenter, single-arm phase II trial of the cdk inhibitor, SCH 727965 (NSC747135). Patients were potentially eligible if they had 0-1 previous treatments, PS of 0-1, and adequate organ function. Ocular melanoma patients and patients with a history of brain metastases were excluded. SCH 727965 50 mg IV every 3 weeks was given until progression with disease assessment occurring every 2 cycles. Co-primary endpoints were 1-year overall survival (OS) and 6-month progression free survival (PFS). Results: 72 patients were enrolled from July 1, 2009 to November 1, 2010 at 24 institutions. 68% of patients had M1c disease and 43% had LDH elevation. 19% had prior therapy for metastatic disease. 28 patients (39%) experienced Grade 4 adverse events, including 20 cases of neutropenia, one case each of cardiac ischemia/infarction, cardiac troponin I elevation, dehydration, abdominal pain, leukopenia, muscle weakness, headache, syncope, and anterior ischemic optic neuropathy. 65 patients are currently evaluable for response. The response rate was 0/65 (95% C.I. (0-6%)). Stable disease was observed in 22%. The estimated median PFS was 1.5 months (95% CI: 1.4 – 1.5); 6-month PFS was 11% (5-20%). Median OS was 8 months (95% CI: 5-11 months); 1-year OS was 36% (95% CI: 24-48%). The null hypothesis of 1-year overall survival=25% was rejected (p=0.04) but 6-month PFS=11% was not (p=0.8). Data Analysis will be updated when missing data are received. Correlative studies of Rb phosphorylation and cyclin expression will be pursued. Conclusions: SCH 727965 appears to be reasonably well tolerated although grade 4 events were relatively common, particularly near the time of infusion. There were no responses but few patients had prolonged disease stabilization that may have resulted in improvement in the 1-year OS rate.
Sensitivity rate of ultrasound (US)-guided fine-needle aspiration cytology (FNAC) using the Berlin morphology criteria for lymph node metastases to reduce the need for surgical sentinel node (SN) staging in melanoma.
Authors: Voit Christiane A. , Van Akkooi Alexander Christopher Jonathan , Gooskens Saskia , Siegel Petra , Schaefer-Hesterberg Gregor , Schoengen Alfred , Roewert-Huber Joachim , Sterry Wolfram , Eggermont Alexander M. 
Published: March 2020

8535 Background: US-guided-FNAC prior to surgical SN staging is emerging as a possible cost-effective addition to the staging of melanoma patients (pts). Formerly, sensitivity (sens) rates of lymph node US in melanoma were disappointing (20–40%). The introduction of the Berlin Morphology Criteria has significantly improved sens rates for US-FNAC (J Clin Oncol 2010;28(5):847-52). The aim of the current study was to report on 1000 patients the sens, specificity (spec), positive (PPV) and negative (NPV) predictive value rates of US-FNAC from our prospective database with prolonged follow-up. Methods: Since 2001, >1000 stage I / II consecutive melanoma pts have undergone US-FNAC prior to SN. All patients underwent lymphoscintigraphy. Peripheral Perfusion (PP), Loss of Central Echoes (LCE), Balloon Shaped (BS) were the Berlin Morphology Criteria which were registered. FNAC was performed in case of presence of any of these factors. SN tumor burden was measured according to the Rotterdam Criteria. All patients underwent SN or LND in case of positive FNAC. Results: Mean/median Breslow thickness was 2.56 / 1.57 mm (0.2 – 44 mm).Mean/median follow-up was 39 / 32 months (0 – 115). Ulceration was present in 24 %. SN positivity rates were 20 % (202 / 1000). Sens was 51 %. Spec, PPV and NPV were 99%, 91% and 89%. Sensitivity was highest for T4 tumors (77%). PP, LCE, BS had sens of 69%, 24%, 25%. SN tumor burden > 1 mm in largest diameter according to the Rotterdam Criteria was identified by US-FNAC in 86%. Threshold for positive FNAC was 0.4 mm in maximum diameter. Conclusions: The new criterion of Periferal Perfusion is of key importance to achieve the high sensitivity of US-FNAC according to the Berlin Morphology Criteria (J Clin Oncol 2010; 28:847-852) to identify lymph node metastases. Especially for T4 patients and in patients with advanced SN tumor burden it can reduce significantly the need for surgical SN staging. The EORTC Melanoma Group will launch the prospective validation study, USE FNAC, in 2012.
Outcomes of ipilimumab treatment-related adverse events in patients with metastatic melanoma (MM) who received systemic corticosteroids in a phase III trial.
Authors: Baurain Jean-Francois , Smylie Michael , Ascierto Paolo Antonio , Roman Laslo , Houston Stephen , Konto Cyril , Chin Kevin M. , Chen Tai-Tsang , Francis Stephen , Wolchok Jedd D. 
Published: March 2020

8539 Background: Ipilimumab (ipi) is a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses. In a phase III trial, ipi at 10 mg/kg plus dacarbazine (DTIC) improved overall survival in previously untreated patients (pts) with MM. In ipi studies, the most common drug-related adverse events (AEs) were immune-related, which were generally reversible using treatment guidelines involving prompt recognition, intervention (corticosteroids, and rarely, alternative immunosuppressive agents), and possible discontinuation of therapy. The purpose of this analysis is to evaluate outcomes of ipi treatment-related AEs with use of systemic corticosteroids. Methods: AEs were reported from the first ipi dose up to 70 days after the last dose. Immune-mediated adverse reactions (imARs) were used to characterize inflammatory AEs in previously untreated pts with MM who received ipi plus DTIC in a phase III trial. This analysis includes the imAR categories of hepatitis, dermatitis, enterocolitis, and endocrinopathies. Results: More than 70% of pts who received corticosteroids had complete resolution of the imAR, ie, last reported Grade (Gr) of 0 (Table). In pts for whom a high-grade imAR had not completely resolved at the last report, ≥50% had improved to Gr 1. Conclusions: In the majority of pts treated with ipi at 10 mg/kg plus DTIC who received corticosteroids for the management of imARs, as recommended per treatment guidelines, the most common imARs had completely resolved or improved to Gr 1. [Table: see text]