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Sample records for melanoma patients vaccinated

  1. Ipilimumab administered to metastatic melanoma patients who progressed after dendritic cell vaccination

    PubMed Central

    Boudewijns, Steve; Koornstra, Rutger H. T.; Westdorp, Harm; Schreibelt, Gerty; van den Eertwegh, Alfons J. M.; Geukes Foppen, Marnix H.; Haanen, John B.; de Vries, I. Jolanda M.; Figdor, Carl G.; Bol, Kalijn F.; Gerritsen, Winald R.

    2016-01-01

    ABSTRACT Background: Ipilimumab has proven to be effective in metastatic melanoma patients. The purpose of this study was to determine the efficacy of ipilimumab in advanced melanoma patients who showed progressive disease upon experimental dendritic cell (DC) vaccination. Methods: Retrospective analysis of 48 stage IV melanoma patients treated with ipilimumab after progression upon DC vaccination earlier in their treatment. DC vaccination was given either as adjuvant treatment for stage III disease (n = 18) or for stage IV disease (n = 30). Ipilimumab (3 mg/kg) was administered every 3 weeks for up to 4 cycles. Results: Median time between progression upon DC vaccination and first gift of ipilimumab was 5.4 mo. Progression-free survival (PFS) rates for patients that received ipilimumab after adjuvant DC vaccination, and patients that received DC vaccination for stage IV melanoma, were 35% and 7% at 1 y and 35% and 3% at 2 y, while the median PFS was 2.9 mo and 3.1 mo, respectively. Median overall survival of patients pre-treated with adjuvant DC vaccination for stage III melanoma was not reached versus 8.0 mo (95% CI, 5.2–10.9) in the group pre-treated with DC vaccination for stage IV disease (HR of death, 0.36; p = 0.017). Grade 3 immune-related adverse events occurred in 19% of patients and one death (2%) was related to ipilimumab. Conclusions: Clinical responses to ipilimumab were found in a considerable number of advanced melanoma patients with progression after adjuvant DC vaccination for stage III disease, while the effect was very limited in patients who showed progression after DC vaccination for stage IV disease. PMID:27622070

  2. Vaccination with Irradiated Autologous Melanoma Cells Engineered to Secrete Human Granulocyte--Macrophage Colony-Stimulating Factor Generates Potent Antitumor Immunity in Patients with Metastatic Melanoma

    NASA Astrophysics Data System (ADS)

    Soiffer, Robert; Lynch, Thomas; Mihm, Martin; Jung, Ken; Rhuda, Catherine; Schmollinger, Jan C.; Hodi, F. Stephen; Liebster, Laura; Lam, Prudence; Mentzer, Steven; Singer, Samuel; Tanabe, Kenneth K.; Benedict Cosimi, A.; Duda, Rosemary; Sober, Arthur; Bhan, Atul; Daley, John; Neuberg, Donna; Parry, Gordon; Rokovich, Joseph; Richards, Laurie; Drayer, Jan; Berns, Anton; Clift, Shirley; Cohen, Lawrence K.; Mulligan, Richard C.; Dranoff, Glenn

    1998-10-01

    We conducted a Phase I clinical trial investigating the biologic activity of vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte--macrophage colony-stimulating factor in patients with metastatic melanoma. Immunization sites were intensely infiltrated with T lymphocytes, dendritic cells, macrophages, and eosinophils in all 21 evaluable patients. Although metastatic lesions resected before vaccination were minimally infiltrated with cells of the immune system in all patients, metastatic lesions resected after vaccination were densely infiltrated with T lymphocytes and plasma cells and showed extensive tumor destruction (at least 80%), fibrosis, and edema in 11 of 16 patients examined. Antimelanoma cytotoxic T cell and antibody responses were associated with tumor destruction. These results demonstrate that vaccination with irradiated autologous melanoma cells engineered to secrete granulocyte--macrophage colony-stimulating factor stimulates potent antitumor immunity in humans with metastatic melanoma.

  3. NGcGM3/VSSP vaccine as treatment for melanoma patients.

    PubMed

    Pérez, Kirenia; Osorio, Marta; Hernández, Julio; Carr, Adriana; Fernández, Luis Enrique

    2013-06-01

    Gangliosides are glycosphingolipids that are present in the plasma membranes of vertebrates and are involved in multiple cellular processes. In the Center of Molecular Immunology an NGcGM3 ganglioside based vaccine has been developed and is conceptualized as a targeted therapy in cancer. NGcGM3/VSSP vaccine had been used as treatment of metastatic melanoma patients and had showed to be safe and immunogenic. The treatment improved antitumoral response or maintain the response obtained with previous onco-specific treatment as chemotherapy. The results indicate that the vaccine improved overall survival of metastatic melanoma patients after first line-chemotherapy. The clinical trial ongoing currently will allow corroborating these results.

  4. Effect of vaccination with N-glycolyl GM3/VSSP vaccine by subcutaneous injection in patients with advanced cutaneous melanoma.

    PubMed

    Osorio, Marta; Gracia, Elias; Reigosa, Edmundo; Hernandez, Julio; de la Torre, Ana; Saurez, Giselle; Perez, Kirenia; Viada, Carmen; Cepeda, Meylán; Carr, Adriana; Avila, Yisel; Rodríguez, Migdalia; Fernandez, Luis E

    2012-01-01

    NeuGc-containing gangliosides have been described in melanoma cells and are an attractive target for cancer immunotherapy because they are minimally or not expressed in normal human tissues. Melanoma patients treated with a vaccine based on N-glycolyl gangliosides have shown benefit in progression free survival and overall survival. We conducted a multicenter Phase I/II clinical trial in patients with metastatic cutaneous melanoma treated with the N-gycolyl GM3/very-small-size proteoliposomes vaccine by the subcutaneous route. Selecting the optimal biological dose of the vaccine was the principal objective based on immunogenicity, efficacy, and safety results. Six dose levels were studied and the treatment schedule consisted of five doses administered every 2 weeks and then monthly until 15 doses had been given. Dose levels evaluated were 150, 300, 600, 900, 1200, and 1500 μg with five patients included in each dose level except the 900 μg dose (n = 10). Immunogenicity was determined by antibody titers generated in patients after vaccination. Antitumor effect was measured by response criteria of evaluation in solid tumors and safety was evaluated by common toxicity criteria of adverse events. The vaccine was safe and immunogenic at all doses levels. The most frequent adverse events related to vaccination were mild to moderate injection site reactions and flu-like symptoms. Vaccination induced specific anti-NeuGcGM3 immunoglobulin M and immunoglobulin G antibody responses in all patients. Disease control (objective response or stable disease) was obtained in 38.46% of patients. Global median overall survival was 20.20 months. Two patients achieved overall survival duration of about 4 and 5 years, respectively. The 900 μg dose resulted in overall survival duration of 19.40 months and was selected as the biological optimal dose.

  5. Inoculation Site from a Cutaneous Melanoma Patient Treated with an Allogeneic Therapeutic Vaccine: A Case Report

    PubMed Central

    Aris, Mariana; Bravo, Alicia Inés; Barrio, María Marcela; Mordoh, José

    2015-01-01

    We have developed a therapeutic vaccine consisting of a mixture of lethally-irradiated allogeneic cutaneous melanoma cell lines with BCG and GM-CSF as adjuvants. The CSF-470 vaccine is currently being assayed in a Phase II–III trial against medium-dose IFN-α2b. All vaccinated patients immunized intradermally developed large edematous erythema reactions, which then transformed into subcutaneous nodules active for several months. However, vaccine injection sites were not routinely biopsied. We describe the case of a female patient, previously classified as stage III, but who, due to the simultaneous discovery of bone metastases only received one vaccination was withdrawn from the study, and continued her treatment elsewhere. This patient developed a post-vaccination nodule which was surgically removed 7 weeks later, and allowed to analyze the reactivity and immune profiling of the inoculation site. An inflammatory reaction with zones of fibrosis, high irrigation, and brisk lymphoid infiltration, primarily composed of CD8+ and CD20+ lymphocytes, was observed. There were no remaining BCG bacilli, and scarce CD4+ and Foxp3+ T cells were determined. MART-1 Ag was found throughout the vaccination site. CD11c+ Ag presenting cells were either dispersed or forming dense nests. Some CD11c+ cells proliferated; most of them contained intracellular MART-1 Ag, and some interacted with CD8+ lymphocytes. These observations suggest a potent, long-lasting local inflammatory response with recruitment of Ag-presenting cells that incorporate melanoma Ags, probably leading to Ag presentation to naïve T cells. PMID:25870600

  6. Epacadostat and Vaccine Therapy in Treating Patients With Stage III-IV Melanoma

    ClinicalTrials.gov

    2017-01-18

    Mucosal Melanoma; Recurrent Melanoma; Recurrent Uveal Melanoma; Stage IIIA Skin Melanoma; Stage IIIA Uveal Melanoma; Stage IIIB Skin Melanoma; Stage IIIB Uveal Melanoma; Stage IIIC Skin Melanoma; Stage IIIC Uveal Melanoma; Stage IV Skin Melanoma; Stage IV Uveal Melanoma

  7. Vaccine Therapy in Treating Patients With Stage IIC-IV Melanoma

    ClinicalTrials.gov

    2014-05-20

    Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Extraocular Extension Melanoma; Iris Melanoma; Metastatic Intraocular Melanoma; Mucosal Melanoma; Recurrent Intraocular Melanoma; Recurrent Melanoma; Stage IIC Melanoma; Stage IIIA Intraocular Melanoma; Stage IIIA Melanoma; Stage IIIB Intraocular Melanoma; Stage IIIB Melanoma; Stage IIIC Intraocular Melanoma; Stage IIIC Melanoma; Stage IV Intraocular Melanoma; Stage IV Melanoma

  8. Booster Vaccination in Preventing Disease Recurrence in Previously Vaccinated Patients With Melanoma That Has Been Removed By Surgery

    ClinicalTrials.gov

    2015-01-23

    Recurrent Melanoma; Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma

  9. Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients

    PubMed Central

    Boudewijns, Steve; Bol, Kalijn F.; Schreibelt, Gerty; Westdorp, Harm; Textor, Johannes C.; van Rossum, Michelle M.; Scharenborg, Nicole M.; de Boer, Annemiek J.; van de Rakt, Mandy W. M. M.; Pots, Jeanne M.; van Oorschot, Tom G. M.; Duiveman-de Boer, Tjitske; Olde Nordkamp, Michel A.; van Meeteren, Wilmy S. E. C.; van der Graaf, Winette T. A.; Bonenkamp, Johannes J.; de Wilt, Johannes H. W.; Aarntzen, Erik H. J. G.; Punt, Cornelis J. A.; Gerritsen, Winald R.; Figdor, Carl G.; de Vries, I. Jolanda M.

    2016-01-01

    ABSTRACT Purpose: To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients. Experimental design: Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8+ T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines. Results: Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8+ T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100:154–162, gp100:280–288, and tyrosinase:369–377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100:154–162, gp100:280–288, and tyrosinase:369–377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0 mo and 36.8 mo, respectively. Conclusions: DC vaccination induces a functional TAA-specific T cell response in the majority of stage III melanoma patients, indicating it is more effective in stage III than in stage IV melanoma patients. Furthermore, performing multiple cycles of vaccinations enhances the chance of a broader immune response. PMID:27622047

  10. Rapid and Continued T-Cell Differentiation into Long-term Effector and Memory Stem Cells in Vaccinated Melanoma Patients.

    PubMed

    Gannon, Philippe O; Baumgaertner, Petra; Huber, Alexandre; Iancu, Emanuela M; Cagnon, Laurène; Abed Maillard, Samia; Maby-El Hajjami, Hélène; Speiser, Daniel E; Rufer, Nathalie

    2016-11-21

    Purpose: Patients with cancer benefit increasingly from T-cell-based therapies, such as adoptive T-cell transfer, checkpoint blockade, or vaccination. We have previously shown that serial vaccinations with Melan-A(MART-1)26-35 peptide, CpG-B, and incomplete Freund adjuvant (IFA) generated robust tumor-specific CD8 T-cell responses in patients with melanoma. Here, we describe the detailed kinetics of early- and long-term establishment of T-cell frequency, differentiation (into memory and effector cells), polyfunctionality, and clonotype repertoire induced by vaccination.Experimental Design: Twenty-nine patients with melanoma were treated with multiple monthly subcutaneous vaccinations consisting of CpG-B, and either the native/EAA (n = 13) or the analogue/ELA (n = 16) Melan-A(MART-1)26-35 peptide emulsified in IFA. Phenotypes and functionality of circulating Melan-A-specific CD8 T cells were assessed directly ex vivo by multiparameter flow cytometry, and TCR clonotypes were determined ex vivo by mRNA transcript analyses of individually sorted cells.Results: Our results highlight the determining impact of the initial vaccine injections on the rapid and strong induction of differentiated effector T cells in both patient cohorts. Moreover, long-term polyfunctional effector T-cell responses were associated with expansion of stem cell-like memory T cells over time along vaccination. Dominant TCR clonotypes emerged early and persisted throughout the entire period of observation. Interestingly, one highly dominant clonotype was found shared between memory and effector subsets.Conclusions: Peptide/CpG-B/IFA vaccination induced powerful long-term T-cell responses with robust effector cells and stem cell-like memory cells. These results support the further development of CpG-B-based cancer vaccines, either alone or as specific component of combination therapies. Clin Cancer Res; 1-12. ©2016 AACR.

  11. A Randomized Phase II Trial of Multi-epitope Vaccination with Melanoma Peptides for Cytotoxic T-Cells and Helper T-Cells for Patients with Metastatic Melanoma (E1602)

    PubMed Central

    Slingluff, Craig L.; Lee, Sandra; Zhao, Fengmin; Chianese-Bullock, Kimberly A.; Olson, Walter; Butterfield, Lisa H.; Whiteside, Theresa; Leming, Philip D.; Kirkwood, John M.

    2013-01-01

    Purpose This multicenter randomized trial was designed to evaluate whether melanoma helper peptides augment cytotoxic T-lymphocyte (CTL) responses to a melanoma vaccine and improve clinical outcome in patients with advanced melanoma. Patients and Methods One hundred seventy-five patients with measurable stage IV melanoma were enrolled into 4 treatment groups, vaccinated with 12 MHC Class I-restricted melanoma peptides (12MP) to stimulate CTL (group A), plus a tetanus peptide (group B) or a mixture of 6 melanoma helper peptides (6MHP, group C) to stimulate helper T lymphocytes (HTL), or with 6MHP alone (group D), in incomplete Freund’s adjuvant (IFA) plus GM-CSF. CTL responses were assessed using an in vitro stimulated IFN-gamma ELIspot assay, and HTL responses using proliferation assay. Results In groups A–D, respectively, CTL response rates to 12MP were 43%, 47%, 28%, and 5%, and HTL response rates to 6MHP were in 3%, 0%, 40% and 41%. Best clinical response was partial response (PR) in 7/148 evaluable patients (4.7%) without significant difference among study arms. Median overall survival (OS) was 11.8 months. Immune response to 6MHP was significantly associated with both clinical response (p=0.036) and OS (p=0.004). Conclusion Each vaccine regimen was immunogenic, but melanoma helper peptides did not augment CTL responses to 12MP. The association of survival and immune response to 6MHP supports further investigation of helper peptide vaccines. For patients with advanced melanoma, multipeptide vaccines should be studied in combination with other potentially synergistic active therapies. PMID:23653149

  12. A cancer vaccine induces expansion of NY-ESO-1-specific regulatory T cells in patients with advanced melanoma.

    PubMed

    Ebert, Lisa M; MacRaild, Sarah E; Zanker, Damien; Davis, Ian D; Cebon, Jonathan; Chen, Weisan

    2012-01-01

    Cancer vaccines are designed to expand tumor antigen-specific T cells with effector function. However, they may also inadvertently expand regulatory T cells (Treg), which could seriously hamper clinical efficacy. To address this possibility, we developed a novel assay to detect antigen-specific Treg based on down-regulation of surface CD3 following TCR engagement, and used this approach to screen for Treg specific to the NY-ESO-1 tumor antigen in melanoma patients treated with the NY-ESO-1/ISCOMATRIX™ cancer vaccine. All patients tested had Treg (CD25(bright) FoxP3(+) CD127(neg)) specific for at least one NY-ESO-1 epitope in the blood. Strikingly, comparison with pre-treatment samples revealed that many of these responses were induced or boosted by vaccination. The most frequently detected response was toward the HLA-DP4-restricted NY-ESO-1(157-170) epitope, which is also recognized by effector T cells. Notably, functional Treg specific for an HLA-DR-restricted epitope within the NY-ESO-1(115-132) peptide were also identified at high frequency in tumor tissue, suggesting that NY-ESO-1-specific Treg may suppress local anti-tumor immune responses. Together, our data provide compelling evidence for the ability of a cancer vaccine to expand tumor antigen-specific Treg in the setting of advanced cancer, a finding which should be given serious consideration in the design of future cancer vaccine clinical trials.

  13. Adoptive transfer of MART-1 T cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma

    PubMed Central

    Chodon, Thinle; Comin-Anduix, Begonya; Chmielowski, Bartosz; Koya, Richard C; Wu, Zhongqi; Auerbach, Martin; Ng, Charles; Avramis, Earl; Seja, Elizabeth; Villanueva, Arturo; McCannel, Tara A.; Ishiyama, Akira; Czernin, Johannes; Radu, Caius G.; Wang, Xiaoyan; Gjertson, David W.; Cochran, Alistair J.; Cornetta, Kenneth; Wong, Deborah J.L.; Kaplan-lefko, Paula; Hamid, Omid; Samlowski, Wolfram; Cohen, Peter A.; Daniels, Gregory A.; Mukherji, Bijay; Yang, Lili; Zack, Jerome A.; Kohn, Donald B.; Heath, James R.; Glaspy, John A.; Witte, Owen N.; Baltimore, David; Economou, James S.; Ribas, Antoni

    2014-01-01

    Purpose It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short one-week manufacture protocol to determine the feasibility, safety and antitumor efficacy of this double cell therapy. Experimnetal Design A clinical trial (NCT00910650) adoptively transferring MART-1 T cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and re-infused with (n = 10) or without (n = 3) prior cryopreservation. Results 14 patients with metastatic melanoma were enrolled and nine out of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within two weeks of ACT indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared to cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using non-cryopreserved T cells. Conclusion Double cell therapy with ACT of TCR engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. PMID:24634374

  14. Immunotherapy of Uveal Melanoma: Vaccination Against Cancer.

    PubMed

    Kummer, Mirko; Schuler-Thurner, Beatrice

    2017-01-01

    Uveal melanoma is the most frequently occurring primary intraocular tumor in adults, with an incidence of about 5 out of 100,000 per year, the incidence rising with increasing age (Lipski, Klin Monbl Augenheilkd 230:1005-1019, 2013; Metz et al., Klin Monbl Augenheilkd 230:686-691, 2013; Singh and Topham, Ophthalmology 110:956-961, 2003). Often diagnosed late due to a lack of early symptoms, this kind of melanoma is associated with a poor prognosis. Approximately 50 % of the patients develop distant metastases (Lipski, Klin Monbl Augenheilkd 230:1005-1019, 2013; Metz et al., Klin Monbl Augenheilkd 230:686-691, 2013; Singh and Topham, Ophthalmology 110:956-961, 2003). In sharp contrast to cutaneous melanoma, uveal melanoma shows a strong liver tropism and spreads exclusively via the hematogenous route (except for tumors with extraocular expansion) (Heindl et al., Arch Ophthalmol 128:1001-1008, 2010). The most likely reason for this observation is the lack of lymphatic vessels in the choroid and alymphatic barrier of the sclera (Schlereth et al., Exp Eye Res 125:203-209, 2014; Schroedl et al., Invest Ophthalmol Vis Sci 49:5222-5229, 2008). Due to its location in the immune-privileged eye, the uveal melanoma is widely protected from the immune system. Therefore, the goal of the approach presented here, of a "personalized vaccination therapy" is to help the immune system recognize and fight the tumor.

  15. [Melanoma immunotherapy: dendritic cell vaccines].

    PubMed

    Lozada-Requena, Ivan; Núñez, César; Aguilar, José Luis

    2015-01-01

    This is a narrative review that shows accessible information to the scientific community about melanoma and immunotherapy. Dendritic cells have the ability to participate in innate and adaptive immunity, but are not unfamiliar to the immune evasion of tumors. Knowing the biology and role has led to generate in vitro several prospects of autologous cell vaccines against diverse types of cancer in humans and animal models. However, given the low efficiency they have shown, we must implement strategies to enhance their natural capacity either through the coexpression of key molecules to activate or reactivate the immune system, in combination with biosimilars or chemotherapeutic drugs. The action of natural products as alternative or adjuvant immunostimulant should not be ruled out. All types of immunotherapy should measure the impact of myeloid suppressor cells, which can attack the immune system and help tumor progression, respectively. This can reduce the activity of cellular vaccines and/or their combinations, that could be the difference between success or not of the immunotherapy. Although for melanoma there exist biosimilars approved by the Food and Drug Administration (FDA), not all have the expected success. Therefore it is necessary to evaluate other strategies including cellular vaccines loaded with tumor antigenic peptides expressed exclusively or antigens from tumor extracts and their respective adjuvants.

  16. Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients.

    PubMed

    Odunsi, Kunle; Matsuzaki, Junko; Karbach, Julia; Neumann, Antje; Mhawech-Fauceglia, Paulette; Miller, Austin; Beck, Amy; Morrison, Carl D; Ritter, Gerd; Godoy, Heidi; Lele, Shashikant; duPont, Nefertiti; Edwards, Robert; Shrikant, Protul; Old, Lloyd J; Gnjatic, Sacha; Jäger, Elke

    2012-04-10

    Recombinant poxviruses (vaccinia and fowlpox) expressing tumor-associated antigens are currently being evaluated in clinical trials as cancer vaccines to induce tumor-specific immune responses that will improve clinical outcome. To test whether a diversified prime and boost regimen targeting NY-ESO-1 will result in clinical benefit, we conducted two parallel phase II clinical trials of recombinant vaccinia-NY-ESO-1 (rV-NY-ESO-1), followed by booster vaccinations with recombinant fowlpox-NY-ESO-1 (rF-NY-ESO-1) in 25 melanoma and 22 epithelial ovarian cancer (EOC) patients with advanced disease who were at high risk for recurrence/progression. Integrated NY-ESO-1-specific antibody and CD4(+) and CD8(+) T cells were induced in a high proportion of melanoma and EOC patients. In melanoma patients, objective response rate [complete and partial response (CR+PR)] was 14%, mixed response was 5%, and disease stabilization was 52%, amounting to a clinical benefit rate (CBR) of 72% in melanoma patients. The median PFS in the melanoma patients was 9 mo (range, 0-84 mo) and the median OS was 48 mo (range, 3-106 mo). In EOC patients, the median PFS was 21 mo (95% CI, 16-29 mo), and median OS was 48 mo (CI, not estimable). CD8(+) T cells derived from vaccinated patients were shown to lyse NY-ESO-1-expressing tumor targets. These data provide preliminary evidence of clinically meaningful benefit for diversified prime and boost recombinant pox-viral-based vaccines in melanoma and ovarian cancer and support further evaluation of this approach in these patient populations.

  17. Dendritic Cell Vaccination Combined with CTLA4 Blockade in Patients with Metastatic Melanoma

    PubMed Central

    Ribas, Antoni; Comin-Anduix, Begoña; Chmielowski, Bartosz; Jalil, Jason; de la Rocha, Pilar; McCannel, Tara A.; Ochoa, Maria Teresa; Seja, Elizabeth; Villanueva, Arturo; Oseguera, Denise K.; Straatsma, Bradley R.; Cochran, Alistair J.; Glaspy, John A.; Hui, Liu; Marincola, Francesco M.; Wang, Ena; Economou, James S.; Gomez-Navarro, Jesus

    2009-01-01

    Purpose Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase 1 clinical trial in patients with advanced melanoma. Experimental Design Autologous DC were pulsed with MART-126-35 peptide and administered with a dose escalation of the CTLA4 blocking antibody tremelimumab. Sixteen patients were accrued to 5 dose levels. Primary endpoints were safety and immune effects; clinical efficacy was a secondary endpoint. Results Dose-limiting toxicities (DLTs) of grade 3 diarrhea and grade 2 hypophysitis developed in 2 out of 3 patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses (PR) and two complete responses (CR), all melanoma-free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B cell function, may be important in predicting response. Conclusion The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone. PMID:19789309

  18. Dacarbazine treatment before peptide vaccination enlarges T-cell repertoire diversity of melan-a-specific, tumor-reactive CTL in melanoma patients.

    PubMed

    Palermo, Belinda; Del Bello, Duilia; Sottini, Alessandra; Serana, Federico; Ghidini, Claudia; Gualtieri, Novella; Ferraresi, Virginia; Catricalà, Caterina; Belardelli, Filippo; Proietti, Enrico; Natali, Pier Giorgio; Imberti, Luisa; Nisticò, Paola

    2010-09-15

    Combination of chemotherapy and immunotherapy to increase the effectiveness of an antitumor immune response is currently regarded as an attractive antitumor strategy. In a pilot clinical trial, we have recently documented an increase of melanoma antigen A (Melan-A)-specific, tumor-reactive, long-lasting effector-memory CD8(+) T cells after the administration of dacarbazine (DTIC) 1 day before peptide vaccination in melanoma patients. Global transcriptional analysis revealed a DTIC-induced activation of genes involved in the immune response and leukocyte activation. To identify the possible mechanisms underlying this improved immune response, we have compared the endogenous and the treatment-induced anti-Melan-A response at the clonal level in patients treated with the vaccine alone or with DTIC plus vaccine. We report a progressive widening of T-cell receptor (TCR) repertoire diversity, accompanied by high avidity and tumor reactivity, only in Melan-A-specific T-cell clones of patients treated with chemoimmunotherapy, with a trend toward longer survival. Differently, patients treated with vaccine alone showed a tendency to narrowing the TCR repertoire diversity, accompanied by a decrease of tumor lytic activity in one patient. Collectively, our findings indicate that DTIC plus vaccination shapes the TCR repertoire in terms of diversity and antitumor response, suggesting that this combined therapy could be effective in preventing melanoma relapse.

  19. Immune-related Adverse Events of Dendritic Cell Vaccination Correlate With Immunologic and Clinical Outcome in Stage III and IV Melanoma Patients

    PubMed Central

    Boudewijns, Steve; Westdorp, Harm; Koornstra, Rutger H.T.; Aarntzen, Erik H.J.G.; Schreibelt, Gerty; Creemers, Jeroen H.A.; Punt, Cornelis J.A.; Figdor, Carl G.; Gerritsen, Winald R.; Bol, Kalijn F.

    2016-01-01

    The purpose of this study was to determine the toxicity profile of dendritic cell (DC) vaccination in stage III and IV melanoma patients, and to evaluate whether there is a correlation between side effects and immunologic and clinical outcome. This is a retrospective analysis of 82 stage III and 137 stage IV melanoma patients, vaccinated with monocyte-derived or naturally circulating autologous DCs loaded with tumor-associated antigens gp100 and tyrosinase. Median follow-up time was 54.3 months in stage III patients and 12.9 months in stage IV patients. Treatment-related adverse events occurred in 84% of patients; grade 3 toxicity was present in 3% of patients. Most common adverse events were flu-like symptoms (67%) and injection site reactions (50%), and both correlated with the presence of tetramer-positive CD8+ T cells (both P<0.001). In stage III melanoma patients experiencing flu-like symptoms, median overall survival (OS) was not reached versus 32.3 months in patients without flu-like symptoms (P=0.009); median OS in patients with an injection site reaction was not reached versus 53.7 months in patients without an injection site reaction (P<0.05). In stage IV melanoma patients (primary uveal and mucosal melanomas excluded), median OS in patients with or without flu-like symptoms was 13.1 versus 8.9 months, respectively (P=0.03); median OS in patients with an injection site reaction was 15.7 months versus 9.8 months in patients without an injection site reaction (P=0.003). In conclusion, DC vaccination is safe and tolerable and the occurrence of the immune-related side effects, such as flu-like symptoms and injection site reactions, correlates with immunologic and clinical outcome. PMID:27227325

  20. Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity.

    PubMed

    Bol, Kalijn F; Aarntzen, Erik H J G; Pots, Jeanette M; Olde Nordkamp, Michel A M; van de Rakt, Mandy W M M; Scharenborg, Nicole M; de Boer, Annemiek J; van Oorschot, Tom G M; Croockewit, Sandra A J; Blokx, Willeke A M; Oyen, Wim J G; Boerman, Otto C; Mus, Roel D M; van Rossum, Michelle M; van der Graaf, Chantal A A; Punt, Cornelis J A; Adema, Gosse J; Figdor, Carl G; de Vries, I Jolanda M; Schreibelt, Gerty

    2016-03-01

    Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRNA encoding tumor antigens gp100 and tyrosinase. Tumor antigen-specific T cell responses were monitored in blood and skin-test infiltrating-lymphocyte cultures. Almost all patients mounted prophylactic vaccine- or KLH-specific immune responses. Both after intranodal injection and after intradermal/intravenous injection, tumor antigen-specific immune responses were detected, which coincide with longer overall survival in stage IV melanoma patients. VAC-DC induce local and systemic CTC grade 2 and 3 toxicity, which is most likely caused by BCG in the maturation cocktail. The side effects were self-limiting or resolved upon a short period of systemic steroid therapy. We conclude that VAC-DC can induce functional tumor-specific responses. Unfortunately, toxicity observed after vaccination precludes the general application of VAC-DC, since in DC maturated with prophylactic vaccines BCG appears to be essential in the maturation cocktail.

  1. Induction of strong and persistent MelanA/MART-1-specific immune responses by adjuvant dendritic cell-based vaccination of stage II melanoma patients.

    PubMed

    Tuettenberg, Andrea; Becker, Christian; Huter, Eva; Knop, Jürgen; Enk, Alexander H; Jonuleit, Helmut

    2006-05-15

    A significant percentage of stage II melanoma patients (tumor thickness>1 mm) remain at risk of tumor recurrence after primary tumor excision. In this study, we used tumor antigen-pulsed dendritic cells as an adjuvant for immunization of these "high-risk" melanoma patients after resection of the primary tumor. A total of 13 patients were included and vaccinated 6 times every 14 days with autologous dendritic cells pulsed with a MelanA/MART-1 peptide in combination with a recall antigen. Antigen-specific immune responses were monitored before, during and up to 1 year after the last vaccination. The majority of patients exhibited increased recall antigen-specific CD4+ T cell responses upon vaccination. MelanA/MART-1-specific CD8+ T cells were expanded in 9/13 patients resulting in increased frequencies of memory cells in these patients. CD8+ T cells acquired the capacity to secrete IFN-gamma, to proliferate in culture in response to the tumor antigen used for vaccination and postvaccine samples contained MelanA/MART-1-specific T cells that recognized also the natural MelanA/MART-1-antigen expressed by tumor cells. Moreover, vaccination induced a long-lived tumor antigen-specific DTH-reactivity in the majority of the patients, detectable even 12 months after the last immunization. These data demonstrate for the first time that vaccination with tumor antigen-pulsed dendritic cells in a clinically adjuvant setting induces strong and persistent antigen-specific T-cell responses in tumor-free stage II melanoma patients, suggesting that tumor protective T cell immunity can be achieved.

  2. Resiquimod as an immunologic adjuvant for NY-ESO-1 protein vaccination in patients with high-risk melanoma.

    PubMed

    Sabado, Rachel Lubong; Pavlick, Anna; Gnjatic, Sacha; Cruz, Crystal M; Vengco, Isabelita; Hasan, Farah; Spadaccia, Meredith; Darvishian, Farbod; Chiriboga, Luis; Holman, Rose Marie; Escalon, Juliet; Muren, Caroline; Escano, Crystal; Yepes, Ethel; Sharpe, Dunbar; Vasilakos, John P; Rolnitzsky, Linda; Goldberg, Judith D; Mandeli, John; Adams, Sylvia; Jungbluth, Achim; Pan, Linda; Venhaus, Ralph; Ott, Patrick A; Bhardwaj, Nina

    2015-03-01

    The Toll-like receptor (TLR) 7/8 agonist resiquimod has been used as an immune adjuvant in cancer vaccines. We evaluated the safety and immunogenicity of the cancer testis antigen NY-ESO-1 given in combination with Montanide (Seppic) with or without resiquimod in patients with high-risk melanoma. In part I of the study, patients received 100 μg of full-length NY-ESO-1 protein emulsified in 1.25 mL of Montanide (day 1) followed by topical application of 1,000 mg of 0.2% resiquimod gel on days 1 and 3 (cohort 1) versus days 1, 3, and 5 (cohort 2) of a 21-day cycle. In part II, patients were randomized to receive 100-μg NY-ESO-1 protein plus Montanide (day 1) followed by topical application of placebo gel [(arm A; n = 8) or 1,000 mg of 0.2% resiquimod gel (arm B; n = 12)] using the dosing regimen established in part I. The vaccine regimens were generally well tolerated. NY-ESO-1-specific humoral responses were induced or boosted in all patients, many of whom had high titer antibodies. In part II, 16 of 20 patients in both arms had NY-ESO-1-specific CD4⁺ T-cell responses. CD8⁺ T-cell responses were only seen in 3 of 12 patients in arm B. Patients with TLR7 SNP rs179008 had a greater likelihood of developing NY-ESO-1-specific CD8⁺ responses. In conclusion, NY-ESO-1 protein in combination with Montanide with or without topical resiquimod is safe and induces both antibody and CD4⁺ T-cell responses in the majority of patients; the small proportion of CD8⁺ T-cell responses suggests that the addition of topical resiquimod to Montanide is not sufficient to induce consistent NY-ESO-1-specific CD8⁺ T-cell responses.

  3. Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells.

    PubMed

    Kyte, Jon Amund; Aamdal, Steinar; Dueland, Svein; Sæbøe-Larsen, Stein; Inderberg, Else Marit; Madsbu, Ulf Erik; Skovlund, Eva; Gaudernack, Gustav; Kvalheim, Gunnar

    2016-01-01

    The most effective anticancer immune responses are probably directed against patient-specific neoantigens. We have developed a melanoma vaccine targeting this individual mutanome based on dendritic cells (DCs) loaded with autologous tumor-mRNA. Here, we report a phase I/II trial evaluating toxicity, immune response and clinical outcome in 31 metastatic melanoma patients. The first cohort (n = 22) received the vaccine without any adjuvant; the next cohort (n = 9) received adjuvant IL2. Each subject received four weekly intranodal or intradermal injections, followed by optional monthly vaccines. Immune response was evaluated by delayed-type hypersensitivity (DTH), T cell proliferation and cytokine assays. Data were collected for 10 y after inclusion of the last patient. No serious adverse events were detected. In the intention-to-treat-cohort, we demonstrated significantly superior survival compared to matched controls from a benchmark meta-analysis (1 y survival 43% vs. 24%, 2 y 23% vs. 6.6%). A tumor-specific immune response was demonstrated in 16/31 patients. The response rate was higher after intradermal than intranodal vaccination (80% vs. 38%). Immune responders had improved survival compared to non-responders (median 14 mo vs. 6 mo; p = 0.030), and all eight patients surviving >20 mo were immune responders. In addition to the tumor-specific response, most patients developed a response against autologous DC antigens. The cytokine profile was polyfunctional and did not follow a Th1/Th2 dichotomy. We conclude that the favorable safety profile and evidence of a possible survival benefit warrant further studies of the RNA/DC vaccine. The vaccine appears insufficient as monotherapy, but there is a strong rationale for combination with checkpoint modulators.

  4. Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients.

    PubMed

    Weide, Benjamin; Pascolo, Steve; Scheel, Birgit; Derhovanessian, Evelyna; Pflugfelder, Annette; Eigentler, Thomas K; Pawelec, Graham; Hoerr, Ingmar; Rammensee, Hans-Georg; Garbe, Claus

    2009-06-01

    In mice, injection of messenger RNA (mRNA) coding for tumor-associated antigens can induce antitumor immune responses and therefore offers a broadly applicable immunotherapy approach. We injected intradermally protamine-stabilized mRNAs coding for Melan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 21 metastatic melanoma patients. In 10 patients keyhole limpet hemocyanin (KLH) was added to the vaccine. Granulocyte macrophage colony-stimulating factor was applied as an adjuvant. Endpoints were toxicity and immune responses. No adverse events more than grade II have been observed. During treatment the frequency of Foxp3+/CD4+ regulatory T cells was significantly decreased upon mRNA vaccination in peripheral blood of the patients in the KLH arm, whereas myeloid suppressor cells (CD11b+HLA-DR lo monocytes) were reduced in the patients not receiving KLH. A reproducible increase of vaccine-directed T cells was observed in 2 of 4 immunologically evaluable patients. One of 7 patients with measurable disease showed a complete response. In conclusion, we show here that direct injection of protamine-protected mRNA is feasible and safe. The significant influence of the treatment on the frequency of immunosuppressive cells, the increase of vaccine-directed T cells upon treatment in a subset of patients together with the demonstration of a complete clinical response encourage further clinical investigation of the protamine-mRNA vaccine.

  5. Melanoma inhibitory activity in Brazilian patients with cutaneous melanoma*

    PubMed Central

    Odashiro, Macanori; Hans Filho, Gunter; Pereira, Patricia Rusa; Castro, Ana Rita Coimbra Motta; Stief, Alcione Cavalheiro; Pontes, Elenir Rose Jardim Cury; Odashiro, Alexandre Nakao

    2015-01-01

    BACKGROUND: Melanoma inhibitory activity is a protein secreted by melanoma cells and has been used as a tumor marker. Increased Melanoma inhibitory activity serum levels are related to metastatic disease or tumor recurrence. Currently there are no studies on Melanoma inhibitory activity and cutaneous melanoma involving Brazilian patients. OBJECTIVE: To evaluate the performance and feasibility of measuring Melanoma inhibitory activity levels in Brazilian patients with cutaneous melanoma. METHODS: Blood was obtained from ten patients with proved metastatic cutaneous melanoma (Group 1), 15 patients resected for cutaneous melanoma without metastasis (Group 2) and 5 healthy donors (Group 3). Melanoma inhibitory activity was measured using a commercially available ELISA kit. RESULTS: There was a statistically significant difference of Melanoma inhibitory activity levels between patients with and without metastasis (p=0.002), and between patients with metastasis and healthy donors (p=0.002). There was no difference between patients without metastasis and healthy donors (p=0.443). CONCLUSION: Melanoma inhibitory activity is a tumor marker for cutaneous melanoma and the Melanoma inhibitory activity-ELISA test can be easily performed. Patients with metastasis have increased Melanoma inhibitory activity serum levels when compared to patients without metastasis and healthy donors. PMID:26131861

  6. Time-dependent transition of the immunoglobulin G subclass and immunoglobulin E response in cancer patients vaccinated with cholesteryl pullulan-melanoma antigen gene-A4 nanogel

    PubMed Central

    Kyogoku, Noriaki; Ikeda, Hiroaki; Tsuchikawa, Takahiro; Abiko, Takehiro; Fujiwara, Aki; Maki, Takehiro; Yamamura, Yoshiyuki; Ichinokawa, Masaomi; Tanaka, Kimitaka; Imai, Naoko; Miyahara, Yoshihiro; Kageyama, Shinichi; Shiku, Hiroshi; Hirano, Satoshi

    2016-01-01

    A phase I+II clinical trial of vaccination with MAGE-A4 protein complexed with cholesteryl pullulan melanoma antigen gene-A4 nanogel (CHP-MAGE-A4) is currently underway in patients with MAGE-A4-expressing cancer. In the present study, the primary phase I endpoint was to test the safety of the administration of 300 µg CHP-MAGE-A4 with and without OK-432. Another aim of the study was to clarify the details of the specific humoral immune response to vaccination. The 9 patients enrolled for phase I were vaccinated 6 times, once every 2 weeks: 3 patients with 100 µg and 3 patients with 300 µg CHP-MAGE-A4, and 3 patients with 300 µg CHP-MAGE-A4 plus 0.5 clinical units of OK-432. Toxicities were assessed using Common Terminology Criteria for Adverse Events v3.0. Clinical response was evaluated by modified Response Evaluation Criteria in Solid Tumours. Immunological monitoring of anti-MAGE-A4-specific antibodies was performed by ELISA of pre- and post-vaccination patient sera. The 6 vaccinations produced no severe adverse events. Stable disease was assessed in 4/9 patients. Anti-MAGE-A4 total immunoglobulin (Ig)G titers increased in 7/9 patients. Efficacious anti-MAGE-A4 IgG1, 2 and 3 antibody responses were observed in 7/9 patients. Among them, positive conversions to T helper 2 (Th2)-type antibody responses (IgG4 and IgE) were observed after frequent vaccination in 4/7 patients. The Th2 conversion was possibly associated with undesirable clinical observations, including progressive disease and the appearance of a new relapse lesion. The present study suggested that frequent vaccinations activated a Th2-dominant status in the cancer patients. The identification of a time-dependent IgG subclass and IgE antibody production during vaccination protocols may be a useful surrogate marker indicating a potentially undesirable change of the immunological environment for an effective antitumor immune response in cancer patients. PMID:28105158

  7. Melanoma.

    PubMed

    Gershenwald, J E

    2001-01-01

    The presentations at the American Society of Clinical Oncology 2001 meeting reported or updated the results of phase I, II, and III randomized trials and also reported important meta-analyses and retrospective studies impacting on the management of patients with melanoma. In the treatment of early stage melanoma, the prognostic significance of pathologic status of sentinel lymph nodes was affirmed. With respect to regional nodal involvement (American Joint Committee on Cancer [AJCC] stage III), investigators presented the interim results of the United Kingdom randomized low-dose interferon (IFN) trial, and up-to-date meta-analyses of several IFN trials including a pooled analysis of the Eastern Cooperative Oncology Group trials evaluating interferon in the adjuvant setting. In the advanced disease setting (AJCC stage IV), several studies elucidated the pros and cons of biochemotherapy in patients with metastatic melanoma, with an emphasis on seeking to improve response in the central nervous system and durability of response in general. Thought provoking was new data regarding the potential for lovastatin to act as a chemopreventive agent for melanoma. Translational studies were presented, one supporting the importance of HLA-typing in developing targeted vaccine therapy. Finally, the results of a novel experimental melanoma vaccine were presented using autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96).

  8. Nano-particle vaccination combined with TLR-7 and -9 ligands triggers memory and effector CD8⁺ T-cell responses in melanoma patients.

    PubMed

    Goldinger, Simone M; Dummer, Reinhard; Baumgaertner, Petra; Mihic-Probst, Daniela; Schwarz, Katrin; Hammann-Haenni, Anya; Willers, Joerg; Geldhof, Christine; Prior, John O; Kündig, Thomas M; Michielin, Olivier; Bachmann, Martin F; Speiser, Daniel E

    2012-11-01

    Optimal vaccine strategies must be identified for improving T-cell vaccination against infectious and malignant diseases. MelQbG10 is a virus-like nano-particle loaded with A-type CpG-oligonucleotides (CpG-ODN) and coupled to peptide(16-35) derived from Melan-A/MART-1. In this phase IIa clinical study, four groups of stage III-IV melanoma patients were vaccinated with MelQbG10, given (i) with IFA (Montanide) s.c.; (ii) with IFA s.c. and topical Imiquimod; (iii) i.d. with topical Imiquimod; or (iv) as intralymph node injection. In total, 16/21 (76%) patients generated ex vivo detectable Melan-A/MART-1-specific T-cell responses. T-cell frequencies were significantly higher when IFA was used as adjuvant, resulting in detectable T-cell responses in all (11/11) patients, with predominant generation of effector-memory-phenotype cells. In turn, Imiquimod induced higher proportions of central-memory-phenotype cells and increased percentages of CD127(+) (IL-7R) T cells. Direct injection of MelQbG10 into lymph nodes resulted in lower T-cell frequencies, associated with lower proportions of memory and effector-phenotype T cells. Swelling of vaccine site draining lymph nodes, and increased glucose uptake at PET/CT was observed in 13/15 (87%) of evaluable patients, reflecting vaccine triggered immune reactions in lymph nodes. We conclude that the simultaneous use of both Imiquimod and CpG-ODN induced combined memory and effector CD8(+) T-cell responses.

  9. CDX-1401 and Poly-ICLC Vaccine Therapy With or Without CDX-301in Treating Patients With Stage IIB-IV Melanoma

    ClinicalTrials.gov

    2016-11-14

    Carcinoma of Unknown Primary Origin; Iris Melanoma; Medium/Large Size Posterior Uveal Melanoma; Mucosal Melanoma; Ocular Melanoma With Extraocular Extension; Small Size Posterior Uveal Melanoma; Stage IIB Skin Melanoma; Stage IIB Uveal Melanoma; Stage IIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIA Uveal Melanoma; Stage IIIB Skin Melanoma; Stage IIIB Uveal Melanoma; Stage IIIC Skin Melanoma; Stage IIIC Uveal Melanoma; Stage IV Skin Melanoma; Stage IV Uveal Melanoma

  10. Therapeutic vaccination for the treatment of malignant melanoma.

    PubMed

    Walden, Peter

    2007-01-01

    With increasing knowledge of tumor-associated antigens and T cell epitopes, and the mechanisms of induction and regulation of T-cellular immune responses, therapeutic vaccination is increasingly being explored as a treatment option for cancer. Several clinical cancer vaccination trials, the majority of them with melanoma patients, have demonstrated efficient induction of tumor-specific cellular immune responses in patients. However, these immune responses, in most cases, do not translate into clinical responses. The clinical response rates in these trials are relatively low. The most likely causes for the lack of correlation of immunological and clinical responsiveness are loss of antigenicity and immune suppression. Nonetheless, many patients in the vaccination trials have experienced extended survival compared to clinical experience. Therapeutic vaccination thus appears suited for maintenance therapy where cure is not possible and is an interesting option for adjuvant therapy after surgical tumor resection. While the clinical efficacy of vaccination is expected to be better for early-stage cancer, advancement of the treatment of advanced-stage disease will require combination with other therapeutic principles.

  11. A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10 -1082 promoter genotype as predictor of disease progression

    PubMed Central

    von Euw, Erika M; Barrio, María M; Furman, David; Levy, Estrella M; Bianchini, Michele; Peguillet, Isabelle; Lantz, Olivier; Vellice, Alejandra; Kohan, Abraham; Chacón, Matías; Yee, Cassian; Wainstok, Rosa; Mordoh, José

    2008-01-01

    Background Sixteen melanoma patients (1 stage IIC, 8 stage III, and 7 stage IV) were treated in a Phase I study with a vaccine (DC/Apo-Nec) composed of autologous dendritic cells (DCs) loaded with a mixture of apoptotic/necrotic allogeneic melanoma cell lines (Apo-Nec), to evaluate toxicity and immune responses. Also, IL-10 1082 genotype was analyzed in an effort to predict disease progression. Methods PBMC were obtained after leukapheresis and DCs were generated from monocytes cultured in the presence of GM-CSF and IL-4 in serum-free medium. Immature DCs were loaded with gamma-irradiated Apo-Nec cells and injected id without adjuvant. Cohorts of four patients were given four vaccines each with 5, 10, 15, or 20 × 106 DC/Apo-Nec cell per vaccine, two weeks apart. Immune responses were measured by ELISpot and tetramer analysis. Il-10 genotype was measured by PCR and corroborated by IL-10 production by stimulated PBMC. Results Immature DCs efficiently phagocytosed melanoma Apo-Nec cells and matured after phagocytosis as evidenced by increased expression of CD83, CD80, CD86, HLA class I and II, and 75.2 ± 16% reduction in Dextran-FITC endocytosis. CCR7 was also up-regulated upon Apo-Nec uptake in DCs from all patients, and accordingly DC/Apo-Nec cells were able to migrate in vitro toward MIP-3 beta. The vaccine was well tolerated in all patients. The DTH score increased significantly in all patients after the first vaccination (Mann-Whitney Test, p < 0.05). The presence of CD8+T lymphocytes specific to gp100 and Melan A/MART-1 Ags was determined by ELISpot and tetramer analysis in five HLA-A*0201 patients before and after vaccination; one patient had stable elevated levels before and after vaccination; two increased their CD8 + levels, one had stable moderate and one had negligible levels. The analysis of IL-10 promoter -1082 polymorphism in the sixteen patients showed a positive correlation between AA genotype, accompanied by lower in vitro IL-10 production by

  12. Randomized Multicenter Trial of the Effects of Melanoma-Associated Helper Peptides and Cyclophosphamide on the Immunogenicity of a Multipeptide Melanoma Vaccine

    PubMed Central

    Slingluff, Craig L.; Petroni, Gina R.; Chianese-Bullock, Kimberly A.; Smolkin, Mark E.; Ross, Merrick I.; Haas, Naomi B.; von Mehren, Margaret; Grosh, William W.

    2011-01-01

    Purpose This multicenter randomized trial was designed to test whether melanoma-associated helper peptides augment CD8+ T-cell responses to a melanoma vaccine and whether cyclophosphamide (CY) pretreatment augments CD4+ or CD8+ T-cell responses to that vaccine. Patients and Methods In all, 167 eligible patients with resected stage IIB to IV melanoma were randomly assigned to four vaccination study arms. Patients were vaccinated with 12 class I major histocompatibility complex–restricted melanoma peptides (12MP) to stimulate CD8+ T cells and were randomly assigned to receive a tetanus helper peptide or a mixture of six melanoma-associated helper peptides (6MHP) to stimulate CD4+ T cells. Before vaccination, patients were also randomly assigned to receive CY pretreatment or not. T-cell responses were assessed by an ex vivo interferon gamma ELISpot assay. Clinical outcomes and toxicities were recorded. Results Vaccination with 12MP plus tetanus induced CD8+ T-cell responses in 78% of patients and CD4+ T-cell responses to tetanus peptide in 93% of patients. Vaccination with 12MP plus 6MHP induced CD8+ responses in 19% of patients and CD4+ responses to 6MHP in 48% of patients. CY had no significant effect on T-cell responses. Overall 3-year survival was 79% (95% CI, 71% to 86%), with no significant differences (at this point) by study arm. Conclusion Melanoma-associated helper peptides paradoxically decreased CD8+ T-cell responses to a melanoma vaccine (P < .001), and CY pretreatment had no immunologic or clinical effect. Prior work showed immunologic and clinical activity of 6MHP alone. Possible explanations for negative effects on CD8 responses include modulation of homing receptor expression or induction of antigen-specific regulatory T cells. PMID:21690475

  13. Adenovirus MART-1-engineered autologous dendritic cell vaccine for metastatic melanoma.

    PubMed

    Butterfield, Lisa H; Comin-Anduix, Begonya; Vujanovic, Lazar; Lee, Yohan; Dissette, Vivian B; Yang, Jin-Quan; Vu, Hong T; Seja, Elizabeth; Oseguera, Denise K; Potter, Douglas M; Glaspy, John A; Economou, James S; Ribas, Antoni

    2008-04-01

    We performed a phase 1/2 trial testing the safety, toxicity, and immune response of a vaccine consisting of autologous dendritic cells (DCs) transduced with a replication-defective adenovirus (AdV) encoding the full-length melanoma antigen MART-1/Melan-A (MART-1). This vaccine was designed to activate MART-1-specific CD+8 and CD4+ T cells. Metastatic melanoma patients received 3 injections of 10(6) or 10(7) DCs, delivered intradermally. Cell surface phenotype and cytokine production of the DCs used for the vaccines were tested, and indicated intermediate maturity. CD8+ T-cell responses to MART-1 27-35 were assessed by both major histocompatibility complex class I tetramer and interferon (IFN)-gamma enzyme-linked immunosorbent spot (ELISPOT) before, during, and after each vaccine and CD4+ T-cell responses to MART-1 51-73 were followed by IFN-gamma ELISPOT. We also measured antigen response breadth. Determinant spreading from the immunizing antigen MART-1 to other melanoma antigens [gp100, tyrosinase, human melanoma antigen-A3 (MAGE-A3)] was assessed by IFN-gamma ELISPOT. Twenty-three patients were enrolled and 14 patients received all 3 scheduled DC vaccines. Significant CD8+ and/or CD4+ MART-1-specific T-cell responses were observed in 6/11 and 2/4 patients evaluated, respectively, indicating that the E1-deleted adenovirus encoding the cDNA for MART-1/Melan-A (AdVMART1)/DC vaccine activated both helper and killer T cells in vivo. Responses in CD8+ and CD4+ T cells to additional antigens were noted in 2 patients. The AdVMART1-transduced DC vaccine was safe and immunogenic in patients with metastatic melanoma.

  14. Adenovirus MART-1–engineered Autologous Dendritic Cell Vaccine for Metastatic Melanoma

    PubMed Central

    Butterfield, Lisa H.; Comin-Anduix, Begonya; Vujanovic, Lazar; Lee, Yohan; Dissette, Vivian B.; Yang, Jin-Quan; Vu, Hong T.; Seja, Elizabeth; Oseguera, Denise K.; Potter, Douglas M.; Glaspy, John A.; Economou, James S.; Ribas, Antoni

    2013-01-01

    Summary We performed a phase 1/2 trial testing the safety, toxicity, and immune response of a vaccine consisting of autologous dendritic cells (DCs) transduced with a replication-defective adenovirus (AdV) encoding the full-length melanoma antigen MART-1/Melan-A (MART-1). This vaccine was designed to activate MART-1–specific CD8+ and CD4+ T cells. Metastatic melanoma patients received 3 injections of 106 or 107 DCs, delivered intradermally. Cell surface phenotype and cytokine production of the DCs used for the vaccines were tested, and indicated intermediate maturity. CD8+ T-cell responses to MART-127-35 were assessed by both major histocompatibility complex class I tetramer and interferon (IFN)-γ enzyme-linked immunosorbent spot (ELISPOT) before, during, and after each vaccine and CD4+ T-cell responses to MART-151-73 were followed by IFN-γ ELISPOT. We also measured antigen response breadth. Determinant spreading from the immunizing antigen MART-1 to other melanoma antigens [gp100, tyrosinase, human melanoma antigen-A3 (MAGE-A3)] was assessed by IFN-γ ELISPOT. Twenty-three patients were enrolled and 14 patients received all 3 scheduled DC vaccines. Significant CD8+ and/or CD4+ MART-1–specific T-cell responses were observed in 6/11 and 2/4 patients evaluated, respectively, indicating that the E1-deleted adeno-virus encoding the cDNA for MART-1/Melan-A (AdV-MART1)/DC vaccine activated both helper and killer T cells in vivo. Responses in CD8+ and CD4+ T cells to additional antigens were noted in 2 patients. The AdVMART1-transduced DC vaccine was safe and immunogenic in patients with metastatic melanoma. PMID:18317358

  15. Exceptional antineoplastic activity of a dendritic-cell-targeted vaccine loaded with a Listeria peptide proposed against metastatic melanoma

    PubMed Central

    Calderon-Gonzalez, Ricardo; Bronchalo-Vicente, Lucia; Freire, Javier; Frande-Cabanes, Elisabet; Alaez-Alvarez, Lidia; Gomez-Roman, Javier; Yañez-Diaz, Sonsóles; Alvarez-Dominguez, Carmen

    2016-01-01

    Vaccination with dendritic cells (DCs) is proposed to induce lasting responses against melanoma but its survival benefit in patients needs to be demonstrated. We propose a DC-targeted vaccine loaded with a Listeria peptide with exceptional anti-tumour activity to prevent metastasis of melanoma. Mice vaccinated with vaccines based on DCs loaded with listeriolysin O peptide (91–99) (LLO91–99) showed clear reduction of metastatic B16OVA melanoma size and adhesion, prevention of lung metastasis, enhanced survival, and reversion of immune tolerance. Robust innate and specific immune responses explained the efficiency of DC-LLO91–99 vaccines against B16OVA melanoma. The noTable features of this vaccine related to melanoma reduction were: expansion of immune-dominant LLO91–99-specific CD8 T cells that helped to expand melanoma-specific CD8+ T cells; high numbers of tumour-infiltrating lymphocytes with a cytotoxic phenotype; and a decrease in CD4+CD25high regulatory T cells. This vaccine might be a useful alternative treatment for advanced melanoma, alone or in combination with other therapies. PMID:26942874

  16. PLX4032 Mediated Melanoma Associated Antigen Potentiation in Patient Derived Primary Melanoma Cells

    PubMed Central

    George, Andrea L.; Suriano, Robert; Rajoria, Shilpi; Osso, Maria C.; Tuli, Neha; Hanly, Elyse; Geliebter, Jan; Arnold, Angelo N.; Wallack, Marc; Tiwari, Raj K.

    2015-01-01

    Over expression of various immunogenic melanoma associated antigens (MAAs) has been exploited in the development of immunotherapeutic melanoma vaccines. Expression of MAAs such as MART-1 and gp100 is modulated by the MAPK signaling pathway, which is often deregulated in melanoma. The protein BRAF, a member of the MAPK pathway, is mutated in over 60% of melanomas providing an opportunity for the identification and approval by the FDA of a small molecule MAPK signaling inhibitor PLX4032 that functions to inactivate mutant BRAFV600E. To this end, we characterized five patient derived primary melanoma cell lines with respect to treatment with PLX4032. Cells were treated with 5μM PLX4032 and harvested. Western blotting analysis, RT-PCR and in vitro transwell migration and invasion assays were utilized to determine treatment effects. PLX4032 treatment modulated phosphorylation of signaling proteins belonging to the MAPK pathway including BRAF, MEK, and ERK and abrogated cell phenotypic characteristics such as migration and invasion. Most significantly, PLX4032 led to an up regulation of many MAA proteins in three of the four BRAF mutated cell lines, as determined at the protein and RNA level. Interestingly, MAGE-A1 protein and mRNA levels were reduced upon PLX4032 treatment in two of the primary lines. Taken together, our findings suggest that the BRAFV600E inhibitor PLX4032 has therapeutic potential over and above its known target and in combination with specific melanoma targeting vaccine strategies may have further clinical utility. PMID:26640592

  17. Safety of administering the canine melanoma DNA vaccine (Oncept) to cats with malignant melanoma - a retrospective study.

    PubMed

    Sarbu, Luminita; Kitchell, Barbara E; Bergman, Philip J

    2017-02-01

    Objectives A xenogeneic human tyrosinase DNA vaccine was developed for treatment of dogs with oral malignant melanoma (Oncept; Merial). No studies have evaluated the safety or efficacy of this vaccine in cats. The purpose of this study was to evaluate the safety of the canine melanoma vaccine in cats diagnosed with melanoma. Methods Medical records were reviewed from cats diagnosed with malignant melanoma and treated with the canine melanoma DNA vaccine (Oncept). Data regarding signalment, melanoma location, treatments received, vaccine adverse effects and cause of death were collected. Results A total of 114 melanoma vaccines were administered to 24 cats. Seven cats (11.4%) had clinical adverse effects from a total of 13 vaccines classified as grade 1 or 2 based on the Veterinary Cooperative Oncology Group's common terminology criteria for adverse events v1.1. These included pain on vaccine administration, brief muscle fasciculation, transient inappetence, depression, nausea and mild increase in pigmentation at the injection site. Nineteen cats were deceased at study close. The most common cause of death was melanoma (14 cats). Hematological and biochemical changes were observed in six cats, five of which had concurrent disease or treatments that likely caused or greatly contributed to the laboratory abnormalities found. Therefore, these adverse events were considered unlikely to be caused by the melanoma vaccine. One cat had transient grade 1 hypoalbuminemia, which was possibly caused by the vaccination but not thoroughly evaluated. Conclusions and relevance The canine melanoma DNA vaccine can be safely administered to cats, with minimal risk of adverse effects.

  18. Cripto-1 vaccination elicits protective immunity against metastatic melanoma.

    PubMed

    Ligtenberg, M A; Witt, K; Galvez-Cancino, F; Sette, A; Lundqvist, A; Lladser, A; Kiessling, R

    2016-05-01

    Metastatic melanoma is a fatal disease that responds poorly to classical treatments but can be targeted by T cell-based immunotherapy. Cancer vaccines have the potential to generate long-lasting cytotoxic CD8(+) T cell responses able to eradicate established and disseminated tumors. Vaccination against antigens expressed by tumor cells with enhanced metastatic potential represents a highly attractive strategy to efficiently target deadly metastatic disease. Cripto-1 is frequently over-expressed in human carcinomas and melanomas, but is expressed only at low levels on normal differentiated tissues. Cripto-1 is particularly upregulated in cancer-initiating cells and is involved in cellular processes such as cell migration, invasion and epithelial-mesenchymal transition, which are hallmarks of aggressive cancer cells able to initiate metastatic disease. Here, we explored the potential of Cripto-1 vaccination to target metastatic melanoma in a preclinical model. Cripto-1 was overexpressed in highly metastatic B16F10 cells as compared to poorly metastatic B16F1 cells. Moreover, B16F10 cells grown in sphere conditions to enrich for cancer stem cells (CSC) progressively upregulated cripto1 expression. Vaccination of C57Bl/6 mice with a DNA vaccine encoding mouse Cripto-1 elicited a readily detectable/strong cytotoxic CD8(+) T cell response specific for a H-2 Kb-restricted epitope identified based on its ability to bind H-2(b) molecules. Remarkably, Cripto-1 vaccination elicited a protective response against lung metastasis and subcutaneous challenges with highly metastatic B16F10 melanoma cells. Our data indicate that vaccination against Cripto-1 represents a novel strategy to be tested in the clinic.

  19. Cripto-1 vaccination elicits protective immunity against metastatic melanoma

    PubMed Central

    Ligtenberg, M. A.; Witt, K.; Galvez-Cancino, F.; Sette, A.; Lundqvist, A.; Lladser, A.; Kiessling, R.

    2016-01-01

    ABSTRACT Metastatic melanoma is a fatal disease that responds poorly to classical treatments but can be targeted by T cell-based immunotherapy. Cancer vaccines have the potential to generate long-lasting cytotoxic CD8+ T cell responses able to eradicate established and disseminated tumors. Vaccination against antigens expressed by tumor cells with enhanced metastatic potential represents a highly attractive strategy to efficiently target deadly metastatic disease. Cripto-1 is frequently over-expressed in human carcinomas and melanomas, but is expressed only at low levels on normal differentiated tissues. Cripto-1 is particularly upregulated in cancer-initiating cells and is involved in cellular processes such as cell migration, invasion and epithelial–mesenchymal transition, which are hallmarks of aggressive cancer cells able to initiate metastatic disease. Here, we explored the potential of Cripto-1 vaccination to target metastatic melanoma in a preclinical model. Cripto-1 was overexpressed in highly metastatic B16F10 cells as compared to poorly metastatic B16F1 cells. Moreover, B16F10 cells grown in sphere conditions to enrich for cancer stem cells (CSC) progressively upregulated cripto1 expression. Vaccination of C57Bl/6 mice with a DNA vaccine encoding mouse Cripto-1 elicited a readily detectable/strong cytotoxic CD8+ T cell response specific for a H-2 Kb-restricted epitope identified based on its ability to bind H-2b molecules. Remarkably, Cripto-1 vaccination elicited a protective response against lung metastasis and subcutaneous challenges with highly metastatic B16F10 melanoma cells. Our data indicate that vaccination against Cripto-1 represents a novel strategy to be tested in the clinic. PMID:27467944

  20. Selecting patients for KIT inhibition in melanoma.

    PubMed

    Carvajal, Richard D; Hamid, Omid; Antonescu, Cristina R

    2014-01-01

    For many years, melanoma has been regarded as a single disease in terms of therapeutic considerations. The more recent identification of multiple molecular mechanisms underlying the development, progression, and prognosis of melanoma has led to a new paradigm for the management of this disease, has created new therapeutic opportunities, and has led to improved clinical outcomes. Such advances, however, are dependent upon methods that can reproducibly identify key molecular alterations within an individual tumor, define clinically relevant genetic subgroups of disease, and permit improved patient selection for targeted therapies.Melanomas harboring genetic alterations of KIT have been demonstrated to constitute one such molecular subgroup of disease. In this chapter, we will discuss the biology of KIT in melanoma, review the rationale for and clinical data regarding KIT inhibition in melanomas harboring activating alterations of KIT, propose guidelines for the selection of patients for KIT inhibitor therapy, and, finally, present laboratory methods for KIT assessment in melanoma.

  1. Interferon γ limits the effectiveness of melanoma peptide vaccines

    PubMed Central

    Cho, Hyun-Il; Lee, Young-Ran

    2011-01-01

    The development of effective therapeutic vaccines to generate tumor-reactive cytotoxic T lymphocytes (CTLs) continues to be a top research priority. However, in spite of some promising results, there are no clear examples of vaccines that eradicate established tumors. Most vaccines are ineffective because they generate low numbers of CTLs and because numerous immunosuppressive factors abound in tumor-bearing hosts. We designed a peptide vaccine that produces large numbers of tumor-reactive CTLs in a mouse model of melanoma. Surprisingly, CTL tumor recognition and antitumor effects decreased in the presence of interferon γ (IFNγ), a cytokine that can provide therapeutic benefit. Tumors exposed to IFNγ evade CTLs by inducing large amounts of noncognate major histocompatibility complex class I molecules, which limit T-cell activation and effector function. Our results demonstrate that peptide vaccines can eradicate large, established tumors in circumstances under which the inhibitory activities of IFNγ are curtailed. PMID:20889921

  2. Adjuvant Autologous Melanoma Vaccine for Macroscopic Stage III Disease: Survival, Biomarkers, and Improved Response to CTLA-4 Blockade

    PubMed Central

    Lotem, Michal; Merims, Sharon; Frank, Stephen; Hamburger, Tamar; Nissan, Aviram; Kadouri, Luna; Cohen, Jonathan; Straussman, Ravid; Eisenberg, Galit; Frankenburg, Shoshana; Carmon, Einat; Alaiyan, Bilal; Shneibaum, Shlomo; Ozge Ayyildiz, Zeynep; Isbilen, Murat; Mert Senses, Kerem; Ron, Ilan; Steinberg, Hanna; Smith, Yoav; Shiloni, Eitan; Gure, Ali Osmay; Peretz, Tamar

    2016-01-01

    Background. There is not yet an agreed adjuvant treatment for melanoma patients with American Joint Committee on Cancer stages III B and C. We report administration of an autologous melanoma vaccine to prevent disease recurrence. Patients and Methods. 126 patients received eight doses of irradiated autologous melanoma cells conjugated to dinitrophenyl and mixed with BCG. Delayed type hypersensitivity (DTH) response to unmodified melanoma cells was determined on the vaccine days 5 and 8. Gene expression analysis was performed on 35 tumors from patients with good or poor survival. Results. Median overall survival was 88 months with a 5-year survival of 54%. Patients attaining a strong DTH response had a significantly better (p = 0.0001) 5-year overall survival of 75% compared with 44% in patients without a strong response. Gene expression array linked a 50-gene signature to prognosis, including a cluster of four cancer testis antigens: CTAG2 (NY-ESO-2), MAGEA1, SSX1, and SSX4. Thirty-five patients, who received an autologous vaccine, followed by ipilimumab for progressive disease, had a significantly improved 3-year survival of 46% compared with 19% in nonvaccinated patients treated with ipilimumab alone (p = 0.007). Conclusion. Improved survival in patients attaining a strong DTH and increased response rate with subsequent ipilimumab suggests that the autologous vaccine confers protective immunity. PMID:27294163

  3. Evaluation of genetic melanoma vaccines in cdk4-mutant mice provides evidence for immunological tolerance against authochthonous melanomas in the skin.

    PubMed

    Steitz, Julia; Büchs, Stefanie; Tormo, Damia; Ferrer, Aleix; Wenzel, Jörg; Huber, Christoph; Wölfel, Thomas; Barbacid, Mariano; Malumbres, Marcos; Tüting, Thomas

    2006-01-15

    We evaluated the efficacy of a candidate melanoma vaccine approach in mice genetically prone to develop melanoma due to the introduction of an oncogenic mutation (R24C) in the germline sequence of the cyclin-dependent kinase 4 (cdk4), a protein critically involved in cell cycle regulation. Melanomas were induced in cdk4-mutant mice by chemical carcinogenesis and UVB irradiation. A genetic prime-boost strategy targeting the clinically relevant differentiation antigen tyrosinase-related protein 2 (TRP2) was performed which was able to stimulate a melanocyte-specific cellular immune response associated with localized autoimmune vitiligo-like depigmentation. However, significant destruction of carcinogen-induced autochthonous melanocytic neoplasms in the skin was not observed following immunization. We provide evidence that autochthonous melanomas expressed TRP2 but not the MHC molecule H2-Kb and are immunologically tolerated in the skin. Our results highlight the importance of assessing melanoma vaccines in genetic mouse models that more adequately represent the expected clinical situation in order to identify strategies, which eventually may be of benefit for melanoma patients.

  4. A novel microparticulate vaccine for melanoma cancer using transdermal delivery.

    PubMed

    Bhowmik, Tuhin; D'Souza, Bernadette; Shashidharamurthy, Rangaiah; Oettinger, Carl; Selvaraj, Periasamy; D'Souza, Martin J

    2011-01-01

    In this study, we formulated a microparticulate melanoma cancer vaccine via the transdermal route. The vaccine was delivered using microneedle-based Dermaroller® which is available for cosmetic purposes. Unlike subcutaneous injections, administration using microneedles is painless and in general can increase the permeability of many compounds ranging in size from small molecules to proteins and microparticles that do not normally penetrate the skin. The vaccine microparticles were taken up by the antigen presenting cells which demonstrated a strong IgG titre level of 930 ug/mL in serum samples. The formulation increased the immunogenicity of the vaccine by incorporating the antigen into an albumin matrix having a size range of around 0.63-1.4 µm which acted as a synthetic adjuvant. The animals were vaccinated with 1 prime and 4 booster doses administered every 14 days over 8 weeks duration, followed by challenge with live tumour cells which showed protection after transdermal vaccination.

  5. Axillary Silicone Granulomas in Patients With Melanoma.

    PubMed

    Fernández Canedo, M I; Blázquez Sánchez, N; Valdés Solís, P; de Troya Martín, M

    2016-05-01

    Subcutaneous lesions may be detected during follow-up of patients with melanoma. The main entities that should be contemplated in the differential diagnosis in such cases are in-transit and regional lymph node metastases. We describe 2 cases of women with breast implants who developed palpable subcutaneous lesions in the axillary region during follow-up of melanoma. In both cases, the ultrasound study showed diffuse hyperechoic signals forming the characteristic snowstorm sign in the subcutaneous tissue. Ultrasound proved to be a key diagnostic tool for ruling out melanoma-related disease, such as in-transit metastases and regional lymph node metastases.

  6. Melanoma-associated chondroitin sulphate proteoglycan as a new target antigen for CD4+ T cells in melanoma patients.

    PubMed

    Erfurt, Cornelia; Müller, Esther; Emmerling, Sonja; Klotz, Claudia; Hertl, Michael; Schuler, Gerold; Schultz, Erwin S

    2009-05-15

    Melanoma-associated chondroitin sulfate proteoglycan (MCSP) (also known as high molecular weight-melanoma-associated antigen) represents an interesting target antigen for cancer immunotherapy which is expressed on human melanomas and other tumors such as breast carcinomas, gliomas, neuroblastomas and acute leukemias. MCSP seems to play an important functional role in melanoma as it is involved in tumor cell migration, invasion and angiogenesis. In this study, we isolated CD4(+) T helper cells from the blood of a healthy donor, recognizing a peptide from the MCSP core protein presented by HLA-DBR1*1101 molecules. T cell reactivity against the identified peptide could be detected in the blood of healthy donors and melanoma patients. MCSP specific T cells from the blood of a patient could be readily expanded by repeated peptide stimulation and recognized MCSP and HLA-DR expressing tumor cells. Our findings suggest that vaccination against MCSP helper T cell epitopes might be a promising approach to fight melanoma.

  7. Preoperative nuclear scans in patients with melanoma

    SciTech Connect

    Au, F.C.; Maier, W.P.; Malmud, L.S.; Goldman, L.I.; Clark, W.H. Jr.

    1984-05-15

    One hundred forty-one liver scans, 137 brain scans, and 112 bone scans were performed in 192 patients with clinical Stage 1 melanoma. One liver scan was interpreted as abnormal; liver biopsy of that patient showed no metastasis. There were 11 suggestive liver scans; three of the patients with suggestive liver scans had negative liver biopsies. The remaining eight patients were followed from 4 to 6 years and none of those patients developed clinical evidence of hepatic metastases. All of the brain scans were normal. Five patients had suggestive bone scans and none of those patients had manifested symptoms of osseous metastases with a follow-up of 2 to 4.5 years. This study demonstrates that the use of preoperative liver, brain and bone scan in the evaluation of patients with clinical Stage 1 melanoma is virtually unproductive.

  8. Phase I trial of a MART-1 peptide vaccine with incomplete Freund's adjuvant for resected high-risk melanoma.

    PubMed

    Wang, F; Bade, E; Kuniyoshi, C; Spears, L; Jeffery, G; Marty, V; Groshen, S; Weber, J

    1999-10-01

    Twenty-five patients with high-risk resected stages IIB, III, and IV melanoma were immunized with a vaccine consisting of the minimal epitope, immunodominant 9-amino acid peptide derived from the MART-1 tumor antigen (AAGIGILTV) complexed with incomplete Freund's adjuvant. The last three patients received the MART-1(27-35) peptide with incomplete Freund's adjuvant mixed with CRL 1005, a block copolymer adjuvant. Patients were immunized with increasing doses of the MART-1(27-35) peptide in a Phase I trial to evaluate the toxicity, tolerability, and immune responses to the vaccine. Immunizations were administered every 3 weeks for a total of four injections, preceded by leukapheresis to obtain peripheral blood mononuclear cells for immune analyses, followed by a post-vaccine leukapheresis 3 weeks after the fourth vaccination. Skin testing with peptide and standard delayed-type hypersensitivity skin test reagents was also performed before and after vaccinations. Local pain and granuloma formation were observed in the majority of patients, as were fevers or lethargy of grade 1 or 2. No vaccine-related grade III/IV toxicity was observed. The vaccine was felt to be well tolerated. Twelve of 25 patients were anergic to skin testing at the initiation of the trial, and 13 of 25 developed a positive skin test response to the MART-1(27-35) peptide. Immune responses were measured by release of IFN-gamma in an ELISA assay by effector cells after multiple restimulations of peripheral blood mononuclear cells in the presence of MART-1(27-35) peptide-pulsed antigen-presenting cells. An ELISPOT assay was also developed to measure more quantitatively the change in numbers of peptide-specific effector cells after vaccination. Ten of 22 patients demonstrated an immune response to peptide-pulsed targets or tumor cells by ELISA assay after vaccination, as did 12 of 20 patients by ELISPOT. Nine of 25 patients have relapsed with a median of 16 months of follow-up, and 3 patients in this

  9. Melanoma

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Melanoma KidsHealth > For Teens > Melanoma Print A A A ... to the moles on your skin. What Is Melanoma? Melanoma is a type of cancer that begins ...

  10. Melanoma

    MedlinePlus

    Melanoma is the most serious type of skin cancer. Often the first sign of melanoma is a change in the size, shape, color, or feel of a mole. Most melanomas have a black or black-blue area. Melanoma ...

  11. Recombinant DNA technology for melanoma immunotherapy: anti-Id DNA vaccines targeting high molecular weight melanoma-associated antigen.

    PubMed

    Barucca, A; Capitani, M; Cesca, M; Tomassoni, D; Kazmi, U; Concetti, F; Vincenzetti, L; Concetti, A; Venanzi, F M

    2014-11-01

    Anti-idiotypic MK2-23 monoclonal antibody (anti-Id MK2-23 mAb), which mimics the high molecular weight melanoma-associated antigen (HMW-MAA), has been used to implement active immunotherapy against melanoma. However, due to safety and standardization issues, this approach never entered extensive clinical trials. In the present study, we investigated the usage of DNA vaccines as an alternative to MK2-23 mAb immunization. MK2-23 DNA plasmids coding for single chain (scFv) MK2-23 antibody were constructed via the insertion of variable heavy (V H) and light (V L) chains of MK2-23 into the pVAC-1mcs plasmids. Two alternative MK2-23 plasmids format V H/V L, and V L/V H were assembled. We demonstrate that both polypeptides expressed by scFv plasmids in vitro retained the ability to mimic HMW-MAA antigen, and to elicit specific anti-HMW-MAA humoral and cellular immunoresponses in immunized mice. Notably, MK2-23 scFv DNA vaccines impaired the onset and growth of transplantable B16 melanoma cells not engineered to express HMW-MAA. This pilot study suggests that optimized MK2-23 scFv DNA vaccines could potentially provide a safer and cost-effective alternative to anti-Id antibody immunization, for melanoma immunotherapy.

  12. Recombinant Interferon Alfa-2b in Treating Patients With Melanoma

    ClinicalTrials.gov

    2016-05-17

    Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma

  13. Vaccination of stage III/IV melanoma patients with long NY-ESO-1 peptide and CpG-B elicits robust CD8(+) and CD4(+) T-cell responses with multiple specificities including a novel DR7-restricted epitope.

    PubMed

    Baumgaertner, P; Costa Nunes, C; Cachot, A; Maby-El Hajjami, H; Cagnon, L; Braun, M; Derré, L; Rivals, J-P; Rimoldi, D; Gnjatic, S; Abed Maillard, S; Marcos Mondéjar, P; Protti, M P; Romano, E; Michielin, O; Romero, P; Speiser, D E; Jandus, C

    2016-01-01

    Long synthetic peptides and CpG-containing oligodeoxynucleotides are promising components for cancer vaccines. In this phase I trial, 19 patients received a mean of 8 (range 1-12) monthly vaccines s.c. composed of the long synthetic NY-ESO-179-108 peptide and CpG-B (PF-3512676), emulsified in Montanide ISA-51. In 18/18 evaluable patients, vaccination induced antigen-specific CD8(+) and CD4(+) T-cell and antibody responses, starting early after initiation of immunotherapy and lasting at least one year. The T-cells responded antigen-specifically, with strong secretion of IFNγ and TNFα, irrespective of patients' HLAs. The most immunogenic regions of the vaccine peptide were NY-ESO-189-102 for CD8(+) and NY-ESO-183-99 for CD4(+) T-cells. We discovered a novel and highly immunogenic epitope (HLA-DR7/NY-ESO-187-99); 7/7 HLA-DR7(+) patients generated strong CD4(+) T-cell responses, as detected directly ex vivo with fluorescent multimers. Thus, vaccination with the long synthetic NY-ESO-179-108 peptide combined with the strong immune adjuvant CpG-B induced integrated, robust and functional CD8(+) and CD4(+) T-cell responses in melanoma patients, supporting the further development of this immunotherapeutic approach.

  14. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice.

    PubMed

    Wang, Zili; Celis, Esteban

    2015-08-01

    Therapeutic vaccines to induce anti-tumor CD8 T cells have been used in clinical trials for advanced melanoma patients, but the clinical response rate and overall survival time have not improved much. We believe that these dismal outcomes are caused by inadequate number of antigen-specific CD8 T cells generated by most vaccines. In contrast, huge CD8 T cell responses readily occur during acute viral infections. High levels of type-I interferon (IFN-I) are produced during these infections, and this cytokine not only exhibits anti-viral activity but also promotes CD8 T cell responses. The studies described here were performed to determine whether promoting the production of IFN-I could enhance the potency of a peptide vaccine. We report that cyclic diguanylate monophosphate (c-di-GMP), which activates the stimulator of interferon genes, potentiated the immunogenicity and anti-tumor effects of a peptide vaccine against mouse B16 melanoma. The synergistic effects of c-di-GMP required co-administration of costimulatory anti-CD40 antibody, the adjuvant poly-IC, and were mediated in part by IFN-I. These findings demonstrate that peptides representing CD8 T cell epitopes can be effective inducers of large CD8 T cell responses in vaccination strategies that mimic acute viral infections.

  15. A multi-antigen vaccine in combination with an immunotoxin targeting tumor-associated fibroblast for treating murine melanoma

    PubMed Central

    Fang, Jinxu; Hu, Biliang; Li, Si; Zhang, Chupei; Liu, Yarong; Wang, Pin

    2016-01-01

    A therapeutically effective cancer vaccine must generate potent antitumor immune responses and be able to overcome tolerance mechanisms mediated by the progressing tumor itself. Previous studies showed that glycoprotein 100 (gp100), tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2) are promising immunogens for melanoma immunotherapy. In this study, we administered these three melanoma-associated antigens via lentiviral vectors (termed LV-3Ag) and found that this multi-antigen vaccine strategy markedly increased functional T-cell infiltration into tumors and generated protective and therapeutic antitumor immunity. We also engineered a novel immunotoxin, αFAP-PE38, capable of targeting fibroblast activation protein (FAP)-expressing fibroblasts within the tumor stroma. When combined with αFAP-PE38, LV-3Ag exhibited greatly enhanced antitumor effects on tumor growth in an established B16 melanoma model. The mechanism of action underlying this combination treatment likely modulates the immune suppressive tumor microenvironment and, consequently, activates cytotoxic CD8+ T cells capable of specifically recognizing and destroying tumor cells. Taken together, these results provide a strong rationale for combining an immunotoxin with cancer vaccines for the treatment of patients with advanced cancer. PMID:27119119

  16. Production and characterization of amplified tumor-derived cRNA libraries to be used as vaccines against metastatic melanomas

    PubMed Central

    Carralot, Jean-Philippe; Weide, Benjamin; Schoor, Oliver; Probst, Jochen; Scheel, Birgit; Teufel, Regina; Hoerr, Ingmar; Garbe, Claus; Rammensee, Hans-Georg; Pascolo, Steve

    2005-01-01

    Background Anti-tumor vaccines targeting the entire tumor antigen repertoire represent an attractive immunotherapeutic approach. In the context of a phase I/II clinical trial, we vaccinated metastatic melanoma patients with autologous amplified tumor mRNA. In order to provide the large quantities of mRNA needed for each patient, the Stratagene Creator™ SMART™ cDNA library construction method was modified and applied to produce libraries derived from the tumors of 15 patients. The quality of those mRNA library vaccines was evaluated through sequencing and microarray analysis. Results Random analysis of bacterial clones of the library showed a rate of 95% of recombinant plasmids among which a minimum of 51% of the clones contained a full-Open Reading Frame. In addition, despite a biased amplification toward small abundant transcripts compared to large rare fragments, we could document a relatively conserved gene expression profile between the total RNA of the tumor of origin and the corresponding in vitro transcribed complementary RNA (cRNA). Finally, listing the 30 most abundant transcripts of patient MEL02's library, a large number of tumor associated antigens (TAAs) either patient specific or shared by several melanomas were found. Conclusion Our results show that unlimited amounts of cRNA representing tumor's transcriptome could be obtained and that this cRNA was a reliable source of a large variety of tumor antigens. PMID:16115316

  17. Therapeutic efficacy of antigen-specific vaccination and toll-like receptor stimulation against established transplanted and autochthonous melanoma in mice.

    PubMed

    Tormo, Damia; Ferrer, Aleix; Bosch, Pilar; Gaffal, Evelyn; Basner-Tschakarjan, Etiena; Wenzel, Jörg; Tüting, Thomas

    2006-05-15

    Malignant melanoma is an attractive model disease for the development of antigen-specific immunotherapy because many antigens recognized by tumor-specific T cells have been identified. In C57BL/6 mice, genetic immunization with recombinant adenovirus encoding xenogeneic human tyrosinase-related protein 2 (Ad-hTRP2) induces protective but not therapeutic cellular immunity against growth of transplanted B16 melanoma cells. Here, we additionally applied CpG DNA and synthetic double-stranded RNA, which activate the innate immune system via Toll-like receptors (TLR). Both adenoviral vaccination and peritumoral injections of TLR ligands were required for rejection of established B16 melanoma in the skin. To more closely mimic the clinical situation in patients with melanoma, we evaluated this combined immunotherapeutic strategy in genetically modified mice, which overexpress hepatocyte growth factor (HGF) and carry an oncogenic mutation in the cyclin-dependent kinase 4 (CDK4)(R24C). HGF x CDK4(R24C) mice rapidly develop multiple invasive melanomas in the skin following neonatal carcinogen treatment, which spontaneously metastasize to lymph nodes and lungs. Vaccination with Ad-hTRP2 followed by injections of TLR ligands resulted in delayed growth of autochthonous primary melanomas in the skin and reduction in the number of spontaneous lung metastases but did not induce tumor regression. Carcinogen-treated HGF x CDK4(R24C) mice bearing multiple autochthonous melanomas did not reject transplanted B16 melanoma despite treatment with Ad-hTRP2 and TLR ligands, suggesting the development of tumor immunotolerance. Further investigations in our novel genetic melanoma model may help to better understand the role of the immune system in the pathogenesis and treatment of this life-threatening disease.

  18. Clinicopathologic features of incident and subsequent tumors in patients with multiple primary cutaneous melanomas

    PubMed Central

    Murali, Rajmohan; Goumas, Chris; Kricker, Anne; From, Lynn; Busam, Klaus J.; Begg, Colin B.; Dwyer, Terence; Gruber, Stephen B.; Kanetsky, Peter A.; Orlow, Irene; Rosso, Stefano; Thomas, Nancy E.; Berwick, Marianne; Scolyer, Richard A.; Armstrong, Bruce K.

    2011-01-01

    Background 0.6–12.7% of patients with primary cutaneous melanoma will develop additional melanomas. Pathologic features of tumors in patients with multiple primary cutaneous melanomas have not been well described. In this large international multi-center case-control study, we compared the clinicopathologic features of a subsequent melanoma with the preceding (usually the first) melanoma in patients with multiple primary cutaneous melanomas, and with those of melanomas in patients with single primary cutaneous melanomas. Methods Multiple primary melanoma (cases) and single primary invasive melanoma (controls) patients from the Genes, Environment and Melanoma (GEM) study were included if their tumors were available for pathologic review and confirmed as melanoma. Clinicopathologic characteristics of invasive subsequent and first melanomas in cases and invasive single melanomas in controls were compared. Results 473 pairs comprising a subsequent and a first melanoma and 1989 single melanomas were reviewed. Forward stepwise regression modeling in 395 pairs with complete data showed that, compared to first melanomas, subsequent melanomas were: more commonly contiguous with a dysplastic nevus; more prevalent on the head/neck and legs than other sites; and thinner. Compared with single primary melanomas, subsequent melanomas were also more likely to be: associated with a contiguous dysplastic nevus; more prevalent on the head/neck and legs; and thinner. The same differences were observed when subsequent melanomas were compared with single melanomas. First melanomas were more likely than single melanomas to have associated solar elastosis and no observed mitoses. Conclusions Thinner subsequent than first melanomas suggest earlier diagnosis, perhaps due to closer clinical scrutiny. The association of subsequent melanomas with dysplastic nevi is consistent with the latter being risk factors or risk markers for melanoma. PMID:21913010

  19. Adjuvant Vaccine Immunotherapy of Resected, Clinically Node-negative Melanoma: Long-Term Outcome and Impact of HLA Class I Antigen Expression on Overall Survival

    PubMed Central

    Carson, William E.; Unger, Joseph M.; Sosman, Jeffrey A.; Flaherty, Lawrence E.; Tuthill, Ralph J.; Porter, Mark J.; Thompson, John A.; Kempf, Raymond A.; Othus, Megan; Ribas, Antoni; Sondak, Vernon K.

    2014-01-01

    Associations between HLA class I antigen expression and efficacy of a melanoma vaccine (Melacine) were initially described in stage IV melanoma. Similar associations were observed in S9035, a phase III adjuvant trial evaluating Melacine for two years versus observation in patients with stage II melanoma. This report provides long-term results. The effects of treatment on relapse-free survival (RFS) and overall survival (OS) were evaluated, and pre-specified analyses investigated associations between treatment and HLA expression. Multivariable analyses were adjusted for tumor thickness, ulceration and site, method of nodal staging and sex. P=.01 was considered significant in subset analyses to account for multiple comparisons. For the entire study population of 689 patients, there were no significant differences in RFS or OS by arm. HLA serotyping was performed on 553 (80%) patients (vaccine 294, observation 259). Among the subpopulation with HLA-A2 and/or HLA-Cw3 serotype, vaccine arm patients (n=178) had marginally improved RFS (adjusted P=.02) and significantly improved OS compared with observation arm patients (n=145), with 10-year OS of 75% and 63%, respectively (hazard ratio 0.62, 99% CI 0.37-1.02, P=.01). There was no impact of HLA-A2 and/or HLA-Cw3 expression among observation arm patients. Analysis of mature data from S9035 indicates a significant OS benefit from adjuvant vaccine therapy for HLA-A2- and/or HLA-Cw3-expressing melanoma patients. The possibility of interactions between HLA type and outcome should be considered in future immunotherapy trials. Further investigations of melanoma-associated antigens present in Melacine and presented by HLA-A2 and HLA-Cw3 may be warranted. PMID:24994597

  20. PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8+ T cells induced by melanoma vaccines

    PubMed Central

    Fourcade, Julien; Sun, Zhaojun; Pagliano, Ornella; Chauvin, Joe-Marc; Sander, Cindy; Janjic, Bratislav; Tarhini, Ahmad A.; Tawbi, Hussein A.; Kirkwood, John M.; Moschos, Stergios; Wang, Hong; Guillaume, Philippe; Luescher, Immanuel F.; Krieg, Arthur; Anderson, Ana C.; Kuchroo, Vijay K.; Zarour, Hassane M.

    2014-01-01

    Although melanoma vaccines stimulate tumor antigen (TA)-specific CD8+ T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8+ T cells with regard to the inhibitory T cell co-receptors PD-1 and Tim-3 in metastatic melanoma patients who were administered tumor vaccines. The vaccines included incomplete Freund's adjuvant (IFA), CpG oligodeoxynucleotide (CpG) and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid TA-specific CD8+ T-cell responses detected ex vivo, however, TA-specific CD8+ T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8+ T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8+ T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8+ T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T cell responses and increase the likelihood of clinical responses in advanced melanoma patients. PMID:24343228

  1. Interactions from complementary and alternative medicine in patients with melanoma.

    PubMed

    Loquai, Carmen; Schmidtmann, Irene; Garzarolli, Marlene; Kaatz, Martin; Kähler, Katharina C; Kurschat, Peter; Meiss, Frank; Micke, Oliver; Muecke, Ralph; Muenstedt, Karsten; Nashan, Dorothee; Stein, Annette; Stoll, Christoph; Dechent, Dagmar; Huebner, Jutta

    2017-03-01

    Biological-based (BbCAM) methods from complementary and alternative medicine (CAM) may interact with cancer treatments, reduce efficacy, or enhance adverse effects. Although CAM usage has been evaluated well in other cancer entities, data on melanoma patients are still missing. The aim of this study was to determine CAM usage of melanoma patients using a standardized questionnaire to identify potential interactions with established and new systemic melanoma therapies. This multicenter study was carried out in seven German skin cancer centers. During routine care contact, CAM usage of former and current melanoma treatment was assessed in melanoma patients. The probability of interaction was classified into four categories ranging from 'interaction unlikely' (I), 'possible' (II), 'likely' (III), or 'no data' (IV). The questionnaire was filled out by 1157 patients, of whom 1089 were eligible for evaluation. CAM usage was reported by 41% of melanoma patients, of whom 63.1% took BbCAM such as vitamins, trace elements, supplements, or phytotherapeuticals. Of 335 patients with former or current therapy, 28.1% used BbCAM. The melanoma treatment included interferon, radiotherapy, chemotherapy, BRAF-inhibitor, or other tyrosine kinase inhibitors and ipilimumab. On the basis of our model of likelihood of interaction, we found that 23.9% of those on cancer therapy and 85.1% of those also using BbCAM were at some risk of interactions. The main limitation of our study is that no reliable and comprehensive database on clinical relevant interactions with CAM in oncology exists. Most patients receiving a melanoma-specific treatment and using BbCAM methods are at risk for interactions, which raises concerns on the safety and treatment efficacy of these patients. To protect melanoma patients from potential harm by the combination of their cancer treatment and CAM usage, patients should systematically be encouraged to report their CAM use, while oncologists should be trained on

  2. High nevus counts confer a favorable prognosis in melanoma patients.

    PubMed

    Ribero, Simone; Davies, John R; Requena, Celia; Carrera, Cristina; Glass, Daniel; Rull, Ramon; Vidal-Sicart, Sergi; Vilalta, Antonio; Alos, Lucia; Soriano, Virtudes; Quaglino, Pietro; Traves, Victor; Newton-Bishop, Julia A; Nagore, Eduardo; Malvehy, Josep; Puig, Susana; Bataille, Veronique

    2015-10-01

    A high number of nevi is the most significant phenotypic risk factor for melanoma and is in part genetically determined. The number of nevi decreases from middle age onward but this senescence can be delayed in patients with melanoma. We investigated the effects of nevus number count on sentinel node status and melanoma survival in a large cohort of melanoma cases. Out of 2,184 melanoma cases, 684 (31.3%) had a high nevus count (>50). High nevus counts were associated with favorable prognostic factors such as lower Breslow thickness, less ulceration and lower mitotic rate, despite adjustment for age. Nevus count was not predictive of sentinel node status. The crude 5- and 10-year melanoma-specific survival rate was higher in melanomas cases with a high nevus count compared to those with a low nevus count (91.2 vs. 86.4% and 87.2 vs. 79%, respectively). The difference in survival remained significant after adjusting for all known melanoma prognostic factors (hazard ratio [HR] = 0.43, confidence interval [CI] = 0.21-0.89). The favorable prognostic value of a high nevus count was also seen within the positive sentinel node subgroup of patients (HR = 0.22, CI = 0.08-0.60). High nevus count is associated with a better melanoma survival, even in the subgroup of patients with positive sentinel lymph node. This suggests a different biological behavior of melanoma tumors in patients with an excess of nevi.

  3. Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma.

    PubMed

    Finocchiaro, L M E; Glikin, G C

    2008-02-01

    We evaluated the safety, efficacy and anti-tumor effects of a surgery adjuvant treatment on canine patients with malignant melanoma. This approach combined suicide gene therapy with a subcutaneous vaccine composed by formolized tumor cells and irradiated xenogeneic cells producing human interleukin-2 and granulocyte-macrophage colony-stimulating factor. The post-surgical margin of the cavity was infiltrated with lipid-complexed thymidine kinase suicide gene coadministrated with ganciclovir. Toxicity was minimal or absent in all patients. With respect to surgery-treated controls (SC), this combined treatment (CT) significantly increased the fraction of patients local disease-free from 6 to 58% and distant metastases-free from 43 to 78% (Fisher's Exact test). In addition, CT significantly improved both SC overall 78 (23-540) and metastasis-free survival 112 (0-467) days to more than 1312 days (respective ranges: 43-1312 and 0-1312) (Kaplan-Meier analysis). In those patients subjected to partial surgery or presenting local recurrence, the efficacy of CT was verified by a 49% of objective responses that averaged 85% of tumor mass loss, while 22% displayed tumor progression as 94% of SC did. Therefore, surgery adjuvant CT controlled tumor growth, delaying or preventing post-surgical recurrence and distant metastasis, significantly extending survival and recovering the quality of life.

  4. A pilot Phase I study combining peptide-based vaccination and NGR-hTNF vessel targeting therapy in metastatic melanoma.

    PubMed

    Parmiani, Giorgio; Pilla, Lorenzo; Corti, Angelo; Doglioni, Claudio; Cimminiello, Carolina; Bellone, Matteo; Parolini, Danilo; Russo, Vincenzo; Capocefalo, Filippo; Maccalli, Cristina

    2014-11-01

    Administration of NGR-TNF, a tumor vessel-targeting and tumor necrosis factor α TNFα) peptide conjugate, with immunotherapy has been shown to inhibit tumor growth in mice. Thus, we planned a Phase I pilot clinical trial to assess safety, immune and clinical response of this combination treatment for advanced melanoma. NA17.A2 and MAGE-3.A1 peptides were used as vaccine. HLA-A*0201 or HLA-A*01 metastatic melanoma patients received human NGR-hTNF i.v. alternating with s.c. weekly injections of either of the peptides emulsified in Montanide. The T-cell response was assessed ex-vivo using peripheral blood mononuclear cells (PBMCs) before, during and after therapy. The serum level of chromogranin A (CgA), soluble TNF receptors (sTNFR1/2), vascular endothelial growth factor (VEGF), and MIP-1β and MCP-1 chemokines, was determined. In 3 subjects, pre- and post-treatment tumor lesions were examined by immunohistochemistry. Clinically, chills were observed in 4 patients during NGR-hTNF infusion and erythema at vaccination site was seen in 7 patients. T-cell response against the vaccine or against other melanoma-associated antigens was detectable after treatment in 6 out of 7 tested patients. Low level or reduction of CgA and sTNFR and increase of MIP-1β and MCP-1 were found in patients sera. In the lesions examined the immune infiltrate was scanty but macrophage number increased in post-therapy lesions. From a clinical standpoint, a long term survival (>4 months) was found in 6 out of 8 evaluable patients (4, 4, 7, 11, 23+, 25+, 25+, 29+ months). The combination of NGR-hTNF and vaccine in metastatic melanoma patients was well tolerated, often associated with an ex-vivo T cell response and long-term overall survival. These findings warrant confirmation in a larger group of patients.

  5. Vaccination with a human high molecular weight melanoma-associated antigen mimotope induces a humoral response inhibiting melanoma cell growth in vitro.

    PubMed

    Wagner, Stefan; Hafner, Christine; Allwardt, Dorothee; Jasinska, Joanna; Ferrone, Soldano; Zielinski, Christoph C; Scheiner, Otto; Wiedermann, Ursula; Pehamberger, Hubert; Breiteneder, Heimo

    2005-01-15

    Peptide mimics of a conformational epitope that is recognized by a mAb with antitumor activity are promising candidates for formulations of anticancer vaccines. These mimotope vaccines are able to induce a polyclonal Ab response focused to the determinant of the mAb. Such attempts at cancer immunotherapy are of special interest for malignant melanoma that is highly resistant to chemotherapy and radiotherapy. In this study, we describe for the first time the design and immunogenicity of a vaccine containing a mimotope of the human high m.w. melanoma-associated Ag (HMW-MAA) and the biological potential of the induced Abs. Mimotopes were selected from a pVIII-9mer phage display peptide library with the anti-HMW-MAA mAb 225.28S. The mimotope vaccine was then generated by coupling the most suitable candidate mimotope to tetanus toxoid as an immunogenic carrier. Immunization of rabbits with this vaccine induced a specific humoral immune response directed toward the epitope recognized by the mAb 225.28S on the native HMW-MAA. The induced Abs inhibited the in vitro growth of the melanoma cell line 518A2 up to 62%. In addition, the Abs mediated 26% lysis of 518A2 cells in Ab-dependent cellular cytotoxicity. Our results indicate a possible application of this mimotope vaccine as a novel immunotherapeutic agent for the treatment of malignant melanoma.

  6. New Therapies Offer Valuable Options for Patients with Melanoma

    Cancer.gov

    Two phase III clinical trials of new therapies for patients with metastatic melanoma presented in June at the 2011 ASCO conference confirmed that vemurafenib and ipilimumab (Yervoy™) offer valuable new options for the disease.

  7. Enrichment of circulating melanoma cells (CMCs) using negative selection from patients with metastatic melanoma

    PubMed Central

    Joshi, Powrnima; Jacobs, Barbara; Derakhshan, Adeeb; Moore, Lee R.; Elson, Paul; Triozzi, Pierre L.; Borden, Ernest; Zborowski, Maciej

    2014-01-01

    Circulating tumor cells have emerged as prognostic biomarkers in the treatment of metastatic cancers of epithelial origins viz., breast, colorectal and prostate. These tumors express Epithelial Cell Adhesion Molecule (EpCAM) on their cell surface which is used as an antigen for immunoaffinity capture. However, EpCAM capture technologies are of limited utility for non-epithelial cancers such as melanoma. We report a method to enrich Circulating Melanoma Cells (CMCs) that does not presuppose malignant cell characteristics. CMCs were enriched by centrifugation of blood samples from healthy (N = 10) and patient (N = 11) donors, followed by RBC lysis and immunomagnetic depletion of CD45-positive leukocytes in a specialized magnetic separator. CMCs were identified by immunocytochemistry using Melan-A or S100B as melanoma markers and enumerated using automated microscopy image analyses. Separation was optimized for maximum sensitivity and recovery of CMCs. Our results indicate large number of CMCs in Stage IV melanoma patients. Analysis of survival suggested a trend toward decreased survival with increased number of CMCs. Moreover, melanoma-associated miRs were found to be higher in CMC-enriched fractions in two patients when compared with the unseparated samples, validating this method as applicable for molecular analyses. Negative selection is a promising approach for isolation of CMCs and other EpCAM -negative CTCs, and is amenable to molecular analysis of CMCs. Further studies are required to validate its efficacy at capturing specific circulating cells for genomic analysis, and xenograft studies. PMID:24811334

  8. Enrichment of circulating melanoma cells (CMCs) using negative selection from patients with metastatic melanoma.

    PubMed

    Joshi, Powrnima; Jacobs, Barbara; Derakhshan, Adeeb; Moore, Lee R; Elson, Paul; Triozzi, Pierre L; Borden, Ernest; Zborowski, Maciej

    2014-05-15

    Circulating tumor cells have emerged as prognostic biomarkers in the treatment of metastatic cancers of epithelial origins viz., breast, colorectal and prostate. These tumors express Epithelial Cell Adhesion Molecule (EpCAM) on their cell surface which is used as an antigen for immunoaffinity capture. However, EpCAM capture technologies are of limited utility for non-epithelial cancers such as melanoma. We report a method to enrich Circulating Melanoma Cells (CMCs) that does not presuppose malignant cell characteristics. CMCs were enriched by centrifugation of blood samples from healthy (N = 10) and patient (N = 11) donors, followed by RBC lysis and immunomagnetic depletion of CD45-positive leukocytes in a specialized magnetic separator. CMCs were identified by immunocytochemistry using Melan-A or S100B as melanoma markers and enumerated using automated microscopy image analyses. Separation was optimized for maximum sensitivity and recovery of CMCs. Our results indicate large number of CMCs in Stage IV melanoma patients. Analysis of survival suggested a trend toward decreased survival with increased number of CMCs. Moreover, melanoma-associated miRs were found to be higher in CMC-enriched fractions in two patients when compared with the unseparated samples, validating this method as applicable for molecular analyses. Negative selection is a promising approach for isolation of CMCs and other EpCAM -negative CTCs, and is amenable to molecular analysis of CMCs. Further studies are required to validate its efficacy at capturing specific circulating cells for genomic analysis, and xenograft studies.

  9. Tumor-reactive CD4+ T cell responses to the melanoma-associated chondroitin sulphate proteoglycan in melanoma patients and healthy individuals in the absence of autoimmunity.

    PubMed

    Erfurt, Cornelia; Sun, Zhaojun; Haendle, Ina; Schuler-Thurner, Beatrice; Heirman, Carlo; Thielemans, Kris; van der Bruggen, Pierre; Schuler, Gerold; Schultz, Erwin S

    2007-06-15

    To avoid immune escape by down-regulation or loss of Ag by the tumor cells, target Ags are needed, which are important for the malignant phenotype and survival of the tumor. We could identify a CD4(+) T cell epitope derived from the human melanoma-associated chondroitin sulfate proteoglycan (MCSP) (also known as high m.w.-melanoma-associated Ag), which is strongly expressed on >90% of human melanoma lesions and is important for the motility and invasion of melanoma cells. However, MCSP is not strictly tumor specific, because it is also expressed in a variety of normal tissues. Therefore, self tolerance should prevent the induction of strong T cell responses against these Ags by vaccination strategies. In contrast, breaking self tolerance to this Ag by effectively manipulating the immune system might mediate antitumor responses, although it would bear the risk of autoimmunity. Surprisingly, we could readily isolate CD4(+) Th cells from the blood of a healthy donor-recognizing peptide MCSP(693-709) on HLA-DR11-expressing melanoma cells. Broad T cell reactivity against this Ag could be detected in the peripheral blood of both healthy donors and melanoma patients, without any apparent signs of autoimmune disease. In some patients, a decline of T cell reactivity was observed upon tumor progression. Our data indicate that CD4(+) T cells are capable of recognizing a membrane glycoprotein that is important in melanoma cell function, and it may be possible that the sizable reactivity to this Ag in most normal individuals contributes to immune surveillance against cancer.

  10. Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher Risk Primary Melanoma

    PubMed Central

    Thomas, Nancy E.; Edmiston, Sharon N.; Alexander, Audrey; Groben, Pamela A.; Parrish, Eloise; Kricker, Anne; Armstrong, Bruce K.; Anton-Culver, Hoda; Gruber, Stephen B.; From, Lynn; Busam, Klaus J.; Hao, Honglin; Orlow, Irene; Kanetsky, Peter A.; Luo, Li; Reiner, Anne S.; Paine, Susan; Frank, Jill S.; Bramson, Jennifer I.; Marrett, Lorraine D.; Gallagher, Richard P.; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Cust, Anne E.; Ollila, David W.; Begg, Colin B.; Berwick, Marianne; Conway, Kathleen

    2015-01-01

    Importance NRAS and BRAF mutations in melanoma inform current treatment paradigms but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. Objective To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. Design, Setting, and Participants A population-based study with median follow-up of 7.6 years for 912 patients with first primary cutaneous melanoma analyzed for NRAS and BRAF mutations diagnosed in the year 2000 from the United States and Australia in the Genes, Environment and Melanoma Study and followed through 2007. Main Outcomes and Measures Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. Results The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype). In a multivariable model including clinicopathologic characteristics, NRAS+ melanoma was associated (P<.05) with mitoses, lower tumor infiltrating lymphocyte (TIL) grade, and anatomic site other than scalp/neck and BRAF+ melanoma was associated with younger age, superficial spreading subtype, and mitoses, relative to wildtype melanoma. There was no significant difference in melanoma-specific survival for melanoma harboring mutations in NRAS (HR 1.7, 95% CI, 0.8–3.4) or BRAF (HR, 1.5, 95% CI, 0.8–2.9) compared to wildtype melanoma adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher risk (T2b or higher stage) tumors with NRAS (HR 2.9; 95% CI 1.1–7.7) or BRAF (HR 3.1; 95% CI 1.2–8.5) mutations but not for lower risk (T2a or lower) tumors (P=.65) adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center

  11. Current clinical overview of cutaneous melanoma.

    PubMed

    Lens, Marko

    This article reviews current evidence on epidemiology, diagnosis and management of cutaneous melanoma. Incidence of cutaneous melanoma is rising in all Caucasian populations across the world; thus, melanoma represents a significant public health burden. Although, incidence of melanoma is in continuous increase, a decrease of mortality and improved survival has been observed in most western European populations. Clinical characteristics of four major types of melanoma (superficial spreading, nodular, lentigo maligna melanoma and acral lentiginous melanoma) have been described. Surgical removal of melanoma remains the standard care in all primary melanomas. Current evidence suggests use of 1 to 2 cm excision margins. Wider margins may be necessary in patients with thicker melanomas with higher risk for local recurrence. In the treatment of regional lymph nodes elective lymphadenectomy has been surpassed by the sentinel lymph node biopsy (SLNB). However, although prognostic value of SLNB has been confirmed, its therapeutical benefit still needs to be evaluated. Currently there is no standard adjuvant therapy for melanoma although interferon-alpha has been the most widely used treatment in the adjuvant setting. The role of metastasectomy (removal of distant metastases) is still controversial. Chemotherapeutic agents have a limited activity in patients with metastatic melanoma with response rates up to 25%. Although different vaccines have been tested in melanoma patients their role still remain to be established in phase III trials. Progresses in molecular biology and genetics of melanoma may lead to the development of novel melanoma therapies.

  12. Melanoma

    MedlinePlus

    ... flat or raised, large or small, light or dark, and can appear anywhere on our bodies. Sometimes, ... can still get melanoma even if they're dark skinned, young, and have no family history. Even ...

  13. Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma: A Trial of the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group (E4697)

    PubMed Central

    Lawson, David H.; Lee, Sandra; Zhao, Fengmin; Tarhini, Ahmad A.; Margolin, Kim A.; Ernstoff, Marc S.; Atkins, Michael B.; Cohen, Gary I.; Whiteside, Theresa L.; Butterfield, Lisa H.; Kirkwood, John M.

    2015-01-01

    Purpose We conducted a double-blind, placebo-controlled trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in patients with resected high-risk melanoma. Patients and Methods Patients with completely resected stage IV or high-risk stage III melanoma were grouped by human leukocyte antigen (HLA) -A2 status. HLA-A2–positive patients were randomly assigned to receive GM-CSF, PV, both, or placebo; HLA-A2–negative patients, GM-CSF or placebo. Treatment lasted for 1 year or until recurrence. Efficacy analyses were conducted in the intent-to-treat population. Results A total of 815 patients were enrolled. There were no significant improvements in OS (stratified log-rank P = .528; hazard ratio, 0.94; 95% repeated CI, 0.77 to 1.15) or RFS (P = .131; hazard ratio, 0.88; 95% CI, 0.74 to 1.04) in the patients assigned to GM-CSF (n = 408) versus those assigned to placebo (n = 407). The median OS times with GM-CSF versus placebo treatments were 69.6 months (95% CI, 53.4 to 83.5 months) versus 59.3 months (95% CI, 44.4 to 77.3 months); the 5-year OS probability rates were 52.3% (95% CI, 47.3% to 57.1%) versus 49.4% (95% CI, 44.3% to 54.3%), respectively. The median RFS times with GM-CSF versus placebo were 11.4 months (95% CI, 9.4 to 14.8 months) versus 8.8 months (95% CI, 7.5 to 11.2 months); the 5-year RFS probability rates were 31.2% (95% CI, 26.7% to 35.9%) versus 27.0% (95% CI, 22.7% to 31.5%), respectively. Exploratory analyses showed a trend toward improved OS in GM-CSF–treated patients with resected visceral metastases. When survival in HLA-A2–positive patients who received PV versus placebo was compared, RFS and OS were not significantly different. Treatment-related grade 3 or greater adverse events were similar between GM-CSF and placebo groups. Conclusion Neither adjuvant GM-CSF nor PV significantly improved RFS or OS in patients with high

  14. The use of interferon in melanoma patients: a systematic review.

    PubMed

    Di Trolio, Rossella; Simeone, Ester; Di Lorenzo, Giuseppe; Buonerba, Carlo; Ascierto, Paolo Antonio

    2015-04-01

    Interferon (IFN) and PEG-IFN are the only drugs approved as adjuvant therapy in patients with melanoma at high-risk of recurrence after surgical resection. Several clinical trials of adjuvant IFN, using different doses and durations of therapy, have been conducted in these patients. Results generally suggest relapse-free survival and overall survival benefits; however, questions over the optimal dose and duration of treatment and concerns over toxicity have limited its use. IFN exerts its biological activity in melanoma via multiple mechanisms of action, most of which can be considered as indirect immunomodulatory effects. As such, IFN may also be of benefit in the neoadjuvant setting, where it may have a role in melanoma patients with locally advanced disease for whom immediate surgical excision is not possible. However, this has not been well studied. The use of IFN in patients with metastatic melanoma is controversial, with limited data and no convincing evidence of a survival benefit. However, IFN therapy combined with novel biological and immunotherapies offers the potential for a synergistic effect and improved clinical outcomes. Predictive and prognostic factors to better select melanoma patients for IFN treatment have been identified (e.g. disease stage, ulceration, various cytokines) and may also enhance its therapeutic efficacy, but their incorporation into the clinical decision-making process requires validation in prospective trials. In conclusion, the modest efficacy of IFN shown in clinical trials is largely a reflection of differences in response between patients. Despite advancements in the understanding of its biological mechanisms of action, the huge potential of IFN remains to be fully explored and utilized in patients with melanoma.

  15. Fine analysis of spontaneous MAGE-C1/CT7–specific immunity in melanoma patients

    PubMed Central

    Curioni-Fontecedro, Alessandra; Matter, Claudia; Soldini, Davide; Tiercy, Jean Marie; von Boehmer, Lotta; Moch, Holger; Dummer, Reinhard; Knuth, Alexander; van den Broek, Maries

    2010-01-01

    Cancer/testis (CT) antigens represent prime candidates for immunotherapy in cancer patients, because their expression is restricted to cancer cells and germ cells of the testis. MAGE-C1/CT7 is a CT antigen that is highly expressed in several types of cancers. Spontaneous occurrence of CT7-specific antibodies was previously detected by SEREX screen in a melanoma patient. However, naturally occurring CT7-specific T-cell responses have thus far not been detected. Peripheral blood mononuclear cells (PBMCs) from 26 metastatic melanoma patients expressing CT7 in their tumor lesions (CT7+) were analyzed for CT7-specific T-cell responses using overlapping peptides. CT7-specific CD4+ T-cell responses were detected in three patients (11.5%). These CT7-specific CD4+ T-cell responses were detectable in melanoma patients’ PBMCs exclusively from preexisting CD45RA− memory CD4+ T-cell pool. Additional CT7-specific memory CD4+ T-cell responses were detected in CT7+ melanoma patients after depletion of CD4+CD25high Treg cells showing that Treg cells impact on CT7-specific CD4+ T cells in melanoma patients. CT7-specific CD4+ T-cell clones were generated and used to define minimal epitopes, restriction elements, and confirm the recognition of naturally processed antigen. Surprisingly, these clones were able to secrete perforin and exert cytotoxicity. This study shows that CT7 can induce specific cellular immunity in melanoma patients. Based on these findings, CT7 will be further explored as a potential vaccine for melanoma immunotherapy. PMID:20696919

  16. Efficiency of Dendritic Cell Vaccination against B16 Melanoma Depends on the Immunization Route

    PubMed Central

    Edele, Fanny; Dudda, Jan C.; Bachtanian, Eva; Jakob, Thilo; Pircher, Hanspeter; Martin, Stefan F.

    2014-01-01

    Dendritic cells (DC) presenting tumor antigens are crucial to induce potent T cell-mediated anti-tumor immune responses. Therefore DC-based cancer vaccines have been established for therapy, however clinical outcomes are often poor and need improvement. Using a mouse model of B16 melanoma, we found that the route of preventive DC vaccination critically determined tumor control. While repeated DC vaccination did not show an impact of the route of DC application on the prevention of tumor growth, a single DC vaccination revealed that both the imprinting of skin homing receptors and an enhanced proliferation state of effector T cells was seen only upon intracutaneous but not intravenous or intraperitoneal immunization. Tumor growth was prevented only by intracutaneous DC vaccination. Our results indicate that under suboptimal conditions the route of DC vaccination crucially determines the efficiency of tumor defense. DC-based strategies for immunotherapy of cancer should take into account the immunization route in order to optimize tissue targeting of tumor antigen specific T cells. PMID:25121970

  17. Prophylactic Dendritic Cell-Based Vaccines Efficiently Inhibit Metastases in Murine Metastatic Melanoma.

    PubMed

    Markov, Oleg V; Mironova, Nadezhda L; Sennikov, Sergey V; Vlassov, Valentin V; Zenkova, Marina A

    2015-01-01

    Recent data on the application of dendritic cells (DCs) as anti-tumor vaccines has shown their great potential in therapy and prophylaxis of cancer. Here we report on a comparison of two treatment schemes with DCs that display the models of prophylactic and therapeutic vaccination using three different experimental tumor models: namely, Krebs-2 adenocarcinoma (primary tumor), melanoma (B16, metastatic tumor without a primary node) and Lewis lung carcinoma (LLC, metastatic tumor with a primary node). Dendritic cells generated from bone marrow-derived DC precursors and loaded with lysate of tumor cells or transfected with the complexes of total tumor RNA with cationic liposomes were used for vaccination. Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-rac-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection. It was shown that DCs loaded with tumor lysate were ineffective in contrast to tumor-derived RNA. Therapeutic vaccination with DCs loaded by lipoplexes RNA/Lipofectamine 2000 was the most efficient for treatment of non-metastatic Krebs-2, where a 1.9-fold tumor growth retardation was observed. Single prophylactic vaccination with DCs loaded by lipoplexes RNA/2D3 was the most efficient to treat highly aggressive metastatic tumors LLC and B16, where 4.7- and 10-fold suppression of the number of lung metastases was observed, respectively. Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found. Failure of double prophylactic vaccination is explained by Th17-response polarization associated with autoimmune and pro-inflammatory reactions. In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless

  18. Cytokine-Enhanced Vaccine and Interferon-β plus Suicide Gene Therapy as Surgery Adjuvant Treatments for Spontaneous Canine Melanoma

    PubMed Central

    Fondello, Chiara; Gil-Cardeza, María L.; Rossi, Úrsula A.; Villaverde, Marcela S.; Riveros, María D.; Glikin, Gerardo C.

    2015-01-01

    Abstract We present here a nonviral immunogene therapy trial for canine malignant melanoma, an aggressive disease displaying significant clinical and histopathological overlapping with human melanoma. As a surgery adjuvant approach, it comprised the co-injection of lipoplexes bearing herpes simplex virus thymidine kinase and canine interferon-β genes at the time of surgery, combined with the periodic administration of a subcutaneous genetic vaccine composed of tumor extracts and lipoplexes carrying the genes of human interleukin-2 and human granulocyte-macrophage colony-stimulating factor. Following complete surgery (CS), the combined treatment (CT) significantly raised the portion of local disease-free canine patients from 11% to 83% and distant metastases-free (M0) from 44% to 89%, as compared with surgery-only-treated controls (ST). Even after partial surgery (PS), CT better controlled the systemic disease (M0: 82%) than ST (M0: 48%). Moreover, compared with ST, CT caused a significant 7-fold (CS) and 4-fold (PS) rise of overall survival, and >17-fold (CS) and >13-fold (PS) rise of metastasis-free survival. The dramatic increase of PS metastasis-free survival (>1321 days) and CS recurrence- and metastasis-free survival (both >2251 days) demonstrated that CT was shifting a rapidly lethal disease into a chronic one. In conclusion, this surgery adjuvant CT was able of significantly delaying or preventing postsurgical recurrence and distant metastasis, increasing disease-free and overall survival, and maintaining the quality of life. The high number of canine patients involved in CT (301) and the extensive follow-up (>6 years) with minimal or absent toxicity warrant the long-term safety and efficacy of this treatment. This successful clinical outcome justifies attempting a similar scheme for human melanoma. PMID:25762364

  19. Cytokine-Enhanced Vaccine and Interferon-β plus Suicide Gene Therapy as Surgery Adjuvant Treatments for Spontaneous Canine Melanoma.

    PubMed

    Finocchiaro, Liliana M E; Fondello, Chiara; Gil-Cardeza, María L; Rossi, Úrsula A; Villaverde, Marcela S; Riveros, María D; Glikin, Gerardo C

    2015-06-01

    We present here a nonviral immunogene therapy trial for canine malignant melanoma, an aggressive disease displaying significant clinical and histopathological overlapping with human melanoma. As a surgery adjuvant approach, it comprised the co-injection of lipoplexes bearing herpes simplex virus thymidine kinase and canine interferon-β genes at the time of surgery, combined with the periodic administration of a subcutaneous genetic vaccine composed of tumor extracts and lipoplexes carrying the genes of human interleukin-2 and human granulocyte-macrophage colony-stimulating factor. Following complete surgery (CS), the combined treatment (CT) significantly raised the portion of local disease-free canine patients from 11% to 83% and distant metastases-free (M0) from 44% to 89%, as compared with surgery-only-treated controls (ST). Even after partial surgery (PS), CT better controlled the systemic disease (M0: 82%) than ST (M0: 48%). Moreover, compared with ST, CT caused a significant 7-fold (CS) and 4-fold (PS) rise of overall survival, and >17-fold (CS) and >13-fold (PS) rise of metastasis-free survival. The dramatic increase of PS metastasis-free survival (>1321 days) and CS recurrence- and metastasis-free survival (both >2251 days) demonstrated that CT was shifting a rapidly lethal disease into a chronic one. In conclusion, this surgery adjuvant CT was able of significantly delaying or preventing postsurgical recurrence and distant metastasis, increasing disease-free and overall survival, and maintaining the quality of life. The high number of canine patients involved in CT (301) and the extensive follow-up (>6 years) with minimal or absent toxicity warrant the long-term safety and efficacy of this treatment. This successful clinical outcome justifies attempting a similar scheme for human melanoma.

  20. The Effect of Vector Silencing during Picornavirus Vaccination against Experimental Melanoma and Glioma

    PubMed Central

    Renner, Danielle N.; Huseby Kelcher, April M.; Jin, Fang; Hansen, Michael J.; Pavelko, Kevin D.; Johnson, Aaron J.

    2016-01-01

    Virus vector-based vaccination against tumor-specific antigens remains a promising therapeutic approach to overcome the immune suppressive tumor microenvironment. However, the extent that the desired CD8 T cell response against the targeted tumor antigen is impacted by the CD8 T cell response against the virus vector is unclear. To address this question, we used picornavirus vaccination with Theiler’s murine encephalomyelitis virus (TMEV) as our vector against tumor-expressed ovalbumin (OVA257-264) antigen in both the B16-OVA murine melanoma and GL261-quad cassette murine glioma models. Prior to vaccination, we employed vector silencing to inhibit the CD8 T cell response against the immunodominant TMEV antigen, VP2121-130. We then monitored the resulting effect on the CD8 T cell response against the targeted tumor-specific antigen, ovalbumin. We demonstrate that employing vector silencing in the context of B16-OVA melanoma does not reduce tumor burden or improve survival, while TMEV-OVA vaccination without vector silencing controls tumor burden. Meanwhile, employing vector silencing during picornavirus vaccination against the GL261-quad cassette glioma resulted in a lower frequency of tumor antigen-specific CD8 T cells. The results of this study are relevant to antigen-specific immunotherapy, in that the virus vector-specific CD8 T cell response is not competing with tumor antigen-specific CD8 T cells. Furthermore, vector silencing may have the adverse consequence of reducing the tumor antigen-specific CD8 T cell response, as demonstrated by our findings in the GL261-quad cassette model. PMID:27560502

  1. Curcumin Micelles Remodel Tumor Microenvironment and Enhance Vaccine Activity in an Advanced Melanoma Model

    PubMed Central

    Lu, Yao; Miao, Lei; Wang, Yuhua; Xu, Zhenghong; Zhao, Yi; Shen, Youqing; Xiang, Guangya; Huang, Leaf

    2016-01-01

    Previously, we have reported a lipid-based Trp2 peptide vaccine for immunotherapy against melanoma. The suppressive immune microenvironment in the tumor is a major hurdle for an effective vaccine therapy. We hypothesized that curcumin (CUR) would remodel the tumor microenvironment to improve the vaccine activity. Curcumin–polyethylene glycol conjugate (CUR–PEG), an amphiphilic CUR-based micelle, was delivered intravenously (i.v.) to the tumor. Indeed, in the B16F10 tumor–bearing mice, the combination of CUR–PEG and vaccine treatment resulted in a synergistic antitumor effect (P < 0.001) compared to individual treatments. In the immune organs, the combination therapy significantly boosted in vivo cytotoxic T-lymphocyte response (41.0 ± 5.0% specific killing) and interferon-γ (IFN-γ) production (sevenfold increase). In the tumor microenvironment, the combination therapy led to significantly downregulated levels of immunosuppressive factors, such as decreased numbers of myeloid-derived suppressor cells and regulatory T cells (Treg) cells and declined levels of interleukin-6 and chemokine ligand 2—in correlation with increased levels of proinflammatory cytokines, including tumor necrosis factor-α and IFN-γ as well as an elevation in the CD8+ T-cell population. The results indicated a distinct M2 to M1 phenotype switch in the treated tumors. Combining CUR–PEG and vaccine also dramatically downregulated the signal transducer and activator of transcription 3 pathway (76% reduction). Thus, we conclude that CUR–PEG is an effective agent to improve immunotherapy for advanced melanoma. PMID:26334519

  2. Design of immunogenic and effective multi-epitope DNA vaccines for melanoma.

    PubMed

    Cho, Hyun-Il; Celis, Esteban

    2012-03-01

    Plasmid DNA vaccination is an attractive way to elicit T cell responses against infectious agents and tumor cells. DNA constructs can be designed to contain multiple T cell epitopes to generate a diverse immune response to incorporate numerous antigens and to reduce limitations due to MHC restriction into a single entity. We have prepared cDNA plasmid constructs containing several mouse T cell epitopes connected by either furin-sensitive or furin-resistant linkers and studied the effects of a cationic cell-penetrating sequence from HIV-tat. Significant CD8 T cell responses were obtained with multi-epitope DNA vaccines followed by in vivo electroporation regardless of the type of linker used and whether the construct had the HIV-tat sequence. The magnitude of immune responses was very similar to all CD8 T cell epitopes contained within each vaccine construct, indicating the absence of immunodominance. Incorporating a T helper epitope into the constructs increased the T cell responses. Prophylactic and therapeutic antitumor responses against B16 melanoma were obtained using a construct containing epitopes from melanosomal proteins, indicating that this vaccination was successful in generating responses to self-antigens that potentially may be subjected to immune tolerance. These findings are useful for designing DNA vaccines for a multitude of diseases where T lymphocytes play a protective or therapeutic role.

  3. Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Stage IV Melanoma

    ClinicalTrials.gov

    2016-05-06

    Acral Lentiginous Malignant Melanoma; Lentigo Maligna Malignant Melanoma; Nodular Malignant Melanoma; Recurrent Melanoma; Solar Radiation-related Skin Melanoma; Stage IV Melanoma; Superficial Spreading Malignant Melanoma

  4. Telomerase reverse transcriptase (TERT) promoter mutations in Korean melanoma patients.

    PubMed

    Roh, Mi Ryung; Park, Kyu-Hyun; Chung, Kee Yang; Shin, Sang Joon; Rha, Sun Young; Tsao, Hensin

    2017-01-01

    Telomerase reverse transcriptase (TERT) is the reverse transcriptase component of the telomeric complex, which synthesizes terminal DNA to protect chromosomal ends and to maintain genomic integrity. In melanoma, mutation in TERT promoter region is a common event and theses promoter variants have been shown to be associated with increased gene expression, decreased telomere length and poorer outcome. In this study, we determined the frequency of TERT promoter mutation in 88 Korean primary melanoma patients and aimed to see the association of TERT promoter mutation status to other major molecular features, such as BRAF, NRAS, KIT mutations and correlate with clinicopathological features. In our study, acral melanoma (n=46, 52.3%) was the most common type. Overall, TERT promoter mutation was observed in 15 cases (17%) with ten c. -124C>T altertions and five c. -146C>T alterations. None of our samples showed CC>TT mutation which is considered pathognomonic of UV induction. Among the 46 acral melanoma patients, 5 patients (10.9%) harbored TERT promoter mutation. Tumors with TERT promoter mutation showed significantly greater Breslow thickness compared to WT tumors (P=0.039). A combined analysis for the presence of TERT promoter and BRAF mutations showed that patients with both TERT promoter and BRAF mutation showed decreased survival compared with those with only TERT promoter mutation, only BRAF mutation, or without mutations in either TERT promoter or BRAF (P=0.035). Our data provides additional evidence that UV-induced TERT promoter mutation frequencies vary depending on melanoma subtype, but preserves its prognostic value.

  5. Telomerase reverse transcriptase (TERT) promoter mutations in Korean melanoma patients

    PubMed Central

    Roh, Mi Ryung; Park, Kyu-Hyun; Chung, Kee Yang; Shin, Sang Joon; Rha, Sun Young; Tsao, Hensin

    2017-01-01

    Telomerase reverse transcriptase (TERT) is the reverse transcriptase component of the telomeric complex, which synthesizes terminal DNA to protect chromosomal ends and to maintain genomic integrity. In melanoma, mutation in TERT promoter region is a common event and theses promoter variants have been shown to be associated with increased gene expression, decreased telomere length and poorer outcome. In this study, we determined the frequency of TERT promoter mutation in 88 Korean primary melanoma patients and aimed to see the association of TERT promoter mutation status to other major molecular features, such as BRAF, NRAS, KIT mutations and correlate with clinicopathological features. In our study, acral melanoma (n=46, 52.3%) was the most common type. Overall, TERT promoter mutation was observed in 15 cases (17%) with ten c. -124C>T altertions and five c. -146C>T alterations. None of our samples showed CC>TT mutation which is considered pathognomonic of UV induction. Among the 46 acral melanoma patients, 5 patients (10.9%) harbored TERT promoter mutation. Tumors with TERT promoter mutation showed significantly greater Breslow thickness compared to WT tumors (P=0.039). A combined analysis for the presence of TERT promoter and BRAF mutations showed that patients with both TERT promoter and BRAF mutation showed decreased survival compared with those with only TERT promoter mutation, only BRAF mutation, or without mutations in either TERT promoter or BRAF (P=0.035). Our data provides additional evidence that UV-induced TERT promoter mutation frequencies vary depending on melanoma subtype, but preserves its prognostic value. PMID:28123854

  6. Systemic Tolerance Mediated by Melanoma Brain Tumors is Reversible by Radiotherapy and Vaccination

    PubMed Central

    Jackson, Christopher M.; Kochel, Christina M.; Nirschl, Christopher J.; Durham, Nicholas M.; Ruzevick, Jacob; Alme, Angela; Francica, Brian J.; Elias, Jimmy; Daniels, Andrew; Dubensky, Thomas W.; Lauer, Peter; Brockstedt, Dirk G.; Baxi, Emily G.; Calabresi, Peter A.; Taube, Janis M.; Pardo, Carlos A.; Brem, Henry; Pardoll, Drew M.; Lim, Michael; Drake, Charles G.

    2016-01-01

    Purpose Immune responses to antigens originating in the CNS are generally attenuated, since collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown. Experimental Design The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGF-β secretion from microglia and in the serum and TGF-β signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. Additionally, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model. Results CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGF-β; however, blocking TGF-β signaling with a small molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios and decreased TGF-β secretion from microglia. Conclusions These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS while antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in more contemporary melanoma models as well as human trials. PMID:26490306

  7. Vaccinations in patients with hematological malignancies.

    PubMed

    Tsigrelis, C; Ljungman, P

    2016-03-01

    Patients with hematological malignancies are at risk for a number of infections that are potentially preventable by vaccinations such as pneumococcal infections and influenza. Treatment, especially with anti-B-cell antibodies and hematopoietic stem cell transplantation (HSCT), negatively impacts the response to vaccination for several months. It is therefore recommended that patients be vaccinated before initiating immunosuppressive therapy if possible. The risk of side-effects with inactivated vaccines is low, but care has to be taken with live vaccines, such as varicella-zoster virus vaccine, since severe and fatal complications have been reported. HSCT patients require repeated doses of most vaccines to achieve long-lasting immune responses. New therapeutic options for patients with hematological malignancies that are rapidly being introduced into clinical practice will require additional research regarding the efficacy of vaccinations. New vaccines are also in development that will require well-designed studies to ascertain efficacy and safety.

  8. Serum copper and zinc levels in melanoma patients

    SciTech Connect

    Fisher, G.L.; Spitler, L.E.; McNeill, K.L.; Rosenblatt, L.S.

    1981-04-01

    Serum copper levels (SCL) and serum zinc levels (SZL) were evaluated in malignant melanoma patients at various clinical stages. Copper levels were generally found to be elevated, reflecting the degree and extent of tumor activity. Zinc levels and, hence, SCL:SZL ratios did not reflect tumor activity. SCL appeared to prognosticate disease progression in that all patients whose values never declined below 150 ..mu..g/100 ml died during the course of the study. However, not all patients who died from tumor metastases displayed persistent elevations of SCL. Patients receiving BCG immunotherapy appeared to have higher SCL than untreated patients.

  9. Vaccines for Patients with COPD.

    PubMed

    Moreno, Dolores; Barroso, Judith; Garcia, Alexis

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic obstruction of lung airflow limitation. This disease is currently the fourth higher cause of death in the world, and it is predicted to be the third by the year 2020. Patients with COPD are frequently exposed to Human Rhinovirus, Respiratory Syncytial and Influenza Virus, as well as to Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. These infectious agents are responsible for exacerbations increasing morbidity and mortality in COPD patients. Prevention of infectious exacerbations by vaccination would improve quality of life and patient survival. A literature search: "vaccination of COPD patients" was performed using Medline, the Cochrane Library and other Non-Indexed Citations for this review. This article presents a brief overview of the different studies found, on the new patents, and the future strategies on the field.

  10. Whole recombinant yeast vaccine induces antitumor immunity and improves survival in a genetically engineered mouse model of melanoma

    PubMed Central

    Tanaka, A; Jensen, JD; Prado, R; Riemann, H; Shellman, YG; Norris, DA; Chin, L; Yee, C; Fujita, M

    2015-01-01

    Malignant melanoma is one of the deadliest forms of skin cancer and its incidence is expected to rise over the next two decades. At present, there are no effective therapies for advanced melanoma. We have previously shown that administration of whole recombinant yeast expressing human MART-1 (hMART-IT) induces protective antimelanoma immunity in a B16F10 transplantable mouse model. In this study, we examine the effectiveness of the hMART-IT vaccine in a congenic strain of genetically engineered mouse model of melanoma, which recapitulates both the underlying genetics and the proper tumor microenvironment of naturally occurring melanoma. Subcutaneous administration of hMART-IT induced cytotoxicity against melanoma cells and antigen-specific production of Th1-specific cytokines by splenocytes. Weekly administration of hMART-IT significantly delayed the development of melanoma and prolonged the survival of mice compared with controls. Although histological analysis demonstrated diffuse infiltration of CD4+ T cells and CD8+ T cells, no reduction of regulatory T cells was observed, suggesting that hMART-IT cannot prevent immunotolerance in the tumor microenvironment. This study provides a proof of concept that genetically engineered mouse models lend valuable insights into immunotherapeutics being tested in the preclinical setting. PMID:21390072

  11. Prognostic models for subgroups of melanoma patients from the Scottish Melanoma Group database 1979-86, and their subsequent validation.

    PubMed Central

    MacKie, R. M.; Aitchison, T.; Sirel, J. M.; McLaren, K.; Watt, D. C.

    1995-01-01

    For the past 20 years thickness of the primary tumour has been accepted as the most important guide to prognosis for patients with primary cutaneous malignant melanoma. The changing epidemiology of melanoma with an increasing number of patients with thin tumours has necessitated a reappraisal of this, with particular reference to interactions among tumour thickness, the patients' sex and the presence or absence of ulceration of the primary tumour. All primary cutaneous malignant melanomas diagnosed in Scotland between 1979 and 1986 were used as the test group (1978 patients). The proportional hazards model was used on all potential risk factors in the database and their two-way interactions, and the resulting models based on stepwise procedures were subsequently validated on 289 melanoma patients first diagnosed in 1987 in the same geographic area. Four distinct subgroups of males and females with ulcerated or non-ulcerated lesions were identified. For females with ulcerated lesions, tumour thickness, mitotic count and anatomical site of primary all gave valuable prognostic information, whereas for females with non-ulcerated lesions only tumour thickness was of prognostic value. For males with ulcerated lesions, level of invasion was the only prognostic guide, while for males with non-ulcerated lesions both tumour thickness and level of invasion contributed significantly to prediction of prognosis. Prognosis markedly different across subgroups of the melanoma population, even to the extent that essential prognostic factors are not the same in the distinct subgroups. Verification of these prognostic guides derived from 1979-86 patients has been achieved for all patients diagnosed with melanoma in 1987 from the same geographic area. These data will therefore be useful aids for clinicians managing patients. PMID:7819035

  12. Personal attributions for melanoma risk in melanoma-affected patients and family members

    PubMed Central

    Hay, Jennifer; DiBonaventura, Marco; Baser, Raymond; Press, Nancy; Shoveller, Jeanne; Bowen, Deborah

    2010-01-01

    Personal attributions for cancer risk involve factors that individuals believe contribute to their risk for developing cancer. Understanding personal risk attributions for melanoma may dictate gene-environment melanoma risk communication strategies. We examined attributions for melanoma risk in a population-based sample of melanoma survivors, first degree family members, and family members who are also parents (N=939). We conducted qualitative examination of open-ended risk attributions and logistic regression examining predictors (demographics, family member type, perceived risk) of the attributions reported (ultraviolet radiation [UVR] exposure, heredity/genetics, phenotype, personal melanoma history, miscellaneous). We found a predominance of risk attributions to UVR and heredity/genetics (80% and 45% of the sample, respectively). Those reporting higher education levels were more likely to endorse attributions to heredity/genetics, as well as to phenotype, than those of lower education levels. First-degree relatives and parent family members were more likely to endorse heredity/genetic attributions than melanoma survivors; melanoma survivors were more likely to endorse personal history of melanoma attributions compared to first-degree relatives and parent family members. These findings inform the development of risk communication interventions for melanoma families. PMID:20809355

  13. Malignant Melanoma of the Foot in Black Patients: A Case Report and Literature Survey

    PubMed Central

    Haverkamp, John; Rodman, O. G.

    1979-01-01

    Malignant melanoma in black patients is not the rare entity previously supposed if the numerous reported accounts are considered. In black patients, the tumor appears most commonly in the pedal region. The plantar surface appears to be most frequently involved. The literature on melanoma in blacks provides confusing statistics. Malignant melanoma in blacks represents a small, well-delineated subset of melanomas possibly with its own incidence and prognosis. A case report is presented, with a search of the Walter Reed Army Medical Center Tumor Registry and a review of pertinent current dermatological literature. ImagesFigure 1 PMID:439168

  14. VEGF Trap in Treating Patients With Recurrent Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2015-02-02

    Ciliary Body and Choroid Melanoma, Medium/Large Size; Extraocular Extension Melanoma; Iris Melanoma; Metastatic Intraocular Melanoma; Recurrent Intraocular Melanoma; Recurrent Melanoma; Stage III Melanoma; Stage IV Melanoma

  15. Lacrimal Gland Radiosensitivity in Uveal Melanoma Patients

    SciTech Connect

    Muller, Karin Nowak, Peter J.C.M.; Naus, Nicole; Pan, Connie de; Santen, Cornelis A. van; Levendag, Peter; Luyten, Gre P.M.

    2009-06-01

    Purpose: To find a dose-volume effect for inhomogeneous irradiated lacrimal glands. Methods and Materials: Between 1999 and 2006, 72 patients (42 men and 30 women) were treated with fractionated stereotactic radiotherapy in a prospective, nonrandomized clinical trial (median follow-up, 32 months). A total dose of 50 Gy was given on 5 consecutive days. The mean of all Schirmer test results obtained {>=}6 months after treatment was correlated with the radiation dose delivered to the lacrimal gland. Also, the appearance of dry eye syndrome (DES) was related to the lacrimal gland dose distribution. Results: Of the 72 patients, 17 developed a late Schirmer value <10 mm; 9 patients developed DES. A statistically significant relationship was found between the received median dose in the lacrimal gland vs. reduced tear production (p = 0.000) and vs. the appearance of DES (p = 0.003), respectively. A median dose of 7 Gy/fraction to the lacrimal gland caused a 50% risk of low Schirmer results. A median dose of 10 Gy resulted in a 50% probability of DES. Conclusion: We found a clear dose-volume relationship for irradiated lacrimal glands with regard to reduced tear production and the appearance of DES.

  16. Identification of different tumor escape mechanisms in several metastases from a melanoma patient undergoing immunotherapy.

    PubMed

    Méndez, Rosa; Ruiz-Cabello, Francisco; Rodríguez, Teresa; Del Campo, Ana; Paschen, Annette; Schadendorf, Dirk; Garrido, Federico

    2007-01-01

    The cytotoxic activity of T cells selects the outgrowth of tumor cells that escape from immune surveillance by different strategies. The different mechanisms that interfere with immune recognition and limit vaccination efficiency are still poorly understood. We analysed six cell lines established from different metastases of melanoma patient UKRV-Mel-20 for specific characteristics known to have an impact on the tumor-T cell interaction: (1) alterations in the HLA class I phenotype, (2) expression of Fas/CD95, and (3) expression of specific cytokines and chemokines. One of the cell lines, UKRV-Mel-20f, exhibited an HLA class I haplotype loss and just this cell line was also characterised by the expression of Fas/CD95 and of relatively high levels of proinflammatory chemokines suggesting that the cytotoxic activity of tumor-infiltrating T cells might have selected the outgrowth of this tumor cell variant. All other cell lines analysed showed no alterations in HLA class I expression, but, in contrast to UKRV-Mel-20f, expressed much lower levels of Fas/CD95 and of proinflammatory chemokines and some of them produced high levels of immunosuppressive TGF-beta1. These results suggest that in patient UKRV-Mel-20, tumor cells interfere with T cell recognition by different strategies which might partially explain why this patient did not have a clinical response to an autologous tumor cell vaccine.

  17. High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients.

    PubMed

    Masaki, Taro; Wang, Yun; DiGiovanna, John J; Khan, Sikandar G; Raffeld, Mark; Beltaifa, Senda; Hornyak, Thomas J; Darling, Thomas N; Lee, Chyi-Chia R; Kraemer, Kenneth H

    2014-05-01

    We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repair. The lesions had a lentiginous appearance with markedly increased numbers of melanocytes. Using laser capture microdissection, we performed DNA sequencing of 18 benign and atypical nevi and 75 melanomas (melanoma in situ and invasive melanomas). The nevi had a similar high frequency of PTEN mutations as melanomas [61% (11/18) versus 53% (39/73)]. Both had a very high proportion of UV-type mutations (occurring at adjacent pyrimidines) [91% (10/11) versus 92% (36/39)]. In contrast to melanomas in the general population, the frequency of BRAF mutations (11%, 7/61), NRAS mutations (21%, 13/62), and KIT mutations (21%, 6/28) in XP melanomas was lower than for PTEN. Phospho-S6 immunostaining indicated activation of the mTOR pathway in the atypical nevi and melanomas. Thus, the clinical and histological appearances and the molecular pathology of these UV-related XP nevi and melanomas were different from nevi and melanomas in the general population.

  18. Pentoxifylline Inhibits WNT Signalling in β-Cateninhigh Patient-Derived Melanoma Cell Populations

    PubMed Central

    Talar, Beata; Gajos-Michniewicz, Anna; Talar, Marcin; Chouaib, Salem; Czyz, Malgorzata

    2016-01-01

    Background The heterogeneity of melanoma needs to be addressed and combination therapies seem to be necessary to overcome intrinsic and acquired resistance to newly developed immunotherapies and targeted therapies. Although the role of WNT/β-catenin pathway in melanoma was early demonstrated, its contribution to the lack of the melanoma patient response to treatment was only recently recognized. Using patient-derived melanoma cell populations, we investigated the influence of pentoxifylline on melanoma cells with either high or low expression of β-catenin. Findings Our results indicate that pentoxifylline inhibits the activity of the canonical WNT pathway in melanoma cell populations with high basal activity of this signalling. This is supported by lowered overall activity of transcription factors TCF/LEF and reduced nuclear localisation of active β-catenin. Moreover, treatment of β-cateninhigh melanoma cell populations with pentoxifylline induces downregulation of genes that are targets of the WNT/β-catenin pathway including connective tissue growth factor (CTGF) and microphthalmia-associated transcription factor (MITF-M), a melanocyte- and melanoma cell-specific regulator. Conclusions These results suggest that pentoxifylline, a drug approved by the FDA in the treatment of peripheral arterial disease, might be tested in a subset of melanoma patients with elevated activity of β-catenin. This pharmaceutical might be tested as an adjuvant drug in combination therapies when the response to immunotherapy is prevented by high activity of the WNT/β-catenin pathway. PMID:27351373

  19. Toxicity management of immunotherapy for patients with metastatic melanoma

    PubMed Central

    Gogas, Helen

    2016-01-01

    Checkpoint inhibitors have revolutionized the treatment of patients with metastatic melanoma offering improved responses and significant survival benefit. These agents are now approved for the treatment of metastatic melanoma, squamous and non-squamous non-small cell lung cancer (NSCLC) and kidney cancer, while they are now being investigated in a range of other malignancies. In addition, another anti-PD-L1 monoclonal antibody (atezolizumab) was recently approved for urothelial cancer. Ipilimumab, an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody and the anti-PD-1 agents nivolumab and pembrolizumab have followed large clinical development programs, therefore, information regarding their safety and toxicity profile is readily available. Unique toxicities have been observed, which stem from and relate to the immune activation by these agents and are thus termed as immune-related adverse events (irAEs). Clinicians and patients should be aware of this different toxicity profile, so as to promptly recognize, identify and manage symptoms related to irAEs. Indeed, clinical experience has shown that these immune events, when they are early recognized and timely managed, are mostly reversible otherwise they can evoke severe or even life-threatening situations. Several recommendations and guidelines have been developed for the management of irAEs and algorithms have been published based primarily on our knowledge from the ipilimumab trials. PMID:27563659

  20. Long-term complete remission following radiosurgery and immunotherapy in a melanoma patient with brain metastasis: immunologic correlates.

    PubMed

    Karbach, Julia; Gnjatic, Sacha; Biskamp, Melina; Atmaca, Akin; Weidmann, Eckhart; Brandt, Kathrin; Wahle, Claudia; Bernhard, Helga; Knuth, Alexander; Jäger, Elke

    2014-05-01

    A melanoma patient with brain metastases was treated by gamma-knife radiosurgery and immunotherapy with autologous tumor-lysate-loaded dendritic cells (DC). Ten years after the combined treatment, the patient remains in complete remission. Remarkable immunologic correlates to the clinical development were the transient induction of NY-ESO-1 antibody and the durable expansion of MAGE-A1p161-169 EADPTGHSY-specific CD8+ T cells. Although the induction of NY-ESO-1 antibody most likely resulted from gamma-knife-mediated "auto-vaccination," the persistence of circulating MAGE-A1-specific T cells, which are still detectable ex vivo in the absence of any tumor manifestation, coincides with DC-based vaccination administered monthly until today.

  1. Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma: 9 years of follow-up.

    PubMed

    Finocchiaro, L M E; Glikin, G C

    2012-12-01

    We present here the updated results after 9 years of the beginning of a trial on canine patients with malignant melanoma. This surgery adjuvant approach combined local suicide gene therapy with a subcutaneous vaccine composed by tumor cells extracts and xenogeneic cells producing human interleukin-2 and granulocyte-macrophage colony-stimulating factor. Toxicity was absent or minimal in all patients (0≤VCOG-CTCAE grade≤1). With respect to surgery-treated controls (ST), the complete surgery (CS) arm of this combined treatment (CT) significantly increased the fraction of local disease-free patients from 13 to 81% and distant metastases free from 32 to 84%. Even though less effective than the CS arm, the partial surgery (PS) arm of this CT was significantly better controlling the disease than only surgery (14% while PS-ST: 0%, P<0.01 and CS-ST: 5%, P<0.05). In addition, CT produced a significant sevenfold (CS) and threefold (PS) increase in overall survival. The CS-CT arm significantly improved both CS-ST metastasis-free- and melanoma overall survival from 99 days (respective ranges: 11-563 and 10-568) to >2848 days (81-2848 and 35-2848). Thus, more of 50% of our CT patients died of melanoma unrelated causes, transforming a lethal disease into a chronic one. Finally, surgery adjuvant CT delayed or prevented post-surgical recurrence and distant metastasis, significantly improved disease-free and overall survival maintaining the quality of life. Long-term safety and efficacy of this treatment are supported by the high number of CT patients (283) and extensive follow-up (>9 years). The successful clinical outcome encourages the further translation of similar approaches to human gene therapy trials.

  2. AZD2171 in Treating Patients With Recurrent or Stage IV Melanoma

    ClinicalTrials.gov

    2015-06-01

    Acral Lentiginous Malignant Melanoma; Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Extraocular Extension Melanoma; Intraocular Melanoma; Iris Melanoma; Lentigo Maligna Malignant Melanoma; Recurrent Melanoma; Stage, Intraocular Melanoma; Stage IV Melanoma; Superficial Spreading Malignant Melanoma

  3. Radioembolization and Ipilimumab in Treating Patients With Uveal Melanoma With Liver Metastases

    ClinicalTrials.gov

    2016-03-09

    Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Extraocular Extension Melanoma; Iris Melanoma; Liver Metastases; Metastatic Intraocular Melanoma; Recurrent Intraocular Melanoma; Stage IV Intraocular Melanoma

  4. Immunological response to hepatitis B vaccine in polytransfused thalassemic patients.

    PubMed

    Alavian, Seyed-Moayed; Tabatabaei, Seyed-Vahid

    2010-05-01

    Hepatitis B is an important infection in thalassemia patients and prevention by vaccination is needed. Immunological response to hepatitis B vaccine in polytransfused thalassmia patients needs more attention.

  5. Study Suggests Smaller Melanoma Excision Margins May Be Option for Some Patients

    Cancer.gov

    A randomized controlled trial of patients with stage IIA–C cutaneous melanoma thicker than 2-mm found that a 2-cm surgical resection margin is sufficient and is as safe for patients as a 4-cm margin.

  6. Clinics, prognosis and new therapeutic options in patients with mucosal melanoma

    PubMed Central

    Schaefer, Tim; Satzger, Imke; Gutzmer, Ralf

    2017-01-01

    Abstract Mucosal melanomas represent a rare entity with different risk factors and molecular features compared to cutaneous melanomas. They arise most commonly from mucosal surfaces in the head/neck region, the female genital tract (FGT) and the anorectal region. The aim of this study was to evaluate clinics, prognosis, and treatment options of patients with mucosal melanoma, in particular with regard to different primary sites. We retrospectively analyzed 75 patients with mucosal melanomas diagnosed in the years 1993 to 2015 in our department. The primary melanomas were located in the head/neck region (n = 32), the FGT (n = 24), and the anorectal region (n = 19). The median age of the patients was 66 years. At initial diagnosis the primary melanoma was not completely resectable in 11 (15%) patients, 18 (24%) patients had regional lymph node metastases, and 7 (9%) patients distant metastases. During follow-up, 22 (29%) patients suffered from a local recurrence, in particular patients with primary melanoma in the head/neck region without postoperative radiotherapy. By multivariate analysis location of the primary melanoma in the head/neck area or anorectal region and presence of metastases at time of diagnosis represented poor prognostic factors for recurrence-free survival. In 62 tested individuals 7 KIT mutations were found, 2 BRAF mutations in 57 tested patients. Four patients received targeted therapies, 14 checkpoint inhibitors, 4 (1/1 on vemurafenib, 1/7 on ipilimumab, and 2/7 on PD-1 inhibitors) patients showed responses of more than 100 days duration. Mucosal melanomas are often locally advanced or metastatic at initial diagnosis, thus they require extensive staging procedures. The high rate of local recurrences in the head/neck region can be significantly reduced by postoperative radiotherapy. For the potential use of medical treatment a mutation analysis for KIT and BRAF genes should be performed. The use of new immunologic and targeted

  7. [Vaccinations in patients with autoimmune diseases].

    PubMed

    Bühler, Silja; Hatz, Christoph

    2016-01-01

    The number of individuals with autoimmune diseases treated with immunosuppressive drugs is increasing steadily. The variety of immunosuppressive drugs and in particular biological therapies is also rising. The autoimmune disease itself as well as the immunosuppressive therapy increases the risk of infection in this population. Particularly the risk of vaccine-preventable infections is elevated. Thus, preventing infections by the means of vaccination is of utmost importance. The Division of Infectious Diseases of the Epidemiology, Biostatistics and Prevention Institute, University of Zurich, performed a literature search on the topic of vaccinations in patients with autoimmune diseases upon request by the Swiss Federal Commission for Vaccination Issues. Overall, data are scarce. The following main points were retrieved from the literature: Inactivated vaccines are safe, but their immunogenicity may be reduced under immunosuppressive therapy. In addition to the generally recommended basic vaccinations, specific vaccinations, such as influenza and pneumococcal vaccination are indicated in these patient groups. Live vaccines are generally contraindicated under immunosuppressive therapy due to safety concerns. However, specific exceptions apply. Furthermore, certain time intervals for the administration of live vaccines after pausing or ceasing an immunosuppressive therapy should be respected.

  8. Clinical significance of serum laminin and type-IV collagen levels in cutaneous melanoma patients.

    PubMed

    Tas, Faruk; Bilgin, Elif; Karabulut, Senem; Duranyildiz, Derya

    2016-07-01

    Laminin and type-IV collagen constitute a significant portion of the extracellular matrix. The objective of the present study was to evaluate whether the serum concentrations of laminin and type-IV collagen may serve as biomarkers for cutaneous melanoma. Sixty pathologically confirmed melanoma patients were enrolled in the study. Serum laminin and type-IV collagen levels were assessed using an ELISA. Thirty healthy controls were also examined. No significant differences in the baseline serum levels of laminin were identified between melanoma patients and healthy controls (P=0.45). However, the baseline serum levels of type-IV collagen were significantly elevated in melanoma patients compared with those in the control group (P<0.001). Clinical parameters, including patient age, gender, localization of lesion, histopathology, stage of disease, serum lactate dehydrogenase concentrations and responsiveness to chemotherapy were found not to be associated with the serum levels of laminin and type-IV collagen (P>0.05). Furthermore, the serum levels of laminin and type-IV collagen had no prognostic value regarding the outcome for melanoma patients (P=0.36 and P=0.26, respectively). While laminin levels showed no diagnostic value, the serum concentrations of type-IV collagen were indicated to serve as a diagnostic marker in patients with cutaneous melanoma. In conclusion, type-IV collagen levels may be used as a diagnostic marker for cutaneous melanoma, while being void of any prognostic value.

  9. Clinical significance of serum laminin and type-IV collagen levels in cutaneous melanoma patients

    PubMed Central

    TAS, FARUK; BILGIN, ELIF; KARABULUT, SENEM; DURANYILDIZ, DERYA

    2016-01-01

    Laminin and type-IV collagen constitute a significant portion of the extracellular matrix. The objective of the present study was to evaluate whether the serum concentrations of laminin and type-IV collagen may serve as biomarkers for cutaneous melanoma. Sixty pathologically confirmed melanoma patients were enrolled in the study. Serum laminin and type-IV collagen levels were assessed using an ELISA. Thirty healthy controls were also examined. No significant differences in the baseline serum levels of laminin were identified between melanoma patients and healthy controls (P=0.45). However, the baseline serum levels of type-IV collagen were significantly elevated in melanoma patients compared with those in the control group (P<0.001). Clinical parameters, including patient age, gender, localization of lesion, histopathology, stage of disease, serum lactate dehydrogenase concentrations and responsiveness to chemotherapy were found not to be associated with the serum levels of laminin and type-IV collagen (P>0.05). Furthermore, the serum levels of laminin and type-IV collagen had no prognostic value regarding the outcome for melanoma patients (P=0.36 and P=0.26, respectively). While laminin levels showed no diagnostic value, the serum concentrations of type-IV collagen were indicated to serve as a diagnostic marker in patients with cutaneous melanoma. In conclusion, type-IV collagen levels may be used as a diagnostic marker for cutaneous melanoma, while being void of any prognostic value. PMID:27330797

  10. Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients.

    PubMed

    Huang, Sharon K; Hoon, Dave S B

    2016-03-01

    Cutaneous melanoma is one of the highest incident-rate cancers with increasing prevalence in Western societies. Despite the advent of new approved therapeutics, the 5-year overall survival rate of stage IV melanoma patients remains below 15%. Current treatments for late stage disease have shown higher efficacy when treated at a lower disease burden. Thus, blood-based biomarkers capable of detecting melanoma prior to clinically evident distant metastasis, will improve the treatment and outcomes for melanoma patients. To that end, effective treatment of melanoma necessitates identification of patients at risk for developing distant metastases. Furthermore, employing blood biomarkers that monitor cancer progression over the course of treatment is a promising solution to post-treatment drug resistance often developed in melanoma patients. Non-invasive blood biomarker assays allow for regular dynamic monitoring of disease. "Liquid Biopsy" of blood, which exploits circulating tumor cells (CTCs), cell-free circulating tumor DNA (ctDNA) and cell-free circulating microRNA (cmiRNA), has been shown to detect prognostic factors for relapse in AJCC stage III and stage IV melanoma patients. Moreover, molecular characterization of CTC and analysis of various forms of ctDNA present promising potential in development of individualized therapy for melanoma patients. New approaches such as massive parallel sequencing (MPS) provide a comprehensive view of the disease progression, allowing for the selection of therapeutic options for individual patients. With advancements of improving molecular assays, liquid biopsy analysis as a powerful, routine clinical assay for melanoma patients, is highly promising prospective.

  11. Intravital Microscopy for Identifying Tumor Vessels in Patients With Stage IA-IV Melanoma That is Being Removed by Surgery

    ClinicalTrials.gov

    2016-01-13

    Recurrent Melanoma; Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma

  12. Immunomodulatory pathways regulate expression of a spliced FKBP51 isoform in lymphocytes of melanoma patients.

    PubMed

    Romano, Simona; D'Angelillo, Anna; Staibano, Stefania; Simeone, Ester; D'Arrigo, Paolo; Ascierto, Paolo Antonio; Scalvenzi, Massimiliano; Mascolo, Massimo; Ilardi, Gennaro; Merolla, Francesco; Jovarauskaite, Egle; Romano, Maria Fiammetta

    2015-07-01

    FKBP51 (gene FKBP5) is an immunophilin capable of immunosuppression expressed in melanoma and lymphocytes. We found increased levels of a spliced FKBP5 variant in the PBMCs of 124 patients with melanoma. This variant encodes for an unknown isoform (FKBP51s). We hypothesized that FKBP51s resulted from tumour interaction with immune cells, through PDL-1/PD-1. To address this issue, we performed melanoma/PBMC cocultures. Furthermore, the immunohistochemistry of 76 melanoma specimens served to investigate whether FKBP51s stained tumour infiltrating lymphocytes. Our results showed that PBMCs expressed FKBP51s when cocultured with melanoma. Tumour PDL-1 knockdown or anti-PD-1 reduced FKBP51s expression in cocultured PBMCs. IHC showed a strong FKBP51s signal in tumour infiltrating lymphocytes, and lymphocytes of the invasion front of the tumour, along with melanoma PDL-1 expression. When overexpressed in melanoma, FKBP51s facilitated PDL-1 expression on the cell surface. In conclusion, our study shows that FKBP51s marks the PBMCs of patients with melanoma and is exploited by the tumour to immunomodulate through PDL-1.

  13. Plasma L-dopa in the diagnosis of patients with melanoma

    SciTech Connect

    Camp, V.M.; Murray, D.R.; Faraj, B.A.

    1984-01-01

    Melanoma is one of a group of neoplasms that is characterized biochemically by abnormal tyrosine metabolism. The main objective of this paper is to establish whether or not the measurement of plasma L-dopa represents a specific indicator for the biochemical diagnosis of melanoma. Two groups of patients were studied: group 1 consisted of 20 patients with stage 2 and 3 disseminated melanoma, and group 2 consisted of 20 patients with non-malignant melanoma. L-dopa in plasma was measured by a radio-enzymatic technique. The method was based upon the incubation (37/sup 0/C, 40 min) of 50 ..mu..l of plasma in the presence of catechol-O-methyltransferase, dopa decarboxylase and S-(3H)-adenosylmethionine (5 ..mu..Ci, sp. act. ci/mmol). The formed methylated decarboxylated metabolite 3H-3-0-methyldopamine was characterized by radiochromatographic analysis. The results of the study showed that plasma L-dopa was elevated significantly in patients with disseminated melanoma (av 4.9 ng/ml) as compared with non-malignant melanoma patients (av 0.9 ng/ml) and control subjects. The measurement of plasm L-dopa represents a specific marker for detection of metastatic melanoma.

  14. MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation.

    PubMed

    Yaddanapudi, Kavitha; Rendon, Beatriz E; Lamont, Gwyneth; Kim, Eun Jung; Al Rayyan, Numan; Richie, Jamaal; Albeituni, Sabrin; Waigel, Sabine; Wise, Ashley; Mitchell, Robert A

    2016-02-01

    Highly aggressive cancers "entrain" innate and adaptive immune cells to suppress antitumor lymphocyte responses. Circulating myeloid-derived suppressor cells (MDSC) constitute the bulk of monocytic immunosuppressive activity in late-stage melanoma patients. Previous studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immunosuppressive function of tumor-associated macrophages and MDSCs in mouse models of melanoma. In the current study, we sought to determine whether MIF contributes to human melanoma MDSC induction and T-cell immunosuppression using melanoma patient-derived MDSCs and an ex vivo coculture model of human melanoma-induced MDSC. We now report that circulating MDSCs isolated from late-stage melanoma patients are reliant upon MIF for suppression of antigen-independent T-cell activation and that MIF is necessary for maximal reactive oxygen species generation in these cells. Moreover, inhibition of MIF results in a functional reversion from immunosuppressive MDSC to an immunostimulatory dendritic cell (DC)-like phenotype that is at least partly due to reductions in MDSC prostaglandin E(2) (PGE(2)). These findings indicate that monocyte-derived MIF is centrally involved in human monocytic MDSC induction/immunosuppressive function and that therapeutic targeting of MIF may provide a novel means of inducing antitumor DC responses in late-stage melanoma patients.

  15. MIF is necessary for late-stage melanoma patient MDSC immune suppression and differentiation

    PubMed Central

    Yaddanapudi, Kavitha; Rendon, Beatriz E.; Lamont, Gwyneth; Kim, Eun Jung; Al Rayyan, Numan; Richie, Jamaal; Albeituni, Sabrin; Waigel, Sabine; Wise, Ashley; Mitchell, Robert A.

    2015-01-01

    Highly aggressive cancers “entrain” innate and adaptive immune cells to suppress anti-tumor lymphocyte responses. Circulating myeloid-derived suppressor cells (MDSCs) constitute the bulk of monocytic immunosuppressive activity in late stage melanoma patients. Previous studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immune suppressive function of tumor-associated macrophages (TAMs) and MDSCs in mouse models of melanoma. In the current study we sought to determine whether MIF contributes to human melanoma MDSC induction and T-cell immunosuppression using melanoma patient-derived MDSCs and an ex vivo co-culture model of human melanoma-induced MDSC. We now report that circulating MDSCs isolated from late stage melanoma patients are reliant upon MIF for suppression of antigen-independent T-cell activation and that MIF is necessary for maximal reactive oxygen species (ROS) generation in these cells. Moreover, inhibition of MIF results in a functional reversion from immune suppressive MDSC to an immunostimulatory dendritic cell (DC)-like phenotype that is at least partly due to reductions in MDSC prostaglandin E2 (PGE2). These findings indicate that monocyte-derived MIF is centrally involved in human monocytic MDSC induction/immune suppressive function and that therapeutic targeting of MIF may provide a novel means of inducing anti-tumor DC responses in late stage melanoma patients. PMID:26603621

  16. Phase I trial of intravenous peptide-pulsed dendritic cells in patients with metastatic melanoma.

    PubMed

    Lau, R; Wang, F; Jeffery, G; Marty, V; Kuniyoshi, J; Bade, E; Ryback, M E; Weber, J

    2001-01-01

    Sixteen patients with metastatic stage IV melanoma were treated with use of intravenous infusions of dendritic cells (DC) derived by incubation of plastic-adherent peripheral blood mononuclear cells (PBMC) with IL-4 and GM-CSF for 8 days in serumless AIM-V medium, followed by overnight pulsing with peptides. The tyrosinase368-376 (370D) and gp100(209-217 (210M)) peptides restricted to HLA class I A*0201 each differed from wild type by one amino acid modified to increase HLA binding. Median age was 49, with nine men and seven women. All patients, except one, had visceral disease. Patients received escalating doses of peptide-pulsed DCs at 10e7, 3 x 10e7, and 10e8 cells/dose twice at 2 weeks apart, with toxicity and clinical and immune responses as the principal endpoints. The first infusion of DCs was fresh, and frozen DCs were given for the second infusion of each cycle. Mean DC purity by flow cytometry was 49%, with a mean HLA-DR level of 57%, CD86 of 41%, CD58 of 46%, and mean CD14 cells of 0.9%. Toxicity was minimal, with two patients having transient grade III DC-related toxicity. Ten patients received one cycle of treatment and six patients received two cycles of treatment. One patient had a complete remission (CR) of lung and pleural disease after two cycles of DC therapy. Two additional patients had stable disease and two patients had mixed responses. Overall immunity was assessed by recall skin testing with peptides, gamma interferon ELISA assays of peptide specific cytolytic T cell (CTL) stimulated twice with peptide, IL-2, and IL-7 over 24 days, and peptide-specific tetramer assays performed before and after vaccination. Five of 16 patients had an immune response to gp100 or tyrosinase by gamma interferon ELISA assay; four of five were clinically stable or had tumor regression. These data suggest that melanoma antigen peptide-pulsed DC given intravenously are not toxic, and regression or stability of tumor appeared to correlate with the detection of a

  17. Very Late Antigen-1 Marks Functional Tumor-Resident CD8 T Cells and Correlates with Survival of Melanoma Patients

    PubMed Central

    Murray, Timothy; Fuertes Marraco, Silvia A.; Baumgaertner, Petra; Bordry, Natacha; Cagnon, Laurène; Donda, Alena; Romero, Pedro; Verdeil, Grégory; Speiser, Daniel E.

    2016-01-01

    A major limiting factor in the success of immunotherapy is tumor infiltration by CD8+ T cells, a process that remains poorly understood. In the present study, we characterized homing receptors expressed by human melanoma-specific CD8+ T cells. Our data reveal that P-selectin binding and expression of the retention integrin, very late antigen (VLA)-1, by vaccine-induced T cells correlate with longer patient survival. Furthermore, we demonstrate that CD8+VLA-1+ tumor-infiltrating lymphocytes (TILs) are highly enriched in melanoma metastases in diverse tissues. VLA-1-expressing TIL frequently co-express CD69 and CD103, indicating tissue-resident memory T cells (TRM) differentiation. We employed a mouse model of melanoma to further characterize VLA-1-expressing TIL. Our data show that VLA-1+ TRM develop in murine tumors within 2 weeks, where they exhibit increased activation status, as well as superior effector functions. In addition, in vivo blockade of either VLA-1 or CD103 significantly impaired control of subcutaneous tumors. Together, our data indicate that VLA-1+ TRM develop in tumors and play an important role in tumor immunity, presenting novel targets for the optimization of cancer immunotherapy. PMID:28018343

  18. Genital melanoma: are we adequately screening our patients?

    PubMed

    Zikry, Joseph; Chapman, Lance W; Korta, Dorota Z; Smith, Janellen

    2017-03-15

    Full-body skin exams (FBSE) play an integral role inearly detection and treatment of skin cancer. Promptdetection of melanoma is especially importantas survival outcomes decrease significantly withpresentation of advanced disease. Given thatmelanoma may grow in areas of skin with little to nosun exposure, genital melanomas are a recognizedentity in cutaneous oncology.

  19. [Genetic counseling and DNA testing in patients with increased risks for malignant melanoma].

    PubMed

    Itin, P H; Fistarol, S K

    2003-08-01

    There are numerous risk factors for the development of malignant melanoma. It has been documented that genetic predisposition exists but exogenous factors are also very important. In familial melanomas it has been well established that mutation in the CDKN2A gene which is located at chromosome 9 leads to a marked risk for malignant melanoma. This tumor-suppressor gene is important for the regulation of the cell cycle and mutation in this gene is associated also with an increased rate of pancreas cancer. The penetrance of this mutation is influenced by UV-energy. In addition it has been shown that a second cluster for the familial atypical nevus syndrome is located at chromosome 1p36. Patients with the rare disease xeroderma pigmentosum have a defect in the DNA-repair mechanism inherited in an autosomal recessive trait and therefore develop within the first 20 years of life numerous malignant skin tumours including malignant melanomas. But also in non-syndromic patients a decrease of DNA-repair ability may occur. It has been shown recently that reduced DNA-repair ability is an independent risk factor for malignant melanoma and may contribute to susceptibility to sunlight-induced melanoma among the general population. Other constitutional risk factors for the development of malignant melanoma are fair skin, red hair and blue eyes. The most important exogenous risk factor is UV-exposition. Extensive and repetitive sunburns before the age of 15 years are especially predisposing to malignant melanoma. The most important preventive measures are continuous sun-protection including avoidance of sun in noon time on tropical and subtropical places, wearing a hut and sunglasses and application of sun-screens with high sun-protection factor. Furthermore a regular check for changing moles is indicated in persons with multiple atypical nevi or a familial melanoma syndrome. Nowadays molecular genetic screenings are available within research projects for members of melanoma

  20. Flu Vaccine Guidance for Patients with Immune Deficiency

    MedlinePlus

    ... Guidance for Patients with Immune Deficiency Share | Flu Vaccine Guidance for Patients with Immune Deficiency This article ... should patients with immune deficiency be given the vaccine? Immune deficient patients have a decreased resistance to ...

  1. Aldesleukin and Pembrolizumab in Treating Patients With Stage III-IV Melanoma

    ClinicalTrials.gov

    2017-04-05

    Metastatic Melanoma; Stage III Mucosal Melanoma of the Head and Neck; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma; Stage IVA Mucosal Melanoma of the Head and Neck; Stage IVB Mucosal Melanoma of the Head and Neck; Stage IVC Mucosal Melanoma of the Head and Neck

  2. Adjuvant Sunitinib or Valproic Acid in High-Risk Patients With Uveal Melanoma

    ClinicalTrials.gov

    2016-10-18

    Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Iris Melanoma; Stage I Intraocular Melanoma; Stage IIA Intraocular Melanoma; Stage IIB Intraocular Melanoma; Stage IIIA Intraocular Melanoma; Stage IIIB Intraocular Melanoma; Stage IIIC Intraocular Melanoma

  3. Melanoma brain metastasis globally reconfigures chemokine and cytokine profiles in patient cerebrospinal fluid.

    PubMed

    Lok, Edwin; Chung, Amy S; Swanson, Kenneth D; Wong, Eric T

    2014-04-01

    The aggressiveness of melanoma is believed to be correlated with tumor-stroma-associated immune cells. Cytokines and chemokines act to recruit and then modulate the activities of these cells, ultimately affecting disease progression. Because melanoma frequently metastasizes to the brain, we asked whether global differences in immunokine profiles could be detected in the cerebrospinal fluid (CSF) of melanoma patients and reveal aspects of tumor biology that correlate with patient outcomes. We therefore measured the levels of 12 cytokines and 12 chemokines in melanoma patient CSF and the resulting data were analyzed to develop unsupervised hierarchical clustergrams and heat maps. Unexpectedly, the overall profiles of immunokines found in these samples showed a generalized reconfiguration of their expression in melanoma patient CSF, resulting in the segregation of individuals with melanoma brain metastasis from nondisease controls. Chemokine CCL22 and cytokines IL1α, IL4, and IL5 were reduced in most samples, whereas a subset including CXCL10, CCL4, CCL17, and IL8 showed increased expression. Further, analysis of clusters identified within the melanoma patient set comparing patient outcome suggests that suppression of IL1α, IL4, IL5, and CCL22, with concomitant elevation of CXCL10, CCL4, and CCL17, may correlate with more aggressive development of brain metastasis. These results suggest that global immunokine suppression in the host, together with a selective increase in specific chemokines, constitute a predominant immunomodulatory feature of melanoma brain metastasis. These alterations likely drive the course of this disease in the brain and variations in the immune profiles of individual patients may predict outcomes.

  4. Vaccinating Patients With Inflammatory Bowel Disease

    PubMed Central

    Reich, Jason; Wasan, Sharmeel

    2016-01-01

    Patients with inflammatory bowel disease (IBD) are not vaccinated at the same rate as general medical patients. IBD places patients at increased risk for developing vaccine-preventable illnesses, and this risk is further exacerbated by immunosuppressive therapy. Therefore, gastroenterologists should familiarize themselves with health maintenance measures pertaining to patients with IBD. This article highlights the vaccinations required for patients with IBD, especially those who are immunosuppressed: influenza; pneumococcal pneumonia; hepatitis A and B viruses; human papilloma virus; meningococcal disease; tetanus, diphtheria, and pertussis; measles, mumps, and rubella; varicella zoster; and herpes zoster. This article also discusses issues regarding patients with IBD who travel outside of the United States, as well as highlights and provides suggestions for areas of quality improvement that are needed in the field. PMID:27917091

  5. Detection of Exosomal miRNAs in the Plasma of Melanoma Patients

    PubMed Central

    Pfeffer, Susan R.; Grossmann, Kenneth F.; Cassidy, Pamela B.; Yang, Chuan He; Fan, Meiyun; Kopelovich, Levy; Leachman, Sancy A.; Pfeffer, Lawrence M.

    2015-01-01

    MicroRNAs (miRNAs) are a class of 22–25 nucleotide RNAs that control gene expression at the post-transcriptional level. MiRNAs have potential as cancer biomarkers. Melanoma is a highly aggressive form of skin cancer accounting for almost 4% of cancers among men and women, and ~80% of skin cancer-related deaths in the US. In the present study we analyzed plasma-derived exosomal miRNAs from clinically affected and unaffected familial melanoma patients (CDKN2A/p16 gene carriers) and compared them with affected (nonfamilial melanoma) and unaffected control subjects in order to identify novel risk biomarkers for melanoma. Intact miRNAs can be isolated from the circulation because of their presence in exosomes. A number of differentially regulated miRNAs identified by NanoString human V2 miRNA array were validated by quantitative PCR. Significantly, miR-17, miR-19a, miR-21, miR-126, and miR-149 were expressed at higher levels in patients with metastatic sporadic melanoma as compared with familial melanoma patients or unaffected control subjects. Surprisingly, no substantial differences in miRNA expression were detected between familial melanoma patients (all inclusive) and unaffected control subjects. The miRNAs differentially expressed in the different patient cohorts, especially in patients with metastatic melanoma, may play important roles in tumor progression and metastasis, and may be used as predictive biomarkers to monitor remission as well as relapse following therapeutic intervention. PMID:26694476

  6. The adoptive transfer of cultured T cells for patients with metastatic melanoma.

    PubMed

    Yang, James C

    2013-01-01

    T cells have been shown to be capable of rejecting a patient's tumor. Weak responses to current vaccines and the toxicity of exogenously administered cytokines limit the intensity of the T-cell response that can be actively generated in vivo. Adoptive T-cell transfer enhances an intrinsically weak immune response to cancer by activating and expanding tumor reactive T cells in vitro and manipulating the environment of the host at the time of transfer. One can frequently find tumor-reactive T cells in metastatic lesions in patients with melanoma, and expand them in vitro for readministration. When successful, this adoptive cellular immunotherapy has resulted in sustainable curative outcomes. Subsequently, the applicability of adoptive T-cell transfer has been greatly expanded by the development of methods to genetically engineer open-repertoire human T-cells to confer tumor reactivity. This re-direction of T-cell specificity can be achieved by introducing a variety of receptors that ligate tumor-associated antigens and then trigger the normal activation mechanism of T cells. Future T-cell engineering will add a new dimension by reprogramming T-cell functions for optimal tumor rejection. The antigens recognized by T cells, the techniques to procure and grow tumor reactive T cells, the conditioning of the recipient to optimize efficacy, and the results of clinical protocols are reviewed herein.

  7. The Experience of Melanoma Follow-Up Care: An Online Survey of Patients in Australia

    PubMed Central

    Street, Jackie; Neuhaus, Susan; Bessen, Taryn

    2014-01-01

    Investigating patients' reports on the quality and consistency of melanoma follow-up care in Australia would assist in evaluating if this care is effective and meeting patients' needs. The objective of this study was to obtain and explore the patients' account of the technical and interpersonal aspects of melanoma follow-up care received. An online survey was conducted to acquire details of patients' experience. Participants were patients treated in Australia for primary melanoma. Qualitative and quantitative data about patient perceptions of the nature and quality of their follow-up care were collected, including provision of melanoma specific information, psychosocial support, and imaging tests received. Inconsistencies were reported in the provision and quality of care received. Patient satisfaction was generally low and provision of reassurance from health professionals was construed as an essential element of quality of care. “Gaps” in follow-up care for melanoma patients were identified, particularly provision of adequate psychosocial support and patient education. Focus on strategies for greater consistency in the provision of support, information, and investigations received, may generate a cost dividend which could be reinvested in preventive and supportive care and benefit patient well-being. PMID:25535589

  8. Augmentation of anti-HLA-E antibodies with concomitant HLA-Ia reactivity in IFNγ-treated autologous melanoma cell vaccine recipients.

    PubMed

    Ravindranath, Mepur H; Selvan, Senthamil R; Terasaki, Paul I

    2012-01-01

    HLA-E expressed on the surface of melanoma cells and shed into circulation are known to inhibit killing of tumor cells by binding to CD94/NKGA2 receptors on cytotoxic T- and NKT cells. Interferon (IFN)-γ is known to promote HLA-E over-expression on the cell surface and shedding. The shed HLA-E heavy chain may expose cryptic epitopes to elicit antibodies (Abs). The anti-HLA-E Abs may bind to shed HLA-E or to the tumor cell surface to block its interaction with CTL/NKT cells. This is the basis for a melanoma cell vaccine that will generate anti-HLA-E Abs. The objective of this study was to characterize the antibody response and characterize the cross-reactivity of the antibodies produced in melanoma patients immunized with autologous melanoma cells treated with IFNγ. Anti-HLA-E murine mAbs and serum anti-HLA-E Abs in healthy individuals were known to react with HLA-Ia alleles, which is attributed to the presence of peptide sequences shared between HLA-E and HLA-Ia. Therefore, pre- and post-immune (weeks 4 and 24) serum Abs reacting to both HLA-E and HLA-Ia alleles were measured by multiplex Luminex®-based immunoassay. To ascertain whether the reactivity of the serum Abs to HLA-Ia was due to anti-HLA-E Abs, the shared-peptides were used to inhibit anti-HLA-E and HLA-Ia reactivities. The level of anti-HLA-E IgG in sera has increased post-immunization from its pre-immune level. Concomitantly, the HLA-Ia reactivity of the sera was also augmented. The reactivity of both anti-HLA-E Abs and HLA-Ia were inhibited by the shared-peptides. The HLA-Ia reactivity of the anti-HLA-E Abs in patients' sera is similar to the HLA-Ia reactivity of the anti-HLA-E mAbs and anti-HLA-E Abs in normal sera. The results establish the immunogenicity of HLA-E and also ascertain that the HLA-Ia reactivity of the anti-HLA-E Abs is due to shared-peptide epitopes.

  9. Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study

    PubMed Central

    Orlow, Irene; Reiner, Anne S.; Thomas, Nancy E.; Roy, Pampa; Kanetsky, Peter A.; Luo, Li; Paine, Susan; Armstrong, Bruce K.; Kricker, Anne; Marrett, Loraine D.; Rosso, Stefano; Zanetti, Roberto; Gruber, Stephen B.; Anton-Culver, Hoda; Gallagher, Richard P.; Dwyer, Terence; Busam, Klaus; Begg, Colin B.; Berwick, Marianne

    2016-01-01

    Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics. PMID:26521212

  10. Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study.

    PubMed

    Orlow, Irene; Reiner, Anne S; Thomas, Nancy E; Roy, Pampa; Kanetsky, Peter A; Luo, Li; Paine, Susan; Armstrong, Bruce K; Kricker, Anne; Marrett, Loraine D; Rosso, Stefano; Zanetti, Roberto; Gruber, Stephen B; Anton-Culver, Hoda; Gallagher, Richard P; Dwyer, Terence; Busam, Klaus; Begg, Colin B; Berwick, Marianne

    2016-01-01

    Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics.

  11. Monitoring the Systemic Human Memory B Cell Compartment of Melanoma Patients for Anti-Tumor IgG Antibodies

    PubMed Central

    Gilbert, Amy E.; Karagiannis, Panagiotis; Dodev, Tihomir; Koers, Alexander; Lacy, Katie; Josephs, Debra H.; Takhar, Pooja; Geh, Jenny L. C.; Healy, Ciaran; Harries, Mark; Acland, Katharine M.; Rudman, Sarah M.; Beavil, Rebecca L.; Blower, Philip J.; Beavil, Andrew J.; Gould, Hannah J.; Spicer, James; Nestle, Frank O.; Karagiannis, Sophia N.

    2011-01-01

    Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer. PMID:21559411

  12. Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies.

    PubMed

    Gilbert, Amy E; Karagiannis, Panagiotis; Dodev, Tihomir; Koers, Alexander; Lacy, Katie; Josephs, Debra H; Takhar, Pooja; Geh, Jenny L C; Healy, Ciaran; Harries, Mark; Acland, Katharine M; Rudman, Sarah M; Beavil, Rebecca L; Blower, Philip J; Beavil, Andrew J; Gould, Hannah J; Spicer, James; Nestle, Frank O; Karagiannis, Sophia N

    2011-04-29

    Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.

  13. Activated CD11b+ CD15+ Granulocytes Increase in the Blood of Patients with Uveal Melanoma

    PubMed Central

    McKenna, Kyle C.; Beatty, Kelly M.; Bilonick, Richard A.; Schoenfield, Lynn; Lathrop, Kira L.; Singh, Arun D.

    2017-01-01

    Purpose To determine whether activated CD11b+ CD15+ granulocytes increase in the blood of patients with uveal melanoma. Methods Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation from the blood of patients with primary choroidal/ciliochoroidal uveal melanomas (six women, four men; age range, 46–91 years) and healthy control donors (14 women, 10 men; age range, 50 – 81 years). The expression of CD15 and CD68 on CD11b+ myeloid cells within PBMCs and primary uveal melanomas was evaluated by flow cytometry. CD3ζ chain expression by CD3ε+ T cells in PBMCs and within primary uveal melanomas was measured as an indirect indication of T-cell function. Results The percentage of CD11b+ cells in PBMCs of patients with uveal melanoma increased 1.8-fold in comparison to healthy donors and comprised three subsets: CD68 negative CD15+ granulocytes, which increased 4.1-fold; CD68− CD15− cells, which increased threefold; and CD68+ CD15low cells, which were unchanged. A significant (2.7-fold) reduction in CD3ζ chain expression on CD3ε+ T cells, a marker of T-cell dysfunction, was observed in PBMCs of patients with uveal melanoma in comparison with healthy control subjects and correlated significantly with the percentage of CD11b+ cells in PBMCs. CD3ζ chain expression on T cells within primary tumors was equivalent to CD3ζ expression in PBMCs of the same patient in four of five patients analyzed. Conclusions Activated CD11b+ CD15+ granulocytes expand in the blood of patients with uveal melanoma and may contribute to immune evasion by ocular tumors by inhibiting T-cell function via decreasing CD3ζ chain expression. PMID:19369244

  14. Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab.

    PubMed

    Weber, Jeffrey; Gibney, Geoffrey; Kudchadkar, Ragini; Yu, Bin; Cheng, Pingyan; Martinez, Alberto J; Kroeger, Jodie; Richards, Allison; McCormick, Lori; Moberg, Valerie; Cronin, Heather; Zhao, Xiuhua; Schell, Michael; Chen, Yian Ann

    2016-04-01

    The checkpoint inhibitor nivolumab is active in patients with metastatic melanoma who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab-refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug-related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. The response rate for ipilimumab-refractory patients was 30% (95% CI, 21%-41%). The median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when patients were followed up for a median of 16 months. One- and 2-year survival rates were 68.4% and 31.2%, respectively. Ipilimumab-naïve and ipilimumab-refractory patients showed no significant difference in survival. The 21 patients with prior grade 3-4 toxicity to ipilimumab that was managed with steroids tolerated nivolumab well, with 62% (95% CI, 38%-82%) having complete or partial responses or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSC) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab.

  15. Inhibition of B16 melanoma growth and metastasis in C57BL mice by vaccination with a syngeneic endothelial cell line

    PubMed Central

    Yoshiura, Kenta; Nishishita, Toshihide; Nakaoka, Takashi; Yamashita, Naohide; Yamashita, Naomi

    2009-01-01

    Background Key role of angiogenesis in tumor growth and metastasis based on accumulating evidence and recent progress of immunotherapy have led us to investigate vaccine therapy targeting tumor angiogenesis. Methods C57BL/6J mice were vaccinated with a syngeneic endothelial cell line Tpit/E by subcutaneous injection once a week. Prior to ninth vaccination, the mice were challenged with B16/F10 melanoma cells by subcutaneous inoculation on the back for the tumor growth model or by tail venous injection for the lung metastasis model. Development of subcutaneous tumor and lung metastasis was monitored by computed tomography scanning, which enabled accurate evaluation with the minimized sacrifice of mice. Results Vaccination with Tpit/E cells inhibited subcutaneous tumor growth and appearance of lung metastasis compared to control. Survival period was elongated in the Tpit/E vaccination in both of the two models. We also obtained hybridomas secreting specific antibodies to Tpit/E cells from a mouse vaccinated with the cells, indicating that specific immune response to the syngeneic endothelial cells was elicited. Conclusion These results suggest that vaccination with an autologous endothelial cell line may be effective against melanoma. PMID:19183492

  16. High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients.

    PubMed

    van den Hurk, Karin; Balint, Balazs; Toomey, Sinead; O'Leary, Patrick C; Unwin, Louise; Sheahan, Kieran; McDermott, Enda W; Murphy, Ian; van den Oord, Joost J; Rafferty, Mairin; FitzGerald, Dara M; Moran, Julie; Cummins, Robert; MacEneaney, Owen; Kay, Elaine W; O'Brien, Cathal P; Finn, Stephen P; Heffron, Cynthia C B B; Murphy, Michelle; Yela, Ruben; Power, Derek G; Regan, Padraic J; McDermott, Clodagh M; O'Keeffe, Allan; Orosz, Zsolt; Donnellan, Paul P; Crown, John P; Hennessy, Bryan T; Gallagher, William M

    2015-06-01

    Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (P<0.001) BRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.

  17. Testing New Drugs for Treatment of Melanoma Patients Applying Connectivity Map Database Analysis with Melanoma Gene Signatures

    DTIC Science & Technology

    2012-10-01

    U133 Plus 2.0 Array; ii) GSE8401: 31 primary melanomas and 52 metastatic melanomas; Affymetrix Human Genome U133A Array; iii) GSE15605: 46 primary...melanomas, 12 regional and distal metastases, 16 normal skins; Affymetrix Human Genome U133 Plus 2.0 Array. Data analysis was executed through the

  18. Immunomodulation by imiquimod in patients with high-risk primary melanoma

    PubMed Central

    Narayan, Rupa; Nguyen, Hong; Bentow, Jason J.; Moy, Lauren; Lee, Diana K.; Greger, Stephanie; Haskell, Jacquelyn; Vanchinathan, Veena; Chang, Pei-Lin; Tsui, Shanli; Konishi, Tamiko; Comin-Anduix, Begonya; Dauphine, Christine; Vargas, Hernan I.; Economou, James S.; Ribas, Antoni; Bruhn, Kevin W.; Craft, Noah

    2011-01-01

    Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80–100% cure rate of lentigo maligna, but studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLN), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A*0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted. PMID:21850019

  19. Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma.

    PubMed

    Soufir, N; Lacapere, J J; Bertrand, G; Matichard, E; Meziani, R; Mirebeau, D; Descamps, V; Gérard, B; Archimbaud, A; Ollivaud, L; Bouscarat, F; Baccard, M; Lanternier, G; Saïag, P; Lebbé, C; Basset-Seguin, N; Crickx, B; Cave, H; Grandchamp, B

    2004-01-26

    Germline anomalies of the INK4a-ARF and Cdk4 genes were sought in a series of 89 patients suspected of having a genetic predisposition to melanoma. Patients were selected based on the following criteria: (a) familial melanoma (23 cases), (b) multiple primary melanoma (MPM; 18 cases), (c) melanoma and additional unrelated cancers (13 cases), (d) age at diagnosis less than 25 years (21 cases), and (e) nonphoto-induced melanoma (NPIM; 14 cases). Mutations of INK4a-ARF and Cdk4 were characterised by automated sequencing, and germline deletions of INK4a-ARF were also examined by real-time quantitative PCR. Seven germline changes of INK4a-ARF, five of which were novel, were found in seven patients (8%). Four were very likely to be pathogenic mutations and were found in three high-risk melanoma families and in a patient who had a pancreatic carcinoma in addition to melanoma. Three variants of uncertain significance were detected in one MPM patient, one patient <25 years, and one NPIM patient. No germline deletion of INK4a-ARF was found in 71 patients, and no Cdk4 mutation was observed in the 89 patients. This study confirms that INK4a-ARF mutations are infrequent outside stringent familial criteria, and that germline INK4a-ARF deletions are rarely involved in genetic predisposition to melanoma.

  20. Interactive Tailored Website to Promote Sun Protection and Skin Self-Check Behaviors in Patients With Stage 0-III Melanoma

    ClinicalTrials.gov

    2017-04-04

    Stage 0 Skin Melanoma; Stage I Skin Melanoma; Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage II Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage III Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma

  1. Clinical characteristics and prognostic indicators for metastatic melanoma: data from 446 patients in north China.

    PubMed

    Hao, Mengze; Zhao, Gang; Du, Xiaoling; Yang, Yun; Yang, Jilong

    2016-08-01

    Melanoma is an extremely rare tumor in Asia. This retrospective study aimed to identify the clinical characteristics and prognostic factors of metastatic melanoma patients at Tianjin Medical University Cancer Hospital over the last 30 years. Survival analysis was performed with Kaplan-Meier, log-rank test, and multivariate Cox regression method using SPSS 19.0 software. The 1-, 2-, and 5-year survival rates of metastatic melanoma patients were 52, 32, and 16 %, respectively. Median overall survival (OS) was 13.5 months, median progression-free survival (PFS) 9.0 months, and median disease-free survival 20.3 months. Furthermore, patients with a single metastatic site achieved better OS and PFS than those with two or more metastatic lesions (OS 21.6 vs. 8.9 months, P < 0.001; PFS 11.3 vs. 7.1 months, P < 0.001). Survival times of patients with visceral metastases were the shortest (OS 8.5 months; PFS 7.5 months). Specifically, patients with primary mucosal lesions had a worse OS (9.7 months) and PFS (6.8 months) than those with acral (19.2 and 15.6 months, respectively) or non-acral primary lesions (11.8 and 11.1 months, respectively). The treatment of advanced melanoma was unitary, and prognoses of patients with metastatic melanoma in China were poor. Visceral metastasis, multiple metastatic sites, and primary mucosal lesions were significant predictors of survival of patients with metastatic melanoma. Those with primary mucosal lesions had significantly worse survivals than those with primary cutaneous lesions. More active involvement in clinical studies and more feedback on various treatment options are required.

  2. B-1 cells promote immunosurveillance against murine melanoma in host absence of CCR5: new perspective in autologous vaccination therapy.

    PubMed

    Vivanco, Bruno C; Viana, Jacqueline D; Perez, Elisabeth C; Konno, Fabiana T C; Guereschi, Marcia G; Xander, Patricia; Keller, Alexandre C; Lopes, José D

    2014-11-01

    Autologous vaccination with tumor-primed dendritic cells increases immune response against tumor, which seems to be improved in host absence of CCR5. Because B-1 lymphocytes modulate the activity of different immune cells, we decided to study their influence in the resistance against murine B16F10 melanoma in a CCR5 deprived environment. Adoptive transfer of peritoneal B-1 CCR5(+/+) lymphocytes to CCR5(-/-) animals inhibited the establishment of lung metastasis and melanoma cell growth, in comparison to saline-treated CCR5(-/-) mice. In loco cell analysis demonstrated that the adoptive transfer of B-1 CCR5(+/+) lymphocytes to CCR5 deficient host was associated with a more intense influx of T CD8(+) to tumor site, indicating that the presence of CCR5(+/+) B-1 cells in the tumor environment induces the migration of T CD8 CCR5(-/-) cells to the implantation site. To corroborate this idea, CCR5(-/-) mice were injected with non B-1 peritoneal cells from wild type (WT) mice before B16F10 inoculation. In this regimen, CCR5(-/-) mice were not protected from tumor growth reinforcing the idea that, in host absence of CCR5, B-1 cells are essential to confer tumor resistance. This work indicates that, in the host absence of CCR5, naive B-1 cells may activate CD8T lymphocytes thereby promoting tumor resistance. Our results strongly suggest that autologous vaccination with B-1 lymphocytes in combination with CCR5 antagonists can be an alternative approach to tumor therapy.

  3. Fully Regressive Melanoma

    PubMed Central

    Ehrsam, Eric; Kallini, Joseph R.; Lebas, Damien; Modiano, Philippe; Cotten, Hervé

    2016-01-01

    Fully regressive melanoma is a phenomenon in which the primary cutaneous melanoma becomes completely replaced by fibrotic components as a result of host immune response. Although 10 to 35 percent of cases of cutaneous melanomas may partially regress, fully regressive melanoma is very rare; only 47 cases have been reported in the literature to date. AH of the cases of fully regressive melanoma reported in the literature were diagnosed in conjunction with metastasis on a patient. The authors describe a case of fully regressive melanoma without any metastases at the time of its diagnosis. Characteristic findings on dermoscopy, as well as the absence of melanoma on final biopsy, confirmed the diagnosis. PMID:27672418

  4. Association of CDK4 germline and BRAF somatic mutations in a patient with multiple primary melanomas and BRAF inhibitor resistance.

    PubMed

    Governa, Maurizio; Caprarella, Evelina; Dalla Pozza, Edoardo; Vigato, Enrico; Maritan, Monia; Caputo, Glenda G; Zannoni, Marina; Rosina, Paolo; Elefanti, Lisa; Stagni, Camilla; Menin, Chiara

    2015-10-01

    Many genetic alterations, including predisposing or somatic mutations, may contribute toward the development of melanoma. Although CDKN2A and CDK4 are high-penetrance genes for melanoma, MC1R is a low-penetrance gene that has been associated most consistently with the disease. Moreover, BRAF is the most frequently somatically altered oncogene and is a validated therapeutic target in melanoma. This paper reports a case of multiple primary melanoma with germline CDK4 mutation, MC1R variant, and somatic BRAF mutation in nine out of 10 melanomas, indicating that a common pathogenesis, because of a predisposing genetic background, may be shared among distinct subsequent melanomas of probable clonal origin. After 3 months of targeted therapy with BRAF inhibitor, our patient developed resistance with rapid progression of the disease leading to death. This is the first case in which early resistance to BRAF inhibitor has been reported in a patient with CDK4 germline mutation.

  5. Protein signatures correspond to survival outcomes of AJCC stage III melanoma patients

    PubMed Central

    Mactier, Swetlana; Kaufman, Kimberley L; Wang, Penghao; Crossett, Ben; Pupo, Gulietta M; Kohnke, Philippa L; Thompson, John F; Scolyer, Richard A; Yang, Jean Y; Mann, Graham J; Christopherson, Richard I

    2014-01-01

    Summary Outcomes for melanoma patients with stage III disease differ widely even within the same subcategory. Molecular signatures that more accurately predict prognosis are needed to stratify patients according to risk. Proteomic analyses were used to identify differentially abundant proteins in extracts of surgically excised samples from patients with stage IIIc melanoma lymph node metastases. Analysis of samples from patients with poor (n = 14, <1 yr) and good (n = 19, >4 yr) survival outcomes identified 84 proteins that were differentially abundant between prognostic groups. Subsequent selected reaction monitoring analysis verified 21 proteins as potential biomarkers for survival. Poor prognosis patients are characterized by increased levels of proteins involved in protein metabolism, nucleic acid metabolism, angiogenesis, deregulation of cellular energetics and methylation processes, and decreased levels of proteins involved in apoptosis and immune response. These proteins are able to classify stage IIIc patients into prognostic subgroups (P < 0.02). This is the first report of potential prognostic markers from stage III melanoma using proteomic analyses. Validation of these protein markers in larger patient cohorts should define protein signatures that enable better stratification of stage III melanoma patients. PMID:24995518

  6. Protein signatures correspond to survival outcomes of AJCC stage III melanoma patients.

    PubMed

    Mactier, Swetlana; Kaufman, Kimberley L; Wang, Penghao; Crossett, Ben; Pupo, Gulietta M; Kohnke, Philippa L; Thompson, John F; Scolyer, Richard A; Yang, Jean Y; Mann, Graham J; Christopherson, Richard I

    2014-11-01

    Outcomes for melanoma patients with stage III disease differ widely even within the same subcategory. Molecular signatures that more accurately predict prognosis are needed to stratify patients according to risk. Proteomic analyses were used to identify differentially abundant proteins in extracts of surgically excised samples from patients with stage IIIc melanoma lymph node metastases. Analysis of samples from patients with poor (n = 14, <1 yr) and good (n = 19, >4 yr) survival outcomes identified 84 proteins that were differentially abundant between prognostic groups. Subsequent selected reaction monitoring analysis verified 21 proteins as potential biomarkers for survival. Poor prognosis patients are characterized by increased levels of proteins involved in protein metabolism, nucleic acid metabolism, angiogenesis, deregulation of cellular energetics and methylation processes, and decreased levels of proteins involved in apoptosis and immune response. These proteins are able to classify stage IIIc patients into prognostic subgroups (P < 0.02). This is the first report of potential prognostic markers from stage III melanoma using proteomic analyses. Validation of these protein markers in larger patient cohorts should define protein signatures that enable better stratification of stage III melanoma patients.

  7. Vitamin D receptor polymorphisms in patients with cutaneous melanoma.

    PubMed

    Orlow, Irene; Roy, Pampa; Reiner, Anne S; Yoo, Sarah; Patel, Himali; Paine, Susan; Armstrong, Bruce K; Kricker, Anne; Marrett, Loraine D; Millikan, Robert C; Thomas, Nancy E; Gruber, Stephen B; Anton-Culver, Hoda; Rosso, Stefano; Gallagher, Richard P; Dwyer, Terence; Kanetsky, Peter A; Busam, Klaus; From, Lynn; Begg, Colin B; Berwick, Marianne

    2012-01-15

    The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. Buccal DNAs were obtained from 1,207 people with incident multiple primary melanoma and 2,469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, haplotype tagging SNPs with ≥ 10% minor allele frequency in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3' gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25 to 33% for six polymorphisms: rs10875712 (odds ratios [OR] 1.28; 95% confidence interval (CI), 1.01-1.62), rs4760674 (OR 1.33; 95% CI, 1.06-1.67), rs7139166 (OR 1.26; 95%CI, 1.02-1.56), rs4516035 (OR 1.25; 95%CI, 1.01-1.55), rs11168287 (OR 1.27; 95%CI, 1.03-1.57) and rs1544410 (OR 1.30; 95%CI, 1.04-1.63); for two polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65-1.02) and rs7965281 (OR, 0.78; 95%CI, 0.62-0.99). We recognize the potential false positive findings because of multiple comparisons; however, the eight significant SNPs in our study outnumbered the two significant tests expected to occur by chance. The VDR may play a role in melanomagenesis.

  8. Vitamin D receptor polymorphisms in patients with cutaneous melanoma

    PubMed Central

    Orlow, Irene; Roy, Pampa; Reiner, Anne S.; Yoo, Sarah; Patel, Himali; Paine, Susan; Armstrong, Bruce K.; Kricker, Anne; Marrett, Loraine D.; Millikan, Robert C.; Thomas, Nancy E.; Gruber, Stephen B.; Anton-Culver, Hoda; Rosso, Stefano; Gallagher, Richard P.; Dwyer, Terence; Kanetsky, Peter A.; Busam, Klaus; From, Lynn; Begg, Colin B.; Berwick, Marianne

    2011-01-01

    The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene SNPs in a large international multi-center population-based case-control study of melanoma. Buccal DNAs were obtained from 1207 people with incident multiple primary melanoma and 2469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, htSNPs with ≥10% MAF in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3’ gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25% to 33% for 6 polymorphisms: rs10875712 (OR 1.28; 95%CI, 1.01–1.62), rs4760674 (OR 1.33; 95% CI, 1.06–1.67), rs7139166 (OR 1.26; 95%CI, 1.02–1.56), rs4516035 (OR 1.25; 95%CI, 1.01–1.55), rs11168287 (OR 1.27; 95%CI, 1.03–1.57), rs1544410 (OR 1.30; 95%CI, 1.04–1.63); for 2 polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65–1.02), rs7965281 (OR, 0.78; 95%CI, 0.62–0.99). We recognize the potential false positive findings due to multiple comparisons; however the 8 significant SNPs in this study outnumbered the 2 significant tests expected to occur by chance. The vitamin D receptor may play a role in melanomagenesis. PMID:21365644

  9. Application of paclitaxel in low non-cytotoxic doses supports vaccination with melanoma antigens in normal mice.

    PubMed

    Sevko, Alexandra; Kremer, Veronika; Falk, Christine; Umansky, Ludmila; Shurin, Michael R; Shurin, Galina V; Umansky, Viktor

    2012-01-01

    Chemotherapeutic agents such as paclitaxel applied in ultra-low, non-cytotoxic doses were previously shown to stimulate dendritic cell activity and anti-tumor immune responses upon vaccination in mouse transplantable tumor models. However, the mechanisms of these alterations-termed chemoimmunomodulation or chemomodulation-are still not clear. This study investigated the effect of paclitaxel applied in ultra-low, non-cytotoxic doses on the efficiency of immunization of healthy C57BL/6 mice with the peptide derived from tyrosinase related protein (TRP)-2 as a model melanoma antigen. Using an IFNγ ELISPOT assay, it was found that administration of 1 mg paclitaxel/kg in combination with the peptide vaccination strongly increased the frequencies of TRP-2 specific spleen T-cells as compared to levels due to the vaccination alone. This was associated with a significant decrease in the levels of regulatory T-cells (T(reg)) and immature myeloid cells (known as a counterpart of myeloid derived suppressor cells [MDSC] in healthy mice). Such impairments of potential immunosuppressive cells were found to correlate with a strong increase in the amount of effector CD8+ and CD4+ T-cells in the bone marrow and spleen. Furthermore, in paclitaxel-treated mice, a significant augmentation of natural killer (NK) cell numbers in the bone marrow and their ability to produce IFNγ were observed. In addition, the level of NK-T-cells in the lymph nodes was also increased. It is suggested that paclitaxel applied in ultra-low, non-cytotoxic doses may potentially enhance the efficacy of anti-tumor vaccinations by neutralizing immunosuppressive T(reg) and MDSC populations in tumor-bearing hosts.

  10. Vaccinations in patients with immune-mediated inflammatory diseases

    PubMed Central

    Rahier, Jean-François; Moutschen, Michel; Van Gompel, Alfons; Van Ranst, Marc; Louis, Edouard; Segaert, Siegfried; Masson, Pierre

    2010-01-01

    Patients with immune-mediated inflammatory diseases (IMID) such as RA, IBD or psoriasis, are at increased risk of infection, partially because of the disease itself, but mostly because of treatment with immunomodulatory or immunosuppressive drugs. In spite of their elevated risk for vaccine-preventable disease, vaccination coverage in IMID patients is surprisingly low. This review summarizes current literature data on vaccine safety and efficacy in IMID patients treated with immunosuppressive or immunomodulatory drugs and formulates best-practice recommendations on vaccination in this population. Especially in the current era of biological therapies, including TNF-blocking agents, special consideration should be given to vaccination strategies in IMID patients. Clinical evidence indicates that immunization of IMID patients does not increase clinical or laboratory parameters of disease activity. Live vaccines are contraindicated in immunocompromized individuals, but non-live vaccines can safely be given. Although the reduced quality of the immune response in patients under immunotherapy may have a negative impact on vaccination efficacy in this population, adequate humoral response to vaccination in IMID patients has been demonstrated for hepatitis B, influenza and pneumococcal vaccination. Vaccination status is best checked and updated before the start of immunomodulatory therapy: live vaccines are not contraindicated at that time and inactivated vaccines elicit an optimal immune response in immunocompetent individuals. PMID:20591834

  11. Correlation of TGF-β1 and oxidative stress in the blood of patients with melanoma: a clue to understanding melanoma progression?

    PubMed

    Santos Bernardes, Sara; de Souza-Neto, Fernando Pinheiro; Pasqual Melo, Gabriella; Guarnier, Flávia Alessandra; Marinello, Poliana Camila; Cecchini, Rubens; Cecchini, Alessandra L

    2016-08-01

    TGF-β1 and oxidative stress are involved in cancer progression, but in melanoma, their role is still controversial. Our aim was to correlate plasma TGF-β1 levels and systemic oxidative stress biomarkers in patients with melanoma, with or without disease metastasis, to understand their participation in melanoma progression. Thirty patients were recruited for melanoma surveillance, together with 30 healthy volunteers. Patients were divided into two groups: Non-metastasis, comprising patients with tumor removal and no metastatic episode for 3 years; and Metastasis, comprising patients with a metastatic episode. The plasmatic cytokines TGF-β1, IL-1 β, and TNF-α were analyzed by ELISA. For oxidative stress, the following assays were performed: malondialdehyde (MDA), advanced oxidation protein products (AOPP) levels, total radical-trapping antioxidant parameter (TRAP) and thiol in plasma, and lipid peroxidation, SOD and catalase activity and GSH in erythrocytes. Patients with a metastatic episode had less circulating TGF-β1 and increased TRAP, thiol, AOPP and lipid peroxidation levels. MDA was increased in both melanoma groups, while catalase, GSH, and IL-1β was decreased in Non-metastasis patients. Significant negative correlations were observed between TGF-β1 levels and systemic MDA, and TGF-β1 levels and systemic AOPP, while a positive correlation was observed between TGF-β1 levels and erythrocyte GSH. Lower levels of TGF-β1 were related to increased oxidative stress in Metastasis patients, reinforcing new evidence that in melanoma TGF-β1 acts as a tumor suppressor, inhibiting tumor relapse. These findings provide new knowledge concerning this cancer pathophysiology, extending the possibilities of investigating new therapies based on this evidence.

  12. Decreased Expression of Nuclear p300 Is Associated with Disease Progression and Worse Prognosis of Melanoma Patients

    PubMed Central

    Rotte, Anand; Bhandaru, Madhuri; Cheng, Yabin; Sjoestroem, Cecilia; Martinka, Magdalena; Li, Gang

    2013-01-01

    Background Genomic instability due to UV radiation is one of the leading causes for melanoma. Histone acetyltransferase p300 plays an indispensible role in DNA repair and maintenance of genomic integrity. The present study was performed to analyze the correlation between p300 expression, melanoma progression and patient survival. Methods Tissue microarray and immunohistochemical analysis was employed to study the expression of p300 in melanoma patients. A total of 358 melanoma patients (250 primary melanoma and 108 metastatic melanoma) were used for the study. Kaplan-Meier, univariate and multivariate Cox regression analysis, and receiver-operating characteristic curves, were used to elucidate the prognostic significance of p300 expression. Results Our results demonstrate that p300 is expressed in both nucleus and cytoplasm but the nuclear expression of p300 is predominant. The progression of disease from dysplastic nevi to primary melanoma and to metastatic melanoma was associated with decreased nuclear and increased cytoplasmic p300 expression. Especially, the loss of nuclear and gain in cytoplasmic p300 was correlated with the progression of melanoma from AJCC stage II to stage III, which requires the migration and metastasis of cancer cells from primary sites to lymph nodes. Similarly, decrease in nuclear, and increase in cytoplasmic p300 expression correlated with worse survival of melanoma patients. Nuclear p300 but not cytoplasmic p300 could predict the patient survival independent of AJCC stage, age and gender. Conclusion Loss of nuclear p300 expression is an indicator of worse patient survival and is an independent prognostic marker for melanoma. PMID:24098694

  13. Recurrent Malignant Melanoma Presenting as Isolated Pleural Metastases in a Patient with Chronic Lymphocytic Leukemia

    PubMed Central

    Anand, Kartik; Cingam, Shashank; Peddi, Prakash

    2017-01-01

    Isolated pleural metastasis with pleural effusion is a rare occurrence in malignant melanoma. We report an unusual case of a patient with chronic lymphocytic leukemia (CLL) and recurrent pleural effusions. The pleural fluid cytology and immunohistochemistry profile were consistent with the diagnosis of CLL. However, chemotherapy with pentostatin, cyclophosphamide, and rituximab did not result in any meaningful clinical response. A video-assisted thoracoscopic surgery and biopsy of the affected nodular parietal layer of the pleura were consistent with malignant melanoma. Our case underlines the importance of having a suspicion for secondary causes of effusion in patients with CLL. We briefly discuss the mechanisms of an increased incidence of secondary cancers in CLL and the diagnosis of isolated pleural metastases in malignant melanoma. PMID:28203169

  14. Fine-mapping naturally occurring NY-ESO-1 antibody epitopes in melanoma patients' sera using short overlapping peptides and full-length recombinant protein.

    PubMed

    Komatsu, Nobukazu; Jackson, Heather M; Chan, Kok-fei; Oveissi, Sara; Cebon, Jonathan; Itoh, Kyogo; Chen, Weisan

    2013-07-01

    The tumor antigen NY-ESO-1 is one of the most antigenic cancer-testis antigens, first identified by serologic analysis of a recombinant cDNA expression library (SEREX). NY-ESO-1 is expressed in different types of cancers including melanoma. NY-ESO-1-specific spontaneous humoral and cellular immune responses are detected in a large proportion of patients with advanced NY-ESO-1-expressing cancers. Therefore NY-ESO-1 is a good candidate antigen for immunotherapy. Although cellular immune responses to NY-ESO-1 are well characterized, much less is known about the humoral immune responses. In this study, we finely mapped linear antibody epitopes using sera from melanoma patients and shorter overlapping peptide sets. We have shown that melanoma patients' humoral immune systems responded to NY-ESO-1 differently in each individual with widely differing antibody specificity, intensity and antibody subtypes. This knowledge will help us further understand anti-tumor immunity and may also help us to monitor cancer progress and cancer vaccine efficacy in the future.

  15. Detection of submicroscopic lymph node metastases with polymerase chain reaction in patients with malignant melanoma.

    PubMed Central

    Wang, X; Heller, R; VanVoorhis, N; Cruse, C W; Glass, F; Fenske, N; Berman, C; Leo-Messina, J; Rappaport, D; Wells, K

    1994-01-01

    BACKGROUND. The presence or absence of lymph node metastases in patients with malignant melanoma is the most powerful prognostic factor for predicting survival. If regional nodal metastases are found, the 5-year survival for the patient decreases approximately 50%. If the presence or absence of regional nodal metastases will determine which patients receive formal dissections or which patients enter adjuvant trials, then a technique is needed to accurately screen lymph node samples for occult disease. Routine histopathologic examination routinely underestimates the number of patients with metastases. This study was initiated to develop a highly sensitive clinically applicable method to detect micrometastases by examining lymph nodes for the presence of tyrosinase messenger RNA (mRNA). The hypothesis was that if mRNA for tyrosinase is found in the lymph node preparation, that finding is good evidence that metastatic melanoma cells are present. METHODS. The assay is accomplished using the combination of reverse transcription and double-round polymerase chain reaction (RT-PCR). The amplified samples are examined on a 2% agarose gel and tyrosinase cDNA is seen as a 207 base pair fragment. Lymph node preparations from 29 patients who were clinically stage I and II and undergoing elective node dissections were analyzed both by standard pathologic staining and RT-PCR. RESULTS. Eleven of 29 lymph node (38%) samples from 29 patients with intermediate thickness melanoma were pathologically positive. Nineteen of the 29 lymph node preparations (66%) were RT-PCR-positive, and these included all of the pathologically positive samples, so that the false-negative rate was 0. In a spiking experiment, one SK-Mel-28 melanoma cell in a background of one million normal lymphocytes could be detected, thus indicating the sensitivity of this method. In addition, analysis by restriction enzyme mapping showed that the amplified 207-bp PCR product produced is part of the tyrosinase gene

  16. Nivolumab-induced vitiligo in a metastatic melanoma patient: A case report.

    PubMed

    Edmondson, Lindsay A; Smith, Leticia V; Mallik, Alka

    2016-09-08

    The programmed-death-1 inhibitors selectively block programmed-death-1 interaction with its receptor, which restores active T-cell response directed at tumor cells, inducing an anti-tumor effect. This nonspecific activation of the immune system can also lead to a wide spectrum of side effects. Nivolumab has been used effectively to prolong survival in patients with metastatic melanoma and is recommended as a category 1 agent for systemic therapy in metastatic or unresectable melanoma per the National Comprehensive Cancer Network guidelines. We present a case of a 64-year-old woman who began nivolumab therapy for metastatic melanoma. After six doses of nivolumab therapy, the patient experienced generalized hypopigmentation on her face, chest, back, arms, and lower extremities. Although vitiligo has been reported in as many as 10.7% of patients undergoing nivolumab therapy in some clinical trials, we believe this is the first case to describe the progression of nivolumab-induced vitiligo in a metastatic melanoma patient. This case provides significant insight into the onset, symptoms, development, and treatment options for patients experiencing vitiligo as a result of nivolumab therapy.

  17. Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts.

    PubMed

    Kemper, Kristel; Krijgsman, Oscar; Cornelissen-Steijger, Paulien; Shahrabi, Aida; Weeber, Fleur; Song, Ji-Ying; Kuilman, Thomas; Vis, Daniel J; Wessels, Lodewyk F; Voest, Emile E; Schumacher, Ton Nm; Blank, Christian U; Adams, David J; Haanen, John B; Peeper, Daniel S

    2015-09-01

    The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAF(V600E) metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole-exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug-resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAF(V600E), we identified a new activating insertion in MEK1. This MEK1(T55delins) (RT) mutation could be traced back to a fraction of the pre-treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient-derived xenografts (PDX) from therapy-refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter- and intra-tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma.

  18. Improving outcomes in patients with melanoma: strategies to ensure an early diagnosis

    PubMed Central

    Voss, Rachel K; Woods, Tessa N; Cromwell, Kate D; Nelson, Kelly C; Cormier, Janice N

    2015-01-01

    Patients with thin, low-risk melanomas have an excellent long-term prognosis and higher quality of life than those who are diagnosed at later stages. From an economic standpoint, treatment of early stage melanoma consumes a fraction of the health care resources needed to treat advanced disease. Consequently, early diagnosis of melanoma is in the best interest of patients, payers, and health care systems. This review describes strategies to ensure that patients receive an early diagnosis through interventions ranging from better utilization of primary care clinics, to in vivo diagnostic technologies, to new “apps” available in the market. Strategies for screening those at high risk due to age, male sex, skin type, nevi, genetic mutations, or family history are discussed. Despite progress in identifying those at high risk for melanoma, there remains a lack of general consensus worldwide for best screening practices. Strategies to ensure early diagnosis of recurrent disease in those with a prior melanoma diagnosis are also reviewed. Variations in recurrence surveillance practices by type of provider and country are featured, with evidence demonstrating that various imaging studies, including ultrasound, computed tomography, positron emission tomography, and magnetic resonance imaging, provide only minimal gains in life expectancy, even for those with more advanced (stage III) disease. Because the majority of melanomas are attributable to ultraviolet radiation in the form of sunlight, primary prevention strategies, including sunscreen use and behavioral interventions, are reviewed. Recent international government regulation of tanning beds is described, as well as issues surrounding the continued use artificial ultraviolet sources among youth. Health care stakeholder strategies to minimize UV exposure are summarized. The recommendations encompass both specific behaviors and broad intervention targets (eg, individuals, social spheres, organizations, celebrities

  19. Survival for patients with single and multiple primary melanomas in the GEM study

    PubMed Central

    Kricker, Anne; Armstrong, Bruce K.; Goumas, Chris; Thomas, Nancy E.; From, Lynn; Busam, Klaus; Kanetsky, Peter A.; Gallagher, Richard P.; Marrett, Loraine D.; Groben, Pamela A.; Gruber, Stephen B.; Anton-Culver, Hoda; Rosso, Stefano; Dwyer, Terence; Berwick, Marianne

    2013-01-01

    Objective Little is known about survival after a diagnosis of a second or higher order (multiple) primary melanoma. We aimed to determine whether survival after diagnosis was better in patients with multiple primary melanomas (MPM) than with single primary melanomas (SPM), as suggested in a recent study. Design Survival analysis with median follow-up of 7.6 years (range 0.4-10.6). Setting The Genes, Environment and Melanoma (GEM) study enrolled incident cases of melanoma notified to population-based cancer registries in Australia, Canada, Italy and the USA. MPM were ascertained over a longer period than SPM. Participants 2372 patients with SPM and 1206 with MPM. Main outcome measures Melanoma-specific fatality hazard ratios (HR) and confidence intervals (CI) associated with clinical and pathologic characteristics of SPM, MPM and both together in Cox regression models. Results Thickness was the main determinant of fatality (HR for >4mm=7.68, 95% CI 4.46 to 13.23); other independent predictors were ulceration, mitoses and scalp location. After adjustment for these other predictors, there was little difference in fatality between MPM and SPM (HR for MPM relative to SPM=1.24, 95% CI 0.91 to 1.69; P = .18). Thicker SPM, however, had higher fatality (HR for >4mm=13.56, 95% CI 6.47-28.40) than thicker MPM (HR for >4mm=2.93, 95% CI 1.17-7.30). Conclusion While overall fatalities from SPM and MPM were similar, relative fatality for thick SPM was greater than for thick MPM. This finding may offer support for a difference in outcome between patients with SPM and MPM that is worth further exploration. PMID:23784017

  20. The impact of selected factors on early diagnosis of multiple primary cancers in patients with uveal melanoma

    PubMed Central

    Romanowska-Dixon, Bożena

    2013-01-01

    Aim of the study To find differences between a group of patients with intraocular melanoma and another primary cancer and a group of patients with no identifiable second primary cancer. Material and methods The analysis involved 240 participants, selected from patients who were treated for uveal melanoma at the Department of Ophthalmology and Ocular Oncology of the Jagiellonian University Medical College between the year 1998 and 2007. Among those patients 97 were diagnosed with one or more independent primary cancers. Those patients were subject to a comparative analysis with a second group of 143 patients who had uveal melanoma with no identifiable second primary cancer. Results Statistically significant differences between the group of patients with intraocular melanoma and another primary cancer, and the group of patients with uveal melanoma (but without another diagnosed primary neoplasm) were as follows: more common family history of cancer, better education, living in cities (especially with a population over 500 thousand), previous surgery except for uveal melanoma, and two or less than two pregnancies in the case of women. Conclusions This analysis revealed that more common family history of cancer, better education, living in cities (especially with a population over 500 thousand), previous surgery, except for uveal melanoma, and two or less than two pregnancies in the case of women, were associated with a higher rate of detection of multiple primary cancers. PMID:24592138

  1. An Orbital Malignant Melanoma Arising in Cellular Blue Nevus in a Patient with Nevus of Ota

    PubMed Central

    Ouyang, Jie; Cartwright, Mont

    2016-01-01

    Melanomas arising from orbital melanocytic proliferations are exceedingly rare. Many questions remain regarding their development and malignant transformation. We report on a 45-year-old Caucasian woman with a nevus of Ota that presented with visual disturbances involving her right eye and was found to have a biopsy-proven cellular blue nevus in the orbital space. Five years later, she presented with proptosis and worsening symptoms. Biopsy at that time showed a cellular blue nevus with areas of melanoma. We conclude that patients with a nevus of Ota or an orbital cellular blue nevus, particularly Caucasians, should be monitored for ocular/orbital involvement and followed closely for signs of rapid growth. There may be a progressive evolution to melanoma from a blue nevus.   PMID:27699140

  2. Towards personalized therapy for patients with malignant melanoma: molecular insights into the biology of BRAF mutations.

    PubMed

    Bradish, Joshua R; Montironi, Rodolfo; Lopez-Beltran, Antonio; Post, Kristin M; MacLennan, Gregory T; Cheng, Liang

    2013-02-01

    BRAF mutations have been identified as the most common oncogene mutation in melanomas, especially important in those originating on nonchronically sun-damaged skin. There is a large and continually growing body of evidence regarding the importance of this mutation in targeted therapy for melanoma. In this review, we outline these findings including: molecular pathways used by BRAF, the importance in nonmalignant neoplasms, histologic associations, the relationship of BRAF to KIT and NRAS mutations, and their impact on survival, as well as resistance mechanisms to BRAF inhibitors employed by melanoma. Understanding these topics and how they relate to one another may facilitate the development of new treatments and eventually improve the prognosis for those patients afflicted with this disease.

  3. Frequency of colour vision deficiencies in melanoma patients: results of a prospective comparative screening study with the Farnsworth panel D 15 test including 300 melanoma patients and 100 healthy controls.

    PubMed

    Pföhler, Claudia; Tschöp, Sabine; König, Jochem; Rass, Knuth; Tilgen, Wolfgang

    2006-10-01

    Patients with melanoma may experience a variety of different vision symptoms, in part associated with melanoma-associated retinopathy. For several melanoma patients with or without melanoma-associated retinopathy, colour vision deficiencies, especially involving the tritan system, have been reported. The frequency of colour vision deficiencies in a larger cohort of melanoma patients has not yet been investigated. The aim of this study was to investigate the frequency of colour vision deficiencies in melanoma patients subject to stage of disease, prognostic factors such as tumour thickness or Clark level, S100-beta and predisposing diseases that may have an impact on colour vision (hypertension, diabetes mellitus, glaucoma or cataract). Three hundred melanoma patients in different tumour stages and 100 healthy age-matched and sex-matched controls were examined with the saturated Farnsworth panel D 15 test. Seventy out of 300 (23.3%) melanoma patients and 12/100 (12%) controls showed pathologic results in colour testing. This discrepancy was significant (P < 0.016; odds ratio = 2.23, 95% confidence interval 1.15-4.32). Increasing age was identified as a highly significant (P = 0.0005) risk factor for blue vision deficiency. Adjusting for the age and predisposing diseases, we could show that melanoma was associated with the risk of blue vision deficiency. The frequency of blue vision deficiency in 52/260 melanoma patients without predisposing diseases (20%) compared with 4/78 controls without predisposing diseases (5.1%) differed significantly (odds ratio 4.441; confidence interval 1.54-12.62; P < 0.004). In 260 melanoma patients without predisposing diseases, blue vision deficiency, as graded on a 6-point scale, showed a weak positive correlation (Spearman) with tumour stage (r = 0.147; P < 0.01), tumour thickness (r = 0.10; P = 0.0035), Clark level (r = 0.12; P = 0.04) and a weak negative correlation with time since initial diagnosis (r = -0.11; P = 0.0455). Blue

  4. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab.

    PubMed

    Chaput, N; Lepage, P; Coutzac, C; Soularue, E; Le Roux, K; Monot, C; Boselli, L; Routier, E; Cassard, L; Collins, M; Vaysse, T; Marthey, L; Eggermont, A; Asvatourian, V; Lanoy, E; Mateus, C; Robert, C; Carbonnel, F

    2017-03-27

    Ipilimumab, an immune checkpoint inhibitor targeting CTLA-4, prolongs survival in a subset of patients with metastatic melanoma but can induce immune-related adverse events, including enterocolitis. We hypothesized that baseline gut microbiota could predict ipilimumab anti-tumor response and/or intestinal toxicity.

  5. Vemurafenib Improves Survival for Patients with Metastatic Melanoma | Division of Cancer Prevention

    Cancer.gov

    Patients with metastatic melanoma whose tumors harbor a specific genetic mutation have improved overall survival with the targeted therapy vemurafenib (Zelboraf), according to longer-term follow-up data from a  |

  6. Ascertaining serum levels of trace elements in melanoma patients using PIXE and HR-ICPMS

    NASA Astrophysics Data System (ADS)

    Bernardes, S.; Tabacniks, M. H.; Santos, I. D. A. O.; Oliveira, A. F.; Shie, J. N.; Sarkis, J. E. S.; Oliveira, T.

    2014-01-01

    Melanoma is a serious and deadly form of skin cancer. However, patients' chances of survival and recovery are considerably increased when it is diagnosed and treated in its early stages. In this study, trace element concentrations in serum samples from patients with melanoma were measured using PIXE (Proton Induced X-ray Emission) and HR-ICPMS (High-Resolution Inductively Coupled Plasma Mass Spectrometry), with the purpose of correlating these concentrations with the disease. Blood samples from 30 melanoma patients and 116 healthy donors were collected at São Paulo Hospital (protocol CEP 1036/08 UNIFESP). Relevant clinical information on the patients has also been included in the statistical analysis. Analysis of the control group showed different P and Mg concentrations in individuals above and below 40 years of age. P, S, Ca, Cu and Zn concentrations in healthy individuals differed according to gender, highlighting the necessity to include age and gender variables in the case-control analysis. There were also differences in K, S, Ca and Se concentrations between the control and melanoma groups.

  7. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab.

    PubMed

    Yuan, Jianda; Adamow, Matthew; Ginsberg, Brian A; Rasalan, Teresa S; Ritter, Erika; Gallardo, Humilidad F; Xu, Yinyan; Pogoriler, Evelina; Terzulli, Stephanie L; Kuk, Deborah; Panageas, Katherine S; Ritter, Gerd; Sznol, Mario; Halaban, Ruth; Jungbluth, Achim A; Allison, James P; Old, Lloyd J; Wolchok, Jedd D; Gnjatic, Sacha

    2011-10-04

    Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA-4), has been shown to improve survival in patients with advanced metastatic melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen expressed in a subset of patients with melanoma. To characterize the association between immune response and clinical outcome, we first analyzed NY-ESO-1 serum antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22 of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following treatment. These NY-ESO-1-seropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1-seronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher test). To understand why some patients with NY-ESO-1 antibody failed to experience clinical benefit, we analyzed NY-ESO-1-specific CD4(+) and CD8(+) T-cell responses by intracellular multicytokine staining in 20 NY-ESO-1-seropositive patients and found a surprising dissociation between NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1-seropositive patients with associated CD8(+) T cells experienced more frequent clinical benefit (10 of 13; 77%) than those with undetectable CD8(+) T-cell response (one of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses may have predictive value for ipilimumab treatment and argue for prospective studies in patients with established NY-ESO-1 immunity. The current findings provide a strong rationale for the clinical use of modulators of immunosuppression with concurrent approaches to favor tumor antigen-specific immune responses, such as vaccines or adoptive transfer, in patients with cancer.

  8. Recommendations for administering the triple viral vaccine and antiinfluenza vaccine in patients with egg allergy.

    PubMed

    Piquer-Gibert, M; Plaza-Martín, A; Martorell-Aragonés, A; Ferré-Ybarz, L; Echeverría-Zudaire, L; Boné-Calvo, J; Nevot-Falcó, S

    2007-01-01

    Actually, food allergy is an emerging pathology; and egg allergy is the most frequent in childhood. The recommendations for measles, mumps and rubella (MMR) and influenza vaccination are increasing each year. This implementation increases the exposure of patients with egg allergy to such vaccines. In Spain, since 2004 the only available vaccine for MMR is grown in cultures of fibroblast from chick embryos; previously, patients with egg allergy were vaccinated with an alternative vaccine cultivated in diploid human cells which is no longer commercialized. Influenza vaccines grow in chick egg and the final product contains egg proteins (large variation in egg protein content has been reported). As controversy exist, the Food Allergy Committee of Spanish Society of Clinical Immunology and Pediatric Allergy decided to report some recommendations for the safe administration of MMR and influenza vaccines in patients with egg allergy. In summary, MMR vaccine is safe for children with egg allergy, only in patients with severe anaphylactic reaction after egg ingestion is recommended the administration in his reference hospital. Influenza vaccine is contraindicated in patients with severe anaphylactic reaction after egg ingestion. The rest can receive influenza vaccine in a 2-dose protocol with a vaccine that contains no more than 1.2 mcg of egg protein for mL.

  9. Two-year patient-reported outcomes following treatment of uveal melanoma.

    PubMed

    Hope-Stone, L; Brown, S L; Heimann, H; Damato, B; Salmon, P

    2016-12-01

    PurposeTreatment of uveal melanoma can impair patients' psychological well-being. We evaluated patient-reported outcome measures (PROMs) of anxiety, depression, and quality of life (QoL) over 2 years following treatment in a consecutive sample of uveal melanoma patients, compared observations to population normative values and examined whether outcomes differed according to patients' age, gender, and whether or not they were treated by enucleation or had a poor prognosis (presence of monosomy 3).DesignProspective longitudinal study.ParticipantsPatients (N=411) with uveal melanoma treated between 2008 and 2011.MethodsSelf-report questionnaire study. We compared mean PROMs scores obtained 6 months, 1 year, and 2 years after treatment to published population normative values using 2-sample t-tests, and tested the association of these scores with gender, age, treatment by enucleation, and monosomy 3 using mixed-model ANOVAs.ResultsOn QoL and depression, patients were similar to or better than normative values at all time points, but there was some evidence that females were more anxious than female normative values (Ps<0.001-<0.05). Younger patients (P<0.01) and female patients (P<0.01) were the most anxious overall. Enucleation was not associated with PROMs. Patients with monosomy 3 showed more depressed mood at all the three time points (P<0.05).ConclusionsPatients treated for uveal melanoma can expect, within 6 months of treatment, to have a QoL that is similar to that of the general population. Younger female patients and patients with monosomy 3 are more likely to be distressed, and clinicians will need to be alert to this.

  10. Limited genomic heterogeneity of circulating melanoma cells in advanced stage patients.

    PubMed

    Ruiz, Carmen; Li, Julia; Luttgen, Madelyn S; Kolatkar, Anand; Kendall, Jude T; Flores, Edna; Topp, Zheng; Samlowski, Wolfram E; McClay, Edward; Bethel, Kelly; Ferrone, Soldano; Hicks, James; Kuhn, Peter

    2015-01-09

    Purpose. Circulating melanoma cells (CMCs) constitute a potentially important representation of time-resolved tumor biology in patients. To date, genomic characterization of CMCs has been limited due to the lack of a robust methodology capable of identifying them in a format suitable for downstream characterization. Here, we have developed a methodology to detect intact CMCs that enables phenotypic, morphometric and genomic analysis at the single cell level. Experimental design. Blood samples from 40 metastatic melanoma patients and 10 normal blood donors were prospectively collected. A panel of 7 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibodies (mAbs) was used to immunocytochemically label CMCs. Detection was performed by automated digital fluorescence microscopy and multi-parametric computational analysis. Individual CMCs were captured by micromanipulation for whole genome amplification and copy number variation (CNV) analysis. Results. Based on CSPG4 expression and nuclear size, 1-250 CMCs were detected in 22 (55%) of 40 metastatic melanoma patients (0.5-371.5 CMCs ml(-1)). Morphometric analysis revealed that CMCs have a broad spectrum of morphologies and sizes but exhibit a relatively homogeneous nuclear size that was on average 1.5-fold larger than that of surrounding PBMCs. CNV analysis of single CMCs identified deletions of CDKN2A and PTEN, and amplification(s) of TERT, BRAF, KRAS and MDM2. Furthermore, novel chromosomal amplifications in chr12, 17 and 19 were also found. Conclusions. Our findings show that CSPG4 expressing CMCs can be found in the majority of advanced melanoma patients. High content analysis of this cell population may contribute to the design of effective personalized therapies in patients with melanoma.

  11. Limited genomic heterogeneity of circulating melanoma cells in advanced stage patients

    NASA Astrophysics Data System (ADS)

    Ruiz, Carmen; Li, Julia; Luttgen, Madelyn S.; Kolatkar, Anand; Kendall, Jude T.; Flores, Edna; Topp, Zheng; Samlowski, Wolfram E.; McClay, Edward; Bethel, Kelly; Ferrone, Soldano; Hicks, James; Kuhn, Peter

    2015-02-01

    Purpose. Circulating melanoma cells (CMCs) constitute a potentially important representation of time-resolved tumor biology in patients. To date, genomic characterization of CMCs has been limited due to the lack of a robust methodology capable of identifying them in a format suitable for downstream characterization. Here, we have developed a methodology to detect intact CMCs that enables phenotypic, morphometric and genomic analysis at the single cell level. Experimental design. Blood samples from 40 metastatic melanoma patients and 10 normal blood donors were prospectively collected. A panel of 7 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibodies (mAbs) was used to immunocytochemically label CMCs. Detection was performed by automated digital fluorescence microscopy and multi-parametric computational analysis. Individual CMCs were captured by micromanipulation for whole genome amplification and copy number variation (CNV) analysis. Results. Based on CSPG4 expression and nuclear size, 1-250 CMCs were detected in 22 (55%) of 40 metastatic melanoma patients (0.5-371.5 CMCs ml-1). Morphometric analysis revealed that CMCs have a broad spectrum of morphologies and sizes but exhibit a relatively homogeneous nuclear size that was on average 1.5-fold larger than that of surrounding PBMCs. CNV analysis of single CMCs identified deletions of CDKN2A and PTEN, and amplification(s) of TERT, BRAF, KRAS and MDM2. Furthermore, novel chromosomal amplifications in chr12, 17 and 19 were also found. Conclusions. Our findings show that CSPG4 expressing CMCs can be found in the majority of advanced melanoma patients. High content analysis of this cell population may contribute to the design of effective personalized therapies in patients with melanoma.

  12. Nivolumab: a review of its use in patients with malignant melanoma.

    PubMed

    Deeks, Emma D

    2014-07-01

    Nivolumab (Opdivo(®)) is a fully human monoclonal antibody against programmed death receptor-1, a negative regulatory checkpoint molecule with a role in immunosuppression. The drug is administered intravenously and is approved for the treatment of unresectable malignant melanoma in Japan. The potential for intravenous nivolumab to be used in the treatment of advanced malignancies such as melanoma was initially demonstrated in phase I dose-ranging trials. Subsequently, in a noncomparative, open-label, phase II trial, almost one-quarter of Japanese patients with previously treated stage III/IV melanoma (recurrent or unresectable) achieved a partial tumour response with intravenous nivolumab 2 mg/kg every 3 weeks. The clinical benefit of the drug was durable, with patients surviving free from progression for a median of 172 days and median overall survival not yet reached. Nivolumab had an acceptable tolerability profile in this trial, with fewer than 18 % of patients experiencing grade 3 or 4 adverse events related to the drug, the most common of which was increased γ-glutamyl transferase. Thus, nivolumab is an emerging, promising option for the treatment of malignant melanoma.

  13. Improved hepatitis B vaccination rates in ESRD patients in California.

    PubMed

    Brown, J; Peters, V

    2000-10-01

    According to the Centers for Disease Control (CDC) Survey of Dialysis Associated Diseases, California, which includes Network 17 and 18, had one of the lowest hepatitis B vaccination rates in the country for 1994, 1995, and 1996. With 3 outbreaks of hepatitis B (HBV) in California in 1994, hepatitis B vaccination was chosen as a quality improvement project in both Network 17 and 18. With input from both Medical Review Boards and HCFA Region X, a project was formulated which focused on the improvement of the number of facilities which had hepatitis B vaccination rates which are greater than 50%. The overall purpose of both projects was to: (1) achieve access to preventative services for end-stage renal disease (ESRD) Medicare beneficiaries; (2) increase the number of ESRD patients in California who are vaccinated for HBV; (3) eliminate dialysis in California as an independent risk factor for contracting HBV; (4) decrease the number of ESRD facilities with HBV vaccination rates of 0%; and (5) increase the number of ESRD facilities with HBV vaccination rates greater than 50%. In 1998, both Network 17 and 18 denominators were adjusted to reflect the population which is eligible for vaccination. Because of historically low vaccination rate in California, the 1998 data collection sought to ascertain precise numbers for the ESRD patient population. Data were used from the 1996 and 1997 CDC Survey of Dialysis Associated Diseases from baseline measurements of HBV vaccination rates for all facilities in both Network 17 and 18. The CDC did not conduct a survey in 1998, however, Network 17 and 18 conducted a survey of dialysis associated diseases for all of California ESRD facilities. A data collection tool was designed to gather information on processes and outcomes in each facility. This allowed a continuous quality improvement (CQI)-based approach to analyze the problem, where tools like cause/effect and Pareto diagrams provided information on factors and issues affecting

  14. Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq.

    PubMed

    Gerber, Tobias; Willscher, Edith; Loeffler-Wirth, Henry; Hopp, Lydia; Schadendorf, Dirk; Schartl, Manfred; Anderegg, Ulf; Camp, Gray; Treutlein, Barbara; Binder, Hans; Kunz, Manfred

    2017-01-03

    Recent technological advances in single-cell genomics make it possible to analyze cellular heterogeneity of tumor samples. Here, we applied single-cell RNA-seq to measure the transcriptomes of 307 single cells cultured from three biopsies of three different patients with a BRAF/NRAS wild type, BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant melanoma metastasis, respectively. Analysis based on self-organizing maps identified sub-populations defined by multiple gene expression modules involved in proliferation, oxidative phosphorylation, pigmentation and cellular stroma. Gene expression modules had prognostic relevance when compared with gene expression data from published melanoma samples and patient survival data. We surveyed kinome expression patterns across sub-populations of the BRAF/NRAS wild type sample and found that CDK4 and CDK2 were consistently highly expressed in the majority of cells, suggesting that these kinases might be involved in melanoma progression. Treatment of cells with the CDK4 inhibitor palbociclib restricted cell proliferation to a similar, and in some cases greater, extent than MAPK inhibitors. Finally, we identified a low abundant sub-population in this sample that highly expressed a module containing ABC transporter ABCB5, surface markers CD271 and CD133, and multiple aldehyde dehydrogenases (ALDHs). Patient-derived cultures of the BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant metastases showed more homogeneous single-cell gene expression patterns with gene expression modules for proliferation and ABC transporters. Taken together, our results describe an intertumor and intratumor heterogeneity in melanoma short-term cultures which might be relevant for patient survival, and suggest promising targets for new treatment approaches in melanoma therapy.

  15. Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq

    PubMed Central

    Loeffler-Wirth, Henry; Hopp, Lydia; Schadendorf, Dirk; Schartl, Manfred; Anderegg, Ulf; Camp, Gray; Treutlein, Barbara; Binder, Hans; Kunz, Manfred

    2017-01-01

    Recent technological advances in single-cell genomics make it possible to analyze cellular heterogeneity of tumor samples. Here, we applied single-cell RNA-seq to measure the transcriptomes of 307 single cells cultured from three biopsies of three different patients with a BRAF/NRAS wild type, BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant melanoma metastasis, respectively. Analysis based on self-organizing maps identified sub-populations defined by multiple gene expression modules involved in proliferation, oxidative phosphorylation, pigmentation and cellular stroma. Gene expression modules had prognostic relevance when compared with gene expression data from published melanoma samples and patient survival data. We surveyed kinome expression patterns across sub-populations of the BRAF/NRAS wild type sample and found that CDK4 and CDK2 were consistently highly expressed in the majority of cells, suggesting that these kinases might be involved in melanoma progression. Treatment of cells with the CDK4 inhibitor palbociclib restricted cell proliferation to a similar, and in some cases greater, extent than MAPK inhibitors. Finally, we identified a low abundant sub-population in this sample that highly expressed a module containing ABC transporter ABCB5, surface markers CD271 and CD133, and multiple aldehyde dehydrogenases (ALDHs). Patient-derived cultures of the BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant metastases showed more homogeneous single-cell gene expression patterns with gene expression modules for proliferation and ABC transporters. Taken together, our results describe an intertumor and intratumor heterogeneity in melanoma short-term cultures which might be relevant for patient survival, and suggest promising targets for new treatment approaches in melanoma therapy. PMID:27903987

  16. Antibody Therapy Targeting CD47 and CD271 Effectively Suppresses Melanoma Metastasis in Patient-Derived Xenografts.

    PubMed

    Ngo, Michael; Han, Arum; Lakatos, Anita; Sahoo, Debashis; Hachey, Stephanie J; Weiskopf, Kipp; Beck, Andrew H; Weissman, Irving L; Boiko, Alexander D

    2016-08-09

    The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271(+) melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts. This therapeutic effect is mediated by drastic changes in the tumor and metastatic site immune microenvironments, both of whichwhich exhibit greatly increased density of differentiated macrophages and significantly fewer inflammatory monocytes, pro-metastatic macrophages (CCR2(+)/VEGFR1(+)), and neutrophils, all of which are associated with disease progression. Thus, antibody therapy that activates the innate immune response in combination with selective targeting of CD271(+) melanoma cells represents a powerful therapeutic approach against metastatic melanoma.

  17. Characterization of the Microenvironment in Positive and Negative Sentinel Lymph Nodes from Melanoma Patients.

    PubMed

    Messaoudene, Meriem; Périer, Aurélie; Fregni, Giulia; Neves, Emmanuelle; Zitvogel, Laurence; Cremer, Isabelle; Chanal, Johan; Sastre-Garau, Xavier; Deschamps, Lydia; Marinho, Eduardo; Larousserie, Frederique; Maubec, Eve; Avril, Marie-Françoise; Caignard, Anne

    2015-01-01

    Melanomas are aggressive skin tumors characterized by high metastatic potential. Our previous results indicate that Natural Killer (NK) cells may control growth of melanoma. The main defect of blood NK cells was a decreased expression of activating NCR1/NKp46 receptor and a positive correlation of NKp46 expression with disease outcome in stage IV melanoma patients was found. In addition, in stage III melanoma patients, we identified a new subset of mature NK cells in macro-metastatic Lymph nodes (LN). In the present studies, we evaluated the numbers of NK cells infiltrating primary cutaneous melanoma and analyzed immune cell subsets in a series of sentinel lymph nodes (SLN). First, we show that NKp46+ NK cells infiltrate primary cutaneous melanoma. Their numbers were related to age of patients and not to Breslow thickness. Then, a series of patients with tumor-negative or -positive sentinel lymph nodes matched for Breslow thickness of the cutaneous melanoma was constituted. We investigated the distribution of macrophages (CD68), endothelial cells, NK cells, granzyme B positive (GrzB+) cells and CD8+ T cells in the SLN. Negative SLN (SLN-) were characterized by frequent adipose involution and follicular hyperplasia compared to positive SLN (SLN+). High densities of macrophages and endothelial cells (CD34), prominent in SLN+, infiltrate SLN and may reflect a tumor favorable microenvironment. Few but similar numbers of NK and GrzB+ cells were found in SLN- and SLN+: NK cells and GrzB+ cells were not correlated. Numerous CD8+ T cells infiltrated SLN with a trend for higher numbers in SLN-. Moreover, CD8+ T cells and GrzB+ cells correlated in SLN- not in SLN+. We also observed that the numbers of CD8+ T cells negatively correlated with endothelial cells in SLN-. The numbers of NK, GrzB+ or CD8+ T cells had no significant impact on overall survival. However, we found that the 5 year-relapse rate was higher in SLN with higher numbers of NK cells.

  18. In situ malignant melanoma on nevus spilus in an elderly patient.

    PubMed

    Corradin, Maria Teresa; Giulioni, Erika; Fiorentino, Renzo; Santeufemia, Davide Adriano; Re, Giovanni Lo; Vettorello, Angelo

    2014-03-01

    Nevus spilus is the term usually given to a pigmented skin lesion, congenital or acquired, that may occur anywhere on the body, consisting of a large light tan patch with numerous superimposed darker scattered maculae or papulae that are flat or slightly raised. For a long time, nevus spilus was believed to be a benign lesion. However, in 1957 Perkinson reported a melanoma appearing on nevus spilus for the first time. Since then other reports about melanomas developing on nevus spilus have been published, sometimes with a fatal outcome. We describe the case of an 80-year-old male patient with a congenital nevus just above his left knee. The lesion had remained unchanged over time, but some months before his checkup the patient noticed a darker area in the lesion that had continued to enlarge. The lesion was removed and histological examination revealed an in situ malignant melanoma. Although nevus spilus is not normally considered a precursor of melanoma, the potentiality of malignant transformation requires regular monitoring, and careful checkups are recommended and justified.

  19. Vaccination of Adult Patients with Systemic Lupus Erythematosus in Portugal

    PubMed Central

    Moraes-Fontes, Maria Francisca; Antunes, Ana Margarida; Gruner, Heidi; Riso, Nuno

    2016-01-01

    In the wake of the Portuguese vaccination program 50th anniversary it seems appropriate to review vaccination in patients with systemic lupus erythematosus. Controversial issues as regards the association between autoimmune diseases, infections, and vaccines are discussed as well as vaccine safety and efficacy issues as regards chronic immunosuppressant (IS) drug therapy. After a brief overview of national policies, specific recommendations are made as regards vaccination for adult patients with SLE with a particular focus on current IS therapy and unmet needs. PMID:27069477

  20. The antibody response against MART-1 differs in patients with melanoma-associated leucoderma and vitiligo.

    PubMed

    Teulings, Hansje-Eva; Willemsen, Karin J; Glykofridis, Iris; Krebbers, Gabrielle; Komen, Lisa; Kroon, Marije W; Kemp, E Helen; Wolkerstorfer, Albert; van der Veen, J P Wietze; Luiten, Rosalie M; Tjin, Esther P M

    2014-11-01

    Patients with melanoma may develop skin depigmentation spontaneously or following therapy, referred to as melanoma-associated leucoderma (MAL). As clinical presentation of MAL may precede primary/metastatic melanoma detection, recognition of MAL is important to prevent its misdiagnosis as vitiligo and the subsequent application of immunosuppressive treatment. To reveal the immunity involved in MAL development, we investigated the presence of antibody and T-cell immune responses directed against the melanocyte-differentiation-antigens MART-1 (Melan-A), tyrosinase and gp100 in patients with MAL, as compared to patients with vitiligo. Autoantibodies to gp100 and tyrosinase were commonly found in both diseases. Interestingly, MART-1 antibodies were only present in patients with MAL. Melanocyte antigen-specific T cells were found in all patients, with relatively more specific T cells in patients with active vitiligo. Although MAL and vitiligo may appear clinically similar, our results indicate that the humoral immune responses against MART-1 differ between these diseases, which can help to differentiate MAL from vitiligo.

  1. Vaccinating HIV patients: focus on human papillomavirus and herpes zoster vaccines.

    PubMed

    Koenig, Helen C; Garland, Joseph M; Weissman, Drew; Mounzer, Karam

    2013-01-01

    Vaccination has been one of our most powerful tools to decrease morbidity and mortality from infectious diseases in the last century. It is critical to understand the evolving safety and efficacy data for vaccines in HIV-infected individuals as the number of people living with HIV in the United States and globally continues to increase. The quadrivalent human papillomavirus vaccine and the herpes zoster vaccine are newly licensed in the general population, and several studies have recently been published on the safety and efficacy of these vaccines in HIV populations. This manuscript reviews recent data for the vaccines most commonly administered in HIV patients and incorporates these data into our body of knowledge about the safety and efficacy of vaccines in this population. In addition, patient factors that predict response for each vaccine are discussed. Given the great burden of human papillomavirus and herpes zoster in HIV patients, we discuss the benefits and the challenges of vaccinating HIV patients with the human papillomavirus and herpes zoster vaccines. This review provides information that clinicians need to make real-time decisions in the absence of large-scale trials in the HIV population.

  2. Pigmentation in the sentinel node correlates with increased sentinel node tumor burden in melanoma patients.

    PubMed

    van Lanschot, Cornelia G F; Koljenović, Senada; Grunhagen, Dirk-Jan; Verhoef, Cornelis; van Akkooi, Alexander C J

    2014-06-01

    The prognosis of sentinel node (SN)-positive melanoma patients is predicted by a number of characteristics such as size and site of the metastases in the SN. The pathway and prognosis of strong pigmentation of melanoma metastases in the SN is unclear. The aim of this study is to evaluate the role of pigmentation and growth pattern of metastases in the SN with respect to survival. A total of 389 patients underwent an SN procedure (1997-2011). Ninety-five patients had a positive SN and material from 75 patients was available for review. The median follow-up time was 75 months (range 6-164). Pigmentation was scored from 0 to 2 using the following scale: 0=absent, 1=slight, and 2=strong. Growth pattern was scored as either eccentric (1) or infiltrative (2). SN tumor burden was measured according to the Rotterdam criteria. The primary melanoma had a median Breslow thickness of 2.90 mm (0.8-12.00 mm). Ulceration was present in 34 patients (45.3%). There was a median SN tumor burden of 0.5 mm (0.05-7.00 mm). In a total of 75 patients, 59 patients (79%) had no pigmentation, 13 patients (17%) had slight pigmentation, and three patients (4%) had strong pigmentation in the SN. Because of the small numbers, the classification was modified to either absent 59 (79%) or present 16 (21%) pigmentation, respectively. The SN tumor burden was significantly higher (P=0.031) for patients with pigmentation. Patients with pigmentation had a 5-year melanoma-specific survival (MSS) of 47% and a 10-year MSS of 33%. Patients without pigmentation had a 5-year MSS of 70% and a 10-year MSS of 59% (P=0.06). There was no difference in MSS for patients with an eccentric or an infiltrative growth pattern, nor did it correlate with other prognostic factors. Multivariate analysis for MSS showed five significant factors associated with worse prognosis: male sex (P=0.036), nodular melanoma (P=0.001), truncal site (P=0.0001), SN tumor burden more than 1.0 mm (P=0.022), and positive completion lymph node

  3. Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAF Mutant Melanoma That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2017-04-13

    BRAF V600E Mutation Present; BRAF V600K Mutation Present; Recurrent Melanoma; Stage III Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma

  4. Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients.

    PubMed Central

    Shields, C L

    2000-01-01

    OBJECTIVE: To identify the risk factors of conjunctival malignant melanoma that predict local tumor recurrence, orbital exenteration, distant metastasis, and tumor-related mortality. DESIGN: The study group consisted of 150 consecutive patients with a diagnosis of conjunctival melanoma. The clinical parameters of the patient, tumor, and treatment were analyzed in a nonrandomized fashion for their relation to 4 main outcome measures using Cox proportional hazards regression models. RESULTS: The Kaplan-Meier estimate of local tumor recurrence was 26% at 5 years, 51% at 10 years, and 65% at 15 years. The mean number of recurrences per patient was 1 (median, 0). Ninety-eight patients (65%) had no recurrences, 28 patients (19%) had 1, 11 patients (7%) had 2, 5 patients (3%) had 3, and 8 patients (5%) had 4 or more recurrences. According to multivariate analysis, the factors that predicted local tumor recurrence were the location of the melanoma (not touching the limbus) (P = .01) and tumor-margin pathology (lateral margin involved) (P = .02). Multivariate analysis for features predictive of ultimate exenteration included initial visual acuity (20/40 or worse) (P = .0007), melanoma color (red) (P = .01), and melanoma location (not touching the limbus) (P = .02). Tumor metastasis occurred in 16% of patients at 5 years, 26% at 10 years, and 32% at 15 years. Metastasis was initially in the regional lymph nodes in 17 cases, brain in 4, liver in 3, lung in 2, and disseminated in 1 case. Risks for metastases with use of multivariate analysis included tumor-margin pathology (lateral margin involved) (P = .002) and melanoma location (not touching limbus) (P = .04). Tumor-related death occurred in 7% of patients at 5 years and 13% at 8 years. Risk factors for death with use of multivariate analysis included initial symptoms (lump) (P = .004) and pathologic findings (de novo melanoma without primary acquired melanosis) (P = .05). In a series of univariate analyses, the technique

  5. Shared decision making in dermato-oncology: preference for involvement of melanoma patients.

    PubMed

    Albrecht, Karoline J; Nashan, Dorothée; Meiss, Frank; Bengel, Jürgen; Reuter, Katrin

    2014-02-01

    Increasing importance is being conferred to the implementation of shared decision making (SDM) in clinical practice for medical, ethical, and sociological reasons. In Germany, SDM has recently been adopted as an explicit goal in the S3-melanoma treatment guideline. The aim of this study is to present data on how melanoma patients want to be involved in treatment decisions and second on the dynamic of these preferences for involvement. This was investigated in consecutively recruited melanoma patients (stages I-III) in two German Skin Cancer Centers as part of a longitudinal questionnaire study. The Control Preference Scale assessed patients' preferences at baseline (n=405) and was readministered 1 year later (n=314) to detect potential changes. In addition, the perceived realization of SDM in the adjuvant interferon-α treatment decision was investigated in a subgroup of patients (n=108) using the nine-item Shared Decision Making Questionnaire (SDM-Q-9). More than 80% of the patients want to play an active role (autonomous or collaborative) in treatment decisions and only 17% want to delegate their decision to the doctor. We found a significant preference shift within a year in 43% of the patients, predominantly toward more active involvement. The results of the SDM-Q-9 indicate a moderate degree of perceived participation, with differing perceived implementation of the individual the SDM process steps. With the majority of melanoma patients preferring an active role in treatment decisions and improvable implementation of the SDM process steps in clinical practice, our findings support the relevance of SDM in dermato-oncology.

  6. CDKN2A and CDK4 variants in Latvian melanoma patients: analysis of a clinic-based population.

    PubMed

    Pjanova, Dace; Engele, Ludmila; Randerson-Moor, Juliette A; Harland, Mark; Bishop, D Timothy; Newton Bishop, Julia A; Taylor, Claire; Debniak, Tadeusz; Lubinski, Jan; Kleina, Regina; Heisele, Olita

    2007-06-01

    Germline mutations of the CDKN2A and CDK4 genes explain a significant proportion of familial melanoma. To date, there have been few published estimations of the prevalence of such mutations in sporadic melanoma patients. In this study, we investigated CDKN2A and CDK4 exon 2 for germline mutations in 125 consecutive cutaneous malignant melanoma patients recruited through the Latvian Oncological Center, using amplicon melting analysis and sequencing. No disease-related CDKN2A germline mutations were identified in any of the melanoma patients analysed but the previously described CDK4 mutation, Arg24His, was found in one patient with a family history of melanoma. CDKN2A polymorphisms were studied as putative low penetrance susceptibility genes. The proportion of cases with polymorphisms in this Latvian melanoma population was Ala148Thr (c.442G>A) (6%), 500 C/G (c.*29C>G) (18%), and 540 C/T (c.*69C>T) (20%); however, only the frequency of the Ala148Thr polymorphism was higher in melanoma patients than in 203 controls (6 versus 1%, P=0.03). Ala148Thr has also been reported in association with melanoma in a Polish series but not in an English series. We therefore examined the Ala148Thr carrier's haplotype in 10 Latvian and 39 Polish samples. No significant difference was seen between these populations and the predominant haplotype observed in English samples, giving no indication that the discrepancy could be explained by population differences in linkage disequilibrium. In summary, our results show that germline mutations at the CDKN2A locus are rare in sporadic melanoma in Latvia. The study does, however, provide some additional evidence for a role for the CDKN2A polymorphism Ala148Thr as a low penetrance susceptibility gene. The detected CDK4 exon 2 mutation was found in only the seventh family identified worldwide with a germline CDK4 mutation.

  7. Circulating Tumor Cells, DNA, and mRNA: Potential for Clinical Utility in Patients With Melanoma

    PubMed Central

    Xu, Melody J.; Dorsey, Jay F.; Amaravadi, Ravi; Karakousis, Giorgos; Simone, Charles B.; Xu, Xiaowei; Xu, Wei; Carpenter, Erica L.; Schuchter, Lynn

    2016-01-01

    Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and messenger RNA (mRNA), collectively termed circulating tumor products (CTPs), represent areas of immense interest from scientists’ and clinicians’ perspectives. In melanoma, CTP analysis may have clinical utility in many areas, from screening and diagnosis to clinical decision-making aids, as surveillance biomarkers or sources of real-time genetic or molecular characterization. In addition, CTP analysis can be useful in the discovery of new biomarkers, patterns of treatment resistance, and mechanisms of metastasis development. Here, we compare and contrast CTCs, ctDNA, and mRNA, review the extent of translational evidence to date, and discuss how future studies involving both scientists and clinicians can help to further develop this tool for the benefit of melanoma patients. Implications for Practice: Scientific advancement has enabled the rapid development of tools to analyze circulating tumor cells, tumor DNA, and messenger RNA, collectively termed circulating tumor products (CTPs). A variety of techniques have emerged to detect and characterize melanoma CTPs; however, only a fraction has been applied to human subjects. This review summarizes the available human data that investigate clinical utility of CTP in cancer screening, melanoma diagnosis, prognosis, prediction, and genetic or molecular characterization. It provides a rationale for how CTPs may be useful for future research and discusses how clinicians can be involved in developing this exciting new technology. PMID:26614709

  8. TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients.

    PubMed

    Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Fankhauser, Manuel; Thrue, Charlotte Albæk; Toebes, Mireille; van Rooij, Nienke; Linnemann, Carsten; van Buuren, Marit M; Urbanus, Jos H M; Beltman, Joost B; Thor Straten, Per; Li, Yong F; Robbins, Paul F; Besser, Michal J; Schachter, Jacob; Kenter, Gemma G; Dudley, Mark E; Rosenberg, Steven A; Haanen, John B A G; Hadrup, Sine Reker; Schumacher, Ton N M

    2012-07-01

    There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8(+) T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products.

  9. TIL therapy broadens the tumor-reactive CD8+ T cell compartment in melanoma patients

    PubMed Central

    Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Fankhauser, Manuel; Thrue, Charlotte Albæk; Toebes, Mireille; van Rooij, Nienke; Linnemann, Carsten; van Buuren, Marit M.; Urbanus, Jos H.M.; Beltman, Joost B.; thor Straten, Per; Li, Yong F.; Robbins, Paul F.; Besser, Michal J.; Schachter, Jacob; Kenter, Gemma G.; Dudley, Mark E.; Rosenberg, Steven A.; Haanen, John B.A.G.; Hadrup, Sine Reker; Schumacher, Ton N.M.

    2012-01-01

    There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8+ T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products. PMID:22754759

  10. Melanoma patients under vemurafenib: prospective follow-up of melanocytic lesions by digital dermoscopy.

    PubMed

    Perier-Muzet, Marie; Thomas, Luc; Poulalhon, Nicolas; Debarbieux, Sébastien; Bringuier, Pierre-Paul; Duru, Gerard; Depaepe, Lauriane; Balme, Brigitte; Dalle, Stephane

    2014-05-01

    Second primary melanomas (SPMs) induced by vemurafenib have been recently described. The aim of this study was to define the dermoscopical signs of melanoma in this context. Patients underwent a total body examination before receiving vemurafenib. Each single melanocytic lesion was registered before therapy by digital dermoscopy (DD), and then repeated monthly until therapy disruption. Forty-two patients were included, the mean duration of follow-up was 6.7 months, and a mean number of 51 lesions per patients were captured and followed. A total number of 2,155 lesions were recorded, of which 56.1% presented at least one change during the study. More common changes concerned the color of the lesions (up to 15%) and appearance or disappearance of globules (14.6%). Thirty-six of the melanocytic lesions were surgically excised, 21 were classified as a nevus, 1 was a lentigo, and 14 as a second new primary melanoma (occurring in 21% of our patients). DD allowed us to excise only 36/2,155 (1.6%) of the lesions and permitted us to detect 14 SPM in the 42 patients with a highly efficient malignant/benign ratio of 63.6%. Although vemurafenib is now tested in an adjuvant setting DD should be systematically used in order to accurately detect SPM and reduce the number of unnecessary excisions.

  11. A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab

    PubMed Central

    Chandra, Ravi A; Wilhite, Tyler J; Balboni, Tracy A; Alexander, Brian M; Spektor, Alexander; Ott, Patrick A; Ng, Andrea K; Hodi, F Stephen; Schoenfeld, Jonathan D

    2015-01-01

    Case reports and preclinical data suggest radiotherapy and immunotherapy may synergize to generate “abscopal” responses outside the radiation field. This phenomenon remains relatively unexplored, prompting our systematic evaluation of metastatic melanoma patients treated with the CTLA-4 inhibitor ipilimumab and palliative radiation therapy. We evaluated 47 consecutive metastatic melanoma patients treated with ipilimumab and 65 courses of radiation. Responses of index lesions outside the radiation field were compared before and after radiotherapy, and parameters associated with favorable response were assessed. Median survival was 28 months, with an estimated 20% 5-y survival. Index lesions shrank in 7 instances prior to radiation therapy (11%), compared with 16 instances (25%) after radiation therapy; in 11 of the latter instances (69%), the index lesion had been increasing in size prior to radiotherapy (P = 0.03). In 68% of cases, radiotherapy was associated with an improved rate of index lesion response (P = 0.006). Radiation fraction size ≤ 3 Gy was the only parameter identified associated with favorable index lesion response (P = 0.014). Our systematic review of melanoma patients treated with radiotherapy and ipilimumab suggests that a subset of patients may have more favorable out-of-field responses following treatment with radiation. Interestingly, we found that multiple fraction radiation regimens were associated with a more favorable response. These results are encouraging regarding potential synergies between radiation and immunotherapy, but suggest that attention and even prospective testing of radiation parameters critical to producing abscopal effects in human patients would be of value. PMID:26451318

  12. Prognostic differences across sexes in melanoma patients: what has changed from the past?

    PubMed

    Sanlorenzo, Martina; Ribero, Simone; Osella-Abate, Simona; Zugna, Daniela; Marenco, Federica; Macripò, Giuseppe; Fierro, Maria T; Bernengo, Maria G; Quaglino, Pietro

    2014-12-01

    Differences across the sexes include epidemiological trends, distribution of clinical features and prognostic relevance in melanoma patients. The aims of this single-institution hospital-based cohort study were as follows: to assess the trends over time of the male/female ratio; to analyse the clinicopathologic features according to sex and their modifications following the introduction in 1999 of sentinel lymph node biopsy; to ascertain the metastatic pathways across sexes and the prognostic role of sex in the disease-free interval (DFI), disease-specific survival (DSS) and survival after recurrence. The patient population included 4310 stage I-II melanoma patients, diagnosed, treated and followed up in our institution from 1975. Patients were divided into two groups on the basis of the introduction of sentinel lymph node biopsy in 1999. A female prevalence was observed until 1999; thereafter, the male/female ratio approached 1 (period 1999-2003), with a subsequent increasing trend suggesting a potential male prevalence. Longer DFI and DSS were observed after 1999 and men showed greater improvement compared with women. In multivariate analyses, sex showed a lower impact on DFI and survival after recurrence following the introduction on sentinel lymph node biopsy. No sex-related differences in terms of DSS were observed before and after 1999 among patients with melanoma located on the trunk. However, among patients with primary lesions not located on the trunk, sex maintained a significant prognostic role in both groups. The results of this study suggest that in the last few years, the prognosis of men could have improved more than that in women. The changing surgical/therapeutic interventions can influence sex disparities in melanoma.

  13. Mutation Profile of B-Raf Gene Analyzed by fully Automated System and Clinical Features in Japanese Melanoma Patients.

    PubMed

    Ide, Masaru; Koba, Shinichi; Sueoka-Aragane, Naoko; Sato, Akemi; Nagano, Yuri; Inoue, Takuya; Misago, Noriyuki; Narisawa, Yutaka; Kimura, Shinya; Sueoka, Eisaburo

    2017-01-01

    BRAF gene mutations have been observed in 30-50 % of malignant melanoma patients. Recent development of therapeutic intervention using BRAF inhibitors requires an accurate and rapid detection system for BRAF mutations. In addition, the clinical characteristics of the melanoma associated with BRAF mutations in Japanese patients have not been investigated on a large scale evaluation. We recently established quenching probe system (QP) for detection of an activating BRAF mutation, V600E and evaluated 113 melanoma samples diagnosed in Saga University Hospital from 1982 to 2011. The QP system includes fully automated genotyping, based on analysis of the probe DNA melting curve, which binds the target mutated site using a fluorescent guanine quenched probe. BRAF mutations were detected in 54 of 115 (47 %) including 51 of V600E and 3 of V600 K in Japanese melanoma cases. Among clinical subtypes of melanoma, nodular melanoma showed high frequency (12 of 15; 80 %) of mutation followed by superficial spreading melanoma (13 of 26; 50 %). The QP system is a simple and sensitive method to determine BRAF V600E mutation, and will be useful tool for patient-oriented therapy with BRAF inhibitors.

  14. MHC Class I Chain-Related Gene A Diversity in Patients with Cutaneous Malignant Melanoma from Southeastern Spain

    PubMed Central

    Campillo, José Antonio; López-Hernández, Ruth; Martínez-Banaclocha, Helios; Bolarín, José Miguel; Gimeno, Lourdes; Mrowiec, Anna; López, Manuela; Heras, Beatriz Las; Minguela, Alfredo; Moya-Quiles, Maria Rosa; Legáz, Isabel; Frías-Iniesta, José Francisco; García-Alonso, Ana María; Álvarez-López, María Rocío; Martínez-Escribano, Jorge Antonio; Muro, Manuel

    2015-01-01

    A limited number of studies have been performed so far on the polymorphism in the transmembrane region (exon 5) of the major histocompatibility complex class I chain-related gene A (MICA) in patients with melanoma. However, the influence of MICA polymorphism in extracellular domains (exons 2, 3, and 4) has not been investigated on melanoma disease. This study aims to characterize the influence of extracellular MICA polymorphism, and its previously described linkage disequilibrium with HLA-B locus, on patients with cutaneous melanoma from southeastern Spain. For this purpose, MICA and HLA-B genotyping was performed in 233 patients and 200 ethnically matched controls by luminex technology. Patients were classified according to the presence of methionine or valine at codon 129 of MICA gene. We found a high frequency of MICA*009 in melanoma patients compared with controls (P = 0.002, Pc = 0.03). Our results also showed an association between MICA*009 and HLA-B*51 alleles in both patients and controls. This association was stronger in patients than controls (P = 0.015). However, a multivariate logistic regression model showed that neither MICA*009 nor the combination MICA*009/HLA-B*51 was associated with melanoma susceptibility. No relationship was observed between MICA-129 dimorphism and melanoma nor when MICA polymorphism was evaluated according to clinical findings at diagnosis. PMID:25838620

  15. MHC class I chain-related gene a diversity in patients with cutaneous malignant melanoma from southeastern Spain.

    PubMed

    Campillo, José Antonio; López-Hernández, Ruth; Martínez-Banaclocha, Helios; Bolarín, José Miguel; Gimeno, Lourdes; Mrowiec, Anna; López, Manuela; Las Heras, Beatriz; Minguela, Alfredo; Moya-Quiles, Maria Rosa; Legáz, Isabel; Frías-Iniesta, José Francisco; García-Alonso, Ana María; Álvarez-López, María Rocío; Martínez-Escribano, Jorge Antonio; Muro, Manuel

    2015-01-01

    A limited number of studies have been performed so far on the polymorphism in the transmembrane region (exon 5) of the major histocompatibility complex class I chain-related gene A (MICA) in patients with melanoma. However, the influence of MICA polymorphism in extracellular domains (exons 2, 3, and 4) has not been investigated on melanoma disease. This study aims to characterize the influence of extracellular MICA polymorphism, and its previously described linkage disequilibrium with HLA-B locus, on patients with cutaneous melanoma from southeastern Spain. For this purpose, MICA and HLA-B genotyping was performed in 233 patients and 200 ethnically matched controls by luminex technology. Patients were classified according to the presence of methionine or valine at codon 129 of MICA gene. We found a high frequency of MICA(*)009 in melanoma patients compared with controls (P = 0.002, Pc = 0.03). Our results also showed an association between MICA(*)009 and HLA-B(*)51 alleles in both patients and controls. This association was stronger in patients than controls (P = 0.015). However, a multivariate logistic regression model showed that neither MICA(*)009 nor the combination MICA(*)009/HLA-B(*)51 was associated with melanoma susceptibility. No relationship was observed between MICA-129 dimorphism and melanoma nor when MICA polymorphism was evaluated according to clinical findings at diagnosis.

  16. Multiple primary cutaneous melanomas in patients with FAMMM syndrome and sporadic atypical mole syndrome (AMS): what's worse?

    PubMed

    Tchernev, Georgi; Ananiev, Julian; Cardoso, José-Carlos; Chokoeva, Anastasiya Atanasova; Philipov, Stanislav; Penev, Plamen Kolev; Lotti, Torello; Wollina, Uwe

    2014-08-01

    Atypical Mole Syndrome is the most important phenotypic risk factor for cutaneous melanoma, a malignancy that accounts for about 80% of deaths from skin cancer. Since early diagnosis of melanoma is of great prognostic relevance, the identification of Atypical Mole Syndrome carriers (sporadic and familial) is essential, as well as the recommendation of preventative measures that must be undertaken by these patients.We report two rare cases concerning patients with multiple primary skin melanomas in the setting of a familial and a sporadic syndrome of dysplastic nevi: the first patient is a 67-year-old patient with a history of multiple superficial spreading melanomas localized on his back. The second patient presented with multiple primary melanomas in advanced stage in the context of the so-called sporadic form of the syndrome of dysplastic nevi-AMS (atypical mole syndrome). In the first case, excision of the melanomas was carried out with an uneventful post-operative period. In the second case, disseminated metastases were detected, involving the right fibula, the abdominal cavity as well as multiple lesions in the brain. The patient declined BRAF mutation tests as well as chemotherapy or targeted therapies, and suffered a rapid deterioration in his general condition leading to death. We classified the second case as a sporadic form of the atypical mole syndrome, associated with one nodular and two superficial spreading melanomas.There are no data in the literature to allow us to understand if, in patients with multiple primary melanomas, there is any difference in terms of prognosis between those with and without a family history of a similar phenotype. To answer this and other questions related to these rare cases, further studies with a significant number of patients should be carried out.

  17. Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma

    PubMed Central

    Zhang, Weikang; Liu, Hongliang; Liu, Zhensheng; Zhu, Dakai; Amos, Christopher I.; Fang, Shenying; Lee, Jeffrey E.; Wei, Qingyi

    2015-01-01

    Background The Notch signaling pathway is constitutively activated in human cutaneous melanoma to promote growth and aggressive metastatic potential of primary melanoma cells. Therefore, genetic variants in Notch pathway genes may affect the prognosis of cutaneous melanoma patients. Methods We identified 6,256 SNPs in 48 Notch genes in 858 cutaneous melanoma patients included in a previously published cutaneous melanoma genome-wide association study dataset. Multivariate and stepwise Cox proportional hazards regression and false-positive report probability corrections were performed to evaluate associations between putative functional SNPs and cutaneous melanoma disease-specific survival. Receiver operating characteristic curve was constructed, and area under the curve was used to assess the classification performance of the model. Results Four putative functional SNPs of Notch pathway genes had independent and joint predictive roles in survival of cutaneous melanoma patients. The most significant variant was NCOR2 rs2342924 T>C (adjusted HR, 2.71; 95% confidence interval, 1.73–4.23; Ptrend = 9.62 × 10−7), followed by NCSTN rs1124379 G>A, NCOR2 rs10846684 G>A, and MAML2 rs7953425 G>A (Ptrend = 0.005, 0.005, and 0.013, respectively). The receiver operating characteristic analysis revealed that area under the curve was significantly increased after adding the combined unfavorable genotype score to the model containing the known clinicopathologic factors. Conclusions Our results suggest that SNPs in Notch pathway genes may be predictors of cutaneous melanoma disease-specific survival. Impact Our discovery offers a translational potential for using genetic variants in Notch pathway genes as a genotype score of biomarkers for developing an improved prognostic assessment and personalized management of cutaneous melanoma patients. PMID:25953768

  18. Guidelines on Vaccinations in Paediatric Haematology and Oncology Patients

    PubMed Central

    Cesaro, Simone; Giacchino, Mareva; Fioredda, Francesca; Barone, Angelica; Battisti, Laura; Bezzio, Stefania; Frenos, Stefano; De Santis, Raffaella; Livadiotti, Susanna; Marinello, Serena; Zanazzo, Andrea Giulio; Caselli, Désirée

    2014-01-01

    Objective. Vaccinations are the most important tool to prevent infectious diseases. Chemotherapy-induced immune depression may impact the efficacy of vaccinations in children. Patients and Methods. A panel of experts of the supportive care working group of the Italian Association Paediatric Haematology Oncology (AIEOP) addressed this issue by guidelines on vaccinations in paediatric cancer patients. The literature published between 1980 and 2013 was reviewed. Results and Conclusion. During intensive chemotherapy, vaccination turned out to be effective for hepatitis A and B, whilst vaccinations with toxoid, protein subunits, or bacterial antigens should be postponed to the less intensive phases, to achieve an adequate immune response. Apart from varicella, the administration of live-attenuated-virus vaccines is not recommended during this phase. Family members should remain on recommended vaccination schedules, including toxoid, inactivated vaccine (also poliomyelitis), and live-attenuated vaccines (varicella, measles, mumps, and rubella). By the time of completion of chemotherapy, insufficient serum antibody levels for vaccine-preventable diseases have been reported, while immunological memory appears to be preserved. Once immunological recovery is completed, usually after 6 months, response to booster or vaccination is generally good and allows patients to be protected and also to contribute to herd immunity. PMID:24868544

  19. Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case series.

    PubMed

    Jones, Pamela S; Cahill, Daniel P; Brastianos, Priscilla K; Flaherty, Keith T; Curry, William T

    2015-03-01

    OBJECT In patients with large or symptomatic brain lesions from metastatic melanoma, the value of resection of metastases to facilitate administration of systemic ipilimumab therapy has not yet been described. The authors undertook this study to investigate whether craniotomy creates the opportunity for patients to receive and benefit from ipilimumab who would otherwise succumb to brain metastasis prior to the onset of regression. METHODS All patients with metastatic melanoma who received ipilimumab and underwent craniotomy for metastasis resection between 2008 and 2014 at the Massachusetts General Hospital were identified through retrospective chart review. The final analysis included cases involving patients who underwent craniotomy within 3 months prior to initiation of therapy or up to 6 months after cessation of ipilimumab administration. RESULTS Twelve patients met the inclusion criteria based on timing of therapy (median age 59.2). The median number of metastases at the time of craniotomy was 2. The median number of ipilimumab doses received was 4. Eleven of 12 courses of ipilimumab were stopped for disease progression, and 1 was stopped for treatment-induced colitis. Eight of 12 patients had improvement in their performance status following craniotomy. Of the 6 patients requiring corticosteroids prior to craniotomy, 3 tolerated corticosteroid dose reduction after surgery. Ten of 12 patients had died by the time of data collection, with 1 patient lost to follow-up. The median survival after the start of ipilimumab treatment was 7 months. CONCLUSIONS In this series, patients who underwent resection of brain metastases in temporal proximity to receiving ipilimumab had qualitatively improved performance status following surgery in most cases. Surgery facilitated corticosteroid reduction in select patients. Larger analyses are required to better understand possible synergies between craniotomy for melanoma metastases and ipilimumab treatment.

  20. TIGIT and PD-1 impair tumor antigen–specific CD8+ T cells in melanoma patients

    PubMed Central

    Chauvin, Joe-Marc; Pagliano, Ornella; Fourcade, Julien; Sun, Zhaojun; Wang, Hong; Sander, Cindy; Kirkwood, John M.; Chen, Tseng-hui Timothy; Maurer, Mark; Korman, Alan J.; Zarour, Hassane M.

    2015-01-01

    T cell Ig and ITIM domain (TIGIT) is an inhibitory receptor expressed by activated T cells, Tregs, and NK cells. Here, we determined that TIGIT is upregulated on tumor antigen–specific (TA-specific) CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) from patients with melanoma, and these TIGIT-expressing CD8+ T cells often coexpress the inhibitory receptor PD-1. Moreover, CD8+ TILs from patients exhibited downregulation of the costimulatory molecule CD226, which competes with TIGIT for the same ligand, supporting a TIGIT/CD226 imbalance in metastatic melanoma. TIGIT marked early T cell activation and was further upregulated by T cells upon PD-1 blockade and in dysfunctional PD-1+TIM-3+ TA-specific CD8+ T cells. PD-1+TIGIT+, PD-1–TIGIT+, and PD-1+TIGIT– CD8+ TILs had similar functional capacities ex vivo, suggesting that TIGIT alone, or together with PD-1, is not indicative of T cell dysfunction. However, in the presence of TIGIT ligand–expressing cells, TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of both TA-specific CD8+ T cells and CD8+ TILs. Collectively, our results show that TIGIT and PD-1 regulate the expansion and function of TA-specific CD8+ T cells and CD8+ TILs in melanoma patients and suggest that dual TIGIT and PD-1 blockade should be further explored to elicit potent antitumor CD8+ T cell responses in patients with advanced melanoma. PMID:25866972

  1. Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma.

    PubMed

    Okano, Yudai; Satoh, Tetsurou; Horiguchi, Kazuhiko; Toyoda, Minoru; Osaki, Aya; Matsumoto, Shunichi; Tomaru, Takuya; Nakajima, Yasuyo; Ishii, Sumiyasu; Ozawa, Atsushi; Shibusawa, Nobuyuki; Shimada, Takehiro; Higuchi, Tetsuya; Chikamatsu, Kazuaki; Yamada, Masanobu

    2016-10-29

    The anti-programmed cell death-1 monoclonal antibody (mab), nivolumab has recently been approved for the treatment of unresectable or metastatic malignant melanoma and non-small-cell lung cancers in Japan. Ipilimumab, an anti-cytotoxic T lymphocyte antigen-4 mab for malignant melanoma that was approved earlier than nivolumab in Western countries, is known to frequently cause endocrine immune-related adverse events such as hypophysitis and thyroid dysfunction. We herein report a patient with advanced melanoma who appeared to develop hypophysitis as a consequence of the inhibition of PD-1 by nivolumab. One week after the 6(th) administration of nivolumab, the patient developed progressive fatigue and appetite loss. Laboratory data on admission for the 7(th) administration of nivolumab showed eosinophilia and hyponatremia. Since ACTH and cortisol levels were low, nivolumab was discontinued and a large dose of hydrocortisone (100 mg/d) was promptly administered intravenously. A magnetic resonance imaging scan revealed the mild enlargement of the anterior pituitary gland and thickening of the stalk with homogenous contrast. A detailed assessment of anterior pituitary functions with hypothalamic hormone challenges showed that hormonal secretions other than ACTH and TSH were normal. With a replacement dose of hydrocortisone (20 mg/d), the 7(th) administration of nivolumab was completed without exacerbating the patient's general condition. The present report provides the first detailed endocrinological presentation of nivolumab-induced hypophysitis showing the enlargement of the pituitary gland and stalk in a malignant melanoma patient in Japan. Oncologists and endocrinologists need to be familiar with potentially life-threatening hypophysitis induced by immune-checkpoint inhibitors.

  2. Limited Genomic Heterogeneity of Circulating Melanoma Cells in Advanced Stage Patients

    PubMed Central

    Ruiz, Carmen; Li, Julia; Luttgen, Madelyn S.; Kolatkar, Anand; Kendall, Jude T.; Flores, Edna; Topp, Zheng; Samlowski, Wolfram E.; McClay, Ed; Bethel, Kelly; Ferrone, Soldano; Hicks, James; Kuhn, Peter

    2015-01-01

    Purpose Circulating melanoma cells (CMCs) constitute a potentially important representation of time-resolved tumor biology in patients. To date, genomic characterization of CMCs has been limited due to the lack of a robust methodology capable of identifying them in a format suitable for downstream characterization. Here, we have developed a methodology to detect intact CMCs that enables phenotypic, morphometric and genomic analysis at the single cell level. Experimental design Blood samples from 40 metastatic melanoma patients and 10 normal blood donors (NBD) were prospectively collected. A panel of 7 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibodies (mAb) was used to immunocytochemically label CMCs. Detection was performed by automated digital fluorescence microscopy and multi-parametric computational analysis. Individual CMCs were captured by micromanipulation for whole genome amplification (WGA) and copy number variation (CNV) analysis. Results Based on CSPG4 expression and nuclear size, 1 to 250 CMCs were detected in 22 (55%) of 40 metastatic melanoma patients (0.5 to 371.5 CMCs/ml). Morphometric analysis revealed that CMCs have a broad spectrum of morphologies and sizes but exhibit a relatively homogeneous nuclear size that was on average 1.5-fold larger than that of surrounding PBMCs. CNV analysis of single CMCs identified deletions of CDKN2A and PTEN, and amplification(s) of TERT, BRAF, KRAS and MDM2. Furthermore, novel chromosomal amplifications in chr12, 17 and 19 were also found. Conclusions Our findings show that CSPG4 expressing CMCs can be found in the majority of advanced melanoma patients. High content analysis of this population may contribute to develop effective therapeutic strategies. PMID:25574741

  3. Elevated Levels of SOX10 in Serum from Vitiligo and Melanoma Patients, Analyzed by Proximity Ligation Assay

    PubMed Central

    Gustafsdottir, Sigrun M.; Vuu, Jimmy; Ullenhag, Gustav; Kämpe, Olle; Landegren, Ulf; Kamali-Moghaddam, Masood; Hedstrand, Håkan

    2016-01-01

    Background The diagnosis of malignant melanoma currently relies on clinical inspection of the skin surface and on the histopathological status of the excised tumor. The serum marker S100B is used for prognostic estimates at later stages of the disease, but analyses are marred by false positives and inadequate sensitivity in predicting relapsing disorder. Objectives To investigate SOX10 as a potential biomarker for melanoma and vitiligo. Methods In this study we have applied proximity ligation assay (PLA) to detect the transcription factor SOX10 as a possible serum marker for melanoma. We studied a cohort of 110 melanoma patients. We further investigated a second cohort of 85 patients with vitiligo, which is a disease that also affects melanocytes. Results The specificity of the SOX10 assay in serum was high, with only 1% of healthy blood donors being positive. In contrast, elevated serum SOX10 was found with high frequency among vitiligo and melanoma patients. In patients with metastases, lack of SOX10 detection was associated with treatment benefit. In two responding patients, a change from SOX10 positivity to undetectable levels was seen before the response was evident clinically. Conclusions We show for the first time that SOX10 represents a promising new serum melanoma marker for detection of early stage disease, complementing the established S100B marker. Our findings imply that SOX10 can be used to monitor responses to treatment and to assess if the treatment is of benefit at stages earlier than what is possible radiologically. PMID:27110718

  4. Combined-modality therapy for patients with regional nodal metastases from melanoma

    SciTech Connect

    Ballo, Matthew T. . E-mail: mballo@mdanderson.org; Ross, Merrick I.; Cormier, Janice N.; Myers, Jeffrey N.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Hwu, Patrick; Zagars, Gunar K.

    2006-01-01

    Purpose: To evaluate the outcome and patterns of failure for patients with nodal metastases from melanoma treated with combined-modality therapy. Methods and Materials: Between 1983 and 2003, 466 patients with nodal metastases from melanoma were managed with lymphadenectomy and radiation, with or without systemic therapy. Surgery was a therapeutic procedure for clinically apparent nodal disease in 434 patients (regionally advanced nodal disease). Adjuvant radiation was generally delivered with a hypofractionated regimen. Adjuvant systemic therapy was delivered to 154 patients. Results: With a median follow-up of 4.2 years, 252 patients relapsed and 203 patients died of progressive disease. The actuarial 5-year disease-specific, disease-free, and distant metastasis-free survival rates were 49%, 42%, and 44%, respectively. By multivariate analysis, increasing number of involved lymph nodes and primary ulceration were associated with an inferior 5-year actuarial disease-specific and distant metastasis-free survival. Also, the number of involved lymph nodes was associated with the development of brain metastases, whereas thickness was associated with lung metastases, and primary ulceration was associated with liver metastases. The actuarial 5-year regional (in-basin) control rate for all patients was 89%, and on multivariate analysis there were no patient or disease characteristics associated with inferior regional control. The risk of lymphedema was highest for those patients with groin lymph node metastases. Conclusions: Although regional nodal disease can be satisfactorily controlled with lymphadenectomy and radiation, the risk of distant metastases and melanoma death remains high. A management approach to these patients that accounts for the competing risks of distant metastases, regional failure, and long-term toxicity is needed.

  5. Reinduction of PD1-inhibitor therapy: first experience in eight patients with metastatic melanoma.

    PubMed

    Blasig, Hanna; Bender, Carolin; Hassel, Jessica C; Eigentler, Thomas K; Sachse, Michael M; Hiernickel, Julia; Koop, Anika; Satzger, Imke; Gutzmer, Ralf

    2017-03-02

    Significant progress has been made in the treatment of metastatic melanoma during the last years. Approval of immune-checkpoint inhibitors and targeted therapies has been achieved recently. The sequencing of these therapies is an important issue. Here, we report our experience with the treatment and retreatment with PD1-inhibitors (PD1i) in eight patients. The patients (two female and seven male with a median age of 70 years, all melanoma stage IV, M1c) underwent a first treatment period with PD1i for a median of 5.5 months. Three (37.5%) patients had a stable disease as best response, two (25%) showed progression, two (25%) showed partial response, and one (12.5%) achieved complete remission. PD1i was discontinued due to disease progression in seven patients and due to side effects (pancreatitis) in one patient. Patients were subsequently treated with ipilimumab (n=2), or chemotherapy (n=4), or no other medical treatment (n=2). All eight patients were subsequently retreated with PD1i for a median of 2.5 months. One (12.5%) developed a partial response, whereas in three patients (37.5%) the disease was stabilized. PD1i have shown a high and durable response rate in the first-line treatment of metastatic melanoma. Our study suggests PD1i retreatment as a reasonable option for selected patients. Further investigations are needed to verify the value of PD1i re-exposure and to identify subgroups of patients who can benefit.

  6. Incidence of Thyroid-Related Adverse Events in Melanoma Patients Treated With Pembrolizumab

    PubMed Central

    Jansen, Yanina; Schreuer, Max; Everaert, Hendrik; Velkeniers, Brigitte; Neyns, Bart; Bravenboer, Bert

    2016-01-01

    Context: Immune checkpoint blockade is associated with endocrine-related adverse events. Thyroid dysfunction during pembrolizumab therapy, an anti-programmed cell death 1 (PD-1) receptor monoclonal antibody, remains to be fully characterized. Objective: To assess the incidence and characteristics of pembrolizumab-associated thyroid dysfunction. Design and Setting: Thyroid function was monitored prospectively in melanoma patients who initiated pembrolizumab within an expanded access program at a referral oncology center. 18Fluorodeoxyglucose uptake on positron emission tomography/computed tomography (18FDG-PET/CT) was reviewed in cases compatible with inflammatory thyroiditis. Patients: Ninety-nine patients with advanced melanoma (age, 26.3–93.6 years; 63.6% females) who received at least one administration of pembrolizumab. Main Outcome Measures: Patient characteristics, thyroid function (TSH, free T4), thyroid autoantibodies, and 18FDG-PET/CT. Results: Eighteen adverse events of thyroid dysfunction were observed in 17 patients. Thyrotoxicosis occurred in 12 patients, of which nine evolved to hypothyroidism. Isolated hypothyroidism was present in six patients. Levothyroxine therapy was required in 10 of 15 hypothyroid patients. Thyroid autoantibodies were elevated during thyroid dysfunction in four of 10 cases. Diffuse increased 18FDG uptake by the thyroid gland was observed in all seven thyrotoxic patients who progressed to hypothyroidism. Conclusions: Thyroid dysfunction is common in melanoma patients treated with pembrolizumab. Hypothyroidism and thyrotoxicosis related to inflammatory thyroiditis are the most frequent presentations. Serial measurements of thyroid function tests are indicated during anti-PD-1 monoclonal antibody therapy. Thyrotoxicosis compatible with inflammatory thyroiditis was associated with diffuse increased 18FDG uptake by the thyroid gland. The prospective role of thyroid autoantibodies should be further investigated, together with the

  7. Which melanoma patient carries a BRAF-mutation? A comparison of predictive models

    PubMed Central

    Eigentler, Thomas; Assi, Zeinab; Hassel, Jessica C.; Heinzerling, Lucie; Starz, Hans; Berneburg, Mark; Bauer, Jürgen; Garbe, Claus

    2016-01-01

    Background In patients with advanced melanoma the detection of BRAF mutations is considered mandatory before the initiation of an expensive treatment with BRAF/MEK inhibitors. Sometimes it is difficult to perform such an analysis if archival tumor tissue is not available and fresh tissue has to be collected. Results 514 of 1170 patients (44%) carried a BRAF mutation. All models revealed age and histological subtype of melanoma as the two major predictive variables. Accuracy ranged from 0.65–0.71, being best in the random forest model. Sensitivity ranged 0.76–0.84, again best in the random forest model. Specificity was low in all models ranging 0.51–0.55. Methods We collected the clinical data and mutational status of 1170 patients with advanced melanoma and established three different predictive models (binary logistic regression, classification and regression trees, and random forest) to forecast the BRAF status. Conclusions Up to date statistical models are not able to predict BRAF mutations in an acceptable accuracy. The analysis of the mutational status by sequencing or immunohistochemistry must still be considered as standard of care. PMID:27150060

  8. BRAF Mutation (V600E) Prevalence in Mexican Patients Diagnosed with Melanoma

    PubMed Central

    Zepeda-Lopez, Priscilla Denise; Salas-Alanis, Julio Cesar; Toussaint-Caire, Sonia; Gutierrez-Mendoza, Daniela; Vega-Memije, Elisa; Silva, Saúl Lino; Fajardo-Ramírez, Oscar Raul; Alcazar, Gregorio; Moreno-Treviño, María Guadalupe; Saldaña, Hugo Alberto Barrera

    2016-01-01

    Background B-Raf is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. It has been shown that 50% of melanomas harbor activating BRAF mutations, with over 90% being the V600E mutation. Objective The goal of this research was to determine the prevalence of the BRAF V600E mutation in patients from Central Mexico diagnosed with primary melanoma. Methods Skin biopsies from 47 patients with melanoma were obtained from the dermatology department of the Hospital General ‘Dr. Manuel Gea González’ in Mexico City. For BRAF mutation determination, after DNA isolation, the gene region where the mutation occurs was amplified by PCR. Subsequently, the presence or absence of the V600E mutation was detected by Sanger sequencing performed at the private molecular diagnostic laboratory Vitagénesis in Monterrey, Mexico. Results Of the 47 patients sampled, 6.4% harbored the V600E mutation. No statistical significance was found between mutations and the type of tumor. PMID:27194985

  9. Prognosis of uveal melanoma based on race in 8100 patients: The 2015 Doyne Lecture.

    PubMed

    Shields, C L; Kaliki, S; Cohen, M N; Shields, P W; Furuta, M; Shields, J A

    2015-08-01

    A retrospective, nonrandomized, interventional case series of 8100 patients with uveal melanoma were evaluated for melanoma-related metastasis based on patient race. The patient race was Caucasian (n=7918, 98%), Hispanic (n=105, 1%), Asian (n=44, <1%), or African American (n=33, <1%). On the basis of race (Caucasian, Hispanic, Asian, and African American), significant differences were noted in mean age at presentation (58, 48, 44, and 52 years; P<0.001), distance of posterior tumor margin to foveola (5, 5, 6, and 4 mm; P<0.001), distance of posterior tumor margin to optic disc (5, 5, 6, and 4 mm) (P<0.001), tumor base (11, 12, 12, and 13 mm; P<0.001), tumor thickness (5.4, 7.1, 6.5, and 7.5 mm; P<0.001), intraocular hemorrhage (10, 14, 11, and 24%; P=0.02), and rupture of Bruch's membrane (20, 27, 39, and 36%; P=0.001). On the basis of multivariate analysis, the rate of metastasis increased with increasing age (P<0.001), ciliary body location (P<0.001), increasing tumor base (P<0.001), increasing tumor thickness (P<0.001), pigmented tumor (P=0.001), subretinal fluid (P=0.001), intraocular hemorrhage (P=0.045), and extraocular extension (P=0.036). Kaplan-Meier estimates of metastasis at 3, 5, and 10 were 8, 15, and 25% in Caucasians; 13, 13, and 13% in Hispanics; 4, 4, and 36% in Asians; and 8, 8, and 8% in African Americans. Compared with Caucasians, despite relative risk for metastasis of 0.31 for African Americans, 0.73 for Hispanics, and 1.42 for Asians, there was no statistical difference in metastasis, or death from uveal melanoma based on race. In summary, uveal melanoma showed similar prognosis for all races.

  10. Comparison between 18F-Fluorodeoxyglucose Positron Emission Tomography and Sentinel Lymph Node Biopsy for Regional Lymph Nodal Staging in Patients with Melanoma: A Review of the Literature

    PubMed Central

    Mirk, Paoletta; Treglia, Giorgio; Salsano, Marco; Basile, Pietro; Giordano, Alessandro; Bonomo, Lorenzo

    2011-01-01

    Aim. to compare 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) to sentinel lymph node biopsy (SLNB) for regional lymph nodal staging in patients with melanoma. Methods. We performed a literature review discussing original articles which compared FDG-PET to SLNB for regional lymph nodal staging in patients with melanoma. Results and Conclusions. There is consensus in the literature that FDG-PET cannot replace SLNB for regional lymph nodal staging in patients with melanoma. PMID:22242204

  11. Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis.

    PubMed

    D'Angelo, Sandra P; Larkin, James; Sosman, Jeffrey A; Lebbé, Celeste; Brady, Benjamin; Neyns, Bart; Schmidt, Henrik; Hassel, Jessica C; Hodi, F Stephen; Lorigan, Paul; Savage, Kerry J; Miller, Wilson H; Mohr, Peter; Marquez-Rodas, Ivan; Charles, Julie; Kaatz, Martin; Sznol, Mario; Weber, Jeffrey S; Shoushtari, Alexander N; Ruisi, Mary; Jiang, Joel; Wolchok, Jedd D

    2017-01-10

    Purpose Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Patients and Methods Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Results Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months (95% CI, 2.2 to 5.4 months) and 6.2 months (95% CI, 5.1 to 7.5 months) for mucosal and cutaneous melanoma, with objective response rates of 23.3% (95% CI, 14.8% to 33.6%) and 40.9% (95% CI, 37.1% to 44.7%), respectively. Median progression-free survival in patients treated with nivolumab combined with ipilimumab was 5.9 months (95% CI, 2.8 months to not reached) and 11.7 months (95% CI, 8.9 to 16.7 months) for mucosal and cutaneous melanoma, with objective response rates of 37.1% (95% CI, 21.5% to 55.1%) and 60.4% (95% CI, 54.9% to 65.8%), respectively. For mucosal and cutaneous melanoma, respectively, the incidence of grade 3 or 4 treatment-related adverse events was 8.1% and 12.5% for nivolumab monotherapy and 40.0% and 54.9% for combination therapy. Conclusion To our knowledge, this is the largest analysis of data for anti-programmed death-1 therapy in mucosal melanoma to date. Nivolumab combined with ipilimumab seemed to have greater efficacy than either agent alone, and although the activity was lower in mucosal melanoma, the safety profile was similar between subtypes.

  12. Updates in vaccination: Recommendations for adult inflammatory bowel disease patients

    PubMed Central

    Chaudrey, Khadija; Salvaggio, Michelle; Ahmed, Aftab; Mahmood, Sultan; Ali, Tauseef

    2015-01-01

    Treatment regimens for inflammatory bowel disease (IBD) incorporate the use of a variety of immunosuppressive agents that increase the risk of infections. Prevention of many of these infections can be achieved by the timely and judicious use of vaccinations. IBD patients tend to be under-immunized. Some of the contributing factors are lack of awareness regarding the significance of vaccinating IBD patients, misperception about safety of vaccinations in immunocompromised patients, ambiguity about the perceived role of the gastroenterologist in contrast to the primary care physician and unavailability of vaccination guidelines focused on IBD population. In general, immunocompetent IBD patients can be vaccinated using standard vaccination recommendations. However there are special considerations for IBD patients receiving immunosuppressive therapy, IBD travelers and pregnant women with IBD. This review discusses current vaccination recommendations with updates for adult IBD patients. Centers for Disease Control and Prevention 2013 vaccination guidelines with 2014 updates and the Advisory Committee on Immunization Practices recommendations have been highlighted as a primary source of recommendations. PMID:25805924

  13. Isolated Limb Perfusion With Melphalan in Treating Patients With Stage IIIB-IV Melanoma or Sarcoma

    ClinicalTrials.gov

    2015-07-22

    Basal Cell Carcinoma of the Skin; Eccrine Carcinoma of the Skin; Recurrent Adult Soft Tissue Sarcoma; Recurrent Melanoma; Recurrent Skin Cancer; Squamous Cell Carcinoma of the Skin; Stage III Adult Soft Tissue Sarcoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Melanoma

  14. Prediction of positron emission tomography/computed tomography (PET/CT) positivity in patients with high-risk primary melanoma.

    PubMed

    Danielsen, Maria; Kjaer, Andreas; Wu, Max; Martineau, Lea; Nosrati, Mehdi; Leong, Stanley Pl; Sagebiel, Richard W; Iii, James R Miller; Kashani-Sabet, Mohammed

    2016-01-01

    Positron emission tomography/computed tomography (PET/CT) is an important tool to identify occult melanoma metastasis. To date, it is controversial which patients with primary cutaneous melanoma should have staging PET/CT. In this retrospective analysis of more than 800 consecutive patients with cutaneous melanoma, we sought to identify factors predictive of PET/CT positivity in the setting of newly-diagnosed high-risk primary melanoma to determine those patients most appropriate to undergo a PET/CT scan as part of their diagnostic work up. 167 patients with newly-diagnosed high-risk primary cutaneous melanoma underwent a PET/CT scan performed as part of their initial staging. Clinical and histologic factors were evaluated as possible predictors of melanoma metastasis identified on PET/CT scanning using both univariate and multivariate logistic regression. In all, 32 patients (19.2%) had a positive PET/CT finding of metastatic melanoma. In more than half of these patients (56.3%), PET/CT scanning identified disease that was not detectable on clinical examination. Mitotic rate, tumor thickness, lymphadenopathy, and bleeding were significantly predictive of PET/CT positivity. A combinatorial index constructed from these factors revealed a significant association between number of high-risk factors observed and prevalence of PET/CT positivity, which increased from 5.8% (with the presence of 0-2 factors) to 100.0%, when all four factors were present. These results indicate that combining clinical and histologic prognostic factors enables the identification of patients with a higher likelihood of a positive PET/CT scan.

  15. Prediction of positron emission tomography/computed tomography (PET/CT) positivity in patients with high-risk primary melanoma

    PubMed Central

    Danielsen, Maria; Kjaer, Andreas; Wu, Max; Martineau, Lea; Nosrati, Mehdi; Leong, Stanley PL; Sagebiel, Richard W; III, James R Miller; Kashani-Sabet, Mohammed

    2016-01-01

    Positron emission tomography/computed tomography (PET/CT) is an important tool to identify occult melanoma metastasis. To date, it is controversial which patients with primary cutaneous melanoma should have staging PET/CT. In this retrospective analysis of more than 800 consecutive patients with cutaneous melanoma, we sought to identify factors predictive of PET/CT positivity in the setting of newly-diagnosed high-risk primary melanoma to determine those patients most appropriate to undergo a PET/CT scan as part of their diagnostic work up. 167 patients with newly-diagnosed high-risk primary cutaneous melanoma underwent a PET/CT scan performed as part of their initial staging. Clinical and histologic factors were evaluated as possible predictors of melanoma metastasis identified on PET/CT scanning using both univariate and multivariate logistic regression. In all, 32 patients (19.2%) had a positive PET/CT finding of metastatic melanoma. In more than half of these patients (56.3%), PET/CT scanning identified disease that was not detectable on clinical examination. Mitotic rate, tumor thickness, lymphadenopathy, and bleeding were significantly predictive of PET/CT positivity. A combinatorial index constructed from these factors revealed a significant association between number of high-risk factors observed and prevalence of PET/CT positivity, which increased from 5.8% (with the presence of 0-2 factors) to 100.0%, when all four factors were present. These results indicate that combining clinical and histologic prognostic factors enables the identification of patients with a higher likelihood of a positive PET/CT scan. PMID:27766186

  16. Uveal Melanoma

    PubMed Central

    Papastefanou, Vasilios P.; Cohen, Victoria M. L.

    2011-01-01

    Uveal melanoma is the most common primary intraocular malignancy and the leading primary intraocular disease which can be fatal in adults. In this paper epidemiologic, pathogenetic, and clinical aspects of uveal melanoma are discussed. Despite the advance in local ocular treatments, there has been no change in patient survival for three decades. Development of metastases affects prognosis significantly. Current survival rates, factors predictive of metastatic potential and metastatic screening algorithms are discussed. Proposed and emerging treatments for uveal melanoma metastases are also overviewed. Current advances in genetics and cytogenetics have provided a significant insight in tumours with high metastatic potential and the molecular mechanisms that underlie their development. Biopsy of those lesions may prove to be important for prognostication and to allow further research into genetic mutations and potential new therapeutic targets in the future. PMID:21773036

  17. Impact of gender and primary tumor location on outcome of patients with cutaneous melanoma.

    PubMed

    S, Voinea; A, Blidaru; E, Panaitescu; A, Sandru

    2016-01-01

    Background. The survival of patients with cutaneous malignant melanoma (MM) depends on multiple factors whose role is continuously updated, as the molecular mechanisms underlying the disease progression are understood. This study intended to assess whether the patient's gender and tumor location affect the disease outcome. Methods. Between 2008 and 2012, 155 patients with cutaneous MM underwent various types of surgeries in our clinic. Patients were staged according to the 2009 TNM classification. There were 90 women and 65 men. Primary tumors were located as it follows head and neck region - 4.5%, limbs - 50.7% and trunk - 44.8%. The disease free and overall survival rates (DFS, OS) were estimated by using the Kaplan-Meier method. Results. Metastases developed in 52.3% of the males and 31.1% of the females (p=0.008). In univariate analysis, distant metastasis risk was significantly higher in men (p = 0.0472 for stage II patients and p = 0.0288 for stage III). In multivariate analysis, male gender almost doubled the risk of relapse (p = 0.044) and death (p = 0.022). Consequently, DFS and OS were significantly higher among females. Primary tumor location seemed to influence the melanoma spreading ability. Half of the trunk MM developed metastases while only a third of limbs MM did. The association between MM location and the recurrence risk was not random (p = 0.033). Conclusions. The patient gender represents an independent prognostic factor for both relapse and death. Although trunk MM had a significantly higher risk of metastasis than limbs MM, the location per se was not an independent prognostic factor for survival (p = 0.078). Abbreviations: MM = malignant melanoma, DFS = disease free survival, OS = overall survival, p = p value, AJCC = American Joint Commission on Cancer, CI = confidence interval.

  18. Population-based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas.

    PubMed

    Helsing, Per; Nymoen, Dag Andre; Ariansen, Sarah; Steine, Solrun J; Maehle, Lovise; Aamdal, Steinar; Langmark, Frøydis; Loeb, Mitchell; Akslen, Lars A; Molven, Anders; Andresen, Per Arne

    2008-02-01

    The presence of multiple primary cutaneous melanomas (MPM) has been advocated as guidance to identifying melanoma families. Frequencies of CDKN2A mutations in materials of sporadic MPM cases from pigmented lesion clinics vary between 8 and 15%. Patients with MPM have therefore been regarded as good candidates for CDKN2A mutational screening. We describe a population-based study where all persons in Norway diagnosed with MPM between 1953 and 2004 (n = 738 alive per April 2004) were invited to participate. Three-hundred-and-ninety patients (52.8%) responded confidentially. Mutations in CDKN2A were found in 6.9% of the respondents. Eighty-one MPM patients (20.8%) reported that they belonged to melanoma families, and 17 (21.0%) of these harboured a CDKN2A mutation, compared to 3.2% of the nonfamilial cases. The probability of finding a CDKN2A mutation increased when the patients had three or more melanomas, or a young age of onset of first melanoma. We identified five novel CDKN2A variants (Ala57Gly, Pro81Arg, Ala118Val, Leu130Val, and Arg131Pro) and four that previously have been reported in melanoma families (Glu27X, Met53Ile, Arg87Trp, and Ala127Pro). A large deletion (g.13623_23772del10150) encompassing exon 1alpha and the 5' part of exon 2 was detected in six patients with a family history of melanoma. Three patients, belonging to the same family, had the CDK4 Arg24His mutation. The frequency of CDKN2A mutations was lower than previously reported in other studies, an observation which probably is due to the population-based design of our study.

  19. Vaccination coverage of patients with inborn errors of metabolism and the attitudes of their parents towards vaccines.

    PubMed

    Cerutti, Marta; De Lonlay, Pascale; Menni, Francesca; Parini, Rossella; Principi, Nicola; Esposito, Susanna

    2015-11-27

    To evaluate vaccination coverage of children and adolescents with inborn errors of metabolism (IEMs) and the attitudes of their parents towards vaccination, the vaccination status of 128 patients with IEM and 128 age- and gender-matched healthy controls was established by consulting the official vaccination chart. In children with IEMs, compared with healthy controls, low vaccination rates and/or delays in administration were observed for pneumococcal conjugate, meningococcus C, measles, mumps, rubella, diphtheria-tetanus-pertussis-inactivated polio, Bacillus Calmette-Guerin, and influenza vaccines. Among the parents of IEM patients, vaccine schedule compliance was primarily driven by the doctors at the hospital's reference centres; among the parents of the healthy controls, compliance was driven by the primary care paediatricians. These results show that IEM patients demonstrate sub-optimal vaccination coverage. Further studies of the different vaccines in each IEM disorder and educational programmes aimed at physicians and parents to increase immunization coverage in these patients are urgently needed.

  20. CD204 suppresses large heat shock protein-facilitated priming of tumor antigen gp100-specific T cells and chaperone vaccine activity against mouse melanoma.

    PubMed

    Qian, Jie; Yi, Huanfa; Guo, Chunqing; Yu, Xiaofei; Zuo, Daming; Chen, Xing; Kane, John M; Repasky, Elizabeth A; Subjeck, John R; Wang, Xiang-Yang

    2011-09-15

    We previously reported that scavenger receptor A (SRA/CD204), a binding structure on dendritic cells (DCs) for large stress/heat shock proteins (HSPs; e.g., hsp110 and grp170), attenuated an antitumor response elicited by large HSP-based vaccines. In this study, we show that SRA/CD204 interacts directly with exogenous hsp110, and lack of SRA/CD204 results in a reduction in the hsp110 binding and internalization by DCs. However, SRA(-/-) DCs pulsed with hsp110 or grp170-reconstituted gp100 chaperone complexes exhibit a profoundly increased capability of stimulating melanoma Ag gp100-specific naive T cells compared with wild-type (WT) DCs. Similar results were obtained when SRA/CD204 was silenced in DCs using short hairpin RNA-encoding lentiviruses. In addition, hsp110-stimulated SRA(-/-) DCs produced more inflammatory cytokines associated with increased NF-κB activation, implicating an immunosuppressive role for SRA/CD204. Immunization with the hsp110-gp100 vaccine resulted in a more robust gp100-specific CD8(+) T cell response in SRA(-/-) mice than in WT mice. Lastly, SRA/CD204 absence markedly improved the therapeutic efficacy of the hsp110-gp100 vaccine in mice established with B16 melanoma, which was accompanied by enhanced activation and tumor infiltration of CD8(+) T cells. Given the presence of multiple HSP-binding scavenger receptors on APCs, we propose that selective scavenger receptor interactions with HSPs may lead to highly distinct immunological consequences. Our findings provide new insights into the immune regulatory functions of SRA/CD204 and have important implications in the rational design of protein Ag-targeted recombinant chaperone vaccines for the treatment of cancer.

  1. FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients.

    PubMed

    Streit, S; Mestel, D S; Schmidt, M; Ullrich, A; Berking, C

    2006-06-19

    A single nucleotide polymorphism in the gene for FGFR4 (-Arg388) has been associated with progression in various types of human cancer. Although fibroblast growth factors (FGFs) belong to the most important growth factors in melanoma, expression of FGF receptor subtype 4 has not been investigated yet. In this study, the protein expression of this receptor was analysed in 137 melanoma tissues of different progression stages by immunohistochemistry. FGFR4 protein was expressed in 45% of the specimens and correlated with pTNM tumour stages (UICC, P = 0.023 and AJCC, P = 0.046), presence of microulceration (P = 0.009), tumour vascularity (P = 0.001), metastases (P = 0.025), number of primary tumours (P = 0.022), overall survival (P = 0.047) and disease-free survival (P = 0.024). Furthermore, FGFR4 Arg388 polymorphism was analysed in 185 melanoma patients by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Arg388 allele was detected in 45% of the melanoma patients and was significantly associated with tumour thickness (by Clark's level of invasion (P = 0.004) and by Breslow in mm (P = 0.02)) and the tumour subtype nodular melanoma (P = 0.002). However, there was no correlation of the FGFR4 Arg388 allele with overall and disease-free survival. In conclusion, the Arg388 genotype and the protein expression of FGFR4 may be potential markers for progression of melanoma.

  2. Genetic and Epigenetic Alterations of TERT Are Associated with Inferior Outcome in Adolescent and Young Adult Patients with Melanoma

    PubMed Central

    Seynnaeve, Brittani; Lee, Seungjae; Borah, Sumit; Park, Yongseok; Pappo, Alberto; Kirkwood, John M.; Bahrami, Armita

    2017-01-01

    Progression of melanoma to distant sites in adolescents and young adults (AYAs) is not reliably predicted by clinicopathologic criteria. TERT promoter mutations when combined with BRAF/NRAS mutations correlate with adverse outcome in adult melanoma. To determine the prognostic value of TERT alterations in AYA melanoma, we investigated the association of TERT promoter mutations, as well as promoter methylation, an epigenetic alteration also linked to TERT upregulation, with TERT mRNA expression and outcome using a well-characterized cohort of 27 patients with melanoma (ages 8–25, mean 20). TERT mRNA expression levels were significantly higher in tumors harboring TERT promoter mutation and/or hypermethylation than those without either aberration (P = 0.046). TERT promoter mutations alone did not predict adverse outcomes (P = 0.50), but the presence of TERT promoter methylation, alone or concurrent with promoter mutations, correlated with reduced recurrence-free survival (P = 0.001). These data suggest that genetic and epigenetic alterations of TERT are associated with TERT upregulation and may predict clinical outcomes in AYA melanoma. A more exhaustive understanding of the different molecular mechanisms leading to increased TERT expression may guide development of prognostic assays to stratify AYA melanoma patients according to clinical risk. PMID:28378855

  3. FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma.

    PubMed

    Barone, Amy; Hazarika, Maitreyee; Theoret, Marc R; Mishra-Kalyani, Pallavi; Chen, Huanyu; He, Kun; Sridhara, Rajeshwari; Subramaniam, Sriram; Pfuma, Elimika; Wang, Yaning; Li, Hongshan; Zhao, Hong; Fourie Zirkelbach, Jeanne; Keegan, Patricia; Pazdur, Richard

    2017-02-08

    On December 18, 2015, the U.S. Food and Drug Administration (FDA) granted regular approval to pembrolizumab (KEYTRUDA®; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma, based on results of two randomized, open-label, active-controlled clinical trials. In Trial PN006, 834 patients with ipilimumab-naïve metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg intravenously (IV) every 2 (q2w) or 3 (q3w) weeks until disease progression or ipilimumab 3 mg/kg q3w for up to four doses. In Trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg IV q3w or to investigator's choice of chemotherapy. In Trial PN006, patients randomized to pembrolizumab demonstrated statistically significant improvement in overall survival compared to ipilimumab (q2w arm, HR= 0.63 [95%CI: 0.47, 0.83; p<0.001]; q3w arm, HR=0.67 [95%CI: 0.52, 0.90; p=0.004]). In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (≥2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of tumor response-based endpoints using Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST (irRC).

  4. Psychosocial predictors of outcome: time to relapse and survival in patients with early stage melanoma

    PubMed Central

    Brown, J E; Butow, P N; Culjak, G; Coates, A S; Dunn, S M

    2000-01-01

    This study explored psychosocial predictors of relapse and survival in early stage melanoma patients. Patients with locoregional melanoma whose tumour thickness exceeded 0.69 mm, seen at the Sydney Melanoma Unit between 1991 and 1996 participated in the study. Questionnaires were sent to participating patients every 3 months for 2 years. Domains measured included cognitive appraisal of threat, coping, psychological adjustment, quality of life and perceived aim of treatment. Disease and demographic data were obtained from medical records. Multivariate analyses from baseline data used the Cox proportional hazards model. Of the 682 patients invited to participate 426 (62%) agreed. 91 (21%) relapsed and 60 (14%) died within the follow-up period, that ended in October 1997. After controlling for known prognostic indicators, several psychosocial variables predicted time to relapse and/or survival duration. Patients who perceived their aim of treatment to be cured, who did not use avoidance as a coping strategy or who were concerned about their disease experienced longer periods without relapse. Shorter survival duration was associated with a positive mood, the use of avoidance as a coping strategy, not being concerned with their disease and concern about the impact of the disease on family. There is still much to learn about the potential relationships between psychological well being, human behaviours and cancer outcome. Research in this area needs to clarify the psychological processes, as well as understand the biological and/or behavioural mechanisms that may link them to outcome. © 2000 Cancer Research Campaign http://www.bjcancer.com PMID:11076652

  5. Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma

    PubMed Central

    Carvajal, Richard D.; Pandit-Taskar, Neeta; Jungbluth, Achim A.; Hoffman, Eric W.; Wu, Bor-Wen; Bomalaski, John S.; Venhaus, Ralph; Pan, Linda; Old, Lloyd J.; Pavlick, Anna C.; Wolchok, Jedd D.

    2014-01-01

    Summary Background Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients and methods Patients with advanced melanoma were treated with 40, 80 or 160 IU/m2 ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by 18FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for >6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had <5 % cells positive. Conclusions ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup. PMID:22864522

  6. Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma.

    PubMed

    Ott, Patrick A; Carvajal, Richard D; Pandit-Taskar, Neeta; Jungbluth, Achim A; Hoffman, Eric W; Wu, Bor-Wen; Bomalaski, John S; Venhaus, Ralph; Pan, Linda; Old, Lloyd J; Pavlick, Anna C; Wolchok, Jedd D

    2013-04-01

    Background Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients and methods Patients with advanced melanoma were treated with 40, 80 or 160 IU/m(2) ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by (18)FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for >6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had <5 % cells positive. Conclusions ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup.

  7. A clinicopathological review of 33 patients with vulvar melanoma identifies c-KIT as a prognostic marker

    PubMed Central

    HEINZELMANN-SCHWARZ, VIOLA A.; NIXDORF, SHERI; VALADAN, MEHRNAZ; DICZBALIS, MONICA; OLIVIER, JAKE; OTTON, GEOFF; FEDIER, ANDRÉ; HACKER, NEVILLE F.; SCURRY, JAMES P.

    2014-01-01

    Vulvar melanoma is the second most common vulvar cancer. Patients with vulvar melanoma usually present with the disease at a late stage and have a poor prognosis. The prognostic predictors reported in the literature are not unequivocal and the role of lichen sclerosus and c-KIT mutations in the aetiology of vulvar melanoma is unclear. Breslow staging currently seems to be the most adequate predictor of prognosis. We thus performed a clinicopathological and literature review to identify suitable predictors of prognosis and survival and investigated the expression of c-KIT (by immunohistochemistry) in patients with vulvar melanoma (n=33) from the Gynaecological Cancer Centres of the Royal Hospital for Women (Sydney, Australia) and John Hunter Hospital (Newcastle, Australia). Our series of 33 patients fitted the expected clinical profile of older women: delayed presentation, high stage, limited response to treatment and poor prognosis. We identified 3 patients (9.1%) with lichen sclerosus associated with melanoma in situ, although no lichen sclerosus was found in the areas of invasive melanoma. No patient had vulvar nevi. We identified a) Breslow’s depth, b) an absence of any of the pathological risk factors, such as satellitosis, in-transit metastasis, lymphovascular space invasion (LVSI) and dermal mitosis, c) removal of inguino-femoral lymph nodes, d) lateral margin of >1 cm, and e) c-KIT expression as valuable prognostic predictors for disease-free survival. We conclude that c-KIT expression is, apart from Breslow’s depth, another valuable predictor of prognosis and survival. Lichen sclerosus may be associated with vulvar melanoma. PMID:24535703

  8. Statin use and its effect on all-cause mortality of melanoma patients: a population-based Dutch cohort study

    PubMed Central

    Livingstone, Elisabeth; Hollestein, Loes M; van Herk-Sukel, Myrthe P P; van de Poll-Franse, Lonneke; Joosse, Arjen; Schilling, Bastian; Nijsten, Tamar; Schadendorf, Dirk; de Vries, Esther

    2014-01-01

    Preclinical data showed anticancer effects of statins in melanoma, but meta-analyses could not demonstrate a reduced melanoma incidence in statin users. Rather than preventing occurrence, statins might reduce growth and metastatic spread of melanomas and ultimately improve survival. In this population-based study, we investigated the relationship between statin use and survival of melanoma patients. Patients ≥18 years who were diagnosed with cutaneous melanoma (Breslow thickness >1 mm) and registered in the Eindhoven Cancer Registry and in PHARMO Database Network between 1 January 1998 and 31 December 2010 were eligible. The hazard ratio (HR) of all-cause mortality was calculated by employing adjusted time-dependent and time-fixed Cox proportional hazard models. Disease-specific survival was estimated by means of 3-year relative survival rates (RSR). A control cohort of randomly selected patients using statins from PHARMO Database Network matched on age and gender was used to compare RSR of statin users to the general population. After melanoma diagnosis, 171 of 709 patients used statins. Use of statins showed a nonsignificantly decreased hazard of death (adjusted HR 0.76, 95% confidence interval [CI] 0.50–1.61). After stratification for gender, male but not female statin users showed a favorable outcome compared to nonusers (HR 0.57, 95% CI 0.32–0.99; HR 1.22, 95% CI 0.62–2.38, respectively). Three-year RSR for male statin users tended to be higher than for nonusers (91% vs. 80.5%, P = 0.06), no differences were observed in women (87.1% vs. 92.5%, P = 0.76). Statin use was not associated with an improved survival of melanoma patients. The trend for better survival of male in contrast to female statin users warrants further research. PMID:24935402

  9. A comparison of noninvasive imaging modalities in the melanoma patient

    SciTech Connect

    Doiron, M.J.; Bernardino, M.E.

    1981-06-01

    The results of radionuclide (RN) liver scans, computed tomography (CT), and ultrasonography (US) were compared in 163 patients. Thirty-eight patients had all three studies, while ten were examined by CT and RN liver scans. One hundred fifteen patients had only US and RN studies. Radionuclide liver scanning demonstrated more false positive and negative studies than CT or US. Also, CT and US demonstrated more areas of metastasis during a single examination than RN liver scans. Ultrasonography displayed roughly the same accuracy of CT when a technically adequate examination was obtained. However, US was hampered by technically inadequate studies in 19% of 153 patients because of interfering intestinal gas. Computed tomography proved the most accurate and reliable modality in 48 patients.

  10. microRNA Expression in Sentinel Nodes from Progressing Melanoma Patients Identifies Networks Associated with Dysfunctional Immune Response

    PubMed Central

    Vallacchi, Viviana; Camisaschi, Chiara; Dugo, Matteo; Vergani, Elisabetta; Deho, Paola; Gualeni, Ambra; Huber, Veronica; Gloghini, Annunziata; Maurichi, Andrea; Santinami, Mario; Sensi, Marialuisa; Castelli, Chiara; Rivoltini, Licia; Rodolfo, Monica

    2016-01-01

    Sentinel node biopsy (SNB) is a main staging biomarker in melanoma and is the first lymph node to drain the tumor, thus representing the immunological site where anti-tumor immune dysfunction is established and where potential prognostic immune markers can be identified. Here we analyzed microRNA (miR) profiles in archival tumor-positive SNBs derived from melanoma patients with different outcomes and performed an integrated analysis of transcriptional data to identify deregulated immune signaling networks. Twenty-six miRs were differentially expressed in melanoma-positive SNB samples between patients with disease progression and non-progressing patients, the majority being previously reported in the regulation of immune responses. A significant variation in miR expression levels was confirmed in an independent set of SNB samples. Integrated information from genome-wide transcriptional profiles and in vitro assessment in immune cells led to the identification of miRs associated with the regulation of the TNF receptor superfamily member 8 (TNFRSF8) gene encoding the CD30 receptor, a marker increased in lymphocytes of melanoma patients with progressive disease. These findings indicate that miRs are involved in the regulation of pathways leading to immune dysfunction in the sentinel node and may provide valuable markers for developing prognostic molecular signatures for the identification of stage III melanoma patients at risk of recurrence. PMID:27983661

  11. Risk of interactions between complementary and alternative medicine and medication for comorbidities in patients with melanoma.

    PubMed

    Loquai, Carmen; Dechent, Dagmar; Garzarolli, Marlene; Kaatz, Martin; Kaehler, Katharina C; Kurschat, Peter; Meiss, Frank; Stein, Annette; Nashan, Dorothee; Micke, Oliver; Muecke, Ralph; Muenstedt, Karsten; Stoll, Christoph; Schmidtmann, Irene; Huebner, Jutta

    2016-05-01

    Complementary and alternative medicine (CAM) is used widely among cancer patients. Beside the risk of interaction with cancer therapies, interactions with treatment for comorbidities are an underestimated problem. The aim of this study was to assess prevalence of interactions between CAM and drugs for comorbidities from a large CAM usage survey on melanoma patients and to classify herb-drug interactions with regard to their potential to harm. Consecutive melanoma outpatients of seven skin cancer centers were asked to complete a standardized CAM questionnaire including questions to their CAM use and their taken medication for comorbidities and cancer. Each combination of conventional drugs and complementary substances was evaluated for their potential of interaction. 1089 questionnaires were eligible for evaluation. From these, 61.6% of patients reported taking drugs regularly from which 34.4% used biological-based CAM methods. Risk evaluation for interaction was possible for 180 CAM users who listed the names or substances they took for comorbidities. From those patients, we found 37.2% at risk of interaction of their co-consumption of conventional and complementary drugs. Almost all patients using Chinese herbs were at risk (88.6%). With a high rate of CAM usage at risk of interactions between CAM drugs and drugs taken for comorbidities, implementation of a regular assessment of CAM usage and drugs for comorbidities is mandatory in cancer care.

  12. Cross-cultural development of a quality-of-life measure for patients with melanoma: phase 3 testing of an EORTC Melanoma Module.

    PubMed

    Winstanley, Julie B; Young, Teresa E; Boyle, Frances M; Bergenmar, Mia; Bottomley, Andrew; Burmeister, Bryan; Campana, Luca G; Garioch, Jennifer J; King, Madeleine; Nikolic, Dejan V; van de Poll-Franse, Lonneke V; Saw, Robyn; Thompson, John F; White, Edward G

    2015-02-01

    Melanoma is an increasingly common skin cancer worldwide. Recent treatment advances have provided patients and healthcare professionals (HCPs) with choices where quality of life (QoL) and toxicity are important considerations. A melanoma-specific QoL questionnaire is being developed in a cross-cultural setting using a four phase process developed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group. In phase 1, a literature search identified a list of pertinent QoL issues; this was shown to HCPs and patients in eight countries and rated for importance and relevance. Questions were constructed for the highest-rated issues (phase 2) and piloted in another patient sample (phase 3). Using EORTC Quality of Life Group criteria and sequential use of factor and Rasch analysis, scales were hypothesized for field testing (phase 4). Seven QoL domains (disease symptoms, treatment issues, financial issues, access/quality of information, satisfaction with care, psychosocial issues and support), comprising 73 QoL issues, were rated by 46 HCPs and 78 patients. Fifty-six issues were rephrased as questions and piloted with 132 patients. A 38-item questionnaire (QLQ-MEL38) is available for field testing in conjunction with the EORTC QLQ-C30. This study has shown that melanoma patients have important QoL issues that have been incorporated into a new cross-culturally validated instrument. Future testing of this EORTC module is planned and will be an important step forward in providing reliable QoL data to aid future decision-making in the management and clinical trials of this complex group of patients.

  13. Preparing patients to travel abroad safely. Part 2: Updating vaccinations.

    PubMed Central

    Thomas, R. E.

    2000-01-01

    OBJECTIVE: To provide, for family physicians without access to a travel clinic, evidence-based recommendations on vaccinating infants and children, adults, pregnant women, and immunocompromised patients traveling to non-Western countries. QUALITY OF EVIDENCE: Searches were undertaken of MEDLINE from 1990 to November 1998 (372 articles); the Cochrane Collaboration Library; publications of the National Action Committee on Immunization and the Committee to Advise on Tropical Medicine and Travel in Canada Communicable Disease Reports; the Canadian Immunization Guide; and Laboratory Centre for Disease Control, United States Centres for Disease Control, and World Health Organization websites. Evidence-based statements, randomized controlled trials, systematic reviews, and meta-analyses were selected. Vaccination recommendations are based on this evidence. MAIN MESSAGE: Physicians should complete vaccination schedules for children whose primary series is incomplete and vaccinate unvaccinated adults. Hepatitis A is widespread, and travelers to areas where it is endemic should be vaccinated. The elderly should be vaccinated against influenza and pneumococcal disease. Pregnant women should receive vaccines appropriate to their trimester. Immunocompromised patients should be vaccinated, but BCG and live vaccines are contraindicated. Travelers to areas where meningitis, typhoid, cholera, Japanese encephalitis, and rabies are endemic should be vaccinated if they are likely to be exposed. Those traveling to areas where tuberculosis is endemic should take precautions and should have skin tests before traveling and 2 to 4 months after return. CONCLUSIONS: Family physicians can administer all necessary vaccinations. They can advise pregnant women and immunocompromised people about the balance of risk of disease and benefits of vaccination. PMID:10752003

  14. Radiation therapy combined with Listeria monocytogenes-based cancer vaccine synergize to enhance tumor control in the B16 melanoma model

    PubMed Central

    Lim, Joanne YH; Brockstedt, Dirk G; Lord, Edith M; Gerber, Scott A

    2014-01-01

    Conceptually, the immune system may profoundly influence the efficacy of radiation therapy. Compelling evidence has recently emerged revealing the capacity of local radiation therapy (RT) to induce antitumor immune responses and sparked interest in combining RT with immunotherapy to promote tumor-specific immunity. A Listeria monocytogenes (Lm)-based cancer vaccine engineered to express tumor-associated antigen has been shown to effectively retard tumor growth by cell-mediated immune mechanisms. We hypothesized that combining RT and Lm vaccine will result in synergistic effects that enhance tumor control. Collectively, our data demonstrate that combination therapy significantly delayed B16 melanoma tumor growth by a mechanism partly dependent on CD8+ T cells. Radiotherapy and Lm vaccine each induce different aspects of antitumor immunity, resulting in an overall increase in intratumoral numbers of activated T cells, antigen-specific CD8+ T cells, natural killer (NK) cells and levels of effector molecules, such as interferon γ (IFNγ) and granzyme B. Thus, radiation and Lm vaccine combination therapy is a promising new strategy for the treatment of malignant disease, and further understanding of the mechanisms that underlie efficacy is required to optimize the dosage and schedule for administering the two treatments. PMID:25083327

  15. Improved Antitumor Activity of a Therapeutic Melanoma Vaccine through the Use of the Dual COX-2/5-LO Inhibitor Licofelone

    PubMed Central

    Neumann, Silke; Shirley, Simon A.; Kemp, Roslyn A.; Hook, Sarah M.

    2016-01-01

    Immune-suppressive cell populations impair antitumor immunity and can contribute to the failure of immune therapeutic approaches. We hypothesized that the non-steroidal anti-inflammatory drug licofelone, a dual cyclooxygenase-2/5-LO inhibitor, would improve therapeutic melanoma vaccination by reducing immune-suppressive cell populations. Therefore, licofelone was administered after tumor implantation, either alone or in combination with a peptide vaccine containing a long tyrosinase-related protein 2-peptide and the adjuvant α-galactosylceramide, all formulated into cationic liposomes. Mice immunized with the long-peptide vaccine and licofelone showed delayed tumor growth compared to mice given the vaccine alone. This protection was associated with a lower frequency of immature myeloid cells (IMCs) in the bone marrow (BM) and spleen of tumor-inoculated mice. When investigating the effect of licofelone on IMCs in vitro, we found that the prostaglandin E2-induced generation of IMCs was decreased in the presence of licofelone. Furthermore, pre-incubation of BM cells differentiated under IMC-inducing conditions with licofelone reduced the secretion of cytokines interleukin (IL)-10 and -6 upon lipopolysaccharides (LPS) stimulation as compared to untreated cells. Interestingly, licofelone increased IL-6 and IL-10 secretion when administered after the LPS stimulus, demonstrating an environment-dependent effect of licofelone. Our findings support the use of licofelone to reduce tumor-promoting cell populations. PMID:27994586

  16. Melanoma of the Umbilicus: A Patient Report, Precaution in Operative Strategy, and the First Histopathological Review of Published Cases

    PubMed Central

    Suzuki, Shuji; Yoshida, Yuichi; Shiomi, Tatsushi; Yanagihara, Shigeto; Kimura, Ryoko; Yamamoto, Osamu

    2016-01-01

    Umbilical melanoma is extremely rare. Among the past English reports on umbilical melanoma, there are only 8 reports in which histopathology was described in detail, and there has been no report with a review of the histopathology of previously reported cases. We experienced a case of umbilical melanoma and reviewed previously reported cases including our case. Because of the anatomical location, it is difficult to become aware of the umbilical melanoma unless there are some concomitant symptoms such as discharge or swelling. Even with these symptoms, patients tend to postpone a hospital visit for unknown reasons, resulting in increased risk of tumor growth and metastasis. When performing resection of umbilical melanoma, a portion of the peritoneum should also be removed. Sentinel lymph nodes can be axilla or inguinal lymph nodes. There is a possibility of metastasis to the preoperative abdominal cavity or to nearby skin through hematogenous spread. Preoperative evaluation of tumor spread and postoperative observation are important for umbilical melanoma in order to detect recurrence or metastasis because of its unique anatomical location. PMID:27493491

  17. Two cases of clinical myasthenia gravis associated with pembrolizumab use in responding melanoma patients.

    PubMed

    Nguyen, Bella H V; Kuo, James; Budiman, Anadian; Christie, Hayden; Ali, Sayed

    2017-04-01

    Immune checkpoint inhibitors have changed the landscape of the treatment of multiple solid malignancies, and have been used increasingly in the recent years. Although usually well tolerated, given the relative inexperience of using immune checkpoint inhibitors, we are still learning of new side effects from the treatment. We report on two cases of ocular myasthenia gravis that occurred after treatment with pembrolizumab, an antiprogrammed-death (anti-PD1) monoclonal antibody for advanced melanoma in responding patients. One case is in an 81-year-old man and the second case in an 86-year-old woman, both with BRAF-negative metastatic melanoma receiving pembrolizumab. These two cases of ocular only associated myasthenic syndrome appeared 7 and 11 weeks after the initiation of pembrolizumab. We conclude that the condition is most likely associated with pembrolizumab as symptoms started after treatment with pembrolizumab, neither patient had other evidence of neurological cause for presentation, and symptoms also improved rapidly with administration of steroids. Both patients showed good oncological response to anti-PD1 treatment and one patient successfully continued to receive ongoing treatment with no further complications.

  18. Vaccination of the immune-compromised patients with focus on patients with autoimmune-inflammatory diseases.

    PubMed

    Bijl, M; Kallenberg, C G M; van Assen, S

    2011-01-01

    Among immunocompromised patients morbidity and mortality due to vaccine-preventable infections is high. Although vaccination seems indicated, controversy exists about which vaccines should be offered, at what moment, and to whom. Guidelines are needed as the number of immunocompromised individuals increases due to the wider use of immunosuppressive drugs and, in particular, because since the introduction of biological agents, the spectrum of immunosuppressive drugs is rapidly expanding. In this review we will highlight controversies about vaccination in immunocompromised patients and will discuss indications for the several vaccines available to prevent infectious diseases with the focus on patients with autoimmune-inflammatory diseases.

  19. Elevated IgG4 in patient circulation is associated with the risk of disease progression in melanoma

    PubMed Central

    Karagiannis, Panagiotis; Villanova, Federica; Josephs, Debra H; Correa, Isabel; Van Hemelrijck, Mieke; Hobbs, Carl; Saul, Louise; Egbuniwe, Isioma U; Tosi, Isabella; Ilieva, Kristina M; Kent, Emma; Calonje, Eduardo; Harries, Mark; Fentiman, Ian; Taylor-Papadimitriou, Joyce; Burchell, Joy; Spicer, James F; Lacy, Katie E; Nestle, Frank O; Karagiannis, Sophia N

    2015-01-01

    Emerging evidence suggests pathological and immunoregulatory functions for IgG4 antibodies and IgG4+ B cells in inflammatory diseases and malignancies. We previously reported that IgG4 antibodies restrict activation of immune effector cell functions and impair humoral responses in melanoma. Here, we investigate IgG4 as a predictor of risk for disease progression in a study of human sera (n = 271: 167 melanoma patients; 104 healthy volunteers) and peripheral blood B cells (n = 71: 47 melanoma patients; 24 healthy volunteers). IgG4 (IgG4/IgGtotal) serum levels were elevated in melanoma. High relative IgG4 levels negatively correlated with progression-free survival (PFS) and overall survival. In early stage (I–II) disease, serum IgG4 was independently negatively prognostic for progression-free survival, as was elevation of IgG4+ circulating B cells (CD45+CD22+CD19+CD3−CD14−). In human tissues (n = 256; 108 cutaneous melanomas; 56 involved lymph nodes; 60 distant metastases; 32 normal skin samples) IgG4+ cell infiltrates were found in 42.6% of melanomas, 21.4% of involved lymph nodes and 30% of metastases, suggesting inflammatory conditions that favor IgG4 at the peripheral and local levels. Consistent with emerging evidence for an immunosuppressive role for IgG4, these findings indicate association of elevated IgG4 with disease progression and less favorable clinical outcomes. Characterizing immunoglobulin and other humoral immune profiles in melanoma might identify valuable prognostic tools for patient stratification and in the future lead to more effective treatments less prone to tumor-induced blockade mechanisms. PMID:26451312

  20. Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk

    PubMed Central

    Salerno, Elise P.; Bedognetti, Davide; Mauldin, Ileana S.; Deacon, Donna H.; Shea, Sofia M.; Obeid, Joseph M.; Coukos, George; Gajewski, Thomas F.; Marincola, Francesco M.; Slingluff, Craig L.

    2016-01-01

    ABSTRACT We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p = 0.0002) and for ovarian cancer (p < 0.01). Interestingly, this association persists for FLG for melanoma (p = 0.012) and ovarian cancer (p = 0.006), whereas DST overexpression is negatively associated with CD8+ gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction. PMID:28123876

  1. Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk.

    PubMed

    Salerno, Elise P; Bedognetti, Davide; Mauldin, Ileana S; Deacon, Donna H; Shea, Sofia M; Pinczewski, Joel; Obeid, Joseph M; Coukos, George; Wang, Ena; Gajewski, Thomas F; Marincola, Francesco M; Slingluff, Craig L

    2016-01-01

    We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p = 0.0002) and for ovarian cancer (p < 0.01). Interestingly, this association persists for FLG for melanoma (p = 0.012) and ovarian cancer (p = 0.006), whereas DST overexpression is negatively associated with CD8(+) gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction.

  2. Radioembolization as Locoregional Therapy of Hepatic Metastases in Uveal Melanoma Patients

    SciTech Connect

    Klingenstein, A.; Haug, A. R.; Zech, C. J.; Schaller, U. C.

    2013-02-15

    To retrospectively evaluate the overall survival, safety, and efficacy of metastatic uveal melanoma patients after radioembolization as salvage therapy. Thirteen patients were treated with radioembolization of branches of the hepatic artery with resin-based yttrium-90 ({sup 90}Y)-labelled microspheres. Twelve patients underwent a single application, and 1 patient underwent 4 interventions. Dosages from 644 to 2,450 MBq (mean activity 1,780) were applied. Treatment response was evaluated by way of liver magnetic resonance imaging and computed tomography (CT) as well as whole-body fluorodeoxyglucose positron emission tomography (PET)/CT with evaluation of percentage changes in SUV{sub max} before and at 2-3 months after therapy. Kaplan-Meier analysis was calculated to determine overall survival. Partial remission (PR) was observed in 8 (62 %), stable disease (SD) in 2 (15 %), and progressive disease (PD) in 3 (23 %) patients under terms of standard criteria and PR in 3 (23 %), SD in 3 (23 %), and PD in 7 (54 %) patients according to PET criteria. Neither RECIST nor PET criteria showed a significant difference in predicting overall survival (P = 0.12 and 0.11, respectively). Median survival time after radioembolization was 7 months. No acute toxicity with in-hospital morbidity was observed. One patient developed hepatomegaly, and 1 patient developed gastric ulceration. Throughout follow-up, progression of extrahepatic metastases was observed. Radioembolization may be a promising therapy in uveal melanoma patients with predominant hepatic metastases. At first follow-up, we observed PR or SD in 77 % patients under terms of standard criteria with an acceptable toxicity profile.

  3. Clinical activity and safety of Pembrolizumab in Ipilimumab pre-treated patients with uveal melanoma

    PubMed Central

    Karydis, Ioannis; Chan, Pui Ying; Wheater, Matthew; Arriola, Edurne; Szlosarek, Peter W.; Ottensmeier, Christian H.

    2016-01-01

    ABSTRACT Background: Untreated metastatic uveal melanoma (UM) carries a grave prognosis. Unlike cutaneous melanoma (CM), there are no established treatments known to significantly improve outcomes for a meaningful proportion of patients. Inhibition of the PD1–PDL1 axis has shown promise in the management of CM and we here report a two center experience of UM patients receiving pembrolizumab. Methods: To assess the efficacy and safety of pembrolizumab, we retrospectively analyzed outcome data of 25 consecutive UM patients participating in the MK3475 expanded access program (EAP) who received pembrolizumab at 2 mg/kg 3 weekly. Tumor assessment was evaluated using RECIST 1.1 and immune-related Response Criteria (irRC) by CT scanning. Toxicity was recorded utilizing Common Terminology Criteria for Adverse Events (“CTCAE”) v4.03. Results: Twenty-five patients were identified receiving a median of six cycles of treatment. Two patients achieved a partial response and six patients stable disease. After a median follow-up of 225 d median progression free survival (PFS) was 91 d and overall survival (OS) was not reached. There was a significant trend for improved outcomes in patients with extrahepatic disease progression as opposed to liver only progression at the outset. Five patients experienced grade 3 or 4 adverse events (AEs); there were no treatment related deaths. Conclusions: Pembrolizumab 2mg/kg q3w is a safe option in UM patients. Disease control rates, particularly in the subgroup of patients without progressive liver disease at the outset are promising; these results merit further investigation in clinical trials possibly incorporating liver targeted treatment modalities. PMID:27467964

  4. Case report: laparoscopic adrenalectomy in a patient with primary adrenal malignant melanoma.

    PubMed

    Liatsikos, Evangelos N; Papathanassiou, Zafiria; Voudoukis, Theodoros; Repanti, Maria; Sklavou, Christina; Filos, Kriton S; Stolzenburg, Jens-Uwe; Athanasopoulos, Anastasios; Perimenis, Petros; Barbalias, George A

    2006-02-01

    We report a case of laparoscopic management of a primary malignant melanoma of the left adrenal gland. A 42-year-old male presented a 55 x 60-mm round, inhomogeneous, noninvasive mass of the left adrenal gland. Hormone-activity values were within normal range. The mass was removed laparoscopically en bloc along with the left adrenal gland, and its histopathologic evaluation was consistent with the features of a malignant melanocytic tumor. Postoperatively, the patient presented no signs of fever or remarkable blood loss and was discharged on the third day in good clinical condition. He is free of disease 1 year later.

  5. Comparison of three methods of recalling patients for influenza vaccination.

    PubMed

    McDowell, I; Newell, C; Rosser, W

    1986-11-01

    Despite recommendations supporting annual influenza vaccination for people aged 65 years or older, vaccination rates remain low. Several studies have evaluated the effect of sending mailed reminders, but few have compared alternative ways of reminding patients to receive the vaccine. In a randomized trial of 939 patients aged 65 years or older in four family practices carried out between Oct. 23 and Dec. 31, 1984, we compared three ways of reminding elderly patients to receive the vaccine: personal reminder by the physician, telephone reminder by the nurse and reminder by letter. The vaccination rates for the three groups were 22.9%, 37% and 35.1% respectively. No reminder was issued to a control group, and the rate was 9.8%. Some patients could not be reached by telephone, and some did not see the physician during the specified time. Among the patients whom the nurse actually contacted, the vaccination rate was 43.5%; the rate for patients whom the doctor actually saw was 45.1%. Overall, a telephone reminder by the nurse was the most effective method, and at an hourly salary of $16 or less this method would also be the most cost-effective. The reminders used in this study were automatically generated from a computerized medical record system. The study shows how a computerized system can be used to identify patients for whom preventive procedures are due.

  6. Recommended vaccinations for asplenic and hyposplenic adult patients

    PubMed Central

    Grazzini, Maddalena; Niccolai, Giuditta; Paolini, Diana; Varone, Ornella; Bartoloni, Alessandro; Bartalesi, Filippo; Santini, Maria Grazia; Baretti, Simonetta; Bonito, Carlo; Zini, Paola; Mechi, Maria Teresa; Niccolini, Fabrizio; Magistri, Lea; Pulci, Maria Beatrice; Bechini, Angela

    2017-01-01

    ABSTRACT Asplenic or hyposplenic (AH) individuals are particularly vulnerable to invasive infections caused by encapsulated bacteria. Such infections have often a sudden onset and a fulminant course. Infectious diseases (IDs) incidence in AH subjects can be reduced by preventive measures such as vaccination. The aim of our work is to provide updated recommendations on prevention of infectious diseases in AH adult patients, and to supply a useful and practical tool to healthcare workers for the management of these subjects, in hospital setting and in outpatients consultation. A systematic literature review on evidence based measures for the prevention of IDs in adult AH patients was performed in 2015. Updated recommendations on available vaccines were consequently provided. Vaccinations against S. pneumoniae, N. meningitidis, H. influenzae type b and influenza virus are strongly recommended and should be administered at least 2 weeks before surgery in elective cases or at least 2 weeks after the surgical intervention in emergency cases. In subjects without evidence of immunity, 2 doses of live attenuated vaccines against measles-mumps-rubella and varicella should be administered 4–8 weeks apart from each other; a booster dose of tetanus, diphtheria and pertussis vaccine should be administered also to subjects fully vaccinated, and a 3-dose primary vaccination series is recommended in AH subjects with unknown or incomplete vaccination series (as in healthy people). Evidence based prevention data support the above recommendations to reduce the risk of infection in AH individuals. PMID:27929751

  7. Epidemiological Profile of Patients with Cutaneous Melanoma in a Region of Southern Brazil

    PubMed Central

    Moreno, Marcelo; Schmitt, Ricardo Ludwig; Lang, Maria Gabriela; Gheno, Vanessa

    2012-01-01

    Cutaneous melanoma (CM) is responsible for 75% of deaths from malignant skin cancer. The incidence of CM in the southern region of Brazil, particularly in the western region of Santa Catarina, is possibly higher than estimated. In this study, the clinical and epidemiological profile of patients with CM treated in the western region of Santa Catarina was examined. A cross-sectional study was performed with patients diagnosed with CM from January 2002 to December 2009, from 78 counties of the western region of the state of Santa Catarina. Data were collected using a protocol adapted from the Brazilian Melanoma Group and 503 patients were evaluated. The incidence and prevalence of CM found in this region are much higher than those found elsewhere in the country. This fact is most likely due to the phenotypic characteristics of the population and the high incidence of UV radiation in this region due to its location in southern Brazil, as is the case in the countries of Oceania. PMID:22548178

  8. Immunohistochemical analysis of immune response in breast cancer and melanoma patients after laser immunotherapy

    NASA Astrophysics Data System (ADS)

    Nordquist, Robert E.; Bishop, Shelly L.; Ferguson, Halie; Vaughan, Melville B.; Jose, Jessnie; Kastl, Katherine; Nguyen, Long; Li, Xiaosong; Liu, Hong; Chen, Wei R.

    2011-03-01

    Laser immunotherapy (LIT) has shown great promise in pre-clinical studies and preliminary clinical trials. It could not only eradicate treated local tumors but also cause regression and elimination of untreated metastases at distant sites. Combining a selective photothermal therapy with an active immunological stimulation, LIT can induce systemic anti-tumor immune responses. Imiquimod (IMQ), a toll-like receptor agonist, was used for the treatment of late-stage melanoma patients and glycated chitosan (GC), a biological immunological modulator, was used for the treatment of late-stage breast cancer patients, in combination of irradiation of a near-infrared laser light. To observe the immunological changes before and after LIT treatment, the pathological tissues of melanoma and breast cancer patients were processed for immunohistochemical analysis. Our results show that LIT changed the expressions of several crucial T cell types. Specifically, we observed significant decreases of CD3+ T-cells and a significant increase of CD4+,CD8+, and CD68+ T-cells in the tumor samples after LIT treatment. While not conclusive, our study could shed light on one the possible mechanisms of anti-tumor immune responses induced by LIT. Further studies will be conducted to identify immunological biomarkers associated with LIT-induced clinical response.

  9. Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response

    PubMed Central

    Felix, Joana; Lambert, Jérome; Roelens, Marie; Maubec, Eve; Guermouche, Hélène; Pages, Cécile; Sidina, Irina; Cordeiro, Debora J.; Maki, Guitta; Chasset, François; Porcher, Raphaël; Bagot, Martine; Caignard, Anne; Toubert, Antoine; Lebbé, Céleste; Moins-Teisserenc, Hélène

    2016-01-01

    ABSTRACT Purpose: Therapy targeting CTLA-4 immune checkpoint provides increased survival in patients with advanced melanoma. However, immunotherapy is frequently associated with delayed and heterogeneous clinical responses and it is important to identify prognostic immunological correlates of clinical endpoints. Experimental design: 77 patients with stage III/IV melanoma were treated with ipilimumab alone every 3 weeks, during 9 weeks. Blood samples were collected at the baseline and before each dose for in depth immune monitoring. Results: The median follow-up was 28 mo with a median survival of 7 mo. Survival and clinical benefit were significantly improved when absolute lymphocyte count at the baseline was above 1 × 109/L. Notably, ipilimumab had a global effect on memory T cells, with an early increase of central and effector subsets in patients with disease control. By contrast, percentages of stem cell memory T cells (TSCM) gradually decreased despite stable absolute counts and sustained proliferation, suggesting a process of differentiation. Higher proportions of eomes+ and Ki-67+ T cells were observed, with enhanced skin homing potential and induction of cytotoxic markers. Conclusion: These results suggest that CTLA-4 blockade is able to reshape the memory subset with the potential involvement of Eomes and memory subsets including TSCM. PMID:27622012

  10. Clinical implication of tumor-associated and immunological parameters in melanoma patients treated with ipilimumab.

    PubMed

    Damuzzo, V; Solito, S; Pinton, L; Carrozzo, E; Valpione, S; Pigozzo, J; Arboretti Giancristofaro, R; Chiarion-Sileni, V; Mandruzzato, S

    2016-01-01

    Ipilimumab, the first immune-checkpoint inhibitor extending overall survival (OS) in metastatic melanoma patients, has a survival benefit only in a proportion of patients and the development of reliable predictive biomarkers is still an unmet need. To meet this request, we used a multivariate statistical approach to test whether myeloid-derived suppressor cells (MDSC) or other tumor-associated and immunological parameters may serve as predictive or prognostic biomarkers in melanoma patients receiving ipilimumab. By using a standardized approach to determine the circulating levels of four MDSC subsets, we observed a significant expansion of three MDSC subsets at baseline, as compared to controls and, upon treatment, that high levels of CD14(+)/IL4Rα(+) MDSCs were an independent prognostic factor of reduced OS. On the contrary, longer OS was associated to low levels of the proinflammatory proteins IL-6 and CRP and tumor-associated factors S100B and LDH both at baseline and after treatment. Increasing number of total T cells and especially of PD-1(+)/CD4(+) T cells were associated with better prognosis, and upregulation of PD-1(+) expression on CD4(+) T cells upon treatment was associated with lower toxicity. As several parameters were associated to OS, we included these factors in a multivariate survival model, and we identified IL-6 and ECOG PS as independent biomarkers associated with improved OS, whereas high levels of LDH and CD14(+)/IL4Rα(+) MDSCs were negative independent markers of reduced OS.

  11. Analysis of the B-RafV600E mutation in cutaneous melanoma patients with occupational sun exposure.

    PubMed

    Candido, Saverio; Rapisarda, Venerando; Marconi, Andrea; Malaponte, Grazia; Bevelacqua, Valentina; Gangemi, Pietro; Scalisi, Aurora; McCubrey, James A; Maestro, Roberta; Spandidos, Demetrios A; Fenga, Concettina; Libra, Massimo

    2014-03-01

    Sun-exposure is one of the risk factors associated with the development of a cutaneous neoplasm. In melanoma, the Ras-Raf-MEK-ERK (MAPK) signaling pathway is constitutively activated through multiple mechanisms, including B-Raf mutation. It has been hypothesized that B-Raf mutations in melanocytic lesions arise from DNA damage induced by ultraviolet (UV) radiation. However, it is still discussed if B-Raf mutations are associated with melanoma patients exposed to the sun. Therefore, in the present study, the known B-RafV600E mutation was analysed in melanoma samples from 30 indoor and 38 outdoor workers. B-RafV600E mutation was detected in 52 and 73% of outdoor workers and indoor workers, respectively. Of note, this mutation was identified in 12 of 14 (85%) melanoma of the trunk diagnosed in indoor workers and in 9 of 19 (47%) samples from outdoor workers (p=0.03). By analyzing melanomas of other body sites, no statistical difference in the frequency of B-RafV600E mutation was identified between the groups of workers. It appears that the mutation detected among indoor workers may be associated with a recreational or intermittent exposure to the sun, as usually the trunk is a sun-protected body site. Overall, these data indicate that the B-RafV600E mutation detected in melanoma is not associated with a chronic exposure to the sun. Mutations detected in other genes may also contribute to melanoma development in the subset of patients exposed to UV radiation.

  12. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study.

    PubMed

    Nakamura, Yasuhiro; Tanaka, Ryota; Asami, Yuri; Teramoto, Yukiko; Imamura, Taichi; Sato, Sayuri; Maruyama, Hiroshi; Fujisawa, Yasuhiro; Matsuya, Taisuke; Fujimoto, Manabu; Yamamoto, Akifumi

    2016-08-11

    Vitiligo is occasionally seen in melanoma patients. Although several studies indicate a correlation between vitiligo occurrence and clinical response in melanoma patients receiving immunotherapy, most studies have included heterogeneous patient and treatment settings. The aim of this study is to investigate the correlation between the occurrence of vitiligo and clinical benefit of nivolumab treatment in advanced melanoma patients. We retrospectively reviewed unresectable stage III or IV melanoma patients treated with nivolumab. Of 35 melanoma patients treated with nivolumab, 25.7% (9/35) developed vitiligo during treatment. The time from the start of nivolumab treatment to occurrence of vitiligo ranged 2-9 months (mean, 5.2). Of nine patients who developed vitiligo, two (22.2%) had a complete response to nivolumab and two (22.2%) had a partial response. The objective response rate was significantly higher in patients with vitiligo than in patients without vitiligo (4/9 [44.4%] vs 2/26 [7.7%]; P = 0.027). The mean time to vitiligo occurrence in patients achieving an objective response was significantly less than that in patients who showed no response (3.1 vs 6.8 months, P = 0.004). Vitiligo occurrence was significantly associated with prolonged progression-free and overall survival (hazard ratio, 0.24 and 0.16; 95% confidence interval, 0.11-0.55 and 0.03-0.79; P = 0.005, and 0.047, respectively). At the 20-week landmark analysis, however, vitiligo was not associated with a statistically significant overall survival benefit (P = 0.28). The occurrence of vitiligo during nivolumab treatment may be correlated with favorable clinical outcome.

  13. The importance of the patient voice in vaccination and vaccine safety-are we listening?

    PubMed

    Holt, D; Bouder, F; Elemuwa, C; Gaedicke, G; Khamesipour, A; Kisler, B; Kochhar, S; Kutalek, R; Maurer, W; Obermeier, P; Seeber, L; Trusko, B; Gould, S; Rath, B

    2016-12-01

    Much has been written about the patient-physician relationship over the years. This relationship is essential in maintaining trust in the complex arena of modern diagnostic techniques, treatment and prevention, including vaccines and vaccine safety. However, a great deal of this material was written from the viewpoint of clinicians and academics. The patient voice may be positive or negative, fragmented or complex. Information sources are weighed and treated differently, according to the value system and risk perceptions of the individual. In post-trust societies, when people have less confidence in health authorities, communication needs to be more than a paternalistic top-down process. Notions of empowerment and individual patient choice are becoming crucial in medical care. The 'voice of the patient', which includes healthy individuals receiving vaccines, needs to be heard, considered and addressed. With respect to childhood immunizations, this will be the voice of the parent or caregiver. The key to addressing any concerns could be to listen more and to develop a communication style that is trust-based and science-informed. Regulatory agencies are encouraging clinical and patient-reported outcomes research under the umbrella of personalized medicine, and this is an important step forward. This paper attempts to reflect the paradigm shift towards increasing attention to the patient voice in vaccination and vaccine safety.

  14. Long-term effects of laser-imiquimod combination in the treatment of late-stage melanoma patients

    NASA Astrophysics Data System (ADS)

    Naylor, Mark F.; Le, Henry; Li, Xiaosong; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

    2012-03-01

    Topical application of a potent immunological modulator, imiquimod, followed by laser irradiation has been used for the treatment of late-stage melanoma patients. This novel approach, laser-assisted laser immunotherapy (LIT), targets the root course of melanoma, a highly metastatic cancer. We started a phase I clinical trial in 2006 with promising initial outcomes. The laser-imiquimod combination showed significant palliative effects for these patients with multiple treatment cycles. For the returning patients, we found that the recurrent tumors were less aggressive than usually seen in untreated patients. The current protocol uses a light-absorbing dye for selective laser photothermal interaction with a non-invasive treatment mode. It has limitations for patient treatment, particularly for large, deeper tumors, and for patients with dark pigmented skins. This study provides some information on the treated patients (both stage IV and stage IV) during the past several years. We also discuss the future directions of LIT, particularly in the area of photothermal treatment mode with a new approach of interstitial irradiation. The current results in melanoma treatment using LIT indicate that the combination of photothermal therapy and immunological stimulation may hold the key for the treatment of late-stage, metastatic cancers, not only for cutaneous cancers such as melanoma and breast cancer, but also for deep and internal tumors using different operations modes such as interstitial laser irradiation.

  15. Soluble interleukin-2 receptor, intercellular adhesion molecule-1 and interleukin-10 serum levels in patients with melanoma.

    PubMed

    Boyano, M D; Garcia-Vázquez, M D; López-Michelena, T; Gardeazabal, J; Bilbao, J; Cañavate, M L; Galdeano, A G; Izu, R; Díaz-Ramón, L; Raton, J A; Díaz-Pérez, J L

    2000-10-01

    Serum soluble interleukin-2 receptor (sIL-2R), intercellular adhesion molecule-1 (sICAM-1) and interleukin-10 (IL-10) have each been reported as useful markers for melanoma progression. To evaluate the clinical relevance of these three markers, we simultaneously analysed their serum levels in patients with melanoma. A longitudinal study with a 3-year follow-up was performed and different stages of the disease were considered. Mean values of sIL-2R were significantly higher than in normal controls in all stages and correlated with the disease progression. The prognosis of patients with levels > 529 U/ml of sIL-2R was significantly poorer than in patients with sIL-2R levels < 529 U/ml. Levels of sICAM-1 were also elevated in melanoma patients, specially at the time of the metastatic disease. Serum IL-10 levels were more frequently detectable in the patients that developed metastasis during follow-up, and the prognosis of patients with detectable IL-10 levels was significantly poorer than in those patients with IL-10 undetected levels. Statistical analysis based on Logistic and Cox regression models showed that only sex, stage and sIL-2R value are factors significantly associated with metastatic progression. Moreover, high levels of sIL-2R could be a risk factor for malignant progression in melanoma.

  16. Preoperative FDG-PET/CT Is an Important Tool in the Management of Patients with Thick (T4) Melanoma

    PubMed Central

    Arrangoiz, Rodrigo; Papavasiliou, Pavlos; Stransky, Carrie A.; Yu, Jian Q.; Tianyu, Li; Sigurdson, Elin R.; Berger, Adam C.; Farma, Jeffrey M.

    2012-01-01

    The yield of preoperative PET/CT (PET/CT) for regional and distant metastases for thin/intermediate thickness melanoma is low. Objective of this study is to determine if PET/CT performed for T4 melanomas helps guide management and alter treatment plans. Methods. Retrospective cohort of 216 patients with T4 melanomas treated at two tertiary institutions. Fifty-six patients met our inclusion criteria (T4 lesion, PET/CT and no clinical evidence of metastatic disease). Results. Fifty-six patients (M: 32, F: 24) with median tumor thickness of 6 mm were identified. PET/CT recognized twelve with regional and four patients with metastatic disease. Melanoma-related treatment plan was altered in 11% of the cases based on PET/CT findings. PET/CT was negative 60% of the time, in 35% of the cases; it identified incidental findings that required further evaluation. Conclusion. Patients with T4 lesions, PET/CT changed the treatment plan 18% of the time. Regional findings changed the surgical treatment plan in 11% and the adjuvant plan in 7% of our cases due to the finding of metastatic disease. Additionally 20 patients had incidental findings that required further workup. In this subset of patients, we feel there is a benefit to PET/CT, and further studies should be performed to validate our findings. PMID:22654898

  17. Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients.

    PubMed

    Nonomura, Yumi; Otsuka, Atsushi; Nakashima, Chisa; Seidel, Judith A; Kitoh, Akihiko; Dainichi, Teruki; Nakajima, Saeko; Sawada, Yu; Matsushita, Shigeto; Aoki, Megumi; Takenouchi, Tatsuya; Fujimura, Taku; Hatta, Naohito; Koreeda, Satoshi; Fukushima, Satoshi; Honda, Tetsuya; Kabashima, Kenji

    2016-01-01

    Although nivolumab is associated with a significant improvement in overall survival and progression-free survival, only 20 to 40% of patients experience long-term benefit. It is therefore of great interest to identify a predictive marker of clinical benefit for nivolumab. To address this issue, the frequencies of CD4(+) T cell subsets (Treg, Th1, Th2, Th9, Th17 and Th22), CD8(+) T cells, and serum cytokine levels (IFNγ, IL-4, IL-9, IL-10, TGF-β) were assessed in 46 patients with melanoma. Eighteen patients responded to nivolumab, and the other 28 patients did not. An early increase in Th9 cell counts during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, the responders displayed elevated serum concentrations of TGF-β compared to non-responders. Th9 induction by IL-4 and TGF-β was enhanced by PD-1/PD-L1 blockade in vitro. The role of IL-9 in disease progression was further assessed using a murine melanoma model. In vivo IL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and the cytotoxic ability of murine melanoma-specific CD8(+) T cells was enhanced in the presence of IL-9 in vitro. These findings suggest that Th9 cells, which produce IL-9, play an important role in the successful treatment of melanoma patients with nivolumab. Th9 cells therefore represent a valid biomarker to be further developed in the setting of anti-PD-1 therapy.

  18. Seroprevalence and vaccination coverage of vaccine-preventable diseases in perinatally HIV-1-infected patients

    PubMed Central

    Sticchi, Laura; Bruzzone, Bianca; Caligiuri, Patrizia; Rappazzo, Emanuela; Lo Casto, Michele; De Hoffer, Laura; Gustinetti, Giulia; Viscoli, Claudio; Di Biagio, Antonio

    2014-01-01

    Background Even in the era of highly active antiretroviral therapy (HAART), HIV-infected subjects are at higher risk of complications from vaccine-preventable diseases than those uninfected. The current international guidelines strongly recommend that these patients should receive all the routine childhood vaccinations. Although these children represent an appropriate target for immunization, the available data indicate suboptimal coverage rates. Methods To evaluate seroprotection/seropositivity rates and vaccination coverage against the common vaccine-preventable diseases, all patients with vertically transmitted HIV-1 infection who attended San Martino Hospital were enrolled. Blood samples were collected for testing antibodies against diphtheria, tetanus, hepatitis A and B viruses by Enzyme-Linked ImmunoSorbent Assay and polioviruses by microneutralization test. In order to assess immunization coverage, retrospectively was recorded the vaccination history collecting data from Regional Immunization Database. Results A total of 39 perinatally HIV-1 infected patients were included in the study. At the time of serum was obtained, the mean age was 18,1 years (range: 6–28). The median CD4+ T-lymphocyte count was 702 cells/mm3 (2–1476 cells/mm3). Twenty-nine (74.4%) patients were found with HIV RNA load < 50 copies/mL. The proportion of subjects with protective anti-tetanus and anti-HBs were 43.6% and 30.8%, respectively. Seroprotection rates about 20% against rubella and measles were found, less than 20% against all the other antigens investigated. In particular, all patients resulted susceptible to mumps. High immunization rates were observed for polio and HBV (100% and 92.3%, respectively) and suboptimal for diphtheria-tetanus (84.6%). For the other recommended vaccines the rates were generally low. None of the patients received varicella vaccine doses. Conclusions As in the HAART era the vertically acquired HIV infection has become a chronic treatable disease

  19. ADAM15 expression is downregulated in melanoma metastasis compared to primary melanoma

    SciTech Connect

    Ungerer, Christopher; Doberstein, Kai; Boehm, Beate; Pfeilschifter, Josef; Mihic-Probst, Daniela; Gutwein, Paul

    2010-10-22

    Research highlights: {yields} Strong ADAM15 expression is found in normal melanocytes. {yields} ADAM15 expression is significantly downregulated in patients with melanoma metastasis. {yields} TGF-{beta} can downregulate ADAM15 expression in melanoma cells. {yields} Overexpression of ADAM15 in melanoma cells inhibits migration, proliferation and invasion of melanoma cells. {yields} Conclusion: ADAM15 represents an tumor suppressor protein in melanoma. -- Abstract: In a mouse melanoma metastasis model it has been recently shown that ADAM15 overexpression in melanoma cells significantly reduced the number of metastatic nodules on the lung. Unfortunately, the expression of ADAM15 in human melanoma tissue has not been determined so far. In our study, we characterized the expression of ADAM15 in tissue micro-arrays of patients with primary melanoma with melanoma metastasis. ADAM15 was expressed in melanocytes and endothelial cells of benign nevi and melanoma tissue. Importantly, ADAM15 was significantly downregulated in melanoma metastasis compared to primary melanoma. We further demonstrate that IFN-{gamma} and TGF-{beta} downregulate ADAM15 protein levels in melanoma cells. To investigate the role of ADAM15 in melanoma progression, we overexpressed ADAM15 in melanoma cells. Importantly, overexpression of ADAM15 in melanoma cells reduced the migration, invasion and the anchorage dependent and independent cell growth of melanoma cells. In summary, the downregulation of ADAM15 plays an important role in melanoma progression and ADAM15 act as a tumorsuppressor in melanoma.

  20. Therapeutic effectiveness of recombinant cancer vaccines is associated with a prevalent T-cell receptor alpha usage by melanoma-specific CD8+ T lymphocytes.

    PubMed

    De Palma, Raffaele; Marigo, Ilaria; Del Galdo, Francesco; De Santo, Carmela; Serafini, Paolo; Cingarlini, Sara; Tüting, Thomas; Lenz, Julia; Basso, Giuseppe; Milan, Gabriella; Zanovello, Paola; Bronte, Vincenzo

    2004-11-01

    Definition of immune variables that correlate with the antitumor activity of cancer vaccines is critical for monitoring immunotherapy protocols. To define surrogate end points predictive of the therapeutic efficacy of recombinant vaccines based on melanoma antigen tyrosinase-related protein (TRP)-2, we evaluated several properties of antigen-specific CD8(+) T lymphocytes in single mice undergoing either prophylactic or therapeutic immunization. Predictive markers for the efficacy of genetic vaccination were identified in the prophylactic model used. Interestingly, the number of tetramer(+) CD8(+) T lymphocytes expanded in vitro after a single cycle of stimulation with the immunodominant TRP-2 peptide was of the highest predictive value. In the therapeutic model, no variable examined at a single mouse level predicted the long-term therapeutic effect. Mice that survived did not show the highest expansion of antigen-specific lymphocytes or the more functionally active effectors, ex vivo or after in vitro culture with the peptide antigen. Successful therapy correlated strictly with the skewing of the T-cell receptor repertoire of tetramer-sorted, TRP-2-specific CD8(+) T lymphocytes, which showed a preferential alpha chain usage with a common CDR3 region.

  1. Efficacy of Tumor-Targeting Salmonella A1-R on a Melanoma Patient-Derived Orthotopic Xenograft (PDOX) Nude-Mouse Model

    PubMed Central

    Yamamoto, Mako; Zhao, Ming; Hiroshima, Yukihiko; Zhang, Yong; Shurell, Elizabeth; Eilber, Fritz C.; Bouvet, Michael; Noda, Makoto; Hoffman, Robert M.

    2016-01-01

    Tumor-targeting Salmonella enterica serovar Typhimurium A1-R (Salmonella A1-R) had strong efficacy on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. GFP-expressing Salmonella A1-R highly and selectively colonized the PDOX melanoma and significantly suppressed tumor growth (p = 0.021). The combination of Salmonella A1-R and cisplatinum (CDDP), both at low-dose, also significantly suppressed the growth of the melanoma PDOX (P = 0.001). Salmonella A1-R has future clinical potential for combination chemotherapy with CDDP of melanoma, a highly-recalcitrant cancer. PMID:27500926

  2. Phase I Trial of Interleukin-12 Plasmid Electroporation in Patients With Metastatic Melanoma

    PubMed Central

    Daud, Adil I.; DeConti, Ronald C.; Andrews, Stephanie; Urbas, Patricia; Riker, Adam I.; Sondak, Vernon K.; Munster, Pamela N.; Sullivan, Daniel M.; Ugen, Kenneth E.; Messina, Jane L.; Heller, Richard

    2008-01-01

    Purpose Gene-based immunotherapy for cancer is limited by the lack of safe, efficient, reproducible, and titratable delivery methods. Direct injection of DNA into tissue, although safer than viral vectors, suffers from low gene transfer efficiency. In vivo electroporation, in preclinical models, significantly enhances gene transfer efficiency while retaining the safety advantages of plasmid DNA. Patients and Methods A phase I dose escalation trial of plasmid interleukin (IL)-12 electroporation was carried out in patients with metastatic melanoma. Patients received electroporation on days 1, 5, and 8 during a single 39-day cycle, into metastatic melanoma lesions with six 100-μs pulses at a 1,300-V/cm electric field through a penetrating six-electrode array immediately after DNA injection. Pre- and post-treatment biopsies were obtained at defined time points for detailed histologic evaluation and determination of IL-12 protein levels. Results Twenty-four patients were treated at seven dose levels, with minimal systemic toxicity. Transient pain after electroporation was the major adverse effect. Post-treatment biopsies showed plasmid dose proportional increases in IL-12 protein levels as well as marked tumor necrosis and lymphocytic infiltrate. Two (10%) of 19 patients with nonelectroporated distant lesions and no other systemic therapy showed complete regression of all metastases, whereas eight additional patients (42%) showed disease stabilization or partial response. Conclusion This report describes the first human trial, to our knowledge, of gene transfer utilizing in vivo DNA electroporation. The results indicated this modality to be safe, effective, reproducible, and titratable. PMID:19029422

  3. Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma

    ClinicalTrials.gov

    2017-04-03

    BRAF V600E Mutation Present; BRAF V600K Mutation Present; Metastatic Melanoma; Recurrent Melanoma; Stage III Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma

  4. [Targeted therapies for melanoma].

    PubMed

    Leiter, U; Meier, F; Garbe, C

    2014-07-01

    Since the discovery of activating mutations in the BRAF oncogene and also stimulation of immune mediated antitumor response in melanoma, there has been remarkable progress in the development of targeted therapies for unresectable and metastatic melanoma. This article addresses the latest developments of BRAF/MEK/ERK pathway signaling. In addition, the development of drugs to attack alternative mutations in melanoma, such as NRAS and KIT is described. Strategies for the management of BRAF inhibitor resistance, such as with combination therapy, are outlined. Antitumor immune therapies with monoclonal antibodies such as ipilimumab which acts by promoting T-cell activation or antibody blockade of programmed death-1 (PD-1) led to a long term response in metastatic melanoma. Results of latest clinical studies including the toxicity profile are described. Due to selective kinase inhibitors and immune checkpoint blockade, the therapy of unresectable metastatic melanoma has greatly improved and long-term survival of patients with metastatic melanoma seems a real possibility.

  5. Absence of germline CDKN2A mutation in Sicilian patients with familial malignant melanoma: Could it be a population-specific genetic signature?

    PubMed Central

    Di Lorenzo, Sara; Fanale, Daniele; Corradino, Bartolo; Caló, Valentina; Rinaldi, Gaetana; Bazan, Viviana; Giordano, Antonio; Cordova, Adriana; Russo, Antonio

    2016-01-01

    ABSTRACT Germline CDKN2A mutations have been described in 25% to 40% of melanoma families from several countries. Sicilian population is genetically different from the people of Europe and Northern Italy because of its historical background, therefore familial melanoma could be due to genes different from high-penetrance CDKN2A gene. Four hundred patients with cutaneous melanoma were observed in a 6-years period at the Plastic Surgery Unit of the University of Palermo. Forty-eight patients have met the criteria of the Italian Society of Human Genetics (SIGU) for the diagnosis of familial melanoma and were screened for CDKN2A and CDK4 mutations. Mutation testing revealed that none of the families carried mutations in CDK4 and only one patient harboured the rare CDKN2A p.R87W mutation. Unlike other studies, we have not found high mutation rate of CDKN2A in patients affected by familial melanoma or multiple melanoma. This difference could be attributed to different factors, including the genetic heterogeneity of the Sicilian population. It is likely that, as in the Australian people, the inheritance of familial melanoma in this island of the Mediterranean Sea is due to intermediate/low-penetrance susceptibility genes, which, together with environmental factors (as latitude and sun exposure), could determine the occurrence of melanoma. PMID:26650572

  6. Absence of germline CDKN2A mutation in Sicilian patients with familial malignant melanoma: Could it be a population-specific genetic signature?

    PubMed

    Di Lorenzo, Sara; Fanale, Daniele; Corradino, Bartolo; Caló, Valentina; Rinaldi, Gaetana; Bazan, Viviana; Giordano, Antonio; Cordova, Adriana; Russo, Antonio

    2016-01-01

    Germline CDKN2A mutations have been described in 25% to 40% of melanoma families from several countries. Sicilian population is genetically different from the people of Europe and Northern Italy because of its historical background, therefore familial melanoma could be due to genes different from high-penetrance CDKN2A gene. Four hundred patients with cutaneous melanoma were observed in a 6-years period at the Plastic Surgery Unit of the University of Palermo. Forty-eight patients have met the criteria of the Italian Society of Human Genetics (SIGU) for the diagnosis of familial melanoma and were screened for CDKN2A and CDK4 mutations. Mutation testing revealed that none of the families carried mutations in CDK4 and only one patient harboured the rare CDKN2A p.R87W mutation. Unlike other studies, we have not found high mutation rate of CDKN2A in patients affected by familial melanoma or multiple melanoma. This difference could be attributed to different factors, including the genetic heterogeneity of the Sicilian population. It is likely that, as in the Australian people, the inheritance of familial melanoma in this island of the Mediterranean Sea is due to intermediate/low-penetrance susceptibility genes, which, together with environmental factors (as latitude and sun exposure), could determine the occurrence of melanoma.

  7. Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma.

    PubMed

    Shirai, Takushi; Sano, Tasuku; Kamijo, Fuminao; Saito, Nana; Miyake, Tomomi; Kodaira, Minori; Katoh, Nagaaki; Nishie, Kenichi; Okuyama, Ryuhei; Uhara, Hisashi

    2016-01-01

    We reported an 81-year-old woman with metastatic melanoma, in whom myasthenia gravis and rhabdomyolysis developed after nivolumab monotherapy. The first symptom of myasthenia gravis was dyspnea. Ultrasonography detected hypokinesis of the bilateral diaphragm suggesting myasthenia gravis, although there was no abnormal finding of the lungs in computed tomography images. Acetylcholine receptor binding antibodies were low-titer positive in the preserved serum before administration of nivolumab, strongly suggesting that the myasthenia gravis was a nivolumab-related immune adverse event. Despite the remarkable clinical benefits of immune checkpoint inhibitors for patients with advanced melanoma, it is important to recognize unexpected immune-related adverse events.

  8. [Immunotherapy of melanoma].

    PubMed

    Dréno, Brigitte

    2010-10-01

    This article describes current concepts and future challenges in non specific immunotherapy, vaccination, and antigen-specific adoptive immunotherapy of melanoma. If these treatments are to realize their full potential, it will be essential to understand how the tumor induces immune tolerance.

  9. Contemporary Diagnostic Imaging Modalities for the Staging and Surveillance of Melanoma Patients: a Meta-analysis

    PubMed Central

    Xing, Yan; Bronstein, Yulia; Ross, Merrick I.; Askew, Robert L.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Royal, Richard

    2011-01-01

    Background Meta-analyses were performed to examine the utility of ultrasonography, computed tomography (CT), positron emission tomography (PET), and a combination of both (PET-CT) for the staging and surveillance of melanoma patients. Method Patient-level data from 74 studies containing 10 528 patients (between January 1, 1990, and June, 30, 2009) were used to derive characteristics of the diagnostic tests used. Meta-analyses were conducted by use of Bayesian bivariate binomial models to estimate sensitivity and specificity. Diagnostic odds ratios [ie, true-positive results/false-negative results)/(false-positive results/true-negative results)] and their 95% credible intervals (CrIs) and positive predictive values were used as indicators of test performance. Results Among the four imaging methods examined for the staging of regional lymph nodes, ultrasonography had the highest sensitivity (60%, 95% CrI = 33% to 83%), specificity (97%, 95% CrI = 88% to 99%), and diagnostic odds ratio (42, 95% CrI = 8.08 to 249.8). For staging of distant metastases, PET-CT had the highest sensitivity (80%, 95% CrI = 53% to 93%), specificity (87%, 95% CrI = 54% to 97%), and diagnostic odds ratio (25, 95% CrI = 3.58 to 198.7). Similar trends were observed for melanoma surveillance of lymph node involvement, with ultrasonography having the highest sensitivity (96%, 95% CrI = 85% to 99%), specificity (99%, 95% CrI = 95% to 100%), and diagnostic odds ratio (1675, 95% CrI = 226.6 to 15,920). For distant metastases, PET-CT had the highest sensitivity (86%, 95% CrI = 76% to 93%), specificity (91%, 95% CrI = 79% to 97%), and diagnostic odds ratio (67, 95% CrI = 20.42 to 229.7). Positive predictive values were likewise highest for ultrasonography in lymph node staging and for PET-CT in detecting distant metastases. Conclusion Among the compared modalities, ultrasonography was superior for detecting lymph node metastases, and PET-CT was superior for the detection of distant metastases in both

  10. The in vitro effect of a calf thymus extract on the peripheral blood lymphocytes of sixty-six melanoma patients.

    PubMed Central

    Bernengo, M G; Capella, G; de Matteis, A; Tovo, P A; Zina, G

    1979-01-01

    The in vitro effect of a calf thymus extract (TP-1) on peripheral blood lymphocytes was evaluated in sixty-six melanoma patients. Twenty out of forty-five stage I and seventeen out of twenty-one stage IIb patients presented depressed T lymphocyte values. A statistically significant increase in E-rosette-forming cells (E-RFC) was observed in seventeen (85%) stage I and twelve (70.5%) stage II patients. In thirteen (65%) stage I and eight (47%) stage II patients E-RFC reached normal values. Our results indicate that the fall of T lymphocytes in the peripheral blood of melanoma patients is often related to an increase in TP-1 sensitive cells which suggests the possibility of a thymic hormone deficiency in these patients. PMID:314368

  11. Redirected lysis of human melanoma cells by a MCSP/CD3-bispecific BiTE antibody that engages patient-derived T cells.

    PubMed

    Torisu-Itakura, Hitoe; Schoellhammer, Hans F; Sim, Myung-Shin; Irie, Reiko F; Hausmann, Susanne; Raum, Tobias; Baeuerle, Patrick A; Morton, Donald L

    2011-10-01

    Melanoma-associated chondroitin sulfate proteoglycan (MCSP; also called HMW-MAA, CSPG4, NG2, MSK16, MCSPG, MEL-CSPG, or gp240) is a well characterized melanoma cell-surface antigen. In this study, a new bispecific T-cell engaging (BiTE) antibody that binds to MCSP and human CD3 (MCSP-BiTE) was tested for its cytotoxic activity against human melanoma cell lines. When unstimulated peripheral mononuclear blood cells (PBMCs) derived from healthy donors were cocultured with melanoma cells at effector:target ratios of 1:1, 1:5, or 1:10, and treated with MCSP-BiTE antibody at doses of 10, 100, or 1000 ng/mL, all MCSP-expressing melanoma cell lines (n=23) were lysed in a dose-dependent and effector:target ratio-dependent manner, whereas there was no cytotoxic activity against MCSP-negative melanoma cell lines (n=2). To investigate whether T cells from melanoma patients could act as effector cells, we cocultured unstimulated PBMCs with allogeneic melanoma cells from 13 patients (4 stage I/II, 3 stage III, and 6 stage IV) or with autologous melanoma cells from 2 patients (stage IV). Although cytotoxic activity varied, all 15 PBMC samples mediated significant redirected lysis by the BiTE antibody. When PBMC or CD8 T cells were prestimulated by anti-CD3 antibody OKT-3 and interleukin-2, the MCSP-BiTE concentrations needed for melanoma cell lysis decreased up to 1000-fold. As MCSP is expressed on most human melanomas, immunotherapy with MCSP/CD3-bispecific antibodies merits clinical investigation.

  12. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

    PubMed

    Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O'Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K

    2014-08-01

    Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

  13. Red meat and fruit intake is prognostic among patients with localized cutaneous melanomas more than 1 mm thick

    PubMed Central

    Gould Rothberg, Bonnie E.; Bulloch, Kaleigh J.; Fine, Judith A.; Barnhill, Raymond L.; Berwick, Marianne

    2014-01-01

    Background As the 10-year mortality for localized cutaneous melanoma more than 1.00 mm thick approaches 40% following complete resection, non-therapeutic interventions that can supplement recommended active surveillance are needed. Although guidelines recommending nutrition, physical activity and tobacco cessation for cancer survivors have been published, data describing their associations with melanoma survivorship are lacking. Methods Analysis of modifiable lifestyle behaviors collected on the 249 cases with melanomas more than 1.00 mm thick enrolled in the Connecticut Case-Control Study of Skin Self-Examination study was conducted. Independent associations with melanoma-specific survival were evaluated through Cox proportional hazards modeling adjusting for age, gender, Breslow thickness, ulceration and the presence of microsatellites. Independently significant variables were then combined into a single model and backwards elimination was employed until all remaining variables were significant at p<0.05. Results Following adjustment for age, Breslow thickness and anatomic site of the index melanoma, daily fruit consumption was associated with improved melanoma-specific survival (HR=0.54; 95% CI: 0.34–0.86) whereas at least weekly red meat consumption was associated with worse outcomes (HR=1.84; 95% CI: 1.02–3.30). Natural red (HR=0.44; 95% CI: 0.22–0.88) or blond (HR=0.52; 95% CI: 0.29–0.94) hair were also favorably prognostic. Higher fish consumption was of borderline significance for improved survival only when considered independently (HR=0.65; 95% CI: 0.40–1.05); no association was seen following adjustment for red meat and fruit consumption (p>0.10). Conclusions Dietary choices at the time of diagnosis are associated with melanoma-specific survival in patients with melanomas more than 1.00 mm thick. Further validation of our findings in larger cohorts with repeated post-diagnostic measures is warranted to further evaluate whether dietary

  14. Melanoma International Foundation

    MedlinePlus

    ... Jason J. Luke, MD January 07, 2016 Surgical Management of Melanoma: A 2015 Primer Presented by Jeffrey Gershenwald, MD May 09, 2015 Our Awards Melanoma International Foundation Our Mission: To develop personalized strategies with patients so they may live longer, better ...

  15. Immunogenicity of hepatitis A vaccination in decompensated cirrhotic patients.

    PubMed

    Arguedas, M R; Johnson, A; Eloubeidi, M A; Fallon, M B

    2001-07-01

    Hepatitis A virus (HAV) vaccination is recommended in chronic liver disease because of an increased morbidity and mortality associated with HAV superinfection. However, data regarding the efficacy of HAV vaccination in patients with advanced chronic liver disease is limited. We assessed the efficacy of a standard HAV vaccination schedule in decompensated chronic liver disease in comparison with compensated disease and defined clinical predictors associated with seroconversion. Eighty-four anti-HAV antibody-negative patients, 49 with compensated liver disease, and 35 with decompensated disease were enrolled. Seroconversion was measured by qualitative and quantitative anti-HAV antibody measurements 1 month after each vaccine dose, and univariate/multivariate analysis was performed to define clinical predictors associated with seroconversion. One month after the primary dose, 71.4% of patients with compensated liver disease had detectable anti-HAV antibody compared with 37.1% with decompensated liver disease (P <.05). One month after the booster dose, 98% of compensated patients seroconverted compared with 65.7% with decompensated disease (P <.05). The median serum antibody concentration in compensated liver disease was 76.4 mIU/mL at month 1 and 327.91 mIU/mL at month 7 compared with 20.0 mIU/mL and 102.57 mIU/mL, respectively, in decompensated disease. On multivariate analysis, Child-Pugh class was the only factor predicting response to vaccination. Seroconversion after HAV vaccination was significantly less common in decompensated liver disease and the presence of advanced disease (Child-Pugh class B/C) predicted a lower response rate. These findings indicate that the response to HAV vaccination in chronic liver disease is optimal when targeted to patients before the development of hepatic decompensation.

  16. Next-generation sequencing in NSCLC and melanoma patients: a cost and budget impact analysis

    PubMed Central

    van Amerongen, Rosa A; Retèl, Valesca P; Coupé, Veerle MH; Nederlof, Petra M; Vogel, Maartje J; van Harten, Wim H

    2016-01-01

    Next-generation sequencing (NGS) has reached the molecular diagnostic laboratories. Although the NGS technology aims to improve the effectiveness of therapies by selecting the most promising therapy, concerns are that NGS testing is expensive and that the ‘benefits’ are not yet in relation to these costs. In this study, we give an estimation of the costs and an institutional and national budget impact of various types of NGS tests in non-small-cell lung cancer (NSCLC) and melanoma patients within The Netherlands. First, an activity-based costing (ABC) analysis has been conducted on the costs of two examples of NGS panels (small- and medium-targeted gene panel (TGP)) based on data of The Netherlands Cancer Institute (NKI). Second, we performed a budget impact analysis (BIA) to estimate the current (2015) and future (2020) budget impact of NGS on molecular diagnostics for NSCLC and melanoma patients in The Netherlands. Literature, expert opinions, and a data set of patients within the NKI (n = 172) have been included in the BIA. Based on our analysis, we expect that the NGS test cost concerns will be limited. In the current situation, NGS can indeed result in higher diagnostic test costs, which is mainly related to required additional tests besides the small TGP. However, in the future, we expect that the use of whole-genome sequencing (WGS) will increase, for which it is expected that additional tests can be (partly) avoided. Although the current clinical benefits are expected to be limited, the research potentials of NGS are already an important advantage. PMID:27899957

  17. Sequential Combination Chemotherapy of Dacarbazine (DTIC) with Carboplatin and Paclitaxel for Patients with Metastatic Mucosal Melanoma of Nasal Cavity and Paranasal Sinuses

    PubMed Central

    Omata, W.; Tsutsumida, A.; Namikawa, K.; Takahashi, A.; Oashi, K.; Yamazaki, N.

    2017-01-01

    By the recent introduction of molecular targeting drugs against BRAF mutation and immune checkpoint inhibitors, the prognosis of patients with melanoma in advanced stage is now improving, but still in the minority. Mucosal melanoma lacks the BRAF mutations, and hence conventional chemotherapeutic regimens must be improved. We have conventionally used dacarbazine (DTIC) for patients with metastatic mucosal melanoma. However, the efficacy of DTIC in patients with metastatic mucosal melanoma has been limited. Therefore, we explored other possibilities to improve the prognosis of patients suffering from metastatic mucosal melanoma. In this communication, we present a retrospective analysis of the sequential combination chemotherapy of DTIC with carboplatin and paclitaxel (CP) for metastatic mucosal melanoma of nasal cavity and paranasal sinuses. The objective response rate of seven patients is 14.3% by RECIST 1.1 and the overall survival (OS) is 12.5 months. These data indicate that the sequential combination chemotherapy of DTIC with CP could be an option for patients with metastatic mucosal melanoma of nasal cavity and paranasal sinuses who are currently ending into dismal prognosis. PMID:28096700

  18. Monitoring changes in circulating tumour cells as a prognostic indicator of overall survival and treatment response in patients with metastatic melanoma

    PubMed Central

    2014-01-01

    Background New effective treatments for metastatic melanoma greatly improve survival in a proportion of patients. However biomarkers to identify patients that are more likely to benefit from a particular treatment are needed. We previously reported on a multimarker approach for the detection of heterogenous melanoma circulating tumour cells (CTCs). Here we evaluated the prognostic value of this multimarker quantification of CTCs and investigated whether changes in CTC levels during therapy can be used as a biomarker of treatment response and survival outcomes. Methods CTCs were captured by targeting the melanoma associated markers MCSP and MCAM as well as the melanoma stem cell markers ABCB5 and CD271. CTCs were quantified in 27 metastatic melanoma patients treated by surgery or with vemurafenib, ipilimumab or dacarbazine. Patients were enrolled prospectively and CTC counts performed at baseline (prior to treatment), during and after treatment. Results Baseline CTC numbers were not found to be prognostic of overall survival nor of progression free survival. However, a low baseline CTC number was associated with a rapid response to vemurafenib therapy. A decrease in CTCs after treatment initiation was associated with response to treatment and prolonged overall survival in vemurafenib treated patients. Conclusions Measuring changes in CTC numbers during treatment is useful for monitoring therapy response in melanoma patients and for providing prognostic information relating to overall survival. Further studies with larger sample sizes are required to confirm the utility of CTC quantification as a companion diagnostic for metastatic melanoma treatment. PMID:24915896

  19. Sequential Combination Chemotherapy of Dacarbazine (DTIC) with Carboplatin and Paclitaxel for Patients with Metastatic Mucosal Melanoma of Nasal Cavity and Paranasal Sinuses.

    PubMed

    Omata, W; Tsutsumida, A; Namikawa, K; Takahashi, A; Oashi, K; Yamazaki, N

    2017-01-01

    By the recent introduction of molecular targeting drugs against BRAF mutation and immune checkpoint inhibitors, the prognosis of patients with melanoma in advanced stage is now improving, but still in the minority. Mucosal melanoma lacks the BRAF mutations, and hence conventional chemotherapeutic regimens must be improved. We have conventionally used dacarbazine (DTIC) for patients with metastatic mucosal melanoma. However, the efficacy of DTIC in patients with metastatic mucosal melanoma has been limited. Therefore, we explored other possibilities to improve the prognosis of patients suffering from metastatic mucosal melanoma. In this communication, we present a retrospective analysis of the sequential combination chemotherapy of DTIC with carboplatin and paclitaxel (CP) for metastatic mucosal melanoma of nasal cavity and paranasal sinuses. The objective response rate of seven patients is 14.3% by RECIST 1.1 and the overall survival (OS) is 12.5 months. These data indicate that the sequential combination chemotherapy of DTIC with CP could be an option for patients with metastatic mucosal melanoma of nasal cavity and paranasal sinuses who are currently ending into dismal prognosis.

  20. Preferences of German melanoma patients for interferon (IFN) α-2b toxicities (the DeCOG "GERMELATOX survey") versus melanoma recurrence to quantify patients' relative values for adjuvant therapy.

    PubMed

    Kaehler, Katharina C; Blome, Christine; Forschner, Andrea; Gutzmer, Ralf; Haalck, Thomas; Heinzerling, Lucie; Kornek, Thomas; Livingstone, Elisabeth; Loquai, Carmen; Maul, Lara Valeska; Lang, Berenice M; Schadendorf, Dirk; Stade, Barbara; Terheyden, Patrick; Utikal, Jochen; Wagner, Tobias; Hauschild, Axel; Garbe, Claus; Augustin, Matthias

    2016-11-01

    Currently interferon alfa-2b (IFNα-2b) is an approved adjuvant drug for high-risk melanoma patients that leads to an improvement in disease-free survival (DFS). However, it is unclear whether it also impacts overall survival. Widespread use of adjuvant high-dose IFNα has been tempered by its significant toxicity and its limited efficacy. Current therapeutic strategies like immune checkpoint blockade or targeted therapy may also be useful in the adjuvant setting. Therefore, it is important to weigh the trade-offs between possible side effects and therapeutic benefit.We assessed patient utilities for health states associated with IFN therapy. Utilities are measures of preference for a specific health state on a scale of 0 (death) to 1 (perfect health).Utilities were determined for health states associated with adjuvant IFN among 130 German low-risk melanoma patients using the standard gamble technique. Four IFNα-2b toxicity scenarios and the following 3 posttreatment outcomes were assessed: disease-free health and melanoma recurrence (with or without previous use of IFNα-2b) resulting in cancer death. Patients were asked to trade-off the improvement in 5-year DFS and the IFN-related side effects.Utilities for melanoma recurrence (mean 0.60) were significantly lower than for all IFNα-2b toxicity scenarios (mean 0.81-0.90). Patients were willing to tolerate mild-to-moderate and severe toxicity for a 50% and 75% chance of 5-year DFS, respectively. Both utilities and threshold benefits were mostly independent from patient characteristics like gender, income, and social situation. Significant impact was only observed by age and previous personal experience with cancer.On average, German patients were willing to trade even severe IFNα-2b toxicity for reducing the rate of melanoma recurrence. This result points out the importance of a relapse-free survival for melanoma patients. The utilities measured in our study can be applied to decision-making processes in

  1. High-Dose Recombinant Interferon Alfa-2B, Ipilimumab, or Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

    ClinicalTrials.gov

    2017-04-12

    Metastatic Non-Cutaneous Melanoma; Non-Cutaneous Melanoma; Recurrent Melanoma of the Skin; Recurrent Non-Cutaneous Melanoma; Stage III Mucosal Melanoma of the Head and Neck; Stage III Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma; Stage IVA Mucosal Melanoma of the Head and Neck; Stage IVB Mucosal Melanoma of the Head and Neck; Stage IVC Mucosal Melanoma of the Head and Neck

  2. Sentinel lymph node dissection in stage I/II melanoma patients: surgical management and clinical follow-up study.

    PubMed

    Macripò, Giuseppe; Quaglino, Pietro; Caliendo, Virginia; Ronco, Anna Maria; Soltani, Shoreh; Giacone, Elena; Pau, Stefano; Fierro, Maria Teresa; Bernengo, Maria Grazia

    2004-04-01

    Selective sentinel lymph node (SLN) dissection is widely used in the management of cutaneous melanoma patients without clinical evidence of nodal metastases. A series of 274 consecutive melanoma patients who underwent melanoma primary excision and SLN mapping at our institutions since 1998, and were thereafter followed up and eventually treated, is reported in this prospective study. The aim was to analyse the parameters associated with a higher risk of occult nodal metastases, to evaluate the clinical outcome of melanoma patients who underwent SLN procedure, and to identify by means of multivariate analysis the prognostic parameters with independent predictive value on disease-free survival (DFS) in node-positive and negative patients. The SLN was tumour-negative in 228 patients (83.2%). A disease progression occurred in 25 (10.9%); among them, 10 patients in whom the initially identified SLN had been negative, developed a clinically and histologically evident positive lymph node in the same basin during follow-up. Five-year DFS and overall survival were 75% and 82%, respectively. In 46 patients (16.8%), the SLN proved to be tumour positive. The percentage of SLN-positive patients varied according to the primary thickness, from 11.8% in patients with Breslow of 2 mm or lower, to 34.7% in patients with Breslow from 2 to 4 mm, up to 55.9% in patients with Breslow greater than 4 mm (P<0.001). Only two patients with Breslow thickness lower than 1 mm had positive SLN biopsy. Five-year DFS and overall survival (OS) were 42 and 69%, respectively, significantly lower than those of negative SLN-patients (P<0.001). Multivariate analyses showed that the parameters with prognostic independent value on DFS were SLN status (micrometastases or macrometastases; P=0.0001), and to a lesser extent, Breslow thickness (P=0.04). In conclusion, our data support the clinical usefulness of SLN dissection as a reliable and accurate staging method in patients with cutaneous melanoma. SLN

  3. Patients are happy to be informed of their final non-melanoma skin cancer results by post.

    PubMed

    Thomson, Penelope; Palamaras, Ioulios; Hill, Virginia; Robles, Wanda; Stevens, Howard

    2010-01-15

    During the past year, because of increasing pressure to see more patients, we have started to write to our patients informing them in a letter of their final skin cancer histology results following surgery for non-melanoma skin cancers: basal cell carcinoma and squamous cell carcinoma only. A questionnaire-based study was carried out to assess whether patients were happy to receive information concerning their non-melanoma skin cancer diagnosis in a carefully worded letter. One-hundred fifty patients were involved with a diagnosis of "completely excised non-melanoma skin cancer (NMSC)" that had previously received their final diagnosis by post. Seventy-seven (51.3%) patients responded to the questionnaire. Eighty-seven percent felt that they had been given the cancer diagnosis in an appropriate manner; 90 percent reported that they had understood the explanation about their skin cancer. In addition, 81 percent stated that they had been sufficiently involved in the discussion about their skin cancer and its treatment. Patients gave an average rating of 7.76 (1 = poor and 10 = excellent) for the overall experience of care that they had received. By writing to the patient with their final histology results, we have reduced the number of follow-up appointments without reducing the quality of patient care.

  4. Is surviving enough? Coping and impact on activities of daily living among melanoma patients with lymphoedema.

    PubMed

    Cromwell, K D; Chiang, Y J; Armer, J; Heppner, P P; Mungovan, K; Ross, M I; Gershenwald, J E; Lee, J E; Royal, R E; Lucci, A; Cormier, J N

    2015-09-01

    We assessed the impact of lymphoedema (defined as ≥ 10% limb volume change) on quality of life (QOL), ability to perform activities of daily living (ADLs) and coping in 277 melanoma patients. Limb volume was measured prospectively, pre-operatively and every 3-6 months for 18 months post-operatively using a perometer. Three questionnaires were administered to measure QOL, coping and impact on ADLs. Statistical analyses were conducted using longitudinal logistic regression models. At 18 months, the cumulative incidence of lymphoedema was 31% in patients with upper extremity nodal basin treatment and 40% in lower extremity nodal basin treatment patients. Patients with lower extremity lymphoedema reported lower QOL scores than those with upper extremity lymphoedema. Over 18 months, both groups with mild and moderate lymphoedema showed improvement in coping [odds ratio (OR): 6.67, 95% confidence interval (CI): 3.30-13.47] and performance of ADLs (OR: 7.46, CI: 3.38-16.47). Over the course of 18 months, men were found to have poorer coping scores than women (OR: 2.91, CI: 1.35-6.27). Lymphoedema was associated with improvement in coping over time (P = 0.08) and a higher reported interference with ADLs (OR: 2.53, CI: 1.29-4.97). Patient education about lymphoedema at the time of surgical consent may improve self-efficacy and coping ability. Effective management of lymphoedema may improve patient QOL and reduce interference with ADLs.

  5. Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-Mhigh melanoma cell populations

    PubMed Central

    Hartman, Mariusz L.; Talar, Beata; Sztiller-Sikorska, Malgorzata; Nejc, Dariusz; Czyz, Malgorzata

    2016-01-01

    The activity of the M isoform of microphthalmia-associated transcription factor (MITF-M) has been attributed to regulation of differentiation, proliferation, survival and senescence of melanoma cells. MITF expression was shown to be antagonized by the activation of transcription factor NF-κB. Parthenolide, an inhibitor of NF-κB, has not been yet reported to affect MITF-M expression. Our results obtained in patient-derived melanoma cell populations indicate that parthenolide efficiently decreases the MITF-M level. This is neither dependent on p65/NF-κB signaling nor RAF/MEK/ERK pathway activity as inhibition of MEK by GSK1120212 (trametinib) and induction of ERK1/2 activity by parthenolide itself do not interfere with parthenolide-triggered depletion of MITF-M in both wild-type BRAF and BRAFV600E melanoma populations. Parthenolide activity is not prevented by inhibitors of caspases, proteasomal and lysosomal pathways. As parthenolide reduces MITF-M transcript level and HDAC1 protein level, parthenolide-activated depletion of MITF-M protein may be considered as a result of transcriptional regulation, however, the influence of parthenolide on other elements of a dynamic control over MITF-M cannot be ruled out. Parthenolide induces diverse effects in melanoma cells, from death to senescence. The mode of the response to parthenolide is bound to the molecular characteristics of melanoma cells, particularly to the basal MITF-M expression level but other cell-autonomous differences such as NF-κB activity and MCL-1 level might also contribute. Our data suggest that parthenolide can be developed as a drug used in combination therapy against melanoma when simultaneous inhibition of MITF-M, NF-κB and HDAC1 is needed. PMID:26824319

  6. Lymph Node Melanosis in a Patient With Metastatic Melanoma of Unknown Primary

    DTIC Science & Technology

    2009-08-01

    1332 Arch Pathol Lab Med—Vol 133, August 2009 Lymph Node Melanosis With Metastatic Melanoma—Malafronte & Sorrells Case Report Lymph Node Melanosis in...lignant melanoma, exhibiting a spectrum of clinico - pathologic features. Partially regressed melanomas most often present clinically as either...tumoral or nodular melanosis, is considered and treated as a variant of com- pletely regressed melanoma.4 Only a small number of cases of tumoral melanosis

  7. Solitary pulmonary metastases in high-risk melanoma patients: a prospective comparison of conventional and computed tomography

    SciTech Connect

    Heaston, D.K.; Putman, C.E.; Rodan, B.A.; Nicholson, E.; Ravin, C.E.; Korobkin, M.; Chen, J.T.; Seigler, H.F.

    1983-07-01

    A prospective comparison of chest radiography, conventional tomography, and computed tomography (CT) in the detection or confirmation of solitary pulmonary nodules was made in 42 patients with high propensity for pulmonary metastases due to advanced local (Clark level IV or V) or regional malignant melanoma. Unequivocal nodules were revealed by chest radiography in 11 patients, conventional tomograhy in 16, and computed tomography in 20 patients. Both plain films and tomography in three of these 20 were normal, but follow-up verified pulmonary metastases. Computed tomography detected more pulmonary nodules than conventional tomography in 11 patients in addition to identifying lesions in extrapulmonary sites. Therefore, chest CT is recommended before institution of immunotherapy or surgical removal of a solitary pulmonary melanoma metastasis. Once chemotherapy had been instituted for bulky regional or cutaneous involvement, however, the findings of either conventional or computed tomography were comparable in this study.

  8. NY-ESO-1-specific immunological pressure and escape in a patient with metastatic melanoma.

    PubMed

    von Boehmer, Lotta; Mattle, Muriel; Bode, Peter; Landshammer, Alexandro; Schäfer, Carolin; Nuber, Natko; Ritter, Gerd; Old, Lloyd; Moch, Holger; Schäfer, Niklaus; Jäger, Elke; Knuth, Alexander; van den Broek, Maries

    2013-01-01

    During cancer progression, malignant cells may evade immunosurveillance. However, evidence for immunological escape in humans is scarce. We report here the clinical course of a melanoma patient whose initial tumor was positive for the antigens NY-ESO-1, MAGE-C1, and Melan-A. Upon immunization with a recombinant vaccinia/fowlpox NY-ESO-1 construct, the patient experienced a mixed clinical response and spreading of the NY-ESO-1 epitopes in the CD4+ T cell compartment. After NY-ESO-1 protein + CpG immunization, the patient's anti-NY-ESO-1 IgG response increased. Over the following years, progressing lesions were resected and found to be NY-ESO-1-negative while being positive for MAGE-C1, Melan-A, and MHC-I. The fatal, inoperable brain metastasis was analyzed after his death and also proved to be NY-ESO-1-negative, while being positive for MAGE-C1 and Melan-A, as well as MHC-I. We propose that cancer control and cancer escape in this patient were governed by NY-ESO-1-specific immunological pressure. Our findings provide evidence for the existence of immunoediting and immunoescape in this cancer patient.

  9. Study of IL-2 receptor expression after chemoimmunotherapy in patients treated for metastatic malignant melanoma.

    PubMed Central

    Mouawad, R; Ichen, M; Rixe, O; Benhammouda, A; Vuillemin, E; Weil, M; Khayat, D; Soubrane, C

    1994-01-01

    Using flow cytometry, cellular IL-2 receptors were studied before and following chemoimmunotherapy combination in 20 patients with metastatic malignant melanoma (MMM). Patients received cisplatin (100 mg/m2) at days 1 and 28, recombinant IL-2 by continuous infusion from days 3 to 6, 17 to 21, 31 to 34, and 45 to 49. Interferon-alpha (IFN-alpha) was given subcutaneously three times weekly. In terms of clinical response, we observed 55% objective response (complete: 15%). When pretreatment blood samples were compared with those of healthy donors, we did not observe any change in low (alpha chain) and high affinity receptor (alpha + beta) expression. In contrast, intermediate affinity p75 (beta chain) expression was decreased significantly (P < or = 0.0001) in MMM patients. During treatment, we found a dramatic increase of beta chain as well as high affinity (alpha + beta) expression in responding patients, as soon as IL-2 therapy began. Furthermore, the increase of beta chain expression was limited to natural killer (NK) cells (CD56+). In non-responding patients, on the other hand, increase of both receptors was seen only at day 31. These data suggest the involvement of beta chain expression in the mechanism of cell activation after chemoimmunotherapy. Moreover, this early beta chain expression is correlated with the clinical response to chemoimmunotherapy. PMID:8082289

  10. Immunization with analog peptide in combination with CpG and montanide expands tumor antigen-specific CD8+ T cells in melanoma patients.

    PubMed

    Fourcade, Julien; Kudela, Pavol; Andrade Filho, Pedro A; Janjic, Bratislav; Land, Stephanie R; Sander, Cindy; Krieg, Arthur; Donnenberg, Albert; Shen, Hongmei; Kirkwood, John M; Zarour, Hassane M

    2008-10-01

    Analog peptides represent a promising tool to further optimize peptide-based vaccines in promoting the expansion of tumor antigen-specific cytotoxic T lymphocytes. Here, we report the results of a pilot trial designed to study the immunogenicity of the analog peptide NY-ESO-1 157-165V in combination with CpG 7909/PF3512676 and Montanide ISA 720 in patients with stage III/IV NY-ESO-1-expressing melanoma. Eight patients were immunized either with Montanide and CpG (arm 1, 3 patients); Montanide and peptide NY-ESO-1 157-165V (arm 2, 2 patients); or with Montanide, CpG, and peptide NY-ESO-1 157-165V (arm 3, 3 patients). Only the 3 patients immunized with Montanide, CpG, and peptide NY-ESO-1 157-165V in arm 3 developed a rapid increase of effector-memory NY-ESO-1-specific CD8+ T cells, detectable ex vivo. The majority of these cells exhibited an intermediate/late-stage differentiated phenotype (CD28-). Our study further demonstrated that our vaccine approach stimulated spontaneous tumor-reactive NY-ESO-1-specific CD8+ T cells in 2 patients with advanced disease, but failed to prime tumor-reactive NY-ESO-1-specific T cells in 1 patient with no spontaneously tumor-induced CD8+ T-cell responses to NY-ESO-1. Collectively, our data support the capability of the analog peptide NY-ESO-1 157-165V in combination with CpG and Montanide to promote the expansion of NY-ESO-1-specific CD8+ T cells in patients with advanced cancer. They also suggest that the presence of tumor-induced NY-ESO-1-specific T cells of well-defined clonotypes is critical for the expansion of tumor-reactive NY-ESO-1-specific CD8+ T cells after peptide-based vaccine strategies.

  11. Anti-melanoma vaccines engineered to simultaneously modulate cytokine priming and silence PD-L1 characterized using ex vivo myeloid-derived suppressor cells as a readout of therapeutic efficacy

    PubMed Central

    Liechtenstein, Therese; Perez-Janices, Noemi; Blanco-Luquin, Idoia; Goyvaerts, Cleo; Schwarze, Julia; Dufait, Ines; Lanna, Alessio; Ridder, Mark De; Guerrero-Setas, David; Breckpot, Karine; Escors, David

    2014-01-01

    Efficacious antitumor vaccines strongly stimulate cancer-specific effector T cells and counteract the activity of tumor-infiltrating immunosuppressive cells. We hypothesised that combining cytokine expression with silencing programmed cell death ligand 1 (PD-L1) could potentiate anticancer immune responses of lentivector vaccines. Thus, we engineered a collection of lentivectors that simultaneously co-expressed an antigen, a PD-L1-silencing shRNA, and various T cell-polarising cytokines, including interferon γ (IFNγ), transforming growth factor β (TGFβ) or interleukins (IL12, IL15, IL23, IL17A, IL6, IL10, IL4). In a syngeneic B16F0 melanoma model and using tyrosinase related protein 1 (TRP1) as a vaccine antigen, we found that simultaneous delivery of IL12 and a PD-L1-silencing shRNA was the only combination that exhibited therapeutically relevant anti-melanoma activities. Mechanistically, we found that delivery of the PD-L1 silencing construct boosted T cell numbers, inhibited in vivo tumor growth and strongly cooperated with IL12 cytokine priming and antitumor activities. Finally, we tested the capacities of our vaccines to counteract tumor-infiltrating myeloid-derived suppressor cell (MDSC) activities ex vivo. Interestingly, the lentivector co-expressing IL12 and the PD-L1 silencing shRNA was the only one that counteracted MDSC suppressive activities, potentially underlying the observed anti-melanoma therapeutic benefit. We conclude that (1) evaluation of vaccines in healthy mice has no significant predictive value for the selection of anticancer treatments; (2) B16 cells expressing xenoantigens as a tumor model are of limited value; and (3) vaccines which inhibit the suppressive effect of MDSC on T cells in our ex vivo assay show promising and relevant antitumor activities. PMID:25954597

  12. Anti-melanoma vaccines engineered to simultaneously modulate cytokine priming and silence PD-L1 characterized using ex vivo myeloid-derived suppressor cells as a readout of therapeutic efficacy.

    PubMed

    Liechtenstein, Therese; Perez-Janices, Noemi; Blanco-Luquin, Idoia; Goyvaerts, Cleo; Schwarze, Julia; Dufait, Ines; Lanna, Alessio; Ridder, Mark De; Guerrero-Setas, David; Breckpot, Karine; Escors, David

    Efficacious antitumor vaccines strongly stimulate cancer-specific effector T cells and counteract the activity of tumor-infiltrating immunosuppressive cells. We hypothesised that combining cytokine expression with silencing programmed cell death ligand 1 (PD-L1) could potentiate anticancer immune responses of lentivector vaccines. Thus, we engineered a collection of lentivectors that simultaneously co-expressed an antigen, a PD-L1-silencing shRNA, and various T cell-polarising cytokines, including interferon γ (IFNγ), transforming growth factor β (TGFβ) or interleukins (IL12, IL15, IL23, IL17A, IL6, IL10, IL4). In a syngeneic B16F0 melanoma model and using tyrosinase related protein 1 (TRP1) as a vaccine antigen, we found that simultaneous delivery of IL12 and a PD-L1-silencing shRNA was the only combination that exhibited therapeutically relevant anti-melanoma activities. Mechanistically, we found that delivery of the PD-L1 silencing construct boosted T cell numbers, inhibited in vivo tumor growth and strongly cooperated with IL12 cytokine priming and antitumor activities. Finally, we tested the capacities of our vaccines to counteract tumor-infiltrating myeloid-derived suppressor cell (MDSC) activities ex vivo. Interestingly, the lentivector co-expressing IL12 and the PD-L1 silencing shRNA was the only one that counteracted MDSC suppressive activities, potentially underlying the observed anti-melanoma therapeutic benefit. We conclude that (1) evaluation of vaccines in healthy mice has no significant predictive value for the selection of anticancer treatments; (2) B16 cells expressing xenoantigens as a tumor model are of limited value; and (3) vaccines which inhibit the suppressive effect of MDSC on T cells in our ex vivo assay show promising and relevant antitumor activities.

  13. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma.

    PubMed

    Weber, Jeffrey S; Hodi, F Stephen; Wolchok, Jedd D; Topalian, Suzanne L; Schadendorf, Dirk; Larkin, James; Sznol, Mario; Long, Georgina V; Li, Hewei; Waxman, Ian M; Jiang, Joel; Robert, Caroline

    2017-03-01

    Purpose We conducted a retrospective analysis to assess the safety profile of nivolumab monotherapy in patients with advanced melanoma and describe the management of adverse events (AEs) using established safety guidelines. Patients and Methods Safety data were pooled from four studies, including two phase III trials, with patients who received nivolumab 3 mg/kg once every 2 weeks. We evaluated rate of treatment-related AEs, time to onset and resolution of select AEs (those with potential immunologic etiology), and impact of select AEs and suppressive immune-modulating agents (IMs) on antitumor efficacy. Results Among 576 patients, 71% (95% CI, 67% to 75%) experienced any-grade treatment-related AEs (most commonly fatigue [25%], pruritus [17%], diarrhea [13%], and rash [13%]), and 10% (95% CI, 8% to 13%) experienced grade 3 to 4 treatment-related AEs. No drug-related deaths were reported. Select AEs (occurring in 49% of patients) were most frequently skin related, GI, endocrine, and hepatic; grade 3 to 4 select AEs occurred in 4% of patients. Median time to onset of select AEs ranged from 5 weeks for skin to 15 weeks for renal AEs. Approximately 24% of patients received systemic IMs to manage select AEs, which in most cases resolved. Adjusting for number of doses, objective response rate (ORR) was significantly higher in patients who experienced treatment-related select AEs of any grade compared with those who did not. ORRs were similar in patients who did and patients who did not receive systemic IMs. Conclusion Treatment-related AEs with nivolumab monotherapy were primarily low grade, and most resolved with established safety guidelines. Use of IMs did not affect ORR, although treatment-related select AEs of any grade were associated with higher ORR, but no progression-free survival benefit.

  14. Vaccinations

    MedlinePlus

    ... vaccinated? For many years, a set of annual vaccinations was considered normal and necessary for dogs and ... to protect for a full year. Consequently, one vaccination schedule will not work well for all pets. ...

  15. [Vaccines and preventive activities in patients with inflammatory arthritis].

    PubMed

    Casals-Sánchez, J L; Casals Vázquez, C; Vázquez Sánchez, M Á; Giménez Basallote, S

    2013-10-01

    Patients with inflammatory arthritis and eligible for immunosuppressive therapy account for more than 1% of general population, and represents a significant workload on family doctors. They are prone to other comorbidities, with an increased cardiovascular risk and a higher incidence of infections than the general population, especially skin infections and pneumonitis. This comorbidity can be considered vulnerable to a prevention program-prevention of cardiovascular risk, cancer screening, vaccination schedule for adults. As for prevention through vaccination, importance should be given to pneumococcal infection - significant in adults aged 50 or over, especially amongst immunosuppressed patients. The 13-valent conjugate vaccine, which has been recently approved for adults, must be considered. An attempt has been made to write a simple, applicable document on preventive measures that should be implemented both at primary and secondary care level for those adults.

  16. PET/CT surveillance detects asymptomatic recurrences in stage IIIB and IIIC melanoma patients: a prospective cohort study.

    PubMed

    Madu, Max F; Timmerman, Pieter; Wouters, Michel W J M; van der Hiel, Bernies; van der Hage, Jos A; van Akkooi, Alexander C J

    2017-02-20

    AJCC stage IIIB and IIIC melanoma patients are at risk for disease relapse or progression. The advent of effective systemic therapies has made curative treatment of progressive disease a possibility. As resection of oligometastatic disease can confer a survival benefit and as immunotherapy is possibly most effective in a low tumor load setting, there is a likely benefit to early detection of progression. The aim of this pilot study was to evaluate a PET/computed tomography (CT) surveillance schedule for resected stage IIIB and IIIC melanoma. From 1-2015, stage IIIB and IIIC melanoma patients at our institution underwent 6-monthly surveillance with PET/CT, together with 3-monthly S100B assessment. When symptoms or elevated S100B were detected, an additional PET/CT was performed. Descriptive statistics were used to evaluate outcomes for this surveillance schedule. Fifty-one patients were followed up, 27 patients developed a recurrence before surveillance imaging, five were detected by an elevated S100B, and one patient was not scanned according to protocol. Eighteen patients were included. Thirty-two scans were acquired. Eleven relapses were suspected on PET/CT. Ten scans were true positive, one case was false positive, and one case was false negative. All recurrences detected by PET/CT were asymptomatic at that time, with a normal range of S100B. The number of scans needed to find one asymptomatic relapse was 3.6. PET/CT surveillance imaging seems to be an effective strategy for detecting asymptomatic recurrence in stage IIIB and IIIC melanoma patients in the first year after complete surgical resection.

  17. Elucidating the immunological effects of 5-azacytidine treatment in patients with myelodysplastic syndrome and identifying new conditional ligands and T-cell epitopes of relevance in melanoma.

    PubMed

    Frøsig, Thomas Mørch

    2015-08-01

    -cell responses against Nodal. We were further able to show processing and presentation on the cell-surface in K562 and melanoma cells expressing relevant protein and HLA molecules of four of these peptide sequences from tyrosinase, gp100 (2 peptides) and Nodal, respectively. However, one of the gp100 peptides has previously been described as a T-cell epitope. In addition to identifying new melanoma-associated T-cell epitopes we could thus describe Nodal as a new immunological antigen found of relevance in melanoma patients. In Paper III we wanted to investigate if the hypomethylating drug 5-azactytidine (Vidaza, Celgene Inc.) modulates the immune system in patients with myeloproliferative diseases. It has previ-ously been shown that 5-azacytidine-mediated demethylation of gene promoter regions results in enhanced transcription and expression of tumor suppressor genes and cancer-testis antigens. Cancer-testis antigens have frequently been recognized by T-cells in many cancers, and we hypothesized that 5-azacytidine treat-ment in the clinic would increase their frequency with resulting enhanced anti-tumor reactivity. We investigated separately the effect on T cells and tumor cells, and found that tumor cells af-fected by the treatment were better recognized, resulting in higher numbers of activated T cells, than tumor cells not exposed to 5-azacytidine. No effects were observed on the T-cell population. A screen of the T-cell recognition of 43 cancer-testis antigens in blood from our patients revealed increased T-cell recognition upon start of therapy which, though, stabilized or declined at later time points. We further investigated the general immune effector and inhibitory cell populations and found only minor effects of drug exposure, suggesting that 5-azacytidine primarily affects the tumor cells. From these results we are currently initiating a phase I clinical trial of cancer-testis antigen-peptide vaccination in combination with 5-azacytidine therapy for patients with

  18. Laser immunotherapy for treatment of patients with advanced breast cancer and melanoma

    NASA Astrophysics Data System (ADS)

    Li, Xiaosong; Hode, Tomas; Guerra, Maria C.; Ferrel, Gabriela L.; Nordquist, Robert E.; Chen, Wei R.

    2011-02-01

    Laser immunotherapy (LIT) was developed for the treatment of metastatic tumors. It combines local selective photothermal interaction and active immunological stimulation to induce a long-term, systemic anti-tumor immunity. During the past sixteen years, LIT has been advanced from bench-top to bedside, with promising outcomes. In our pre-clinical and preliminary clinical studies, LIT has demonstrated the capability in inducing immunological responses, which not only can eradicate the treated primary tumors, but also can eliminate untreated metastases at distant sites. Specifically, LIT has been used to treat advanced melanoma and breast cancer patients during the past five years. LIT was shown to be effective in controlling both primary tumors and distant metastases in late-stage patients, who have failed conventional therapies such as surgery, chemotherapy, radiation, and other more advanced approaches. The methodology and the development of LIT are presented in this paper. The patients' responses to LIT are also reported in this paper. The preliminary results obtained in these studies indicated that LIT could be an effective modality for the treatment of patients with late-stage, metastatic cancers, who are facing severely limited options.

  19. Akt Inhibitor MK2206 and Hydroxychloroquine in Treating Patients With Advanced Solid Tumors, Melanoma, Prostate or Kidney Cancer

    ClinicalTrials.gov

    2017-02-06

    Adult Solid Neoplasm; Hormone-Resistant Prostate Cancer; Recurrent Melanoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma

  20. Self-Checks Help Spot Melanoma's Return

    MedlinePlus

    ... news/fullstory_163682.html Self-Checks Help Spot Melanoma's Return Patient-detected symptoms were most common way ... Feb. 20, 2017 (HealthDay News) -- Self-checks by melanoma skin cancer patients play an important role in ...

  1. Comparison of prognostic indices in patients who undergo melanoma brain metastasis radiosurgery.

    PubMed

    Kano, Hideyuki; Morales-Restrepo, Alejandro; Iyer, Aditya; Weiner, Gregory M; Mousavi, Seyed H; Kirkwood, John M; Tarhini, Ahmad A; Flickinger, John C; Lunsford, L Dade

    2017-01-20

    OBJECTIVE The goal of this study was to use 4 prognostic indices to compare survival times of patients who underwent Gamma Knife stereotactic radiosurgery (SRS) to treat melanoma brain metastases. METHODS The authors analyzed 422 consecutive patients (1440 brain metastases) who underwent Gamma Knife SRS. The median total brain tumor volume was 4.7 cm(3) (range 0.3-69.3 cm(3)), and the median number of metastases was 2 (range 1-32). One hundred thirty-two patients underwent whole-brain radiation therapy. Survival times were compared using recursive partitioning analysis (RPA), the Score Index for Radiosurgery (SIR), the Basic Score for Brain Metastases (BSBM), and the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA). RESULTS The overall survival times after SRS were compared. With the RPA index, survival times were 2.6 months (Class III, n = 27), 5.5 months (Class II, n = 348), and 13.0 months (Class I, n = 47). With the DS-GPA index, survival times were 2.8 months (Scores 0-1, n = 67), 4.2 months (Scores 1.5-2.0, n = 143), 6.6 months (Scores 2.5-3.0, n = 111), and 9.4 months (Scores 3.5-4.0, n = 101). With the SIR, survival times were 3.2 months (Scores 0-3, n = 56), 5.8 months (Scores 4-7, n = 319), and 12.7 months (Scores 8-10, n = 47). With the BSBM index, survival times were 2.6 months (BSBM0, n = 47), 5.4 months (BSBM1, n = 282), 11.0 months (BSBM2, n = 86), and 8.8 months (BSBM3, n = 7). The DS-GPA index was the most balanced by case numbers in each class and provided the overall best prognostic index for overall survival. CONCLUSIONS The DS-GPA index proved most balanced and predictive of survival for patients with melanoma who underwent SRS as part of management for brain metastases. Patients whose DS-GPA score was ≥ 2.5 had predictably improved survival times after SRS.

  2. MGMT expression levels predict disease stabilisation, progression-free and overall survival in patients with advanced melanomas treated with DTIC.

    PubMed

    Busch, Christian; Geisler, Jürgen; Lillehaug, Johan R; Lønning, Per Eystein

    2010-07-01

    Metastatic melanoma responds poorly to systemic treatment. We report the results of a prospective single institution study evaluating O(6)-methylguanine-DNA methyltransferase (MGMT) status as a potential predictive and/or prognostic marker among patients treated with dacarbazine (DTIC) 800-1000 mg/m(2) monotherapy administered as a 3-weekly schedule for advanced malignant melanomas. The study was approved by the Regional Ethical Committee. Surgical biopsies from metastatic or loco-regional deposits obtained prior to DTIC treatment were snap-frozen immediately upon removal and stored in liquid nitrogen up to processing. Median time from enrolment to end of follow-up was 67 months. MGMT expression levels evaluated by qRT-PCR correlated significantly to DTIC benefit (CR/PR/SD; p=0.005), time to progression (TTP) (p=0.005) and overall survival (OS) (p=0.003). MGMT expression also correlated to Breslow thickness in the primary tumour (p=0.014). While MGMT promoter hypermethylation correlated to MGMT expression, MGMT promoter hypermethylation did not correlate to treatment benefit, TTP or OS, suggesting that other factors may be critical in determining MGMT expression levels in melanomas. In a Cox proportional regression analysis, serum lactate dehydrogenase (LDH, p<0.001), MGMT expression (p=0.022) and p16(INK4a) expression (p=0.037) independently predicted OS, while TTP correlated to DTIC benefit after 6 weeks only (p=0.001). Our data reveal MGMT expression levels to be associated with disease stabilisation and prognosis in patients receiving DTIC monotherapy for advanced melanoma. The role of MGMT expression as a predictor to DTIC sensitivity versus a general prognostic factor in advanced melanomas warrants further evaluation.

  3. Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: a phase II study.

    PubMed

    Yamazaki, Naoya; Kiyohara, Yoshio; Uhara, Hisashi; Uehara, Jiro; Fujimoto, Manabu; Takenouchi, Tatsuya; Otsuka, Masaki; Uchi, Hiroshi; Ihn, Hironobu; Minami, Hironobu

    2017-03-25

    Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T-cell activation via overexpression of the inhibitory receptor programmed death 1 (PD-1) ligands. The PD-1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has demonstrated promising anti-cancer activity in various cancers. We conducted a single-arm, open-label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty-four patients with stage III/IV or recurrent melanoma were enrolled and received intravenous nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee-assessed overall response rate was 34.8% (90% confidence interval [CI]: 20.8, 51.9), and the overall survival rate at 18 months was 56.5% (90% CI: 38.0, 71.4). Treatment-related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype and that patients with treatment-related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab demonstrated favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. This article is protected by copyright. All rights reserved.

  4. Uveal melanoma: estimating prognosis.

    PubMed

    Kaliki, Swathi; Shields, Carol L; Shields, Jerry A

    2015-02-01

    Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, higher expression of insulin-like growth factor-1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms "uvea," "iris," "ciliary body," "choroid," "melanoma," "uveal melanoma" and "prognosis," "metastasis," "genetic testing," "gene expression profiling." Relevant English language articles were extracted, reviewed, and referenced appropriately.

  5. Motor function and survival following radiotherapy alone for metastatic epidural spinal cord compression in melanoma patients.

    PubMed

    Huttenlocher, Stefan; Sehmisch, Lena; Rudat, Volker; Rades, Dirk

    2014-12-01

    The major goal of this study was the identification of predictors for motor function and survival after irradiation alone for metastatic epidural spinal cord compression (MESCC) from melanoma. Ten variables (age, gender, performance status, number of involved vertebrae, pre-radiotherapy ambulatory status, further bone metastases, visceral metastases, interval from melanoma diagnosis to MESCC, time developing motor deficits before radiotherapy, fractionation regimen) were investigated for post-radiotherapy motor function, ambulatory status and survival in 27 patients. On multivariate analysis, motor function was significantly associated with time developing motor deficits (P = 0.006). On univariate analysis, post-radiotherapy ambulatory rates were associated with pre-radiotherapy ambulatory status (P < 0.001) and performance status (P = 0.046). Variables having a significant impact on survival in the univariate analysis were performance status (P < 0.001), number of involved vertebrae (P = 0.007), pre-radiotherapy ambulatory status (P = 0.020), further bone metastases (P = 0.023), visceral metastases (P < 0.001), and time developing motor deficits (P = 0.038). On multivariate analysis of survival, the Eastern Cooperative Oncology Group (ECOG) performance status (risk ratio [RR] = 4.35; 95% confidence interval [CI] = 1.04-16.67; P = 0.044) and visceral metastases (RR = 3.70; 95% CI = 1.10-12.50; P = 0.034) remained significant and were included in a survival score. Scoring points were obtained from 6-month survival rates divided by 10. Total scores represented the sum scores of both variables and were 3, 9 or 15 points. Six-month survival rates were 7%, 29% and 100% (P = 0.004). Thus, three predictors for functional outcomes were identified. The newly developed survival score included three prognostic groups. Patients with 3 points may receive 1 × 8 Gy, patients with 9 points 5 × 4 Gy and patients achieving 15 points longer

  6. Dormancy of metastatic melanoma

    PubMed Central

    Ossowski, Liliana; Aguirre-Ghiso, Julio A.

    2010-01-01

    Summary Metastatic dormancy of melanoma has not received sufficient attention, most likely because once detectable, metastasis is almost invariably fatal and, understandably, the focus has been on finding ways to prolong life of patients with overt recurrences. Nevertheless, analysis of the published clinical and experimental data on melanoma indicates that some aspect of melanoma biology imitate traits recently associated with dormancy in other solid cancers. Among them the ability of some melanomas to disseminate early during primary tumor progression and once disseminated, to remain undetected (dormant) for years. Comparison of cutaneous and uveal melanoma indicates that, in spite of being of the same origin, they differ profoundly in their clinical progression. Importantly for this discussion, between 40 and 50% of uveal melanoma remain undetected for longer than a decade, while less than 5% of cutaneous melanoma show this behavior. Both types of melanoma have activating oncogene mutations that provide autonomous pro-proliferative signals, yet the consensus is that those are not sufficient for tumor progression. If that is the case, it is possible to envision that signals from outside the tumor cell, (microenvironment) shape the fate of an individual disseminated cell, regardless of an oncogene mutation, to progress or to pause in a state of dormancy. To stimulate further debate and inquiry we describe here a few examples of potential signals that might modify the fate of disseminated cell and provide brief description of the current knowledge on dormancy in other cancers. Our hope is to convince the reader that disseminated melanoma cells do enter periods of prolonged dormancy and that finding ways to induce it, or to prolong it, might mean an extension of symptoms-free life for melanoma patients. Ultimately, understanding the biology of dormancy and the mechanisms of dormant cell survival, might allow for their specific targeting and elimination. PMID

  7. Deep venous thromboembolism in patients undergoing inguinal lymph node dissection for melanoma

    SciTech Connect

    Arbeit, J.M.; Lowry, S.F.; Line, B.R.; Jones, D.C.; Brennan, M.F.

    1981-01-01

    Deep venous thromboembolism (DVT) was studied in 44 patients with clinical Stage I, II, and III melanoma undergoing staging and therapeutic inguinal lymph node dissection. The ability of two noninvasive methods of surveillance, the phleborheograph (PRG) and the /sup 125/I fibrinogen scan to detect deep venous thrombosis was determined by comparison with prospective bilateral lower extremity venograms. In addition, the therapeutic impact, both beneficial and detrimental, of low dose heparin, 5000 units administered subcutaneously two hours prior to and every eight hours after operation was determined in a double blind study. The sensitivity of the PRG and /sup 125/I fibrinogen scan were both 20%. There were five deep venous thrombi, and two pulmonary emboli for a combined incidence of DVT of 13.6% for the entire patient population. However, there was no significant difference in the incidence of DVT between the two groups. The heparin-treated patients had an increased total volume (796 +/- 516 versus 388 +/- 208 ml; p less than 0.05), and duration of wound drainage (9 +/- 4 versus 13 +/- 6 days; p less than 0.05).

  8. Deep venous thromboembolism in patients undergoing inguinal lymph node dissection for melanoma

    SciTech Connect

    Arbeit, J.M.; Lowry, S.F.; Line, B.R.

    1981-11-01

    Deep venous thromboembolism (DVT) was studied in 44 patients with clinical Stage I, II, and III melanoma undergoing staging and therapeutic inguinal lymph node dissection. The ability of two noninvasive methods of surveillance, the phleborheograph (PRG) and the /sup 125/I fibrinogen scan to detect deep venous thrombosis was determined by comparison with prospective bilateral lower extremity venograms. In addition, the therapeutic impact, both beneficial and detrimental, of low dose heparin, 5000 units administered subcutaneously two hours prior to and every eight hours after operation was determined in a double blind study. The sensitivity of the PRG and /sup 125/I fibrinogen scan were both 20%. There were five deep venous thrombi, and two pulmonary emboli for a combined incidence of DVT of 13.6% for the entire patient population. However, there was no significant difference in the incidence of DVT between the two groups. The heparin-treated patients had an increased total volume (796 +/- 516 versus 388 +/- 208 ml; p < 0.05), and duration of wound drainage (9 +/- 4 versus 13 +/- 6 days; p < 0.05).

  9. Adoptive TIL transfer in the adjuvant setting for melanoma: long-term patient survival.

    PubMed

    Khammari, Amir; Knol, Anne-Chantal; Nguyen, Jean-Michel; Bossard, Céline; Denis, Marc-Guillaume; Pandolfino, Marie-Christine; Quéreux, Gaëlle; Bercegeay, Sylvain; Dréno, Brigitte

    2014-01-01

    Two first analyses of our clinical trial on TIL as adjuvant therapy for melanoma were published in 2002 and 2007. We present here an update of the clinical results after a 17-year median followup. In this trial, disease-free patients were randomly assigned to receive either TIL/IL-2 or IL-2. The relapse-free survival (RFS) was the primary objective. Eighty-eight patients were enrolled. A new analysis performed in May 2013 did not show significant changes in RFS or OS duration. However, our first finding on the association between the number of invaded lymph nodes and TIL effectiveness was strengthened. The Cox model adjusted on this interaction showed for the first time a significant treatment effect when considering the overall population, both on the RFS and OS. Patients treated with TIL had a longer RFS (P = 0.023) or OS (P = 0.020). This study being with a very long followup (17 years), confirmed the association between TIL effectiveness and the number of invaded lymph nodes, indicating that a low tumor burden could be a crucial factor enhancing the curative effect of TIL in possible microscopic residual disease. Moreover, we confirmed that a prolonged survival was associated with the presence of specific TIL and a decrease in Foxp3 expression.

  10. Vaccination of patients with auto-immune inflammatory rheumatic diseases requires careful benefit-risk assessment.

    PubMed

    Bijl, M; Agmon-Levin, N; Dayer, J-M; Israeli, E; Gatto, M; Shoenfeld, Y

    2012-06-01

    Will vaccination raise the incidence of autoimmune diseases, what is the impact of increasingly crowded vaccination schedules, the vaccination in age groups and the risk of coincidental temporal association? All these issues are still under debate. However, for the time being, to avoid confusion in the medical community and the media, we have to adhere to guidelines established consensually by experts while ensuring a strict surveillance and reporting possible side effects. Recommendation for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD) based on the currently available evidence and expert opinion were recently formulated by an EULAR task force. Major recommendations for AIIRD include: i) vaccination should ideally be administered during stable disease; ii) influenza vaccination and pneumococcal vaccination should be strongly considered; iii) vaccination can be administered during the use of DMARDs and TNF-inhibitors, but before starting rituximab; iv) live attenuated vaccines should be avoided whenever possible in immunosuppressed patients; v) BCG vaccination is not recommended.

  11. Primary cerebral malignant melanoma

    PubMed Central

    Tang, Kai; Kong, Xiangyi; Mao, Gengsheng; Qiu, Ming; Zhu, Haibo; Zhou, Lei; Nie, Qingbin; Xu, Yi; Du, Shiwei

    2017-01-01

    Abstract Primary intracranial melanomas are uncommon and constitute approximately 1% of all melanoma cases and 0.07% of all brain tumors. In nature, these primary melanomas are very aggressive and can spread to other organs. We report an uncommon case of primary cerebral malignant melanoma—a challenging diagnosis guided by clinical presentations, radiological features, and surgical biopsy results, aiming to emphasize the importance of considering primary melanoma when making differential diagnoses of intracranial lesions. We present a rare case of a primary cerebral melanoma in the left temporal lobe. The mass appeared iso-hypodense on brain computed tomography (CT), short signal on T1-weighted magnetic resonance images (T1WI) and long signal on T2WI. It was not easy to make an accurate diagnosis before surgery. We showed the patient's disease course and reviewed related literatures, for readers’ reference. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Because of this, there is no need to conduct special ethic review and the ethical approval is not necessary. After surgery, the pathological examination confirmed the diagnosis of melanoma. The patient was discharged without any complications and went on to receive adjuvant radiochemotherapy. It is difficult to diagnose primary cerebral melanoma in the absence of any cutaneous melanosis. A high index of clinical suspicion along with good pathology reporting is the key in diagnosing these extremely rare tumors. PMID:28121927

  12. An innovative influenza vaccination policy: targeting last season's patients.

    PubMed

    Yamin, Dan; Gavious, Arieh; Solnik, Eyal; Davidovitch, Nadav; Balicer, Ran D; Galvani, Alison P; Pliskin, Joseph S

    2014-05-01

    Influenza vaccination is the primary approach to prevent influenza annually. WHO/CDC recommendations prioritize vaccinations mainly on the basis of age and co-morbidities, but have never considered influenza infection history of individuals for vaccination targeting. We evaluated such influenza vaccination policies through small-world contact networks simulations. Further, to verify our findings we analyzed, independently, large-scale empirical data of influenza diagnosis from the two largest Health Maintenance Organizations in Israel, together covering more than 74% of the Israeli population. These longitudinal individual-level data include about nine million cases of influenza diagnosed over a decade. Through contact network epidemiology simulations, we found that individuals previously infected with influenza have a disproportionate probability of being highly connected within networks and transmitting to others. Therefore, we showed that prioritizing those previously infected for vaccination would be more effective than a random vaccination policy in reducing infection. The effectiveness of such a policy is robust over a range of epidemiological assumptions, including cross-reactivity between influenza strains conferring partial protection as high as 55%. Empirically, our analysis of the medical records confirms that in every age group, case definition for influenza, clinical diagnosis, and year tested, patients infected in the year prior had a substantially higher risk of becoming infected in the subsequent year. Accordingly, considering individual infection history in targeting and promoting influenza vaccination is predicted to be a highly effective supplement to the current policy. Our approach can also be generalized for other infectious disease, computer viruses, or ecological networks.

  13. An Innovative Influenza Vaccination Policy: Targeting Last Season's Patients

    PubMed Central

    Yamin, Dan; Gavious, Arieh; Solnik, Eyal; Davidovitch, Nadav; Balicer, Ran D.; Galvani, Alison P.; Pliskin, Joseph S.

    2014-01-01

    Influenza vaccination is the primary approach to prevent influenza annually. WHO/CDC recommendations prioritize vaccinations mainly on the basis of age and co-morbidities, but have never considered influenza infection history of individuals for vaccination targeting. We evaluated such influenza vaccination policies through small-world contact networks simulations. Further, to verify our findings we analyzed, independently, large-scale empirical data of influenza diagnosis from the two largest Health Maintenance Organizations in Israel, together covering more than 74% of the Israeli population. These longitudinal individual-level data include about nine million cases of influenza diagnosed over a decade. Through contact network epidemiology simulations, we found that individuals previously infected with influenza have a disproportionate probability of being highly connected within networks and transmitting to others. Therefore, we showed that prioritizing those previously infected for vaccination would be more effective than a random vaccination policy in reducing infection. The effectiveness of such a policy is robust over a range of epidemiological assumptions, including cross-reactivity between influenza strains conferring partial protection as high as 55%. Empirically, our analysis of the medical records confirms that in every age group, case definition for influenza, clinical diagnosis, and year tested, patients infected in the year prior had a substantially higher risk of becoming infected in the subsequent year. Accordingly, considering individual infection history in targeting and promoting influenza vaccination is predicted to be a highly effective supplement to the current policy. Our approach can also be generalized for other infectious disease, computer viruses, or ecological networks. PMID:24851863

  14. Association of Vitamin D Levels With Outcome in Patients With Melanoma After Adjustment For C-Reactive Protein

    PubMed Central

    Fang, Shenying; Sui, Dawen; Wang, Yuling; Liu, Huey; Chiang, Yi-Ju; Ross, Merrick I.; Gershenwald, Jeffrey E.; Cormier, Janice N.; Royal, Richard E.; Lucci, Anthony; Wargo, Jennifer; Hu, Mimi I.; Gardner, Julie M.; Reveille, John D.; Bassett, Roland L.; Wei, Qingyi; Amos, Christopher I.

    2016-01-01

    Purpose To evaluate for an association between 25-hydroxyvitamin D levels (vitamin D) and outcome measures in patients with melanoma after evaluation is controlled for systemic inflammatory response (SIR) on the basis of simultaneous C-reactive protein (CRP) measurement. Materials and Methods Plasma samples from 1,042 prospectively observed patients with melanoma were assayed for vitamin D and CRP. The associations of demographics and CRP with vitamin D were determined, followed by a determination of the association between vitamin D and stage and outcome measures from the date of blood draw. The vitamin D level was considered sufficient if it was 30 to 100 ng/mL. Kaplan-Meier and Cox regression analyses were performed. Results The median vitamin D level was 25.0 ng/mL. The median follow-up time was 7.1 years. A lower vitamin D was associated with the blood draw during fall/winter months (P < .001), older age (P = .001), increased CRP (P < .001), increased tumor thickness (P < .001), ulcerated tumor (P = .0105), and advanced melanoma stage (P = .0024). On univariate analysis, lower vitamin D was associated with poorer overall (OS; P < .001), melanoma-specific survival (MSS; P = .0025), and disease-free survival (DFS; P = .0466). The effect of vitamin D on these outcome measures persisted after adjustment for CRP and other covariates. Multivariable hazards ratios per unit decrease of vitamin D were 1.02 for OS (95% CI, 1.01 to 1.04; P = .0051), 1.02 for MSS (95% CI, 1.00 to 1.04; P = .048), and 1.02 for DFS (95% CI, 1.00 to 1.04; P = .0427). Conclusion Lower vitamin D levels in patients with melanoma were associated with poorer outcomes. Although lower vitamin D was strongly associated with higher CRP, the associations of lower vitamin D with poorer OS, MSS, and DFS were independent of this association. Investigation of mechanisms responsible for these associations may be of value to patients with melanoma. PMID:27001565

  15. An ethical dilemma: malignant melanoma in a 51-year-old patient awaiting simultaneous kidney and pancreas transplantation for type 1 diabetes.

    PubMed

    Kirby, L C; Banerjee, A; Augustine, T; Douglas, J F

    2016-07-01

    Malignant melanoma is a high-risk skin cancer that, in potential transplant recipients, is considered a substantial contraindication to solid organ transplantation due to significant risk of recurrence with immunosuppression. Current guidelines stipulate waiting between 3 and 10 years after melanoma diagnosis. However, in young patients with end-stage organ failure and malignant melanoma, complex ethical and moral issues arise. Assessment of the true risk associated with transplantation in these patients is difficult due to lack of prospective data, but an autonomous patient can make a decision that clinicians may perceive to be high risk. The national and worldwide shortage of available organs also has to be incorporated into the decision to maximize the net benefit and minimize the risk of graft failure and mortality. The incidence of malignant melanoma worldwide is increasing faster than that of any other cancer and continues to pose ethically challenging decisions for transplant specialists evaluating recipients for solid organ transplantation.

  16. A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma

    PubMed Central

    Meek, Stephanie M.; Bowen, Randy C.; Grossmann, Kenneth F.; Andtbacka, Robert H.I.; Bowles, Tawnya L.; Hyngstrom, John R.; Leachman, Sancy A.; Grossman, Douglas; Bowen, Glen M.; Holmen, Sheri L.; VanBrocklin, Matthew W.; Suneja, Gita; Khong, Hung T.

    2016-01-01

    Purpose Intratumoral interleukin-2 (IL-2) is effective but does not generate systemic immunity. Intravenous ipilimumab produces durable clinical response in a minority of patients, with potentially severe toxicities. Circulating anti-tumor T cells activated by ipilimumab may differ greatly from tumor-infiltrating lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality. The objective of this study was to primarily assess the safety of intratumoral ipilimumab/IL-2 combination and to obtain data on clinical efficacy. Results There was no dose limiting toxicity. While local response of injected lesions was observed in 67% patients (95% CI, 40%-93%), an abscopal response was seen in 89% (95% CI, 68%-100%). The overall response rate and clinical benefit rate by immune-related response criteria (irRC) was 40% (95% CI, 10%-70%) and 50% (95% CI, 19%-81%), respectively. Enhanced systemic immune response was observed in most patients and correlated with clinical responses. Experimental Design Twelve patients with unresectable stages III/IV melanoma were enrolled. A standard 3+3 design was employed to assess highest tolerable intratumoral dose of ipilimumab and IL-2 based on toxicity during the first three weeks. Escalated doses of ipilimumab was injected into only one lesion weekly for eight weeks in cohorts of three patients. A fixed dose of IL-2 was injected three times a week into the same lesion for two weeks, followed by two times a week for six weeks. Conclusions Intratumoral injection with the combination of ipilimumab/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients. PMID:27391442

  17. BRAF, KIT and NRAS mutations and expression of c-KIT, phosphorylated extracellular signal-regulated kinase and phosphorylated AKT in Japanese melanoma patients.

    PubMed

    Oyama, Satomi; Funasaka, Yoko; Watanabe, Atsushi; Takizawa, Toshihiro; Kawana, Seiji; Saeki, Hidehisa

    2015-05-01

    To clarify the status of gene mutation and activation of growth signal in melanoma of Japanese patients in vivo, we analyzed the mutation of BRAF exon 15, NRAS exon 2, and KIT exons 9, 11, 13, 17 and 18 in melanoma cells obtained by laser capture microdissection, and performed direct sequencing in 20 cases of acral lentiginous melanoma (ALM) and 17 cases of superficial spreading melanoma (SSM). In the study of the mutation of BRAF, pyrosequencing was also done. To examine the cell proliferation signaling, immunohistochemistry for phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated AKT (phosphorylated AKT) and c-KIT was done. The mutation of BRAF p.V600E was detected in 13 cases of ALM (65.0%) and 12 cases of SSM (70.6%). No NRAS mutation was found in all cases. The mutation in exons 9, 11, and 18 of KIT was detected in nine cases. The mutation of BRAF and KIT showed no correlation with clinical stage, lymph node metastasis, tumor thickness, ulceration and histology. pERK and pAKT was observed in small population of melanoma cells and there was no correlation with gene mutation. Our results indicate that the mutations of BRAF and KIT exist in Japanese melanoma patients, however, the cell growth signaling may be regulated by not only these mutated genes, but by other unknown regulatory factors, which may affect the prognosis of melanoma.

  18. GNA11 Mutation in a Patient With Cutaneous Origin Melanoma: A Case Report.

    PubMed

    Patel, Sapna P; Kim, Dae Won; Lacey, Carol L; Hwu, Patrick

    2016-01-01

    The rapid advances in the molecular biology and genetics have improved the understanding of molecular pathogenesis of v-Raf murine sarcoma viral oncogene homolog B (BRAF), feline sarcoma viral oncogene v-kit (KIT), and neuroblastoma v-Ras oncogene homolog (NRAS) mutant melanomas with the subsequent development of targeted therapeutic agents. However, only limited data are available for melanoma harboring other somatic than BRAF, KIT, and NRAS mutations. Mutations in guanine nucleotide-binding protein Q polypeptide (GNAQ) and guanine nucleotide-binding protein alpha-11 (GNA11), alpha subunits of heterotrimeric G proteins, constitutively activate mitogen-activated protein kinase (MAPK) pathway in uveal melanoma. However, there are no reports of GNA11 mutations in cutaneous melanomas. A 48-year-old woman was diagnosed with cutaneous nodular melanoma on the left scalp. Mutation analysis of the tumor revealed a GNA11 Q209L mutation. There was no evidence of uveal melanoma or malignant blue nevus in ophthalmologic exam, imaging studies, and pathology review. To our knowledge, this is the first case report to demonstrate cutaneous origin melanoma harboring a GNA11 Q209L mutation.

  19. BM-16INCREASED ACUTE RADIATION EFFECT (ARE) WITH IPILUMUMAB AND RADIOSURGERY IN PATIENTS WITH MELANOMA BRAIN METASTASES

    PubMed Central

    Khoja, Leila; Kurtz, Goldie; Zadeh, Gelareh; Laperriere, Normand; Menard, Cynthia; Millar, Barbara-Ann; Bernstein, Mark; Kongkham, Paul; Joshua, Anthony; Hogg, David; Butler, Marcus; Chung, Caroline

    2014-01-01

    BACKGROUND: Ipilumumab (Ipi), an antibody that enhances T-cell activation, has been shown to improve survival in patients with metastatic melanoma. Ipilumumab may have synergistic effects with radiotherapy but this may result in increased toxicity. This study investigated the incidence of acute radiation effect (ARE) in patients with melanoma brain metastases treated with Ipi and radiosurgery (SRS) or whole brain radiotherapy (WBRT). METHODOLOGY: This retrospective study included metastatic melanoma patients treated at our institution from 2008-2013 who received SRS or WBRT for brain metastases within 4 months of Ipi treatment. We evaluated the incidence, timing and factors associated with acute radiation effect (ARE). RESULTS: From 159 patients treated with Ipi, 22 patients also received brain RT within 4 months of treatment. Three patients were excluded for lack of follow-up brain imaging, thus 19 were analysed: 14 males and 5 females, with median age 58 years (range 24-82). Ten were treated with SRS, 7 with WBRT, and 2 with SRS plus WBRT. Median dose for SRS was 21 Gy (range: 15-24 Gy). Five of 13 patients treated with SRS (38%) experienced symptomatic edema requiring steroids within 1 month of starting Ipi, and within 4 months of RT. One patient had a haemorrhage and 1 required surgical resection, which demonstrated viable disease. Therefore 3 patients (23%) treated with SRS developed isolated ARE. These metastases had volumes less than 4.2 cm3 and were treated within 4 months of Ipi to a median dose of 19.5 Gy (range 15-21 Gy). No patients with WBRT alone developed ARE. CONCLUSIONS: Following SRS for brain mets and Ipi, ARE was seen in 23% of patients within 4 months of starting Ipi treatment. This is greater than the commonly reported 10% risk of ARE after SRS alone for brain metastasis. No increased toxicity was seen with WBRT and Ipi.

  20. Monitoring of dynamic changes in Keyhole Limpet Hemocyanin (KLH)-specific B cells in KLH-vaccinated cancer patients

    PubMed Central

    Wimmers, Florian; de Haas, Nienke; Scholzen, Anja; Schreibelt, Gerty; Simonetti, Elles; Eleveld, Marc J.; Brouwers, Huberdina M. L. M.; Beldhuis-Valkis, Marjo; Joosten, Irma; de Jonge, Marien I.; Gerritsen, Winald R.; de Vries, I. Jolanda M.; Diavatopoulos, Dimitri A.; Jacobs, Joannes F. M.

    2017-01-01

    Keyhole limpet hemocyanin (KLH) is used as an immunogenic neo-antigen for various clinical applications and during vaccine development. For advanced monitoring of KLH-based interventions, we developed a flow cytometry-based assay for the ex vivo detection, phenotyping and isolation of KLH-specific B cells. As proof-of-principle, we analyzed 10 melanoma patients exposed to KLH during anti-cancer dendritic cell vaccination. Our assay demonstrated sensitive and specific detection of KLH-specific B cells in peripheral blood and KLH-specific B cell frequencies strongly correlated with anti-KLH serum antibody titers. Profiling of B cell subsets over the vaccination course revealed that KLH-specific B cells matured from naïve to class-switched memory B cells, confirming the prototypic B cell response to a neo-antigen. We conclude that flow-cytometric detection and in-depth phenotyping of KLH-specific B cells is specific, sensitive, and scalable. Our findings provide novel opportunities to monitor KLH-specific immune responses and serve as a blueprint for the development of new flow-cytometric protocols. PMID:28344338

  1. TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients.

    PubMed

    Chauvin, Joe-Marc; Pagliano, Ornella; Fourcade, Julien; Sun, Zhaojun; Wang, Hong; Sander, Cindy; Kirkwood, John M; Chen, Tseng-hui Timothy; Maurer, Mark; Korman, Alan J; Zarour, Hassane M

    2015-05-01

    T cell Ig and ITIM domain (TIGIT) is an inhibitory receptor expressed by activated T cells, Tregs, and NK cells. Here, we determined that TIGIT is upregulated on tumor antigen-specific (TA-specific) CD8⁺ T cells and CD8⁺ tumor-infiltrating lymphocytes (TILs) from patients with melanoma, and these TIGIT-expressing CD8⁺ T cells often coexpress the inhibitory receptor PD-1. Moreover, CD8⁺ TILs from patients exhibited downregulation of the costimulatory molecule CD226, which competes with TIGIT for the same ligand, supporting a TIGIT/CD226 imbalance in metastatic melanoma. TIGIT marked early T cell activation and was further upregulated by T cells upon PD-1 blockade and in dysfunctional PD-1⁺TIM-3⁺ TA-specific CD8⁺ T cells. PD-1⁺TIGIT⁺, PD-1⁻TIGIT⁺, and PD-1⁺TIGIT⁻ CD8⁺ TILs had similar functional capacities ex vivo, suggesting that TIGIT alone, or together with PD-1, is not indicative of T cell dysfunction. However, in the presence of TIGIT ligand-expressing cells, TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of both TA-specific CD8⁺ T cells and CD8⁺ TILs. Collectively, our results show that TIGIT and PD-1 regulate the expansion and function of TA-specific CD8⁺ T cells and CD8⁺ TILs in melanoma patients and suggest that dual TIGIT and PD-1 blockade should be further explored to elicit potent antitumor CD8⁺ T cell responses in patients with advanced melanoma.

  2. Anorectal melanoma. An update.

    PubMed

    Reina, Angel; Errasti, José; Espín, Eloy

    2014-10-01

    Anorectal melanoma is an uncommon and aggressive disease. Because the patients often present with non specific complaints, a high clinical suspicion is important to avoid a delayed diagnosis. Patients undergoing radical surgery have no significant survival difference compared to those undergoing wide local excision. Abdominoperineal resection should be reserved for selected patients in whom local excision is not technically possible or cannot obtain a clear margin. The indiscriminate use of groin dissection is not advisable in anorectal melanoma and should be use in selected cases. Systemic chemotherapy is generally a non effective treatment and continues be studied. Radiation therapy can be used as hypofractionated radiation therapy combined with local excision or in a palliative setting. The oncological outcomes in anorectal melanoma are very poor. The aim of the present study is to review clinicopathology features and management of anorectal melanoma.

  3. Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

    PubMed

    Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice; Algazy, Kenneth M; Evans, Tracey L; Fecher, Leslie A; Schuchter, Lynn M; Torigian, Drew A; Panosian, Jeffrey T; Troxel, Andrea B; Tan, Kay-See; Heitjan, Daniel F; DeMichele, Angela M; Vaughn, David J; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; O'Dwyer, Peter J; Amaravadi, Ravi K

    2014-08-01

    The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

  4. Etiology of melanoma.

    PubMed

    Koh, H K; Sinks, T H; Geller, A C; Miller, D R; Lew, R A

    1993-01-01

    Although the precise etiology of melanoma remains unknown, much data link sunlight to melanoma. The imperfect evidence associating sun exposure (particularly UVB radiation) with melanoma emerges from human data, obviating problems inherent in extrapolation from animal and other models. However, the mechanism by which sunlight might possibly initiate or promote melanoma remains obscure. Some clarification should emerge from the potential isolation of genes that carry susceptibility to melanoma in families prone to the disease; such work could serve as a basis to distinguish genetic and environmental influences in melanoma [167]. Continued studies of faulty DNA repair in XP patients may elucidate the steps in mutagenesis and carcinogenesis. Future case-control studies must address the limits on the accuracy of recall and the limits on statistical methods to separate the cluster of phenotypic risk needed in determining biologically effective dose. Animal and in vitro studies must contribute more insight. Further research in the South American opossum models appears promising [72]. Although ozone depletion has been documented, there has been little definitive evidence of subsequent increase of UVB at the Earth's surface. Nevertheless, the threat posed by ozone depletion deserves continued environmental action and public education. The role of precursor lesions, particularly dysplastic nevi/atypical moles, must be clarified with future research. The distribution of melanoma among various work forces suggests that occupational risk factors may play an important role in the etiology of this disease [168-170]. The consistent reports of excess melanoma among accountants, clerical workers, professional workers, and teachers deserve further study. Furthermore, evidence of excesses in printing and press, petrochemical, and the telecommunications industries require follow-up. Carefully planned studies that account for nonoccupational risk factors are recommended. Research over

  5. [Protocol proposal for the histological report of the primary tumor in patients with cutaneous melanoma from the Task Force for Cutaneous Melanoma of the Valencian Community].

    PubMed

    Nagore, E; Monteagudo, C; Pinazo, M I; Botella-Estrada, R; Oliver, V; Bañuls, J; Moragón, M; Valcuende, F; Calatrava, A; Mayol-Belda, M J; Lázaro, R; Niveiro, M; Guillén, C

    2007-09-01

    This text compiles a histological protocol proposal for cutaneous melanoma agreed by the Task Force for Cutaneous Melanoma of the Valencian Community. It brings together the protocol itself and, in addition, includes a description of each of the proposed variables that has shown to have a greater prognostic impact in previous works.

  6. Metastatic Malignant Melanoma With Complete Loss of Differentiation Markers (Undifferentiated/Dedifferentiated Melanoma): Analysis of 14 Patients Emphasizing Phenotypic Plasticity and the Value of Molecular Testing as Surrogate Diagnostic Marker.

    PubMed

    Agaimy, Abbas; Specht, Katja; Stoehr, Robert; Lorey, Thomas; Märkl, Bruno; Niedobitek, Gerald; Straub, Melanie; Hager, Thomas; Reis, Anna-Carinna; Schilling, Bastian; Schneider-Stock, Regine; Hartmann, Arndt; Mentzel, Thomas

    2016-02-01

    Metastatic malignant melanoma is notorious for its phenotypic diversity and loss of differentiation markers. We herein summarized our experience with 14 metastatic melanomas showing complete loss of immunohistochemical melanocytic markers (with or without heterologous differentiation). Patients included 11 men and 3 women aged 24 to 78 years (median, 67 y). Thirteen patients had histologically confirmed primary skin melanoma, and 1 had metastatic melanoma of unknown primary. Undifferentiated metastasis was diagnosed synchronous to primary tumor (n=1), following skin melanoma by 3 months to 9 years (n=11) and preceding it by 1 year (n=1). Sites of undifferentiated metastases were axillary (3), inguinal (1), or submandibular (1) lymph nodes, digestive tract (2), bone/soft tissue (2), lung/pleura (2), and disseminated (n=3). Histology of metastases mimicked undifferentiated pleomorphic or spindle cell sarcoma with variable myxoid and giant cell areas (n=10) and cytokeratin-positive undifferentiated small cell sarcoma (n=1). Three cases showed heterologous dedifferentiation: pleomorphic rhabdomyosarcoma (n=1), teratocarcinosarcoma-like with prominent rhabdomyoblasts (n=1), and adenocarcinoma-like with metaplastic bone (n=1). All cases were negative for S100, melanoma cocktail, HMB45, Melan A, and SOX10. Other markers showed following results: smooth muscle actin (1/14), p16 (1/14), TP53 (2/12), pancytokeratin (4/14), desmin (5/14), h-caldesmon (0/9), and MDM2/CDK4 (0/5). SMARCB1 was intact in 8/8 cases. Genotyping showed BRAF(V600E) mutation (5/14), NRAS mutation (5/14), and BRAF/NRAS wild-type (4/14). In conclusion, undifferentiated/dedifferentiated metastatic melanoma is likely underrecognized and frequently mistaken for undifferentiated sarcoma or other neoplasms. Diagnosis of undifferentiated sarcoma at sites where melanoma metastasis are frequent (eg, inguinal and axillary region) should be made with great caution and warrants exploration of the remote history

  7. BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts.

    PubMed

    Kemper, Kristel; Krijgsman, Oscar; Kong, Xiangjun; Cornelissen-Steijger, Paulien; Shahrabi, Aida; Weeber, Fleur; van der Velden, Daphne L; Bleijerveld, Onno B; Kuilman, Thomas; Kluin, Roel J C; Sun, Chong; Voest, Emile E; Ju, Young Seok; Schumacher, Ton N M; Altelaar, A F Maarten; McDermott, Ultan; Adams, David J; Blank, Christian U; Haanen, John B; Peeper, Daniel S

    2016-06-28

    The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.

  8. Expression of MAGE-C1/CT7 and MAGE-C2/CT10 Predicts Lymph Node Metastasis in Melanoma Patients

    PubMed Central

    Mihic-Probst, Daniela; Seifert, Burkhardt; Soldini, Davide; Dummer, Reinhard; Knuth, Alexander; van den Broek, Maries; Moch, Holger

    2011-01-01

    MAGE-C1/CT7 and MAGE-C2/CT10 are members of the large MAGE family of cancer-testis (CT) antigens. CT antigens are promising targets for immunotherapy in cancer because their expression is restricted to cancer and germ line cells and a proportion of cancer patients presents with immune responses against CT antigens, which clearly demonstrates their immunogenicity. This study investigates the expression of MAGE-C1/CT7 and MAGE-C2/CT10 in primary and metastatic melanoma. Immunohistochemical staining of tissue microarrays that consisted of 59 primary malignant melanomas of the skin, 163 lymph node and distant melanoma metastases and 68 melanoma cell lines was performed. We found MAGE-C1/CT7 expression in 15 out of 50 (24%) primary melanomas and 15 out of 50 (24%) cell lines, whereas MAGE-C2/CT10 was detected in 17 out of 51 (33%) primary melanomas and 14 out of 68 (17%) cell lines. MAGE-C1/CT7 and MAGE-C2/CT10 were both detected in 40% of melanoma metastases. Patients with MAGE-C1/CT7 or MAGE-C2/CT10 positive primary melanoma had significantly more lymph node metastases (p = 0.005 and p<0.001, resp.). Prediction of lymph node metastasis by MAGE-C1/CT7 and MAGE-C2/CT10 was independent of tumor cell proliferation rate (Ki67 labeling index) in a multivariate analysis (p = 0.01). Our results suggest that the expression of MAGE-C1/CT7 and MAGE-C2/CT10 in primary melanoma is a potent predictor of sentinel lymph node metastasis. PMID:21738656

  9. Quality of life in the follow-up of uveal melanoma patients after CyberKnife treatment.

    PubMed

    Klingenstein, Annemarie; Fürweger, Christoph; Nentwich, Martin M; Schaller, Ulrich C; Foerster, Paul I; Wowra, Berndt; Muacevic, Alexander; Eibl, Kirsten H

    2013-12-01

    To assess quality of life in uveal melanoma patients within the first and second year after CyberKnife radiosurgery. Overall, 91 uveal melanoma patients were evaluated for quality of life through the Short-form (SF-12) Health Survey at baseline and at every follow-up visit over 2 years after CyberKnife radiosurgery. Statistical analysis was carried out using SF Health Outcomes Scoring Software and included subgroup analysis of patients developing secondary glaucoma and of patients maintaining a best corrected visual acuity (BCVA) of the treated eye of 0.5 log(MAR) or better. Analysis of variance, Greenhouse-Geisser correction, Student's t-test, and Fisher's exact test were used to determine statistical significance. Physical Functioning (PF) and Role Physical (RP) showed a significant decrease after CyberKnife radiosurgery, whereas Mental Health (MH) improved (P=0.007, P<0.0001 and P=0.023). MH and Social Functioning (SF) increased significantly (P=0.0003 and 0.026) in the no glaucoma group, MH being higher compared with glaucoma patients (P=0.02). PF and RP were significantly higher in patients with higher BCVA at the second follow-up (P=0.02). RP decreased in patients with BCVA<0.5 log(MAR) (P=0.013). Vitality (VT) increased significantly in patients whose BCVA could be preserved (P=0.031). Neither tumor localization nor size influenced the development of secondary glaucoma or change in BCVA. Although PF and RP decreased over time, MH improved continuously. Prevention of secondary glaucoma has a significant influence on both SF and MH, whereas preservation of BCVA affects VT. Emotional stability throughout follow-up contributes positively toward overall quality of life. CyberKnife radiosurgery may contribute to attenuation of emotional distress in uveal melanoma patients.

  10. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients.

    PubMed

    Gros, Alena; Parkhurst, Maria R; Tran, Eric; Pasetto, Anna; Robbins, Paul F; Ilyas, Sadia; Prickett, Todd D; Gartner, Jared J; Crystal, Jessica S; Roberts, Ilana M; Trebska-McGowan, Kasia; Wunderlich, John R; Yang, James C; Rosenberg, Steven A

    2016-04-01

    Detection of lymphocytes that target tumor-specific mutant neoantigens--derived from products encoded by mutated genes in the tumor--is mostly limited to tumor-resident lymphocytes, but whether these lymphocytes often occur in the circulation is unclear. We recently reported that intratumoral expression of the programmed cell death 1 (PD-1) receptor can guide the identification of the patient-specific repertoire of tumor-reactive CD8(+) lymphocytes that reside in the tumor. In view of these findings, we investigated whether PD-1 expression on peripheral blood lymphocytes could be used as a biomarker to detect T cells that target neoantigens. By using a high-throughput personalized screening approach, we identified neoantigen-specific lymphocytes in the peripheral blood of three of four melanoma patients. Despite their low frequency in the circulation, we found that CD8(+)PD-1(+), but not CD8(+)PD-1(-), cell populations had lymphocytes that targeted 3, 3 and 1 unique, patient-specific neoantigens, respectively. We show that neoantigen-specific T cells and gene-engineered lymphocytes expressing neoantigen-specific T cell receptors (TCRs) isolated from peripheral blood recognized autologous tumors. Notably, the tumor-antigen specificities and TCR repertoires of the circulating and tumor-infiltrating CD8(+)PD-1(+) cells appeared similar, implying that the circulating CD8(+)PD-1(+) lymphocytes could provide a window into the tumor-resident antitumor lymphocytes. Thus, expression of PD-1 identifies a diverse and patient-specific antitumor T cell response in peripheral blood, providing a novel noninvasive strategy to develop personalized therapies using neoantigen-reactive lymphocytes or TCRs to treat cancer.

  11. NY-ESO-1 specific antibody and cellular responses in melanoma patients primed with NY-ESO-1 protein in ISCOMATRIX and boosted with recombinant NY-ESO-1 fowlpox virus.

    PubMed

    Chen, Ji-Li; Dawoodji, Amina; Tarlton, Andrea; Gnjatic, Sacha; Tajar, Abdelouahid; Karydis, Ioannis; Browning, Judy; Pratap, Sarah; Verfaille, Christian; Venhaus, Ralph R; Pan, Linda; Altman, Douglas G; Cebon, Jonathan S; Old, Lloyd L; Nathan, Paul; Ottensmeier, Christian; Middleton, Mark; Cerundolo, Vincenzo

    2015-03-15

    Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX particles (NY-ESO-1 ISCOMATRIX) have shown to elicit combined NY-ESO-1 specific antibody and T cell responses. However, it remains unclear whether heterologous prime-boost strategies based on the combination with NY-ESO-1 ISCOMATRIX with different NY-ESO-1 boosting reagents could be used to increase NY-ESO-1 CD8(+) or CD4(+) T cell responses. To address this question, we carried out a randomized clinical trial in 39 high-risk, resected melanoma patients vaccinated with NY-ESO-1 ISCOMATRIX, and then boosted with repeated injections of either recombinant fowlpox virus encoding full length NY-ESO-1 (rF-NY-ESO-1) (Arm A) or NY-ESO-1 ISCOMATRIX alone (Arm B). We have comprehensively analyzed NY-ESO-1 specific T cells and B cells response in all patients before and after vaccination for a total of seven time points per patient. NY-ESO-1 ISCOMATRIX alone elicited a strong NY-ESO-1 specific CD4(+) T cell and antibody response, which was maintained by both regiments at similar levels. However, CD8(+) T cell responses were significantly boosted in 3 out of 18 patients in Arm A after the first rF-NY-ESO-1 injection and such responses were maintained until the end of the trial, while no patients in Arm B showed similar CD8(+) T cell responses. In addition, our results clearly identified immunodominant regions in the NY-ESO-1 protein: NY-ESO-179-102 and NY-ESO-1115-138 for CD4+ T cells and NY-ESO-185-108 for CD8+ T cells in a large proportion of vaccinated patients. These regions of NY-ESO-1 protein should be considered in future clinical trials as immunodominant epitopes.

  12. Antibody response to 7-valent conjugated pneumococcal vaccine in patients with chronic lymphocytic leukaemia.

    PubMed

    Sinisalo, Marjatta; Vilpo, Juhani; Itälä, Maija; Väkeväinen, Merja; Taurio, Jyrki; Aittoniemi, Janne

    2007-12-21

    Chronic lymphocytic leukaemia (CLL) is a common adulthood mature B-cell neoplasm. Infections are the most important cause of mortality in this condition, and Streptococcus pneumoniae has been considered the most important single pathogen. We investigated the immunogenicity of 7-valent pneumococcal conjugate vaccine in patients with CLL. The study material comprised 52 patients with CLL and 25 age- and sex-matched controls. The subjects were vaccinated with Prevenar pneumococcal conjugate vaccine. Serum samples were taken for antibody determinations before and four weeks after vaccination. Antibody response rates to vaccine antigens were lower in patients with CLL compared to controls. However, if the vaccine had been administered at an early stage of the disease, i.e. before commencement of chemotherapy and the development of hypogammaglobulinaemia, a significant vaccination response to at least six antigens was obtained in almost 40% of the CLL patients. Our results indicate that early administration of conjugate vaccine may be beneficial in CLL.

  13. Comparison of participants and non-participants in a randomized psychosocial intervention study among patients with malignant melanoma.

    PubMed

    Boesen, Ellen; Boesen, Sidsel; Christensen, Søren; Johansen, Christoffer

    2007-01-01

    The authors investigated barriers for entering a randomized psychosocial intervention study among patients with malignant melanoma. Data on age, sex, prognostic factors, social class, marital status, mood, coping, social relations, and social desirability from participants and non-participants were compared in a regression model. More patients in lower socioeconomic classes declined participation. Non-participation was associated with low levels of distress and adaptive coping and higher levels of empathy and congruence from spouses. The type of intervention offered in this study may have more appeal to patients belonging to higher socioeconomic classes.

  14. Antibody response of patients after postexposure rabies vaccination with small intradermal doses of purified chick embryo cell vaccine or purified Vero cell rabies vaccine.

    PubMed Central

    Briggs, D. J.; Banzhoff, A.; Nicolay, U.; Sirikwin, S.; Dumavibhat, B.; Tongswas, S.; Wasi, C.

    2000-01-01

    Although the introduction of tissue culture vaccines for rabies has dramatically improved the immunogenicity and safety of rabies vaccines, they are often prohibitively expensive for developing countries. To examine whether smaller doses of these vaccines could be used, we tested the safety and immunogenicity of purified chick embryo cell vaccine (PCECV) on 211 patients in Thailand with World Health Organization (WHO) category II and III exposures to rabies. The patients presented at two Thai hospitals and were randomized into three groups. Patients in Group 1 received 0.1 ml PCECV intradermally at two sites on days 0, 3, 7, and at one site on days 30 and 90. Group 2 was treated similarly, except that purified Vero cell rabies vaccine (PVRV) was used instead of PCECV. Group 3 received 1.0 ml PCECV intramuscularly on days 0, 3, 7, 14, 30 and 90. After 0, 3, 7, 14, 30 and 90 days serum was collected from the subjects and the geometric mean titres (GMTs) of rabies virus neutralizing antibody determined. After 14 days the GMT of 59 patients vaccinated intradermally with PCECV was equivalent to that of patients who received PVRV. Adverse reactions were more frequent in patients who received vaccines intradermally, indicating the reactions were associated with the route of injection, rather than the vaccine per se. We conclude that PCECV is a safe and highly immunogenic vaccine for postexposure rabies vaccination when administered intradermally in 0.1-ml doses using the two-site method ("2,2,2,0,1,1") recommended by WHO. PMID:10859864

  15. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients

    PubMed Central

    Radvanyi, Laszlo G.; Bernatchez, Chantale; Zhang, Minying; Fox, Patricia S.; Miller, Priscilla; Chacon, Jessica; Wu, Richard; Lizee, Gregory; Mahoney, Sandy; Alvarado, Gladys; Glass, Michelle; Johnson, Valen E.; McMannis, John D.; Shpall, Elizabeth; Prieto, Victor; Papadopoulos, Nicholas; Kim, Kevin; Homsi, Jade; Bedikian, Agop; Hwu, Wen-Jen; Patel, Sapna; Ross, Merrick I.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Lucci, Anthony; Royal, Richard; Cormier, Janice N.; Davies, Michael A.; Mansaray, Rahmatu; Fulbright, Orenthial J.; Toth, Christopher; Ramachandran, Renjith; Wardell, Seth; Gonzalez, Audrey; Hwu, Patrick

    2012-01-01

    Purpose Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing Phase II clinical trial testing the efficacy of ACT using TIL in metastatic melanoma patients and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL followed by two cycles of high-dose (HD) IL-2 therapy. The effects of patient clinical features and the phenotypes of the T-cells infused on clinical response were determined. Results Overall, 15/31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC), with two patients (6.5%) having a complete response. Progression-free survival of >12 months was observed for 9/15 (60%) of the responding patients. Factors significantly associated with objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T-cells in the infusion product, a more differentiated effector phenotype of the CD8+ population and a higher frequency of CD8+ T-cells co-expressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in telomere lengths of TIL between responders and non-responders was identified. Conclusion These results indicate that immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in metastatic melanoma patients and that CD8+ T-cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. PMID:23032743

  16. Uveal Melanoma Recurrence After Fractionated Proton Beam Therapy: Comparison of Survival in Patients Treated With Reirradiation or With Enucleation

    SciTech Connect

    Marucci, Laura; Ancukiewicz, Marek; Lane, Anne Marie; Collier, John M.; Gragoudas, Evangelos S.; Munzenrider, John E.

    2011-03-01

    Purpose: To retrospectively compare survival in recurrent uveal melanoma, between patients treated by enucleation or by a second course of fractionated proton beam therapy (PBT). Methods and Materials: Tumor recurrence was documented in 73 patients treated with PBT for uveal melanoma. Of the patients, 31 received a second course of PBT and 42 underwent enucleation. The mean patient age was 56 and 61 years for those undergoing enucleation and those undergoing reirradiation, respectively. Both primary and recurrent tumors were larger in patients undergoing enucleation. Tumor location and the presence or absence of ciliary body involvement did not differ significantly between the groups. The median follow-up after enucleation and after re-treatment was 79 and 59 months, respectively. Cumulative rates of outcomes and differences in rates between the reirradiated and enucleation groups were calculated by the Cox proportional hazards model and the log-rank test, respectively. Results: The median survival duration in the enucleated and reirradiated groups was 42 and 90 months, respectively. The median time free of metastases was 38 months in enucleated patients and 97 months in reirradiated patients. At 5 years after enucleation and after reirradiation, the probability of overall survival was 36% and 63%, respectively (p = 0.040, log-rank test); the probability of freedom from metastases was 31% and 66%, respectively (p = 0.028, log-rank test). These differences persisted after adjustment for recurrent tumor largest diameter and volume at the time of reirradiation or enucleation. Conclusions: This retrospective analysis suggests that survival in reirradiated patients is not compromised by administration of a second course of PBT for recurrent uveal melanoma.

  17. 12-Chemokine Gene Signature Identifies Lymph Node-like Structures in Melanoma: Potential for Patient Selection for Immunotherapy?

    NASA Astrophysics Data System (ADS)

    Messina, Jane L.; Fenstermacher, David A.; Eschrich, Steven; Qu, Xiaotao; Berglund, Anders E.; Lloyd, Mark C.; Schell, Michael J.; Sondak, Vernon K.; Weber, Jeffrey S.; Mulé, James J.

    2012-10-01

    We have interrogated a 12-chemokine gene expression signature (GES) on genomic arrays of 14,492 distinct solid tumors and show broad distribution across different histologies. We hypothesized that this 12-chemokine GES might accurately predict a unique intratumoral immune reaction in stage IV (non-locoregional) melanoma metastases. The 12-chemokine GES predicted the presence of unique, lymph node-like structures, containing CD20+ B cell follicles with prominent areas of CD3+ T cells (both CD4+ and CD8+ subsets). CD86+, but not FoxP3+, cells were present within these unique structures as well. The direct correlation between the 12-chemokine GES score and the presence of unique, lymph nodal structures was also associated with better overall survival of the subset of melanoma patients. The use of this novel 12-chemokine GES may reveal basic information on in situ mechanisms of the anti-tumor immune response, potentially leading to improvements in the identification and selection of melanoma patients most suitable for immunotherapy.

  18. Response to hepatitis A vaccine in HIV patients in the HAART era.

    PubMed

    Rimland, David; Guest, Jodie L

    2005-10-14

    We evaluated the development of hepatitis A antibody after vaccination in a large cohort of patients studied in a clinical setting after the introduction of HAART. Overall, 130 of 214 vaccinated individuals developed hepatitis A antibody. In a multivariate analysis, only the CD4 cell count at the time of vaccination was associated with an absence of response. The lack of association with the nadir CD4 cell count suggests that patients will respond to vaccine after immunological reconstitution in response to HAART.

  19. Eosinophilic Fasciitis and Acute Encephalopathy Toxicity from Pembrolizumab Treatment of a Patient with Metastatic Melanoma.

    PubMed

    Khoja, Leila; Maurice, Catherine; Chappell, MaryAnne; MacMillan, Leslie; Al-Habeeb, Ayman S; Al-Faraidy, Nada; Butler, Marcus O; Rogalla, Patrik; Mason, Warren; Joshua, Anthony M; Hogg, David

    2016-03-01

    Anti-PD-1 inhibitors have significant activity in metastatic melanoma. Responses often occur early and may be sustained. The optimal duration of treatment with these agents is unknown. Here, we report the case of a 51-year-old woman treated with pembrolizumab, as part of the Keynote-001 trial, as first-line treatment for metastatic disease. She experienced a complete response after 13.8 months of treatment with no adverse events. One month after the last drug infusion and 18 months from starting treatment, the patient presented with eosinophilic fasciitis. She then developed acute confusion and weakness, thought to be due to intracranial vasculitis. High-dose steroids were initiated with resolution of the fasciitis. Aspirin was commenced for presumed vasculitis with resolution of the neurologic symptoms. To our knowledge, there are no previous reports of eosinophilic fasciitis or cerebral vasculitis due to anti-PD-1 agents. This case demonstrates that toxicity may occur in association with pembrolizumab treatment after a prolonged period of treatment without toxicity. Future trials should explore the optimal duration of treatment with pembrolizumab.

  20. Phase II Trial of Combination Thalidomide plus Temozolomide in Patients with Metastatic Malignant Melanoma: Southwest Oncology Group S0508

    PubMed Central

    Clark, Joseph I.; Moon, James; Hutchins, Laura F.; Sosman, Jeffrey A.; Kast, W. Martin; Da Silva, Diane M.; Liu, P.Y.; Thompson, John A.; Flaherty, Lawrence E.; Sondak, Vernon K.

    2009-01-01

    Purpose In limited institution Phase II studies, thalidomide and temozolomide has yielded response rates (RR) up to 32% for advanced melanoma, leading to the use of this combination as “standard” by some. We conducted a multi-center Phase II trial to better define the clinical efficacy of thalidomide and temozolomide and the immune modulatory effects of thalidomide, when combined with temozolomide, in patients with metastatic melanoma. Patients and Methods Patients must have had stage IV cutaneous melanoma, no active brain metastases, Zubrod PS 0–1, up to 1 prior systemic therapy excluding thalidomide, temozolomide or dacarbazine, adequate organ function, and given informed consent. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included survival (OS), RR, toxicities, and assessment of relationships between biomarkers and clinical outcomes. Patients received thalidomide (200mg/d escalated to 400mg/d for patients <70, or 100mg/d escalated to 250mg/d for patients ≥70) plus temozolomide (75mg/m2/d × 6 weeks then 2 weeks rest). Results Sixty-four patients were enrolled; 2 refused treatment. The 6-month PFS was 15% (95% CI, 6%–23%); 1-year OS was 35% (95% CI, 24%–47%); RR was 13% (95% CI, 5%–25%), all partial. One treatment-related death occurred from myocardial infarction; 3 other Grade 4 events occurred including pulmonary embolism, neutropenia and CNS ischemia. There was no significant correlation between biomarkers and PFS or OS. Conclusion This combination of thalidomide and temozolomide does not appear to have a clinical benefit that exceeds dacarbazine alone. We would not recommend it further for phase III trials or for standard community use. PMID:19918923

  1. Vaccines

    MedlinePlus Videos and Cool Tools

    Vaccinations are injections of antigens into the body. Once the antigens enter the blood, they circulate along ... suppressor T cells stop the attack. After a vaccination, the body will have a memory of an ...

  2. Evaluation of the response to vaccination with hepatitis B vaccine in pediatric patients diagnosed with celiac disease

    PubMed Central

    Egberg, Matthew; Nelson, Catherine; Eickoff, Jens

    2014-01-01

    Background: A gap exists in the literature on celiac disease populations and the response to hepatitis B vaccination. Objective: To identify pediatric patients with celiac disease who received the primary hepatitis B vaccination and investigate their response to vaccine. Design/Methods: Patients underwent blood draw for hepatitis B surface antibody titers. Patients with undetectable or non-protective HBsAb titers were contacted. Study outcome measures and patient characteristics variables were summarized by means, standard deviations, medians, and ranges. A two-sample t-test was used to compare normally distributed continuous variables between responders and non-responders. Results: In all, 58% of patients did not meet the threshold for “protective” antibody titers. The mean time between completion of hepatitis B vaccination and diagnosis of celiac disease was 8.1 years for responders versus 10.5 years for non-responders. In a multivariate analysis, time between completion of vaccine and diagnosis of celiac disease was statistically significant predictor of response with an adjusted odds ratio of 0.69 (95% confidence interval: 0.50–0.95; p = 0.021). Conclusion: Our celiac disease population shows a high hepatitis B vaccine failure. The time between completion of vaccine series and diagnosis of celiac disease is an independent predictor for response. PMID:26770758

  3. Molecular staging by multimarker reverse transcriptase-polymerase chain reaction assay of lymphatic drainage and blood from melanoma patients after lymph node dissection.

    PubMed

    Rutkowski, Piotr; Nowecki, Zbigniew I; Kulik, Jadwiga; Ruka, Wlodzimierz; Siedlecki, Janusz A

    2008-08-01

    Reverse transcriptase-polymerase chain reaction (RT-PCR)-mediated detection of melanoma cells may be a prognostic factor for disease outcome. We investigated the presence of melanoma cells in lymphatic drainage and blood in melanoma patients after lymph node dissection (LND) via the highly sensitive multimarker (MM) RT-PCR assay. We collected 24-h lymph fluid (LY) and peripheral blood (BL) from 107 stage III melanoma patients after radical LND (59 axillary and 48 ilioinguinal LND). Tyrosinase, MART1 and uMAGE mRNA levels were determined by RT-PCR to detect melanoma cells, and the presence of at least one marker signified a positive result. All patients underwent follow-up (median for survivors, 21 months, range: 4-37 months). Forty patients (37.4%) were positive for LY MM RT-PCR and 28 (26.2%) were positive based on BL MM RT-PCR. No differences for disease-free survival (DFS) curves according to BL MM RT-PCR were observed, but we found significant differences in the estimated 24-month DFS rate for patients with at least one marker and those without any marker in lymph fluid [18.9% (95% confidence interval: 1.4-37.5%) and 42.1% (95% confidence interval: 29.7-54.5%), median: 9.9 and 15.3 months, respectively] (P=0.04). Detection of multiple markers in lymph fluid correlated with shorter DFS. Approximately 37% of lymph fluid after radical LND were positive by MM RT-PCR, which correlated significantly with early melanoma recurrences and shorter survival. The LY MM RT-PCR seems to be an effective prognostic tool for stage III melanoma patients. The MM RT-PCR analysis of single peripheral blood sample in these patients did not have additional prognostic value.

  4. Hepatitis A and B screening and vaccination rates among patients with chronic liver disease.

    PubMed

    Ramirez, Jonathan C; Ackerman, Kimberly; Strain, Sasha C; Ahmed, Syed T; de Los Santos, Mario J; Sears, Dawn

    2016-01-01

    Vaccinations against hepatitis A virus (HAV) and hepatitis B virus (HBV) are recommended for patients with chronic liver disease (CLD), yet implementation of these recommendations is lacking. This study reviewed HAV and HBV antibody testing and vaccination status of patients with CLD. In 2008, we began using pre-printed liver order sets, which included vaccination options. We compared Scott & White liver clinic CLD patient records from 2005 (238) with patient records from 2008 (792). Screening rates for immunity and vaccination rates of those lacking immunity were calculated. In 2005, 66% of CLD patients were screened for HAV immunity. In 2008, 56% of CLD patients were screened. The HAV vaccination completion rate was 37% in 2005, while in 2008, the rate was 46%. In 2005, 66% of CLD patients were screened for HBV immunity; in 2008, 56 % CLD patients were screened. The HBV vaccination completion rate was 26% in 2005 compared with 36% in 2008. Although there was a lower percentage of screening in 2008, the overall number of patients tripled between 2005 and 2008. There was a significant increase in the total number of patients screened and vaccinated in 2008. Some physicians may have vaccinated their patients without checking for immunity. In January 2008, we implemented pre-printed order sets with checkboxes to help remind providers to order labs to screen for immunity against HAV and HBV and to order vaccinations for those who lacked immunity. The use of these sets may have aided in the increase of vaccination completion rates.

  5. In situ photoimmunotherapy for melanoma: preliminary clinical results

    NASA Astrophysics Data System (ADS)

    Naylor, Mark F.; Nordquist, Robert E.; Teauge, T. Kent; Perry, Lisa A.; Chen, Wei R.

    2006-02-01

    Although melanoma accounts for only 4% of skin cancer cases, it causes 79% of all skin cancer deaths. Patients with metastatic melanoma have a poor prognosis, and long term survival is only about 5% [1, 2]. Conventional therapies such as surgery and radiation therapy usually do not cure stage III or stage IV melanoma, while traditional chemotherapy is primarily palliative. Over the last decade we have been developing new methods for treating solid tumors like melanoma, first in animal models and now in humans. We present here preliminary results from a new technique that utilizes a combination of laser stimulation and drug therapy to stimulate brisk immunological responses in cases of advanced melanoma with cutaneous metastases. A high-power, near-infrared diode laser (805 nm) is used to kill tumors in situ and a topical toll-like receptor agonist (imiquimod cream, 5%) is used to intensify the resulting immunological response. This is essentially an in situ, tumor vaccine approach to treating solid tumors.

  6. Stereotactic Radiosurgery for Melanoma Brain Metastases in Patients Receiving Ipilimumab: Safety Profile and Efficacy of Combined Treatment

    SciTech Connect

    Kiess, Ana P.; Wolchok, Jedd D.; Barker, Christopher A.; Postow, Michael A.; Tabar, Viviane; Huse, Jason T.; Chan, Timothy A.; Yamada, Yoshiya; Beal, Kathryn

    2015-06-01

    Purpose: Ipilimumab (Ipi), a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, has been shown to improve survival in patients with metastatic melanoma. In this single-institution study, we investigated the safety and efficacy of stereotactic radiosurgery (SRS) for patients with melanoma brain metastases (BMs) who also received Ipi. Methods and Materials: From 2005 to 2011, 46 patients with melanoma received Ipi and underwent single-fraction SRS for BMs. A total of 113 BMs (91% intact, 9% postoperative) were treated with a median dose of 21 Gy (range, 15-24 Gy). Ipi was given at 3 mg/kg (54%) or 10 mg/kg (46%) for a median of 4 doses (range, 1-21). Adverse events were recorded with the use of the Common Terminology Criteria for Adverse Events 3.0. Kaplan-Meier methods were used to estimate survival, and Cox regression was used to investigate associations. Results: Fifteen patients received SRS during Ipi, 19 received SRS before Ipi, and 12 received SRS after Ipi. Overall survival (OS) was significantly associated with the timing of SRS/Ipi (P=.035) and melanoma-specific graded prognostic assessment (P=.013). Patients treated with SRS during or before Ipi had better OS and less regional recurrence than did those treated with SRS after Ipi (1-year OS 65% vs 56% vs 40%, P=.008; 1-year regional recurrence 69% vs 64% vs 92%, P=.003). SRS during Ipi also yielded a trend toward less local recurrence than did SRS before or after Ipi (1-year local recurrence 0% vs 13% vs 11%, P=.21). On magnetic resonance imaging, an increase in BM diameter to >150% was seen in 50% of patients treated during or before Ipi but in only 13% of patients treated after Ipi. Grade 3 to 4 toxicities were seen in 20% of patients. Conclusion: Overall, the combination of Ipi and SRS appears to be well tolerated. Concurrent delivery of Ipi and SRS is associated with favorable locoregional control and possibly longer survival. It may also cause a temporary increase in tumor size, possibly

  7. Positron emission tomography in the follow-up of cutaneous malignant melanoma patients: a systematic review

    PubMed Central

    Danielsen, Maria; Højgaard, Liselotte; Kjær, Andreas; Fischer, Barbara MB

    2014-01-01

    Cutaneous malignant melanoma (CMM) has a high risk of dissemination to regional lymph nodes and visceral organs. Recurrences are most frequently seen within the first 2-3 years after initial treatment, but these patients have a life-long risk of relapse. The prognosis is highly dependent on lymph node involvement and distant metastases, accentuating the importance of close surveillance to identify disease progression at an early stage, and thereby detect recurrences amenable to treatment. Positron emission tomography (PET) has already been proven useful in the staging of CMM, but the utility of PET in follow-up programs for asymptomatic patients in high risk of relapse to detect systemic recurrences has yet to be investigated. We performed a systematic literature search in PUBMED, EMBASE and the Cochrane Controlled Trials Register, and identified 7 original studies on the diagnostic value of FDG-PET in the follow-up of CMM. Sensitivity, specificity, positive and negative predictive values were calculated to examine PET’s diagnostic value in detecting relapse. The mean sensitivity of PET was 96% and the specificity was 92%. The positive and negative predictive values were, respectively, 92% and 95%. Overall, PET has a high diagnostic value and the many advantages of PET indicate utility in the routine follow-up program of CMM. However, the number of prospective studies of high quality is scarce, and as the use of PET and PET/CT is becoming more widespread and the technology is expensive, there is an urgent need for systematic assessment of the diagnostic value. PMID:24380042

  8. Common glycoproteins expressing polylactosamine-type glycans on matched patient primary and metastatic melanoma cells show different glycan profiles.

    PubMed

    Kinoshita, Mitsuhiro; Mitsui, Yosuke; Kakoi, Naotaka; Yamada, Keita; Hayakawa, Takao; Kakehi, Kazuaki

    2014-02-07

    Recently, we reported comparative analysis of glycoproteins which express cancer-specific N-glycans on various cancer cells and identified 24 glycoproteins having polylactosamine (polyLacNAc)-type N-glycans that are abundantly present in malignant cells [ Mitsui et al., J. Pharm. Biomed. Anal. 2012 , 70 , 718 - 726 ]. In the present study, we applied the technique to comparative studies on common glycoproteins present in the matched patient primary and metastatic melanoma cell lines. Metastatic melanoma cells (WM266-4) contained a large amount of polyLacNAc-type N-glycans in comparison with primary melanoma cells (WM115). To identify the glycoproteins expressing these N-glycans, glycopeptides having polyLacNAc-type N-glycans were captured by a Datura stramonium agglutinin (DSA)-immobilized agarose column. The captured glycopeptides were analyzed by LC/MS after removing N-glycans, and some glycoproteins such as basigin, lysosome-associated membrane protein-1 (LAMP-1), and chondroitin sulfate proteoglycan 4 (CSPG4) were identified in both WM115 and WM266-4 cells. The expression level of polyLacNAc of CSPG4 in WM266-4 cells was significantly higher than that in WM115 cells. In addition, sulfation patterns of chondroitin sulfate (CS) chains in CSPG4 showed dramatic changes between these cell lines. These data show that characteristic glycans attached to common proteins observed in different stages of cancer cells will be useful markers for determining degree of malignancies of tumor cells.

  9. Energy balance in patients with advanced NSCLC, metastatic melanoma and metastatic breast cancer receiving chemotherapy--a longitudinal study.

    PubMed

    Harvie, M N; Howell, A; Thatcher, N; Baildam, A; Campbell, I

    2005-02-28

    Chemotherapy exerts a variable effect on nutritional status. It is not known whether loss of body fat or fat-free mass (FFM) during chemotherapy relates to diminished dietary intake, failure to meet elevated energy requirements, or to the presence of an acute-phase response. We sought to determine prospective measurements of body mass and composition, resting energy expenditure, energy and protein intake, and C-reactive protein over a course of chemotherapy in 82 patients with advanced cancer. There was a large dropout from the study. Prospective measurements were obtained in 19 patients with non-small-cell lung cancer (NSCLC), 12 with metastatic melanoma and 10 with metastatic breast cancer. There were significant increases in energy intake among patients with metastatic breast cancer, 873 (266-1480) kJ (mean 95% CI; P<0.01), and metastatic melanoma, 2513 (523-4503) kJ (P<0.01). Breast cancer patients gained percentage body fat over the course of treatment, 2.1 (0.8-3.5%). Gain or loss of body fat correlated to mean energy intake throughout chemotherapy in patients with NSCLC (Rs=0.751; P<0.01) and metastatic breast cancer (Rs=0.617; P<0.05). The ability to meet or exceed energy requirements led to gains in body fat among patients with metastatic breast cancer and NSCLC, but did not prevent loss of FFM in these groups.

  10. The DecisionDx-UM Gene Expression Profile Test Provides Risk Stratification and Individualized Patient Care in Uveal Melanoma.

    PubMed

    Harbour, J William; Chen, Royce

    2013-04-09

    Uveal melanoma (UM) is the most common primary cancer of the eye and has a strong propensity for metastasis. Although there have been many recent improvements in the diagnosis and treatment of UM, and only 2-4% of patients present with detectable metastasis, up to half of patients are at risk for dying of metastatic disease. Clinicopathologic factors are not accurate enough for individualized patient care. Chromosomal alterations have been used for prognostic purposes, but the routine clinical use of these methods is limited by their susceptibility to sampling error resulting from tumor heterogeneity, limited clinical validation, lack of standardized testing platforms, and high technical failure rates. In contrast, the DecisionDx-UM gene expression profile test is a stand-alone platform which requires no other information for maximal prognostic accuracy and which circumvents many of the drawbacks of chromosomal methods through the use of a highly sensitive microfluidics, PCR-based platform that simultaneously measures the expression of 15 carefully selected genes from primary uveal melanoma samples obtained by fine needle biopsy. Low metastatic risk is reported as Class 1, and high metastatic risk as Class 2. The test allows patients to be stratified into risk categories such that high-risk patients can be offered intensive metastatic surveillance and adjuvant therapy while low-risk patients can be spared these interventions. This test is now used as part of the standard of care in many ocular oncology centers.

  11. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients.

    PubMed

    Wheeler, Christopher J; Black, Keith L; Liu, Gentao; Mazer, Mia; Zhang, Xiao-xue; Pepkowitz, Samuel; Goldfinger, Dennis; Ng, Hiushan; Irvin, Dwain; Yu, John S

    2008-07-15

    Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans.

  12. The Danish Melanoma Database

    PubMed Central

    Hölmich, Lisbet Rosenkrantz; Klausen, Siri; Spaun, Eva; Schmidt, Grethe; Gad, Dorte; Svane, Inge Marie; Schmidt, Henrik; Lorentzen, Henrik Frank; Ibfelt, Else Helene

    2016-01-01

    Aim of database The aim of the database is to monitor and improve the treatment and survival of melanoma patients. Study population All Danish patients with cutaneous melanoma and in situ melanomas must be registered in the Danish Melanoma Database (DMD). In 2014, 2,525 patients with invasive melanoma and 780 with in situ tumors were registered. The coverage is currently 93% compared with the Danish Pathology Register. Main variables The main variables include demographic, clinical, and pathological characteristics, including Breslow’s tumor thickness, ± ulceration, mitoses, and tumor–node–metastasis stage. Information about the date of diagnosis, treatment, type of surgery, including safety margins, results of lymphoscintigraphy in patients for whom this was indicated (tumors > T1a), results of sentinel node biopsy, pathological evaluation hereof, and follow-up information, including recurrence, nature, and treatment hereof is registered. In case of death, the cause and date are included. Currently, all data are entered manually; however, data catchment from the existing registries is planned to be included shortly. Descriptive data The DMD is an old research database, but new as a clinical quality register. The coverage is high, and the performance in the five Danish regions is quite similar due to strong adherence to guidelines provided by the Danish Melanoma Group. The list of monitored indicators is constantly expanding, and annual quality reports are issued. Several important scientific studies are based on DMD data. Conclusion DMD holds unique detailed information about tumor characteristics, the surgical treatment, and follow-up of Danish melanoma patients. Registration and monitoring is currently expanding to encompass even more clinical parameters to benefit both patient treatment and research. PMID:27822097

  13. Influenza Vaccination among Pregnant Women: Patient Beliefs and Medical Provider Practices

    PubMed Central

    Samelson, Renee; Siddiqui, Maryam M.; Paglia, Michael J.; Strassberg, Emmie R.; Kelly, Elizabeth; Murtough, Katie L.; Schulkin, Jay

    2016-01-01

    ACOG's research department recruited four medical centers to participate in a study on the attitudes and practices of medical providers and pregnant patients regarding influenza vaccination. Medical providers and patients were given voluntary surveys and medical record data was collected over two flu seasons, from 2013 to 2015. Discrepancies between self-reports of medical providers and patients and medical records were observed. Nearly 80% of patients self-reported accepting the influenza vaccine, but medical record data only reported 36% of patients accepting the vaccine. Similarly, all medical providers reported giving recommendations for the vaccine, but only 85% of patients reported receiving a recommendation. Age, education, a medical provider's recommendation, and educational materials were found to positively influence patient beliefs about the influenza vaccine. Accepting the vaccine was influenced by a patient's previous actions, beliefs, and a medical provider's recommendation. Patients who reported previously not accepting the vaccine and had negative feelings towards the vaccine but accepted it while pregnant reported concern for the health and safety of their baby. Future research should focus on groups that may be less likely to accept the vaccine and ways to dispel negative myths. Medical provider should continue to strongly recommend the vaccine and provide educational materials. PMID:27559272

  14. Preferences of German melanoma patients for interferon (IFN) α-2b toxicities (the DeCOG “GERMELATOX survey”) versus melanoma recurrence to quantify patients’ relative values for adjuvant therapy

    PubMed Central

    Kaehler, Katharina C.; Blome, Christine; Forschner, Andrea; Gutzmer, Ralf; Haalck, Thomas; Heinzerling, Lucie; Kornek, Thomas; Livingstone, Elisabeth; Loquai, Carmen; Maul, Lara Valeska; Lang, Berenice M.; Schadendorf, Dirk; Stade, Barbara; Terheyden, Patrick; Utikal, Jochen; Wagner, Tobias; Hauschild, Axel; Garbe, Claus; Augustin, Matthias

    2016-01-01

    Abstract Currently interferon alfa-2b (IFNα-2b) is an approved adjuvant drug for high-risk melanoma patients that leads to an improvement in disease-free survival (DFS). However, it is unclear whether it also impacts overall survival. Widespread use of adjuvant high-dose IFNα has been tempered by its significant toxicity and its limited efficacy. Current therapeutic strategies like immune checkpoint blockade or targeted therapy may also be useful in the adjuvant setting. Therefore, it is important to weigh the trade-offs between possible side effects and therapeutic benefit. We assessed patient utilities for health states associated with IFN therapy. Utilities are measures of preference for a specific health state on a scale of 0 (death) to 1 (perfect health). Utilities were determined for health states associated with adjuvant IFN among 130 German low-risk melanoma patients using the standard gamble technique. Four IFNα-2b toxicity scenarios and the following 3 posttreatment outcomes were assessed: disease-free health and melanoma recurrence (with or without previous use of IFNα-2b) resulting in cancer death. Patients were asked to trade-off the improvement in 5-year DFS and the IFN-related side effects. Utilities for melanoma recurrence (mean 0.60) were significantly lower than for all IFNα-2b toxicity scenarios (mean 0.81–0.90). Patients were willing to tolerate mild-to-moderate and severe toxicity for a 50% and 75% chance of 5-year DFS, respectively. Both utilities and threshold benefits were mostly independent from patient characteristics like gender, income, and social situation. Significant impact was only observed by age and previous personal experience with cancer. On average, German patients were willing to trade even severe IFNα-2b toxicity for reducing the rate of melanoma recurrence. This result points out the importance of a relapse-free survival for melanoma patients. The utilities measured in our study can be applied to decision

  15. Adjuvant Treatment of Melanoma

    PubMed Central

    Moreno Nogueira, J. A.; Valero Arbizu, M.; Pérez Temprano, R.

    2013-01-01

    Melanomas represent 4% of all malignant tumors of the skin, yet account for 80% of deaths from skin cancer.While in the early stages patients can be successfully treated with surgical resection, metastatic melanoma prognosis is dismal. Several oncogenes have been identified in melanoma as BRAF, NRAS, c-Kit, and GNA11 GNAQ, each capable of activating MAPK pathway that increases cell proliferation and promotes angiogenesis, although NRAS and c-Kit also activate PI3 kinase pathway, including being more commonly BRAF activated oncogene. The treatment of choice for localised primary cutaneous melanoma is surgery plus lymphadenectomy if regional lymph nodes are involved. The justification for treatment in addition to surgery is based on the poor prognosis for high risk melanomas with a relapse index of 50–80%. Patients included in the high risk group should be assessed for adjuvant treatment with high doses of Interferon-α2b, as it is the only treatment shown to significantly improve disease free and possibly global survival. In the future we will have to analyze all these therapeutic possibilities on specific targets, probably associated with chemotherapy and/or interferon in the adjuvant treatment, if we want to change the natural history of melanomas. PMID:23476798

  16. Tumor DNA in cerebral spinal fluid reflects clinical course in a patient with melanoma leptomeningeal brain metastases.

    PubMed

    Li, Yingmei; Pan, Wenying; Connolly, Ian D; Reddy, Sunil; Nagpal, Seema; Quake, Stephen; Gephart, Melanie Hayden

    2016-05-01

    Cerebral spinal fluid (CSF) from brain tumor patients contains tumor cellular and cell-free DNA (cfDNA), which provides a less-invasive and routinely accessible method to obtain tumor genomic information. In this report, we used droplet digital PCR to test mutant tumor DNA in CSF of a patient to monitor the treatment response of metastatic melanoma leptomeningeal disease (LMD). The primary melanoma was known to have a BRAF (V600E) mutation, and the patient was treated with whole brain radiotherapy and BRAF inhibitors. We collected 9 CSF samples over 6 months. The mutant cfDNA fraction gradually decreased from 53 % (time of diagnosis) to 0 (time of symptom alleviation) over the first 6 time points. Three months after clinical improvement, the patient returned with severe symptoms and the mutant cfDNA was again detected in CSF at high levels. The mutant DNA fraction corresponded well with the patient's clinical response. We used whole exome sequencing to examine the mutation profiles of the LMD tumor DNA in CSF before therapeutic response and after disease relapse, and discovered a canonical cancer mutation PTEN (R130*) at both time points. The cellular and cfDNA revealed similar mutation profiles, suggesting cfDNA is representative of LMD cells. This study demonstrates the potential of using cellular or cfDNA in CSF to monitor treatment response for LMD.

  17. Radiogenic Side Effects After Hypofractionated Stereotactic Photon Radiotherapy of Choroidal Melanoma in 212 Patients Treated Between 1997 and 2007

    SciTech Connect

    Dunavoelgyi, Roman; Dieckmann, Karin; Gleiss, Andreas; Sacu, Stefan; Kircher, Karl; Georgopoulos, Michael; Georg, Dietmar; Zehetmayer, Martin; Poetter, Richard

    2012-05-01

    Purpose: To evaluate side effects of hypofractionated stereotactic photon radiotherapy for patients with choroidal melanoma. Patients and Methods: Two hundred and twelve patients with choroidal melanoma unsuitable for ruthenium-106 brachytherapy or local resection were treated stereotactically at the Medical University of Vienna between 1997 and 2007 with a Linac with 6-MV photon beams in five fractions with 10, 12, or 14 Gy per fraction. Examinations for radiogenic side effects were performed at baseline and every 3 months in the first 2 years, then every 6 months until 5 years and then once a year thereafter until 10 years after radiotherapy. Adverse side effects were assessed using slit-lamp examination, funduscopy, gonioscopy, tonometry, and, if necessary, fundus photography and fluorescein angiography. Evaluations of incidence of side effects are based on an actuarial analysis. Results: One hundred and eighty-nine (89.2%) and 168 (79.2%) of the tumors were within 3 mm of the macula and the optic disc, respectively. The five most common radiotherapy side effects were retinopathy and optic neuropathy (114 cases and 107 cases, respectively), cataract development (87 cases), neovascular glaucoma (46 cases), and corneal epithelium defects (41 cases). In total, 33.6%, 38.5%, 51.2%, 75.5%, and 77.6% of the patients were free of any radiation retinopathy, optic neuropathy, cataract, neovascular glaucoma, or corneal epithelium defects 5 years after radiotherapy, respectively. Conclusion: In centrally located choroidal melanoma hypofractionated stereotactic photon radiotherapy shows a low to moderate rate of adverse long-term side effects comparable with those after proton beam radiotherapy. Future fractionation schemes should seek to further reduce adverse side effects rate while maintaining excellent local tumor control.

  18. Effects of commonly used chronic medications on the outcomes of ipilimumab therapy in patients with metastatic melanoma.

    PubMed

    Failing, Jarrett J; Finnes, Heidi D; Kottschade, Lisa A; Allred, Jacob B; Markovic, Svetomir N

    2016-12-01

    Ipilimumab can induce long-term survival in 20% of patients with metastatic melanoma. Concurrent chronic medications may impact the patient's immune system, possess antimelanoma properties, and potentially affect clinical outcomes. This retrospective study sought to describe the efficacy and toxicity effects of 12 classes of chronic medications in metastatic melanoma patients treated with ipilimumab. A total of 159 adults who received ipilimumab for metastatic melanoma at Mayo Clinic (Rochester, Minnesota, USA) from 1 March 2011 through 31 December 2014 were included. Classes of chronic medications included statins, metformin, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, calcium channel blockers, aspirin, non-steroidal anti-inflammatory drugs, H1 and H2 receptor antagonists, proton pump inhibitors (PPIs), antidepressants, and vitamin D supplements. Of the 12 medication classes, only PPIs were found to have an increased odds of experiencing a partial response or a complete response to ipilimumab [odds ratio: 3.73; confidence interval (CI): 1.26-11.04; P=0.02] on the basis of a case-control analysis. Although not significant, PPI use also trended toward improved overall survival and progression-free survival (hazard ratio: 0.44; CI: 0.17-1.15; P=0.09; and hazard ratio: 0.6; CI: 0.34-1.06; P=0.08, respectively) on the basis of Kaplan-Meier and Cox proportional hazard modeling. No medication class was associated with an increased risk of grades 3-5 immune-related adverse events with ipilimumab on the basis of case-control analysis. In summary, patients on PPIs may be more likely to experience a partial response/complete response following ipilimumab therapy. Because of the small sample size and the retrospective nature of this work, these findings are only descriptive and further study should be carried out. Other classes of chronic medications did not produce statistically significant effects for any of the measured outcomes.

  19. A multi-trimeric fusion of CD40L and gp100 tumor antigen activates dendritic cells and enhances survival in a B16-F10 melanoma DNA vaccine model.

    PubMed

    Gupta, Sachin; Termini, James M; Rivas, Yaelis; Otero, Miguel; Raffa, Francesca N; Bhat, Vikas; Farooq, Amjad; Stone, Geoffrey W

    2015-09-11

    Vaccination with tumor-associated antigens can induce cancer-specific CD8+ T cells. A recent improvement has been the targeting of antigen to dendritic cells (DC) using antibodies that bind DC surface molecules. This study explored the use of multi-trimers of CD40L to target the gp100 melanoma tumor antigen to DC. The spontaneously-multimerizing gene Surfactant Protein D (SPD) was used to fuse gp100 tumor antigen and CD40L, creating the recombinant protein SPD-gp100-CD40L. This "third generation" DC-targeting vaccine was designed to both target antigen to DC and optimally activate dendritic cells by aggregating CD40 trimers on the DC membrane surface. SPD-gp100-CD40L expressed as a 110kDa protein. Analytical light scattering analysis gave elution data corresponding to 4-trimer and multi-trimer SPD-gp100-CD40L oligomers. The protein was biologically active on dendritic cells and induced CD40-mediated NF-κB signaling. DNA vaccination with SPD-gp100-CD40L plasmid, together with plasmids encoding IL-12p70 and GM-CSF, significantly enhanced survival and inhibited tumor growth in a B16-F10 melanoma model. Expression of gp100 and SPD-CD40L as separate molecules did not enhance survival, highlighting the requirement to encode gp100 within SPD-CD40L for optimal vaccine activity. These data support a model where DNA vaccination with SPD-gp100-CD40L targets gp100 to DC in situ, induces activation of these DC, and generates a protective anti-tumor response when given in combination with IL-12p70 and GM-CSF plasmids.

  20. Vaccination Against Hepatitis A for Hemophilic Patients: Is It Necessary?

    PubMed Central

    Mirzaei, Jamal; Ziaee, Masood; Farsad, Seyed Ali; Fereydooni, Mohammad; Anani Sarab, Gholamreza; Rezvani Khorashad, Mohammad Reza

    2016-01-01

    Background Hemophilic patients require long-life intravenous infusion of factor concentrates to treat bleedings. This could increase the risk of transmission of blood-borne infections like hepatitis C. Objectives The current study was aimed at investigating the immunity status against hepatitis A in hemophilic patients in south Khorasan and evaluating the necessity of hepatitis A vaccination for this population. Patients and Methods A cross-sectional descriptive study was conducted between 2014 and 2015 on all hemophilic patients of south Khorasan province, Iran (n = 108) for anti-HAV total, anti- HCV, HBs-Ag, anti-HIV, and anti-HTLV-I /II. Note that no one had already received a hepatitis A vaccine. Results As our results show, 77.8% of the participants (59% under 20 and 88.4% above 20 years old) were seropositive for anti-HAV total; 20.4% and 2.8% (three patients) of the cases were anti-HCV positive and anti-HTLV-1 positive, respectively, while none of the subjects were HBS-Ag or HIV-Ab positive. Seventeen of the patients (15.75%) showed a co-infection of HAV with HCV, and five HCV-infected patients (22.73%) had no immunity against hepatitis A. There was a significant relationship between age, rural life, and anti-HAV positive state in our patients (P < 0.001). No significant relationship between positive anti-HAV status and sex (P = 0.16), severity of hemophilia (P = 0.23), and infection with HIV, HCV, HTLV-1, and hepatitis B (P > 0.05) was detected. Conclusions More than 40% of the hemophilic patients under 20 years of age in the present study had no immunity against hepatitis A, and 23% of hepatitis C patients had not had a hepatitis A co-infection yet. Since hepatitis A can show a fulminant course in hepatitis C patients, vaccination against hepatitis A seems necessary in hemophilic patients in the region. PMID:27257430

  1. Experimental models of uveal melanoma.

    PubMed

    Blanco, Paula L; Caissie, Amanda L; Burnier, Miguel N

    2004-06-01

    Over the past several decades, considerable effort has been directed toward developing suitable experimental models for the study of uveal melanoma. Animal models of uveal melanoma have undergone many improvements, leading to the development of experimental systems that better represent the disease in human beings. A major advance has come from the use of human uveal melanoma cell lines capable of inducing tumour growth and metastatic disease in immunodeficient hosts. Knowledge gained from the use of experimental models will ultimately be translated into better diagnostic and therapeutic strategies for patients with uveal melanoma. In this review the authors describe the current state-of-the-art designs of experimental models of uveal melanoma, highlighting the advantages and disadvantages of the available models. Novel findings from a rabbit model of uveal melanoma are also presented.

  2. Ovarian metastasis from uveal melanoma with MLH1/PMS2 protein loss in a patient with germline MLH1 mutated Lynch syndrome: consequence or coincidence?

    PubMed

    Lobo, João; Pinto, Carla; Freitas, Micaela; Pinheiro, Manuela; Vizcaino, Rámon; Oliva, Esther; Teixeira, Manuel R; Jerónimo, Carmen; Bartosch, Carla

    2017-03-01

    Currently, uveal melanoma is not considered within the Lynch syndrome tumor spectrum. However, there are studies suggesting a contribution of microsatellite instability in sporadic uveal melanoma tumorigenesis. We report a 45-year-old woman who was referred for genetic counseling due to a family history of Lynch syndrome caused by a MLH1 mutation. She originally underwent enucleation of the right eye secondary to a uveal spindle cell melanoma diagnosed at age 25. The tumor recurred 22 years later presenting as an ovarian metastasis and concurrently a microscopic endometrial endometrioid carcinoma, grade 1/3 was diagnosed. Subsequent studies highlighted that the uveal melanoma showed high microsatellite instability and loss of MLH1 and PMS2 protein expression, with no MLH1 promoter methylation or BRAF mutation. Additionally, a GNAQ mutation was found. We conclude that our patient's uveal melanoma is most likely related to MLH1 germline mutation and thus Lynch syndrome related. To the best of our knowledge, this is the first report of uveal melanoma showing MLH1/PMS2 protein loss in the context of Lynch syndrome.

  3. Oncogenes in melanoma: an update.

    PubMed

    Kunz, Manfred

    2014-01-01

    Melanoma is a highly aggressive tumour with poor prognosis in the metastatic stage. BRAF, NRAS, and KIT are three well-known oncogenes involved in melanoma pathogenesis. Targeting of mutated BRAF kinase has recently been shown to significantly improve overall survival of metastatic melanoma patients, underscoring the particular role of this oncogene in melanoma biology. However, recurrences regularly occur within several months, which supposedly involve further oncogenes. Moreover, oncogenic driver mutations have not been described for up to 30% of all melanomas. In order to obtain a more complete picture of the mutational landscape of melanoma, more recent studies used high-throughput DNA sequencing technologies. A number of new oncogene candidates such as MAPK1/2, ERBB4, GRIN2A, GRM3, RAC1, and PREX2 were identified. Their particular role in melanoma biology is currently under investigation. Evidence for the functional relevance of some of these new oncogene candidates has been provided in in vitro and in vivo experiments. However, these findings await further validation in clinical studies. This review provides an overview on well-known melanoma oncogenes and new oncogene candidates, based on recent high-throughput sequencing studies. The list of genes discussed herein is of course not complete but highlights some of the most significant of recent findings in this area. The new candidates may support more individualized treatment approaches for metastatic melanoma patients in the future.

  4. Lymphoscintigraphy in malignant melanoma

    SciTech Connect

    Berman, C.G.; Norman, J.; Cruse, C.W.; Reintgen, D.S.; Clark, R.A. )

    1992-01-01

    The development and rationale for the use of lymphoscintigraphy in the preoperative evaluation of patients with malignant melanoma being considered for elective lymph node dissection is reviewed. This overview is updated by an analysis of 135 patients with early stage malignant melanoma involving the head, neck, shoulders, and trunk at Moffitt Cancer Center and Research Institute at the University of South Florida (Tampa, FL). High discordancy rates (overall, 41%) were seen between drainage patterns predicted from historical anatomical guidelines and those revealed by the lymphoscintigraphic examination. The high discordancy rate was most pronounced in the head (64%) and the neck (73%). Surgical management was changed in 33% of the patients, overall. A preoperative lymphoscintigram is recommended for all patients with melanoma with head, neck, and truncal lesions evaluated for elective lymph node dissection as the lymphatic drainage patterns are often unpredictable and variable.

  5. Clinico-pathological features of patients with melanoma and positive sentinel lymph node biopsy: a single institution experience.

    PubMed

    Homolak, Damir; Šitum, Mirna; Čupić, Hrvoje

    2015-01-01

    Sentinel lymph node biopsy (SLNB) is an established method for the assessment of tumor aggressiveness in patients with primary cutaneous melanoma (PCM). To improve the criteria for the selection of SLNB candidates, the aim of our study was to determine clinico-pathohistological parameters that can serve as predictors of metastatic progression. We retrospectively evaluated all available clinico-pathohistological parameters in 844 patients with PCM diagnosed between January 1, 2005 and December 31, 2010. SLNB was conducted in 484 (57.3%) patients, 122 (14.5%) of whom had a positive node. The association between predictors and SLNB outcomes (positive SLNB and metastatic development) was tested using logistic regression analysis. The main predictors of positive SLNB were Breslow thickness (adjusted odds ratio (AOR)=1.22; 95% confidence interval (CI)=1.11-1.33), Clark levels (AOR=1.78; 95% CI=1.31-2.40), ulceration (AOR=3.1; 95% CI=1.65-5.81), microsatellitosis, gender, and tumor localization. The predictors of metastatic spread were Breslow thickness (AOR=1,69; 95% CI=1.51-1.89), Clark level (AOR=3.59; 95% CI=2.79-4.62), nodular type of melanoma (AOR=8.21; 95% CI=1.70-39.53), ulceration, mitotic rate, microsatellitosis, gender, and tumor localization. It seems that these parameters should be taken into consideration when selecting patients for SLNB since tumor thickness is not a sufficient predictor of SLNB outcome, particularly in case of very thin lesions.

  6. Increased Levels of miRNA-146a in Serum and Histologic Samples of Patients with Uveal Melanoma.

    PubMed

    Russo, Andrea; Caltabiano, Rosario; Longo, Antonio; Avitabile, Teresio; Franco, Livio M; Bonfiglio, Vincenza; Puzzo, Lidia; Reibaldi, Michele

    2016-01-01

    Purpose: To analyze MiRs expression in serum of UM patients, respect to healthy donors, and to compare this data with MiRs expressed in formalin-fixed, paraffin-embedded UM samples. Methods: Expression profile of 754 miRNAs was performed in serum of patients with uveal melanoma who underwent primary enucleation. The level of miRNAs increased in serum was individually analyzed on FFPE UM samples and compared to choroidal melanocytes from unaffected eyes. Results: Fourteen patients with uveal melanoma were included in the study. We found 8 serum miRNAs differentially expressed compared to normal controls: 2 upregulated miRNAs (miRNA-146a, miR-523); 6 downregulated miRNAs (miR-19a, miR-30d, miR-127, miR-451, miR-518f, miR-1274B). When data on upregulated miRNAs were singularly validated only a significant overexpression of miRNA-146a was found. A statistically significant upregulation of miRNA-146a was also found on FFPE UM samples, compared to choroidal melanocytes from unaffected eyes. Conclusions: miRNA-146a is increased in serum of patients with UM and in FFPE tumor samples. Further studies will show if it could be considered a potential marker of UM in the blood.

  7. Increased Levels of miRNA-146a in Serum and Histologic Samples of Patients with Uveal Melanoma

    PubMed Central

    Russo, Andrea; Caltabiano, Rosario; Longo, Antonio; Avitabile, Teresio; Franco, Livio M.; Bonfiglio, Vincenza; Puzzo, Lidia; Reibaldi, Michele

    2016-01-01

    Purpose: To analyze MiRs expression in serum of UM patients, respect to healthy donors, and to compare this data with MiRs expressed in formalin-fixed, paraffin-embedded UM samples. Methods: Expression profile of 754 miRNAs was performed in serum of patients with uveal melanoma who underwent primary enucleation. The level of miRNAs increased in serum was individually analyzed on FFPE UM samples and compared to choroidal melanocytes from unaffected eyes. Results: Fourteen patients with uveal melanoma were included in the study. We found 8 serum miRNAs differentially expressed compared to normal controls: 2 upregulated miRNAs (miRNA-146a, miR-523); 6 downregulated miRNAs (miR-19a, miR-30d, miR-127, miR-451, miR-518f, miR-1274B). When data on upregulated miRNAs were singularly validated only a significant overexpression of miRNA-146a was found. A statistically significant upregulation of miRNA-146a was also found on FFPE UM samples, compared to choroidal melanocytes from unaffected eyes. Conclusions: miRNA-146a is increased in serum of patients with UM and in FFPE tumor samples. Further studies will show if it could be considered a potential marker of UM in the blood. PMID:27895580

  8. Immunogenicity and immunization costs of adjuvanted versus non-adjuvanted hepatitis B vaccine in chronic kidney disease patients.

    PubMed

    Vilajeliu, Alba; Sequera, Víctor-Guillermo; García-Basteiro, Alberto L; Sicuri, Elisa; Aldea, Marta; Velasco, César; Bayas, José M

    2016-09-01

    Hepatitis B virus (HBV) vaccination is recommended for all susceptible chronic pre-hemodialysis and hemodialysis patients. This study assessed the immunogenicity of HBV vaccines (adjuvanted and non-adjuvanted) in chronic kidney disease patients vaccinated at the Hospital Clinic of Barcelona (Spain) between January 2007 and July 2012. In addition, the costs for the health system were evaluated accor-ding to the proportion of vaccine responders after receiving either vaccine. Patients receiving 3 doses of hepatitis B adjuvanted vaccine were 3 times more likely to seroconvert than patients immunized with non-adjuvanted vaccines, OR 3.56 (95% CI 1.84-6.85). This resulted in fewer patients requiring a second course of HBV vaccination and fewer outpatient visits, saving more than €9,500 per 100 patients. The higher immunogenicity of the adjuvanted HBV vaccine would counterbalance the lower costs associated with the non-adjuvanted vaccine.

  9. Retinal vasculitis and ocular vitreous metastasis following complete response to PD-1 inhibition in a patient with metastatic cutaneous melanoma.

    PubMed

    Manusow, Joshua S; Khoja, Leila; Pesin, Nataly; Joshua, Anthony M; Mandelcorn, Efrem D

    2014-01-01

    We report on a 36-year-old woman treated with the anti PD-1 antibody Pembrolizumab for metastatic cutaneous melanoma in the first line setting. She achieved a complete response and then relapsed with metastases to the vitreous cavity with an associated angiographically determined retinal vasculitis. Vitreous metastasis without choroidal involvement is unusual and may be due to individual cell extravasation, vitreous hemorrhage containing malignant cells, or direct spread through the optic nerve. This finding highlights the need for immune sanctuary sites to be monitored in the presence of PD-1 inhibition and we hypothesize that the use of PD-1 inhibitor potentiated the patient's angiographically determined retinal vasculitis.

  10. Melanoma risk loci as determinants of melanoma recurrence and survival

    PubMed Central

    2013-01-01

    Background Steadily high melanoma mortality rates urge for the availability of novel biomarkers with a more personalized ability to predict melanoma clinical outcomes. Germline risk variants are promising candidates for this purpose; however, their prognostic potential in melanoma has never been systematically tested. Methods We examined the effect of 108 melanoma susceptibility single nucleotide polymorphisms (SNPs), associated in recent GWAS with melanoma and melanoma-related phenotypes, on recurrence-free survival (RFS) and overall survival (OS), in 891 prospectively accrued melanoma patients. Cox proportional hazards models (Cox PH) were used to test the associations between 108 melanoma risk SNPs and RFS and OS adjusted by age at diagnosis, gender, tumor stage, histological subtype and other primary tumor characteristics. Results We identified significant associations for rs7538876 (RCC2) with RFS (HR = 1.48, 95% CI = 1.20-1.83, p = 0.0005) and rs9960018 (DLGAP1) with both RFS and OS (HR = 1.43, 95% CI = 1.07-1.91, p = 0.01, HR = 1.52, 95% CI = 1.09-2.12, p = 0.01, respectively) using multivariable Cox PH models. In addition, we developed a logistic regression model that incorporates rs7538876, rs9960018, primary tumor histological type and stage at diagnosis that has an improved discriminatory ability to classify 3-year recurrence (AUC = 82%) compared to histological type and stage alone (AUC = 78%). Conclusions We identified associations between melanoma risk variants and melanoma outcomes. The significant associations observed for rs7538876 and rs9960018 suggest a biological implication of these loci in melanoma progression. The observed predictive patterns of associated variants with clinical end-points suggest for the first time the potential for utilization of genetic risk markers in melanoma prognostication. PMID:24188633

  11. Response to conjugate pneumococcal and Haemophilus influenzae type b vaccines in asplenic patients.

    PubMed

    Meerveld-Eggink, A; de Weerdt, O; van Velzen-Blad, H; Biesma, D H; Rijkers, G T

    2011-01-17

    We determined the immunogenicity of conjugated Haemophilus influenzae type b and pneumococcal vaccines by quantitative analysis of the antibody response in asplenic patients. To that end, we vaccinated 92 patients with a conjugated Hib vaccine and 54 received two doses of conjugated pneumococcal vaccine (PCV7), followed at six months by a plain polysaccharide pneumococcal vaccine (PPV23). Antibody concentrations were measured before and three weeks after vaccination. After one dose of pneumococcal conjugate vaccine, 46% of the patients reached the antibody threshold of ≥ 1.0 μg/mL for all 7 tested vaccine serotypes. This percentage rose to 54% after the second dose of PCV7 and did not increase further after PPV23. Over 90% of patients had antibody concentrations ≥ 1.0 μg/mL for at least 5 out of the 7 conjugated pneumococcal serotypes after 2 doses of PCV7. For serotypes, included in the PPV23 vaccine only, 25% (PPS3)-100% (PPS19A) of the patients reached antibody concentrations ≥ 1.0 μg/mL after one dose of PPV23. For Hib, 97% of the patients reached the threshold concentration of ≥ 1.0 μg/mL after one dose of vaccine. It can be concluded that the majority of asplenic patients had a sufficient response to conjugated vaccines against Streptococcus pneumoniae and Hib, reflected by a ≥ 1.0 μg/mL antibody response. Inclusion of conjugated pneumococcal polysaccharide vaccines might be of additional value in the vaccination schedule for asplenic patients because of their high immunogenicity.

  12. Community pharmacist–administered influenza immunization improves patient access to vaccination

    PubMed Central

    Folkins, Chris; Li, Wilson; Zervas, John

    2014-01-01

    Objectives: To describe the demographic characteristics and risk factors of patients receiving influenza vaccination in community pharmacies and to understand patient experiences and perceptions surrounding being vaccinated by a pharmacist. Methods: Survey data were collected by research pharmacists at 4 different community pharmacy locations in Toronto throughout a period of 8 weeks during October and November 2013. Participation in the survey was voluntary, and all patients vaccinated by pharmacists were invited to complete a survey following immunization. Results: During the course of the study, 2498 vaccine doses were administered among all study sites, and 1502 surveys were completed. Our data showed a high degree of patient satisfaction, with 92% of patients indicating they were very satisfied with the pharmacist’s injection technique and the services they received. Furthermore, 86% of patients were very comfortable with being vaccinated by a pharmacist, and 99% of patients reported they would recommend that friends and family be vaccinated by a pharmacist. Convenience and accessibility were major determinants of patient satisfaction, as shown by 46% of all written comments specifically addressing these factors. Of the patients surveyed, 25% were not regular annual vaccine recipients, and 47% were classified as being at high risk for influenza complications according to Public Health Agency of Canada criteria. Notably, 28% of total patients and 21% of high-risk patients reported that they would not have been immunized this year if pharmacy-based vaccination were not available. Conclusions: Our findings suggest that pharmacists provide a highly convenient and accessible option for seasonal flu vaccination that is viewed favourably by patients. Administration of the flu vaccine by pharmacists has the potential to positively affect public health by improving vaccination rates among high-risk patients, first-time or occasional vaccine recipients, and patients

  13. Defective STAT1 activation associated with impaired IFN-γ production in NK and T lymphocytes from metastatic melanoma patients treated with IL-2.

    PubMed

    Sim, Geok Choo; Wu, Sheng; Jin, Lei; Hwu, Patrick; Radvanyi, Laszlo G

    2016-06-14

    High dose (HD) IL-2 therapy has been used for almost two decades as an immunotherapy for metastatic melanoma. IL-2 promotes the proliferation and effector function of T and NK cells through the tyrosine phosphorylation and activation of signal transducer and activator of transcription factors (STAT), especially STAT5. However, whether any defects in STAT activation exist in T and NK lymphocytes from melanoma patients are under debate. Here, we measured the extent of HD IL-2-induced phosphorylation of STAT5 and STAT1 in lymphocyte subsets from metastatic melanoma patients and healthy controls at a single cell level using flow cytometry. We found no defects in IL-2-induced STAT5 phosphorylation and induction of proliferation in T and NK cell subsets in vitro. This was confirmed by measuring ex vivo STAT5 activation in whole blood collected from patients during their first bolus HD IL-2 infusion. IL-2 also induced STAT1 phosphorylation via IFN-γ receptors in T and NK cell subsets through the release of IFN-γ by CD56hi and CD56lo NK cells. Further analysis revealed that melanoma patients had a sub-optimal STAT1 activation response linked to lower IL-2-induced IFN-γ secretion in both CD56hi and CD56low NK cell subsets. STAT1 activation in response to IL-2 also showed an age-related decline in melanoma patients not linked to tumor burden indicating a premature loss of NK cell function. Taken together, these findings indicate that, although STAT5 activation is normal in metastatic melanoma patients in response to IL-2, indirect STAT1 activation is defective owing to deficiencies in the NK cell response to IL-2.

  14. Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts.

    PubMed

    Bhadury, Joydeep; Einarsdottir, Berglind O; Podraza, Agnieszka; Bagge, Roger Olofsson; Stierner, Ulrika; Ny, Lars; Dávila López, Marcela; Nilsson, Jonas A

    2016-04-26

    Cell line-derived xenografts (CDXs) are an integral part of drug efficacy testing during development of new pharmaceuticals against cancer but their accuracy in predicting clinical responses in patients have been debated. Patient-derived xenografts (PDXs) are thought to be more useful for predictive biomarker identification for targeted therapies, including in metastatic melanoma, due to their similarities to human disease. Here, tumor biopsies from fifteen patients and ten widely-used melanoma cell lines were transplanted into immunocompromised mice to generate PDXs and CDXs, respectively. Gene expression profiles generated from the tumors of these PDXs and CDXs clustered into distinct groups, despite similar mutational signatures. Hypoxia-induced gene signatures and overexpression of the hypoxia-regulated miRNA hsa-miR-210 characterized CDXs. Inhibition of hsa-miR-210 with decoys had little phenotypic effect in vitro but reduced sensitivity to MEK1/2 inhibition in vivo, suggesting down-regulation of this miRNA could result in development of resistance to MEK inhibitors.

  15. Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts

    PubMed Central

    Bhadury, Joydeep; Einarsdottir, Berglind O.; Podraza, Agnieszka; Bagge, Roger Olofsson; Stierner, Ulrika; Ny, Lars; López, Marcela Dávila; Nilsson, Jonas A.

    2016-01-01

    Cell line-derived xenografts (CDXs) are an integral part of drug efficacy testing during development of new pharmaceuticals against cancer but their accuracy in predicting clinical responses in patients have been debated. Patient-derived xenografts (PDXs) are thought to be more useful for predictive biomarker identification for targeted therapies, including in metastatic melanoma, due to their similarities to human disease. Here, tumor biopsies from fifteen patients and ten widely-used melanoma cell lines were transplanted into immunocompromised mice to generate PDXs and CDXs, respectively. Gene expression profiles generated from the tumors of these PDXs and CDXs clustered into distinct groups, despite similar mutational signatures. Hypoxia-induced gene signatures and overexpression of the hypoxia-regulated miRNA hsa-miR-210 characterized CDXs. Inhibition of hsa-miR-210 with decoys had little phenotypic effect in vitro but reduced sensitivity to MEK1/2 inhibition in vivo, suggesting down-regulation of this miRNA could result in development of resistance to MEK inhibitors. PMID:27009863

  16. SNPase-ARMS qPCR: Ultrasensitive Mutation-Based Detection of Cell-Free Tumor DNA in Melanoma Patients

    PubMed Central

    Stadler, Julia; Eder, Johanna; Pratscher, Barbara; Brandt, Sabine; Schneller, Doris; Müllegger, Robert; Vogl, Claus; Trautinger, Franz; Brem, Gottfried; Burgstaller, Joerg P.

    2015-01-01

    Cell-free circulating tumor DNA in the plasma of cancer patients has become a common point of interest as indicator of therapy options and treatment response in clinical cancer research. Especially patient- and tumor-specific single nucleotide variants that accurately distinguish tumor DNA from wild type DNA are promising targets. The reliable detection and quantification of these single-base DNA variants is technically challenging. Currently, a variety of techniques is applied, with no apparent “gold standard”. Here we present a novel qPCR protocol that meets the conditions of extreme sensitivity and specificity that are required for detection and quantification of tumor DNA. By consecutive application of two polymerases, one of them designed for extreme base-specificity, the method reaches unprecedented sensitivity and specificity. Three qPCR assays were tested with spike-in experiments, specific for point mutations BRAF V600E, PTEN T167A and NRAS Q61L of melanoma cell lines. It was possible to detect down to one copy of tumor DNA per reaction (Poisson distribution), at a background of up to 200 000 wild type DNAs. To prove its clinical applicability, the method was successfully tested on a small cohort of BRAF V600E positive melanoma patients. PMID:26562020

  17. Cost-Effectiveness of Skin Surveillance Through a Specialized Clinic for Patients at High Risk of Melanoma.

    PubMed

    Watts, Caroline G; Cust, Anne E; Menzies, Scott W; Mann, Graham J; Morton, Rachael L

    2017-01-01

    Purpose Clinical guidelines recommend that people at high risk of melanoma receive regular surveillance to improve survival through early detection. A specialized High Risk Clinic in Sydney, Australia was found to be effective for this purpose; however, wider implementation of this clinical service requires evidence of cost-effectiveness and data addressing potential overtreatment of suspicious skin lesions. Patients and Methods A decision-analytic model was built to compare the costs and benefits of specialized surveillance compared with standard care over a 10-year period, from a health system perspective. A high-risk standard care cohort was obtained using linked population data, comprising the Sax Institute's 45 and Up cohort study, linked to Medicare Benefits Schedule claims data, the cancer registry, and hospital admissions data. Benefits were measured in quality-adjusted life-years gained. Sensitivity analyses were undertaken for all model parameters. Results Specialized surveillance through the High Risk Clinic was both less expensive and more effective than standard care. The mean saving was A$6,828 (95% CI, $5,564 to $8,092) per patient, and the mean quality-adjusted life-year gain was 0.31 (95% CI, 0.27 to 0.35). The main drivers of the differences were detection of melanoma at an earlier stage resulting in less extensive treatment and a lower annual mean excision rate for suspicious lesions in specialized surveillance (0.81; 95% CI, 0.72 to 0.91) compared with standard care (2.55; 95% CI, 2.34 to 2.76). The results were robust when tested in sensitivity analyses. Conclusion Specialized surveillance was a cost-effective strategy for the management of individuals at high risk of melanoma. There were also fewer invasive procedures in specialized surveillance compared with standard care in the community.

  18. Perineural Invasion of the Orbit by Neurotropic Nondesmoplastic Melanoma.

    PubMed

    Chua, Su Jen; Sun, Michelle T; James, Craig; Huilgol, Shyamala C; Selva, Dinesh

    2016-01-18

    The authors report a case of neurotropic nondesmoplastic melanoma involving the ophthalmic division of the trigeminal nerve and the cavernous sinus in a patient with recurrent scalp melanoma. This case highlights the importance of earlier diagnosis of local recurrence of melanoma and the rare association of neurotropic melanoma and orbital metastasis.

  19. miRNA profiling in vitreous humor, vitreal exosomes and serum from uveal melanoma patients: Pathological and diagnostic implications

    PubMed Central

    Ragusa, Marco; Barbagallo, Cristina; Statello, Luisa; Caltabiano, Rosario; Russo, Andrea; Puzzo, Lidia; Avitabile, Teresio; Longo, Antonio; Toro, Mario D; Barbagallo, Davide; Valadi, Hadi; Di Pietro, Cinzia; Purrello, Michele; Reibaldi, Michele

    2015-01-01

    Uveal melanoma (UM) represents approximately 5–6% of all melanoma diagnoses and up to 50% of patients succumb to their disease. Although several methods are available, accurate diagnosis is not always easily feasible because of potential accidents (e.g., intraocular hemorrhage). Based on the assumption that the profile of circulating miRNAs is often altered in human cancers, we verified whether UM patients showed different vitreous humor (VH) or serum miRNA profiles with respect to healthy controls. By using TaqMan Low Density Arrays, we analyzed 754 miRNAs from VH, vitreal exosomes, and serum of 6 UM patients and 6 healthy donors: our data demonstrated that the UM VH profile was unique and only partially overlapping with that from serum of the same patients. Whereas, 90% of miRNAs were shared between VH and vitreal exosomes, and their alterations in UM were statistically overlapped with those of VH and vitreal exosomes, suggesting that VH alterations could result from exosomal dysregulation. We report 32 miRNAs differentially expressed in UM patients in at least 2 different types of samples analyzed. We validated these data on an independent cohort of 12 UM patients. Most alterations were common to VH and vitreal exosomes (e.g., upregulation of miR-21,-34 a,-146a). Interestingly, miR-146a was upregulated in the serum of UM patients, as well as in serum exosomes. Upregulation of miR-21 and miR-146a was also detected in formalin-fixed, paraffin-embedded UM, suggesting that VH or serum alterations in UM could be the consequence of disregulation arising from tumoral cells. Our findings suggest the possibility to detect in VH and serum of UM patients “diagnostic” miRNAs released by the affected eye: based on this, miR-146a could be considered a potential circulating marker of UM. PMID:25951497

  20. Epidermotropic chondroid metastasis of melanoma: report of a case of metastatic melanoma with previously unreported morphological features.

    PubMed

    Piana, Simonetta; Valli, Riccardo; Ricci, Cinzia

    2009-05-01

    A potential diagnostic pitfall in the management of patients with melanoma is the inability to recognize metastatic melanoma, especially if it shows unusual features. We describe a case of multiple epidermotropic metastatic melanoma, which finally recurred with an extensive chondroid differentiation. To our knowledge, this is the first description of a case of epidermotropic chondroid metastatic melanoma.

  1. Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study.

    PubMed

    Doniņa, Simona; Strēle, Ieva; Proboka, Guna; Auziņš, Jurgis; Alberts, Pēteris; Jonsson, Björn; Venskus, Dite; Muceniece, Aina

    2015-10-01

    An oncolytic, nonpathogenic ECHO-7 virus adapted for melanoma that has not been genetically modified (Rigvir) is approved and registered for virotherapy, an active and specific immunotherapy, in Latvia since 2004. The present retrospective study was carried out to determine the effectiveness of Rigvir in substage IB, IIA, IIB and IIC melanoma patients on time to progression and overall survival. White patients (N=79) who had undergone surgical excision of the primary melanoma tumour were included in this study. All patients were free from disease after surgery and classified into substages IB, IIA, IIB and IIC. Circulating levels of clinical chemistry parameters were recorded. Survival was analysed by Cox regression. Rigvir significantly (P<0.05) prolonged survival in substage IB-IIC melanoma patients following surgery compared with patients who were under observation (according to current guidelines). The hazard ratio for patients under observation versus treated with Rigvir was statistically significantly different: hazard ratio 6.27 for all, 4.39 for substage IIA-IIB-IIC and 6.57 for substage IIB-IIC patients. The follow-up period was not statistically different between both treatment groups. These results indicate that the patients treated with Rigvir had a 4.39-6.57-fold lower mortality than those under observation. In this study, there was no untoward side effect or discontinuation of Rigvir treatment. Safety assessment of adverse events graded according to NCI CTCAE did not show any value above grade 2 in Rigvir-treated patients. In conclusion, Rigvir significantly prolongs survival in early-stage melanoma patients without any side effect.

  2. Phase II study of second-line therapy with DTIC, BCNU, cisplatin and tamoxifen (Dartmouth regimen) chemotherapy in patients with malignant melanoma previously treated with dacarbazine.

    PubMed

    Propper, D J; Braybrooke, J P; Levitt, N C; O'Byrne, K; Christodoulos, K; Han, C; Talbot, D C; Ganesan, T S; Harris, A L

    2000-06-01

    This study assessed response rates to combination dacarbazine (DTIC), BCNU (carmustine), cisplatin and tamoxifen (DBPT) chemotherapy in patients with progressive metastatic melanoma previously treated with DTIC, as an evaluation of DBPT as a second-line regimen, and as an indirect comparison of DBPT with DTIC. Thirty-five consecutive patients received DBPT. The patients were divided into two groups. Group 1 comprised 17 patients with progressive disease (PD) on DTIC + tamoxifen therapy who were switched directly to DBPT. Group 2 comprised 18 patients not immediately switched to DBPT and included patients who had either a partial response (PR; one patient) or developed stable disease (SD; four patients) with DTIC, or received adjuvant DTIC (nine patients). All except four patients had received tamoxifen at the time of initial DTIC treatment. Median times since stopping DTIC were 22 days (range 20-41) and 285 days (range 50-1,240) in Groups 1 and 2 respectively. In Group 1, one patient developed SD for 5 months and the remainder had PD. In Group 2, there were two PRs, four patients with SD (4, 5, 6, and 6 months), and 11 with PD. These results indicate that the DBPT regimen is not of value in melanoma primarily refractory to DTIC. There were responses in patients not directly switched from DTIC to DBPT, suggesting combination therapy may be of value in a small subgroup of melanoma patients.

  3. Analysis of patient survival in a Phase I trial of systemic targeted α-therapy for metastatic melanoma.

    PubMed

    Allen, Barry J; Singla, Apresh A; Rizvi, Syed M Abbas; Graham, Peter; Bruchertseifer, Frank; Apostolidis, Christos; Morgenstern, Alfred

    2011-09-01

    Targeted α-therapy is an experimental approach to the management of cancer. Short range α-particle radiation from a radioisotope attached to a targeting monoclonal antibody kills targeted cancer cells. Survival results are analyzed from a previously reported Phase I study of systemic targeted α-therapy for patients with stage IV metastatic melanoma or in-transit metastases. Following intravenous administration of 46-925 MBq of the α-immunoconjugate, (213)Bi-cDTPA-9.2.27, 38 patients were followed to observe response and toxicity. Responses were measured by physical examination, computed tomography at 8 weeks and blood sampling. Toxicity was monitored by blood pathology, urine analysis, glomerular filtration rate and human antimouse antibody response. The maximum tolerance dose was not achieved as there were no adverse events of any type or level. However, an objective partial response rate of 10% was observed, with 40% stable disease at 8 weeks and a median survival of 8.9 months. These results were unexpected because of the short half-life of the (213)Bi and short range of the α-radiation. Survival analysis demonstrated melanoma-inhibitory activity, disease stage, lactate dehydrogenase and treatment effects to be significant prognostic indicators for survival.

  4. Human Single-Chain Fv Immunoconjugates Targeted to a Melanoma-Associated Chondroitin Sulfate Proteoglycan Mediate Specific Lysis of Human Melanoma Cells by Natural Killer Cells and Complement

    NASA Astrophysics Data System (ADS)

    Wang, Baiyang; Chen, Yi-Bin; Ayalon, Oran; Bender, Jeffrey; Garen, Alan

    1999-02-01

    Two antimelanoma immunoconjugates containing a human single-chain Fv (scFv) targeting domain conjugated to the Fc effector domain of human IgG1 were synthesized as secreted two-chain molecules in Chinese hamster ovary and Drosophila S2 cells, and purified by affinity chromatography on protein A. The scFv targeting domains originally were isolated as melanoma-specific clones from a scFv fusion-phage library, derived from the antibody repertoire of a vaccinated melanoma patient. The purified immunoconjugates showed similar binding specificity as did the fusion-phage clones. Binding occurred to human melanoma cells but not to human melanocytes or to several other types of normal cells and tumor cells. A 250-kDa melanoma protein was immunoprecipitated by the immunoconjugates and analyzed by mass spectrometry, using two independent procedures. A screen of protein sequence databases showed an exact match of several peptide masses between the immunoprecipitated protein and the core protein of a chondroitin sulfate proteoglycan, which is expressed on the surface of most human melanoma cells. The Fc effector domain of the immunoconjugates binds natural killer (NK) cells and also the C1q protein that initiates the complement cascade; both NK cells and complement can activate powerful cytolytic responses against the targeted tumor cells. An in vitro cytolysis assay was used to test for an immunoconjugate-dependent specific cytolytic response against cultured human melanoma cells by NK cells and complement. The melanoma cells, but not the human fibroblast cells used as the control, were efficiently lysed by both NK cells and complement in the presence of the immunoconjugates. The in vitro results suggest that the immunoconjugates also could activate a specific cytolytic immune response against melanoma tumors in vivo.

  5. Factors Associated with Influenza Vaccination of Hospitalized Elderly Patients in Spain

    PubMed Central

    Domínguez, Àngela; Soldevila, Núria; Toledo, Diana; Godoy, Pere; Castilla, Jesús; Force, Lluís; Morales, María; Mayoral, José María; Egurrola, Mikel; Tamames, Sonia; Martín, Vicente; Astray, Jenaro

    2016-01-01

    Vaccination of the elderly is an important factor in limiting the impact of influenza in the community. The aim of this study was to investigate the factors associated with influenza vaccination coverage in hospitalized patients aged ≥65 years hospitalized due to causes unrelated to influenza in Spain. We carried out a cross-sectional study. Bivariate analysis was performed comparing vaccinated and unvaccinated patients, taking in to account sociodemographic variables and medical risk conditions. Multivariate analysis was performed using multilevel regression models. We included 1038 patients: 602 (58%) had received the influenza vaccine in the 2013–14 season. Three or more general practitioner visits (OR = 1.61; 95% CI 1.19–2.18); influenza vaccination in any of the 3 previous seasons (OR = 13.57; 95% CI 9.45–19.48); and 23-valent pneumococcal polysaccharide vaccination (OR = 1.97; 95% CI 1.38–2.80) were associated with receiving the influenza vaccine. Vaccination coverage of hospitalized elderly people is low in Spain and some predisposing characteristics influence vaccination coverage. Healthcare workers should take these characteristics into account and be encouraged to proactively propose influenza vaccination to all patients aged ≥65 years. PMID:26824383

  6. Factors Associated with Influenza Vaccination of Hospitalized Elderly Patients in Spain.

    PubMed

    Domínguez, Àngela; Soldevila, Núria; Toledo, Diana; Godoy, Pere; Castilla, Jesús; Force, Lluís; Morales, María; Mayoral, José María; Egurrola, Mikel; Tamames, Sonia; Martín, Vicente; Astray, Jenaro

    2016-01-01

    Vaccination of the elderly is an important factor in limiting the impact of influenza in the community. The aim of this study was to investigate the factors associated with influenza vaccination coverage in hospitalized patients aged ≥ 65 years hospitalized due to causes unrelated to influenza in Spain. We carried out a cross-sectional study. Bivariate analysis was performed comparing vaccinated and unvaccinated patients, taking in to account sociodemographic variables and medical risk conditions. Multivariate analysis was performed using multilevel regression models. We included 1038 patients: 602 (58%) had received the influenza vaccine in the 2013-14 season. Three or more general practitioner visits (OR = 1.61; 95% CI 1.19-2.18); influenza vaccination in any of the 3 previous seasons (OR = 13.57; 95% CI 9.45-19.48); and 23-valent pneumococcal polysaccharide vaccination (OR = 1.97; 95% CI 1.38-2.80) were associated with receiving the influenza vaccine. Vaccination coverage of hospitalized elderly people is low in Spain and some predisposing characteristics influence vaccination coverage. Healthcare workers should take these characteristics into account and be encouraged to proactively propose influenza vaccination to all patients aged ≥ 65 years.

  7. Patient-provider communication and human papillomavirus vaccine acceptance.

    PubMed

    Rand, Cynthia M; Schaffer, Stanley J; Humiston, Sharon G; Albertin, Christina S; Shone, Laura P; Heintz, Eric V; Blumkin, Aaron K; Stokley, Shannon; Szilagyi, Peter G

    2011-02-01

    The authors performed telephone interviews of parents of adolescents (n = 430) and their older adolescents (n = 208) in Monroe County, New York to measure parent and adolescent acceptance of human papillomavirus (HPV) vaccine, its association with ratings of provider communication, and vaccine-related topics discussed with the adolescent's provider. More than half of adolescent girls had already received an HPV vaccination, with fewer than one quarter refusing. Parent and teen ratings of provider communication was high, and not related to HPV vaccine refusal. Parents were more likely to refuse if they were Hispanic (odds ratio [OR] = 5.88, P = .05) or did not consider vaccines "very safe" (OR = 2.76, P = .04). Most parents of boys (85%) believed males should be given HPV vaccine if recommended. Few parents and teens recalled discussing that vaccination does not preclude future Pap smear testing. Providers should address cultural and vaccine safety concerns in discussions about HPV vaccine.

  8. Genotyping of cutaneous melanoma.

    PubMed

    Glitza, Isabella C; Davies, Michael A

    2014-09-01

    Until recently, treatment options for patients with metastatic melanoma were very limited. This landscape has evolved dramatically since the discovery of activating mutations in the BRAF gene in ~45% of cutaneous melanomas. Vemurafenib, dabrafenib, and trametinib have all received regulatory approval for the treatment of metastatic melanoma patients with a BRAF(V600) mutation. Based on the necessity to document the presence of a BRAF(V600) mutation to prescribe these agents, molecular testing is now the standard of care in this disease. However, the options and rationale for testing are evolving rapidly due to an improved understanding of the molecular drivers and heterogeneity of melanoma. Such testing may identify rational combinatorial approaches to prevent or overcome resistance for the approved BRAF inhibitors. In addition, new clinical strategies have been identified for a number of other molecular changes that are detected in this disease, including somatic changes in NRAS, PTEN, CDKN2A, and c-KIT, among others. This review summarizes the current understanding of the genetic landscape of mutations in melanoma, their associations with clinicopathological features, and their implications for clinical testing and treatment.

  9. Mucosal malignant melanoma - a clinical, oncological, pathological and genetic survey.

    PubMed

    Mikkelsen, Lauge H; Larsen, Ann-Cathrine; von Buchwald, Christian; Drzewiecki, Krzysztof T; Prause, Jan U; Heegaard, Steffen

    2016-06-01

    Mucosal melanomas constitute 1.3% of all melanomas and they may develop in any mucosal membrane. Conjunctival melanomas (0.5/million/year) and melanomas in the sinonasal cavity (0.5/million/year) are the most common, followed by anorectal melanomas (0.4/million/year) and melanomas in the oral cavity (0.2/million/year). Anorectal melanoma occurs slightly more often in females, whereas oral melanoma has a male predilection. Mucosal melanoma most commonly develops in a patient's sixth or seventh decade of life, and no differences between races have been found except for sinonasal melanoma and conjunctival melanoma, which are very rare in Black people. The symptoms are not tumour-specific and are related to the organ system affected, and the disease is most often diagnosed at an advanced clinical stage. The diagnosis of a primary tumour is difficult, and metastatic cutaneous melanoma and choroidal melanoma must be excluded. Mutations in KIT are frequently found, while BRAF and NRAS mutations are rarely found - except in conjunctival melanomas that carry BRAF mutations. Mutations in the TERT promotor region are also found in mucosal melanomas. Complete surgical resection with free margins is the treatment of choice. The prognosis is poor, with the 5-year survival rate ranging from 0% (gastric melanoma) to 80% (conjunctival melanoma).

  10. Levamisole Usage as an Adjuvant to Hepatitis B Vaccine in Hemodialysis Patients, Yes or No?

    PubMed Central

    Sanadgol, Houshang

    2012-01-01

    Background Hepatitis B virus (HBV) infection is much more common in hemodialysis patients than the general population. These patients have an impaired immune response to HBV vaccination; to that end there are certain studies that have evaluated levamisole as an immunomodulator agent improving HBV vaccination response rate in hemodialysis patients. Objectives In the current review, we have assembled all of the results to determine whether lavamisole is of value as an adjuvant to HBV vaccination in hemodialysis patients. Materials and Methods Science Direct (Elsevier), ProQuest, Springer, MD Consult, BMJ Journals, Pubmed and Wiley were searched for levamisole application to HBV vaccination in hemodialysis patients. All studies revealed a seroconversion response level between levamisole plus HBV vaccine versus HBV vaccine alone. Results From 10 relevant studies, 5 studies fulfilled our inclusion criteria. Three of them suggested the significant benefit of adding levamisole to the HBV vaccine to increase augment seroprotection level in hemodialysis patients. Another study reported a decrease in seroprotection level and another study showed no significant difference caused by levamisole administration. Conclusions Due to the limited number of studies evaluated, it is challenging to perform a definite decision about routinely administering levamisole in addition to the HBV vaccine for all hemodialysis patients. However, it does seem reasonable to recommend administration of levamisole for impaired immune response patients. PMID:23577329

  11. Reduction of circulating regulatory T cells by intravenous high-dose interferon alfa-2b treatment in melanoma patients.

    PubMed

    Mozzillo, Nicola; Ascierto, Paolo

    2012-10-01

    High-dose interferon alfa-2b (IFNα-2b) is the only approved adjuvant systemic therapy for resected, high risk melanoma in the United States (Fecher and Flaherty, in Natl Compr Cancer Netw 7:295-304, 2009). Recently, two important meta-analyses of randomized trials (Wheatley et al., in J Clin Oncol, 2007; Mocellin et al. in J Natl Cancer Inst, 2010) investigating IFNα-2b versus observation in high risk melanoma patients, showed that adjuvant IFNα-2b has an impact both on relapse-free survival (RFS) and overall survival (OS) independently by dosage, duration and route compared with observation in high risk melanoma patients. Despite of an absolute benefits of 3 % (Wheatley et al., in J Clin Oncol, 2007), this treatment is associated with significant toxicity, which impacts on patient quality of life. A better understanding of the mechanism of action may help to potentiate the clinical efficacy and reduce the toxicity of IFNα-2b/Peg-IFNα-2b. Numerous studies suggest that interferon's mechanism of action in melanoma is primarily immunomodulatory (Table 1) (de La Salmoniere, in Clin Cancer Res 6:4713-4718, 2000; Stuckert, in J Clin Oncol 25:8506, 2007; Gogas et al., in N Engl J Med 354:709-718, 2006; Moschos et al., in J Clin Oncol 24:3164-3171, 2006; Ascierto and Kirkwood, in J Transl Med 6:62, 2008) Recent efforts to elucidate the mechanism of action for interferon have focused upon signal transducers and activators of transcription (STAT) (Simons et al., in J Transl Med 9:52, 2011) signaling and immunoregulatory responses mediated by regulatory T cells (Tregs) (Wang et al., in Clin Cancer Res 13:1523-1531, 2007; Clin Cancer Res 14:8314-8320, 2008). Tregs are a suppressive CD4+ T cell population that is present, along with primed effector T cells, in tumor and tumor-draining lymph nodes (Hiura et al. in J Immunol 175:5058-5066, 2005). Tregs express high levels of surface antigens such as CD25, cytotoxic T lymphocyte associated antigen 4 (CTLA-4), and

  12. Efficacy of vaccination against influenza in patients with multiple sclerosis: The role of concomitant therapies.

    PubMed

    Pellegrino, Paolo; Carnovale, Carla; Perrone, Valentina; Pozzi, Marco; Antoniazzi, Stefania; Radice, Sonia; Clementi, Emilio

    2014-08-20

    Multiple sclerosis is a chronic progressive demyelinating disease affecting over 2.1 million patients worldwide. Patients affected by MS are exposed to an increased risk of infection from communicable diseases, which may lead to severe disease relapses. Studies have analysed the issue of vaccination of MS-affected patients. These studies, however, deal mostly with safety-related issues documenting that most vaccines have been proven to be safe in MS patients and that vaccination is not associated with an increased risk of relapses. By contrast, evidence on the efficacy is comparatively scant and not yet systematised in a comprehensive picture. This aspect is however important, as both MS and its treatment alter the immune responses, a situation that may be associated with a reduced vaccine efficacy. We have now reviewed the literature and assessed the effects of the therapy for MS on vaccine efficacy; we focused on the vaccine against influenza as for the other vaccines the information is still too scant. The majority of drugs appear not associated with a reduced response to vaccination against influenza, with the notable exception of mitoxantrone and glatiramer acetate. For a few drugs, among which natalizumab, information is not sufficiently clear and additional studies are needed to draw a definite conclusion. These results highlight the importance to evaluate the efficacy of vaccination in patients treated with immunosuppressant drugs.

  13. Uveal melanoma: Estimating prognosis

    PubMed Central

    Kaliki, Swathi; Shields, Carol L; Shields, Jerry A

    2015-01-01

    Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, higher expression of insulin-like growth factor-1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms “uvea,” “iris,” “ciliary body,” “choroid,” “melanoma,” “uveal melanoma” and “prognosis,” “metastasis,” “genetic testing,” “gene expression profiling.” Relevant English language articles were extracted, reviewed, and referenced appropriately. PMID:25827538

  14. Hsp90 Inhibitor AT13387, Dabrafenib, and Trametinib in Treating Patients With Recurrent Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2017-03-13

    BRAF V600E Mutation Present; BRAF V600K Mutation Present; Metastatic Malignant Solid Neoplasm; Recurrent Malignant Solid Neoplasm; Recurrent Melanoma; Stage III Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma; Unresectable Solid Neoplasm

  15. Yellow fever vaccine used in a psoriatic arthritis patient treated with methotrexate: a case report.

    PubMed

    Stuhec, Matej

    2014-01-01

    The yellow fever vaccines on the market are contraindicated for immunocompromised and elderly patients. A case of yellow fever vaccine used in a 27-year-old Slovenian male with psoriatic arthritis during treatment with methotrexate is described. We demonstrate a positive case, since there were no adverse effects in concurrent administration of yellow fever vaccine and methotrexate. This patient did not show severe adverse reactions and did not contract yellow fever despite potential exposure. More research is needed on possible adverse effects of concurrent administration of yellow fever vaccine and methotrexate to determine the potential of this method for more frequent use.

  16. Applications for quantitative measurement of BRAF V600 mutant cell-free tumor DNA in the plasma of patients with metastatic melanoma.

    PubMed

    Schreuer, Max; Meersseman, Geert; van Den Herrewegen, Sari; Jansen, Yanina; Seremet, Teofila; Bott, Ambre; Chevolet, Ines; Wilgenhof, Sofie; Maertens, Geert; Neyns, Bart

    2016-04-01

    Small fragments of cell-free DNA that are shed by normal and tumor cells can be detected in the plasma of patients with advanced melanoma. Quantitative measurement of BRAF V600 mutant DNA within the cell-free DNA holds promise as a tumor-specific biomarker for diagnosis and therapeutic monitoring in patients with BRAF V600 mutant melanoma. Allele-specific quantitative PCR analysis for BRAF V600 E/E2/D/K/R/M mutations on DNA extracted from 1 ml of plasma is currently under evaluation in a number of ongoing prospective clinical studies. We report five patient cases that indicate the potential applications and utility of quantitative measurements of BRAF V600 mutant cell-free tumor DNA as a diagnostic test and as a therapeutic monitoring tool in stage IV melanoma patients treated with BRAF-targeted therapy or immunotherapy. Finally, we offer novel insights into the dynamics of cell-free tumor DNA in melanoma.

  17. Long-term Survival and Clinical Benefit from Adoptive T-cell Transfer in Stage IV Melanoma Patients Is Determined by a Four-Parameter Tumor Immune Signature.

    PubMed

    Melief, Sara M; Visconti, Valeria V; Visser, Marten; van Diepen, Merel; Kapiteijn, Ellen H W; van den Berg, Joost H; Haanen, John B A G; Smit, Vincent T H B M; Oosting, Jan; van der Burg, Sjoerd H; Verdegaal, Els M E

    2017-02-01

    The presence of tumor-infiltrating immune cells is associated with longer survival and a better response to immunotherapy in early-stage melanoma, but a comprehensive study of the in situ immune microenvironment in stage IV melanoma has not been performed. We investigated the combined influence of a series of immune factors on survival and response to adoptive cell transfer (ACT) in stage IV melanoma patients. Metastases of 73 stage IV melanoma patients, 17 of which were treated with ACT, were studied with respect to the number and functional phenotype of lymphocytes and myeloid cells as well as for expression of galectins-1, -3, and -9. Single factors associated with better survival were identified using Kaplan-Meier curves and multivariate Cox regression analyses, and those factors were used for interaction analyses. The results were validated using The Cancer Genome Atlas database. We identified four parameters that were associated with a better survival: CD8(+) T cells, galectin-9(+) dendritic cells (DC)/DC-like macrophages, a high M1/M2 macrophage ratio, and the expression of galectin-3 by tumor cells. The presence of at least three of these parameters formed an independent positive prognostic factor for long-term survival. Patients displaying this four-parameter signature were found exclusively among patients responding to ACT and were the ones with sustained clinical benefit. Cancer Immunol Res; 5(2); 170-9. ©2017 AACR.

  18. [Choroidal melanoma].

    PubMed

    Desjardins, Laurence

    2016-03-01

    Choroidal melanoma is the most common form of eye cancer in adults. Treatments enabling the tumour to be destroyed or removed while preserving the eye socket are mainly based on surgery, proton therapy and brachytherapy.

  19. Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers

    PubMed Central

    Mercer, Louise K; Askling, Johan; Raaschou, Pauline; Dreyer, Lene; Hetland, Merete Lund; Strangfeld, Anja; Zink, Angela; Mariette, Xavier; Finckh, Axel; Canhao, Helena; Iannone, Florenzo; Zavada, Jakub; Morel, Jacques; Gottenberg, Jacques-Eric; Listing, Joachim

    2017-01-01

    Objectives Some studies have reported a possible association between exposure to tumour necrosis factor (TNF) inhibitors and an increased risk of melanoma. The aim of this study was to investigate the incidence of invasive cutaneous melanomas in patients with rheumatoid arthritis (RA) treated with TNF inhibitors (TNFi), other biologic disease modifying drugs and non-biologic therapy. Methods Eleven biologic registers from nine European countries participated in this collaborative project. According to predefined exposure definitions, cohorts of patients with RA were selected. Using the country-specific general population of each register as reference, age, sex and calendar year standardised incidence ratios (SIRs) of invasive histology-confirmed cutaneous melanoma were calculated within each register. Pooled SIR and incidence rate ratios (IRRs) comparing biologic cohorts to biologic-naïve were calculated across countries by taking the size of the register into account. Results Overall 130 315 RA patients with a mean age of 58 years contributing 579 983 person-years were available for the analysis and 287 developed a first melanoma. Pooled SIRs for biologic-naïve, TNFi and rituximab-exposed patients were 1.1 (95% CI 0.9 to 1.4), 1.2 (0.99 to 1.6) and 1.3 (0.6 to 2.6), respectively. Incidence rates in tocilizumab and abatacept-exposed patients were also not significantly increased. IRR versus biologic-naïve patients were: TNFi 1.1 (95% CI 0.8 to 1.6); rituximab 1.2 (0.5 to 2.9). Conclusions This large European collaborative project did not confirm an overall increased risk of melanoma following exposure to TNFi. PMID:27307502

  20. Analysis of the miR-34a locus in 62 patients with familial cutaneous melanoma negative for CDKN2A/CDK4 screening.

    PubMed

    Cozzolino, Angela M; Pedace, Lucia; Castori, Marco; De Simone, Paola; Preziosi, Nicoletta; Sperduti, Isabella; Panetta, Chiara; Mogini, Valerio; De Bernardo, Carmelilia; Morrone, Aldo; Catricalà, Caterina; Grammatico, Paola

    2012-06-01

    MicroRNAs are small non-coding RNAs, which inhibit expression of specific target genes at the post-transcriptional level and are often misregulated in human cancer. Among them, miR-34a is considered a tumor suppressor with a hypothetical role in melanoma tumorigenesis. In this work, 62 Italian index patients with familial melanoma and negative for CDKN2A/CDK4 screening were investigated for miR-34a germline mutations. Eight novel miR-34a sequence variants were identified at both the heterozygous (c.+259G>A, c.+424G>A, c.+1465C>T, c.+1769C>T, c.+2456T>G, c.+2603C>T, c.+2972T>A, c.+3069T>C) and homozygous (c.+424G>A, c.+1465C>T, c.+1769C>T) states. Molecular screening identified all nucleotide changes in a healthy population of 150 controls and demonstrated that they are common polymorphisms. However, statistically significant differences of allele and genotype frequencies were detected for c.+1465C>T and c.+1769C>T, and borderline values for c.+2456T>G. By stratifying patients by relevant clinical features (presence/absence of multiple primary melanoma, Breslow's thickness, phototype and number of nevi), no significant findings were noted except for an association between the c.+424G>A (heterozygous individual GA) and multiple primary melanoma and phototype III-IV. Our preliminary study suggests that miR-34a, although having a role in late tumorigenesis, does not contribute to the inherited susceptibility to cutaneous melanoma. A function as phenotypic modulator in familial melanoma cannot be excluded.

  1. The effect of physicians' awareness on influenza and pneumococcal vaccination rates and correlates of vaccination in patients with diabetes in Turkey: an epidemiological Study "diaVAX".

    PubMed

    Satman, Ilhan; Akalin, Sema; Cakir, Bekir; Altinel, Serdar

    2013-12-01

    We aimed to examine the effect of increased physician awareness on the rate and determinants of influenza and pneumococcal vaccinations in diabetic patients. Diabetic patients (n = 5682, mean [SD] age: 57.3 [11.6] years, 57% female) were enrolled by 44 physicians between Sept 2010 and Jan 2011. The physicians were initially questioned regarding vaccination practices, and then, they attended a training program. During the last five years, the physicians recommended influenza and pneumococcal vaccinations to 87.9% and 83.4% of the patients, respectively; however; only 27% of the patients received the influenza and 9.8% received the pneumococcal vaccines. One year after the training, the vaccination rates increased to 63.3% and 40.7%, respectively. The logistic regression models revealed that variables which increased the likelihood of having been vaccinated against influenza were: longer duration of diabetes, presence of hyperlipidemia and more use of concomitant medications whereas more use of anti-hyperglycemic medications was associated with increased odds of vaccination. On the other hand, older age, longer duration of diabetes and presence of a cardiovascular disease were variables which decreased the likelihood of having been vaccinated against pneumococcal disease during the past five years. However, during the study period, variables which decreased the odds of having been vaccinated included: older age and anti-hyperglycemic medications for influenza, and presence of hyperlipidemia and a family history of hypertension for pneumococcal disease. While variables which increased the likelihood of vaccination in the same period were: increased number of co-morbidities for influenza, and family history of diabetes for pneumococcal disease. We conclude that increased awareness of physicians may help improve vaccination rates against influenza and pneumococcal disease. However, diabetic patients with more severe health conditions are less likely to having been

  2. Vitamins and Melanoma

    PubMed Central

    Russo, Irene; Caroppo, Francesca; Alaibac, Mauro

    2015-01-01

    A tremendous amount of information was published over the past decades in relation to the role of vitamins in various neoplastic diseases. In particular, several studies showed an inverse relationship between selected vitamins intake and cancer risk. In this review we will focus on the role played by vitamins in melanoma with particular regard to vitamin A, D, K, E and C. Given that vitamin supplementation is easy, convenient, and readily accepted by patients, in the future the use of vitamins in chemoprevention and therapy of melanoma could be encouraged if supported by pre-clinical and clinical evidence. PMID:26213971

  3. Hepatitis B vaccine by intradermal route in non responder patients: An update

    PubMed Central

    Filippelli, Martina; Lionetti, Elena; Gennaro, Alessia; Lanzafame, Angela; Arrigo, Teresa; Salpietro, Carmelo; La Rosa, Mario; Leonardi, Salvatore

    2014-01-01

    Vaccination is the main prophylactic measure to reduce the mortality caused by hepatitis B virus (HBV) infection in healthy subjects since the immune response to hepatitis B recombinant vaccination occurs in over 90% of general population. Individuals who develop an anti-HBs titer less than 10 mIU/mL after primary vaccination cycle are defined “no responders”. Many factors could cause a non response to the HBV vaccination, such as administration of the vaccine in buttocks, impaired vaccine storage conditions, drug abuse, smoking, infections and obesity. Moreover there are some diseases, like chronic kidney disease, human immunodeficiency virus infection, chronic liver disease, celiac disease, thalassaemia, type I diabetes mellitus, down’s syndrome and other forms of mental retardation that are characterized by a poorer response to HBV vaccination than healthy subjects. To date it is still unclear how to treat this group of patients at high risk of hepatitis B infection. Recent studies seem to indicate that the administration of HBV recombinant vaccine by the intradermal route is very effective and could represent a more useful strategy than intramuscular route. This review focuses on the use of anti hepatitis B vaccine by intradermal route as alternative to conventional intramuscular vaccine in all non responder patients. A comprehensive review of the literature using PubMed database, with appropriate terms, was undertaken for articles in English published since 1983. The literature search was undertaken in September 2013. PMID:25132754

  4. Nivolumab for Metastatic Melanoma.

    PubMed

    Gupta, A K; Daigle, D

    2016-03-01

    Melanoma is an aggressive skin cancer with a generally poor prognosis at Stage III-IV disease. Traditionally, metastatic melanoma was treated by surgical resection, when possible, and with systemic chemotherapy. New developments in molecular biology have led to the identification of immune checkpoints which are exploited by malignant cells, allowing them to go undetected by the immune system. Nivolumab (Opdivo®) is a human monoclonal antibody which prevents immune inhibition by interacting with PD-1 on tumor cells; thus, increasing tumor-specific T cell proliferation. Nivolumab has demonstrated efficacy superior to that of standard chemotherapy and relative safety in clinical trials. Indeed, the outcomes for patients with advanced melanoma are being improved by novel biologic agents such as nivolumab.

  5. Prevalence of influenza vaccination and pneumococcal vaccination in elderly and high-risk patients seen in a university general medicine clinic.

    PubMed

    Lai, Hoang; Aronow, Wilbert S; Gutwein, Andrew H

    2008-01-01

    Charts of 240 unselected patients (149 women and 91 men), mean age 74 +/- 7 years (range, 64-95 years), seen in a university general medicine clinic at Westchester Medical Center/New York Medical College between April 2004 and April 2007 were reviewed for the use of influenza vaccination and pneumococcal vaccination. Of the 240 patients, 108 (45%) had cardiovascular disease, 183 (76%) had hypertension, 70 (29%) had diabetes mellitus, 32 (13%) had chronic pulmonary disease, 30 (13%) had cancer, 26 (11%) had chronic renal disease, and 19 (8%) had no chronic illness. Of the 240 patients, 24 (10%) refused influenza vaccination and two (1%) had a hypersensitivity to eggs. Of 240 patients, 18 (8%) refused pneumococcal vaccination. Of 94 patients who did not refuse influenza vaccination or were allergic to eggs during the winter season of October 2004 through January 2005, 58 (62%) had influenza vaccination. Ninety-two of 172 patients (54%) had influenza vaccination during October 2005 through January 2006. Ninety-seven of 136 patients (71%) had influenza vaccination during October 2006 through January 2007. Of 222 patients, 111 (50%) had pneumococcal vaccination during 2004 through 2007.

  6. [Colorectal melanoma: review of two distinct forms of presentation].

    PubMed

    Díaz-Sánchez, Antonio; Lara, Miguel Ángel; Ortega, Patricia; Aramendi, Teresa; González, Carmen; Alberdi, José M; Del Valle, Emilio; Casado, Isabel; Campos, Rocío; Aldeguer, Mercedes

    2011-02-01

    Malignant melanoma of the colon and rectum is an infrequent disease. Primary anorectal melanoma accounts for 0.1-4.6% of all malignant neoplasms of the anal canal. Melanoma metastatic to the colon is symptomatic only in 4.4% of patients with a primary melanoma at another site and most of these tumors are diagnosed postmortem. We report two cases of colorrectal malignant melanoma. The first case concerned a patient with rectal bleeding who was diagnosed with a rectal lesion compatible with melanoma. Abdominoperineal resection was performed due to positivity of the sentinel lymph node. We discuss the utility of sentinel lymph node detection in this kind of tumor. In the second case, we discovered a polyp compatible with metastatic melanoma in the transverse colon in a patient with a previous diagnosis of melanoma. In both surgical specimens, the diagnosis of melanoma was confirmed by positivity for protein S-100, Melan-A and HMB-45.

  7. Delay in cutaneous melanoma diagnosis

    PubMed Central

    Xavier, Marcus H.S.B.; Drummond-Lage, Ana P.; Baeta, Cyntia; Rocha, Lorena; Almeida, Alessandra M.; Wainstein, Alberto J.A.

    2016-01-01

    Abstract Advanced melanoma is an incurable disease with complex and expensive treatments. The best approach to prevent melanoma at advanced stages is an early diagnosis. A knowledge of factors associated with the process of detecting cutaneous melanomas and the reasons for delays in diagnosis is essential for the improvement of the secondary prevention of the disease. Identify sociodemographic, individual, and medical aspects related to cutaneous melanoma diagnosis delay. Interviews evaluated the knowledge of melanoma, signals, symptoms, persons who were suspected, delays in seeking medical attention, physician's deferrals, and related factors of 211 patients. Melanomas were self-discovered in 41.7% of the patients; healthcare providers detected 29.9% of patients and others detected 27%. The main component in delay was patient-related. Only 31.3% of the patients knew that melanoma was a serious skin cancer, and most thought that the pigmented lesion was not important, causing a delay in seeking medical assistance. Patients (36.4%) reported a wait interval of more than 6 months from the onset of an observed change in a pigmented lesion to the first visit to a physician. The delay interval from the first physician visit to a histopathological diagnosis was shorter (<1 month) in 55.5% of patients. Improper treatments without a histopathological confirmation occurred in 14.7% of patients. A professional delay was related to both inappropriate treatments performed without histopathological confirmation (P = 0.003) and long requirements for medical referrals (P < 0.001). A deficient knowledge in the population regarding melanoma and physicians’ misdiagnoses regarding suspicious lesions contributed to delays in diagnosis. PMID:27495055

  8. [Choroidal melanoma - evolution and prognosis].

    PubMed

    Chiruţa, Daria; Stan, Cristina

    2014-01-01

    Choroidal melanoma is the most common primary intraocular malignant tumor. We present the case of a 62 year old patient who was diagnosed with intraocular tumor in his right eye, for about three years. Regarding the fact that the patient refused any kind of treatment during this period, we just had the opportunity to monitor this case. Finally, the diagnosis was choroidal melanoma, confirmed by the histopathological exam.

  9. Effects of biological and non-biological immunomodulatory therapies on the immunogenicity of vaccines in patients with rheumatic diseases.

    PubMed

    McMahan, Zsuzsanna H; Bingham, Clifton O

    2014-12-23

    Vaccinations are administered to patients to induce a protective immune response, resulting in immunological memory. Preventing infection through the use of vaccines is particularly important in immunocompromised and immunosuppressed individuals given their increased frequency and severity of infections relative to healthy individuals. Recent surveys show that the vaccination rate is still alarmingly low in patients with rheumatic disease. In this review we briefly discuss the different types of vaccines and then critically examine evidence related to vaccination efficacy in patients with autoimmune disease and the effects of immunomodulatory therapy, with an aim to provide guidance and optimize the administration of vaccines in such individuals.

  10. Novel Targeted Therapies for Metastatic Melanoma.

    PubMed

    Iams, Wade T; Sosman, Jeffrey A; Chandra, Sunandana

    Oncogene-targeted therapy is a major component of precision oncology, and although patients with metastatic melanoma have experienced improved outcomes with this strategy, there are a number of potential therapeutic targets currently under study that may further increase the drug armamentarium for this patient population. In this review, we discuss the landscape of targeted therapies for patients with advanced melanoma, focusing on oncogene mutation-specific targets. In patients with typical BRAF V600-mutant melanoma, combination BRAF and MEK inhibition has surpassed outcomes compared with monotherapy with BRAF or MEK inhibition alone, and current strategies seek to address inevitable resistance mechanisms. For patients with NRAS-mutant melanoma, MEK inhibitor monotherapy and combined MEK and CDK4/6 inhibition are burgeoning strategies; for patients with KIT-mutant melanoma, tyrosine kinase inhibition is being leveraged, and for NF-1-mutant melanoma, mTOR and MEK inhibition is being actively evaluated. In patients with atypical, non-V600 BRAF-mutant melanoma, MEK inhibitor monotherapy is the potential novel targeted approach on the horizon. For advanced uveal melanoma, novel targets such as IMCgp100 and glembatumumab have shown activity in early studies. We review additional strategies that remain in the preclinical and early clinical pipeline, so there is much hope for the future of targeted agents for distinct molecular cohorts of patients with advanced melanoma.

  11. Enucleation versus plaque irradiation for choroidal melanoma

    SciTech Connect

    Straatsma, B.R.; Fine, S.L.; Earle, J.D.; Hawkins, B.S.; Diener-West, M.; McLaughlin, J.A.

    1988-07-01

    The Collaborative Ocular Melanoma Study (COMS) is an international, multicenter-controlled study. The organization includes an Executive Committee, Steering Committee, 6 Central Units, 32 Clinical Centers, and a Data and Safety Monitoring Committee. Scientifically, the COMS consists of (1) a randomized trial of patients with medium choroidal melanoma treated with enucleation versus iodine-125 plaque irradiation, (2) a randomized trial of patients with large choroidal melanoma treated with enucleation versus preenucleation external beam irradiation and enucleation, and (3) a prospective observational study of patients with small choroidal melanoma to determine whether a randomized trial of treatment is appropriate. In design and conduct of the COMS, special consideration is given to biostatistics and sample size considerations, iodine-125 plaque irradiation of choroidal melanoma, and coordinated ocular melanoma research. Recruitment is in progress. However, the pool of eligible patients is limited and the COMS needs the continued support and cooperation of ophthalmologists throughout the United States and Canada.

  12. A word of caution: do not wake sleeping dogs; micrometastases of melanoma suddenly grew after progesterone treatment

    PubMed Central

    2013-01-01

    Background Hormonal treatment might affect the immune response to tumor antigens induced in cancer patients who are being vaccinated. Case presentation A 33 years-old woman was diagnosed with cutaneous melanoma in May 2009. Her melanoma was located in the intermammary sulcus, had a Breslow thickness of 4 mm, a Clark’s level IV, it was ulcerated and highly melanotic. The bilateral sentinel node biopsy was negative. She entered into a randomized Phase II/III clinical study comparing a vaccine composed of irradiated melanoma cells plus BCG plus GM-CSF versus IFN-alpha 2b and she was assigned to the vaccine arm. During the two years treatment she remained disease-free; the final CAT scan being performed in August 2011. Between November and December 2011, her gynecologist treated her with three cycles of 200 mg progesterone/day for ten days, every two weeks, for ovary dysfunction. In November 2011 the patient returned to the Hospital for clinical and imaging evaluation and no evidence of disease was found. At the next visit in March 2012 an ultrasound revealed multiple, large metastases in the liver. A CAT scan confirmed the presence of liver, adrenal glands and spleen metastases. A needle biopsy of a liver lesion revealed metastatic melanoma of similar characteristics to the original tumor. We suggest that progesterone treatment triggered proliferation of so far dormant micrometastases that were controlled during CSF470 vaccine treatment. Conclusion The use of progesterone in patients with melanoma that are under immunological treatments should be carefully considered, since progesterone could modify the balance of pro-inflammatory and Th1 functions to a regulatory and anti-inflammatory profile of the immune system that could have an impact in tumor progression. PMID:23510193

  13. Long-term outcome in BRAFV600E melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression

    PubMed Central

    Puzanov, Igor; Amaravadi, Ravi K.; McArthur, Grant A.; Flaherty, Keith T.; Chapman, Paul B.; Sosman, Jeffrey A.; Ribas, Antoni; Shackleton, Mark; Hwu, Patrick; Chmielowski, Bartosz; Nolop, Keith B.; Lin, Paul S.; Kim, Kevin B.

    2016-01-01

    Introduction Vemurafenib induces tumour regression in most patients with BRAFV600E-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAFV600E melanoma treated in the phase 1 vemurafenib trial is reported. Methods Patients received vemurafenib 240–1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by RECIST. Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded. Results Forty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (≥240 mg twice daily). Forty-three patients had PD by the time of this analysis, and 5 remained progression free (follow-up time, 1.2–56.1 months). Median OS was 14 months (range, 1.2–56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7–56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1–26.6). In the extension cohort, 6 and 5 patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy. Conclusions Some patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition. PMID:25980594

  14. Antibody therapies for melanoma: New and emerging opportunities to activate immunity (Review)

    PubMed Central

    MALAS, SADEK; HARRASSER, MICAELA; LACY, KATIE E.; KARAGIANNIS, SOPHIA N.

    2014-01-01

    The interface between malignant melanoma and patient immunity has long been recognised and efforts to treat this most lethal form of skin cancer by activating immune responses with cytokine, vaccine and also antibody immunotherapies have demonstrated promise in limited subsets of patients. In the present study, we discuss different antibody immunotherapy approaches evaluated in the context of melanoma, each designed to act on distinct targets and to employ different mechanisms to restrict tumour growth and spread. Monoclonal antibodies recognising melanoma-associated antigens such as CSPG4/MCSP and targeting elements of tumour-associated vasculature (VEGF) have constituted long-standing translational approaches aimed at reducing melanoma growth and metastasis. Recent insights into mechanisms of immune regulation and tumour-immune cell interactions have helped to identify checkpoint molecules on immune (CTLA4, PD-1) and tumour (PD-L1) cells as promising therapeutic targets. Checkpoint blockade with antibodies to activate immune responses and perhaps to counteract melanoma-associated immunomodulatory mechanisms led to the first clinical breakthrough in the form of an anti-CTLA4 monoclonal antibody. Novel modalities to target key mechanisms of immune suppression and to redirect potent effector cell subsets against tumours are expected to improve clinical outcomes and to provide previously unexplored avenues for therapeutic interventions. PMID:24969320

  15. Antibody therapies for melanoma: new and emerging opportunities to activate immunity (Review).

    PubMed

    Malas, Sadek; Harrasser, Micaela; Lacy, Katie E; Karagiannis, Sophia N

    2014-09-01

    The interface between malignant melanoma and patient immunity has long been recognised and efforts to treat this most lethal form of skin cancer by activating immune responses with cytokine, vaccine and also antibody immunotherapies have demonstrated promise in limited subsets of patients. In the present study, we discuss different antibody immunotherapy approaches evaluated in the context of melanoma, each designed to act on distinct targets and to employ different mechanisms to restrict tumour growth and spread. Monoclonal antibodies recognising melanoma-associated antigens such as CSPG4/MCSP and targeting elements of tumour-associated vasculature (VEGF) have constituted long-standing translational approaches aimed at reducing melanoma growth and metastasis. Recent insights into mechanisms of immune regulation and tumour-immune cell interactions have helped to identify checkpoint molecules on immune (CTLA4, PD-1) and tumour (PD-L1) cells as promising therapeutic targets. Checkpoint blockade with antibodies to activate immune responses and perhaps to counteract melanoma-associated immunomodulatory mechanisms led to the first clinical breakthrough in the form of an anti-CTLA4 monoclonal antibody. Novel modalities to target key mechanisms of immune suppression and to redirect potent effector cell subsets against tumours are expected to improve clinical outcomes and to provide previously unexplored avenues for therapeutic interventions.

  16. Benefit of adjuvant interferon alfa-2b (IFN-α) therapy in melanoma patients with high serum MMP-8 levels.

    PubMed