bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective clinical study evaluating current models for risk of progression from smoldering multiple myeloma (SMM) to multiple myeloma (MM).
Authors: Cherry Benjamin M. , Korde Neha , Kwok Mary , Manasanch Elisabet E. , Bhutani Manisha , Yancey Mary Ann , Mulquin Marcia , Maric Irina , Calvo Katherine R. , Braylan Raul , Stetler-Stevenson Maryalice , Yuan Constance , Tembhare Prashant , Zingone Adriana , Costello Rene , Roschewski Mark J. , Landgren Ola 
Published: March 2020

8088 Background: The updated (2010) International Myeloma Working Group criteria emphasize individual follow-up and development of early treatment trials for high risk SMM patients. To facilitate these goals, it is important to have reliable models for risk of progression to MM derived from prospective clinical studies. Current clinical risk models by the Mayo Clinic and the Spanish PETHEMA group stratify SMM patients as low (LR), intermediate (IR), or high risk (HR) of progression using bone marrow plasma cell fraction and protein levels (Mayo) and abnormal plasma cell fraction on flow cytometry with or without immunoparesis (Spanish). We report the first comparison of these models in a prospective natural history study. Methods: We evaluated 70 patients with SMM and determined the risk classifications of each using the Mayo and Spanish models. P values of comparisons between risk groups were calculated using Fisher’s exact test. Results: Among SMM patients classified as HR by the Spanish model (n=31), 2 patients (6%) were HR by the Mayo model; the remaining 17 (55%) and 12 (39%) patients were classified as IR and LR by the Mayo model, respectively. Among 2 SMM patients classified as HR by the Mayo model, both patients (100%) were HR by the Spanish model. There was significant disagreement between the models in identifying HR patients (HR v. non-HR, p<0.0001). Similarly, of SMM patients classified as LR by the Spanish model (n=17), 11 patients (65%) were LR by the Mayo model; 6 (35%) were IR and 0 (0%) were HR by the Mayo model. Among SMM patients classified as LR by the Mayo model (n=36), 11 (31%) patients were classified as LR by the Spanish model; 13 (36%) were IR and 12 (33%) were HR by the Spanish model. There was significant disagreement between the models in identifying LR patients (LR v. non-LR, p=0.0016). Conclusions: The significant discordance between the Mayo Clinic and Spanish PETHEMA clinical risk models underscores the urgent need for biologically derived models that rely on molecular markers to predict disease progression. Such models are critical for counseling individual patients and for the development of early treatment studies that seek to prevent or delay progression to MM.
Predicting bortezomib-related severe neurologic adverse events by measuring proteasome activity in PBMCs.
Authors: Cho Yukiko , Hori Mitsuo , Okoshi Yasushi , Komeno Takuya , Yoshida Chikashi , Katsura Yukitaka , Ota Ikuyo , Shinagawa Atsushi , Kudo Daisuke , Shimizu Seiichi , Sasaki Katsuhiro , Tanaka Keiji , Mukai Harumi , Kojima Hiroshi ,   Ibaraki Hematology Oncology Palliation Expert Meeting
Published: March 2020

8094 Background: Although a proteasome inhibitor bortezomib (BOR) is one of the backbone drugs for the treatment of multiple myeloma, severe neurologic adverse event (sNE) is a major obstacle for continuing the treatment. As there is no clinically available biomarker for predicting the occurrence of sNAE, we measured the proteasome activity (PrsAtv) in peripheral blood mononuclear cells (PBMCs). Methods: Patients (Pts) were treated by either standard Q3wks or weekly (BOR 1.3mg/m2: day 1, 8, 15, 22; Q5wks) schedule depending on physician’s decision. PBMCs were collected from 21 Pts and 99 healthy volunteers. Pts’ samples were collected before treatment, 1 hour after the 1st injection of BOR, and at the end of the 1st course. PrsAtv in PBMCs was measured by using a specific substrate SUC-LLVY-AMC, which becomes fluorescent upon cleavage by proteasome. Results: Levels of PrsAtv among volunteers were highly variable with no certain correlation with age and sex. Pretreatment levels of PrsAtv among Pts were also variable, and didn't correlate with the occurrence of sNAE. After 1 hour of BOR injection, PrsAtv decreased to 33.2±20.5% (mean ± SD) of the pretreatment level, and it generally recovered (112.5±77.6%) at the end of the 1st course. However, in 12 out of 21 Pts, it didn’t recover to ≥ 100%. Among these Pts, 5 manifested with sNAE (≥G3) during the 2nd or 3rd course of the chemotherapy. In a sharp contrast, no patients whose PrsAtv recovered to ≥100% manifested with sNAE. Pts who manifested with sNAE (5 Pts) showed the lower levels of PrsAtv at the end of the 1st course than those without sNAE (16 Pts) (67.4±11.8 vs 126.6±83.8%, p=0.075). It should be also strengthened that all the Pts who manifested with sNAE were treated by the standard Q3wks schedule, although levels of PrsAtv at the end of the 1st course were not significantly different between Q3 and Q5wks groups (109.0±68.3 vs 121.1±96.4 %, p=0.38). Contrary, there was no significant difference of the bortezomib response between these two treatment groups. Conclusions: Pts whose PrsAtv does not recover to ≥100% at the end of the 1st course are at high risk of manifesting with sNAE, and these Pts should not be treated by the standard Q3wks schedule in the subsequent courses.
Regional differences in the treatment approaches for relapsed multiple myeloma: An IMF study.
Authors: Durie Brian G. , Moreau Philippe , Sonneveld Pieter , Morgan Gareth J , Lahuerta Juan José , Beksac Meral , Terpos Evangelos , Hajek Roman , Hungria Vânia Tietsche de Moraes , Maiolino Angelo , Chng WeeJoo , Lee Jae Hoon , Jian Hou , Richardson Paul Gerard Guy , Chen Wenming , Knop Stefan , Hoerring Antje , Leleu Xavier , San-Miguel Jesùs F. , Kumar Shaji ,   International Myeloma Working Group
Published: March 2020

8095 Background: Multiple myeloma (MM) remains incurable and invariably relapses after initial therapy. There is no uniform approach to management of relapsed MM and is dictated by type of initial therapy and the response seen, and availability of new drugs. The outcomes associated with current approaches have not been systematically examined. Methods: We enrolled 383 patients (pts) with myeloma who had a documented relapse between Jan 2007 and June 2010, including 220 from Europe, 106 from Asia, and 31 from South America and 26 from North America. Time Zero (T0) was defined as date of treatment after first relapse. Results: Across the study, 61% were male and 49% were over 65 years at T0. ISS stage distribution at diagnosis included 26, 40 and 33% of patients in stages 1, 2 and 3, respectively. Among regimens used at first relapse; bortezomib (Btz) containing regimens were most common (54%), followed by lenalidomide (Len, 25%) and cyclophosphamide (21%). The overall response rate (>=PR) to first therapy after relapse was 58% including 14% with a CR. There was a progressive decrease in the response rates with successive regimen; 45%, 30% and 15% for regimens 2, 3 and 4 respectively. Len use was considerably lower in the Asian cohort, while Btz use was comparable across the regions. The median PFS from T0 was 13 mos and OS was 35 mos, for the entire cohort. The PFS to first salvage regimen was similar across the regions, while OS was shorter for the Asian and South American cohorts. In a univariate analysis, ISS stage 3, presence of cytogenetic abnormalities, history of plasma cell leukemia or extramedullary disease (EMD), bone marrow PC% > 33% and presence of renal insufficiency were all associated with a shorter PFS as well as shorter OS (P<=0.01). In a multivariate model, ISS stage 3 and presence of EMD were most associated with short OS. Conclusions: Median PFS for current second line regimens, typically containing Btz or Len appear to be 1 yr with an OS from first relapse of about 3 yrs. The OS from first relapse is nearly double that seen in a cohort of patients in first relapse prior to introduction of new drugs. Clear-cut regional differences can be seen in terms of patterns of drug use and likely reflect drug availability and healthcare costs.
An open-label, multicenter safety study of vemurafenib (PLX4032, RO5185426) in patients with metastatic melanoma.
Authors: Larkin James M. G. , Queirolo Paola , Arance Ana M , Brown Michael Paul , Hauschild Axel , Del Vecchio Michele , McArthur Grant A. , Neyns Bart , Becker Jürgen C. , Hansson Johan , Hogg David , Ascierto Paolo Antonio , Loquai Carmen , Espinosa Enrique , Garbe Claus , Patel Poulam M , Schachter Jacob , Mitchell Lada , Veronese Maria Luisa , Blank Christian U. 
Published: March 2020

8517 Background: Vemurafenib, a BRAF inhibitor, is associated with improved PFS and OS in patients (pts) with BRAFV600-mutant metastatic melanoma (mM). We present preliminary safety and efficacy findings from a safety study of vemurafenib in pts with unresectable stage IIIC/IV mM with BRAFV600 mutations. Methods: Pts with untreated or previously treated stage IIIC/IV BRAFV600 mutation-positive (cobas 4800 BRAF V600 Mutation Test) melanoma were enrolled. Pts received continuous oral vemurafenib 960 mg bid. Primary study endpoint was safety; efficacy (RECIST V 1.1) was a secondary endpoint. Results: Of 1,964 screened pts between Mar and Sep 2011, 914 (47%) were enrolled and 834 were evaluable for safety. Median age was 53 (21–88 years), 55% males. Median time since first mM diagnosis was 7.6 months (0–18 years). At baseline, 80% of pts had ECOG PS 0–1, 11% ECOG PS 2 (missing 9%); 27% of pts had brain metastases, and 31% had elevated LDH. Most pts had received prior systemic therapy (70%) including ipilimumab (14%), MEK and BRAF inhibitors (2%). At data cut-off (Sep 30, 2011), median treatment duration was 68 days (1–223 days) with 87% of pts still on treatment. Of 834 pts, 553 (66%) to date have reported AEs. Of 553 pts reporting AEs, 88% were related to vemurafenib, 33% Grade 3, and 1.9% Grade 4. The most common (>1%) Grade 3/4 AEs were rash (3.6%), arthralgia (3.1%), and cutaneous squamous cell carcinoma/keratoacanthoma (4.3%). Most common AEs (>10%) of any grade were arthralgia (31%), rash (29%), fatigue (22%), photosensitivity (21%), nausea (15%), and were similar irrespective of brain metastases and ECOG PS. AEs caused treatment interruption in 141 (17%) pts. Of 109 pts who discontinued treatment (13%), main reasons for withdrawal were progressive disease (60%), death (20%), AEs (6%; most commonly arthritis and abdominal pain). Tumor assessments at Week 8 of treatment were available for 302/834 (36%) pts, 61% pts achieved CR or PR, and 29% had SD. Conclusions: In a setting representative of routine clinical practice, vemurafenib is seen to be well tolerated and both safety profile and activity resemble the phase I–III data although this analysis is limited by the study duration.
Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: Phase II trial with correlative studies.
Authors: Slingluff Craig L. , Petroni Gina R. , Molhoek Kerrington R. , Brautigan David L , Chianese-Bullock Kimberly A. , Shada Amber L , Smolkin Mark E , Gaucher Alison , Murphy Cheryl F. , Grosh William W. , Weiss Geoffrey R. , Wagenseller Aubrey G , Olszanski Anthony J. , Martin Lainie P. , Shea Sofia M , Erdag Gulsun , Ram Prahlad T , Gershenwald Jeffrey E. , Weber Michael J 
Published: March 2020

8530 Background: A CTEP-sponsored phase II trial was performed to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma. Correlative studies assessed mTOR signaling in tumor biopsies and evidence of induced immunologic dysfunction systemically. Methods: 17 patients with stage III or IV melanoma were enrolled and treated with temsirolimus (25 mg IV weekly) and bevacizumab (10 mg/kg IV every 14d, starting d.8) for up to 13 months. Clinical response was determined by RECIST criteria. Adverse events were assessed (CTCAE v3.0). Blood was collected d.1, 2, and 23 (to assess immune function), and tumor biopsies were obtained (to assess protein kinase activity and melanoma cell proliferation). Results: Treatment-related grade 3 or 4 adverse events occurred in 5 and 1 patients, respectively; 1 patient developed reversible leukoencephalopathy. In 16 patients evaluable for clinical response, best overall response was a partial response (PR) in 3 patients (19%), stable disease at 8 weeks (SD) in 9 patients (56%), and progressive disease in 4 patients. Thus, disease control rate (DCR = PR + SD) was 75%. Ten of the patients had BRAF wild-type (BRAFwt) melanomas: these accounted for the 3 PRs (30%), and a DCR of 100%. Maximal response duration has exceeded 3 years for a BRAFwt patient. mTOR signaling was inhibited in melanoma metastases, based on decreased phospho-S6 kinase after 24h temsirolimus. Ki67+ melanoma cells in tumor biopsies decreased significantly by day 23 (p = 0.007, F-test), most notably in clinical responders. There was no significant alteration of T cell and NK function with combination treatment, by ELIspot and cytotoxicity assays. Conclusions: Combination therapy with temsirolimus and bevacizumab is well-tolerated in patients with advanced melanoma and has intriguing clinical activity. The most notable responses were in patients with BRAFwt tumors, a population with no accepted effective targeted therapy. Decreases in Ki67+ melanoma cells may be associated with clinical response. The lack of immunologic dysfunction supports future combination with immune therapies.
Gene expression profile signature (DecisionDx-Melanoma) to predict visceral metastatic risk in patients with stage I and stage II cutaneous melanoma.
Authors: Dhillon Navneet , Rogers Anna R , Delman Keith A. , Maetzold Derek , Oelschlager Kristen M. , Lyle Stephen , Jackson Gilchrist L. , Greisinger Anthony , Parker Douglas , Cook Robert W. , Lawson David H. 
Published: March 2020

8543 Background: The current AJCC TNM staging system has poor specificity for predicting visceral metastatic risk in patients diagnosed with stage I or stage II cutaneous melanoma. We, therefore, developed a gene expression profile signature (GEP) following in silico investigation of previously published microarray analyses. Methods: 60 formalin fixed paraffin embedded primary cutaneous melanoma samples from patients with stage I or II cutaneous melanoma with at least a follow up period of at least 6 years were macrodissected and analyzed blindly. RNA was isolated, converted to cDNA and RT-PCR was performed to assess the expression of the gene set. Expression data and biostatistical analysis was performed using GeNorm and JMP Genomics (SAS) Predictive modeling included Radial Basis Machine (RBM) and Partition Tree Analysis (PTA) Metastasis-free survival (MFS) was assessed using Kaplan-Meier analysis. The following clinical data was retrieved from medical records: survival, metastases, types of metastases. 20 out of 60 patients had developed visceral metastases in the follow up period. Results: GEP was developed following multiple analytical approaches.Two types of signatures emerged: Low risk (Class 1) and High risk (Class 2). Without optimizing for sensitivity, the analyses of the 60 sample cohort by radial basis machine (RBM) resulted in 92% ROC (met. accuracy = 90%, non-met. accuracy = 85%), while partition tree analysis (PTA) yielded 99% ROC (met. accuracy = 100%, non-met. accuracy = 95%). RBM classification showed 6-year MFS rates of 97% for Class 1 and 19% for predicted Class 2 of metastasis (median MFS = NR and 5.6 yrs, resp., P<0.0001 Log-Rank respectively). PTA showed 6-year MFS rates of 100% for predicted Class 1 and 14% for Class 2 of metastasis (median MFS = NR and 5.4 yrs, resp., P<0.0001 Log-Rank respectively). Conclusions: This study shows that DecisionDx-Melanoma GEP signature can provide excellent accuracy in predicting metastatic risk in stage I and II cutaneous melanoma.To our knowledge, the GEP provides the most accurate predictor to date for development of visceral metastases in patients with Stage I and II cutaneous melanoma.
Positron emission tomography/computed tomography to improve staging and restaging in Merkel cell carcinoma.
Authors: Hawryluk Elena B. , O'Regan Kevin N. , Sheehy Niall , Guo Ye , Dorosario Andrew , Sakellis Chris , Jacene Heather A. , Wang Linda C 
Published: March 2020

8552 Background: Merkel cell carcinoma (MCC) is a rare (~1,500 cases per year) and highly aggressive (33% mortality) cutaneous neuroendocrine carcinoma that occurs in older white patients on the UV-exposed skin of the head, neck, and extremities. As a patient’s stage at presentation is a strong predictor of survival, and there is a high propensity for locoregional recurrence and distant progression, imaging remains crucial for initial and subsequent management. There is, however, no consensus on the timing or method of imaging for MCC. Methods: We retrospectively reviewed 270 2-fluoro-[18F]-deoxy-2-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) scans performed in 97 patients at the Dana-Farber/Brigham and Women’s Cancer Center from August 2003 to December 2010. Results: The mean SUVmax was 6.5 for primary tumors, 6.4 for regional lymph nodes, 7.2 for distant metastases (all sites), 8.0 for bone/bone marrow metastases, and 9.4 for non-regional metastases in those patients with no identified primary. PET/CT imaging performed for initial management tended to upstage patients with more advanced disease (50% of stage IIIB patients). Metastases to bone/bone marrow (12 patients, 38%) was the 2nd most common site of distant spread after non-regional lymph nodes (19 patients, 59%), followed by skin (8 patients, 25%), liver (6 patients, 19%), lung/pleura (5 patients, 16%), adrenal (3 patients, 9%), muscle (3 patients, 9%), pancreas (2 patients, 6%), and peritoneum (1 patient, 3%). In 10 of 12 patients, PET identified bone/bone marrow metastases that were not seen on CT imaging, which resulted in either upstaging or initiation of more targeted palliative therapy. Conclusions: Added value of PET over CT, such as in the detection of bone/bone marrow metastases, may lead to more accurate staging, and thus prognostication, as well as earlier detection of relapse and initiation of salvage treatment. Its use should be considered in the staging and restaging of MCC.
Effect of the BH3 mimetic ABT-737 on human melanoma cells to apoptosis induced by selective BRAF inhibitors.
Authors: Hersey Peter , Wroblewski David , Mijatov Branka , Zhang Xu Dong , Haass Nikolas 
Published: March 2020

8553 Background: Although the introduction of selective BRAF inhibitors has been a major advance in treatment of metastatic melanoma, approximately 50% of patients have limited responses including stabilisation of disease or no response at all. The present study aims to identify a novel means of overcoming resistance of melanoma to killing by BRAF inhibitors. Methods: We examined the influence of the BH3 mimetic ABT-737 on induction of apoptosis by the selective BRAF inhibitor PLX4720 on a panel of melanoma cells with BRAF V600E mutations with or without mutations of CDK4 and BRAF wildtype cells with or without NRAS mutations. Included in the studies were cell lines established from 4 patients before and during treatment with selective BRAF inhibitors. Results: Cell lines with no or low sensitivity to PLX 4720 underwent synergistic increases and increased rates of apoptosis when combined with ABT-737. This degree of synergism was not seen in cell lines without BRAF V600E mutations. Apoptosis was mediated through the mitochondrial pathway and was due in part to upregulation of Bim as shown by inhibition of apoptosis following siRNA knockdown of Bim. Similar effects were seen in cell lines established from patients prior to treatment but not in lines from patients clinically resistant to the selective BRAF inhibitors. Conclusions: These results suggest that combination of selective BRAF inhibitors with ABT-737 or the oral form ABT-263 may increase the degree and rate of responses in previously untreated patients with V600E melanoma but not in those with acquired resistance to these agents.
The melanoma risk loci as determinants of melanoma prognosis.
Authors: Rendleman Justin , Shang Shulian , Brocia Christine , Ma Michelle W. , Shapiro Richard L. , Berman Russell S. , Pavlick Anna C. , Shao Yongzhao , Osman Iman , Kirchhoff Tomas 
Published: March 2020

8557 Background: Genetic risk factors of human cancer emerge as promising markers of clinical outcome. The recent melanoma genome-wide scans (GWAS) have identified loci associated with the disease risk, nevi or UV/pigmentation, but the prognostic potential of these variants is yet to be determined. In this study, we performed the first-to-date systematic evaluation of the association between established melanoma risk loci and melanoma progression. Methods: 891 melanoma patients prospectively accrued and followed up at NYU Medical Center were studied. We examined the association of 108 melanoma susceptibility single nucleotide polymorphisms (SNPs), selected or imputed from recent GWASs on melanoma, nevi or pigmentation, with recurrence-free survival (RFS) and overall survival (OS). The genotyping was performed using Sequenom I-plex. Cox PH model was used to test the association between each SNP and RFS and OS adjusted by age at diagnosis, gender, tumor stage and histological subtype. ROC curves were used to measure predictive utility of SNPs in predicting 3-year recurrence. Results: The strong association was observed for rs7538876 (RCC2) with RFS (HR=2.445, 95% CI 1.57 – 3.8, p=0.0006) and rs9960018 (DLGAP1) with both RFS and OS (HR=4.7, 95% CI=2.11-10.43, p=0.0061, HR=1.55, 95% CI=1.11-2.17, p=0.0094, respectively) using adjusted multivariate analysis. In addition, we identified the classifier with rs7538876 and rs9960018, stage and histological type at primary tumor diagnosis, achieving a higher area under the ROC curve (AUC=84%) compared to the baseline (AUC=78%) in predicting 3-year recurrence. Univariate survival analyses have identified associations of several SNPs with ulceration and/or tumor thickness. Conclusions: Our data revealed an association between specific melanoma susceptibility variants and worse clinicopathological variables at the time of diagnosis as well as worse disease outcome. The strength of associations observed for rs7538876 and rs9960018 suggest biological implication of these loci in melanoma recurrence. The observed predictive patterns of associated variants with clinical outcome provide for the first time evidence for the potential utilization of genetic markers in melanoma prognostication.