bluuebunny/crossref_metadata_2025 huggingface dataset:
Disruption of the eIF4F translation initiation complex as a determinant of diffuse large B-cell lymphoma responsiveness to enzastaurin (LY317615.HCl) and its primary metabolite (LY326020).
Authors: Graff Jeremy Richard , McNulty Ann M , Dumstorf Chad A , Parsons Stephen H , Konicek Bruce W , Hall Chad A
Published: March 2020

8082

Background: Enzastaurin (enza) is in ph 3 registration trials for DLBCL patients at high risk of relapse following R-CHOP therapy. In a phase 2 DLBCL study, 4 of 55 treated patients were progression- free after prolonged, continuous oral enza therapy with 3 of these 4 confirmed as complete responders (Robertson et al., JCO, 2007). The molecular mechanism for this differential response is unclear. Methods: In clinical trials, Enza yields 2-4 µM total circulating drug, comprised of ~50% enza, ~50% primary metabolite, LY326020. We therefore evaluated the sensitivity of a DLBCL cell panel representing both Activated B Cell (ABC) and Germinal Center (GC) subtypes to enza and LY326020. Gene expression analyses, western blotting to explore intracellular signaling and mRNA cap analogue co-capture assays were used to identify the critical effectors of drug sensitivity. Results: For the first time, we show the profound biological activity of LY326020, the primary metabolite that accounts for ~ 50% of circulating drug in patients. Like Enza, though more potently, LY326020 inhibits PKC and PI3K-AKT-TOR pathway signaling and robustly induces apoptosis in both ABC and GC DLBCL cells. In both sensitive and resistant cells, enza and LY326020 reduced phosphorylation of numerous proteins in the PI3K-AKT-TOR pathway (e.g. pGSK3βser9) in a dose and time-dependent manner. However, only sensitive DLBCL cells showed reduced 4EBP1ser65 phosphorylation. Accordingly, we show a dose and time-dependent increase in 4EBP1: eIF4E binding. This increase is most pronounced by LY326020. Moreover, cells selected for resistance to enza show reduced 4EBP1 expression and cells lacking 4EBP1 are insensitive to the pro-apoptotic effects of enza and LY326020. Conclusions: These data demonstrate that sensitivity of DLBCL to both enza and LY326020 is critically dependent upon 4EBP1 modulation and subsequent disruption of the eIF4F translation complex. Moreover, these data are the first to show the potent biologic activity of LY326020, the primary metabolite of enza that accounts for ~50% of total circulating drug in patients and in preclinical models.
Hematologic safety data from four phase II studies of single-agent carfilzomib in relapsed and/or refractory multiple myeloma
Authors: Nooka Ajay K. , Badros Ashraf Z. , Patel Priti , McCulloch Leanne , Lonial Sagar , Kaufman Jonathan L.
Published: March 2020

8086

Background: Carfilzomib (CFZ) is a next-generation proteasome inhibitor that is currently being evaluated in patients (pts) with multiple myeloma (MM). Given that the majority of pts with MM exhibit either disease- or therapy-related myelosuppression sometime in the course of their disease, detailed evaluation of treatment-emergent hematologic safety data with CFZ is of significant interest. In the following analysis, we report the hematologic safety profile for single-agent CFZ from 526 pts treated in four phase 2 studies. Methods: Pts treated with CFZ in trials 003-A0, 003-A1, 004, and 005 were included in the analysis. Pts with preexisting hematologic abnormalities of Grade (G) 0–2 (G0–3 for 005) were eligible to enroll. CFZ was dosed in all studies 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). Incidence, frequency, and severity of thrombocytopenia, lymphopenia, neutropenia, and anemia were analyzed in terms of adverse events (AEs) of interest. Laboratory data were analyzed for trends over time. Results: See table below for summary of hematologic events. In general, platelet counts trended down, reached a nadir by Day 8 of a 28-day treatment cycle, and normalized before the start of next cycle. There was no evidence of cumulative thrombocytopenia or clinically significant episodes of bleeding associated with thrombocytopenia. Febrile neutropenia was reported in 1% of pts. No mortality due to hematologic events was reported. Conclusions: Hematologic AEs, although common with CFZ treatment, were infrequently dose limiting. Clinically significant G3/4 cytopenias were both infrequent and transient. In summary, the hematological safety profile of CFZ was similar to or better than currently approved MM therapies, providing further evidence of its acceptable safety profile in heavily pretreated MM pts. Summary of hematologic events. [Table: see text]
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.
Tim-3 expression and function in natural killer cells from advanced melanoma patients.
Authors: Pires Da Silva Ines Esteves Domingues , Jimenez-Baranda Sonia , Gallois Anne , Kuchroo Vijay , Osman Iman , Bhardwaj Nina
Published: March 2020

8571

Background: The concept of CD8+ T cell exhaustion in the context of metastatic cancer has been reinforced by the recent success of immunotherapies targeting the exhaustion markers CTLA-4 and PD-1 in advanced melanoma. T-cell immunoglobulin 3 (Tim-3), another exhaustion marker, is also expressed in natural killer (NK) cells, however its role is still unknown. Recent reports have shown that NK cells, innate immune cells that eliminate tumors through cytotoxicity and IFN-g production, are functionally impaired in advanced melanoma patients, although no receptor has been linked with that phenotype so far. In this study, we characterize the role of Tim-3 in NK cells, particularly in the presence of its natural ligand, Galectin-9 (Gal-9), that is known to be expressed/secreted by some tumor cells including melanoma. Methods: We compared 20 advanced melanoma donors NK cells with 40 healthy donors NK cells as it relates to Tim-3 expression (by flow cytometry) and function (cytotoxicity, IFN-γ production and proliferation). NK cells cytotoxicity was measured by lamp-1 expression, and two different target cells were used: i) K562 cells (Gal-9-) and ii) Gmel Gal-9+ and Gmel Gal-9- sorted melanoma cells. Proliferation was quantified by CFSE after 6 days in the presence of rhIL-2. Recombinant rhGal9 effect was tested in cytotoxicity and IFN-γ production. Results: Melanoma patients NK cells express higher levels of Tim-3 compared to healthy donors NK cells (p<0.05). Melanoma patients NK cells have a defect in cytotoxicity, proliferation and IFN-γ production. Tim-3 expression by itself (without engagement of specific ligands) does not negatively affect NK cell functions (p<0.05). However, when rhGal9 is added to the system, a decrease in NK cell cytotoxicity and IFN-γ production (p<0.05) was observed. Finally, the expression of Gal-9 by the target cells induces a defect in NK cell cytotoxicity (Gmel Gal-9+ vs Gmel Gal-9-). Conclusions: These data suggest that advanced melanoma patients NK cells are exhausted, although it still remains unclear if Tim-3 is involved in this phenotype. In addition,the expression/secretion of Galectin-9, immunosuppressive for NK cells, may be a possible mechanism for tumors to evade immune surveillance.
Surgery for patients receiving ipilimumab: Safety profile and immunological insights.
Authors: Gyorki David E. , Yuan Jianda , Mu Zhenyu , Zaidi Bushra , Gallardo Humilidad F. , Brady Mary Susan , Gutin Philip H. , Coit Daniel G. , Wolchok Jedd D. , Ariyan Charlotte Eielson
Published: March 2020

8583

Background: Ipilimumab (ipi), a monoclonal antibody blocking CTLA-4, demonstrated survival benefit in metastatic melanoma in two randomized controlled trials. With its approval by the FDA, the use of this immunotherapy is increasing. The surgical safety of ipi has not been reported. Methods: From our prospective database, we identified patients undergoing surgery within 30 days of receiving a dose of ipi or on maintenance ipi between October 2007 and August 2011. Surgical toxicity was graded 1-5 by the Clavien classification. In 10 patients matched blood and tumor infiltrating lymphocytes were harvested. Phenotype of T cell subsets were analyzed by flow cytometry. Results: 23 patients were identified who underwent 34 operations a median of 27 weeks after initiation of ipi (1-123 weeks). Indications for surgery were symptomatic, progressive, or isolated persistent disease in 52%, 39% and 9% respectively. Subcutaneous resections were the most frequent, followed by intra-abdominal and nodal procedures (Table). Grade 1 wound complications were seen in 17% of patients. One patient had a Grade 2 wound complication. No Grade 3-5 complications were seen. With a median follow up from starting ipi of 86 weeks, 3 patients have no evidence of disease, 10 are alive with disease and 10 have died of disease. Analysis of the T cell infiltrate and peripheral blood from 10 patients with progressive or symptomatic disease shows an elevated % of CD4+FOXP3+ T regulatory cells and a 2.8 fold reduction in CD8+/ CD4+FOXP3+ T regulatory ratio in the tumor compared to blood (p=0.02). Conclusions: Results from this single-center experience suggest that surgery is safe in patients receiving ipi. Immune modulation caused by CTLA-4 blockade does not appear to impact wound healing, even in the bowel. In carefully selected patients metastectomy may be appropriate for breakthrough metastases. The high percentage of T regulatory cells and low T effector cells in the progressive tumors suggests a mechanism of immune escape. [Table: see text]
Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-mediate gastrointestinal adverse events.
Authors: Shahabi Vafa , Berman David Mark , Chasalow Scott D. , Wang Lisu , Tsuchihashi Zenta , Hu Beihong , Panting Lisa , Jure-Kunkel Maria , Ji Rui-Ru
Published: March 2020

8593

Background: Treatment with ipilimumab, a fully human anti-CTLA-4 antibody approved for treatment of metastatic melanoma (MM), is associated with a number of immune-mediated Adverse Events (imAEs) such as colitis and skin rash. Predictive biomarkers that can help identify patients (pts) who might experience these imAEs could enhance the management of these toxicities. Methods: Gene expression profiling (using Affymetrix gene chip HT-HG-U133A) was performed on the whole blood samples from 162 MM pts at baseline, 3 and 11 weeks after the start of ipilimumab treatment in two phase II clinical trials (CA184004 and -007). Overall, 49 pts experienced Grade 2 or higher GI-imAE (G2+) during the course of treatment. A repeated measures ANOVA was used to evaluate the differences in mean expression levels between the two groups and at the three time points. Uncorrected p-value of 0.05 was used as a cutoff for this analysis. Results: In baseline samples, 27 probe sets showed differential mean expression (≥ 1.5 fold, p < 0.05) between G2+ pts and others. Most of these genes belonged to three functional categories: immune system, cell cycle or intracellular trafficking. Changes in gene expression over time were also characterized. In the G2+ pts, 58 and 247 genes had a ≥ 1.5 fold (p < 0.05) change in expression from baseline to week 3 and 11 post-treatment, respectively, compared to 17 and 73 in other pts. In particular, the on-treatment increases of the expression of CD177 and CEACAM1, two neutrophil activation markers, were closely associated with G2+ GI-imAE, suggesting a possible role of neutrophils in ipilimumab associated GI-imAEs. In addition, the expression of several Ig genes increased over time, with higher increases in the G2+ pts. These observations were reproduced in another ipilimumab monotherapy study in MM (CA184078). Conclusions: Gene expression profiling of peripheral blood resulted in the identification of a set of potential biomarkers that may be predictive of severe GI-imAEs before, or early in the course of treatment with ipilimumab. Further validation of these biomarkers in a larger patient cohort is warranted.
Detection of BRAF mutations in melanoma: Rate of mutation detection at codon 600 using Sanger sequencing as compared to the cobas 4800 method.
Authors: Qu Kevin Z. , Pan Qiulu , Zhang Xi , Rodriguez Luis , Uyeji Jennifer , Li Hairong , Ho Albert , Sanders Heather , Sferruzza Anthony , Jones Daniel , Waldman Frederic ,   Quest Diagnostics Nichols Institute
Published: March 2020

8596

Background: Detection of BRAF V600 mutations is currently a prerequisite for approved use of vemurafenib in patients with metastatic melanoma. The cobas 4800 BRAF V600 Mutation Test (Roche Molecular Diagnostics), a PCR-based assay approved to aid in selecting patients for vemurafenib therapy, primarily detects V600E. It is also reported to detect V600K, which has been associated with vemurafenib response as well. We compared the mutation detection rate of the cobas assay with that of Sanger sequencing. Methods: 125 de-identified FFPE tissues submitted for BRAF mutation analysis that all showed histologically-confirmed melanoma were tested. BRAF mutations were detected using both the cobas kit and bidirectional Sanger sequencing using BigDye kits (Applied Biosystems). DNA was extracted from 5-um sections without macrodissection using the cobas DNA extraction kit (for the cobas test) or from 5-10-um sections using Agencourt extraction kits (Beckman Coulter) following macrodissection. Results: The two methods showed agreement in 104/125 (83.2%) of cases (Table). Sanger sequencing detected V600 dinucleotide mutations in 9 samples that were negative by the cobas assay. Sanger sequencing produced no results in 10 cases owing to suboptimal PCR, including 2 that were positive by the cobas assay. The cobas assay produced 2 invalid results, including 1 that was positive for V600E by Sanger.The cobas assay detected 7/11 V600K mutations. Conclusions: Overall agreement between cobas and Sanger sequencing was 83.2%. The Sanger method had higher analytic sensitivity, resulting in nine additional V600 mutations not called by cobas compared to the two seen by cobas but not Sanger sequencing. Thus, 16% (9/57) more patients would be identified as candidates for vemurafenib therapy using the Sanger method. [Table: see text]
Dexamethasone (DM) for cancer-related fatigue: A double-blinded, randomized, placebo-controlled trial.
Authors: Yennurajalingam Sriram , Frisbee-Hume Susan , Delgado-Guay Marvin Omar , Bull Janet , Phan Alexandria T. , Tannir Nizar M. , Litton Jennifer Keating , Palmer J. Lynn , Reddy Akhila Sunkepally , Hui David , Dalal Shalini , Massie Lisa , Vadhan-Raj Saroj , Reddy Suresh K. , Reuben James M. , Bruera Eduardo
Published: March 2020

9002

Background: Cancer-related-fatigue (CRF) is the most common and distressing symptoms in patients with advanced cancer. Currently, there is no standard treatment for CRF. Although corticosteroids have been used in the treatment of CRF, there are no well-powered placebo-controlled trials that used a validated CRF outcome measure. The primary objective of this prospective, randomized, double-blind, placebo-controlled study is to compare the effect of DM versus placebo on CRF. Methods: Advanced cancer patients with fatigue ≥ 4/10 on the Edmonton Symptom Assessment Scale (ESAS) and at least 2 other CRF-related symptoms (pain, nausea, appetite, depression, anxiety or sleep disturbance ≥ 4/10), normal cognition, no infections and hemoglobin ≥ 9 g/L were eligible for enrollment. Patients were randomized to either receive dexamethasone 4 mg orally twice a day for 15 days (primary end point) or matching placebo. The primary outcome was the day 15 change in Functional Assessment of Chronic Illness-Fatigue (FACIT-F) subscale scores. Differences in the group means (normal distribution) were analyzed using the two-sample t-test. Results: In 83 evaluable patients (43 DM and 40 placebo), median age was 60 years, 61% were white, and 53% were female. There was no difference in the demographics and fatigue (FACIT-F subscale) between DM and placebo groups except for sex (p=0.02). The mean (SD) FACIT-F subscores at baseline and at day 15 for DM were 18 (11) and 27 (11) (p<0.001) and for placebo were 21 (9) and 24 (12) (p=0.06), respectively. Mean improvement in FACIT-F subscale was significantly higher in the DM group compared to placebo (9.6 (11) vs. 3.1 (9.7), p=0.005). We found a significant difference in ESAS physical distress (p=0.02), but no differences in ESAS overall symptom distress (p=0.11) and ESAS psychological distress (P=0.88) between DM and placebo. There were insignificantly higher numbers of grade ≥3 toxicities in patients who received DM than in patients who received placebo (20/42 vs. 18/47, p=0.37). Conclusions: Dexamethasone was more effective than placebo in reducing CRF in patients with advanced cancer. Long-term safety studies are needed.
Cluster-randomized trial of early palliative care for patients with metastatic cancer.
Authors: Zimmermann Camilla , Swami Nadia , Rodin Gary , Tannock Ian , Krzyzanowska Monika K. , Leighl Natasha B. , Oza Amit M. , Moore Malcolm J. , Rydall Anne , Donner Allan
Published: March 2020

9003

Background: Patients with metastatic cancer have compromised quality of life (QOL), which tends to worsen towards the end of life. We conducted a cluster-randomized trial of early versus routine palliative care in patients with metastatic cancer, to assess impact on QOL, symptom control and satisfaction with care. Methods: Twenty-four medical oncology clinics were randomized, stratified by tumour site (4 lung clinics, 8 gastrointestinal, 4 genito-urinary, 6 breast, 2 gynecological), to intervention and follow-up (at least monthly) by a palliative care team, or to routine cancer care. Eligible patients had ECOG performance status 0-2 and a clinical prognosis of 6 months to 2 years. Patients completed measures of QOL (FACIT-Sp, including physical, social, emotional, functional and spiritual well-being; range 0-156, with higher scores indicating better QOL), symptom severity (Edmonton Symptom Assessment System; range 0-90, with higher scores indicating worse symptom severity), and satisfaction with care (FAMCARE-P16; score range 16-80) at baseline and monthly for 4 months. The primary outcome was the change in FACIT-Sp at 3 months. The planned sample size was 225 patients per arm, assuming 80% power and a 2-sided significance level of 0.05. Results: From December 2006 to September 2010, 461 patients completed baseline measures (228 intervention, 233 control); 442 patients completed at least one follow-up assessment (mean patients/cluster 18.8±11.6 control, 18.1±12.6 intervention). At 3 months, patients in the intervention group had marginally improved QOL (mean change in intervention vs. control, 1.6±14.5 vs. -2.0±13.6, p=0.07) but not symptom severity (0.1±16.9 vs. 2.1±13.9, p=0.34). At 4 months the change in QOL was more marked (2.5±15.5 vs. -4.0±14.2, p=0.008) and symptom severity was marginally better (-1.3±16.0 vs. 3.2±13.9, p=0.05). Improvement in satisfaction with care was evident at one month (p=0.001) and remained significant at both 3 months (2.3±9.1 vs.-1.8±8.2, p=0.001) and 4 months (3.7±8.6 vs. -2.4±8.3, p<0.001). Conclusions: In patients with metastatic cancer, early palliative care intervention immediately improved satisfaction with care, while QOL and symptom control improved later.
ZOOM: A prospective, randomized trial of zoledronic acid (ZOL; q 4 wk vs q 12 wk) for long-term treatment in patients with bone-metastatic breast cancer (BC) after 1 yr of standard ZOL treatment.
Authors: Amadori Dino , Aglietta Massimo , Alessi Barbara , Gianni Lorenzo , Ibrahim Toni , Farina Gabriella , Gaion Fernando , Bertoldo Francesco , Santini Daniele , Rondena Roberta , Bogani Paola , Ripamonti Carla
Published: March 2020

9005

Background: ZOL (4 mg q 4 wk) is an established therapy for reducing the risk of debilitating skeletal-related events (SREs) in patients (pts) with bone metastases (mets) from BC. As BC treatments continue to improve pt survival, long-term SRE-reduction is increasingly important, and evaluation of modified ZOL dosing to retain efficacy with reduced adverse events (AEs) is warranted. Methods: ZOOM, a phase III prospective, randomized, open-label, multicenter study, assessed the safety and efficacy of quarterly (4 mg q 12 wk; Arm 1) vs monthly (4 mg q 4 wk; Arm 2) ZOL for ~1 yr in pts with BC who have ≥ 1 bone met, and have received ~1 yr of prior ZOL treatment (9 to 12 doses over ≤ 15 months; last dose ≤ 3 months prior). The primary endpoint was skeletal morbidity rate (SMR; number of SREs/pt/yr). Sample size to detect non-inferiority with 80% power (1-sided a = 0.025) was 420 pts. Secondary endpoints included time to first SRE, bone pain, bone marker (N-telopeptide of type I collagen; NTX) levels, and safety. Results: 425 pts were enrolled (209 in Arm 1; 216 in Arm 2); arms were well balanced for pt and disease characteristics, and anticancer therapies. SMR was similar between arms: 0.26 (95% confidence interval [CI] = 0.15, 0.37) in Arm 1 vs 0.22 (95% CI = 0.14, 0.29) in Arm 2; between-arms difference = 0.04 (upper limit of 1-tailed 97.5% CI = 0.17). Despite the proximity of 0.17 to the adjusted non-inferiority margin (0.19), the non-inferiority of Arm 1 vs 2 remains statistically significant. Safety analyses showed that ZOL was well tolerated. Renal AEs were reported in similar proportions of pts in both arms; 7 cases of osteonecrosis of the jaw were reported (1.65% overall; 4 cases in Arm 1 vs 3 in Arm 2). Conclusions: ZOOM is the first randomized trial to compare ZOL q 12 wk vs ZOL q 4 wk in BC pts after 1 yr of standard ZOL therapy. SMR was similar between arms. Limitations in study design suggest the need to confirm non-inferiority of ZOL q 12 wk in other ongoing phase III trials.
Cognitive function and fatigue in colorectal cancer (CRC) patients: A prospective longitudinal controlled study.
Authors: Vardy Janette L. , Dhillon Haryana M. , Pond Gregory Russell , Rourke Sean , Xu Wei , Renton Corrinne , Dodd Anna , Beale Philip James , Clarke Stephen John , Tannock Ian
Published: March 2020

9021

Background: A subset of cancer patients has cognitive impairment and fatigue after chemotherapy (CTh). We evaluated these symptoms and potential mechanisms in CRC patients and healthy controls (HC). Methods: Cognitive function was evaluated in CRC patients and HC at baseline (pre-CTh), 6 and 12 months. Group 1A (Stage II/III) received CTh and Gr 1B (Stage I/II) no CTh. Gr 2 had limited metastatic CRC. All subjects completed cognitive assessment and questionnaires for fatigue, QOL, anxiety/depression, and perceived cognitive function. Blood tests evaluated: 10 cytokines, clotting factors, sex hormones, CEA, CBC and apolipoprotein genotyping as potential causal factors. Primary endpoints: cognitive function and fatigue (Gr. 1A & 1B) at 12 months. Associations between results and demographic and disease-related factors were sought. Results: 359 CRC patients (173 Gr 1A, 116 Gr 1B, 70 Gr. 2) and 72 HC were assessed. Median age 58 (23-75 years); 58% male. Cognitive impairment: baseline Gr 1A 34% vs 1B 32.5% (p=.9), Gr 1 33% vs HC 10% (p<0.001); 12 months Gr 1A 21% vs 1B 16% (p=0.43), Gr 1 19% vs HC 2% (p=0.001). Cognitive domains most affected: verbal & visual memory, processing speed. Men had greater impairment than women (p<0.009). Cognitive decline from 0-12 months: Gr 1A 30%, Gr 1B 19%, Gr 2 24%, and HC 16%. Perceived cognitive impairment at 12 months: Gr 1A 19% vs 1B 7% (p=.04), Gr 1 14% vs HC 0% (p=.009). Fatigue was greatest in Gr 1A (70%) at 6 months; at 12 months Gr. 1A 46% vs 1B 31% (p=0.056), Gr 2 60%, HC 36%. Cytokines were elevated in CRC patients compared to HC. No association was found with cognitive function and: fatigue, QOL, anxiety/depression, cytokines, sex hormones, clotting factors, CEA or apoE genotype. Objective cognitive function was associated with perceived cognitive function at baseline only. Fatigue at baseline was associated with hemoglobin and at 12 months with neutrophil count. Conclusions: Compared to HC, CRC patients had more cognitive impairment at baseline, 6 and 12 months; but impairment was not significantly different between those who did and did not receive CTh. The mechanisms of cognitive impairment remain unknown. Fatigue improved with time.