bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical significance of nuclear kappa B and chemokine receptor CXCR4 expression in patients with diffuse large B-cell lymphoma.
Authors: Kang Byung Woog , Kim Jong Gwang , Chae Yee Soo , Lee Soo Jung , Sohn Sang Kyun , Moon Joon Ho , Choi Jun Young , Lee Yoo Jin , Baek Jin Ho
Published: March 2020

e18533

Background: This study investigated the activation of nuclear factor kB (NFkB) and the chemokine receptor CXCR4 co-expression in patients with diffuse large B-cell lymphoma (DLBCL) who received rituximab-based therapy. Methods: Seventy patients with DLBCL and treated with rituximab-CHOP (RCHOP) were included. Tissue microarray blocks were created from 70 cases of DLBCL. Sections were stained with antibodies to IKKα, p-IkB, p50, p52, and CXCR4. To classify cases of DLBCL into GCB (germinal center B-cell-like) and non-GCB, additional immunohistochemical expression of CD10, bcl-6, or MUM1 has been used in this study. A numeric intensity score of 0-3 was assigned each case. Negative was scored if 0/+1 and positive was scored if 2+/3+. Results: The median age was 66.5 years (range, 17-87) and 58.6% were male. Twenty-seven patients (38.6%) had stage III and IV at diagnosis. Twenty-three patients (32.9%) were categorized as high or high-intermediate risk according to their IPI. The overall incidence of BM involvement was 5.7%. Positive expression for NFkB and CXCR4 were more than 80%. In NFkB and CXCR4 status, there are no significant difference between GCB and non-GCB. High NFkB expression is associated with CXCR4 expression and they are co-expressed in about two thirds of patients. With a median follow-up duration of 28.7 months (range, 0.1-76.1), the 5-year overall survival (OS) and event-free survival (EFS) rate was 67.4% and 79.8%, respectively. Neither NFkB nor CXCR4 were associated with DLBCL outcomes. Conclusions: In concolusion, none of the NFkB and CXCR4 expression profiles investigated in this study was found to be an independent prognostic marker for Korean patients with DLBCL. However, further studies on a larger scale are warranted to clarify the role of NFkB and CXCR4 as a prognostic marker.
What is the significance of CCR5 status in HIV-associated non-Nodgkin lymphoma (NHL)?
Authors: Zaia John , Gaal Karl , Palmer Joycelynne , Li Shirley , Simpson Jennifer , Forman Stephen J. , Krishnan Amrita Y.
Published: March 2020

e18542

Background: The chemokine receptor CCR5 is a co-receptor for HIV. Carriers of the delta 32 gene (D32) mutation who lack CCR5 are protected from HIV infection by the R5 variant of the virus. Heterozygotes have slower progression to AIDS. For HIV NHL patients, the effects of the presence of the gene mutation are unclear. Methods: 93samples obtained from the ASCR (AIDS and Cancer Specimen Resource ) tissue bank of patients with HIV NHL were assayed for the presence of the mutation. We then studied if there was an association with the mutation and subtype of diffuse large cell lymphoma (DLBCL) (germinal center GC vs non GC), EBV status, or cell activation markers. Date of NHL diagnosis was from 1989 to 2005. Samples predating 1996 were characterized as pre HAART (highly active antiretroviral therapy) and all others post HAART. Results: There were 87 DLBCL, 3 plasmablastic lymphoma, 2 plasmacytoma and 1 anaplastic large cell T-cell subtype. Of the DLBCL, 48 were GC subtype and 39 were non GC subtype. GC subtype was 8.3 % (4/48) heterozygous for the D32. Non GCB subtype was 10.3 % (4/29) heterozygous. There was no difference in the percent heterozygosity for D32 pre or post HAART (14.8% vs 11.1%). The pre HAART specimens had greater EBV+ (44% vs 29% P=0.16) and more frequent BLIMP(B lymphocyte induced maturation protein) positivity ( 27% vs 17%. P=0.39) ). CCR5 heterozygous mutants were less often BLIMP positive (10% vs 21.4% P=0.68) and more often overexpressed p53 by immunostain (40% vs 23.9% P=0.47) compared to wild type CCR5. There was no correlation between EBV status and the presence of the mutation (36.3% vs 33.3%). Conclusions: CCR5 gene mutation status did not influence the subtype of DLCL. but the differences seen in BLIMP expression may have implications. Additional larger studies are needed to bear out suggested but statistically non-significant trends. BLIMP is a known repressor of p53. The overexpression of p53 and decreased BLIMP seen in CCR5 heterozygotes suggests alternate oncogenic pathways may be operative compared to wild type CCR5 lymphoma patients. Our ongoing clinical trial of HIV NHL pts undergoing transplant is assessing CCR5 status to see if there is a correlation with disease free and overall survival.
Autologous stem cell transplant in older patients with multiple myeloma (MM): Analysis of the nationwide inpatient sample (NIS).
Authors: Wildes Tanya Marya , Hellstrom Anita , Vij Ravi , Owens Pamela , Colditz Graham A.
Published: March 2020

e18551

Background: Autologous stem cell transplant (ASCT) improves survival in MM patients <65 years and is applied to select patients ≥ age 65. We hypothesized that comorbidities (CM) are associated with increased length of stay (LOS), hospital charges, toxicity, and in-hospital mortality in older patients with MM undergoing ASCT. Methods: This is a retrospective cohort study of patients over the age of 65 with MM admitted to U.S. hospitals for ASCT in the 2008 NIS. CM were coded using the Comorbidity Software; toxicities were determined by ICD-9-CM codes. Relationships between CM and toxicities, LOS, hospital charges, and in-hospital mortality were analyzed. Results: 206 patients MM ≥ 65 years who underwent ASCT were identified. Median age was 68 years (range 65-82). As defined by Elixhauser (Medical Care 1998), 83.5% of patients had ≥ 1 CM. Median LOS was 17 days (range 1-152). Median total charges were $162,998 (range $4289-$953,789). The most common complications coded were: neutropenic fever (29.6%), diarrhea (28.6%), bacteremia (13.6%), mucositis (8.7%) and pneumonia (6.8%). In-hospital mortality was <5% (precise percentage cannot be reported due to cell size <10). Elixhauser CM did not predict LOS, total charges, in-hospital mortality, or toxicities. When CM were restricted to those in the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI, Sorror et al 2005), only 35.4% of patients had CM. The presence of CM using a modified HCT-CI was associated with longer LOS (23.5 vs 17.6 days, p=0.0047) higher mean total charges [$189,896 (95% CI $154,333-225,459) vs $148,234 (95%CI $121,887-174,581), p=0.02] and increased risk of “complications of transplant” or “delirium” codes (p=0.035; precise percentage cannot be reported due to cell size <10). Conclusions: ASCT was well-tolerated with low in-hospital mortality in a population-based cohort of older patients with MM.The Elixhauser CM method did not predict outcomes. Using a modified HCT-CI CM index predicted longer LOS, greater hospital charges, and some toxicities, highlighting differences in the utility of different CM indices. Further investigation must define the optimal CM index for studying hematopoietic cell transplantation using administrative data.
Efficacy and safety of biosimilar epoetin alpha in treated patients with multiple myeloma.
Authors: Antolino Giusy , Moscetti Alessandro , Saltarelli Francesca , Monarca Bruno , Resci Federica , De Benedittis Daniela , Naso Virginia , Bianchi Maria Paola , La Verde Giacinto
Published: March 2020

e18563

Background: The biologic drugs are pharmaceutical products derived from living organisms through biotechnology. For some of the biotech drugs patent coverage is now decayed. This has allowed other companies to produce, at lower costs, similar products called biosimilar pharmaceuticals. Among the first biosimilar products marketed there were two growth factors, epoetin alpha and filgrastim. Methods: We retrospectively analyzed 15 chemo-treated patients with Multiple Myeloma (MM) referred to UOS Diagnosi e Cura delle Discrasie Plasmacellulari e delle Amiloidosi of Sant’Andrea Hospital in Rome, who were treated with biosimilar epoetin alpha between November 2010 and November 2011. In particular, 6 males and 9 females (median age 70 years) had started therapy with subcutaneous biosimilar epoetin alpha 40,000 IU weekly for haemoglobin level below 10 g/dl. In these patients, we evaluated the Hb levels before treatment, after 4 weeks and, in those who continued therapy, after 8 weeks from the drug administration start. Results: In all cases there was a significant and steady increase of Hb values: we observed an increase of 1 g/dl after 4 weeks in 80% of patients. In 5 of 11 patients the data are not available at 8 weeks because it was observed a so quick increase in Hb values as to cause discontinuation of treatment; in 100% of the remaining patients we observed an increase ≥2 g/dl after 8 weeks. None of patients needed supportive therapy with red blood cells transfusion. Although the duration of treatment in our patients was limited, we did not observe any adverse event in the short and medium term by the administration. Conclusions: The results reported do not fall in a comparative study and our initial data are still limited, however in our analysis biosimilar epoetin alpha was effective in increasing Hb values in MM patients against lower costs. It should be emphasized that this growth factor has been used in overtreated patients with impaired bone marrow reserve. In our analysis biosimilar epoetin alpha has shown efficacy and safety data to suggest the possibility of their use in alternative to biotech generators.
Preclinical activity of the JAK1/2 inhibitor ruxolitinib on malignant plasma cell growth and survival.
Authors: Burger Renate , Bugdahn Tim , Staudinger Matthias , Peipp Matthias , Günther Andreas , Gramatzki Martin
Published: March 2020

e18565

Background: In multiple myeloma, cytokines in the tumor environment, in particular interleukin-6 (IL-6), support the growth and survival of malignant plasma cells. Binding of IL-6 to its receptor leads to gp130 dimerization and activation of JAKs and STAT3. Ruxolitinib (INC424)is the first small molecule JAK inhibitor approved for the treatment of patients with myelofibrosis. The aim of our study was to evaluate the effects of ruxolitinib on malignant plasma cells. Methods: Cell growth was studied in seven myeloma cell lines including the IL-6 dependent INA-6. Ruxolitinib was tested at 0.0625 µmol/L to 8 µmol/L. Proliferation of plasma cell enriched patient samples was measured by [3]H-thymidine uptake, apoptosis by flow cytometry upon annexin V/7-AAD staining. Levels of STAT3 and ERK1/2 phosphorylation were determined by Westernblot analysis. IC50 concentrations and combination index were calculated with CalcuSyn. IL-6 levels were determined by ELISA. Results: A significant inhibition of plasma cell growth with ruxolitinib was achieved in IL-6 dependent INA-6 cells (IC50 0.22 µmol/L). Complete growth inhibition at 1 µmol/L was seen in the absence and presence of bone marrow stromal cells. Stromal cell viability and IL-6 production were not affected. The number of apoptotic INA-6 cells upon treatment with ruxolitinib at 1 µmol/L increased 3.6- and 7.2-fold (after 48 and 72 hours, respectively), consistent with the reduction of IL-6 induced STAT3 phosphorylation. A similar strong inhibitory activity of ruxolitinib (IC50 0.16 µmol/L) was observed in tumor cells of a patient with plasma cell leukemia proliferating in response to IL-6. In contrast, none of the myeloma cell lines that grow autonomously were sensitive, pointing to the kinase specificity of the drug. Using INA-6 as a model, combinations with other signaling inhibitors revealed additive to synergistic effects with PI3K, mToR and IGF-1R inhibitors. Conclusions: In multiple myeloma, ruxolitinib has a strong cytotoxic activity against malignant plasma cells that require IL-6 for growth and survival. This warrants further clinical testing but also points to the need of identifying molecular markers to predict benefit from JAK inhibitor treatment.
Epigenetic inactivation to target the arginine biosynthetic pathway in multiple myeloma.
Authors: Hatzimichael Eleftheria , Dasoula Aggeliki , Syed Nelofer , Szlosarek Peter Wojciech , Dranitsaris George , Crook Tim , Briasoulis Evangelos C.
Published: March 2020

e18567

Background: Argininoosuccinate synthetase-1 (ASS1) catalyses the rate-limiting step in arginine biosynthesis, the conversion of citruline to arginine. Argininosuccinate lyase (ASL) is an enzyme that catalyses the reversible breakdown of arginosuccinate producing arginine and fumerate. Arginine deprivation using arginine deiminase (ADI-PEG20) is currently considered as a novel therapeutic intervention for cancer. In this perspective, we investigated the methylation status of the ASS1 and ASL CpG islands in multiple myeloma (MM) and analyzed for clinical relevance. Methods: Genomic DNA was extracted from bone marrow aspirate samples from 46 MM patients (28 male, 18 female, median age 64 years) obtained at diagnosis. Methylation-specific PCR was employed to study the methylation in the ASS1 and ASL CpG islands. DNA was isolated and bisulphite modified using commercially available kits. Logistic regression analyses were used to measure the association between gene methylation and sex, age>65, ISS stage, presence of extramedullary disease, renal failure and bone disease. Kaplan-Meier curves were used to estimate the probabilities of survival and the Log-rank test to assess the statistical significance of differences in event rates. Results: Methylation in the CpG island of ASS1 was detected in 71.7% patients and of ASL in 37% patients, while simultaneous methylation in both genes was present in 10 patients. None of the two genes was detectably methylated in the control group. Patients with ASS1 methylation were less likely to have bone disease (p=0.04, OR=0.22) and extramedullary disease (p=0.05, OR=0.22) and a trend was also noted that these patients were less likely to be >65 years of age (p=0.2, OR=0.37). We did not detect any statistically significant difference in overall survival by methylation status of the studied genes in this small study size. Conclusions: We demonstrate for the first time that arginine biosynthesis genes ASS1 and ASL are methylated in MM.Methylation of ASS1 was found to be more frequent and negatively associated with bone or extramedullary disease. Further evaluation of ASS1 and ASL is warranted in MM and supports the expansion of arginine deprivation trials in these patients
Comparative response assessment by total serum IgM and IgM M-component in Waldenstrom’s macroglobulinemia.
Authors: Tripsas Christina , Ioakimidis Leukothea I , Hunter Zachary R , Patterson Christopher J , Manning Robert J , Sheehy Patricia S , Turnbull Barry , Treon Steven P.
Published: March 2020

e18575

Background: Changes in total IgM and the electrophoretically determined IgM M-component are used as surrogate serum response markers in Waldenstrom’s Macroglobulinemia (WM). Their ability to reflect underlying disease burden changes have not been compared. Methods: 73 rituximab-naïve patients were studied who underwent rituximab-based therapy on a study, and for whom serial total serum IgM levels, IgM M-component, and bone marrow (BM) assessments were available. Baseline: Median age 61 years; serum IgM 3,960 mg/dL; IgM M-component 2.55 g/dL; BM disease by core biopsy 60%. 5 patients had serum IgM levels <1,000 mg/dL, and 23 > 5,000 mg/dL. 39 patients had adenopathy and/or splenomegaly by baseline CT scans. Post-therapy, serum IgM declined from 3,960 to 1,800 mg/dL (p<0.0001); IgM M-component from 2.55 to 1.28 g/dL (p<0.0001); and BM involvement from 60% to 10% (p<0.0001). Among 39 patients with extramedullary disease, post-therapy CT scans were improved for 18, unchanged for 14, and worse for 7. Results: By linear regression analysis, reductions in serum total IgM and IgM M-component correlated with decreased BM disease involvement, though were relatively moderate (r=0.4490, p<0.0001; and r=0.4051; p=0.0004, respectively). To assess the difference between serum IgM and IgM M-component for correlation with BM response, an r to z transformation was performed. Serum IgM and IgM M-component were not significantly different as predictors for BM response (p=0.3745). Moreover, total serum IgM and the IgM M-component were poor estimators of BM response in patients with IgM levels <1,000 mg/dL (r=0.3635, p=0.2815 for serum IgM; r=0.1869, p=0.4672 for IgM M-component) or >5,000 mg/dL (r=0.0762, p=0.2022 for serum IgM; r=0.0306, p=0.4246 for IgM M-component). Extramedullary disease presence had no impact on serum IgM or IgM M-component correlations with BM disease involvement. Conclusions: Serum IgM levels and IgM M-component show similar correlations to changes in BM disease burden following therapy in WM patients, though overall the strength of these correlations are moderate, and particularly poor among patients with either low (<1,000 mg/dL) or high (>5,000 mg/dL) serum IgM levels.
The National Cancer Data Base report on the utilization of an adjuvant immunotherapy in stage III melanoma in relation to age.
Authors: Fredeking Arden , Venna Suraj S. , Jang Sekwon
Published: March 2020

e19000

Background: The 5-year survival of Stage III melanoma ranges from 30-70%. High dose interferon alfa-2b (IFN) is an adjuvant immunotherapy approved in 1995 for stage III melanoma, however, its use has been limited by its significant toxicity and modest benefit. We hypothesized the utilization of adjuvant immunotherapy is less in older age group compared to younger patients. Methods: Using the National Cancer Data Base (NCDB) aggregate data, demographic, socioeconomic, insurance information, and treatment data were analyzed. Proportions were compared using Pearson Chi squared tests. Results: From 2000-2008, 27,365 cases of stage III melanoma were reported to NCDB. Most patients were male (63%) and Caucasian (94.2%). Twenty-nine percent were over the age of 70. Educational and socioeconomic factors across all age groups were not significantly different. The primary insurer for patients younger than 60 was a managed care plan (54.3%) as compared to Medicare with supplemental insurance for patients older than 60 (47.4%). In terms of systemic therapy, 23% received immunotherapy alone, 6% received chemotherapy alone, 2% received both, and 66% received no therapy. When compared to patients under age 39, older age groups were significantly less likely to receive adjuvant immunotherapy as shown in the table below. Conclusions: There is an inverse relationship between age and the use of adjuvant immunotherapy. Further study is planned to adjust for comorbidity, socioeconomic status using patient-level data. [Table: see text]
Determination of the BRAF V600E mutation in Uruguayan melanoma patients.
Authors: Mazzei Maria Eugenia , Hochman Jimena , Manrique Gonzalo , Marino Ana Luisa , Delgado Lucia Beatriz , Martínez Miguel Angel ,   Cátedra de Dermatología
Published: March 2020

e19007

Background: Vemurafenib approval by the FDA determines a new era for the treatment of metastatic melanoma in those patients with BRAF V600E mutation. This mutation is reported in about 50% of melanomas and is more common in melanomas on skin without chronic sun induced damage. The aim of this study was to evaluate the frequency of BRAF V600E mutation in Uruguayan melanoma patients, in order to analyze whether the use of vemurafenib would impact on our population. Methods: Formalin fixed, paraffin embedded tissues from 27 primary cutaneous melanomas, were obtained from files of the the Dermatopathology Unit, Department of Dermatology, Hospital de Clínicas in Montevideo, Uruguay. Most were Superficial Spreading Melanomas from skin without chronic sun induced damage. Microdissection of melanoma cells from paraffin embedded tissue was performed under microscopic visualization using a micromanipulator equipment. ADN extraction was performed and the BRAF V600E was detected by ASO-PCR. Results: Of the 27 melanoma samples analyzed, we detected the BRAF V600E mutation in 21. This determines a 77.8% frequency of mutation, a higher percentage than reported in the literature. This could be explained in different ways. The demographic characteristics of Uruguayan population are very peculiar, complying with a genetic admixture of Europeans(mostly from Spain), Amerindians (10%) and alow percentage of Africans (6%), which could explain the high incidence of BRAF V600E mutation. On the other hand, these melanomas were from skin without chronic sun induced damage, this type of melanomas have the highest rate of mutation. Finally, this mutation was analyzed in samples microdissected from melanoma biopsies, the fact that the cells were precisely removed from the tumor could also explain the high frequency of mutation. Conclusions: In this study we found a high frequency of BRAF V600E mutation in Uruguayan malignant melanoma patients, this could be explained by population genetic admixture, the melanoma subtype or technical characteristics. Further studies comparing techniques should be performed in our country to clarify this point.
Phase I study of nab-paclitaxel (NP) in combination with biochemotherapy (BCT) in patients (pts) with metastatic melanoma (MM).
Authors: Alrwas Anas , Papadopoulos Nicholas E. , Cain Suzanne , Patel Sapna Pradyuman , Kim Kevin B. , Deburr Tawania L , Bassett Roland , Hwu Wen-Jen , Bedikian Agop Y. , Davies Michael A. , Woodman Scott Eric , Hwu Patrick
Published: March 2020

e19009

Background: NP has shown anti-tumor activity in MM in a phase II trial. The objective of this study was to determine MTD of NP as part of BCT, consisted of cisplatin (C), temozolomide (T), interleukin-2 (IL2) and interferon-alpha (IFN). Secondary objectives were to evaluate the anti-tumor activity of this combination in MM, and its benefit in preventing central nervous system (CNS) metastasis (mets). Methods: Previously untreated MM patients evaluable by RECIST 1.0 with no history of CNS mets between the ages of 18 and 65 and with ECOG 0-1 were enrolled. NP was given intravenously (IV) on Day (d) 1 and 5 of each cycle. The starting dose on d1 was 100 mg/ m2, and the dose on d5 was 70 mg/ m2, if toxicities permitted. The remainder of the regimen consisted of IV C 20 mg/ m2 daily d1-4, oral T 250 mg/ m2 d1-3, 9 million international units (MIU)/m2 of IL2 via continuous IV infusion for 96 hours, and IFN 5 MIU/m2 via subcutaneous injection d1-5. Treatment was repeated in cycles of 21 d to a maximum of 6 cycles. Prophylactic hematologic growth factors were not allowed in the first cycle. A standard 3+3 escalation method was used for NP d1 dose. Results: Ten pts were enrolled and evaluable for toxicities. Five completed six courses. Because 2 of 5 pts at the starting dose level had dose-limiting toxicities (DLTs) (diarrhea; transaminasemia-TA), the next cohort received d1 NP dose of 80mg/m2. Two of 5 pts at that dose level had DLTs (TA; neutropenia). Overall, the day 5 dose was omitted in 3 patients post third cycle due to thrombocytopenia (TP). There was no grade 5 toxicity. Common grade 3 and 4 toxicities were leucopenia, neutropenia, lymphopenia, anemia, TP, hyponatremia, diarrhea, skin rash, infection, tinnitus, neuropathy and TA. Five of 9 evaluable pts had partial response (PR). The median time-to-progression was 5.3 months (m). The median overall survival was 8.73 m. Six pts developed CNS mets with an overall median time of 5.33 m from treatment start. Conclusions: Additional studies are needed to determine the optimal dosing and schedule of NP as a part of BCT. Despite significant antitumor activity on sites outside the CNS, this combination therapy did not prevent the development of CNS mets.
Identification of melanoma-specific alterations in cell surface glycosylation.
Authors: Friedman Erica Brooke , Rakus John Frank , Zavadil Jiri , Hernando Eva , Mahal Lara K , Osman Iman
Published: March 2020

e19018

Background: Cell surface glycans, oligosaccharides present on proteins and lipids, play important roles in a range of biological processes. Our group recently reported on the role of aberrant glycosylation in promoting melanoma cell invasion and immunosuppression (Cancer Cell, 2011). In this study, we further exploit the ability of glycomic profiling of melanoma, using lectin microarrays, to identify differences in melanoma-associated glycosylation for new melanoma biomarkers and/or targets of treatment. Methods: We utilized a ratiometric dual colored 90-lectin microarray to examine differences in glycosylation between 13 primary and 14 metastatic melanoma cell lines, 5 human melanoma tissues and 4 human epidermal melanocytes (HEM). One HEM was used as a biological reference for hybridization. A subset of melanoma cell lines (n=4) was used for comparison with the glycomic profiles of the NCI-60 lines using a mixed reference. Hierarchical clustering of lectins with significant differences in binding to the sample sets (t-tests, p<0.05) was used to visualize and infer differences in glycosylation patterns. Results: A shift in the glycome related to reduction in expression of high mannose and core fucosylated complex N-glycans was seen in melanoma cell lines and tissues compared to HEMs. Glycomic profiles of primary and metastatic melanoma were similar. Interestingly, enrichment of high mannose and potentially a-2,3 sialic acid was seen in BRAF mutant (n=19) compared to BRAF wild type (n=8) cell lines. Our tested melanoma cell lines showed similar glycosylation patterns compared to melanoma lines of the NCI-60 panel, which all show higher expression of high mannose and complex N-glycans compared to other cancers. Comparison of melanoma cell lines to tissues shows similar glycomic profiles, suggesting that glycosylation of melanoma cells is not significantly altered (or blunted) due to culture. Conclusions: Our data suggest that alterations in cell surface glycosylation may be an early event in the malignant transformation of melanocytes to melanoma. Further analysis of the melanoma glycome will be needed to elucidate the biological implications and clinical potential of altered glycosylation.
Analysis of BRAF mutation status in high-risk malignant melanoma patients having received HD IFNa therapy in adjuvant setting.
Authors: Hlavata Zuzana , Salek Tomas , Andrezalova Iveta , Dolinsky Jozef , Svabova Veronika , Porsok Stefan , Berkovcova Jitka , Waczulikova Iveta
Published: March 2020

e19020

Background: Mutation in BRAF gene is considered to be a predictor of response to vemurafenib. However, it still remains to be demonstrated wheter BRAF mutational status is a prognostic factor in high risk melanomas. Methods: Between May 2003 till July 2011, there were 100 patients with a wide local excision of high risk malignant melanoma removed, who received HD IFNa adjuvant treatment. We retrospectively analyzed the data of 57 patients, who had determined BRAF V600 mutation status by real-time PCR assay (Cobas 4800 BRAF V600 Mutation Test). 48 patients were identified as a high-risk melanoma initialy, 9 after locoregional recurrence. Results: We have analysed samples from primary tumors (N35), lymph nodes (N16) and mets (N6). BRAF V600 mutation was found in 35 cases (61.4%). The median age was 52 yrs (range 19-66 yrs) in the whole group, in the subgroup of BRAF MT/WT it was 52.5/51 yrs (nonsignificant). The female/male ratio was 22/35, with no sex dependent differences for the BRAF MT or WT. The most frequent tumor stage T4N0M0 (29.8%) was the most common indication to the IFN treatment. The recurrence (distant mets) of melanoma was observed in 33 patients (57.8%); BRAF MT/WT 21 vs 12, HR 0.74, (95%CI 0.37-1.48) p =0.25. We observed 24 deaths (42.1%); BRAF MT/WT 16 vs 8, HR 0.72 (95%CI 0.32-1.62) p =0.46. We found a statistically significant higher risk of death associated with lower age in the whole group (p =0.006; OR =0,92). Logistic regression in the subgroup of BRAF MT patients revealed that the positivity of lymph nodes was associated with 5.6-times higher probability of death (OR =0.89, p =0.094). Additionally, a higher age was significantly associated with better overall survival (OS) p=0.012. On the other hand, in the subgroup of BRAF WT patients neither the age nor the positivity of lymph nodes influenced OS. Conclusions: We confirmed that BRAF mutation occurs in approximately 60% high-risk malignant melanomas. There were no statistically significant differences in DFS or OS between BRAF MT/WT form. However, our analysis corroborates the notion that BRAF MT patients have higher risk of death or recurrence, which we consider to be clinically relevant.
Multicentric ipilimumab experience in Turkish patients with metastatic melanoma: MIPI-TURK.
Authors: Sevinc Alper , Turna Hande , Ozdogan Mustafa , Buyukberber Suleyman , Demir Gokhan , Gokmen Erhan , Mandel Nil Molinas , Paydas Semra , Akbulut Hakan , Celik Ismail
Published: March 2020

e19024

Background: Ipilimumab, an anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen) monoclonal antibody has been shown to enhance immune responses and induce durable clinical responses in patients with metastatic melanoma. The authors report retrospectively on metastatic melanoma patients treated under Expanded Access Program in Turkey among 13 centers. Methods: Patients with metastatic melanoma were treated with ipilimumab 3 mg/kg for 4 doses on weeks 1, 4, 7, 10 as induction. Response evaluation was done on week 12. Patients with complete response (CR), partial response (PR) and stable disease (SD) at week 12 were eligible for re-induction. Results: A total of 75 patients enrolled with 70 evaluable. Ipilumumab treatment was given as 2nd, 3rd and 4th line in 20.0%, 64.3% and 15.7% of patients respectively. The numbers of patients receiving ipilimumab for 1, 2, 3 and 4 doses were 9, 12, 13 and 36, respectively. Seven of 70 patients were eligible for re-induction. G1/2 adverse events were reported in 32.8% (23/70) of patients whereas G3/4 was 14.3% (10/70). The most common G1/2 immune related adverse event was skin rash (14.3%) followed by muscle weakness (10.0%) and gastrointestinal side effects (8.6%). There were seven G3 side effects (diarrhea in 4, muscle weakness in 1, hypothyroidism in 1 and GI bleeding in 1 patient). There was one reversible G4 thrompocytopenia and two deaths were associated with hepatic AEs. Thirty-six of 70 patients (51.4%) completed 4 doses ipilimumab treatment were available for response evaluation. There was no CR. The disease control rate (DCR) was 36.1% (PR: 8.3% and SD 27.8%). Median time to progression (TTP) was 2.7 months (95% CI, 2.1-4.2 months). Median overall survival was not reached with 61.3% of patients surviving within 12 months of follow up period. Conclusions: As a conclusion, ipilimumab treatment resulted in favorable clinical benefit for metastatic melanoma patients. Data generated by our 13 centers revealed an efficacy and safety profile consistent with the currently avaliable knowledge.
Prognostic significance of metastatic cascade in melanoma.
Authors: Kidner Travis Brad , Yoon Jeong Lim , Faries Mark B. , Morton Donald L.
Published: March 2020

e19029

Background: The ability of metastases to spawn subsequent generations of metastatic lesions is controversial, and its prognostic significance is unknown. We hypothesize that melanoma metastases that have spread to draining lymph nodes will have a worse prognosis than those that have not. Methods: One hundred consecutive patients who had undergone pulmonary resection for metastatic melanoma and who had concomitant hilar and/or mediastinal lymph node evaluation available were identified. Patient demographics, tumor characteristics, mediastinal lymph node status, and overall survival were analyzed. Results: 100 patients (71%) were male and the mean age at metastasectomy was 55 years (mean age at diagnosis 47 years.) The average Breslow thickness was 2.43mm (range 0.46 – 20.55). Twenty-one (21%) of the patients had evidence of metastatic disease present in regional lymph nodes during pulmonary resection. The 5-year overall survival for patients with positive mediastinal lymph nodes was 16% versus 36% with node negative disease (p=0.0005). On multivariate analysis, age at pulmonary resection (HR 1.018, 95% CI 1.002-1.035) and regional lymph nodes status (HR 3.203, 95% CI 1.774-5.781) were found to be independent prognostic indicators of 5-year overall survival. Conclusions: Regional lymph node status is an important prognostic factor in patients with pulmonary metastatic melanoma, and regional nodal assessment should be considered during metastasectomy. The metastatic cascade appears to be a strong prognostic factor in melanoma.
Neuropsychiatric side effects of high-dose IL-2 on patient with advanced melanoma or renal cell carcinoma.
Authors: Ray Vani , Guan Ran , Treisman Jonathan S , Nilakantan Vani , Chen Han Yang , Sinha Ishan , Offutt Julie
Published: March 2020

e19030

Background: Treatment of patients with end stage renal cell carcinoma (RCC) or melanoma remains difficult. Immunotherapy with high-dose bolus interleukin (IL-2) is the first biological product clinically approved for the treatment of these cancers. Although effective in 15-20% of patients, high-dose IL-2 treatment has significant neuropsychiatric side effects that mandate treatment cessation. Currently, there is little information available on patients who are prone to these neuro-psychiatric side effects. The main objective was to investigate whether occult brain metastases predispose the patient to developing neuro-psychiatric side effects. Methods: We performed retrospective medical chart reviews of patients who had either RCC or malignant melanoma. Variables considered include patient demographics, cancer type, IL-2 treatment, response to treatment, location of metastasis, prior surgery, prior psychiatric history, and substance abuse. We conducted multivariable log-binomial regression analyses to examine the association between risk factors and neuro-psychiatric side effects. Results: Our study population included 261 cancer patients, among them 54% had melanoma (N=141) and 31% had post neuro-psychiatric disorders (N=81). We found that nicotine abstinence in past smokers (remission) was significantly associated with increased neuro psychiatric side-effects (RR=1.88, P=.015) among melanoma patients, but not RCC patients. The multivariable regression analysis showed that having pre-existing psychiatric disorders was the only factor significantly associated with neuropsychiatric effects (aRR=1.92, P<0.0001), after adjusting for potential confounders. Having brain metastasis, however, was not significantly associated with neuropsychiatric effects (aRR=1.10, P=0.627). Conclusions: Contrary to our original hypothesis, prior psychiatric history was the only significant factor predisposing patients to develop neuro-psychiatric side effects during IL-2 treatment and not occult brain metastases. Future studies with larger patient numbers and longitudinal design will help to refine the findings from this research.
Systemic therapy in advanced cutaneous squamous cell carcinoma (CSCC): The Roswell Park experience.
Authors: Jarkowski Anthony , Hare Ryan B , Loud Peter , Skitzki Jospeh J. , Kane John Michael , Salerno May Kilian , Zeitouni Nathalie , Nestico Jill , Vona Karen L , Groman Adrienne E. , Khushalani Nikhil I.
Published: March 2020

e19041

Background: Treatment of locally advanced unresectable (LAU) or metastaticCSCC (mCSCC) is sub-optimal with a paucity of robust data on systemic therapy. Platinum or fluorouracil-based chemotherapy is commonly used. This retrospective study aimed to evaluate the efficacy and outcomes of patients (pts) with LAU or mCSCC treated with systemic therapy. Methods: Records ofpts with CSCC treated with systemic therapy from Jan ‘01 – Jan ‘11 were reviewed. Response was assessed using WHO criteria. Descriptive results were assessed using Wilcoxon Rank Sum test for ordinal responses and Pearson Chi-square test for categorical responses. Survival was calculated by the Kaplan-Meier method. Results: Of 28 pts identified, 25 pts (M:F – 18:7), median age 66 yrs (39, 85) had required data for final analysis. 11 pts (44%) had facial primary tumors (including 7 of the external ear). 19 pts (76%) had LAU and 6 pts had mCSCC. 17 pts (68%) received multi-agent 1st-line chemotherapy (CT). 72%, 76% and 48% pts received platinum, taxane or cetuximab respectively as part of their regimens. 14 pts got 2nd line therapy and 4 pts received concurrent radiation therapy. Partial response (PR) was 44% and 24% pts had stable disease (SD) for a disease control rate of 68%. With a median follow-up of 42.8m, the median progression-free (PFS) and overall survival (OS) were 5.5m (2.3, 13.2) and 10.9m (5.3, 21.3) respectively; 3-yr OS was 22%. Pts with WHO response had improved PFS (20.8m; 4.4, NR; p<.0001) and OS (37.5m; 10.3, NR; p=.0003) compared to pts with SD/PD (PFS 2.7m; OS 5.9m). Use of platinum-based therapy significantly improved PFS and OS, while taxanes and cetuximab had no impact in this small cohort. 91% (n=10) of pts who had a PR received a platinum drug. There was no difference in PFS or OS between face and non-face primary site CSCC and multi-agent versus single agent therapy. Conclusions: Platinum-based therapy remains a standard option in advanced CSCC management. Agents to improve response rates are needed and future trials should address the role of other therapies in CSCC, including novel targeted and CT combinations.
DTIC and GM-CSF in the treatment of patients with metastatic melanoma.
Authors: Barber Beth , Zhao Zhongyun , Wang Song , Wagner Volker Jean
Published: March 2020

e19045

Background: To describe patients with metastatic melanoma being treated with mono-therapy, dacarbazine (DTIC) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Methods: Using a large U.S. medical claims database, patients were identified between 2005 and 2010 using ≥2 melanoma diagnoses (ICD-9-CM: 172.xx, V10.82) and ≥2 diagnoses for metastasis (ICD-9-CM: 197.xx, 198.xx). Patients who received mono-therapy with DTIC or GM-CSF as the first documented drug therapy after metastatic diagnosis were identified. Patient demographic and clinical characteristics and treatment duration were compared between patients treated with DTIC and those who received GM-CSF. Furthermore, comparisons were also made between the two treatment groups after 1-to-1 matching on age, gender, and baseline comorbidities. Results: A total of 81 patients with metastatic melanoma receiving first-line DTIC and 24 patients with metastatic melanoma receiving first-line GM-CSF were included in this analysis. On average, DTIC patients were 8.5 years older (p = 0.009) and had higher baseline Charlson Comorbidity Index scores (D0.43, p = 0.005) than GM-CSF patients. The mean duration of first line treatment was 94 days on DTIC and 135 days on GM-CSF. The mean length of follow-up from the start of first line was 257 days on DTIC and 451 days on GM-CSF. After each GM-CSF patient was matched with a DTIC patient on age, gender, and baseline Charlson Comorbidity Index score, the mean duration of first line treatment was 79 days on matched DTIC and 135 days on GM-CSF, and the mean length of follow-up from the start of first line was 317 days on matched DTIC and 451 days on GM-CSF. Conclusions: Patients with metastatic melanoma who received DTIC treatment were older and had higher comorbidity index scores but shorter treatment duration than those who received GM-CSF; the difference in treatment duration remained after DTIC patients were matched with GM-CSF patients on age, gender and comorbidity index scores.
Immune monitoring of phase II trial of hu14.18-IL2 for patients with metastatic melanoma.
Authors: Albertini Mark R. , Hank Jacquelyn A , Gadbaw Brian Christopher , Kostlevy Jordan , Haldeman Jennifer , Gan Jacek , Kim KyungMann , Eickhoff Jens C. , Gillies Stephen , Sondel Paul M.
Published: March 2020

e19047

Background: Phase I testing of the hu14.18-IL2 immunocytokine (IC) in patients (pts) with melanoma showed immune activation, reversible toxicities, and a maximal tolerated dose (MTD) of 7.5 mg/m2/day. Methods: In this phase II study, 14 metastatic melanoma pts were scheduled to receive hu14.18-IL2 at 6 mg/m2/day as 4-hour intravenous infusions on days 1, 2 and 3 of each 28 day cycle. Pts with stable disease (SD) or regression following cycle 2 could receive 2 additional treatment cycles. The primary objective was to evaluate anti-tumor activity and response duration. Secondary objectives evaluated adverse events and immunologic activation. Results: All pts received 2 cycles of treatment. One pt had a partial response (PR) [1 PR of 14 pts = response rate of 7.1%; confidence interval 0.2%-33.9%] and 4 pts had SD and received cycles 3 and 4. The PR and SD responses lasted 3-4 months. All toxicities were reversible. Analysis of serum IC for all pts showed a mean value of 1.42 ug/ml on C1D1 and 1.38 ug/ml on C1D3. Pts had a peripheral blood lymphocytosis on day 8 and increased C-reactive protein (CRP). A significant increase in sIL2R levels was seen in all courses from baseline to day 3 (p<0.001 for both courses 1 and 2). Infusion of the IC into these pts enabled their serum to mediate antibody dependent cell-mediated cytotoxicity using the circulating IC. Eight pts developed a “positive” anti-idiotype antibody against hu14.18-IL2 based on a bridging assay, and 13 developed a detectible anti-idiotypic antibody based on a binding inhibition assay. There was no significant effect of this anti-idiotypic antibody response on the in vivo level of hu14.18-IL2. While one PR in 14 pts met protocol criteria to proceed to stage 2 and enter 16 additional pts, we suspended stage 2 due to limited availability of hu14.18-IL2 at that time and the brief duration of PR and SD. Conclusions: We conclude that subsequent testing of hu14.18-IL2 should involve melanoma pts with minimal residual disease based on compelling preclinical data as well as the confirmed immune activation with some antitumor activity in this study. In addition, the demonstrated immunological activation of hu14.18-IL2 with manageable toxicities suggests the potential for combination treatments.
Evaluation of mobile gamma camera imaging in sentinel lymph node biopsy for melanoma independent of pre-operative lymphscintigraphy.
Authors: Judge Joshua Marshall , Slingluff Craig L. , Dengel Lynn Thacher , Williams Mark , Popovic Kosta
Published: March 2020

e19062

Background: Sentinel lymph node biopsy (SLNB) is the standard method for staging cutaneous melanoma and involves identifying the first node(s) draining a tumor, by detecting an intradermally-injected radioactive colloid tracer. Intra-operatively the sentinel node(s) are identified with a hand-held gamma probe. Pre-operative lymphoscintigraphy is obtained to identify draining lymph node basins, but requires coordinating schedules between nuclear medicine and the operating room. A pilot study utilizing Mobile Gamma Camera (MGC) devices in conjunction with conventional lymphoscintigraphy for intraoperative sentinel node localization provided clinical benefit in 20% of patients. However, utilizing MGC devices to localize lymph node basins at the time of surgery independent of conventional lymphoscintigraphy with a fixed gamma camera (FGC) has not been adequately studied. Here, we present the results of a clinical trial utilizing MGC devices to localize lymph node basins in a manner blinded to the FGC images in order to compare the modalities directly. Methods: In 2011-12 18 patients underwent Tc99 sulfur colloid lymphoscintigraphy, and MGC survey immediately pre-operative by the study surgeon. The study surgeon established an operative plan using the MGC survey, while blinded to lymphoscintigraphy results. SLNB was then performed with use of a gamma probe and intra-operative MGC imaging. Results: 22 lymph node basins were detected in 18 imaged patients by lymphoscintigraphy. All of these basins were identified by the study surgeon using the MGC device in the pre-operative setting prior to un-blinding. In every case the operative plan established based on pre-operative MGC imaging was confirmed by the FGC images. In two cases, additional information from the MGC images aided surgical decision-making. 5 of 22 lymph node basins were positive for metastasis. All of these basins were identified by pre-operative MGC imaging, and all individual positive nodes were identified by intra-operative MGC imaging. Conclusions: Pre-operative MGC imaging in sentinel lymph node biopsy can provide comparable information for operative planning, compared to standard FGC imaging.
Ambulatory serial drainage of ascitis or pleural effusion by a multiperforated catheter port system.
Authors: Polycarpe Emmanuel Mohandas , Meunier Katy Luce
Published: March 2020

e19500

Background: Symptomatic pleural effusion or recurrent ascitis effusions are frequent in end-stage malignancies, induce serial drainage and impair quality of live. Methods: We report our experience with a multiperforated 10 Fr silicone catheter totally implanted in pleural or peritoneal cavities, by Seldinger access, connected to a subcutaneous port system surgically implanted, with local anaesthesia. To avoid tumour seeding along the catheter , it is used a purse string technique to water-tight the entry point of catheter. Patient on demand serial drainage of serosal effusion by percutaneous access to the port can be performed in outpatient department. To reduce risk of device obstruction, we rinse with saline serum under pressure to generate a turbulent outflow to flush any deposit after drainage. Results: Between January 2008 and April 2010, 28 patients underwent implants of 12 peritoneal and 18 pleural (2 bilateral) implantable multiperforated catheter port systems with a prospective follow up. There were 10 men and 18 women with a mean age of 64 years (range: 39-84 years). Primary malignancies were breast (9), pancreas (4), ovarian (4), stomach (2), endometrial (2), kidney (2), skin melanoma (2), prostate (1), peritoneum (1), and lymphoma with cardiac insufficiency (1). Twenty-seven patients obtained partial or complete relief of their symptoms. The number of aspirations performed was between 2 and 25 over a period of 8 to 454 days for 2,560 days of catheter implantation. Eight patients died within 3 weeks after placement of the system and 6 survived more than 6 months. One case of pneumothorax has been diagnosed after early symptoms recurrence and successfully aspirated throw the port. One case of infection of pleural fluid had been detected by systematic bacteriological sampling without clinical manifestation. One case of port infection was du to a previous asymptomatic infection of ascitis with multiple fluid collections and requires port removal. No case of tumour seeding or port system obstruction was observed. Conclusions: This outpatient management palliative technique is an easy option with high rate of efficacy, safety and comfort to control symptoms induced by pleural or ascitis recurrent effusion.