bluuebunny/crossref_metadata_2025_split huggingface dataset:
Profile of multiple myeloma in the inner city: Disease presentation and clinical course.
Authors: Goldrich Adam , Melanthiou Andriane , Kriplani Anuja , Helzner Elizabeth , Babu Arvind , Fein Daniel , Sidhu Juhee , Gonsky Jason Parker , Batuman Olcay 
Published: March 2020

8594 Background: Multiple myeloma (MM) is the most common hematologic neoplasm in blacks in the US. Based on SEER data of all Americans, the disease is more common in men, has a median diagnosis age of 70 and median survival of 3-6 years. The subclinical syndrome MGUS precedes MM, and blacks have a 2-3-fold higher risk of developing MGUS and MM. Further, recent improvements in survival observed for white patients are not observed in blacks. To gain new insight into pathogenesis and to optimize patient care, we characterized our inner city, largely Caribbean-African population in Brooklyn, NY, in terms of disease presentation and course. Methods: MM patients were identified by tumor registries based on histopathology. Data including survival were collected from records of patients diagnosed between 2001-2011 (n=242). Data analysis was performed using SPSS Advanced Statistics. Results: Median age was 64 (range 35-91), male: female ratio was 0.70. The most common presenting pathology was the presence of multiple skeletal lesions with fractures (67% of patients). Spinal cord compression and spinal compression fractures occurred in 33% and 32% of patients, respectively. Renal disease was present in 26%, indicated by serum creatinine >2 mg/dL. Consistent with advanced stage and renal failure, median serum beta-2 microglobulin was 4.25 (range 0.96-82.8). Chromosome banding and FISH was available on 133 patients and showed no cytogenetic abnormalities in 53%; hyperdiploidy (30.4%). Common trisomies included chr 1, 5, 15 and 19. Other abnormalities were del 13 (13%) and chr 14 translocations (11%). Comorbidities include hypertension (65%), diabetes (35%) and obesity (BMI over 30 in 24%). While recent improvements in acquiring health insurance have improved access, less than 10% of patients received HDCT and ASCT. As of October 1, 2012, 36% of all patients are living. Survival analyses are underway. Conclusions: MM presents at an advanced stage and affects younger AA’s in the Downstate community. Strategies for identifying and treating patients with progressive MGUS and at earlier disease stages may enhance survival.
Altered cytokine profiles in multiple myeloma (MM) and precursor disease: Predictors of progression and potential targets for treatment.
Authors: Tageja Nishant , Wang Weixin , Plyler Ryan , Corrigan-Cummins Meghan , Korde Neha , Manasanch Elisabet E. , Bhutani Manisha , Kwok Mary , Flanders Aaron W. , Zuchlinski Diamond , Mulquin Marcia , Costello Rene , Roschewski Mark J. , Landgren Ola , Calvo Katherine R. , Zingone Adriana 
Published: March 2020

8597 Background: Presently, there is no reliable biomarker for predicting clinical progression from smoldering (SMM) to symptomatic MM for individual patients. To improve our understanding on the pathogenesis from SMM to MM, we conducted a screening study of circulating cytokines using peripheral blood (PB) and bone marrow supernatant (BM) collected from treatment naïve SMM and MM patients as well as healthy donors as controls. Methods: PB samples from 14 SMM and 38 MM patients and 7 controls and BM obtained from 17 MM patients and 9 controls were assayed in duplicates using ultra-sensitive Human TH1/TH2 10-plex multi-spot plate and multi-array plate for interleukin-(IL)-6. Two-tailed Mann-Whitney test was used for statistical analysis. Results: PB of SMM patients (vs controls) had increased levels of several cytokines, including IL-8 (p=0.008) and IFN-gamma (p=0.002). In PB, MM patients (compared to SMM patient and controls) had increased levels of IL-6 (p=0.006 and 0.001, respectively), IL-8 (p=0.0001 and 0.008), IL-10 (p=0.02 and 0.02), TNF-alpha (p=0.01 and 0.009), and IFN-gamma (p=0.01 and 0.02). Analysis of BM revealed a similar profile with increased levels of IL-2, IL-6, IL-8, and TNF-alpha in MM patients compared with controls (p=0.007, p=0.0003, p=0.0001 and p=0.0008). Conclusions: We found significantly increased levels of key cytokines associated with progressive disease state (controls→SMM→MM). Patterns of cytokines were similar in BM and PB, suggesting that serum based cytokines may have a future role as biomarkers for disease progression, and could potentially be assessed as novel targets for treatment.
Clinical outcomes after intensive VDT-PACE therapy for relapsed multiple myeloma.
Authors: Singh Preet Paul , Gonsalves Wilson I. , Gupta Vinay , Buadi Francis , Lacy Martha , Dispenzieri Angela , Gertz Morie , Hayman Suzanne R. , Dingli David , Russell Stephen J. , Lust John Anthony , Zeldenrust Steven R. , Kapoor Prashant , McCurdy Arleigh Robertson , Rajkumar S. Vincent , Kumar Shaji 
Published: March 2020

8600 Background: The combination of bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (VDTPACE) was developed as an intense regimen for disease control prior to tandem transplantation for multiple myeloma (MM) in total therapy protocols. The regimen is very effective in this setting, and since has also been used in the relapsed setting. We examined the outcomes of a set of patients undergoing VDTPACE therapy for relapsed MM at our institution. Methods: We identified 71 patients who received VDTPACE for relapsed MM, at Mayo Clinic from 7/2006 to 7/2012. Plasma cell leukemia was excluded. All data was extracted from clinical records. Results: The median age of patients was 59 years (range, 39-80); 48 (67.6%) were male. The median time from diagnosis to initiation of VDTPACE was 38.2 months (range, 2-125). The median number of cycles given was 1 (range, 1-9). The overall response rate after one cycle was 57.1% (14.3% VGPR, 22.2% PR and 20.6% MR) in the 63 patients in whom the response was evaluable. The median overall survival (OS) post-VDTPACE was 8.2 months (95% CI, 5.7-10.9). Eighteen (25.4%) patients went on to autologous stem cell transplantation (SCT), and 7 (9.9%) received matched allogeneic SCT following VDTPACE, and the median OS post-VDTPACE was significantly longer for these groups compared to those who were not transplanted (15.3 and 20.5 months, respectively vs 5 months, p-value <0.001). Thirty eight of 66 (57.6%) patients were rehospitalized after initial admission for infusion therapy for a median duration of 6 days (range, 1-26). The median platelet and red cell transfusions were 4 (range, 0-21) and 5 (range, 0-22) units, respectively. Renal toxicity was seen in 13/62 (21%) patients and 27/65 (41.5%) patients developed neutropenic fever. The median duration to absolute neutrophil and platelet count recovery was 18 (range 12-42) and 27 (range, 12-42) days, respectively. Three (4.2%) patients died within 30 days and 11 (15.5%) within 8 weeks of initiating VDTPACE. Conclusions: VDTPACE is an effective therapy in relapsed MM but is associated with significant morbidity and short-term mortality. It appears to be more effective when followed by an autologous or allogeneic SCT.
Factors that predict successful remobilization after autologous hematopoietic progenitor cell transplant (aHCT) for multiple myeloma.
Authors: Papanikolaou Xenofon Dimitrios , Rosenbaum Eric , Tyler Lisa , Barlogie Bart , Cottler-Fox Michele 
Published: March 2020

8610 Background: aHCT is a proven therapeutic modality in treating relapsed multiple myeloma (MM). However, previously transplanted patients may have no hematopoietic progenitor cells (HPC) left in storage. Methods: Collection of HPC after aHCT was studied in 221 MM patients who underwent 333 mobilization attempts between 10/2000 and 06/2012. Results: The median number of CD34+ collected was 4.7 ×106/kg, with 74% of collections yielding at least 2.5×106/kg. Mobilization with chemotherapy and G-CSF was most efficient, yielding a median of 6.84×106/kg (p<0.001). Growth factor-only mobilization was least effective, with a median of 3.01×106/kg (p<0.001). The addition of plerixafor yielded a significant increase if there was a previous “poor” (<2.5×106/kg) collection (1.83 vs. 3.43×106/kg, p<0.001). In univariate statistical analysis female sex (p=0.048), platelets (PLT) ≤100×106/L (p<0.001), hemoglobin ≤11g/dL (p=0.032), and albumin ≤3.5 g/dL (p=0.003) prior to mobilization correlated with a “poor” collection. In multivariate analysis only PLT ≤100×106/L was significant (p<0.001). Of the 221 patients collected, 154 underwent subsequent aHCT. Infusion of HPC procured after previous aHCT did not yield a difference in treatment-related mortality (p=0.766). Use of only cells collected after aHCT was related to a delayed platelet engraftment ≥50×106/L (p<0.001). Conclusions: Remobilization and collection of an adequate number of HPC after previous aHCT is feasible. PLT ≤100×106/L suggest the need for plerixafor for a successful collection. Infusion of the graft procured is safe and effective, but use of only cells collected after aHCT is associated with delayed platelet engraftment >50×106/L.
Next-generation sequencing of genomic and cDNA to identify a high frequency of kinase fusions involving ROS1, ALK, RET, NTRK1, and BRAF in Spitz tumors.
Authors: Stephens Phil , Wiesner Thomas , He Jie , Yelensky Roman , Esteve-Puig Rosaura , Otto Geoff , Berger Michael F. , Lipson Doron , Brennan Kristina , Miller Vincent A. , Cronin Maureen T. , Bastian Boris C. 
Published: March 2020

9002 Background: Spitz tumors are melanocytic neoplasms with characteristic morphologic features that can overlap with melanoma. Predicting biologic behavior, which can range from an indolent disease to metastasis confined to regional lymph nodes and infrequent incidences of widespread metastatic disease with lethal outcome, is unreliable based on histopathological criteria and the genetic underpinnings of the disease as a whole are poorly understood. Methods: Genomic DNA and total RNA was isolated from 40 microns of FFPE sections from 20 benign Spitz nevi and 8 atypical Spitz tumors (with morphological features inconsistent with HRAS or BRAF/BAP1 mutations) in a CLIA-certified lab (Foundation Medicine). DNA sequencing was performed for 3230 exons of 182 cancer-related genes plus 37 introns of 14 genes commonly fused on indexed hybridization-captured libraries to an average unique coverage of 997x, with 99.96% of exons being sequenced at ≥100x coverage. RNA sequencing was performed on indexed libraries captured using the cDNA Kinome hybridization kit (Agilent) generating >50,000,000 unique pairs per specimen. Results: Only a single case harbored a point mutation in a gene known to be recurrently mutated in melanocytic neoplasms, HRAS Q61L and no known alterations were found in BRAF, NRAS, KIT, GNAQ or GNA11. Remarkably, genomic rearrangements were observed in 19/28 (68%) of cases. The rearrangements fused the intact kinase domains of ROS1 (36%), ALK (14%), RET (7%), NTRK1 (7%) and BRAF (4%) to a wide range of predominantly novel 5’ partners including PWWP2A, PPFIBP1, ERC1, MYO5A, CLIP1, HLA-A, ZCCHC8, DCNT1, LMNA and CEP89. These gene rearrangements, which were all expressed, formed constitutively activated chimeric oncogenes. All fusions occurred in a mutually exclusive pattern and were more common in younger patients compared to patients whose tumors did not harbor fusions (median age 14 versus 24 years, p=0.02). Conclusions: Next generation sequencing identified gene fusions in two thirds of Spitz tumors which are likely to be useful as diagnostic markers that may also serve as therapeutic targets for the rare subset of these tumors that metastasize.
Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL).
Authors: Wolchok Jedd D. , Kluger Harriet M. , Callahan Margaret K. , Postow Michael Andrew , Gordon Ruth Ann , Segal Neil Howard , Rizvi Naiyer A. , Lesokhin Alexander M. , Reed Kathleen , Burke Matthew M. , Caldwell Anne , Kronenberg Stephanie Anne , Agunwamba Blessing , Feely William , Hong Quan , Horak Christine E. , Korman Alan J. , Wigginton Jon M. , Gupta Ashok Kumar , Sznol Mario 
Published: March 2020

9012^ Background: CTLA-4 and PD-1 are critical immune checkpoint receptors. In MEL pts, ipilimumab (anti-CTLA-4) prolonged survival in two phase III trials, and nivolumab (anti-PD-1) produced an objective response rate (ORR) of 31% (n=106) in a phase I trial. PD-1 is induced by CTLA-4 blockade, and combined blockade of CTLA-4/PD-1 showed enhanced antitumor activity in murine models. Thus, we initiated the first phase 1 study to evaluate nivolumab/ipilimumab combination therapy. Methods: MEL pts with ≤3 prior therapies received IV nivolumab and ipilimumab concurrently, q3 wk × 4 doses, followed by nivolumab alone q3 wk × 4 (Table). At wk 24, combined treatment was continued q12 wk × 8 in pts with disease control and no DLT. In two sequenced-regimen cohorts, pts with prior standard ipilimumab therapy were treated with nivolumab (q2 wk × 48). Results: As of Dec. 6, 2012, 69 pts were treated. We report efficacy data on 37 pts with concurrent therapy in completed cohorts 1-3 (Table); ORR was 38% (95% CI: 23-55). In cohort 2 (MTD), ORR was 47% and 41% of pts had ≥80% tumor reduction at 12 wk (Table) with some pts showing rapid responses, prompt symptom resolution, and durable CRs. Related adverse events (rAEs) for concurrent therapy were similar in nature with some higher in frequency than those typically seen for the monotherapies and were generally manageable using immunosuppressants. Cohort 3 exceeded the MTD (DLT: gr 3-4 ↑ lipase). At the MTD, gr 3-4 rAEs occurred in 59% of pts and included uveitis/choroiditis, colitis, and reversible lab abnormalities. Conclusions: Nivolumab and ipilimumab can be combined with a manageable safety profile. Clinical activity for concurrent therapy appears to exceed that of published monotherapy data, with rapid and deep tumor responses (≥80% tumor reduction at 12 wk) in 30% (11/37) of pts. A phase III trial is planned to compare concurrent combination dosing with each monotherapy. Clinical trial information: NCT01024231. [Table: see text]
Analysis of plasma-based BRAF and NRAS mutation detection in patients with stage III and IV melanoma.
Authors: Polsky David , Tadepalli Jyothirmayee S. , Hafner Shria , Chang Gregory , Fleming Nathaniel H. , Shao Yongzhao , Darvishian Farbod , Pavlick Anna C. , Berman Russell S. , Shapiro Richard L. , Osman Iman , Spittle Cynthia 
Published: March 2020

9023 Background: Patients with metastatic melanoma are eligible for BRAF inhibitor therapy if the BRAF V600E mutation can be identified in their tumor specimen. Patients lacking an available specimen for genotyping are unable to receive inhibitor therapy. We developed two mutation-specific genotyping platforms and tested their ability to detect BRAF and NRAS mutations in archived plasma and tumor samples to determine the potential utility of blood-based tumor genotyping in melanoma. Methods: We analyzed a group of 96 patients with stage III or IV melanoma, prospectively enrolled and followed in the NYU Melanoma Biorepository program. Each patient had a plasma sample and one or more tumor samples available for analysis. We used a combination of allele-specific PCR (Taqman) and SNaPshot assays to identify BRAF V600 and NRAS Q61 mutations in the tumor and plasma samples. Results: Among the 96 patients, 51 had stage III disease at the time of analysis; 45 had stage IV disease. Seventy-two patients had 2 or more tumor samples available for analysis, for a total of 204 tumors analyzed. In total, 52/96 (54%) patients had one or more BRAF or NRAS mutant tumors, including one patient with separate BRAF and NRAS mutant tumors (BRAF, n=35 (36%); NRAS, n=18 (19%)). We successfully amplified plasma DNA from 39/52 (75%) patients with tumor-associated mutations. Among those patients with amplifiable plasma DNA we detected mutations in 7 (18%) patients including 3 BRAF V600E, one V600K, 2 NRAS Q61K and one Q61L. Plasma-based mutations matched tumor-associated mutations in all 7 patients. All 7 patients had active disease at the time of blood draw. There were 32 patients with tumor-associated mutations in which a mutation could not be detected in the plasma. Only 15 of those 32 (47%) had active disease at the time of blood draw. There were no mutations detected in the plasma of the 44 patients whose tumors lacked BRAF or NRAS mutations. Conclusions: These data suggest that plasma-based detection of BRAF and NRAS mutations has a high specificity for tumor-associated mutations. It may prove to be a useful adjunct to tumor-based genotyping in patients with active disease, especially those lacking an available tumor specimen.
Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma (aBCC): 18-month update of the pivotal ERIVANCE BCC study.
Authors: Sekulic Aleksandar , Migden Michael R. , Basset-Seguin Nicole , Garbe Claus , Gesierich Anja , Lao Christopher D. , Miller Chris , Mortier Laurent , Murrell Dedee F. , Hamid Omid , Quevedo Fernando , Schadendorf Dirk , Hou Jeannie , Yue Huibin 
Published: March 2020

9037 Background: Therapies for aBCC, which includes metastatic (m) and locally advanced (la) BCC, are limited. Abnormal Hedgehog pathway signaling is a key driver in BCC pathogenesis. Primary analysis of the pivotal ERIVANCE BCC trial of vismodegib, an oral hedgehog pathway inhibitor (HPI), demonstrated an objective response rate (ORR) of 30% and 43%, in mBCC and laBCC patients, respectively, with a median duration of response (DOR) of 7.6 months. We present safety and investigator (INV) assessed efficacy results 18 months (29 May 2012) after primary analysis (26 Nov 2010). Methods: Multicenter, international, nonrandomized study in patients (N=104) with radiographically measurable mBCC or laBCC (surgery inappropriate due to multiple recurrence, or substantial morbidity or deformity anticipated) receiving 150 mg oral vismodegib daily until disease progression or intolerable toxicity. Key secondary endpoints included INV-assessed ORR, progression-free survival (PFS), DOR, overall survival (OS), and safety. Results: At data cutoff, 21 patients continued to undergo protocol-specified assessments and 56 patients were in survival follow-up. The median dose intensity was comparable with primary analysis. ORR was 48.5%, mBCC; 60.3%, laBCC, comparable with primary analysis. However, median DOR improved (mBCC=14.7; laBCC=20.3 months). The median OS for mBCC was 30.9 months but not estimable in laBCC. Adverse events remained consistent, with muscle spasm, alopecia, dysgeusia, weight decrease, and fatigue most frequently reported. Eleven more deaths were reported in the update period after primary analysis; these occurred in survival follow-up and were not drug-related. Conclusions: Vismodegib is the first FDA-approved HPI; thus, long-term efficacy and safety data are particularly relevant. 18-month update data confirmed prolonged responses and consistent safety in vismodegib-treated aBCC patients. Clinical trial information: NCT00833417.
Investigation of the diagnostic precision and utility of sentinel lymph node biopsy in the treatment of patients with Merkel cell carcinoma (MCC).
Authors: Paulus Elena Mantas , Shaw Fawwaz Ridwan , Fleming Martin D. 
Published: March 2020

9042 Background: Merkel cell carcinoma (MCC) is a relatively uncommon and aggressive cutaneous neuroendocrine neoplasm with a high incidence of local recurrence and regional and distant metastasis. The management and identification of prognostic factors remains of value in the treatment of these patients. Although the optimal multidisciplinary treatment of MCC has yet to be determined, the purpose of this study was to investigate whether sentinel lymph node biopsy confers a lower risk of recurrent disease in patients with Merkel cell carcinoma at our institution. Methods: After obtaining institutional review board approvals, all patients with a diagnosis of MCC from 2002-2012 were obtained from our tumor registries. Clinical features, pathologic characteristics, management modalities, and patient outcomes were retrospectively reviewed. Results: Of 20 patients with MCC, nine patients underwent sentinel lymph node biopsy, another four received therapeutic lymph node dissections, and seven patients did not have lymph node evaluation at the initial operation. The most common nodal basins involved were cervical and axillary. Recurrent disease was observed in seven patients (35%). Three patients underwent complete regional lymph node dissection after developing clinically positive nodal disease subsequent to only wide local excision at the index operation (15%). Three patients developed locoregional recurrence and the seventh patient developed metastatic disease to the liver. Of these seven patients with recurrent disease, only two (28.57%) had initial lymph node evaluation. Twelve patients (60%) received adjuvant therapy with chemotherapy (carboplatin/etoposide) and/ or radiation therapy. Conclusions: Merkel cell carcinoma continues to demonstrate its propensity for high rates of recurrence and metastatic disease. Of the seven patients with recurrent locoregional and/or nodal disease in our study, only two patients had initial lymph node evaluation, which was statistically significant with a p value of 0.01175. Further analysis focusing on additional prognostic factors is necessary to optimize our management algorithms and patient outcomes.
Current management of advanced melanoma: A European perspective.
Authors: Jones Clare Frances , Zhao Zhongyun , Barber Beth L. , Bagijn Marloes , Saltman Deborah 
Published: March 2020

9045 Background: Melanoma is a rare but serious subtype of skin cancer that can infiltrate deep skin layers and commonly metastasizes. Although it makes up only a small proportion (<5%) of all skin cancer cases, it causes 75% of deaths from skin cancer. Melanoma affects all ages with 38% of patients less than 55 years old causing significant work productivity and life impact. Median survival of patients with advanced (unresectable or metastatic) melanoma is less than a year. Conventional chemotherapy provides no overall survival benefit. Within the last 2 years, the EMA approved two new drugs for advanced melanoma: ipilimumab for second-line and vemurafenib for patients with BRAF mutation-positive tumors; both drugs provide survival benefits. The objective of this study was to investigate physicians' perceptions of the unmet need in the treatment of advanced melanoma in the new treatment landscape. Methods: 150 oncologists and dermatologists from France, Germany, Italy, Spain, and the UK who had treated at least 12 patients with advanced melanoma in the last 12 months prior to September 2012 were asked by a web-based survey to describe their treatment of advanced melanoma and the current issues in treatment. Results: Overall, 76% of respondents had used ipilimumab and 79% had used vemurafenib in the 12 months prior to September 2012. Toxicity and tolerability of treatment was the most commonly mentioned issue (cited by 43% of respondents). Limited treatment effectiveness (29% respondents) was also highlighted by respondents in all countries. Limited treatment options were identified as a key issue by 30% of respondents in Germany, France, and the UK. Other commonly mentioned issues were low response rates and poor survival. Conclusions: The majority of physicians surveyed had experience using vemurafenib and ipilimumab. However, a number of issues remain in the treatment of advanced melanoma, suggesting that unmet need remains high.