Science.gov

Sample records for advanced stage melanoma

  1. Dabrafenib Alone and in Combination With Trametinib Before Surgery in Treating Patients With Locally or Regionally Advanced Melanoma That Can Be Removed By Surgery

    ClinicalTrials.gov

    2013-03-29

    Recurrent Melanoma; Stage IIB Melanoma (Locally Advanced); Stage IIC Melanoma (Locally Advanced); Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma (Limited, Resectable)

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

    ClinicalTrials.gov

    2016-10-31

    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

  3. 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

  4. 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

  5. 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.

  6. 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

  7. 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

  8. Morphogenesis of early stage melanoma

    NASA Astrophysics Data System (ADS)

    Chatelain, Clément; Amar, Martine Ben

    2015-08-01

    Melanoma early detection is possible by simple skin examination and can insure a high survival probability when successful. However it requires efficient methods for identifying malignant lesions from common moles. This paper provides an overview first of the biological and physical mechanisms controlling melanoma early evolution, and then of the clinical tools available today for detecting melanoma in vivo at an early stage. It highlights the lack of diagnosis methods rationally linking macroscopic observables to the microscopic properties of the tissue, which define the malignancy of the tumor. The possible inputs of multiscale models for improving these methods are shortly discussed.

  9. 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

  10. Surgical treatment of advanced melanoma.

    PubMed

    Hussussian, Christopher J

    2010-01-01

    Primary surgical treatment should be considered for patients with metastatic melanoma. Because of the poor response of melanoma to chemotherapy or radiation therapy, surgery can be the best approach to quickly eliminate detectable disease and return the patient to normal activities. In properly selected patients, surgery can lead to significant palliation and prolongation of survival. This article reviews the principles of patient selection and the potential benefits of surgical management of melanoma metastatic to various sites. Novel adjuvant therapies are being developed to augment the benefits of surgical treatment of advanced melanoma in the future.

  11. Melanoma staging: facts and controversies.

    PubMed

    Forschner, Andrea; Eigentler, Thomas Kurt; Pflugfelder, Annette; Leiter, Ulrike; Weide, Benjamin; Held, Laura; Meier, Friedegund; Garbe, Claus

    2010-01-01

    The value of staging examinations remains controversial for the initial staging in melanoma patients at the time of the primary diagnosis and for surveillance. Issues concerning tumor recurrences and progression must be discussed separately for different risk groups. For low-risk patients (stage IA; tumor thickness less than 1 mm), staging examinations like sentinel lymph node biopsy (SLNB), blood tests, or imaging can generally be abandoned. Baseline staging with simple techniques is at the discretion of the physician. In intermediate-risk patients (stages IB and IIA), an initial staging examination involving SLNB and computed tomography (CT) scans is recommended. Further follow-up may be restricted to physical examinations, blood tests of tumor marker protein S100beta, and to lymph node ultrasonography. If findings are suspicious, further imaging procedures may be involved. In high-risk patients (stages IIB to III), an initial staging examination with CT is recommended, and regular follow-up every 6 months with whole body imaging by CT or magnetic resonance imaging seems useful. Physical examinations, blood tests of tumor marker protein S100beta, and lymph node ultrasound imaging should be routine. This intense follow-up may enable surgical treatments with complete removal of all recognizable metastases in about 15% to 25% of patients and improve their prognosis. The risk of recurrence or tumor progression is very high in stage IV patients, and their management is individualized. PMID:20541679

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

    ClinicalTrials.gov

    2016-10-26

    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

  13. 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

  14. Phase I clinical study with multiple peptide vaccines in combination with tetanus toxoid and GM-CSF in advanced-stage HLA-A*0201-positive melanoma patients.

    PubMed

    Bins, Adriaan; Mallo, Henk; Sein, Johan; van den Bogaard, Colette; Nooijen, Willem; Vyth-Dreese, Florry; Nuijen, Bastiaan; de Gast, Gijsbert C; Haanen, John B A G

    2007-01-01

    Successful induction of functional tumor-specific T cells by peptide vaccination in animal models has resulted in many clinical trials to test this approach in advanced-stage melanoma patients. In this phase I clinical trial, 11 end-stage melanoma patients were vaccinated intradermally with 3 peptides: MART-1(26-35) E27L (ELAGIGILTV), tyrosinase(368-376) N375Q (YMDGTMSQV), and gp100(209-217) T210M (IMQVPFSV), admixed with tetanus toxoid and granulocyte-monocyte colony stimulating factor. The peptide vaccine was well tolerated at all tested doses, and led to grade 1-2 toxicity only. Although all patients did show a rise in antitetanus IgG titers, in only 3 patients peptide-specific CD8 T-cells were induced. In 2 cases, the response was directed against MART-1(26-35) and consisted of 0.2% and 3.3% of the CD8 population; however, in both instances these cells did not produce interferon-gamma on stimulation with the unmodified peptide. The third patient mounted a small (0.1%) response against gp100. In a fourth patient, a nonfunctional tyrosinase-specific response (0.6%) was found that was present before vaccination, but was not affected in size nor in function by the vaccine. None of the 11 patients responded clinically according to response evaluation criteria in solid tumors criteria. Although this study is a small scale phase I clinical trial, the efficacy that was observed was disappointingly low. In accordance with previously published peptide vaccination studies, these results add to the increasing evidence that peptide vaccination in itself is not potent enough as an effective melanoma immunotherapy in advanced-stage patients.

  15. Regression of advanced melanoma upon withdrawal of immunosuppression: case series and literature review

    PubMed Central

    Thomas, N.; Sharpless, N.; Collichio, F.

    2013-01-01

    We report two cases of stage IV malignant melanoma arising in patients treated with azathioprine for myasthenia gravis. In both cases, the melanoma metastases regressed upon withdrawal of immunosuppression. One patient remains melanoma free at 10 years, and the second patient experienced an 18-month disease free period. There is one prior case report in the medical literature to support full immune reconstitution for treatment in advanced immunosuppression-related melanoma, and one case series suggesting that transplant patients developing melanoma may benefit from a switch to sirolimus. Virtually, no data exist for the medical management of early stage melanoma in the immunosuppressed patients. We review the limited preclinical data in support of immune reconstitution and the data on immunosuppression as a risk factor for melanoma. We conclude that reduction or withdrawal of immunosuppression may be beneficial in patients with advanced stage melanoma and warrants further consideration in patients with early stage melanoma. PMID:19890737

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

    ClinicalTrials.gov

    2016-06-21

    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

  17. Cutaneous melanoma: new advances in treatment*

    PubMed Central

    Foletto, Michele Ceolin; Haas, Sandra Elisa

    2014-01-01

    Cutaneous melanoma is a challenge to treat. Over the last 30 years, no drug or combination of drugs demonstrated significant impact to improve patient survival. From 1995 to 2000, the use of cytokines such as interferon and interleukin become treatment options. In 2011, new drugs were approved by the U.S. Food and Drug Administration, including peginterferon alfa-2b for patients with stage III disease, vemurafenib for patients with metastatic melanoma with the BRAF V600E mutation, and ipilimumab, a monoclonal antibody directed to the CTLA-4 T lymphocyte receptor, to combat metastatic melanoma in patients who do not have the BRAF V600E mutation. Both ipilimumab and vemurafenib showed results in terms of overall survival. Other trials with inhibitors of other genes, such as the KIT gene and MEK, are underway in the search for new discoveries. The discovery of new treatments for advanced or metastatic disease aims to relieve symptoms and improve patient quality of life. PMID:24770508

  18. Nivolumab-Based Treatments for Advanced Melanoma

    Cancer.gov

    A summary of results from an international, double-blind, randomized phase III trial testing the combination of nivolumab (Opdivo®) and ipilimumab (Yervoy®) against nivolumab alone and ipilimumab alone in patients with advanced melanoma.

  19. Immunotherapy for advanced melanoma: fulfilling the promise.

    PubMed

    Gogas, Helen; Polyzos, Aristidis; Kirkwood, John

    2013-12-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past thirty years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma, have contributed in the development of new agents. Based on the molecular and immunological background of the disease, the new drugs have shown benefit in overall and progression free survival. As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:23725878

  20. Immunotherapy for advanced melanoma: future directions.

    PubMed

    Valpione, Sara; Campana, Luca G

    2016-02-01

    As calculated by the meta-analysis of Korn et al., the prognosis of metastatic melanoma in the pretarget and immunological therapy era was poor, with a median survival of 6.2 and a 1-year life expectancy of 25.5%. Nowadays, significant advances in melanoma treatment have been gained, and immunotherapy is one of the promising approaches to get to durable responses and survival improvement. The aim of the present review is to highlight the recent innovations in melanoma immunotherapy and to propose a critical perspective of the future directions of this enthralling oncology subspecialty.

  1. Testing Adjuvant Ipilimumab in Advanced Melanoma

    Cancer.gov

    In this clinical trial, patients with stage III or stage IV melanoma that has been completely resected will be randomly assigned to receive post-surgical treatment with either ipilimumab or high-dose interferon alfa-2b, the current standard of care.

  2. Major Changes in Systemic Therapy for Advanced Melanoma.

    PubMed

    Thompson, John A

    2016-05-01

    Over the past 5 years, a host of new agents have radically changed the therapeutic landscape in advanced melanoma; gone are the days when the only active agents were interferon and dacarbazine. Nearly 25 years ago, few patients with stage IV melanoma reached 2-year survival; today, these survival curves have risen substantially. At the NCCN 21st Annual Conference, John A. Thompson, MD, discussed updates with longer duration of patient follow-up for immune checkpoint therapies. He also reviewed some of the newer approvals in advanced melanoma, including the combination of ipilimumab and nivolumab, high-dose ipilimumab, the oncolytic virus therapy talimogene laherparepvec, and the molecularly targeted combination of the BRAF and MEK inhibitors vemurafenib and cobimetinib. PMID:27226502

  3. Updates in Therapy for Advanced Melanoma.

    PubMed

    Singh, Bhavana P; Salama, April K S

    2016-01-15

    Cutaneous melanoma is one of the most aggressive forms of skin cancer, and is correlated with a large proportion of skin cancer-related deaths. Therapy for cutaneous melanoma has advanced greatly through careful identification of therapeutic targets and the development of novel immunotherapeutic approaches. The identification of BRAF as well as other driver mutations, have allowed for a specialized approach to treatment. In addition, immune checkpoint inhibition has dramatically changed the treatment landscape over the past 5-10 years. The successful targeting of CTLA-4, as well as PD-1/PD-L1, has been translated into meaningful clinical benefit for patients, with multiple other potential agents in development. Systemic therapy for cutaneous melanoma is becoming more nuanced and often takes a multifaceted strategy. This review aims to discuss the benefits and limitations of current therapies in systemic melanoma treatment as well as areas of future development.

  4. 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

    2016-11-03

    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 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

  5. Adoptive immunotherapy of advanced melanoma.

    PubMed

    Shapira-Frommer, Ronnie; Schachter, Jacob

    2012-09-01

    Adoptive cell therapy (ACT) has emerged as an effective therapy for patients with metastatic melanoma. Since the first introduction of the protocol in 1988 [1], major improvements have been achieved with response rates of 40%-72% among patients who were resistant to previous treatment lines. Both cell product and conditioning regimen are major determinants of treatment efficacy; therefore, developing ACT protocols explore diverse ways to establish autologous intra-tumoral lymphocyte cultures or peripheral effector cells as well as different lymphodepleting regimens. While a proof of feasibility and a proof of concept had been established with previous published results, ACT will need to move beyond single-center experiences, to confirmatory, multi-center studies. If ACT is to move into widespread practice, it will be necessary to develop reproducible high quality cell production methods and accepted lymphodepleting regimen. Two new drugs, ipilimumab (Yervoy, Bristol-Myers Squibb) and vemurafenib (Zelboraf, Roche), were approved in 2011 for the treatment of metastatic melanoma based on positive phase III trials. Both drugs show a clear overall survival benefit, so the timing of when to use ACT will need to be carefully thought out. In contrast to these 2 new, commercially available outpatient treatments, ACT is a personally-specified product and labor-intensive therapy that demands both acquisition of high standard laboratory procedures and close clinical inpatient monitoring during treatment. It is unique among other anti-melanoma treatments, providing the potential for a durable response following a single, self-limited treatment. This perspective drives the efforts to make this protocol accessible for more patients and to explore modifications that may optimize treatment results.

  6. 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

  7. Axitinib in Treating Patients With Melanoma That is Metastatic or Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-05-31

    Extraocular Extension Melanoma; Metastatic Intraocular Melanoma; Recurrent Intraocular Melanoma; Recurrent 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. Gene Network Rewiring to Study Melanoma Stage Progression and Elements Essential for Driving Melanoma

    PubMed Central

    Kaushik, Abhinav; Bhatia, Yashuma; Ali, Shakir; Gupta, Dinesh

    2015-01-01

    Metastatic melanoma patients have a poor prognosis, mainly attributable to the underlying heterogeneity in melanoma driver genes and altered gene expression profiles. These characteristics of melanoma also make the development of drugs and identification of novel drug targets for metastatic melanoma a daunting task. Systems biology offers an alternative approach to re-explore the genes or gene sets that display dysregulated behaviour without being differentially expressed. In this study, we have performed systems biology studies to enhance our knowledge about the conserved property of disease genes or gene sets among mutually exclusive datasets representing melanoma progression. We meta-analysed 642 microarray samples to generate melanoma reconstructed networks representing four different stages of melanoma progression to extract genes with altered molecular circuitry wiring as compared to a normal cellular state. Intriguingly, a majority of the melanoma network-rewired genes are not differentially expressed and the disease genes involved in melanoma progression consistently modulate its activity by rewiring network connections. We found that the shortlisted disease genes in the study show strong and abnormal network connectivity, which enhances with the disease progression. Moreover, the deviated network properties of the disease gene sets allow ranking/prioritization of different enriched, dysregulated and conserved pathway terms in metastatic melanoma, in agreement with previous findings. Our analysis also reveals presence of distinct network hubs in different stages of metastasizing tumor for the same set of pathways in the statistically conserved gene sets. The study results are also presented as a freely available database at http://bioinfo.icgeb.res.in/m3db/. The web-based database resource consists of results from the analysis presented here, integrated with cytoscape web and user-friendly tools for visualization, retrieval and further analysis. PMID

  9. Melanoma: diagnosis, staging, and treatment. Consensus group recommendations.

    PubMed

    Berrocal, Alfonso; Cabañas, Luis; Espinosa, Enrique; Fernández-de-Misa, Ricardo; Martín-Algarra, Salvador; Martínez-Cedres, José Carlos; Ríos-Buceta, Luis; Rodríguez-Peralto, José Luis

    2014-09-01

    The incidence of malignant melanoma is increasing worldwide. In Spain, its incidence is increasing faster than any other cancer type, with a 5-year survival rate of about 85%. The impact and characteristics of malignant melanoma in the Spanish population can be ascertained from the national melanoma registry of the Academia Española de Dermatología y Venereología. This review presents consensus group recommendations for the diagnosis, staging and treatment of malignant melanoma in Spain. Incidence and mortality are discussed, as well as evaluation of various prevention and treatment strategies. Prognostic factors, such as BRAF and C-KIT mutations, which are expected to become routine staging procedures over the next few years, are outlined, especially in relation to treatment options. The use of recently approved targeted agents such as ipilimumab, a cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitor, and vemurafenib, a BRAF inhibitor, in metastatic disease are also discussed.

  10. 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

  11. Pembrolizumab: A Review in Advanced Melanoma.

    PubMed

    Deeks, Emma D

    2016-03-01

    Pembrolizumab (Keytruda(®)) is a humanized monoclonal antibody against programmed death receptor-1 (PD-1), a key immunoinhibitory checkpoint protein implicated in down-regulating anti-tumour immune responses. This intravenous drug is indicated for the treatment of advanced (unresectable or metastatic) melanoma, on the basis of its clinical benefit in this setting in the phase I KEYNOTE 001 trial (expansion cohorts) and the phase II and III trials, KEYNOTE 002 and 006. These studies were conducted in ipilimumab-naïve and/or ipilimumab-experienced patients and assessed varying pembrolizumab regimens administered every 2 or 3 weeks, all of which helped to determine the recommended dosage of 2 mg/kg every 3 weeks. In the trials with active comparator arms, pembrolizumab regimens significantly improved progression-free survival (PFS), overall survival (OS) and overall response rates (ORR) relative to ipilimumab in ipilimumab-naïve patients (KEYNOTE 006), and significantly improved PFS and ORR, but not OS (although OS data are immature), relative to chemotherapy in ipilimumab-refractory patients, who had also received BRAF/MEK inhibitor therapy if BRAF-mutation positive (KEYNOTE 002). Pembrolizumab has an acceptable tolerability profile, with immune-related adverse events that are generally manageable/reversible. Thus, pembrolizumab is a valuable treatment option for patients with advanced melanoma, including those who have progressed on ipilimumab and BRAF/MEK inhibitors.

  12. Staged Excision for Lentigo Maligna and Lentigo Maligna Melanoma

    PubMed Central

    Wilson, Joshua B.; Walling, Hobart W.; Scupham, Richard K.; Bean, Andrew K.; Ceilley, Roger I.

    2016-01-01

    Introduction: Lentigo maligna is a form of in situ melanoma that occurs commonly on sun-exposed skin of middle-aged to elderly adults. Margin-control surgery offers the highest cure rate for lentigo maligna/lentigo maligna melanoma. Materials and methods: Charts from the authors’ private office from the 20-year period from January 1986 to December 2005 were reviewed to identify patients with histologically confirmed lentigo maligna or lentigo maligna melanoma treated by staged excision. Results: Sixty-eight patients (39 men, 29 women; mean age at diagnosis 67.4±10.2 years, range 48-87 years) with 68 tumors were treated in the authors’ office for lentigo maligna (58) or lentigo maligna melanoma (10) between January 1986 and December 2005. After excision, patients were followed clinically for a minimum of three years. The mean follow-up duration was 138 months (median 139 months; range 37-330 months). The overall margin for tumor clearance was 7.0±0.55mm with a recurrence rate of 5.9 percent. Limitations: The limitations of this study include the retrospective nature of the authors’ review, and data collected from a single, private practice setting. Conclusion: The authors’ findings support staged excision as an effective method of treating lentigo maligna and lentigo maligna melanoma, offering a high cure rate while maximally preserving normal tissue. PMID:27386048

  13. Primary advanced esophago-gastric melanoma: A rare case

    PubMed Central

    Wang, Lin; Zong, Liang; Nakazato, Hidetsugu; Wang, Wen-Yue; Li, Chao-Feng; Shi, Yan-Fen; Zhang, Guo-Chao; Tang, Tao

    2016-01-01

    Primary esophageal or gastric melanoma is a very rare disease with early metastasis. Due to its atypical symptom and less efficiency of chemotherapy and radiotherapy, the prognosis of esophageal or gastric melanoma is still very poor. Surgical resection remains the preferential treatment for esophageal or gastric melanoma. Here we present an extremely rare case of primary advanced esophago-gastric melanoma. Debulking surgery was performed without chemotherapy or radiotherapy. However, abdominal recurrence and hepatic metastases were found within one month by a postoperative follow-up computed tomography. Three and a half months after surgical resection, the patient died of extensive abdominal metastasis. PMID:27004009

  14. 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

  15. Akt Inhibitor MK2206 and Hydroxychloroquine in Treating Patients With Advanced Solid Tumors, Melanoma, Prostate or Kidney Cancer

    ClinicalTrials.gov

    2016-02-05

    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

  16. Integrating first-line treatment options into clinical practice: what's new in advanced melanoma?

    PubMed

    Dummer, Reinhard; Schadendorf, Dirk; Ascierto, Paolo A; Larkin, James; Lebbé, Celeste; Hauschild, Axel

    2015-12-01

    Melanoma remains a serious form of skin cancer in Europe and worldwide. Localized, early-stage melanomas can usually be treated with surgical excision. However, the prognosis is poorer for patients with advanced disease. Before 2011, treatment for advanced melanoma included palliative surgery and/or radiotherapy, and chemotherapy with or without immunotherapy, such as interleukin-2. As none of these treatments had shown survival benefits in patients with advanced melanoma, European guidelines had recommended that patients be entered into clinical trials. The lack of approved first-line options and varying access to clinical trials meant that European clinicians relied on experimental regimens and chemotherapy-based treatments when no other options were available. Since 2011, ipilimumab, an immuno-oncology therapy, and vemurafenib and dabrafenib, targeted agents that inhibit mutant BRAF, have been approved by the European Medicines Agency for the treatment of advanced melanoma. More recently, the MEK inhibitor, trametinib, received European marketing authorization for use in patients with BRAF mutation-positive advanced melanoma. In 2014, the anti-PD-1 antibody nivolumab was approved as a first-line therapy in Japan. Whereas nivolumab and another anti-PD-1 antibody, pembrolizumab, were approved as second-line therapies in the USA, their recent approval in Europe are for first-line use based on new clinical trial data in this setting. Together these agents are changing clinical practice and making therapeutic decisions more complex. Here, we discuss current and emerging therapeutic options for the first-line treatment of advanced melanoma, and how these therapies can be optimized to provide the best possible outcomes for patients. PMID:26426764

  17. Advances in noninvasive imaging of melanoma.

    PubMed

    Menge, Tyler D; Pellacani, Giovanni

    2016-03-01

    Melanoma is the most dangerous type of skin cancer and its incidence has risen sharply in recent decades. Early detection of disease is critical for improving patient outcomes. Any pigmented lesion that is clinically concerning must be removed by biopsy for morphologic investigation on histology. However, biopsies are invasive and can cause significant morbidity, and their accuracy in detecting melanoma may be limited by sampling error. The advent of noninvasive imaging devices has allowed for assessment of intact skin, thereby minimizing the need for biopsy; and these technologies are increasingly being used in the diagnosis and management of melanoma. Reflectance confocal microscopy, optical coherence tomography, ultrasonography, and multispectral imaging are noninvasive imaging techniques that have emerged as diagnostic aids to physical exam and/or conventional dermoscopy. This review summarizes the current knowledge about these techniques and discusses their practical applications and limitations. PMID:26963113

  18. Advances in Personalized Targeted Treatment of Metastatic Melanoma and Non-Invasive Tumor Monitoring

    PubMed Central

    Klinac, Dragana; Gray, Elin S.; Millward, Michael; Ziman, Mel

    2013-01-01

    Despite extensive scientific progress in the melanoma field, treatment of advanced stage melanoma with chemotherapeutics and biotherapeutics has rarely provided response rates higher than 20%. In the past decade, targeted inhibitors have been developed for metastatic melanoma, leading to the advent of more personalized therapies of genetically characterized tumors. Here we review current melanoma treatments and emerging targeted molecular therapies. In particular we discuss the mutant BRAF inhibitors Vemurafenib and Dabrafenib, which markedly inhibit tumor growth and advance patients’ overall survival. However this response is almost inevitably followed by complete tumor relapse due to drug resistance hampering the encouraging initial responses. Several mechanisms of resistance within and outside the MAPK pathway have now been uncovered and have paved the way for clinical trials of combination therapies to try and overcome tumor relapse. It is apparent that personalized treatment management will be required in this new era of targeted treatment. Circulating tumor cells (CTCs) provide an easily accessible means of monitoring patient relapse and several new approaches are available for the molecular characterization of CTCs. Thus CTCs provide a monitoring tool to evaluate treatment efficacy and early detection of drug resistance in real time. We detail here how advances in the molecular analysis of CTCs may provide insight into new avenues of approaching therapeutic options that would benefit personalized melanoma management. PMID:23515890

  19. Vaccine Therapy With or Without Sargramostim in Treating Patients Who Have Undergone Surgery for Melanoma

    ClinicalTrials.gov

    2015-04-14

    Ciliary Body and Choroid Melanoma, Medium/Large Size; Extraocular Extension Melanoma; Iris Melanoma; Stage IIB Melanoma; Stage IIC Melanoma; Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma

  20. [Incidence of melanoma and changes in stage-specific incidence after implementation of skin cancer screening in Schleswig-Holstein].

    PubMed

    Eisemann, N; Waldmann, A; Katalinic, A

    2014-01-01

    A pilot project in skin cancer screening (SCREEN) was conducted in Schleswig-Holstein from July 2003 to June 2004. Although the impact of this screening on the stage-specific incidence of melanoma is of great importance for screening evaluation, it remains unknown. In theory, an effective skin cancer screening program should result in a medium-term incidence decrease of melanomas with a prognostically unfavorable stage. This is studied on a population-based level by using cancer registry data. Based on data from the Cancer Registry of Schleswig-Holstein for 1999-2009, stage-specific (T-category of the TNM-classification system) age-standardized incidence rates were calculated. After implementation of the SCREEN project, the incidence of prognostically favorable melanomas (in situ and T1) was higher than before, while the incidence of advanced melanomas (T2, T3, and for women also T4) decreased considerably. The classification of tumor stages changed during the project period, which may have contributed to an artificial decrease of the stages with a poor prognosis. Nevertheless, the results are in agreement with the observed decrease of melanoma mortality in the screening region.

  1. Dabrafenib Plus Trametinib for Advanced Melanoma

    Cancer.gov

    A summary of results from two phase III trials show that patients with metastatic melanoma whose tumors have specific mutations in the BRAF gene lived longer following treatment with dabrafenib (Tafinlar®), a BRAF inhibitor, plus trametinib (Mekinist®), a

  2. Management of a patient with advanced BRAF-mutant melanoma.

    PubMed

    Ashworth, Michelle T; Daud, Adil

    2014-03-01

    A 49-year-old man initially diagnosed in 1995 with cutaneous melanoma presented to the authors' institution in 2009 with metastatic, BRAF V600E-mutant melanoma. His treatment course to date has included surgery, adjuvant radiotherapy, and interferon, metastasectomies, granulocyte-macrophage colony-stimulating factors, a clinical trial with the BRAF inhibitor vemurafenib (PLX-4032), clinical trial with combination BRAF plus MEK inhibition with vemurafenib plus GDC-0973, and combination targeted and immune therapy with vemurafenib plus the anti-CTLA4 antibody ipilimumab. This case report illustrates the long-term management of a patient with metastatic melanoma using targeted and immune therapy, evolution in treatment guidelines, next directions in research, and the critical role of clinical trials in advancement of patient care.

  3. Novel Approaches to Treatment of Advanced Melanoma: A Review on Targeted Therapy and Immunotherapy

    PubMed Central

    Niezgoda, Anna; Niezgoda, Piotr; Czajkowski, Rafał

    2015-01-01

    The incidence of malignant melanoma is increasing. The majority of patients are diagnosed in early stages when the disease is highly curable. However, the more advanced or metastatic cases have always been a challenge for clinicians. The poor prognosis for patients with melanoma is now changing as numerous of promising approaches have appeared recently. The discovery of aberrations of pathways responsible for intracellular signal transduction allowed us to introduce agents specifically targeting the mutated cascades. Numerous clinical studies have been conducted to improve effectiveness of melanoma treatment. From 2011 until now, the U.S. FDA has approved seven novel agents, such as BRAF-inhibitors (vemurafenib 2011, dabrafenib 2013), MEK-inhibitors (trametinib 2013), anti-PD1 antibodies (nivolumab 2014, pembrolizumab 2014), anti-CTLA-4 antibody (ipilimumab 2011), or peginterferon-alfa-2b (2011) intended to be used in most advanced cases of melanoma. Nevertheless, clinicians continue working on new possible methods of treatment as resistance to the novel drugs is a commonly observed problem. This paper is based on latest data published until the end of January 2015. PMID:26171394

  4. Cixutumumab in Treating Patients With Metastatic Melanoma of the Eye

    ClinicalTrials.gov

    2015-06-25

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

  5. Pembrolizumab for Treatment of Patients with Advanced or Unresectable Melanoma.

    PubMed

    Sullivan, Ryan J; Flaherty, Keith T

    2015-07-01

    From Coley's toxin to combination immune checkpoint inhibition, strategies to activate the immune system and generate anticancer immunity have been ongoing for well over a century. Over the past decade, the so-called immune checkpoint inhibitors, generally monoclonal antibodies that target key regulators of T-cell activation, emerged as the most effective immune-targeted agents. Pembrolizumab is the first anti-programmed death 1 (PD-1) antibody approved by the FDA for the treatment of metastatic melanoma. With responses seen in 25% to 40% of patients, depending on dose and setting (i.e., before or after ipilimumab), pembrolizumab specifically and anti-PD-1 antibodies generally are revolutionizing the treatment of melanoma. However, in the setting of other recent advances in the field, a number of practical issues are emerging that need to be addressed to optimize the care of patients with melanoma. First, the optimal sequencing of therapy (first-line immunotherapy over molecular targeted therapy, ipilimumab versus pembrolizumab as initial immune checkpoint inhibitor) is unknown and must be evaluated through randomized trials. Second, there is a strong rationale to combine immune checkpoint inhibitors (i.e., anti-PD-1 with ipilimumab) and to combine immune therapies with targeted therapy agents, so determining whether combination therapy is better than direct sequencing is another critical issue that needs to be addressed in carefully carried out studies.

  6. Conditional survival estimates improve over time for patients with advanced melanoma: results from a population-based analysis

    PubMed Central

    Xing, Yan; Chang, George J.; Hu, Chung-Yuan; Askew, Robert L.; Ross, Merrick I.; Gershenwald, Jeffrey E.; Lee, Jeffrey E.; Mansfield, Paul F.; Lucci, Anthony; Cormier, Janice N.

    2009-01-01

    Background Conditional survival (CS) has emerged as a clinically relevant measure of prognosis for cancer survivors. The objective of this analysis was to provide melanoma-specific CS estimates to help clinicians promote more informed patient decision-making. Methods Patients with melanoma and at least 5 years of follow-up were identified from the Surveillance Epidemiology and End Results (SEER) registry (1988–2000). Using the methods of Kaplan and Meier, stage-specific 5-year CS estimates were independently calculated for survivors for each year following diagnosis. Stage-specific multivariate Cox regression models including baseline survivor functions were used to calculate adjusted melanoma-specific CS for different subgroups of patients further stratified by age, gender, race, marital status, anatomic tumor location, and tumor histology. Results Five-year CS estimates for stage I patients remained constant at 97% annually, while for patients with stages II, III and IV disease, 5-year CS estimates from time 0 (diagnosis) to 5 years improved from 72% to 86%, 51% to 87%, and 19% to 84%, respectively. Multivariate CS analysis revealed that differences in stages II through IV CS based on age, gender and race decreased over time. Conclusions Five-year melanoma-specific CS estimates improve dramatically over time for survivors with advanced stages of disease. These prognostic data are critical to patients for both treatment and non-treatment related life decisions. PMID:20187100

  7. Comparative study between two different staging systems (AJCC TNM VS BALLANTYNE’S) for mucosal melanomas of the Head & Neck

    PubMed Central

    Aguilar-Romero, Madeleine; Villavicencio-Valencia, Verónica; Zepeda-Castilla, Ernesto; Vidrio-Morgado, Horacio; Peteuil, Nathalie; Mosqueda-Taylor, Adalberto

    2016-01-01

    Background Mucosal melanoma (MM) of head and neck (H &N) is a rare entity with a quite poor prognosis. Ballantyne’s staging system has been commonly used since 1970. In the 7th edition of the AJCC Staging Manual a new chapter for the staging of TNM Classification system for mucosal melanoma (MM) of the head and neck (H &N) has been introduced to reflect the particularly aggressive biological behavior of this neoplasm. The aim of this study was to analyze and compare among Ballantyne’s staging system vs TNM H &N in terms of overall survival (OS) and disease-free survival (DFS) in a consecutive population of patients with MM in a cancer centre. Material and Methods Descriptive analysis of demographic, clinical and pathological variables of MM of the Head & Neck were performed. We compared the survival curves for both systems according to the Kaplan-Meier method using the Log-rank test. Results An up-staging migration effect from Ballantyne’s localized disease to moderately and very advanced disease according to AJCC staging system. The 5-year DFS and OS for Ballantyne’s Localized Disease and AJCC Stage III were 31% and 36% vs. 47% and 50%, respectively. For locoregional disease the 5-year DFS / OS were 5% / 10% for Bal-lantyne’s system vs. 13.8% / 17.8% and 0 / 0% for AJCC Stages IVA and IVB, respectively. Conclusions In this series, the TNM staging system for MM of the H &N predicted better the prognosis of the disease when comparing with Ballantyne’s system. Key words:Head and neck, mucosal melanoma, AJCC TNM, Ballantynes´s staging system. PMID:27031071

  8. [Immune Checkpoint Inhibitors for Advanced Melanoma - Evidences and Future Perspectives].

    PubMed

    Nakamura, Yasuhiro; Teramoto, Yukiko; Asami, Yuri; Matsuya, Taisuke; Yamamoto, Akifumi

    2016-09-01

    Recently developed immune checkpoint inhibitors, such as anti-PD-1 antibodies, have shown a clear improvement in clinical efficacy compared with conventional cytotoxic chemotherapy in the treatment of patients with advanced melanoma. Treatment with anti-PD-1 antibodies has resulted in improved objective response rates, longer durations of response, and longer overall survival rates. Although the incidence rate of adverse events associated with anti-PD-1 antibodies is lower than that associated with cytotoxic agents, characteristic severe adverse events such as pneumonia, endocrinopathy, and colitis can occur. A recent clinical trial that evaluated the utility of an anti-PD-1 antibody in combination with an anti-CTLA-4 antibody reported that the treatment enhanced clinical efficacy in terms of response rate and progression-free survival. However, the incidence of adverse events and treatment discontinuation also increased. For optimal selection of immune checkpoint inhibitors for treating patients with advanced melanoma, biomarkers capable of predicting clinical efficacy, prognosis, and adverse events in each patient need to be identified. In addition, novel combination therapies, including immune checkpoint inhibitors and MAP kinase pathway-targeting agents, should result in more favorable clinical responses and prolonged overall survival rates. PMID:27628544

  9. Management options for metastatic melanoma in the era of novel therapies: a primer for the practicing dermatologist: part I: Management of stage III disease.

    PubMed

    Fox, Matthew C; Lao, Christopher D; Schwartz, Jennifer L; Frohm, Marcus L; Bichakjian, Christopher K; Johnson, Timothy M

    2013-01-01

    The incidence of melanoma has increased for decades, and while surgical treatment of early stage disease is often curative, metastatic disease continues to carry a significantly less promising outlook with high associated health burden and economic cost. An expanding number of dermatologists are playing a key role in coordinating the care of patients with melanoma, including in an increasingly important role among multidisciplinary melanoma clinics, many of which are anchored in dermatology departments. Advances in the understanding of the genetic and immunoregulatory aspects of melanoma development and progression have yielded a wave of novel therapeutics that has made significant impact on the approach to patients with metastatic disease. Frequently updated management guidelines and unfamiliarity with approved adjuvant treatment options, including interferon, clinical trials, or radiation therapy, can pose a challenge for dermatologists seeking to effectively coordinate the care of and establish proper expectations for patients with stage III disease. Moreover, greater awareness of treatment modalities for in-transit disease may allow dermatologists to play a more active role in the treatment of these patients and to expand their ability to explain and coordinate options, such as limb perfusion or infusion. Part I of this continuing medical education article will use clinical scenarios to outline the current management options for patients with stage III melanoma, including both adjuvant treatment options for resected stage III disease and primary treatment options for in-transit metastases. Part II of this series will address stage IV disease. PMID:23244383

  10. Management options for metastatic melanoma in the era of novel therapies: a primer for the practicing dermatologist: part I: Management of stage III disease.

    PubMed

    Fox, Matthew C; Lao, Christopher D; Schwartz, Jennifer L; Frohm, Marcus L; Bichakjian, Christopher K; Johnson, Timothy M

    2013-01-01

    The incidence of melanoma has increased for decades, and while surgical treatment of early stage disease is often curative, metastatic disease continues to carry a significantly less promising outlook with high associated health burden and economic cost. An expanding number of dermatologists are playing a key role in coordinating the care of patients with melanoma, including in an increasingly important role among multidisciplinary melanoma clinics, many of which are anchored in dermatology departments. Advances in the understanding of the genetic and immunoregulatory aspects of melanoma development and progression have yielded a wave of novel therapeutics that has made significant impact on the approach to patients with metastatic disease. Frequently updated management guidelines and unfamiliarity with approved adjuvant treatment options, including interferon, clinical trials, or radiation therapy, can pose a challenge for dermatologists seeking to effectively coordinate the care of and establish proper expectations for patients with stage III disease. Moreover, greater awareness of treatment modalities for in-transit disease may allow dermatologists to play a more active role in the treatment of these patients and to expand their ability to explain and coordinate options, such as limb perfusion or infusion. Part I of this continuing medical education article will use clinical scenarios to outline the current management options for patients with stage III melanoma, including both adjuvant treatment options for resected stage III disease and primary treatment options for in-transit metastases. Part II of this series will address stage IV disease.

  11. Evaluating cost benefits of combination therapies for advanced melanoma

    PubMed Central

    Jensen, Ivar S.; Zacherle, Emily; Blanchette, Christopher M.; Zhang, Jie; Yin, Wes

    2016-01-01

    Background: Although a number of monoimmunotherapies and targeted therapies are available to treat BRAF+ advanced melanoma, response rates remain relatively low in the range of 22–53% with progression-free survival (PFS) in the range of 4.8–8.8 months. Recently, combination targeted therapies have improved response rates to about 66–69%, PFS to 11.0–12.6 months and overall survival (OS) to 25.1–25.6 months. While combination immunotherapies have improved response rates of 67 compared with 19–29% with monotherapies and improved PFS of 11.7 compared with 4.4–5.8 months with monotherapies, the OS benefit is yet to be established in phase 3 trials. As healthcare costs continue to rise, US payers have a predominant interest in assessing the value of available treatments. Therefore, a cost-benefit model was developed to evaluate the value of treating BRAF+ advanced melanoma with two combination therapies: nivolumab + ipilimumab (N+I) and dabrafenib + trametinib (D+T). Scope: The model was used to estimate total costs, total costs by expenditure category, cost per month of PFS and cost per responder for the payer, and societal perspectives of treating advanced melanoma patients with the BRAF V600 mutation using combination targeted therapy (D+T) or combination immunotherapy (N+I). The model followed patients from initiation of treatment to the point of progression or death. Deterministic and probabilistic sensitivity analyses were conducted to evaluate the robustness of the results and to understand the dispersion of simulated results. Findings: Based on a hypothetical payer with one million covered lives, it was expected that fourteen metastatic melanoma patients with the BRAF V600 mutation would be treated each year. Cost-benefit with N+I and D+T was simulated from the payer perspective. The cost per month of PFS for N+I was $22,162, while that for D+T was $17,716 (−$4,446 cost difference); the cost per responder for N+I was $388,746 and that for D+T was

  12. [Clinical studies and accepted therapies of advanced melanoma].

    PubMed

    Liszkay, Gabriella

    2016-03-01

    The objective of the work is presentation of the available therapeutic results of the clinical trials with anti CTLA-4 and anti PD-1 treatment, which are operating on the immune checkpoints registered in advanced melanoma, and the results of T-VEC vaccination (NCT00094653, NCT00324155, KEYNOTE-001, -002, -006, CheckMate-066, -037, -067, NCT00769704). With ipilimumab therapy, long-term survival can be achieved in the case of 20% of patients, with low (10%) therapeutic response, and grade 3-4 treatment related, predominantly autoimmune adverse events occurring in 10-15% of patients. Anti-PD-1 therapy proved more effective compared to ipilimumab, resulting in 21-40% therapeutic response, with 60-74% one-year survival rate and significantly less severe and frequent side effects. Progression-free survival achieved with ipilimumab/nivolumab combination was 11.5 months with grade 3-4 side effects occurring in 55% of patients. T-VEC therapy resulted in 26.4% objective response rate without a significant survival advantage. In the possession of the new immunotherapeutic possibilities, knowledge of the results of clinical studies is essential for the optimal complex therapy of melanoma. PMID:26934345

  13. Biology of Advanced Uveal Melanoma and Next Steps for Clinical Therapeutics

    PubMed Central

    Luke, Jason J.; Triozzi, Pierre L.; McKenna, Kyle C.; Van Meir, Erwin G.; Gershenwald, Jeffrey E.; Bastian, Boris C.; Gutkind, J. Silvio; Bowcock, Anne M.; Streicher, Howard Z.; Patel, Poulam M.; Sato, Takami; Sossman, Jeffery A.; Sznol, Mario; Welch, Jack; Thurin, Magdalena; Selig, Sara; Flaherty, Keith T.; Carvajal, Richard D.

    2014-01-01

    Summary Uveal melanoma is the most common intraocular malignancy though it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15 year period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease and median survival remains poor. Here, as a joint effort between CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherpies are reviewed and next steps in the development of clinical therapeutics are discussed. PMID:25113308

  14. Recombinant Interleukin-15 in Treating Patients With Advanced Melanoma, Kidney Cancer, Non-small Cell Lung Cancer, or Squamous Cell Head and Neck Cancer

    ClinicalTrials.gov

    2016-05-05

    Head and Neck Squamous Cell Carcinoma; Recurrent Head and Neck Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIA Skin Melanoma; Stage IIIB Non-Small Cell Lung Cancer; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Non-Small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma

  15. Metastasectomy for Stage IV Melanoma in the Era of Effective Systemic Agents.

    PubMed

    Ollila, David W; Lopez, Nicole E; Hsueh, Eddy C

    2016-01-01

    There is an increasing body of literature that strongly suggests that complete metastasectomy for stage IV melanoma can improve overall survival. Before 2011, the efficacy of systemic therapy for melanoma was poor, making surgical resection the mainstay for treatment and the only realistic chance for cure. Now, in just a short time span (2011-2014), we have six Food & Drug Administration (FDA)-approved drugs for patients with stage IV metastatic melanoma. In the absence of prospective clinical trials evaluating the most advantageous sequence and timing for systemic therapy and surgical resection in the setting of stage IV melanoma, the treating surgical and medical oncologists must jointly devise individual treatment plans that take into account the advantages and disadvantages of each modality. This multidisciplinary approach gives the patient the best chance for prolonged survival. This article briefly reviews the FDA-approved systemic therapy options, discusses the data for site-specific metastasectomy, critiques the previous stage IV metastasectomy trials, and presents a view for moving forward with a multidisciplinary approach in mind. PMID:27481001

  16. Melanoma

    MedlinePlus

    ... have melanoma that has spread. Help the patient’s immune system fight the cancer Ipilimumab (Yervoy®), which was FDA ... How ipilimumab works : This drug helps the patient’s immune system to recognize, target, and attack cancer cells. Healthy ...

  17. Cutaneous melanoma.

    PubMed

    Eggermont, Alexander M M; Spatz, Alan; Robert, Caroline

    2014-03-01

    In the past decade, major advances have been made in the understanding of melanoma. New predisposition genes have been reported and key somatic events, such as BRAF mutation, directly translated into therapeutic management. Surgery for localised melanoma and regional lymph node metastases is the standard of care. Sentinel-node biopsy provides precise staging, but has not been reported to affect survival. The effect of lymph-node dissection on survival is a topic of investigation. Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF-mutated melanoma. The combination of BRAF inhibitors and MEK inhibitors might improve progression-free survival further and, possibly, increase overall survival. Response patterns differ substantially-anti-CTLA4 immunotherapy can induce long-term responses, but only in a few patients, whereas targeted drugs induce responses in most patients, but nearly all of them relapse because of pre-existing or acquired resistance. Thus, the long-term prognosis of metastatic melanoma remains poor. Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability. Biomarkers that have predictive value remain elusive in melanoma, although emerging data for adjuvant therapy indicate that interferon sensitivity is associated with ulceration of the primary melanoma. Intense investigation continues for clinical and biological markers that predict clinical benefit of immunotherapeutic drugs, such as interferon alfa or anti-CTLA4 antibodies, and the mechanisms that lead to resistance of targeted drugs.

  18. Hemostatic alterations are unrelated to the stage of tumor in untreated malignant melanoma and breast carcinoma.

    PubMed

    Mannucci, P M; Vaglini, M; Maniezzo, M; Magni, E; Mari, D; Cascinelli, N

    1985-06-01

    A study of hemostatic variables was carried out in 80 untreated patients with breast adenocarcinoma or malignant melanoma, chosen as examples of tumors that can be accurately staged for localization or spread. The most marked abnormalities were high levels of clotting factors V and VIII, plasminogen, von Willebrand factor and fibrogen-fibrin degradation products. These abnormalities occurred in both types of tumors, albeit slightly more markedly in melanomas, and were also present in localized tumors. Our data indicate that in tumors, abnormalities of the hemostatic system are an early phenomenon unrelated to the presence of widespread malignancy.

  19. Advanced two-stage incinerator

    SciTech Connect

    Rehmat, A.; Khinkis, M.

    1991-01-01

    The Institute of Gas Technology (IGT) is developing an advanced incinerator that combines the fluidized-bed agglomeration/incineration and cyclonic combustion/incineration technologies that have been developed separately at IGT over many years. This combination results in a unique and extremely flexible incinerator for solid, sludge, liquid, and gaseous wastes. This system can operate over a wide range of conditions in the first stage, from low temperature (desorption) to high temperature (agglomeration), including gasification of high-Btu wastes. In the combined system, solid, liquid, and gaseous organic wastes would be easily and efficiently destroyed (>99.99% destruction and removal efficiency (DRE)), whereas solid inorganic contaminants would be contained within a glassy matrix, rendering them benign and suitable for disposal in an ordinary landfill. This technology is different from other existing technologies because of its agglomeration and encapsulation capability and its flexibility with respect to the types wastes it can handle. Both the fluidized-bed as well as the cyclonic incineration technologies have been fully developed and tested separately at pilot scales. 12 refs., 4 figs., 4 tabs.

  20. Analysis of the Clinical and Histopathological Patterns of 100 Consecutive Cases of Primary Cutaneous Melanoma and Correlation with Staging

    PubMed Central

    Nam, Kyung Wook; Bae, Seong Hwan; Song, Kyung Ho; Kim, Hoon Soo; Choi, Young Jin

    2015-01-01

    Background This study analyzed 100 consecutive patients with primary cutaneous melanoma over the course of 13 years to determine whether epidemiological differences correspond to different stages of the disease. We also investigated whether epidemiological characteristics affected the survival rate. Our results were compared with those of selected descriptive studies of melanoma in other East Asian populations, in order to determine whether cutaneous melanoma patterns are similar in East Asian populations. Methods The patients' medical records were reviewed retrospectively, and we analyzed the relationship of epidemiological characteristics to staging and survival rate. Additionally, papers from Hong Kong and Japan describing these phenomena in East Asian populations were subjected to a statistical comparison. Results The ratio of males to females was 1:1.8, and the foot was the most frequent tumor site (49%). Acral lentiginous melanoma occurred most frequently (55%). Nodular melanoma was associated with a higher stage. Stage III-IV tumors with Clark levels of IV-V were significantly associated with a low survival rate. A statistical analysis of comparable papers reported in Hong Kong and Japan showed similar results with regard to age, tumor location, and histopathological subtypes. Conclusions This study provides the first full epidemiological description of 100 consecutive cases of primary cutaneous melanoma in Korea, with results similar to those observed in other East Asian populations. Corresponding to previous findings, nodular melanoma tended to occur at a higher stage than other types, and tumors with high Clark levels and high stages showed a lower survival rate. PMID:26618123

  1. Spotlight on pembrolizumab in the treatment of advanced melanoma.

    PubMed

    Rajakulendran, Thanashan; Adam, David N

    2015-01-01

    Metastatic melanoma is an aggressive cancer with a poor prognosis. Many approved therapies often do not achieve durable responses in patients. This underscores the need for novel therapeutic strategies. Recruiting a robust immune response is an important antineoplastic treatment strategy. Immune checkpoints offer a molecular target for modulating the immune response and a promising therapeutic target in metastatic melanoma. Here we discuss the recent approval of pembrolizumab by the US Food and Drug Administration for the treatment of metastatic melanoma and its impact on future management of the disease.

  2. 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.

  3. Neoadjuvant therapy for locally advanced melanoma: new strategies with targeted therapies.

    PubMed

    La Greca, Michele; Grasso, Giuseppe; Antonelli, Giovanna; Russo, Alessia Erika; Bartolotta, Salvatore; D'Angelo, Alessandro; Vitale, Felice Vito; Ferraù, Francesco

    2014-01-01

    Neoadjuvant chemotherapy has been successfully tested in several bulky solid tumors, but it has not been utilized in advanced cutaneous melanoma, primarily because effective medical treatments for this disease have been lacking. However, with the development of new immunotherapies (monoclonal antibodies specific for cytotoxic T lymphocyte-associated antigen 4 [anti-CTLA-4] and programmed death protein-1 [anti-PD1]) and small molecules interfering with intracellular pathways (anti-BRAF and mitogen-activated protein kinase kinase [anti- MEK]) the use of this approach is becoming a viable treatment strategy for locally advanced melanoma. The neoadjuvant setting provides a double opportunity for a better knowledge of these drugs: a short-term evaluation of their intrinsic activity, and a deeper analysis of their action and resistance-induction mechanisms. BRAF inhibitors seem to be ideal candidates for the neoadjuvant setting, because of their prompt, repeatedly confirmed response in V600E BRAF-mutant metastatic melanoma. In this report we summarize studies focused on the neoadjuvant use of traditional medical treatments in advanced melanoma and anecdotal cases of this approach with the use of biologic therapies. Moreover, we discuss our experience with neoadjuvant targeted therapy as a priming for radical surgery in a patient with BRAF V600E mutation-positive advanced melanoma.

  4. Neoadjuvant therapy for locally advanced melanoma: new strategies with targeted therapies

    PubMed Central

    La Greca, Michele; Grasso, Giuseppe; Antonelli, Giovanna; Russo, Alessia Erika; Bartolotta, Salvatore; D’Angelo, Alessandro; Vitale, Felice Vito; Ferraù, Francesco

    2014-01-01

    Neoadjuvant chemotherapy has been successfully tested in several bulky solid tumors, but it has not been utilized in advanced cutaneous melanoma, primarily because effective medical treatments for this disease have been lacking. However, with the development of new immunotherapies (monoclonal antibodies specific for cytotoxic T lymphocyte-associated antigen 4 [anti-CTLA-4] and programmed death protein-1 [anti-PD1]) and small molecules interfering with intracellular pathways (anti-BRAF and mitogen-activated protein kinase kinase [anti- MEK]) the use of this approach is becoming a viable treatment strategy for locally advanced melanoma. The neoadjuvant setting provides a double opportunity for a better knowledge of these drugs: a short-term evaluation of their intrinsic activity, and a deeper analysis of their action and resistance-induction mechanisms. BRAF inhibitors seem to be ideal candidates for the neoadjuvant setting, because of their prompt, repeatedly confirmed response in V600E BRAF-mutant metastatic melanoma. In this report we summarize studies focused on the neoadjuvant use of traditional medical treatments in advanced melanoma and anecdotal cases of this approach with the use of biologic therapies. Moreover, we discuss our experience with neoadjuvant targeted therapy as a priming for radical surgery in a patient with BRAF V600E mutation-positive advanced melanoma. PMID:24971022

  5. Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I-II early-stage melanoma.

    PubMed

    Ortega-Martínez, Idoia; Gardeazabal, Jesús; Erramuzpe, Asier; Sanchez-Diez, Ana; Cortés, Jesús; García-Vázquez, María D; Pérez-Yarza, Gorka; Izu, Rosa; Luís Díaz-Ramón, Jose; de la Fuente, Ildefonso M; Asumendi, Aintzane; Boyano, María D

    2016-10-01

    Like many cancers, an early diagnosis of melanoma is fundamental to ensure a good prognosis, although an important proportion of stage I-II patients may still develop metastasis during follow-up. The aim of this work was to discover serum biomarkers in patients diagnosed with primary melanoma that identify those at a high risk of developing metastasis during the follow-up period. Proteomic and mass spectrophotometry analysis was performed on serum obtained from patients who developed metastasis during the first years after surgery for primary tumors and compared with that from patients who remained disease-free for more than 10 years after surgery. Five proteins were selected for validation as prognostic factors in 348 melanoma patients and 100 controls by ELISA: serum amyloid A and clusterin; immune system proteins; the cell adhesion molecules plakoglobin and vitronectin and the antimicrobial protein dermcidin. Compared to healthy controls, melanoma patients have high serum levels of these proteins at the moment of melanoma diagnosis, although the specific values were not related to the histopathological stage of the tumors. However, an analysis based on classification together with multivariate statistics showed that tumor stage, vitronectin and dermcidin levels were associated with the metastatic progression of patients with early-stage melanoma. Although melanoma patients have increased serum dermcidin levels, the REPTree classifier showed that levels of dermcidin <2.98 μg/ml predict metastasis in AJCC stage II patients. These data suggest that vitronectin and dermcidin are potent biomarkers of prognosis, which may help to improve the personalized medical care of melanoma patients and their survival. PMID:27216146

  6. Treatment patterns in advanced melanoma: findings from a survey of European oncologists.

    PubMed

    Jones, C; Zhao, Z; Barber, B; Bagijn, M; Corrie, P; Saltman, D

    2015-11-01

    With the emergence of new therapies, established patterns of treating advanced melanoma are changing. The aim of this study was to understand how advanced melanoma is treated in clinical practice in Europe following the introduction of ipilimumab and vemurafenib. An online survey was conducted between August and November 2012 with 150 oncologists and dermatologists, from France, Germany, Italy, Spain and the U.K.; respondents reported treating the majority of patients with one or two lines of therapy. For BRAF mutant melanoma, the most frequently used first-line treatments were vemurafenib and dacarbazine. For BRAF wild-type melanoma, the most frequently used first-line treatment was dacarbazine. There was no single preferred agent for the second-line treatment of BRAF mutant or BRAF wild-type disease. Most sequencing from first- to second-line was from conventional dacarbazine to newer agents such as ipilimumab and vemurafenib. The treatment of advanced melanoma is rapidly evolving due to the introduction of new agents. This study presents an early insight into access to the new agents, ipilimumab and vemurafenib, and clinical practice in several European countries.

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

    ClinicalTrials.gov

    2016-07-25

    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

  8. DNA aptamer raised against advanced glycation end products inhibits melanoma growth in nude mice.

    PubMed

    Ojima, Ayako; Matsui, Takanori; Maeda, Sayaka; Takeuchi, Masayoshi; Inoue, Hiroyoshi; Higashimoto, Yuichiro; Yamagishi, Sho-ichi

    2014-04-01

    Epidemiological studies have suggested that diabetes is associated with an increased risk of cancer. However, the underlying molecular mechanism remains unclear. We investigated here whether DNA aptamer directed against advanced glycation end products (AGE-aptamer) inhibited melanoma growth in nude mice. G361 melanoma cells were injected intradermally into the upper flank of athymic nude mice. Mice received continuous intraperitoneal infusion (0.136 μg/day) of either AGE-aptamer (n=9) or Control-aptamer (n=8) by an osmotic mini pump. Tumor volume was measured at 4-day interval, and G361 melanoma was excised at day 43 after the aptamer treatment. We further examined the effects of AGE-aptamer on proliferation of AGE-exposed endothelial cells and G361 cells. AGE-aptamer significantly inhibited the in vivo-tumor growth of G361 melanoma. Immunohistochemical and western blotting analyses of G361 melanoma revealed that AGE-aptamer decreased expression levels of proliferating nuclear antigen, CD31 and Mac-3, markers of endothelial cells and macrophages, respectively. AGE-aptamer significantly decreased the number of tumor-associated vessels. AGE, receptor for AGE (RAGE) and vascular endothelial growth factor levels were also reduced in AGE-aptamer-treated G361 melanoma. AGE-aptamer inhibited the AGE-induced proliferation and tube formation of endothelial cells as well as the growth of G361 cells in vitro. The present findings suggest that AGE-aptamer could inhibit the AGE-RAGE axis in G361 melanoma and resultantly suppress the tumor growth in nude mice by blocking the angiogenesis. AGE-aptamer might be a novel therapeutic strategy for preventing the progression of malignant melanoma in diabetes.

  9. New strategies in metastatic melanoma: oncogene-defined taxonomy leads to therapeutic advances.

    PubMed

    Flaherty, Keith T; Fisher, David E

    2011-08-01

    The discovery of BRAF and KIT mutations provided the first basis for a molecular classification of cutaneous melanoma on therapeutic grounds. As BRAF-targeted therapy quickly moves toward regulatory approval and incorporation as standard therapy for patients with metastatic disease, proof of concept has also been established for targeting mutated KIT in melanoma. NRAS mutations have long been known to be present in a subset of melanomas and represent an elusive subgroup for targeted therapies. Matching patient subgroups defined by genetic aberrations in the phosphoinositide 3-kinase and p16/cyclin dependent kinase 4 (CDK4) pathways with appropriate targeted therapies has not yet been realized. And, an increasing understanding of lineage-specific transcriptional regulators, most notably MITF, and how they may play a role in melanoma pathophysiology, has provided another axis to approach with therapies. The foundation has been established for individual oncogene targeting, and current investigations seek to understand the intersection of these susceptibilities and other described potential targets and pathways. The melanoma field stands poised to take the lead among cancer subtypes in advancing combination therapy strategies that simultaneously target multiple biologic underpinnings of the disease. PMID:21670085

  10. 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

  11. [Sentinel lymph node procedure in melanoma patients: a staging procedure, not a therapy].

    PubMed

    van Akkooi, Alexander C J; Kukutsch, Nicole A; Soetekouw, Patricia M M B

    2014-01-01

    The definitive results of the MSLT-1 study in melanoma patients were published recently. The sentinel lymph node (SLN) procedure shows no survival benefit compared with observation. The authors reported, however, that there was a survival benefit with "biopsy management" of patients. This statement is based on subgroup analyses that we find to be incorrect for three reasons: (a) patients with a false negative SLN were incorrectly left out of consideration; (b) accelerated failure time latent subgroup analysis is an unproven statistical hypothesis, which was developed on interim data from the MSLT-1 study, and therefore cannot be used as validation; (c) there is a significant difference in terms of the percentage of patients with affected lymph nodes between the SLN group and the observation group. This excess of "prognostic false positive" patients would have incorrectly falsely improved the survival of the SLN group. We concluded that the SLN procedure does not give a survival benefit and that its role in melanoma patients should be for staging purposes and not for therapeutic purposes.

  12. Chemotherapy for Melanoma.

    PubMed

    Wilson, Melissa A; Schuchter, Lynn M

    2016-01-01

    Prior to the recent therapeutic advances, chemotherapy was the mainstay of treatment options for advanced-stage melanoma. A number of studies have investigated various chemotherapy combinations in order to expand on the clinical responses achieved with single-agent dacarbazine, but these have not demonstrated an improvement in overall survival. Similar objective responses were observed with the combination of carboplatin and paclitaxel as were seen with single-agent dacarbazine. The combination of chemotherapy and immunotherapy, known as biochemo-therapy, has shown high clinical responses; however, biochemo-therapy has not been shown to improve overall survival and resulted in increased toxicities. In contrast, palliation and long-term responses have been observed with localized treatment with isolated limb perfusion or infusion in limb-isolated disease. Although new, improved therapeutic options exist for first-line management of advanced-stage melanoma, chemotherapy may still be important in the palliative treatment of refractory, progressive, and relapsed melanoma. We review the various chemotherapy options available for use in the treatment and palliation of advanced-stage melanoma, discuss the important clinical trials supporting the treatment recommendations, and focus on the clinical circumstances in which treatment with chemotherapy is useful.

  13. 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.

  14. Unmet clinical needs in the management of advanced melanoma: findings from a survey of oncologists.

    PubMed

    Jones, C; Clapton, G; Zhao, Z; Barber, B; Saltman, D; Corrie, P

    2015-11-01

    Advanced melanoma is a life-threatening cancer with limited life expectancy. The recent introduction of new targeted systemic therapies has provided clinicians with the means to potentially extend survival for the first time. However, the chance of cure remains very low and treatment-induced toxicity is well described. This qualitative study was undertaken to evaluate clinicians' assessment regarding the key concerns in managing advanced melanoma following the introduction of these new treatments. Three hundred and forty-three oncologists were surveyed online between August and November 2012 (in 11 countries) and March and April 2013 (in an additional country). Analysis of free-text responses identified 23 clinical issues of concern across all countries. Of these, the most common clinical concerns were drug toxicity and tolerability, followed by limited treatment effectiveness and limited treatment options. These results suggest that despite the promise of the two new agents in the field, clinicians are still concerned about the limitations of current treatment options, recognising that there remains a significant unmet need in the treatment of advanced melanoma.

  15. 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

  16. 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.

  17. The evolution of combined molecular targeted therapies to advance the therapeutic efficacy in melanoma: a highlight of vemurafenib and cobimetinib

    PubMed Central

    Medina, Theresa M; Lewis, Karl D

    2016-01-01

    Metastatic melanoma is an aggressive, rapidly progressive disease which historically had very few effective treatment options. However, since 2011, the therapeutic landscape of melanoma has undergone a dramatic transformation with two distinct approaches and has catalyzed the successful advancement in the clinical field of immuno-oncology. In addition, the recognition of a key oncogenic driver mutation in melanoma, BRAF, stimulated the development of multiple potent kinase inhibitors which has also influenced the expansion and use of targeted agents in the practice of oncology. Vemurafenib, the initial BRAF inhibitor approved for the treatment of melanoma, was the first agent to demonstrate rapid clinical responses and significantly improved survival which was a clinical breakthrough in the treatment of melanoma. Although exciting and practice changing, the unparalleled responses with vemurafenib are usually not sustained. Further investigations delineated several mechanisms of acquired resistance which are most often mediated by the upregulation of the MAPK pathway. MEK inhibitors, another class of small-molecule inhibitors, were developed as an alternative agent to suppress the MAPK pathway downstream, independent from BRAF activation. Multiple studies have demonstrated the improvement in antitumor activity when MEK inhibitors are used in combination with BRAF inhibitors in the treatment of metastatic melanoma. This is a review of the investigations that led to the US Food and Drug Administration approval in 2015 of the combination of vemurafenib and cobimetinib, adding to the quickly growing armament for the treatment of advanced or metastatic melanoma with a BRAF V600 mutation. PMID:27382311

  18. New developments in the management of advanced melanoma - role of pembrolizumab.

    PubMed

    Improta, Giuseppina; Leone, Isabella; Donia, Marco; Gieri, Stefania; Pelosi, Giuseppe; Fraggetta, Filippo

    2015-01-01

    Cancer immunotherapy is now recognized to be fundamental in modern oncology, because immune system recruitment may represent a powerful and innovative strategy in cancer therapy. Pembrolizumab, a highly selective humanized monoclonal antibody directly blocking the interaction between programmed cell death-1 expressed by tumor-associated T-cells and its ligand programmed cell death-L1 present on tumor and stromal cells, was recently approved by US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma and disease progression upon ipilimumab and BRAF inhibitor. This review will focus on the clinical development and use of pembrolizumab in the clinical practice and in the management of advanced melanoma.

  19. New developments in the management of advanced melanoma - role of pembrolizumab.

    PubMed

    Improta, Giuseppina; Leone, Isabella; Donia, Marco; Gieri, Stefania; Pelosi, Giuseppe; Fraggetta, Filippo

    2015-01-01

    Cancer immunotherapy is now recognized to be fundamental in modern oncology, because immune system recruitment may represent a powerful and innovative strategy in cancer therapy. Pembrolizumab, a highly selective humanized monoclonal antibody directly blocking the interaction between programmed cell death-1 expressed by tumor-associated T-cells and its ligand programmed cell death-L1 present on tumor and stromal cells, was recently approved by US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma and disease progression upon ipilimumab and BRAF inhibitor. This review will focus on the clinical development and use of pembrolizumab in the clinical practice and in the management of advanced melanoma. PMID:26396529

  20. New developments in the management of advanced melanoma – role of pembrolizumab

    PubMed Central

    Improta, Giuseppina; Leone, Isabella; Donia, Marco; Gieri, Stefania; Pelosi, Giuseppe; Fraggetta, Filippo

    2015-01-01

    Cancer immunotherapy is now recognized to be fundamental in modern oncology, because immune system recruitment may represent a powerful and innovative strategy in cancer therapy. Pembrolizumab, a highly selective humanized monoclonal antibody directly blocking the interaction between programmed cell death-1 expressed by tumor-associated T-cells and its ligand programmed cell death-L1 present on tumor and stromal cells, was recently approved by US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma and disease progression upon ipilimumab and BRAF inhibitor. This review will focus on the clinical development and use of pembrolizumab in the clinical practice and in the management of advanced melanoma. PMID:26396529

  1. Restoration of tumor equilibrium after immunotherapy for advanced melanoma: three illustrative cases.

    PubMed

    Wilgenhof, Sofie; Pierret, Lauranne; Corthals, Jurgen; Van Nuffel, An M T; Heirman, Carlo; Roelandt, Truus; De Coninck, Arlette; Verfaillie, Guy; Vandenbroucke, Frederik; Van Riet, Ivan; Bonehill, Aude; Thielemans, Kris; Neyns, Bart

    2011-04-01

    Metastatic melanoma runs a predictable detrimental course in the vast majority of patients. New modalities of immunotherapy, such as melanoma antigen-specific therapeutic vaccination and cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor blockade by monoclonal antibodies (mAbs), have been associated with atypical kinetics of tumor response that differ from those observed during cytotoxic treatment. Recently, new tumor response criteria have been proposed based on the tumor response characteristics observed in clinical studies with ipilimumab (the so-called 'immune-related response criteria'). We report three illustrative cases of the American Joint Committee on Cancer stage IV-M1c melanoma patients who experienced atypical kinetics of tumor response to the treatment with the CTLA-4-blocking mAb, ipilimumab (case 1), or an autologous dendritic cell vaccine in combination with interferon α-2b (cases 2 and 3). These cases show that atypical response patterns not only relate to the outcome of CTLA-4-blocking mAb therapy but also to the treatment with therapeutic vaccines and interferon α-2b.

  2. Phase I/II Trial of Imatinib and Bevacizumab in Patients With Advanced Melanoma and Other Advanced Cancers

    PubMed Central

    Hamilton, Betty K.; Rosen, Mark A.; Amaravadi, Ravi K.; Schuchter, Lynn M.; Gallagher, Maryann; Chen, Helen; Sehgal, Chandra; O’Dwyer, Peter J.

    2015-01-01

    Background. Vascular endothelial growth factor and platelet-derived growth factor signaling in the tumor microenvironment appear to cooperate in promoting tumor angiogenesis. Patients and Methods. We conducted a phase I trial combining bevacizumab (i.v. every 2 weeks) and imatinib (oral daily). Once a recommended phase II dose combination was established, a phase II trial was initiated in patients with metastatic melanoma. A Simon 2-stage design was used with 23 patients required in the first stage and 41 patients in total should the criteria to proceed be met. We required that 50% of the patients be progression-free at 16 weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and power Doppler ultrasonography were performed in patients with metastatic tumors amenable to imaging with these methods at baseline and after 4 weeks. Results. A total of 17 patients were accrued to 4 dose and combination levels. Bevacizumab 10 mg/kg every 2 weeks could be safely combined with imatinib 800 mg daily. Common toxicities included fatigue, nausea, vomiting, edema, proteinuria, and anemia, but were not commonly severe. A total of 23 patients with metastatic melanoma (48% with American Joint Commission on Cancer stage M1c; median age, 63 years) were enrolled in the first stage of phase II. The 16-week progression-free survival rate was 35%, leading to termination of phase II after the first stage. In the small subset of patients who remained on study with lesions evaluable by DCE-MRI, significant decreases in tumor vascular permeability were noted, despite early disease progression using the Response Evaluation Criteria In Solid Tumors. Conclusion. Bevacizumab and imatinib can be safely combined at the maximum doses used for each agent. We did not observe significant clinical activity with this regimen in melanoma patients. Implications for Practice: Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy has proven clinical efficacy as a

  3. 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

  4. Lock-in thermal imaging for the early-stage detection of cutaneous melanoma: a feasibility study.

    PubMed

    Bonmarin, Mathias; Le Gal, Frédérique-Anne

    2014-04-01

    This paper theoretically evaluates lock-in thermal imaging for the early-stage detection of cutaneous melanoma. Lock-in thermal imaging is based on the periodic thermal excitation of the specimen under test. Resulting surface temperature oscillations are recorded with an infrared camera and allow the detection of variations of the sample's thermophysical properties under the surface. In this paper, the steady-state and transient skin surface temperatures are numerically derived for a different stage of development of the melanoma lesion using a two-dimensional axisymmetric multilayer heat-transfer model. The transient skin surface temperature signals are demodulated according to the digital lock-in principle to compute both a phase and an amplitude image of the lesions. The phase image can be advantageously used to accurately detect cutaneous melanoma at an early stage of development while the maximal phase shift can give precious information about the lesion invasion depth. The ability of lock-in thermal imaging to suppress disturbing subcutaneous thermal signals is demonstrated. The method is compared with the previously proposed pulse-based approaches, and the influence of the modulation frequency is further discussed.

  5. Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression.

    PubMed

    Ferguson, B; Ram, R; Handoko, H Y; Mukhopadhyay, P; Muller, H K; Soyer, H P; Morahan, G; Walker, G J

    2015-05-28

    Susceptibility to most common cancers is likely to involve interaction between multiple low risk genetic variants. Although there has been great progress in identifying such variants, their effect on phenotype and the mechanisms by which they contribute to disease remain largely unknown. We have developed a mouse melanoma model harboring two mutant oncogenes implicated in human melanoma, CDK4(R24C) and NRAS(Q61K). In these mice, tumors arise from benign precursor lesions that are a recognized strong risk factor for this neoplasm in humans. To define molecular events involved in the pathway to melanoma, we have for the first time applied the Collaborative Cross (CC) to cancer research. The CC is a powerful resource designed to expedite discovery of genes for complex traits. We characterized melanoma genesis in more than 50 CC strains and observed tremendous variation in all traits, including nevus and melanoma age of onset and multiplicity, anatomical site predilection, time for conversion of nevi to melanoma and metastases. Intriguingly, neonatal ultraviolet radiation exposure exacerbated nevus and melanoma formation in most, but not all CC strain backgrounds, suggesting that genetic variation within the CC will help explain individual sensitivity to sun exposure, the major environmental skin carcinogen. As genetic variation brings about dramatic phenotypic diversity in a single mouse model, melanoma-related endophenotype comparisons provide us with information about mechanisms of carcinogenesis, such as whether melanoma incidence is dependent upon the density of pre-existing nevus cells. Mouse models have been used to examine the functional role of gene mutations in tumorigenesis. This work represents their next phase of development to study how biological variation greatly influences lesion onset and aggressiveness even in the setting of known somatic driver mutations.

  6. Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression.

    PubMed

    Ferguson, B; Ram, R; Handoko, H Y; Mukhopadhyay, P; Muller, H K; Soyer, H P; Morahan, G; Walker, G J

    2015-05-28

    Susceptibility to most common cancers is likely to involve interaction between multiple low risk genetic variants. Although there has been great progress in identifying such variants, their effect on phenotype and the mechanisms by which they contribute to disease remain largely unknown. We have developed a mouse melanoma model harboring two mutant oncogenes implicated in human melanoma, CDK4(R24C) and NRAS(Q61K). In these mice, tumors arise from benign precursor lesions that are a recognized strong risk factor for this neoplasm in humans. To define molecular events involved in the pathway to melanoma, we have for the first time applied the Collaborative Cross (CC) to cancer research. The CC is a powerful resource designed to expedite discovery of genes for complex traits. We characterized melanoma genesis in more than 50 CC strains and observed tremendous variation in all traits, including nevus and melanoma age of onset and multiplicity, anatomical site predilection, time for conversion of nevi to melanoma and metastases. Intriguingly, neonatal ultraviolet radiation exposure exacerbated nevus and melanoma formation in most, but not all CC strain backgrounds, suggesting that genetic variation within the CC will help explain individual sensitivity to sun exposure, the major environmental skin carcinogen. As genetic variation brings about dramatic phenotypic diversity in a single mouse model, melanoma-related endophenotype comparisons provide us with information about mechanisms of carcinogenesis, such as whether melanoma incidence is dependent upon the density of pre-existing nevus cells. Mouse models have been used to examine the functional role of gene mutations in tumorigenesis. This work represents their next phase of development to study how biological variation greatly influences lesion onset and aggressiveness even in the setting of known somatic driver mutations. PMID:25088201

  7. Treatment of advanced-stage Hodgkin lymphoma.

    PubMed

    Vassilakopoulos, Theodoros P; Johnson, Peter W M

    2016-07-01

    There is now good evidence that the escalated BEACOPP regimen (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) is more effective in controlling advanced-stage Hodgkin lymphoma (HL) than the widely used ABVD regimen (adriamycin, bleomycin, vinblastine, dacarbazine), but the extra efficacy comes at the expense of both short- and long-term toxicity, and there is debate as to whether overall survival is affected. Baseline prognostic factors have proven of limited utility for determining which patients require more intensive therapy and recent studies have sought to use interim fluoro-deoxyglucose positron emission tomography (FDG-PET) evaluation as a means to guide the modulation of treatment, both upwards and downwards in intensity. These suggest that if treatment starts with ABVD then patients remaining PET-positive after 2 months can be salvaged with escalated BEACOPP in around 65% of cases, but those becoming PET-negative may still experience recurrences in 15%-20%, an event that is more common in those with more advanced disease at presentation. There are early data to suggest that starting with escalated BEACOPP may reduce the rate of recurrence after a negative interim PET to less than 10%. This may be an attractive approach for those with very high-risk features at presentation, but risks overtreating many patients if applied nonselectively. New regimens incorporating antibody-drug conjugates may shift the balance of efficacy and toxicity once again, and further studies are underway to evaluate this. PMID:27496308

  8. A new understanding in the epidemiology of melanoma

    PubMed Central

    Erdei, Esther; Torres, Salina M

    2011-01-01

    The incidence of melanoma is continuing to increase worldwide. UV exposure is a known risk factor for melanoma. Geographic location is known to influence UV exposure and the distribution of the incidence of melanoma. Furthermore, epidemiologic data suggest that gender and genetics may influence the distribution of melanoma on the body surface and histopathologic characteristics of the lesion. This article describes what is known about the impact of gender, ethnicity and geography on the progression of melanoma. Advanced-stage cutaneous melanoma has a median survival time of less than 1 year. Surgical removal, radiotherapy, chemotherapy, targeted therapies and a variety of immunotherapies have been utilized in the treatment of melanoma. Current treatment strategies and the results of recent clinical trials are also discussed in this article. PMID:21080806

  9. 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

  10. Endothelin-1 in the tumor microenvironment correlates with melanoma invasion.

    PubMed

    Chiriboga, Luis; Meehan, Shane; Osman, Iman; Glick, Michael; de la Cruz, Gelo; Howell, Brittny S; Friedman-Jiménez, George; Schneider, Robert J; Jamal, Sumayah

    2016-06-01

    Endothelin-1 (ET-1) is a vasoactive peptide that also plays a role in the tanning response of the skin. Animal and cell culture studies have also implicated ET-1 in melanoma progression, but no association studies have been performed to link ET-1 expression and melanoma in humans. Here, we present the first in-vivo study of ET-1 expression in pigmented lesions in humans: an ET-1 immunohistochemical screen of melanocytic nevi, melanoma in situ lesions, invasive melanomas, metastatic melanomas, and blue nevi was performed. Twenty-six percent of melanocytic nevi and 44% of melanoma in situ lesions demonstrate ET-1 expression in the perilesional microenvironment, whereas expression in nevus or melanoma cells was rare to absent. In striking contrast, 100% of moderately to highly pigmented invasive melanomas contained numerous ET-1-positive cells in the tumor microenvironment, with 79% containing ET-1-positive melanoma cells, confirmed by co-staining with melanoma tumor marker HMB45. Hypopigmented invasive melanomas had reduced ET-1 expression, suggesting a correlation between ET-1 expression and pigmented melanomas. ET-1-positive perilesional cells were CD68-positive, indicating macrophage origin. Sixty-two percent of highly pigmented metastatic melanomas demonstrated ET-1 expression in melanoma cells, in contrast to 28.2% of hypopigmented specimens. Eighty-nine percent of benign nevi, known as blue nevi, which have a dermal localization, were associated with numerous ET-1-positive macrophages in the perilesional microenvironment, but no ET-1 expression was detected in the melanocytes. We conclude that ET-1 expression in the microenvironment increases with advancing stages of melanocyte transformation, implicating a critical role for ET-1 in melanoma progression, and the importance of the tumor microenvironment in the melanoma phenotype.

  11. Comparative analysis of BRAF, NRAS and c-KIT mutation status between tumor tissues and autologous tumor cell-lines of stage III/IV melanoma.

    PubMed

    Knol, Anne-Chantal; Pandolfino, Marie-Christine; Vallée, Audrey; Nguyen, Frédérique; Lella, Virginie; Khammari, Amir; Denis, Marc; Puaux, Anne-Laure; Dréno, Brigitte

    2015-01-01

    In the last decade, advances in molecular biology have provided evidence of the genotypic heterogeneity of melanoma. We analysed BRAF, NRAS and c-KIT alterations in tissue samples from 63 stage III/IV melanoma patients and autologous cell-lines, using either allele-specific or quantitative PCR. The expression of BRAF V600E protein was also investigated using an anti-BRAF antibody in the same tissue samples. 81% of FFPE samples and tumor cell-lines harboured a genetic alteration in either BRAF (54%) or NRAS (27%) oncogenes. There was a strong concordance (100%) between tissue samples and tumor cell-lines. The BRAF V600E mutant-specific antibody showed high sensitivity (96%) and specificity (100%) for detecting the presence of a BRAF V600E mutation. The correlation was of 98% between PCR and immunohistochemistry results for BRAF mutation. These results suggest that BRAF and NRAS mutation status of tumor cells is not affected by culture conditions.

  12. Ipilimumab for advanced melanoma: experience from the Spanish Expanded Access Program

    PubMed Central

    Arance, Ana; Lopez Martin, Jose Antonio; Soriano, Virtudes; Muñoz, Eva; Alonso, Lorenzo; Espinosa, Enrique; Lopez Criado, Pilar; Valdivia, Javier; Martin Algarra, Salvador

    2014-01-01

    Ipilimumab, a fully human, recombinant, monoclonal antibody to cytotoxic T-lymphocyte antigen 4 improves overall survival (OS) in previously treated and untreated metastatic melanoma. This retrospective analysis reports data gathered by a questionnaire on the demographics, outcomes, and toxicity of ipilimumab administered through an Expanded Access Program (EAP). Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for four cycles to adults with metastatic melanoma. Efficacy outcomes included complete response, partial response (PR), progressive disease, stabilized disease, and OS. EAP data were collected from EAP physicians. A subgroup analysis examined efficacy in elderly patients (≥70 years) and factors predictive of survival were identified. Of 355 requests for ipilimumab, resulting in 288 treatments, completed questionnaires were received for 153 ipilimumab recipients (median age 58 years, 57.2% men). Efficacy was evaluated in 144 patients: complete response in 1.3%, PR in 9.6%, PR with previous progression 8.4%, stabilized disease in 14.5%, and progressive disease in 66.2%. The median OS was 6.5 months (199 days); 1-year survival was 32.9%. Predictive survival factors included lymphocytes over 1000/ml (P=0.0008) and lactate dehydrogenase more than 1.5×upper limit of normal (P=0.003). Cutaneous, hepatic, and gastrointestinal toxicities were mild. In 30 patients aged more than 70 years, ipilimumab efficacy and tolerability was similar to that of the overall population. In the clinical practice setting, ipilimumab is effective and well tolerated in patients with advanced melanoma, including elderly patients, when administered at the recommended dosage. Ipilimumab improves treatment options for patients who, until recently, have had little hope of an improved prognosis. PMID:25046550

  13. A subpopulation that may correspond to granulocytic myeloid-derived suppressor cells reflects the clinical stage and progression of cutaneous melanoma.

    PubMed

    Stanojevic, Ivan; Miller, Karolina; Kandolf-Sekulovic, Lidija; Mijuskovic, Zeljko; Zolotarevski, Lidija; Jovic, Milena; Gacevic, Milomir; Djukic, Mirjana; Arsenijevic, Nebojsa; Vojvodic, Danilo

    2016-02-01

    Seventy-eight melanoma patients and 10 healthy individuals were examined. Follow-up examinations of all melanoma patients were performed regularly every three months. Myeloid-derived suppressor cells (MDSC) were defined as lineage negative (CD3(-), CD19(-), CD56(-)), HLA-DR(-/low), CD11b(+) and CD33(+). Classification of granulocytic (GrMDSC) and monocytic (MoMDSC) subsets was based on the CD15 and CD14 expression, respectively. Unlike the MoMDSC, that were present in 60% of healthy controls and 15% of melanoma patients, the GrMDSC were present in all examined participants, and the melanoma patients were found to have statistically higher frequencies compared with healthy controls. Accordingly, we kept focused on GrMDSC frequencies in relation to the melanoma stages and course of the disease. The GrMDSC values are highest in stage IV melanoma patients, with statistical significance compared with stages IA, IB, IIA and IIB. Patients with progression had statistically higher GrMDSC counts comparing with those with stable disease (P = 0.0079). Patients who had progression-free interval (PFI) < 12 months showed significantly higher GrMDSC values compared with those with PFI > 12 months (P = 0.0333). GrMDSC showed significant negative correlation with PFI intervals (P = 0.0095). The GrMDSC subset was predominant in all our patients. We confirmed that GrMDSC do accumulate early in the peripheral blood of melanoma patients and their frequencies correlate narrowly with the clinical stage and the spread of the disease. The increase in GrMDSC frequencies correlates well with a progressive disease and could be considered a potential predictive biomarker of high-risk melanoma cases that are more likely to have a shorter PFI. PMID:26391013

  14. Real-world treatment practice in patients with advanced melanoma in the era before ipilimumab: results from the IMAGE study.

    PubMed

    Middleton, Mark R; Dalle, Stéphane; Claveau, Joel; Mut, Pilar; Hallmeyer, Sigrun; Plantin, Patrice; Highley, Martin; Kotapati, Srividya; Le, Trong Kim; Brokaw, Jane; Abernethy, Amy P

    2016-07-01

    The therapeutic landscape for advanced melanoma has recently been transformed by several novel agents (immune checkpoint inhibitors and molecular-targeted agents). The prospective, multi-site, observational study IMAGE (ipilimumab: management of advanced melanoma in real practice) included a retrospective cohort to describe real-world treatment prior to approval of the immune checkpoint inhibitor ipilimumab. This retrospective cohort of patients, who started second-line/subsequent treatment (index therapy) for advanced melanoma within 3 years before ipilimumab approval, was selected randomly by chart review. Collected data included treatment history, patient outcomes, and healthcare resource utilization. All patients had ≥1 year of follow-up data. This analysis included 177 patients from Europe (69%) and North America (31%). The most common index therapies (used alone or in combination) were fotemustine (23%), dacarbazine (21%), temozolomide (14%), and platinum-based chemotherapy (14%). Most patients (89%) discontinued index treatment during the study period; the most common reason was disease progression (59%). Among patients with tumor assessment (153/177; 86%), 2% had complete response, 5% had partial response, and 12% had stable disease on last tumor assessment. At 1-year study follow-up, median progression-free survival was 2.6 months (95% confidence interval [CI], 2.1-2.9) and median overall survival was 8.8 months (95% CI, 6.5-9.7). During follow-up, 95% of the patients had healthcare visits for advanced melanoma, 74% of whom were hospitalized or admitted to a hospice facility. These results provide insights into patient care with advanced melanoma in the era before ipilimumab and may serve as a benchmark for new agents in future real-world studies.

  15. Real-world treatment practice in patients with advanced melanoma in the era before ipilimumab: results from the IMAGE study.

    PubMed

    Middleton, Mark R; Dalle, Stéphane; Claveau, Joel; Mut, Pilar; Hallmeyer, Sigrun; Plantin, Patrice; Highley, Martin; Kotapati, Srividya; Le, Trong Kim; Brokaw, Jane; Abernethy, Amy P

    2016-07-01

    The therapeutic landscape for advanced melanoma has recently been transformed by several novel agents (immune checkpoint inhibitors and molecular-targeted agents). The prospective, multi-site, observational study IMAGE (ipilimumab: management of advanced melanoma in real practice) included a retrospective cohort to describe real-world treatment prior to approval of the immune checkpoint inhibitor ipilimumab. This retrospective cohort of patients, who started second-line/subsequent treatment (index therapy) for advanced melanoma within 3 years before ipilimumab approval, was selected randomly by chart review. Collected data included treatment history, patient outcomes, and healthcare resource utilization. All patients had ≥1 year of follow-up data. This analysis included 177 patients from Europe (69%) and North America (31%). The most common index therapies (used alone or in combination) were fotemustine (23%), dacarbazine (21%), temozolomide (14%), and platinum-based chemotherapy (14%). Most patients (89%) discontinued index treatment during the study period; the most common reason was disease progression (59%). Among patients with tumor assessment (153/177; 86%), 2% had complete response, 5% had partial response, and 12% had stable disease on last tumor assessment. At 1-year study follow-up, median progression-free survival was 2.6 months (95% confidence interval [CI], 2.1-2.9) and median overall survival was 8.8 months (95% CI, 6.5-9.7). During follow-up, 95% of the patients had healthcare visits for advanced melanoma, 74% of whom were hospitalized or admitted to a hospice facility. These results provide insights into patient care with advanced melanoma in the era before ipilimumab and may serve as a benchmark for new agents in future real-world studies. PMID:27118102

  16. 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

  17. Favorable overall survival in stage III melanoma patients after adjuvant dendritic cell vaccination

    PubMed Central

    Bol, Kalijn F; Aarntzen, Erik H J G; Hout, Florentien E M in 't; Schreibelt, Gerty; Creemers, Jeroen H A; Lesterhuis, W Joost; Gerritsen, Winald R; Grunhagen, Dirk J; Verhoef, Cornelis; Punt, Cornelis J A; Bonenkamp, Johannes J; de Wilt, Johannes H W; Figdor, Carl G; de Vries, I Jolanda M

    2016-01-01

    Melanoma patients with regional metastatic disease are at high risk for recurrence and metastatic disease, despite radical lymph node dissection (RLND). We investigated the immunologic response and clinical outcome to adjuvant dendritic cell (DC) vaccination in melanoma patients with regional metastatic disease who underwent RLND with curative intent. In this retrospective study, 78 melanoma patients with regional lymph node metastasis who underwent RLND received autologous DCs loaded with gp100 and tyrosinase and were analyzed for functional tumor-specific T cell responses in skin-test infiltrating lymphocytes. The study shows that adjuvant DC vaccination in melanoma patients with regional lymph node metastasis is safe and induced functional tumor-specific T cell responses in 71% of the patients. The presence of functional tumor-specific T cells was correlated with a better 2-year overall survival (OS) rate. OS was significantly higher after adjuvant DC vaccination compared to 209 matched controls who underwent RLND without adjuvant DC vaccination, 63.6 mo vs. 31.0 mo (p = 0.018; hazard ratio 0.59; 95%CI 0.42–0.84). Five-year survival rate increased from 38% to 53% (p < 0.01). In summary, in melanoma patients with regional metastatic disease, who are at high risk for recurrence and metastatic disease after RLND, adjuvant DC vaccination is well tolerated. It induced functional tumor-specific immune responses in the majority of patients and these were related to clinical outcome. OS was significantly higher compared to matched controls. A randomized clinical trial is needed to prospectively validate the efficacy of DC vaccination in the adjuvant setting. PMID:26942068

  18. Comparison of clinicopathologic features and survival of histopathologically amelanotic and pigmented melanomas: a population-based study.

    PubMed

    Thomas, Nancy E; Kricker, Anne; Waxweiler, Weston T; Dillon, Patrick M; Busman, Klaus J; From, Lynn; Groben, Pamela A; Armstrong, Bruce K; Anton-Culver, Hoda; Gruber, Stephen B; Marrett, Loraine D; Gallagher, Richard P; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Venn, Alison; Kanetsky, Peter A; Orlow, Irene; Paine, Susan; Ollila, David W; Reiner, Anne S; Luo, Li; Hao, Honglin; Frank, Jill S; Begg, Colin B; Berwick, Marianne

    2014-12-01

    , anatomic site, and study design variables, but survival did not differ once AJCC tumor stage was also taken into account (HR, 0.8; 95%CI, 0.5-1.2)(P = .36).CONCLUSIONS AND RELEVANCE At the population level, survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biological properties of amelanotic melanoma are warranted.

  19. Mechanisms Underpinning Increased Plasma Creatinine Levels in Patients Receiving Vemurafenib for Advanced Melanoma

    PubMed Central

    Hurabielle, Charlotte; Pillebout, Evangéline; Stehlé, Thomas; Pagès, Cécile; Roux, Jennifer; Schneider, Pierre; Chevret, Sylvie; Chaffaut, Cendrine; Boutten, Anne; Mourah, Samia; Basset-Seguin, Nicole; Vidal-Petiot, Emmanuelle; Lebbé, Céleste; Flamant, Martin

    2016-01-01

    Context Serum creatinine has been reported to increase in patients receiving Vemurafenib, yet neither the prevalence nor the mechanism of this adverse event are known. Objective We aimed to evaluate the frequency and the mechanisms of increases in plasma creatinine level in patients receiving Vemurafenib for advanced melanoma. Methods We performed a retrospective monocentric study including consecutive patients treated with Vemurafenib for an advanced melanoma. We collected clinical and biological data concerning renal function before introduction of Vemurafenib and in the course of monthly follow-up visits from March 2013 to December 2014. Cystatin C-derived glomerular filtration rate was evaluated before and after Vemurafenib initiation, as increase in serum cystatin C is specific to a decrease in the glomerular filtration rate. We also performed thorough renal explorations in 3 patients, with measurement of tubular secretion of creatinine before and after Vemurafenib initiation and a renal biopsy in 2 patients. Results 70 patients were included: 97% of them displayed an immediate, and thereafter stable, increase in creatinine (+22.8%) after Vemurafenib initiation. In 44/52 patients in whom Vemurafenib was discontinued, creatinine levels returned to baseline. Serum cystatin C increased, although proportionally less than serum creatinine, showing that creatinine increase under vemurafenib was indeed partly due to a renal function impairment. In addition, renal explorations demonstrated that Vemurafenib induced an inhibition of creatinine tubular secretion. Conclusion Thus, Vemurafenib induces a dual mechanism of increase in plasma creatinine with both an inhibition of creatinine tubular secretion and slight renal function impairment. However, this side effect is mostly reversible when Vemurafenib is discontinued, and should not lead physicians to discontinue the treatment if it is effective. PMID:26930506

  20. Iridociliary melanoma – Clinical case

    PubMed Central

    Schmitzer, S; Butea-Simionescu, C; Gheorghe, A; Zemba, M; Cioboata, M

    2016-01-01

    Abstract Iris and ciliary body melanoma is an aggressive tumor, which, unfortunately, presents symptoms only in advanced stages and is often discovered accidentally during a routine eye examination. There are several treatment options, ranging from in time monitorization in order to observe the tumor’s evolution to more aggressive methods such as radiotherapy and enucleation. We present a case of iridociliary melanoma, who underwent conservative surgery, iridocyclectomy under scleral flap, with good results, and maintenance of the function and integrity of the eyeball. PMID:27713771

  1. Primary Malignant Vaginal Melanoma – Case Report and Review of the Literature

    PubMed Central

    Kühn, F.; Dieterich, M.; Klar, E.; Gerber, B.; Prinz, C.

    2012-01-01

    With fewer than 250 cases published worldwide, primary vaginal melanoma is an extremely rare malignant entity which is mostly diagnosed in advanced stages. The estimated incidence of vaginal melanoma is 0.026/100 000 women per year. The poor prognosis for advanced tumour stages and different therapies used in very limited numbers of patients require precise preoperative staging and a planned interdisciplinary therapeutic approach. PMID:25258467

  2. Comparison of Clinicopathologic Features and Survival of Histopathologically Amelanotic and Pigmented Melanomas: A Population-Based Study

    PubMed Central

    Thomas, Nancy E.; Kricker, Anne; Waxweiler, Weston T.; Dillon, Patrick M.; Busam, Klaus J.; From, Lynn; Groben, Pamela A.; Armstrong, Bruce K.; Anton-Culver, Hoda; Gruber, Stephen B.; Marrett, Loraine D.; Gallagher, Richard P.; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Venn, Alison; Kanetsky, Peter A.; Orlow, Drs. Irene; Paine, Susan; Ollila, David W.; Reiner, Anne S.; Luo, Li; Hao, Honglin; Frank, Jill S.; Begg, Colin B.; Berwick, Marianne

    2014-01-01

    , survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biology of amelanotic melanoma are warranted. PMID:25162299

  3. Expression of Molecular Markers of Angiogenesis, Lymphangiogenesis, and Proliferation Depending on the Stage of Skin Melanoma.

    PubMed

    Bgatova, N P; Lomakin, A I; Fursov, S A; Kachesov, I V; Chepko, S A; Isakova, N B; Borodin, Yu I; Voytsitsky, V E; Konenkov, V I

    2016-08-01

    The expression of molecular markers characterizing activity of the tumor process and metastases (proliferation marker Ki-67, angiogenesis marker CD34, and lymphangiogenesis markers podoplanin and LYVE-1) was assessed by immunohictochemical method in the primary tumor specimens collected during surgery for cutaneous melanoma (40 patients). Proliferative activity of the tumor tissue and volume density of peritumoral blood and lymph vessels increased with increasing tumor malignancy, which could indicate the risk of metastases. PMID:27590758

  4. Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies

    PubMed Central

    2010-01-01

    Cutaneous melanoma is a very aggressive neoplasia of melanocytic origin with constantly growing incidence and mortality rates world-wide. Epigenetic modifications (i.e., alterations of genomic DNA methylation patterns, of post-translational modifications of histones, and of microRNA profiles) have been recently identified as playing an important role in melanoma development and progression by affecting key cellular pathways such as cell cycle regulation, cell signalling, differentiation, DNA repair, apoptosis, invasion and immune recognition. In this scenario, pharmacologic inhibition of DNA methyltransferases and/or of histone deacetylases were demonstrated to efficiently restore the expression of aberrantly-silenced genes, thus re-establishing pathway functions. In light of the pleiotropic activities of epigenetic drugs, their use alone or in combination therapies is being strongly suggested, and a particular clinical benefit might be expected from their synergistic activities with chemo-, radio-, and immuno-therapeutic approaches in melanoma patients. On this path, an important improvement would possibly derive from the development of new generation epigenetic drugs characterized by much reduced systemic toxicities, higher bioavailability, and more specific epigenetic effects. PMID:20540720

  5. Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis.

    PubMed

    Heppt, Markus V; Eigentler, Thomas K; Kähler, Katharina C; Herbst, Rudolf A; Göppner, Daniela; Gambichler, Thilo; Ulrich, Jens; Dippel, Edgar; Loquai, Carmen; Schell, Beatrice; Schilling, Bastian; Schäd, Susanne G; Schultz, Erwin S; Matheis, Fanny; Tietze, Julia K; Berking, Carola

    2016-08-01

    Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate. PMID:27294607

  6. Melanoma Brain Metastasis: Mechanisms, Models, and Medicine.

    PubMed

    Kircher, David A; Silvis, Mark R; Cho, Joseph H; Holmen, Sheri L

    2016-01-01

    The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases. PMID:27598148

  7. Melanoma Brain Metastasis: Mechanisms, Models, and Medicine

    PubMed Central

    Kircher, David A.; Silvis, Mark R.; Cho, Joseph H.; Holmen, Sheri L.

    2016-01-01

    The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases. PMID:27598148

  8. 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

  9. Inclusion of populations at risk of advanced melanoma in an opportunistic targeted screening project involving general practitioners

    PubMed Central

    Rat, Cédric; Quereux, Gaelle; Grimault, Charlotte; Fernandez, Jérémy; Poiraud, Mickael; Gaultier, Aurélie; Chaslerie, Anicet; Pivette, Jacques; Khammari, Amir; Dreno, Brigitte; Nguyen, Jean-Michel

    2016-01-01

    Objective The study objective was to measure the rates of inclusion of populations at risk of advanced melanoma in a pilot targeted screening project involving general practitioners. Design This cross-sectional database study compared the inclusion rates of patients who signed inclusion in a targeted screening project with those of patients who did not, during a period in which both groups of patients consulted investigators. Setting Data were extracted from the national healthcare insurance records in western France from 11 April to 30 October 2011. Patients Patients, older than 18, considered for the data extraction had consulted one of the 78 participating GPs during the study period, and were affiliated with the national healthcare insurance. Main outcome measures Inclusion in the screening was the main outcome measure. Patients at risk of advanced melanoma were characterized by male gender, age over 50, low income, rural residence, farmer, and presence of chronic disease. Results A total of 57,279 patients consulted GPs during the inclusion period and 2711 (4.73%) were included in the targeted screening. Populations at risk of advanced melanoma were less included: men (OR = 0.67; 95%CI [0.61–0.73]; p < 0.001), older than 50 (OR = 0.67; 95%CI [0.60–0.74]; p < 0.001), low income (OR = 0.65; 95%CI [0.55–0.77]; p < 0.001), farmer (OR = 0.23; 95%CI [0.17–0.30]; p < 0.001) and presence of a chronic disease (OR = 0.87; 95%CI [0.77–0.98]; p < 0.028). Conclusion This study demonstrated inequalities in the inclusion of patients in a melanoma screening. Patients at risk of advanced cancer were screened less often. Further studies should focus on GPs ability to identify and screen these patients. Key Points Advanced melanoma is more frequently diagnosed in men, older patients and socioeconomically disadvantaged populations, which leads to survival inequalities.• Despite the involvement of general practitioners, the

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

    PubMed

    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; de Vries, I Jolanda M; 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

  11. 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

  12. A phase 2, multicenter, open-label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma

    PubMed Central

    Kudchadkar, Ragini; Ernst, Scott; Chmielowski, Bartosz; Redman, Bruce G; Steinberg, Joyce; Keating, Anne; Jie, Fei; Chen, Caroline; Gonzalez, Rene; Weber, Jeffrey

    2015-01-01

    Survivin is a microtubule-associated protein believed to be involved in preserving cell viability and regulating tumor cell mitosis, and it is overexpressed in many primary tumor types, including melanoma. YM155 is a first-in-class survivin suppressant. The purpose of this Phase 2 study was to evaluate the 6-month progression-free survival (PFS) rate in patients with unresectable Stage III or IV melanoma receiving a combination of YM155 plus docetaxel. The study had two parts: Part 1 established the dose of docetaxel that was tolerable in combination with YM155, and Part 2 evaluated the tolerable docetaxel dose (75 mg/m2) in combination with YM155 (5 mg/m2 per day continuous infusion over 168 h every 3 weeks). The primary endpoint was 6-month PFS rate. Secondary endpoints were objective response rate (ORR), 1-year overall survival (OS) rate, time from first response to progression, clinical benefit rate (CBR), and safety. Sixty-four patients with metastatic melanoma were treated with docetaxel and YM155. Eight patients received an initial docetaxel dose of 100 mg/m2 and 56 patients received 75 mg/m2 of docetaxel. Six-month PFS rate per Independent Review Committee (IRC) was 34.8% (n = 64; 95% CI, 21.3–48.6%), and per Investigator was 31.3% (n = 64; 95% CI, 19.5–43.9%). The best ORR (complete response [CR] + partial response [PR]) per IRC was 12.5% (8/64). The stable disease (SD) rate was 51.6% (33/64), leading to a CBR (CR + PR + SD) of 64.1% (41/64). Estimated probability of 1-year survival was 56.3%. YM155 is a novel agent showing modest activity when combined with docetaxel for treating patients with melanoma. YM155 was generally well tolerated, but the predetermined primary efficacy endpoint (i.e., 6-month PFS rate ≥20%) was not achieved. PMID:25533314

  13. The receptor for advanced glycation end products influences the expression of its S100 protein ligands in melanoma tumors.

    PubMed

    Meghnani, Varsha; Wagh, Anil; Indurthi, Venkata S K; Koladia, Mohit; Vetter, Stefan W; Law, Benedict; Leclerc, Estelle

    2014-12-01

    Recent studies have suggested that the receptor for advanced glycation end products (RAGE) participates in melanoma progression by promoting tumor growth. However, the mechanisms of RAGE activation in melanoma tumors are not clearly understood. To get deeper insights into these mechanisms, we transfected a melanoma cell line, which was established from a human melanoma primary tumor, with RAGE, and studied the effect of RAGE overexpression on cell proliferation and migration in vitro. We observed that overexpression of RAGE in these cells not only resulted in significantly increased migration rates compared to control cells, but also in decreased proliferation rates (Meghnani et al., 2014). In the present study, we compared the growth of xenograft tumors established from RAGE overexpressing WM115 cells, to that of control cells. We observed that when implanted in mice, RAGE overexpressing cells generated tumors faster than control cells. Analysis of protein tumor extracts showed increased levels of the RAGE ligands S100B, S100A2, S100A4, S100A6 and S100A10 in RAGE overexpressing tumors compared to control tumors. We show that the tumor growth was significantly reduced when the mice were treated with anti-RAGE antibodies, suggesting that RAGE, and probably several S100 proteins, were involved in tumor growth. We further demonstrate that the anti-RAGE antibody treatment significantly enhanced the efficacy of the alkylating drug dacarbazine in reducing the growth rate of RAGE overexpressing tumors. PMID:25310905

  14. Stage III Melanoma in the Axilla: Patterns of Regional Recurrence After Surgery With and Without Adjuvant Radiation Therapy

    SciTech Connect

    Pinkham, Mark B.; Foote, Matthew C.; Burmeister, Elizabeth; Thomas, Janine; Meakin, Janelle; Smithers, B. Mark; Burmeister, Bryan H.

    2013-07-15

    Purpose: To describe the anatomic distribution of regionally recurrent disease in patients with stage III melanoma in the axilla after curative-intent surgery with and without adjuvant radiation therapy. Methods and Materials: A single-institution, retrospective analysis of a prospective database of 277 patients undergoing curative-intent treatment for stage III melanoma in the axilla between 1992 and 2012 was completed. For patients who received radiation therapy and those who did not, patterns of regional recurrence were analyzed, and univariate analyses were performed to assess for potential factors associated with location of recurrence. Results: There were 121 patients who received adjuvant radiation therapy because their clinicopathologic features conferred a greater risk of regional recurrence. There were 156 patients who received no radiation therapy. The overall axillary control rate was 87%. There were 37 patients with regional recurrence; 17 patients had received adjuvant radiation therapy (14%), and 20 patients (13%) had not. The likelihood of in-field nodal recurrence was significantly less in the adjuvant radiation therapy group (P=.01) and significantly greater in sites adjacent to the axilla (P=.02). Patients with high-risk clinicopathologic features who did not receive adjuvant radiation therapy also tended to experience in-field failure rather than adjacent-field failure. Conclusions: Patients who received adjuvant radiation therapy were more likely to experience recurrence in the adjacent-field regions rather than in the in-field regions. This may not simply reflect higher-risk pathology. Using this data, it may be possible to improve outcomes by reducing the number of adjacent-field recurrences after adjuvant radiation therapy.

  15. Biomarkers in melanoma.

    PubMed

    Griewank, Klaus G

    2016-01-01

    Malignant melanoma remains the skin cancer with the highest number of mortalities worldwide. While early diagnosis and complete surgical excision remain the best possibility for curing disease, prognosis at the stage of metastasis is still poor. Recent years have brought about considerable advances in terms of understanding the pathogenesis of melanoma and treating advanced disease. The discovery of activating BRAF mutations in around 50% of tumors has led to the introduction of targeted therapies downregulating BRAF signaling output. These have been further refined as combination therapies, which by targeting multiple targets have further improved the clinical outcome. A comparable, potentially even superior therapeutic alternative has been the introduction of immunotherapeutic approaches, including PD-1 and CTLA-4 checkpoint blockade therapies. Despite all genetic knowledge acquired in recent years, a clearly applicable prognostic signature of clinical value has not been established. General prognostic assessment of cutaneous melanoma remains based on clinical and pathological criteria (most importantly tumor thickness). The main challenges lying ahead are to establish a reliable prognostic test effectively determining which tumors will metastasize. Additionally establishing biomarkers which will allow patients to be stratified according to the most promising systemic therapy (immunotherapies and/or BRAF inhibitor therapies) is of utmost importance for patients with metastasized disease. Identifying serum biomarkers enabling disease to be monitored as well as determining tumor properties (i.e. resistance) would also be of great value. While initial results have proven promising, there remains much work to be done. PMID:27467728

  16. Recent advances in sunlight-induced carcinogenesis using the Xiphophorus melanoma model✰

    PubMed Central

    Fernandez, André A.; Paniker, Lakshmi; Garcia, Rachel; Mitchell, David L.

    2011-01-01

    Unlike breast and prostate cancers, the nature and sequence of critical genetic and epigenetic events involved in the initiation and progression of melanoma is not well understood. A contributing factor to this dilemma, especially given our current understanding of the importance of UV light in melanoma etiology, is the lack of quality UV-inducible melanoma animal models. In this study we elaborate on the capability of UV light to induce cutaneous malignant melanomas (CMM) in Xiphophorus fishes, which were previously found to develop melanomas after acute neonatal UVB irradiation. In two separate tumorigenesis experiments, we exposed adult Xiphophorus hybrids to either acute UVB irradiations (5 consecutive daily treatments) or chronic solar irradiations (continuous UVA/UVB treatment for 9 months). Acute adult UVB irradiation resulted in the significant induction of melanomas, and moreover, this induction rate is equivalent to that of animals exposed to acute neonatal UVB irradiation. This study represents the first evidence that acute adult UVB irradiation, in the absence of any early life exposures, induces CMM. Similar to the findings conducted on other divergent melanoma models, including HGF/SF transgenic mice and Monodelphis domestica, prolonged chronic solar UV was not a factor in melanomagenesis. PMID:21457786

  17. Recent advances in sunlight-induced carcinogenesis using the Xiphophorus melanoma model.

    PubMed

    Fernandez, André A; Paniker, Lakshmi; Garcia, Rachel; Mitchell, David L

    2012-01-01

    Unlike breast and prostate cancers, the nature and sequence of critical genetic and epigenetic events involved in the initiation and progression of melanoma are not well understood. A contributing factor to this dilemma, especially given our current understanding of the importance of UV light in melanoma etiology, is the lack of quality UV-inducible melanoma animal models. In this study we elaborate on the capability of UV light to induce cutaneous malignant melanomas (CMM) in Xiphophorus fishes, which were previously found to develop melanomas after acute neonatal UVB irradiation. In two separate tumorigenesis experiments, we exposed adult Xiphophorus hybrids to either acute UVB irradiations (5 consecutive daily treatments) or chronic solar irradiations (continuous UVA/UVB treatment for 9 months). Acute adult UVB irradiation resulted in the significant induction of melanomas, and moreover, this induction rate is equivalent to that of animals exposed to acute neonatal UVB irradiation. This study represents the first evidence that acute adult UVB irradiation, in the absence of any early life exposures, induces CMM. Similar to the findings conducted on other divergent melanoma models, including HGF/SF transgenic mice and Monodelphis domestica, prolonged chronic solar UV was not a factor in melanomagenesis.

  18. Melanoma Diagnosis

    NASA Astrophysics Data System (ADS)

    Horsch, Alexander

    The chapter deals with the diagnosis of the malignant melanoma of the skin. This aggressive type of cancer with steadily growing incidence in white populations can hundred percent be cured if it is detected in an early stage. Imaging techniques, in particular dermoscopy, have contributed significantly to improvement of diagnostic accuracy in clinical settings, achieving sensitivities for melanoma experts of beyond 95% at specificities of 90% and more. Automatic computer analysis of dermoscopy images has, in preliminary studies, achieved classification rates comparable to those of experts. However, the diagnosis of melanoma requires a lot of training and experience, and at the time being, average numbers of lesions excised per histology-proven melanoma are around 30, a number which clearly is too high. Further improvements in computer dermoscopy systems and their competent use in clinical settings certainly have the potential to support efforts of improving this situation. In the chapter, medical basics, current state of melanoma diagnosis, image analysis methods, commercial dermoscopy systems, evaluation of systems, and methods and future directions are presented.

  19. Current State of Animal (Mouse) Modeling in Melanoma Research

    PubMed Central

    Kuzu, Omer F.; Nguyen, Felix D.; Noory, Mohammad A.; Sharma, Arati

    2015-01-01

    Despite the considerable progress in understanding the biology of human cancer and technological advancement in drug discovery, treatment failure remains an inevitable outcome for most cancer patients with advanced diseases, including melanoma. Despite FDA-approved BRAF-targeted therapies for advanced stage melanoma showed a great deal of promise, development of rapid resistance limits the success. Hence, the overall success rate of melanoma therapy still remains to be one of the worst compared to other malignancies. Advancement of next-generation sequencing technology allowed better identification of alterations that trigger melanoma development. As development of successful therapies strongly depends on clinically relevant preclinical models, together with the new findings, more advanced melanoma models have been generated. In this article, besides traditional mouse models of melanoma, we will discuss recent ones, such as patient-derived tumor xenografts, topically inducible BRAF mouse model and RCAS/TVA-based model, and their advantages as well as limitations. Although mouse models of melanoma are often criticized as poor predictors of whether an experimental drug would be an effective treatment, development of new and more relevant models could circumvent this problem in the near future. PMID:26483610

  20. Current State of Animal (Mouse) Modeling in Melanoma Research.

    PubMed

    Kuzu, Omer F; Nguyen, Felix D; Noory, Mohammad A; Sharma, Arati

    2015-01-01

    Despite the considerable progress in understanding the biology of human cancer and technological advancement in drug discovery, treatment failure remains an inevitable outcome for most cancer patients with advanced diseases, including melanoma. Despite FDA-approved BRAF-targeted therapies for advanced stage melanoma showed a great deal of promise, development of rapid resistance limits the success. Hence, the overall success rate of melanoma therapy still remains to be one of the worst compared to other malignancies. Advancement of next-generation sequencing technology allowed better identification of alterations that trigger melanoma development. As development of successful therapies strongly depends on clinically relevant preclinical models, together with the new findings, more advanced melanoma models have been generated. In this article, besides traditional mouse models of melanoma, we will discuss recent ones, such as patient-derived tumor xenografts, topically inducible BRAF mouse model and RCAS/TVA-based model, and their advantages as well as limitations. Although mouse models of melanoma are often criticized as poor predictors of whether an experimental drug would be an effective treatment, development of new and more relevant models could circumvent this problem in the near future.

  1. Clinical utilities and biological characteristics of melanoma sentinel lymph nodes

    PubMed Central

    Han, Dale; Thomas, Daniel C; Zager, Jonathan S; Pockaj, Barbara; White, Richard L; Leong, Stanley PL

    2016-01-01

    An estimated 73870 people will be diagnosed with melanoma in the United States in 2015, resulting in 9940 deaths. The majority of patients with cutaneous melanomas are cured with wide local excision. However, current evidence supports the use of sentinel lymph node biopsy (SLNB) given the 15%-20% of patients who harbor regional node metastasis. More importantly, the presence or absence of nodal micrometastases has been found to be the most important prognostic factor in early-stage melanoma, particularly in intermediate thickness melanoma. This review examines the development of SLNB for melanoma as a means to determine a patient’s nodal status, the efficacy of SLNB in patients with melanoma, and the biology of melanoma metastatic to sentinel lymph nodes. Prospective randomized trials have guided the development of practice guidelines for use of SLNB for melanoma and have shown the prognostic value of SLNB. Given the rapidly advancing molecular and surgical technologies, the technical aspects of diagnosis, identification, and management of regional lymph nodes in melanoma continues to evolve and to improve. Additionally, there is ongoing research examining both the role of SLNB for specific clinical scenarios and the ways to identify patients who may benefit from completion lymphadenectomy for a positive SLN. Until further data provides sufficient evidence to alter national consensus-based guidelines, SLNB with completion lymphadenectomy remains the standard of care for clinically node-negative patients found to have a positive SLN. PMID:27081640

  2. Advances take stage - Office of Cancer Clinical Proteomics Research

    Cancer.gov

    Regulatory advances in proteomics will be taking center stage at a Symposia scheduled to occur at the 2011 American Association for Clinical Chemistry (AACC) Annual Meeting. The symposium entitled "Enabling Translational Proteomics with NCI's Clinical Proteomic Technologies for Cancer" is scheduled for July 25, 2011 at AACC's annual Meeting.

  3. Melanoma immunotherapy.

    PubMed

    Sivendran, Shanthi; Glodny, Bradley; Pan, Michael; Merad, Miriam; Saenger, Yvonne

    2010-01-01

    Melanoma immunotherapy has been an area of intense research for decades, and this work is now yielding more tangible results for patients. Work has focused on 4 main areas: cytokine therapy, administration of immune-modulating antibodies, adoptive T-cell therapy, and vaccines. Cytokine therapy is an established treatment for advanced melanoma, and immune-modulating antibodies have recently emerged as an exciting new area of drug development with efficacy now established in a phase III trial. Adoptive T-cell therapy provides the proof of principle that T cells can attack and eliminate tumors. It has been challenging, however, to adapt this treatment for widespread use. Vaccines have generally yielded poor results, but intratumor pathogen-based strategies have shown encouraging results in recent trials, perhaps due to stronger immune stimulation. A review of the field of melanoma immunotherapy is provided here, with emphasis on those agents that have reached clinical testing. Novel strategies to induce the immune system to attack melanomas are reviewed. In the future, it is envisioned that immunotherapy will have further application in combination with cytotoxic and targeted therapies.

  4. The outcomes of Polish patients with advanced BRAF-positive melanoma treated with vemurafenib in a safety clinical trial

    PubMed Central

    Rutkowski, Piotr; Mackiewicz, Jacek; Krzemieniecki, Krzysztof; Nawrocki, Sergiusz; Wasilewska-Teśluk, Ewa; Kwinta, Łukasz; Wysocki, Piotr; Koseła-Paterczyk, Hanna; Świtaj, Tomasz

    2015-01-01

    Aim of the study The BRAF inhibitor vemurafenib has improved progression-free survival and overall survival in patients with BRAFV600-mutation-positive metastatic melanoma. Here we present the results of an open-label safety study with vemurafenib in patients with metastatic melanoma enrolled in Polish oncological centres. Material and methods Patients with untreated or previously treated Stage IIIC/IV BRAFV600 mutation-positive melanoma were treated with oral vemurafenib in an initial dose of 960 mg twice daily. Assessments for safety and efficacy were made every 28 days. For the survival analysis the Kaplan-Meier estimator was used with the log-rank tests for bivariate comparisons. Results In total, 75 Polish patients were enrolled in the safety study across four centres. At data cut-off, 28 patients died (37%), mainly (26) due to disease progression; 33 (44%) patients continued vemurafenib after disease progression. The objective response rate was 46%, including two patients with a complete response and 29 with a partial response. Median progression-free survival was 7.4 months. The one-year overall survival rate was 61.9% (median overall survival was not reached). Seventy-three (97.3%) patients reported adverse events (AEs), and grade 3–5 toxicity was reported in 49.4% (37) patients. The most common AEs were: skin lesions (including rash and photosensitivity), arthralgia, and fatigue. Conclusions The overall safety profile and response rate of vemurafenib were comparable to those reported in previous studies of this drug. Our study confirmed the value of well-established prognostic features for overall survival, such as initial LDH (lactate dehydrogenase) level and AJCC staging. PMID:26557775

  5. Translational research in melanoma.

    PubMed

    Ray, Madhury; Farma, Jeffrey M; Hsu, Cary

    2013-10-01

    Recent breakthroughs in the fundamental understanding of the cellular and molecular basis of melanoma have culminated in new therapies with unquestionable efficacy. Immunotherapy and targeted therapy strategies have completely transformed the contemporary management of advanced melanoma. The translational research behind these developments is discussed, with an emphasis on immune checkpoint blockade and inhibition of the mitogen-activated protein kinase signaling pathway.

  6. Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma: Review of the Literature

    PubMed Central

    Gönül, Müzeyyen

    2016-01-01

    The incidence of melanoma has recently been increasing. BRAF mutations have been found in 40–60% of melanomas. The increased activity of BRAF V600E leads to the activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway, which plays a key role as a regulator of cell growth, differentiation, and survival. The use of BRAF inhibitors in metastatic melanoma with BRAF mutation ensures clinical improvement of the disease. Vemurafenib and dabrafenib are two selective BRAF inhibitors approved by the Food and Drug Administration (FDA). Both drugs are well tolerated and successfully used in clinical practice. However, some adverse reactions have been reported in patients in the course of treatment. Cutaneous side effects are the most common adverse events among them with a broad spectrum. Both the case reports and several original clinical trials reported cutaneous reactions during the treatment with BRAF inhibitors. In this review, the common cutaneous side effects of BRAF inhibitors in the treatment of metastatic melanoma with BRAF V600E mutation were reviewed. PMID:27042173

  7. Melanoma resistance to photodynamic therapy: new insights

    PubMed Central

    Huang, Ying-Ying; Vecchio, Daniela; Avci, Pinar; Yin, Rui; Garcia-Diaz, Maria; Hamblin, Michael R.

    2012-01-01

    Melanoma is the most dangerous form of skin cancer, with a steeply rising incidence and a poor prognosis in its advanced stages. Melanoma is highly resistant to traditional chemotherapy and radiotherapy, although modern targeted therapies such as BRAF inhibitors are showing some promise. Photodynamic therapy (PDT, the combination of photosensitizing dyes and visible light) has been tested for melanoma with some promising results, but melanoma is generally considered to also be resistant to PDT. Optical interference by the highly-pigmented melanin, the anti-oxidant effect of melanin, the sequestration of photosensitizers inside melanosomes, defects in apoptotic pathways, and the efflux of photosensitizers by ATP-binding cassette (ABC) transporters have all been implicated in melanoma resistance to PDT. Approaches to overcoming melanoma resistance to PDT include: the discovery of highly active photosensitizers absorbing in the 700–800-nm near infrared spectral region; interventions that can temporarily reduce the amount or the pigmentation of the melanin; compounds that can reverse apoptotic defects or inhibit drug-efflux of photosensitizers; and immunotherapy approaches that can take advantage of the ability of PDT to activate the host immune system to the treated tumor. PMID:23152406

  8. Future perspectives in melanoma research. Meeting report from the “Melanoma Bridge. Napoli, December 2nd-4th 2012”

    PubMed Central

    2013-01-01

    Recent insights into the genetic and somatic aberrations have initiated a new era of rapidly evolving targeted and immune-based treatments for melanoma. After decades of unsuccessful attempts to finding a more effective cure in the treatment of melanoma now we have several drugs active in melanoma. The possibility to use these drugs in combination to improve responses to overcome the resistance, to potentiate the action of immune system with the new immunomodulating antibodies, and identification of biomarkers that can predict the response to a particular therapy represent new concepts and approaches in the clinical management of melanoma. The third “Melanoma Research: “A bridge from Naples to the World” meeting, shortened as “Bridge Melanoma Meeting” took place in Naples, December 2 to 4th, 2012. The four topics of discussion at this meeting were: advances in molecular profiling and novel biomarkers, combination therapies, novel concepts toward integrating biomarkers and therapies into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage, and the knowledge gained from the biology of tumor microenvironment across different tumors as a bridge to impact on prognosis and response to therapy in melanoma. This international congress gathered more than 30 international faculty members who in an interactive atmosphere which stimulated discussion and exchange of their experience regarding the most recent advances in research and clinical management of melanoma patients. PMID:23731854

  9. Advanced statistical methods for the definition of new staging models.

    PubMed

    Kates, Ronald; Schmitt, Manfred; Harbeck, Nadia

    2003-01-01

    Adequate staging procedures are the prerequisite for individualized therapy concepts in cancer, particularly in the adjuvant setting. Molecular staging markers tend to characterize specific, fundamental disease processes to a greater extent than conventional staging markers. At the biological level, the course of the disease will almost certainly involve interactions between multiple underlying processes. Since new therapeutic strategies tend to target specific processes as well, their impact will also involve interactions. Hence, assessment of the prognostic impact of new markers and their utilization for prediction of response to therapy will require increasingly sophisticated statistical tools that are capable of detecting and modeling complicated interactions. Because they are designed to model arbitrary interactions, neural networks offer a promising approach to improved staging. However, the typical clinical data environment poses severe challenges to high-performance survival modeling using neural nets, particularly the key problem of maintaining good generalization. Nonetheless, it turns out that by using newly developed methods to minimize unnecessary complexity in the neural network representation of disease course, it is possible to obtain models with high predictive performance. This performance has been validated on both simulated and real patient data sets. There are important applications for design of studies involving targeted therapy concepts and for identification of the improvement in decision support resulting from new staging markers. In this article, advantages of advanced statistical methods such as neural networks for definition of new staging models will be illustrated using breast cancer as an example.

  10. Dissection of immune gene networks in primary melanoma tumors critical for antitumor surveillance of patients with stage II-III resectable disease.

    PubMed

    Sivendran, Shanthi; Chang, Rui; Pham, Lisa; Phelps, Robert G; Harcharik, Sara T; Hall, Lawrence D; Bernardo, Sebastian G; Moskalenko, Marina M; Sivendran, Meera; Fu, Yichun; de Moll, Ellen H; Pan, Michael; Moon, Jee Young; Arora, Sonali; Cohain, Ariella; DiFeo, Analisa; Ferringer, Tammie C; Tismenetsky, Mikhail; Tsui, Cindy L; Friedlander, Philip A; Parides, Michael K; Banchereau, Jacques; Chaussabel, Damien; Lebwohl, Mark G; Wolchok, Jedd D; Bhardwaj, Nina; Burakoff, Steven J; Oh, William K; Palucka, Karolina; Merad, Miriam; Schadt, Eric E; Saenger, Yvonne M

    2014-08-01

    Patients with resected stage II-III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II-III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data.

  11. Dissection of Immune Gene Networks in Primary Melanoma Tumors Critical for Antitumor Surveillance of Patients with Stage II–III Resectable Disease

    PubMed Central

    Sivendran, Shanthi; Chang, Rui; Pham, Lisa; Phelps, Robert G.; Harcharik, Sara T.; Hall, Lawrence D.; Bernardo, Sebastian G.; Moskalenko, Marina M.; Sivendran, Meera; Fu, Yichun; de Moll, Ellen H.; Pan, Michael; Moon, Jee Young; Arora, Sonali; Cohain, Ariella; DiFeo, Analisa; Ferringer, Tammie C.; Tismenetsky, Mikhail; Tsui, Cindy L.; Friedlander, Philip A.; Parides, Michael K.; Banchereau, Jacques; Chaussabel, Damien; Lebwohl, Mark G.; Wolchok, Jedd D.; Bhardwaj, Nina; Burakoff, Steven J.; Oh, William K.; Palucka, Karolina; Merad, Miriam; Schadt, Eric E.; Saenger, Yvonne M.

    2014-01-01

    Patients with resected stage II–III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II–III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data. PMID:24522433

  12. Autophagy- An emerging target for melanoma therapy.

    PubMed

    Ndoye, Abibatou; Weeraratna, Ashani T

    2016-01-01

    Melanoma accounts for only 5% of all cancers but is the leading cause of skin cancer death due to its high metastatic potential. Patients with metastatic melanoma have a 10-year survival rate of less than 10%. While the clinical landscape for melanoma is evolving rapidly, lack of response to therapies, as well as resistance to therapy remain critical obstacles for treatment of this disease. In recent years, a myriad of therapy resistance mechanisms have been unravelled, one of which is autophagy, the focus of this review. In advanced stages of malignancy, melanoma cells hijack the autophagy machinery in order to alleviate drug-induced and metabolic stress in the tumor microenvironment, thereby promoting resistance to multiple therapies, tumor cell survival, and progression.  Autophagy is an essential cellular process that maintains cellular homeostasis through the recycling of intracellular constituents. Early studies on the role of autophagy in cancer generated controversy as to whether autophagy was pro- or anti-tumorigenic. Currently, there is a consensus that autophagy is tumor-suppressive in the early stages of cancer and tumor-promoting in established tumors.  This review aims to highlight current understandings on the role of autophagy in melanoma malignancy, and specifically therapy resistance; as well as to evaluate recent strategies for therapeutic autophagy modulation. PMID:27583134

  13. Autophagy- An emerging target for melanoma therapy

    PubMed Central

    Ndoye, Abibatou; Weeraratna, Ashani T.

    2016-01-01

    Melanoma accounts for only 5% of all cancers but is the leading cause of skin cancer death due to its high metastatic potential. Patients with metastatic melanoma have a 10-year survival rate of less than 10%. While the clinical landscape for melanoma is evolving rapidly, lack of response to therapies, as well as resistance to therapy remain critical obstacles for treatment of this disease. In recent years, a myriad of therapy resistance mechanisms have been unravelled, one of which is autophagy, the focus of this review. In advanced stages of malignancy, melanoma cells hijack the autophagy machinery in order to alleviate drug-induced and metabolic stress in the tumor microenvironment, thereby promoting resistance to multiple therapies, tumor cell survival, and progression.  Autophagy is an essential cellular process that maintains cellular homeostasis through the recycling of intracellular constituents. Early studies on the role of autophagy in cancer generated controversy as to whether autophagy was pro- or anti-tumorigenic. Currently, there is a consensus that autophagy is tumor-suppressive in the early stages of cancer and tumor-promoting in established tumors.  This review aims to highlight current understandings on the role of autophagy in melanoma malignancy, and specifically therapy resistance; as well as to evaluate recent strategies for therapeutic autophagy modulation. PMID:27583134

  14. Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Bevacizumab in Treating Patients With Stage IV Melanoma That Cannot Be Removed by Surgery or Gynecological Cancers

    ClinicalTrials.gov

    2016-10-20

    Cervical Adenosarcoma; Cervical Adenosquamous Carcinoma; Cervical Carcinosarcoma; Cervical Squamous Cell Carcinoma, Not Otherwise Specified; Endometrial Clear Cell Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Transitional Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Fallopian Tube Adenocarcinoma; Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Epithelial Tumor; Malignant Peritoneal Neoplasm; Ovarian Carcinosarcoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Melanoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IV Skin Melanoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma; Uterine Corpus Carcinosarcoma

  15. Dermoscopy of Nodular Melanoma: Review of the Literature and Report of 3 Cases.

    PubMed

    Đorđević Brlek, Zorica; Jurakić Tončić, Ružica; Radoš, Jaka; Marinović, Branka

    2016-08-01

    Nodular melanoma is the most aggressive subtype of melanoma, with rapid growth rate and metastatic potential. It is usually diagnosed at a locally advanced stage (Breslow thickness <2 mm) and is therefore associated with a poor prognosis. Nodular melanoma often does not fit the classic clinical ABCD criteria, but rather the EFG rule or 3 Cs criteria. Missing the diagnosis of nodular melanoma is a dermatologist's worst nightmare, especially since nodular melanomas can have a non-alarming clinical appearance and imitate a wide range of benign lesions. All evolving nodular lesions, despite their size, symmetry, and color, which cannot be confidently diagnosed as benign, should be excised in order to rule out nodular melanoma. Almost all melanoma-specific dermoscopic criteria are described in context of superficial spreading melanoma. Thus, physicians are not familiar and aware enough of dermoscopic features for early detection of nodular melanomas. Herein we present 3 cases of nodular melanomas from our Department and give a review of the current literature. PMID:27663921

  16. Advanced technologies for rocket single-stage-to-orbit vehicles

    NASA Astrophysics Data System (ADS)

    Wilhite, Alan W.; Bush, Lance B.; Cruz, Christopher I.; Lepsch, Roger A.; Morris, W. Douglas; Stanley, Douglas O.; Wurster, Kathryn E.

    1991-01-01

    A single-stage-to-orbit vertical takeoff/horizontal landing rocket vehicle was studied to determine the benefits of advanced technology. Advanced technologies that were included in the study were variable mixture ratio oxygen/hydrogen rocket engines and materials, structures, and subsystem technologies currently being developed in the National Aero-Space Plane Program. The application of advanced technology results in an 85 percent reduction in vehicle dry weight. With advanced materials, an external thermal protection system, like the Space Shuttle tiles, was not required. Compared to an all-airbreathing horizontal takeoff/horizontal landing vehicle using the same advanced technologies and mission requirements, the rocket vehicle is lighter in dry weight and has fewer subsystems. To increase reliability and safety, operational features were included in the rocket vehicle-robust subsystems, 5 percent additional margin, no slush hydrogen, fail-operational with an engine out, and a crew escape module. The resulting vehicle grew in dry weight and was still lower in dry weight than the airbreathing vehicle.

  17. Advanced Low-Noise Research Fan Stage Design

    NASA Technical Reports Server (NTRS)

    Neubert, Robert; Bock, Larry; Malmborg, Eric; Owen-Peer, William

    1997-01-01

    This report describes the design of the Advanced Low-Noise Research Fan stage. The fan is a variable pitch design, which is designed at the cruise pitch condition. Relative to the cruise setting, the blade is closed at takeoff and opened for reverse thrust operation. The fan stage is a split flow design with fan exit guide vanes (FEGVs) and core stators. The fan stage design is combined with a nacelle and engine core duct to form a powered fan/nacelle subscale model. This model is intended for use in combined aerodynamic, acoustic, and structural testing in a wind tunnel. The fan has an outer diameter of 22 in. and a hub-to-tip of 0.426 in., which allows the use of existing NASA fan and cowl force balance and rig drive systems. The design parameters were selected to permit valid acoustic and aerodynamic comparisons with the Pratt & Whitney (P&W) 17- and 22-in. rigs previously tested under NASA contract. The fan stage design is described in detail. The results of the design axisymmetric and Navier-Stokes aerodynamic analysis are presented at the critical design conditions. The structural analysis of the fan rotor and attachment is included. The blade and attachment are predicted to have adequate low-cycle fatigue life and an acceptable operating range without resonant stress or flutter. The stage was acoustically designed with airfoil counts in the FEGV and core stator to minimize noise. A fan/FEGV tone analysis developed separately under NASA contract was used to determine the optimum airfoil counts. The fan stage was matched to the existing nacelle, designed under the previous P&W low-noise contract, to form a fan/nacelle model for wind tunnel testing. It is an axisymmetric nacelle for convenience in testing and analysis. Previous testing confirmed that the nacelle performed as required at various aircraft operating conditions.

  18. Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib

    PubMed Central

    Sosman, Jeffrey A.; Kim, Kevin B.; Schuchter, Lynn; Gonzalez, Rene; Pavlick, Anna C.; Weber, Jeffrey S.; McArthur, Grant A.; Hutson, Thomas E.; Moschos, Stergios J.; Flaherty, Keith T.; Hersey, Peter; Kefford, Richard; Lawrence, Donald; Puzanov, Igor; Lewis, Karl D.; Amaravadi, Ravi K.; Chmielowski, Bartosz; Lawrence, H. Jeffrey; Shyr, Yu; Ye, Fei; Li, Jiang; Nolop, Keith B.; Lee, Richard J.; Joe, Andrew K.; Ribas, Antoni

    2013-01-01

    BACKGROUND Approximately 50% of melanomas harbor activating (V600) mutations in the serine–threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600–mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600–mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600–mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann–La Roche; ClinicalTrials.gov number, NCT00949702.) PMID:22356324

  19. [Acral lentiginous melanoma: the current state of the problem].

    PubMed

    Myasnyankin, M Yu; Gafton, G I; Anisimov, V V; Matsko, D E; Imyanitov, E N; Semiletova, Yu V

    2015-01-01

    This review is aimed at the analysis the current state of acral lentiginous melanoma. This tumor has rather aggressive course and is the main cause of death in skin cancer patients. In Russia the incidence of melanoma during the period 2000-2010 increased from 3.18 to 3.95 cases per 100000 of population. The average annual growth rate was 1.99% and the total growth rate was 21.81%. Although skin melanoma is a visual tumor, more than one third of patients visit oncologists at advanced stages of the disease. Primary melanoma with localizations on the skin of fingers, interdigital spaces, soles, palms and nail plates is especially difficult for early diagnostics.

  20. Combined low-dose ipilimumab and pembrolizumab after sequential ipilimumab and pembrolizumab failure in advanced melanoma.

    PubMed

    Kirchberger, Michael C; Hauschild, Axel; Schuler, Gerold; Heinzerling, Lucie

    2016-09-01

    With the wide use of anti-PD-1 therapy, an increasing number of patients progress under treatment. Combined immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies induces higher response rates as first-line treatment in comparison to single-agent therapy, however, with substantial toxicity since the combination of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) induced 55% grade 3/4 treatment-related adverse events and treatment discontinuation rates of 39%. In this case series, we investigated the efficacy and toxicity of the combined immunotherapy with low-dose ipilimumab (1 mg/kg) plus pembrolizumab (2 mg/kg) in patients with metastatic melanoma with progressive disease under sequential monotherapy with both agents. All patients had received at least three lines of treatment, 78% of patients were M1c, and 67% had brain metastases. Stable disease was observed in 3 out of 9 patients with a median overall survival of 8 months after double checkpoint inhibition. No treatment-related grade 3/4 adverse events occurred, and none of the patients needed to discontinue the treatment due to toxicity. Further trials are needed to investigate combined immunotherapy as rescue treatment in heavily pretreated melanoma patients to find optimal dosage in regard to outcome and toxicity.

  1. Neuropsychological resiliency after treatment for advanced stage neuroblastoma.

    PubMed

    Carpentieri, S C; Diller, L R

    2005-06-01

    The purpose of this study was to describe the neuropsychological functioning of survivors of advanced stage neuroblastoma. In all, 16 survivors, diagnosed at a median of 2.8 years, who had received intensive chemotherapy and surgical treatments, were identified; 11 had received myeloablative consolidation therapy, eight with total body irradiation (TBI). All patients were evaluated with a neuropsychological assessment battery at a median age of 8.8 years. Analyses included comparison of the performances of the TBI group vs the no-TBI group; determination of whether the proportion of individuals with impaired or superior performance on each measure exceeded normative expectations; and performance indexes reflecting patterns of performance. Results indicate no significant deleterious impact of TBI and/or presence or absence of myeloablative therapy on neurocognitive and neurobehavioral functioning. For this cohort, resilience to neuropsychological vulnerability was observed, which included the emergence of a profile of full-scale IQ, verbal IQ, and mathematical achievement well above average expectations. We concluded that the results document a lack of neuropsychological morbidity among this cohort of survivors of advanced stage neuroblastoma, regardless of the inclusion of TBI. Moreover, a striking pattern of excellent neurocognitive functioning with intact neurobehavioral functioning was observed.

  2. Can advanced-stage ovarian cancer be cured?

    PubMed

    Narod, Steven

    2016-04-01

    Approximately 20% of women with advanced-stage ovarian cancer survive beyond 12 years after treatment and are effectively cured. Initial therapy for ovarian cancer comprises surgery and chemotherapy, and is given with the goal of eradicating as many cancer cells as possible. Indeed, the three phases of therapy are as follows: debulking surgery to remove as much of the cancer as possible, preferably to a state of no visible residual disease; chemotherapy to eradicate any microscopic disease that remains present after surgery; and second-line or maintenance therapy, which is given to delay disease progression among patients with tumour recurrence. If no cancer cells remain after initial therapy is completed, a cure is expected. By contrast, if residual cancer cells are present after initial treatment, then disease recurrence is likely. Thus, the probability of cure is contingent on the combination of surgery and chemotherapy effectively eliminating all cancer cells. In this Perspectives article, I present the case that the probability of achieving a cancer-free state is maximized through a combination of maximal debulking surgery and intraperitoneal chemotherapy. I discuss the evidence indicating that by taking this approach, cures could be achieved in up to 50% of women with advanced-stage ovarian cancer. PMID:26787282

  3. Stages of Melanoma

    MedlinePlus

    ... and treatments will also be taken. Lymph node mapping and sentinel lymph node biopsy : Procedures in which ... has spread to the lymph nodes . Lymph node mapping and sentinel lymph node biopsy are done to ...

  4. Cyberknife treatment for advanced or terminal stage hepatocellular carcinoma

    PubMed Central

    Kato, Hiroyuki; Yoshida, Hideo; Taniguch, Hiroyoshi; Nomura, Ryutaro; Sato, Kengo; Suzuki, Ichiro; Nakata, Ryo

    2015-01-01

    AIM: To investigate the safety and efficacy of the Cyberknife treatment for patients with advanced or terminal stage hepatocellular carcinoma (HCC). METHODS: Patients with HCC with extrahepatic metastasis or vascular or bile duct invasion were enrolled between May 2011 and June 2015. The Cyberknife was used to treat each lesion. Treatment response scores were based on Response Evaluation Criteria in Solid Tumors v1.1. The trends of tumor markers, including alpha fetoprotein (AFP) and proteins induced by vitamin K absence II (PIVKA II) were assessed. Prognostic factors for tumor response and tumor markers were evaluated with Fisher’s exact test and a logistic regression model. Survival was evaluated with the Kaplan-Meier method and multivariate analysis was performed using the Cox proportional hazards model. RESULTS: Sixty-five patients with 95 lesions were enrolled. Based on the Barcelona Clinic Liver Cancer classification, all patients were either in the advanced or terminal stage of the disease. The target lesions were as follows: 52 were bone metastasis; 9, lung metastasis; 7, brain metastasis; 9, portal vein invasion; 4, hepatic vein invasion; 4, bile duct invasion; and 10 other lesion types. The response rate and disease control rate were 34% and 53%, respectively. None of the clinical factors correlated significantly with tumor response. Fiducial marker implantation was associated with better control of both AFP (HR = 0.152; 95%CI: 0.026-0.887; P = 0.036) and PIVKA II (HR = 0.035; 95%CI: 0.003-0.342; P = 0.004). The median survival time was 9 mo (95%CI: 5-15 mo). Terminal stage disease (HR = 9.809; 95%CI: 2.589-37.17, P < 0.001) and an AFP of more than 400 ng/mL (HR = 2.548; 95%CI: 1.070-6.068, P = 0.035) were associated with worse survival. A radiation dose higher than 30 Gy (HR = 0.274; 95%CI: 0.093-0.7541, P = 0.012) was associated with better survival. In the 52 cases of bone metastasis, 36 patients (69%) achieved pain relief. One patient had cerebral

  5. Impact of BRAF mutation status in the prognosis of cutaneous melanoma: an area of ongoing research

    PubMed Central

    Bhatia, Parisha; Friedlander, Paul; Zakaria, Elmageed A.

    2015-01-01

    This review is intended to provide an updated role of molecular genetics and various targeted therapies that have been developed to treat advanced stages of melanoma. Because of the declining success in melanoma therapy, the curative treatment for advanced stage melanoma has been a challenge for clinicians. Several mutations such as N-RAS, p53, BRAF including mutant-BRAF that lead to activation of kinase pathway, are implicated in the development of malignant melanoma. However, the current literature depicts that the prognostic role of BRAF mutation in disease progression is still controversial. While its higher level in advanced stage disease is associated with decreased overall survival (OS), some studies show that it failed to confer as an independent prognostic predictor of the disease. This has also led researchers to accomplish newer therapeutic strategies that lead to improved disease-response and grant survival benefits. Vemurafenib, a BRAF inhibitor agent, is one of the few available targeted therapies that is FDA approved and provides promising results in metastatic disease. However, its resistance at an early stage is of great concern. Recent implementation of combinational therapies including “targeted therapy”, immunotherapy, and biological agents has appealed many researchers to define the adjunctive role of available therapies and their limitations in advanced stage and metastatic melanoma. This commends the need for future multi-institutional studies to confirm the clinical validity of different therapeutic strategies on a large scale population. PMID:25738144

  6. Advances in Medical Management of Early Stage and Advanced Breast Cancer: 2015.

    PubMed

    Witherby, Sabrina; Rizack, Tina; Sakr, Bachir J; Legare, Robert D; Sikov, William M

    2016-01-01

    Standard management of early stage and advanced breast cancer has been improved over the past few years by knowledge gained about the biology of the disease, results from a number of eagerly anticipated clinical trials and the development of novel agents that offer our patients options for improved outcomes or reduced toxicity or both. This review highlights recent major developments affecting the systemic therapy of breast cancer, broken down by clinically relevant patient subgroups and disease stage, and briefly discusses some of the ongoing controversies in the treatment of breast cancer and promising therapies on the horizon.

  7. The transcription factor ATF2 promotes melanoma metastasis by suppressing protein fucosylation

    PubMed Central

    Lau, Eric; Feng, Yongmei; Claps, Giuseppina; Fukuda, Michiko N.; Perlina, Ally; Donn, Dylan; Jilaveanu, Lucia; Kluger, Harriet; Freeze, Hudson H.; Ronai, Ze’ev A.

    2016-01-01

    Melanoma is one of the most lethal skin cancers worldwide, primarily because of its propensity to metastasize. Thus, the elucidation of mechanisms that govern metastatic propensity is urgently needed. We found that protein kinase Cε (PKCε)–mediated activation of activating transcription factor 2 (ATF2) controls the migratory and invasive behaviors of melanoma cells. PKCε-dependent phosphorylation of ATF2 promoted its transcriptional repression of the gene encoding fucokinase (FUK), which mediates the fucose salvage pathway and thus global cellular protein fucosylation. In primary melanocytes and cell lines representing early-stage melanoma, the abundance of PKCε-phosphorylated ATF2 was low, thereby enabling the expression of FUK and cellular protein fucosylation, which promoted cellular adhesion and reduced motility. In contrast, increased expression of the gene encoding PKCε and abundance of phosphorylated, transcriptionally active ATF2 were observed in advanced-stage melanomas and correlated with decreased FUK expression, decreased cellular protein fucosylation, attenuated cell adhesion, and increased cell motility. Restoring fucosylation in mice either by dietary fucose supplementation or by genetic manipulation of murine Fuk expression attenuated primary melanoma growth, increased the number of intratumoral natural killer cells, and decreased distal metastasis in murine isograft models. Tumor microarray analysis of human melanoma specimens confirmed reduced fucosylation in metastatic tumors and a better prognosis for primary melanomas that had high abundance of fucosylation. Thus, inhibiting PKCε or ATF2 or increasing protein fucosylation in tumor cells may improve clinical outcome in melanoma patients. PMID:26645581

  8. FK506 binding protein 51 positively regulates melanoma stemness and metastatic potential

    PubMed Central

    Romano, S; Staibano, S; Greco, A; Brunetti, A; Nappo, G; Ilardi, G; Martinelli, R; Sorrentino, A; Di Pace, A; Mascolo, M; Bisogni, R; Scalvenzi, M; Alfano, B; Romano, M F

    2013-01-01

    Melanoma is the most aggressive skin cancer; there is no cure in advanced stages. Identifying molecular participants in melanoma progression may provide useful diagnostic and therapeutic tools. FK506 binding protein 51 (FKBP51), an immunophilin with a relevant role in developmental stages, is highly expressed in melanoma and correlates with aggressiveness and therapy resistance. We hypothesized a role for FKBP51 in melanoma invasive behaviour. FKBP51 promoted activation of epithelial-to-mesenchymal transition (EMT) genes and improved melanoma cell migration and invasion. In addition, FKBP51 induced some melanoma stem cell (MCSC) genes. Purified MCSCs expressed high EMT genes levels, suggesting that genetic programs of EMT and MCSCs overlap. Immunohistochemistry of samples from patients showed intense FKBP51 nuclear signal and cytoplasmic positivity for the stem cell marker nestin in extravasating melanoma cells and metastatic brains. In addition, FKBP51 targeting by small interfering RNA (siRNA) prevented the massive metastatic substitution of liver and lung in a mouse model of experimental metastasis. The present study provides evidence that the genetic programs of cancer stemness and invasiveness overlap in melanoma, and that FKBP51 plays a pivotal role in sustaining such a program. PMID:23559012

  9. Concomitant cetuximab and radiation therapy: A possible promising strategy for locally advanced inoperable non-melanoma skin carcinomas

    PubMed Central

    DELLA VITTORIA SCARPATI, GIUSEPPINA; PERRI, FRANCESCO; PISCONTI, SALVATORE; COSTA, GIUSEPPE; RICCIARDIELLO, FILIPPO; DEL PRETE, SALVATORE; NAPOLITANO, ALBERTO; CARRATURO, MARCO; MAZZONE, SALVATORE; ADDEO, RAFFAELE

    2016-01-01

    Non-melanoma skin cancers (NMSCs) include a heterogeneous group of malignancies arising from the epidermis, comprising squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Merkel cell carcinoma and more rare entities, including malignant pilomatrixoma and sebaceous gland tumours. The treatment of early disease depends primarily on surgery. In addition, certain patients present with extensive local invasion or metastasis, which renders these tumours surgically unresectable. Improving the outcome of radiotherapy through the use of concurrent systemic therapy has been demonstrated in several locally advanced cancer-treatment paradigms. Recently, agents targeting the human epidermal growth factor receptor (EGFR) have exhibited a consolidated activity in phase II clinical trials and case series reports. Cetuximab is a monoclonal antibody that binds to and completely inhibits the EGFR, which has been revealed to be up-regulated in a variety of SCCs, including NMSCs. The present review aimed to summarize the role of anti-EGFR agents in the predominant types of NMSC, including SCC and BCC, and focuses on the cetuximab-based studies, highlighting the biological rationale of this therapeutic option. In addition, the importance of the association between cetuximab and radiotherapy for locally advanced NMSC is discussed. PMID:27073643

  10. Advanced bronchoscopic techniques in diagnosis and staging of lung cancer.

    PubMed

    Zaric, Bojan; Stojsic, Vladimir; Sarcev, Tatjana; Stojanovic, Goran; Carapic, Vladimir; Perin, Branislav; Zarogoulidis, Paul; Darwiche, Kaid; Tsakiridis, Kosmas; Karapantzos, Ilias; Kesisis, Georgios; Kougioumtzi, Ioanna; Katsikogiannis, Nikolaos; Machairiotis, Nikolaos; Stylianaki, Aikaterini; Foroulis, Christophoros N; Zarogoulidis, Konstantinos

    2013-09-01

    The role of advanced brochoscopic diagnostic techniques in detection and staging of lung cancer has steeply increased in recent years. Bronchoscopic imaging techniques became widely available and easy to use. Technical improvement led to merging in technologies making autofluorescence or narrow band imaging incorporated into one bronchoscope. New tools, such as autofluorescence imagining (AFI), narrow band imaging (NBI) or fuji intelligent chromo endoscopy (FICE), found their place in respiratory endoscopy suites. Development of endobronchial ultrasound (EBUS) improved minimally invasive mediastinal staging and diagnosis of peripheral lung lesions. Linear EBUS proven to be complementary to mediastinoscopy. This technique is now available in almost all high volume centers performing bronchoscopy. Radial EBUS with mini-probes and guiding sheaths provides accurate diagnosis of peripheral pulmonary lesions. Combining EBUS guided procedures with rapid on site cytology (ROSE) increases diagnostic yield even more. Electromagnetic navigation technology (EMN) is also widely used for diagnosis of peripheral lesions. Future development will certainly lead to new improvements in technology and creation of new sophisticated tools for research in respiratory endoscopy. Broncho-microscopy, alveoloscopy, optical coherence tomography are some of the new research techniques emerging for rapid technological development.

  11. Racial disparities in advanced stage colorectal cancer survival

    PubMed Central

    Wallace, Kristin; Hill, Elizabeth G.; Lewin, David N.; Williamson, Grace; Oppenheimer, Stephanie; Ford, Marvella E.; Wargovich, Michael J.; Berger, Franklin G.; Bolick, Susan W.; Thomas, Melanie B.; Alberg, Anthony J.

    2013-01-01

    Purpose African Americans (AA) have a higher incidence and lower survival from colorectal cancer (CRC) compared to European Americans (EA). In the present study, statewide, population-based data from South Carolina Central Cancer Registry (SCCCR) is used to investigate the relationship between race and age on advanced stage CRC survival. Methods The study population was comprised of 3865 advanced pathologically documented colon and rectal adenocarcinoma cases diagnosed between 01 January 1996 and 31 December 2006: 2673 (69%) EA and 1192 (31%) AA. Kaplan-Meier methods were used to generate median survival time and corresponding 95% confidence intervals (CI) by race, age, and gender. Factors associated with survival were evaluated by fitting Cox proportional hazards (CPH) regression models to generate Hazard Ratios (HR) and 95% CI. Results We observed a significant interaction between race and age on CRC survival (p = 0.04). Among younger patients (< 50 years), AA race was associated with a 1.34 (95% CI 1.06-1.71) higher risk of death compared to EA. Among older patients, we observed a modest increase risk of death among AA men compared to EA (HR 1.16 (95% CI 1.01-1.32) but no difference by race among women (HR 0.94 (95% CI 0.82-1.08)). Moreover, we observed that the disparity in survival has worsened over the past 15 years. Conclusions Future studies that integrate clinical, molecular, and treatment-related data are needed for advancing understanding of the racial disparity in CRC survival, especially for those < 50 years old. PMID:23296454

  12. Impact of MAPK Pathway Activation in BRAF(V600) Melanoma on T Cell and Dendritic Cell Function.

    PubMed

    Ott, Patrick A; Bhardwaj, Nina

    2013-10-28

    Constitutive upregulation of the MAPK pathway by a BRAF(V600) mutation occurs in about half of melanomas. This leads to increased oncogenic properties such as tumor cell invasion, metastatic potential, and resistance to apoptosis. Blockade of the MAPK pathway with highly specific kinase inhibitors induces unprecedented tumor response rates in patients with advanced BRAF(V600) mutant melanoma. Immune checkpoint blockade with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 and programed death-1/PD-L1 has also demonstrated striking anti-tumor activity in patients with advanced melanoma. Tumor responses are likely limited by multiple additional layers of immune suppression in the tumor microenvironment. There is emerging preclinical and clinical evidence suggesting that MAPK inhibition has a beneficial effect on the immunosuppressive tumor microenvironment, providing a strong rationale for combined immunotherapy and MAPK pathway inhibition in melanoma. The T cell response has been the main focus in the studies reported to date. Since dendritic cells (DCs) are important in the induction of tumor-specific T cell responses, the impact of MAPK pathway activation in melanoma on DC function is critical for the melanoma directed immune response. BRAF(V600E) melanoma cells modulate DCs through the MAPK pathway because its blockade in melanoma cells can reverse suppression of DC function. As both MEK/BRAF inhibition and immune checkpoint blockade have recently taken center stage in the treatment of melanoma, a deeper understanding of how MAPK pathway inhibition affects the tumor immune response is needed.

  13. Contrary melanoma-associated antigen-A expression at the tumor front and center: A comparative analysis of stage I and IV head and neck squamous cell carcinoma

    PubMed Central

    Hartmann, Stefan; Brisam, Muna; Rauthe, Stephan; Driemel, Oliver; Brands, Roman C.; Rosenwald, Andreas; Kübler, Alexander C.; Müller-Richter, Urs D. A.

    2016-01-01

    There is a growing body of evidence indicating that several melanoma-associated antigen-A (MAGE-A) subgroups contribute to the malignancy of head and neck cancer. The present study retrospectively analyzed the expression of all known MAGE-A subgroups in the tumor front and center of 38 head and neck cancer patients (Union for International Cancer Control stage I or IV) by immunohistochemistry. MAGE-A1, -A6, -A8, -A9 and -A11 were expressed at significantly higher levels at the tumor front of stage IV specimens compared with the tumor front of stage I specimens. In stage I cancer, the tumor center and front ratio (C/F ratio) for each subgroup was >1.0. In stage IV cancer, the C/F ratio was <1.0 in 9/11 subgroups. The most significant change in the expression pattern was observed for MAGE-A11. These results indicated that there is a marked alteration and shift to the invasive front of almost all MAGE-A subgroups, but particularly MAGE-A11, during the progression of head and neck squamous cell carcinoma. PMID:27703530

  14. Stage-specific survival and recurrence in patients with cutaneous malignant melanoma in Europe – a systematic review of the literature

    PubMed Central

    Svedman, Fernanda Costa; Pillas, Demetris; Taylor, Aliki; Kaur, Moninder; Linder, Ragnar; Hansson, Johan

    2016-01-01

    Background Given the increasing incidence in cutaneous malignant melanoma (CMM) and the recent changes in the treatment landscape, it is important to understand stage-specific overall and recurrence-free survival patterns in Europe. Despite publications such as EUROCARE-5, there is limited information on stage-specific survival for CMM in Europe. Method We carried out a systematic literature review to provide an up-to-date summary of stage-specific survival and recurrence-free survival patterns in patients with CMM in Europe. Studies were included if they were published in Medline during the past 12 years and included information on stage-specific survival and/or recurrence in CMM. Results Of the 8,749 studies identified, 26 studies were included, representing nine countries. Collectively, the studies covered a population of 152,422 patients and included data from 1978 to 2011. Randomized clinical trials and single-center observational studies comprised the most common study designs, including five large registry-based studies. Stage-specific information for survival and recurrence varied: 5-year overall survival: 95%–100% (stage I), 65%–92.8% (stage II), 41%–71% (stage III), and 9%–28% (stage IV); 5-year relapse-free survival was reported less frequently: 56% (stage II), and 28%–44% (stage III). Studies reporting survival by sentinel node (SN) status reported 5-year overall survival as 80%–95% for negative SN (stage I/II) and 35%–75% for positive SN (stage III) status; recurrence-free survival at 5 years: 76%–90% for negative and 35%–58% for positive SN status. Some studies included comparisons of survival by key patient sociodemographic characteristics, suggesting that these have a substantial influence on survival and recurrence estimates. Conclusion The studies identified in this review show large variations in stage-specific overall and recurrence-free survival by study type and by country. Owing to differing study designs and populations, it

  15. Exploiting in situ antigen generation and immune modulation to enhance chemotherapy response in advanced melanoma: A combination nanomedicine approach.

    PubMed

    Lu, Yao; Wang, Yuhua; Miao, Lei; Haynes, Matthew; Xiang, Guangya; Huang, Leaf

    2016-08-28

    Therapeutic anticancer vaccine development must address a number of barriers to achieve successful tumor specific killing, including effective antigen presentation and antigen-specific T-cell activation to mediate cytotoxic cellular effects, inhibition of an immune-suppressive tumor microenvironment in order to facilitate and enhance CTL activity, and induction of memory T-cells to prolong tumor rejection. While traditional as well as modern vaccines rely upon delivery of both antigen and adjuvant, a variety of clinically relevant cancers lack ideal immunogenic antigens. Building upon recent efforts, we instead chose to exploit chemotherapy-induced apoptosis to allow for in situ antigen generation in a combination, nanomedicine-based approach. Specifically, lipid-coated cisplatin nanoparticles (LPC) and CpG-encapsulated liposomes (CpG-Lipo) were prepared for the temporally-controlled and multifaceted treatment of an advanced in vivo model of melanoma. Such combination therapy established strong synergistic effects, both in apoptotic extent and subsequent abrogation of tumor growth, which were due largely to both an enhanced cytotoxic T-cell recruitment and a reduction of immune-suppressive mediators in the microenvironments of both spleens and tumor. These results underlie a prolonged host lifespan in the combination approach (45 days) as compared with control (25 days, p < 0.02), providing promise toward a personalized approach to nanomedicine by establishing effect synergy in host-specific immunotherapy following chemotherapy.

  16. Exploiting in situ antigen generation and immune modulation to enhance chemotherapy response in advanced melanoma: A combination nanomedicine approach.

    PubMed

    Lu, Yao; Wang, Yuhua; Miao, Lei; Haynes, Matthew; Xiang, Guangya; Huang, Leaf

    2016-08-28

    Therapeutic anticancer vaccine development must address a number of barriers to achieve successful tumor specific killing, including effective antigen presentation and antigen-specific T-cell activation to mediate cytotoxic cellular effects, inhibition of an immune-suppressive tumor microenvironment in order to facilitate and enhance CTL activity, and induction of memory T-cells to prolong tumor rejection. While traditional as well as modern vaccines rely upon delivery of both antigen and adjuvant, a variety of clinically relevant cancers lack ideal immunogenic antigens. Building upon recent efforts, we instead chose to exploit chemotherapy-induced apoptosis to allow for in situ antigen generation in a combination, nanomedicine-based approach. Specifically, lipid-coated cisplatin nanoparticles (LPC) and CpG-encapsulated liposomes (CpG-Lipo) were prepared for the temporally-controlled and multifaceted treatment of an advanced in vivo model of melanoma. Such combination therapy established strong synergistic effects, both in apoptotic extent and subsequent abrogation of tumor growth, which were due largely to both an enhanced cytotoxic T-cell recruitment and a reduction of immune-suppressive mediators in the microenvironments of both spleens and tumor. These results underlie a prolonged host lifespan in the combination approach (45 days) as compared with control (25 days, p < 0.02), providing promise toward a personalized approach to nanomedicine by establishing effect synergy in host-specific immunotherapy following chemotherapy. PMID:27235608

  17. 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.

  18. Evolving molecularly targeted therapies for advanced-stage thyroid cancers.

    PubMed

    Bible, Keith C; Ryder, Mabel

    2016-07-01

    Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid cancer (MTC), and two agents (sorafenib and lenvatinib) for the treatment of radioactive- iodine refractory differentiated thyroid cancer (DTC) in both the USA and in the EU. The effects of these and other therapies on overall survival and quality of life among patients with thyroid cancer, however, remain to be more-clearly defined. When applied early in the disease course, intensive multimodality therapy seems to improve the survival outcomes of patients with anaplastic thyroid cancer (ATC), but salvage therapies for ATC are of uncertain benefit. Additional innovative, rationally designed therapeutic strategies are under active development both for patients with DTC and for patients with ATC, with multiple phase II and phase III randomized clinical trials currently ongoing. Continued effort is being made to identify further signalling pathways with potential therapeutic relevance in thyroid cancers, as well as to elaborate on the complex interactions between signalling pathways, with the intention of translating these discoveries into effective and personalized therapies. Herein, we summarize the progress made in molecular medicine for advanced-stage thyroid cancers of different histotypes, analyse how these developments have altered - and might further refine - patient care, and identify open questions for future research. PMID:26925962

  19. Zebrafish Melanoma.

    PubMed

    Kaufman, Charles K

    2016-01-01

    Melanoma skin cancer is a potentially deadly disease in humans and has remained extremely difficult to treat once it has metastasized. In just the last 10 years, a number of models of melanoma have been developed in the zebrafish that are biologically faithful to the human disease and have already yielded important insights into the fundamental biology of melanoma and offered new potential avenues for treatment. With the diversity and breadth of the molecular genetic tools available in the zebrafish, these melanoma models will continue to be refined and expanded upon to keep pace with the rapidly evolving field of melanoma biology. PMID:27165365

  20. Phase 1b study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma

    PubMed Central

    Hong, David S.; Kurzrock, Razelle; Falchook, Gerald S.; Andresen, Corina; Kwak, Jennifer; Ren, Min; Xu, Lucy; George, Goldy C.; Kim, Kevin B.; Nguyen, Ly M.; O'Brien, James P.; Nemunaitis, John

    2015-01-01

    Objective and Methods In this phase 1b study, patients with stage 4 or unresectable stage 3 melanoma were treated with escalating doses of lenvatinib (once daily) and temozolomide (TMZ) (days 1–5) in 28-day cycles, to determine the maximum tolerated dose (MTD) of the combination. Dose Level (DL)1: lenvatinib 20 mg, TMZ 100 mg/m2; DL2: lenvatinib 24 mg, TMZ 100 mg/m2; DL3: lenvatinib 24 mg, TMZ 150 mg/m2. Adverse events (AEs) were recorded and tumor response assessed per RECIST 1.0. Results Dose-limiting toxicity occurred in 1 of 32 treated patients (DL1); MTD was not reached. The highest dose administered was lenvatinib 24 mg + TMZ 150 mg/m2. Most common treatment-related AEs included fatigue (56.3%), hypertension (53.1%), and proteinuria (46.9%). Overall objective response rate was 18.8% (6 patients), all partial response; (DL1, n = 1; DL3, n = 5). Stable disease (SD) ≥ 16 weeks was observed in 28.1% of patients (DL1 and DL2, n = 1 each; DL3, n = 7); 12.5% of patients had SD ≥ 23 weeks. Single and repeat-dose pharmacokinetics of lenvatinib were comparable across cycles and with concomitant TMZ administration. Conclusion Lenvatinib 24 mg/day + TMZ 150 mg/m2/day (days 1–5) demonstrated modest clinical activity, an acceptable safety profile, and was administered without worsening of either lenvatinib- or TMZ-related toxicities in this patient group. PMID:26503473

  1. [Hyperthermic-antiblastic isolation perfusion for advanced melanoma of the limbs. The technic, immediate results and a review of the literature].

    PubMed

    Decian, F; Balletto, N; Camerini, G; Depaoli, M; D'Aniello, R; Ameri, A; Brisighella, A; Bonalumi, U; Bachi, V; Civalleri, D

    1990-10-15

    Hyperthermic antiblastic isolated perfusion is a method largely used for the treatment of locally advanced limb melanoma. The method requires vascular isolation and hyperthermic perfusion of the limb using an extracorporeal circuit and administering the melphalan as antiblastic drug. Twenty-six patients with primary or recurrent melanoma of the limbs have undergone this treatment at our Institute. There were no cases of operative mortality and systemic toxicity was negligible. The local complications were transitory and no patient showed symptoms of nervous toxicity or permanent functional damage. Two cases of deep thrombophlebitis and two of lymphocele were documented a few months after treatment. Four clinically complete responses, 3 partial and 2 cases of stable disease were observed in the 9 patients treated with unexcised lesions. Our data like the totality of the present experience points to the safety of this method in the therapy of locally advanced limb melanoma. Nevertheless further controlled studies are required to define its role in order to improve survival.

  2. The changing hope trajectory in patients with advanced-stage cancer: a nursing perspective.

    PubMed

    Sanders, Judith Brown; Seda, Julie S; Kardinal, Carl G

    2012-06-01

    As patients with advanced-stage cancer move from the initial diagnosis through treatment, remission, recurrence, and advanced-stage disease, the hope trajectory undergoes a dynamic transformation. By identifying the hope trajectory, nurses can help patients focus on obtainable hope objects while balancing the need to present a realistic prognosis. This, in turn, may help patients find meaning and purpose in advanced-stage cancer and facilitate realistic hope when faced with a life-threatening illness.

  3. 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. PMID:26778792

  4. Melanoma: oncogenic drivers and the immune system

    PubMed Central

    Karachaliou, Niki; Pilotto, Sara; Teixidó, Cristina; Viteri, Santiago; González-Cao, María; Riso, Aldo; Morales-Espinosa, Daniela; Molina, Miguel Angel; Chaib, Imane; Santarpia, Mariacarmela; Richardet, Eduardo; Bria, Emilio

    2015-01-01

    Advances and in-depth understanding of the biology of melanoma over the past 30 years have contributed to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. The finding that oncogenic BRAF mutations drive tumor growth in up to 50% of melanomas led to a molecular therapy revolution for unresectable and metastatic disease. Moving beyond BRAF, inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided targets for cancer immunotherapy. In this review, we discuss the molecular biology of melanoma and we focus on the recent advances of molecularly targeted and immunotherapeutic approaches. PMID:26605311

  5. Genome-wide methylated CpG island profiles of melanoma cells reveal a melanoma coregulation network

    PubMed Central

    Li, Jian-Liang; Mazar, Joseph; Zhong, Cuncong; Faulkner, Geoffrey J.; Govindarajan, Subramaniam S.; Zhang, Zhan; Dinger, Marcel E.; Meredith, Gavin; Adams, Christopher; Zhang, Shaojie; Mattick, John S.; Ray, Animesh; Perera, Ranjan J.

    2013-01-01

    Metastatic melanoma is a malignant cancer with generally poor prognosis, with no targeted chemotherapy. To identify epigenetic changes related to melanoma, we have determined genome-wide methylated CpG island distributions by next-generation sequencing. Melanoma chromosomes tend to be differentially methylated over short CpG island tracts. CpG islands in the upstream regulatory regions of many coding and noncoding RNA genes, including, for example, TERC, which encodes the telomerase RNA, exhibit extensive hypermethylation, whereas several repeated elements, such as LINE 2, and several LTR elements, are hypomethylated in advanced stage melanoma cell lines. By using CpG island demethylation profiles, and by integrating these data with RNA-seq data obtained from melanoma cells, we have identified a co-expression network of differentially methylated genes with significance for cancer related functions. Focused assays of melanoma patient tissue samples for CpG island methylation near the noncoding RNA gene SNORD-10 demonstrated high specificity. PMID:24129253

  6. The CASC15 long intergenic non-coding RNA locus is involved in melanoma progression and phenotype-switching

    PubMed Central

    Lessard, Laurent; Liu, Michelle; Marzese, Diego M.; Wang, Hongwei; Chong, Kelly; Kawas, Neal; Donovan, Nicholas C; Kiyohara, Eiji; Hsu, Sandy; Nelson, Nellie; Izraely, Sivan; Sagi-Assif, Orit; Witz, Isaac P; Ma, Xiao-Jun; Luo, Yuling; Hoon, Dave SB

    2015-01-01

    In recent years, considerable advances have been made in the characterization of protein-coding alterations involved in the pathogenesis of melanoma. However, despite their growing implication in cancer, little is known about the role of long non-coding RNAs in melanoma progression. We hypothesized that copy number alterations of intergenic non-protein coding domains could help identify long intergenic non-coding RNAs (lincRNAs) associated with metastatic cutaneous melanoma. Among several candidates, our approach uncovered the chromosome 6p22.3 CASC15 lincRNA locus as a frequently gained genomic segment in metastatic melanoma tumors and cell lines. The locus was actively transcribed in metastatic melanoma cells, and up-regulation of CASC15 expression was associated with metastatic progression to brain metastasis in a mouse xenograft model. In clinical specimens, CASC15 levels increased during melanoma progression and were independent predictors of disease recurrence in a cohort of 141 patients with AJCC stage III lymph node metastasis. Moreover, siRNA knockdown experiments revealed that CASC15 regulates melanoma cell phenotype switching between proliferative and invasive states. Accordingly, CASC15 levels correlated with known gene signatures corresponding to melanoma proliferative and invasive phenotypes. These findings support a key role for CASC15 in metastatic melanoma. PMID:26016895

  7. miR-194 is a negative regulator of GEF-H1 pathway in melanoma.

    PubMed

    Guo, Bingyu; Hui, Qiang; Zhang, Yu; Chang, Peng; Tao, Kai

    2016-10-01

    The incidence and associated mortality of melanoma continues to increase worldwide. At present, there is no curative therapy for advanced stage of melanoma. It is necessary to find new indicators of prognosis and therapeutic targets. Increasing evidence shows that miRNA can provide potential candidate biomarkers for melanoma and therapeutic targets. GEF-H1, a regulator of RhoA, as oncogenic driver in melanoma, promotes the growth and invasion of melanoma. miR-194 is a tumor-suppressor gene in multiple tumors, such as bladder and non-small cell lung cancer, and clear cell renal cell carcinoma. In the present study, we demonstrated that GEF-H1 serves as target of miR-194. Overexpression of miR-194 downregulates the GEF-H1/RhoA pathway, inhibits melanoma cancer cell proliferation and metastasis. Furthermore, miR-194 expression is negatively associated with tumor-node-metastasis (TNM) stages. Briefly, our findings provided new theoretical basis for melanoma treatment. PMID:27573550

  8. 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.

  9. Decitabine in Treating Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2013-02-06

    Male Breast Cancer; Recurrent Bladder Cancer; Recurrent Breast Cancer; Recurrent Melanoma; Stage III Melanoma; Stage IV Bladder Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Unspecified Adult Solid Tumor, Protocol Specific

  10. Dabrafenib for Treating Unresectable, Advanced or Metastatic BRAF V600 Mutation-Positive Melanoma: An Evidence Review Group Perspective.

    PubMed

    Fleeman, Nigel; Bagust, Adrian; Beale, Sophie; Boland, Angela; Dickson, Rumona; Dwan, Kerry; Richardson, Marty; Dundar, Yenal; Davis, Helen; Banks, Lindsay

    2015-09-01

    The National Institute for Health and Care Excellence (NICE) invited GlaxoSmithKline, the manufacturer of dabrafenib, to submit evidence for the clinical and cost effectiveness of dabrafenib for the treatment of unresectable, advanced or metastatic BRAF V600 mutation-positive melanoma in accordance with the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarizes the ERG's review of the evidence submitted by the company and provides a summary of the Appraisal Committee's (AC) final decision in October 2014. The clinical evidence for dabrafenib was derived from an ongoing phase III, randomized, double-blind, placebo-controlled, international, multicentre clinical trial (BREAK-3) involving 230 patients randomized 2:1 to receive either dabrafenib or dacarbazine. A significant improvement in median progression-free survival (PFS) but not overall survival (OS) was reported in the dabrafenib arm compared with dacarbazine. Vemurafenib is considered a more appropriate comparator than is dacarbazine. The clinical evidence for vemurafenib was derived from a completed phase III, randomized, double-blind, placebo-controlled, international, multicentre clinical trial (BRIM-3) involving 675 patients randomized 1:1 to receive either vemurafenib or dacarbazine. A significant improvement in median PFS and OS was reported in the vemurafenib arm compared with dacarbazine. As there is no direct evidence comparing dabrafenib versus vemurafenib, the company presented an indirect treatment comparison (ITC) that demonstrated no statistical differences between dabrafenib and vemurafenib for PFS or OS. The ERG expressed concerns with the ITC, mainly in relation to the validity of the assumptions underpinning the methodology; the ERG concluded this resulted in findings that are unlikely to be robust or reliable. Dabrafenib and

  11. 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. PMID:24468268

  12. Immunotherapy in a rare case of primary pelvic retroperitoneal melanoma.

    PubMed

    Talag, Maria Monica; Alsharedi, Mohamed; Bou Zgheib, Nadim; Lebowicz, Yehuda

    2016-01-01

    Recent advances in novel immunotherapeutic and targeted therapeutic agents have increased treatment options in patients with advanced metastatic melanoma. However, evidence in the literature on whether or not extracutaneous melanoma will acquire an equivalent advantage from these therapies is very scarce. In general, extracutaneous melanomas are rare and aggressive melanomas, which are clinically and biologically unique, with higher incidence of metastatic disease and poor prognosis. In this case report, we present a very rare case of a 54-year-old woman with primary pelvic retroperitoneal melanoma treated with an anti-PD-1 antibody, pembrolizumab. Furthermore, we explore the role of novel immunotherapies in the treatment of advanced melanoma. PMID:27624447

  13. Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: A Phase I/II dose-escalation study

    SciTech Connect

    Tsuji, Hiroshi . E-mail: h_tsuji@nirs.go.jp; Ishikawa, Hitoshi; Yanagi, Takeshi; Hirasawa, Naoki; Kamada, Tadashi; Mizoe, Jun-Etsu; Kanai, Tatsuaki; Tsujii, Hirohiko; Ohnishi, Yoshitaka

    2007-03-01

    Purpose: To evaluate the applicability of carbon ion beams for the treatment of choroidal melanoma with regard to normal tissue morbidity and local tumor control. Methods and Materials: Between January 2001 and February 2006, 59 patients with locally advanced or unfavorably located choroidal melanoma were enrolled in a Phase I/II clinical trial of carbon-ion radiotherapy at the National Institute of Radiologic Sciences. The primary endpoint of this study was normal tissue morbidity, and secondary endpoints were local tumor control and patient survival. Of the 59 subjects enrolled, 57 were followed >6 months and analyzed. Results: Twenty-three patients (40%) developed neovascular glaucoma, and three underwent enucleation for eye pain due to elevated intraocular pressure. Incidence of neovascular glaucoma was dependent on tumor size and site. Five patients had died at analysis, three of distant metastasis and two of concurrent disease. All but one patient, who developed marginal recurrence, were controlled locally. Six patients developed distant metastasis, five in the liver and one in the lung. Three-year overall survival, disease-free survival, and local control rates were 88.2%, 84.8%, and 97.4%, respectively. No apparent dose-response relationship was observed in either tumor control or normal tissue morbidity at the dose range applied. Conclusion: Carbon-ion radiotherapy can be applied to choroidal melanoma with an acceptable morbidity and sufficient antitumor effect, even with tumors of unfavorable size or site.

  14. 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.

  15. 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

  16. Advanced two-stage incineration: Research and development

    SciTech Connect

    Rehmat, A.; Khinkis, M.

    1991-01-01

    IGT is currently developing a two-stage fluidized-bed/cyclonic agglomerating incineration system that is based on combining the fluidized-bed agglomeration/incineration and cyclonic combustion technologies, both of which have been developed individually at IGT over many years. This combination has resulted in a unique and extremely flexible incinerator for solid, liquid, and gaseous wastes. The system can operate over a wide range of conditions in the first stage, from low temperature (desorption) to high temperature (agglomeration), including gasification of high-Btu wastes. In the combined system, solid, liquid, and gaseous organic wastes are expected to be easily and efficiently destroyed (>99.99% destruction and removal efficiency (DRE)) while solid inorganic contaminants are expected to be contained within a glassy matrix, rendering them benign and suitable for disposal in an ordinary landfill. The development of the two-stage incinerator is a culmination of extensive research and development efforts on each stage of the incinerator. A variety of data obtained for both stages includes agglomeration of ash, incineration and reclamation of used blast grit and foundry sand, partial combustion of carbonaceous fuels, in-situ desulfurization, combustion of low-Btu gases, incineration of industrial wastewater, and incineration of carbon tetrachloride.

  17. 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.

  18. Methods of Melanoma Detection.

    PubMed

    Leachman, Sancy A; Cassidy, Pamela B; Chen, Suephy C; Curiel, Clara; Geller, Alan; Gareau, Daniel; Pellacani, Giovanni; Grichnik, James M; Malvehy, Josep; North, Jeffrey; Jacques, Steven L; Petrie, Tracy; Puig, Susana; Swetter, Susan M; Tofte, Susan; Weinstock, Martin A

    2016-01-01

    Detection and removal of melanoma, before it has metastasized, dramatically improves prognosis and survival. The purpose of this chapter is to (1) summarize current methods of melanoma detection and (2) review state-of-the-art detection methods and technologies that have the potential to reduce melanoma mortality. Current strategies for the detection of melanoma range from population-based educational campaigns and screening to the use of algorithm-driven imaging technologies and performance of assays that identify markers of transformation. This chapter will begin by describing state-of-the-art methods for educating and increasing awareness of at-risk individuals and for performing comprehensive screening examinations. Standard and advanced photographic methods designed to improve reliability and reproducibility of the clinical examination will also be reviewed. Devices that magnify and/or enhance malignant features of individual melanocytic lesions (and algorithms that are available to interpret the results obtained from these devices) will be compared and contrasted. In vivo confocal microscopy and other cellular-level in vivo technologies will be compared to traditional tissue biopsy, and the role of a noninvasive "optical biopsy" in the clinical setting will be discussed. Finally, cellular and molecular methods that have been applied to the diagnosis of melanoma, such as comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH), and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), will be discussed. PMID:26601859

  19. Quantitative Histone Mass Spectrometry Identifies Elevated Histone H3 Lysine 27 (Lys27) Trimethylation in Melanoma.

    PubMed

    Sengupta, Deepanwita; Byrum, Stephanie D; Avaritt, Nathan L; Davis, Lauren; Shields, Bradley; Mahmoud, Fade; Reynolds, Matthew; Orr, Lisa M; Mackintosh, Samuel G; Shalin, Sara C; Tackett, Alan J

    2016-03-01

    Normal cell growth is characterized by a regulated epigenetic program that drives cellular activities such as gene transcription, DNA replication, and DNA damage repair. Perturbation of this epigenetic program can lead to events such as mis-regulation of gene transcription and diseases such as cancer. To begin to understand the epigenetic program correlated to the development of melanoma, we performed a novel quantitative mass spectrometric analysis of histone post-translational modifications mis-regulated in melanoma cell culture as well as patient tumors. Aggressive melanoma cell lines as well as metastatic melanoma were found to have elevated histone H3 Lys(27) trimethylation (H3K27me3) accompanied by overexpressed methyltransferase EZH2 that adds the specific modification. The altered epigenetic program that led to elevated H3K27me3 in melanoma cell culture was found to directly silence transcription of the tumor suppressor genes RUNX3 and E-cadherin. The EZH2-mediated silencing of RUNX3 and E-cadherin transcription was also validated in advanced stage human melanoma tissues. This is the first study focusing on the detailed epigenetic mechanisms leading to EZH2-mediated silencing of RUNX3 and E-cadherin tumor suppressors in melanoma. This study underscores the utility of using high resolution mass spectrometry to identify mis-regulated epigenetic programs in diseases such as cancer, which could ultimately lead to the identification of biological markers for diagnostic and prognostic applications. PMID:26621846

  20. The new seventh edition American Joint Committee on Cancer staging of cutaneous non-melanoma skin cancer: a critical review.

    PubMed

    Warner, Christina L; Cockerell, Clay J

    2011-06-01

    The seventh edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual includes a major revision of the staging protocol for cutaneous carcinomas. There are several significant improvements to the Tumor, Nodes, and Metastases (TNM) staging system, including consideration of high-risk factors within the primary T grade, a decrease in the tumor size threshold from 5 cm to 2 cm, improved stratification of patient lymph node status, as well as exclusion of Merkel cell carcinomas from the staging system for squamous cell carcinoma (SCC) and other cutaneous carcinomas. However, some important variables in cutaneous SCC were excluded from consideration. In addition, the AJCC Cancer Staging Manual makes some recommendations that will likely prove difficult to apply in clinical practice, particularly that Clark level, depth of invasion, and presence or absence of perineural invasion should be recorded for each peripheral SCC. In this review, we examine the new recommendations with an emphasis on their utility and practicality. PMID:21469759

  1. Computer-Aided Diagnosis of Micro-Malignant Melanoma Lesions Applying Support Vector Machines.

    PubMed

    Jaworek-Korjakowska, Joanna

    2016-01-01

    Background. One of the fatal disorders causing death is malignant melanoma, the deadliest form of skin cancer. The aim of the modern dermatology is the early detection of skin cancer, which usually results in reducing the mortality rate and less extensive treatment. This paper presents a study on classification of melanoma in the early stage of development using SVMs as a useful technique for data classification. Method. In this paper an automatic algorithm for the classification of melanomas in their early stage, with a diameter under 5 mm, has been presented. The system contains the following steps: image enhancement, lesion segmentation, feature calculation and selection, and classification stage using SVMs. Results. The algorithm has been tested on 200 images including 70 melanomas and 130 benign lesions. The SVM classifier achieved sensitivity of 90% and specificity of 96%. The results indicate that the proposed approach captured most of the malignant cases and could provide reliable information for effective skin mole examination. Conclusions. Micro-melanomas due to the small size and low advancement of development create enormous difficulties during the diagnosis even for experts. The use of advanced equipment and sophisticated computer systems can help in the early diagnosis of skin lesions. PMID:27382567

  2. Computer-Aided Diagnosis of Micro-Malignant Melanoma Lesions Applying Support Vector Machines

    PubMed Central

    2016-01-01

    Background. One of the fatal disorders causing death is malignant melanoma, the deadliest form of skin cancer. The aim of the modern dermatology is the early detection of skin cancer, which usually results in reducing the mortality rate and less extensive treatment. This paper presents a study on classification of melanoma in the early stage of development using SVMs as a useful technique for data classification. Method. In this paper an automatic algorithm for the classification of melanomas in their early stage, with a diameter under 5 mm, has been presented. The system contains the following steps: image enhancement, lesion segmentation, feature calculation and selection, and classification stage using SVMs. Results. The algorithm has been tested on 200 images including 70 melanomas and 130 benign lesions. The SVM classifier achieved sensitivity of 90% and specificity of 96%. The results indicate that the proposed approach captured most of the malignant cases and could provide reliable information for effective skin mole examination. Conclusions. Micro-melanomas due to the small size and low advancement of development create enormous difficulties during the diagnosis even for experts. The use of advanced equipment and sophisticated computer systems can help in the early diagnosis of skin lesions. PMID:27382567

  3. Factors related to advanced stage oral squamous cell carcinoma in southern Thailand.

    PubMed

    Kerdpon, D; Sriplung, H

    2001-04-01

    A critical factor that indicates a poor prognosis of oral squamous cell carcinoma (OSCC) is advanced stage disease. This study, therefore, aimed to identify the factors related to advanced stage (TNM staging III, IV) OSCC in Thailand. There were 161 patients with squamous cell carcinoma of the oral cavity and lip (ICD-9 140, 141, 143-5), included in the study. Sixty-two per cent of the patients presented with advanced stage disease. Information on demographic characteristics, risk habits, health-seeking behaviour prior to health care professional (HCP) consultation, tumour characteristics and patient and professional delay was obtained by questionnaire-based interview of the patients. These variables were included as initial variables in a logistic regression to calculate the odds ratio (OR) of advanced versus early stage OSCC. Having traditional herbal medication before HCP consultation significantly increased the risk of advanced stage OSCC (OR 5.77; 95% C.I. 1.25-26.62). Floor of mouth location of tumour was associated with a lower risk of advanced stage disease (OR 0.27; 95% C.I. 0.09-0.82) as was having an ulcer (OR 0.43, 95% C.I. 0.02-0.89). The findings indicate that having traditional herbal medication before HCP consultation increased the risk of advanced stage disease. The lower risk of advanced stage OSCC associated with ulcerative tumours and those on the floor of the mouth may be due to their being more readily detected by the patients. PMID:11287274

  4. Melanoma immunotherapy dominates the field.

    PubMed

    Diamantopoulos, Panagiotis; Gogas, Helen

    2016-07-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimens failed to show a significant improvement in overall survival (OS). Recent advances and in-depth understanding of the biology of melanoma, have contributed to the development of new agents. Based on the molecular and immunological background of the disease, these new drugs have shown benefit in overall and progression-free survival (PFS). As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in the present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:27563656

  5. Melanoma immunotherapy dominates the field

    PubMed Central

    Diamantopoulos, Panagiotis

    2016-01-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimens failed to show a significant improvement in overall survival (OS). Recent advances and in-depth understanding of the biology of melanoma, have contributed to the development of new agents. Based on the molecular and immunological background of the disease, these new drugs have shown benefit in overall and progression-free survival (PFS). As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in the present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:27563656

  6. Diagnostic Challenge of Desmoplastic Melanoma

    PubMed Central

    Andreevscaia, Olga; Theate, Ivan; Goossens, Cathy; Vanhooteghem, Olivier

    2016-01-01

    Desmoplastic melanoma (DM) is a rare variant of spindle-cell malignant melanoma. DM is easily misdiagnosed at an early stage because it can be confused with benign entities. Histological analysis, including careful attention to the presence of atypical spindle cells, as well as to lymphocytic aggregates in an abundant fibrotic stroma in the dermis, provides clues for diagnosis. The adjunction of an immunohistochemical panel, and particularly testing for S-100 protein, is needed for the final diagnosis. PMID:27134705

  7. Prospective Multicenter Phase II Trial of Systemic ADH-1 in Combination With Melphalan via Isolated Limb Infusion in Patients With Advanced Extremity Melanoma

    PubMed Central

    Beasley, Georgia M.; Riboh, Jonathan C.; Augustine, Christina K.; Zager, Jonathan S.; Hochwald, Steven N.; Grobmyer, Stephen R.; Peterson, Bercedis; Royal, Richard; Ross, Merrick I.; Tyler, Douglas S.

    2011-01-01

    Purpose Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity. Patients and Methods Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one). Conclusion To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study. PMID:21343562

  8. Pre-Appointment Testing for BRAF/KIT Mutation in Advanced Melanoma: A Model in Molecular Data Delivery for Individualized Medicine

    PubMed Central

    Mounajjed, Taofic; Brown, Char. L.; Stern, Therese K.; Bjorheim, Annette M.; Bridgeman, Andrew J.; Rumilla, Kandelaria M.; McWilliams, Robert R.; Flotte, Thomas J.

    2015-01-01

    The emergence of individualized medicine is driven by developments in precision diagnostics, epitomized by molecular testing. Because treatment decisions are being made based on such molecular data, data management is gaining major importance. Among data management challenges, creating workflow solutions for timely delivery of molecular data has become pivotal. This study aims to design and implement a scalable process that permits pre-appointment BRAF/KIT mutation analysis in melanoma patients, allowing molecular results necessary for treatment plans to be available before the patient's appointment. Process implementation aims to provide a model for efficient molecular data delivery for individualized medicine. We examined the existing process of BRAF/KIT testing in melanoma patients visiting our institution for oncology consultation. We created five working groups, each designing a specific segment of an alternative process that would allow pre-appointment BRAF/KIT testing and delivery of results. Data was captured and analyzed to evaluate the success of the alternative process. Over one year, 35 of 55 (59%) patients had prior BRAF/KIT testing. The remaining 20 patients went through the new process of pre-appointment testing; results were available at the time of appointment for 12 patients (overall pre-appointment results availability = 85.5%). The overall process averaged 13.4 ± 4.7 days. In conclusion, we describe successful implementation of a scalable workflow solution that permits pre-appointment BRAF/KIT mutation analysis and result delivery in melanoma patients. This sets the stage for further applications of this model to other conditions, answering an increasing demand for robust delivery of molecular data for individualized medicine. PMID:25179409

  9. [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. PMID:26944641

  10. 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

    2011-10-01

    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.

  11. Exprimental Results of the First Two Stages of an Advanced Transonic Core Compressor Under Isolated and Multi-Stage Conditions.

    NASA Technical Reports Server (NTRS)

    Prahst, Patricia S.; Kulkarni, Sameer; Sohn, Ki H.

    2015-01-01

    NASA's Environmentally Responsible Aviation (ERA) Program calls for investigation of the technology barriers associated with improved fuel efficiency for large gas turbine engines. Under ERA, the highly loaded core compressor technology program attempts to realize the fuel burn reduction goal by increasing overall pressure ratio of the compressor to increase thermal efficiency of the engine. Study engines with overall pressure ratio of 60 to 70 are now being investigated. This means that the high pressure compressor would have to almost double in pressure ratio while keeping a high level of efficiency. NASA and GE teamed to address this challenge by testing the first two stages of an advanced GE compressor designed to meet the requirements of a very high pressure ratio core compressor. Previous test experience of a compressor which included these front two stages indicated a performance deficit relative to design intent. Therefore, the current rig was designed to run in 1-stage and 2-stage configurations in two separate tests to assess whether the bow shock of the second rotor interacting with the upstream stage contributed to the unpredicted performance deficit, or if the culprit was due to interaction of rotor 1 and stator 1. Thus, the goal was to fully understand the stage 1 performance under isolated and multi-stage conditions, and additionally to provide a detailed aerodynamic data set for CFD validation. Full use was made of steady and unsteady measurement methods to understand fluid dynamics loss source mechanisms due to rotor shock interaction and endwall losses. This paper will present the description of the compressor test article and its measured performance and operability, for both the single stage and two stage configurations. We focus the paper on measurements at 97% corrected speed with design intent vane setting angles.

  12. The Critical Technologies and Applications on Advanced Upper Stage Vehicles

    NASA Astrophysics Data System (ADS)

    Qi, Feng; Wang, Guo-hui

    2016-07-01

    Upper Stage Vehicle(USV) is a kind of independent one-stop-into-space launching vehicles. In this article, different new-conception USVs are mentioned and out of them, on basis of the possibility in future application, laser propelling USV and nuclear-thermal propelling USV are selected and discussed in technical details, especially in critical technologies and recent relative technical improvements about new propelling methods within these two kinds. Furthermore, laser propelled USV and nuclear-thermal propelled USV both seem to have important roles to play in future space exploring projects. And several possible applications of the two kinds of USVs emphasized above are carried out at the end of this piece of article.

  13. Fas-mediated apoptosis of melanoma cells and infiltrating lymphocytes in human malignant melanomas.

    PubMed

    Shukuwa, Tetsuo; Katayama, Ichiro; Koji, Takehiko

    2002-04-01

    In a rodent system, melanoma cells expressing Fas ligand (FasL) could kill Fas-positive lymphocytes, suggesting that FasL expression was an essential factor for melanoma cell survival in vivo. These findings led us to investigate apoptosis, and to histochemically analyze involvement of Fas and FasL in the induction of apoptosis, in human malignant melanoma tissues. The percentages of terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end-labeling (TUNEL)-positive melanoma cells and of proliferating cell nuclear antigen (PCNA)-positive melanoma cells in melanoma tissues (n = 22) were greater than those in melanocytes in uninvolved skin (n = 6) and nevus cells in nevi tissues (n = 9). The infiltrating lymphocytes around melanomas were also TUNEL positive. Immunohistochemistry revealed expression of Fas and FasL in melanoma cells and lymphocytes, whereas no Fas or FasL expression was detected in normal skin melanocytes and nevus cells. There was significant correlation between Fas-positive indices and TUNEL indices in melanoma tissues. Moreover, TUNEL-, Fas-, and FasL-positive indices of melanoma cells from patients with Stage 3 melanomas were significantly lower than those with Stage 2 melanomas. The PCNA index of Stage 1 melanoma was significantly lower than that of the other stages, although the difference of PCNA index was insignificant among Stages 2 to 4. Among Stages 1 to 4, there was no difference in the PCNA, TUNEL-, and Fas-positive indices of lymphocytes, although the FasL-positive index of lymphocytes from Stage 3 melanomas was significantly lower than in that from Stage 2. These data reveal that melanoma cells and infiltrating lymphocytes have the potential to induce their own apoptosis regulated by Fas and FasL in an autocrine and/or paracrine fashion and that the decline of Fas-mediated apoptosis of melanoma cells, rather than the apoptosis of infiltrating lymphocytes, may affect the prognosis of melanoma patients, possibly through the

  14. Increasing radiation dose improves immunotherapy outcome and prolongation of tumor dormancy in a subgroup of mice treated for advanced intracerebral melanoma.

    PubMed

    Smilowitz, Henry M; Micca, Peggy L; Sasso, Daniel; Wu, Qian; Dyment, Nathanial; Xue, Crystal; Kuo, Lynn

    2016-02-01

    Previously, we developed a clinically relevant therapy model for advanced intracerebral B16 melanomas in syngeneic mice combining radiation and immunotherapies. Here, 7 days after B16-F10-luc2 melanoma cells were implanted intracerebrally (D7), syngeneic mice with bioluminescent tumors that had formed (1E10(5) to 7E10(6) photons per minute (>1E10(6), large; <1E10(6), small) were segregated into large-/small-balanced subgroups. Then, mice received either radiation therapy alone (RT) or radiation therapy plus immunotherapy (RT plus IT) (single injection of mAbPC61 to deplete regulatory T cells followed by multiple injections of irradiated granulocyte macrophage colony stimulating factor transfected B16-F10 cells) (RT plus IT). Radiation dose was varied (15, 18.75 or 22.5 Gy, given on D8), while immunotherapy was provided similarly to all mice. The data support the hypothesis that increasing radiation dose improves the outcome of immunotherapy in a subgroup of mice. The tumors that were greatly delayed in beginning their progressive growth were bioluminescent in vivo-some for many months, indicating prolonged tumor "dormancy," in some cases presaging long-term cures. Mice bearing such tumors had far more likely received radiation plus immunotherapy, rather than RT alone. Radiotherapy is a very important adjunct to immunotherapy; the greater the tumor debulking by RT, the greater should be the benefit to tumor immunotherapy.

  15. Experimental Results of the First Two Stages of an Advanced Transonic Core Compressor Under Isolated and Multi-Stage Conditions

    NASA Technical Reports Server (NTRS)

    Prahst, Patricia S.; Kulkarni, Sameer; Sohn, Ki H.

    2015-01-01

    NASA's Environmentally Responsible Aviation (ERA) Program calls for investigation of the technology barriers associated with improved fuel efficiency of large gas turbine engines. Under ERA the task for a High Pressure Ratio Core Technology program calls for a higher overall pressure ratio of 60 to 70. This mean that the HPC would have to almost double in pressure ratio and keep its high level of efficiency. The challenge is how to match the corrected mass flow rate of the front two supersonic high reaction and high corrected tip speed stages with a total pressure ratio of 3.5. NASA and GE teamed to address this challenge by using the initial geometry of an advanced GE compressor design to meet the requirements of the first 2 stages of the very high pressure ratio core compressor. The rig was configured to run as a 2 stage machine, with Strut and IGV, Rotor 1 and Stator 1 run as independent tests which were then followed by adding the second stage. The goal is to fully understand the stage performances under isolated and multi-stage conditions and fully understand any differences and provide a detailed aerodynamic data set for CFD validation. Full use was made of steady and unsteady measurement methods to isolate fluid dynamics loss source mechanisms due to interaction and endwalls. The paper will present the description of the compressor test article, its predicted performance and operability, and the experimental results for both the single stage and two stage configurations. We focus the detailed measurements on 97 and 100 of design speed at 3 vane setting angles.

  16. Bronchial involvement in advanced stage lymphangioleiomyomatosis: histopathologic and molecular analyses.

    PubMed

    Hayashi, Takuo; Kumasaka, Toshio; Mitani, Keiko; Okada, Yoshinori; Kondo, Takashi; Date, Hiroshi; Chen, Fengshi; Oto, Takahiro; Miyoshi, Shinichiro; Shiraishi, Takeshi; Iwasaki, Akinori; Hara, Kieko; Saito, Tsuyoshi; Ando, Katsutoshi; Kobayashi, Etsuko; Gunji-Niitsu, Yoko; Kunogi, Makiko; Takahashi, Kazuhisa; Yao, Takashi; Seyama, Kuniaki

    2016-04-01

    Lymphangioleiomyomatosis (LAM), a rare progressive disease that almost exclusively affects women, is characterized by pulmonary cysts and neoplastic proliferation of smooth muscle-like cells (LAM cells). Airflow obstruction is a physiologic consequence that is commonly observed in LAM and has been attributed to narrowing of peripheral airways. However, histopathologic examinations of the entire airway have been precluded by the limited availability of such specimens. Here, we used explanted lung tissues from 30 LAM patients for a thorough histologic analysis with a special emphasis on the bronchi. We found bronchial involvement by LAM cells and lymphatics in all patients examined. Furthermore, a moderate to severe degree of chronic inflammation (73%), goblet cell hyperplasia (97%), squamous cell metaplasia (83%) of the epithelium, and thickening of basal lamina (93%) were identified in the bronchi. Because LAM cells are transformed by the functional loss of the TSC genes leading to a hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, we confirmed the expression of phospho-p70S6K, phospho-S6, phospho-4E-BP1, and vascular endothelial growth factor (VEGF)-D in LAM cells from all of the patients examined. In contrast, no protein expression of hypoxia-inducible factor 1α, a downstream molecule indicative of mTORC1 activation and leading to VEGF production, was detected in any patient. Our study indicates that late-stage LAM patients commonly have bronchi involved by the proliferation of both LAM cells and lymphatics and that chronic inflammation complicated their disease. Furthermore, the up-regulation of hypoxia-inducible factor 1α, a common event in mTORC1-driven tumor cells, does not occur in LAM cells and plays no role in VEGF-D expression in LAM cells. PMID:26997436

  17. Choroidal melanoma

    PubMed Central

    Singh, Parul; Singh, Abhishek

    2012-01-01

    Choroidal melanoma is the most common primary intra-ocular malignant tumor and second most common site of ten malignant melanoma sites in the body. Current diagnosis of choroidal melanoma is based on both the clinical experience of the specialist and modern diagnostic techniques such as indirect ophthalmoscopy, A- and B-ultrasonography scans, fundus fluorescein angiography, and transillumination. Invasive studies such as fine needle aspiration cytology can have significant morbidity and should only be considered if therapeutic intervention is indicated and diagnosis cannot be established by any other means. Several modes of treatment are available for choroidal melanoma. Multiple factors are taken into account when deciding one approach over other approaches, such as visual acuity of the affected eye, visual acuity of the contralateral eye, tumor size, location, ocular structures involved and presence of metastases. A comprehensive review of literature available in books and indexed journals was done. This article discusses in detail epidemiology, diagnosis, current available treatment options, and prognosis and survival of choroidal melanoma. PMID:22557869

  18. Targeted Radionuclide Therapy of Melanoma.

    PubMed

    Norain, Abdullah; Dadachova, Ekaterina

    2016-05-01

    An estimated 60,000 individuals in the United States and 132,000 worldwide are yearly diagnosed with melanoma. Until recently, treatment options for patients with stages III-IV metastatic disease were limited and offered marginal, if any, improvement in overall survival. The situation changed with the introduction of B-RAF inhibitors and anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death protein 1 immunotherapies into the clinical practice. With only some patients responding well to the immune therapies and with very serious side effects and high costs of immunotherapy, there is still room for other approaches for the treatment of metastatic melanoma. Targeted radionuclide therapy of melanoma could be divided into the domains of radioimmunotherapy (RIT), radiolabeled peptides, and radiolabeled small molecules. RIT of melanoma is currently experiencing a renaissance with the clinical trials of alpha-emitter (213)Bi-labeled and beta-emitter (188)Rhenium-labeled monoclonal antibodies in patients with metastatic melanoma producing encouraging results. The investigation of the mechanism of efficacy of melanoma RIT points at killing of melanoma stem cells by RIT and involvement of immune system such as complement-dependent cytotoxicity. The domain of radiolabeled peptides for targeted melanoma therapy has been preclinical so far, with work concentrated on radiolabeled peptide analogues of melanocyte-stimulating hormone receptor and on melanin-binding peptides. The field of radiolabeled small molecule produced radioiodinated benzamides that cross the cellular membrane and bind to the intracellular melanin. The recent clinical trial demonstrated measurable antitumor effects and no acute or midterm toxicities. We are hopeful that the targeted radionuclide therapy of metastatic melanoma would become a clinical reality as a stand-alone therapy or in combination with the immunotherapies such as anti-PD1 programmed cell death protein 1 monoclonal antibodies

  19. Immunotherapy of metastatic melanoma by reversal of immune suppression

    SciTech Connect

    Biggs, M.W.; Eiselein, J.E.

    1997-01-01

    Beginning with the observation that the human enteorvirus, Poliovirus Sabin 1, will lyse human melanoma cells in culture, clinical trials involving two patients with advance melanoma were performed. Parenteral injection of the viable Poliovirus into cutaneous melanoma metastases followed in 24 hours by oral administration of cyclophosphamide. The results of these two trials are described.

  20. Immunohistochemical diagnostic and prognostic markers for melanoma.

    PubMed

    Nosrati, Mehdi; Kashani-Sabet, Mohammed

    2014-01-01

    Recent studies in our laboratory have identified novel molecular diagnostic and prognostic markers based on analyses in large cohorts of melanoma patients. These markers were initially derived from gene expression profiling analyses of distinct stages of melanoma progression. Immunohistochemical analyses confirmed the differential expression of these markers, and immunohistochemistry-based multimarker assays were developed to assess melanoma diagnosis and prognosis at the molecular level. In this chapter we review the development of these assays and the methodologies used to assess marker expression in both nevi and primary melanomas. PMID:24258983

  1. Primary mucosal melanomas: a comprehensive review

    PubMed Central

    Mihajlovic, Marija; Vlajkovic, Slobodan; Jovanovic, Predrag; Stefanovic, Vladisav

    2012-01-01

    Primary mucosal melanomas arise from melanocytes located in mucosal membranes lining respiratory, gastrointestinal and urogenital tract. Although a majority of mucosal melanomas originate from the mucosa of the nasal cavity and accessory sinuses, oral cavity, anorectum, vulva and vagina, they can arise in almost any part of mucosal membranes. Most of mucosal melanomas occur in occult sites, which together with the lack of early and specific signs contribute to late diagnosis, and poor prognosis. Because of their rareness the knowledge about their pathogenesis and risk factors is insufficient, and also there are not well established protocols for staging and treatment of mucosal melanomas. Surgery is the mainstay of treatment, with trends toward more conservative treatment since radical surgery did not show an advantage for survival. Radiotherapy can provide better local control in some locations, but did not show improvement in survival. There is no effective systemic therapy for these aggressive tumors. Compared with cutaneous and ocular melanoma, mucosal melanomas have lowest percent of five-year survival. Recently revealed molecular changes underlying mucosal melanomas offer new hope for development of more effective systemic therapy for mucosal melanomas. Herein we presented a comprehensive review of various locations of primary melanoma along mucosal membranes, their epidemiological and clinical features, and treatment options. We also gave a short comparison of some characteristics of cutaneous and mucosal melanomas. PMID:23071856

  2. Histone variants and melanoma: facts and hypotheses.

    PubMed

    Konstantinov, Nikifor K; Ulff-Møller, Constance J; Dimitrov, Stefan

    2016-07-01

    Melanoma is the most aggressive form of skin cancer with rising incidence and morbidity. Despite advances in treatment, the 10-yr survival for patients with metastatic disease is less than 10%. During the past few years, ongoing research on different epigenomic aberrations in melanoma has catalyzed better understanding of its pathogenesis and identification of new therapeutics. In our review, we will focus on the role of histone variants, key epigenetic players in melanoma initiation and progression. Specifically, incorporation of histone variants enables additional layers of chromatin structure, and here, we will describe how alterations in this epigenetic behavior impact melanoma.

  3. Genetic and environmental melanoma models in fish

    PubMed Central

    Patton, E Elizabeth; Mitchell, David L; Nairn, Rodney S

    2010-01-01

    Experimental animal models are extremely valuable for the study of human diseases, especially those with underlying genetic components. The exploitation of various animal models, from fruitflies to mice, has led to major advances in our understanding of the etiologies of many diseases, including cancer. Cutaneous malignant melanoma is a form of cancer for which both environmental insult (i.e., UV) and hereditary predisposition are major causative factors. Fish melanoma models have been used in studies of both spontaneous and induced melanoma formation. Genetic hybrids between platyfish and swordtails, different species of the genus Xiphophorus, have been studied since the 1920s to identify genetic determinants of pigmentation and melanoma formation. Recently, transgenesis has been used to develop zebrafish and medaka models for melanoma research. This review will provide a historical perspective on the use of fish models in melanoma research, and an updated summary of current and prospective studies using these unique experimental systems. PMID:20230482

  4. Melanoma Disparities among US Hispanics: Use of the Social Ecological Model to Contextualize Reasons for Inequitable Outcomes and Frame a Research Agenda.

    PubMed

    Harvey, Valerie M; Oldfield, Charlene W; Chen, Jarvis T; Eschbach, Karl

    2016-01-01

    Cutaneous melanoma is a significant public health concern, accounting for thousands of deaths annually in the US. Early detection and diagnosis are critical given the poor prognosis and limited treatment options of advanced-stage disease. While non-Hispanic whites have higher incidence rates of melanoma, Hispanics are typically diagnosed at later disease stages and suffer higher morbidity and mortality. Currently, there is a paucity of literature investigating the root causes underlying these trends among Hispanics. Given that Hispanics are the most rapidly expanding demographic segment in the US, it is essential for cancer control efforts to elucidate the major determinants of their poor melanoma outcomes. Herein, we use the social ecological model as a framework to explore the multitude of influences on melanoma disparities among Hispanics and provide recommendations for planning future studies and interventions. PMID:27651954

  5. Melanoma Disparities among US Hispanics: Use of the Social Ecological Model to Contextualize Reasons for Inequitable Outcomes and Frame a Research Agenda

    PubMed Central

    Oldfield, Charlene W.; Chen, Jarvis T.; Eschbach, Karl

    2016-01-01

    Cutaneous melanoma is a significant public health concern, accounting for thousands of deaths annually in the US. Early detection and diagnosis are critical given the poor prognosis and limited treatment options of advanced-stage disease. While non-Hispanic whites have higher incidence rates of melanoma, Hispanics are typically diagnosed at later disease stages and suffer higher morbidity and mortality. Currently, there is a paucity of literature investigating the root causes underlying these trends among Hispanics. Given that Hispanics are the most rapidly expanding demographic segment in the US, it is essential for cancer control efforts to elucidate the major determinants of their poor melanoma outcomes. Herein, we use the social ecological model as a framework to explore the multitude of influences on melanoma disparities among Hispanics and provide recommendations for planning future studies and interventions.

  6. Melanoma Disparities among US Hispanics: Use of the Social Ecological Model to Contextualize Reasons for Inequitable Outcomes and Frame a Research Agenda

    PubMed Central

    Oldfield, Charlene W.; Chen, Jarvis T.; Eschbach, Karl

    2016-01-01

    Cutaneous melanoma is a significant public health concern, accounting for thousands of deaths annually in the US. Early detection and diagnosis are critical given the poor prognosis and limited treatment options of advanced-stage disease. While non-Hispanic whites have higher incidence rates of melanoma, Hispanics are typically diagnosed at later disease stages and suffer higher morbidity and mortality. Currently, there is a paucity of literature investigating the root causes underlying these trends among Hispanics. Given that Hispanics are the most rapidly expanding demographic segment in the US, it is essential for cancer control efforts to elucidate the major determinants of their poor melanoma outcomes. Herein, we use the social ecological model as a framework to explore the multitude of influences on melanoma disparities among Hispanics and provide recommendations for planning future studies and interventions. PMID:27651954

  7. BRAF Mutation Is Rare in Advanced-Stage Low-Grade Ovarian Serous Carcinomas

    PubMed Central

    Wong, Kwong-Kwok; Tsang, Yvonne T.M.; Deavers, Michael T.; Mok, Samuel C.; Zu, Zhifei; Sun, Charlotte; Malpica, Anais; Wolf, Judith K.; Lu, Karen H.; Gershenson, David M.

    2010-01-01

    Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. PMID:20802181

  8. Malignant melanoma at a scientific laboratory

    SciTech Connect

    Shy, C.M.; Checkoway, H.; Marshall, E.G.

    1985-11-15

    The general consensus of the seven reviewers is that occupational exposures at Lawrence Livermore National Laboratory have not been established as a causal factor for the observed excess of malignant melanoma. Several observations support the impression that some or all of the observed melanoma excess may be attributable to intense surveillance and enhanced detection of early stage melanoma lesions. Since the incidence of melanomas among Laboratory employees has not diminished, an early harvesting effect is unlikely. This suggests the distinct possibility that localized, in situ melanomas that would normally not be detected are being reported, and that in the absence of this enhanced detection, many of these early stage lesions would show little or no clinical progression. This phenomenon would explain the continued high incidence of melanomas in the absence of a physical or chemical inciting cause. A key point in this reasoning is the issue of the rate of growth of early stage melanomas, and this point remains a key question for study. Even if the observed excess cannot be explained by detection bias, the reviewers agree that the Austin and Reynolds' study does not make a convincing case for occupational factors being a cause of the high melanoma incidence. 6 refs.

  9. Malignant Melanoma of the Foot

    MedlinePlus

    ... Javascript in your browser. Malignant Melanoma of the Foot What is Malignant Melanoma? Melanoma is a cancer ... age groups, even the young. Melanoma in the Foot Melanoma that occurs in the foot or ankle ...

  10. Implications of age and conditional survival estimates for patients with melanoma.

    PubMed

    Banerjee, Mousumi; Lao, Christopher D; Wancata, Lauren M; Muenz, Daniel G; Haymart, Megan R; Wong, Sandra L

    2016-02-01

    Overall cancer incidence is decreasing, whereas melanoma cases are increasing. Conditional survival estimates offer a more accurate prognosis for patients the farther they are from time of diagnosis. The effect of age and stage on a melanoma patient's conditional survival estimate is unknown. Surveillance, Epidemiology, and End Results data were utilized to identify newly diagnosed cutaneous melanoma patients (N=95 041), from 1998 to 2005, with up to 12 years of follow-up. Estimates of disease-specific survival by stage and age were determined by Cox regression analysis and transformed to estimated conditional 5-year survival. Localized melanoma patients have an excellent 5-year survival at diagnosis and over subsequent years. For patients with localized and regional disease, an age effect is present for disease-specific mortality when comparing older patients (70-79 years) with younger patients (<30 years): hazard ratio (HR) for mortality 3.79 [95% confidence interval (CI) 3.01-4.84] and HR 2.36 (95% CI 1.93-2.91), respectively. No age effect difference is observed in disease-specific survival for advanced disease: HR 1.14 (95% CI 0.87-1.53). Over time, conditional survival estimates improve for older patients with localized and regional disease. This improvement is not seen in distant disease, neither is the age gradient. Disease-specific mortality and conditional survival for patients with localized and regional melanomas are initially impacted by older age, with effects dissipating over time. Age does not affect survival in patients with advanced disease. Understanding the conditional 5-year disease-specific survival of melanoma based on age and stage can help patients and physicians, informing decision-making about treatment and surveillance. PMID:26479218

  11. Implications of age and conditional survival estimates for patients with melanoma

    PubMed Central

    Banerjee, Mousumi; Lao, Christopher D.; Wancata, Lauren M.; Muenz, Daniel G.; Haymart, Megan R.; Wong, Sandra L.

    2016-01-01

    Objective Overall cancer incidence is decreasing while melanoma cases increase. Conditional survival estimates offer a more accurate prognosis for patients as they survive past diagnosis. It is unknown the effect age and stage has on a melanoma patient’s conditional survival estimate. Methods Surveillance, Epidemiology, End Results (SEER) data was utilized, identifying new diagnosis cutaneous melanoma patients (N=95,041), from 1998–2005, with up to 12 year follow up. Estimates of disease-specific survival by stage and age were determined by Cox regression and transformed to estimate conditional five-year survival. Results Localized melanoma patients have an excellent five-year survival at diagnosis and subsequent years. For patients with localized and regional disease, an age effect is present for disease-specific mortality when comparing older patients (70–79 years) to younger patients (<30 years): hazard ratio (HR) for mortality 3.79 (95% confidence interval (CI) 3.01–4.84) and HR 2.36 (95% CI 1.93–2.91), respectively. No age effect difference is observed in disease-specific survival for advanced disease: HR 1.14 (95% CI 0.87–1.53). Over time conditional survival estimates improve for older patients with localized and regional disease. This improvement is not seen in distant disease nor is the age gradient. Conclusions Disease-specific mortality and conditional survival for patients with localized and regional melanoma is initially impacted by older age with effects dissipating over time. Age does not affect survival in patients with advanced disease. Understanding the conditional five-year disease-specific survival of melanoma based on age and stage can help patients and physicians, informing decision making about treatment and surveillance. PMID:26479218

  12. 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

  13. Treatment Options by Stage (Melanoma)

    MedlinePlus

    ... and treatments will also be taken. Lymph node mapping and sentinel lymph node biopsy : Procedures in which ... has spread to the lymph nodes . Lymph node mapping and sentinel lymph node biopsy are done to ...

  14. Stages of Intraocular (Uveal) Melanoma

    MedlinePlus

    ... eye : A procedure in which high-energy sound waves (ultrasound) are bounced off the internal tissues of ... a small probe that sends and receives sound waves is placed gently on the surface of the ...

  15. Treatment of malignant melanoma by selective thermal neutron capture therapy using melanoma-seeking compound.

    PubMed

    Mishima, Y; Ichihashi, M; Tsuji, M; Hatta, S; Ueda, M; Honda, C; Suzuki, T

    1989-05-01

    As pigment cells undergo melanoma genesis, accentuated melanogenesis concurrently occurs in principle. Subsequent to the understanding of intrinsic factors controlling both processes, we found our selective melanoma neutron capture therapy (NCT) using 10B-dopa (melanin substrate) analogue, 10B1-p-boronophenylalanine (10B1-BPA), followed by 10B(n, alpha)7Li reaction, induced by essentially harmless thermal neutrons, which releases energy of 2.33 MeV to 14 mu, the diameter of melanoma cells. In vitro/in vivo radiobiological analysis revealed the highly enhanced melanoma killing effect of 10B1-BPA. Chemical and prompt gamma ray spectrometry assays of 10B accumulated within melanoma cells after 10B1-BPA administration in vitro and in vivo show high affinity, e.g., 10B melanoma/blood ratio of 11.5. After successfully eradicating melanoma transplanted into hamsters with NCT, we advanced to preclinical studies using spontaneously occurring melanoma in Duroc pig skin. We cured three melanoma cases, 4.6 to 12 cm in diameter, by single neutron capture treatment. Complete disappearance of melanoma was obtained without substantial side effects. Acute and subacute toxicity as well as pharmacodynamics of 10B1-BPA have been studied in relation to therapeutic dosage requirements. Clinical radiation dosimetry using human phantom has been carried out. Further preclinical studies using human melanoma transplanted into nude mouse have been a useful model for obtaining optimal results for each melanoma type. We recently treated the first human melanoma patient with our NCT, using essentially the method for Duroc pig melanoma, and obtained similar regression time course leading to cure.

  16. Treatment of malignant melanoma by selective thermal neutron capture therapy using melanoma-seeking compound

    SciTech Connect

    Mishima, Y.; Ichihashi, M.; Tsuji, M.; Hatta, S.; Ueda, M.; Honda, C.; Suzuki, T.

    1989-05-01

    As pigment cells undergo melanoma genesis, accentuated melanogenesis concurrently occurs in principle. Subsequent to the understanding of intrinsic factors controlling both processes, we found our selective melanoma neutron capture therapy (NCT) using 10B-dopa (melanin substrate) analogue, 10B1-p-boronophenylalanine (10B1-BPA), followed by 10B(n, alpha)7Li reaction, induced by essentially harmless thermal neutrons, which releases energy of 2.33 MeV to 14 mu, the diameter of melanoma cells. In vitro/in vivo radiobiological analysis revealed the highly enhanced melanoma killing effect of 10B1-BPA. Chemical and prompt gamma ray spectrometry assays of 10B accumulated within melanoma cells after 10B1-BPA administration in vitro and in vivo show high affinity, e.g., 10B melanoma/blood ratio of 11.5. After successfully eradicating melanoma transplanted into hamsters with NCT, we advanced to preclinical studies using spontaneously occurring melanoma in Duroc pig skin. We cured three melanoma cases, 4.6 to 12 cm in diameter, by single neutron capture treatment. Complete disappearance of melanoma was obtained without substantial side effects. Acute and subacute toxicity as well as pharmacodynamics of 10B1-BPA have been studied in relation to therapeutic dosage requirements. Clinical radiation dosimetry using human phantom has been carried out. Further preclinical studies using human melanoma transplanted into nude mouse have been a useful model for obtaining optimal results for each melanoma type. We recently treated the first human melanoma patient with our NCT, using essentially the method for Duroc pig melanoma, and obtained similar regression time course leading to cure.

  17. Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment

    SciTech Connect

    Sustarsic, Elahu G.; Junnila, Riia K.; Kopchick, John J.

    2013-11-08

    Highlights: •Most cancer types of the NCI60 have sub-sets of cell lines with high GHR expression. •GHR is highly expressed in melanoma cell lines. •GHR is elevated in advanced stage IV metastatic tumors vs. stage III. •GH treatment of metastatic melanoma cell lines alters growth and cell signaling. -- Abstract: Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute’s NCI60 panel includes 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation. Based on

  18. Pembrolizumab superior to ipilimumab in melanoma.

    PubMed

    2015-06-01

    In the first randomized trial to compare FDA-approved immune checkpoint inhibitors as first-line therapy for patients with advanced melanoma, pembrolizumab yielded significantly better treatment outcomes than ipilimumab.

  19. Systematic genomic identification of colorectal cancer genes delineating advanced from early clinical stage and metastasis

    PubMed Central

    2013-01-01

    Background Colorectal cancer is the third leading cause of cancer deaths in the United States. The initial assessment of colorectal cancer involves clinical staging that takes into account the extent of primary tumor invasion, determining the number of lymph nodes with metastatic cancer and the identification of metastatic sites in other organs. Advanced clinical stage indicates metastatic cancer, either in regional lymph nodes or in distant organs. While the genomic and genetic basis of colorectal cancer has been elucidated to some degree, less is known about the identity of specific cancer genes that are associated with advanced clinical stage and metastasis. Methods We compiled multiple genomic data types (mutations, copy number alterations, gene expression and methylation status) as well as clinical meta-data from The Cancer Genome Atlas (TCGA). We used an elastic-net regularized regression method on the combined genomic data to identify genetic aberrations and their associated cancer genes that are indicators of clinical stage. We ranked candidate genes by their regression coefficient and level of support from multiple assay modalities. Results A fit of the elastic-net regularized regression to 197 samples and integrated analysis of four genomic platforms identified the set of top gene predictors of advanced clinical stage, including: WRN, SYK, DDX5 and ADRA2C. These genetic features were identified robustly in bootstrap resampling analysis. Conclusions We conducted an analysis integrating multiple genomic features including mutations, copy number alterations, gene expression and methylation. This integrated approach in which one considers all of these genomic features performs better than any individual genomic assay. We identified multiple genes that robustly delineate advanced clinical stage, suggesting their possible role in colorectal cancer metastatic progression. PMID:24308539

  20. Dietary flavonoid intake, black tea consumption, and risk of overall and advanced stage prostate cancer.

    PubMed

    Geybels, Milan S; Verhage, Bas A J; Arts, Ilja C W; van Schooten, Frederik J; Goldbohm, R Alexandra; van den Brandt, Piet A

    2013-06-15

    Flavonoids are natural antioxidants found in various foods, and a major source is black tea. Some experimental evidence indicates that flavonoids could prevent prostate cancer. We investigated the associations between flavonoid intake, black tea consumption, and prostate cancer risk in the Netherlands Cohort study, which includes 58,279 men who provided detailed baseline information on several cancer risk factors. From 1986 to 2003, 3,362 prostate cancers were identified, including 1,164 advanced (stage III/IV) cancers. Cox proportional hazards regression using the case-cohort approach was used to estimate hazard ratios and 95% confidence intervals. Intake of total catechin, epicatechin, kaempferol, and myricetin and consumption of black tea were associated with a decreased risk of stage III/IV or stage IV prostate cancer. Hazard ratios of stage III/IV and stage IV prostate cancer for the highest versus the lowest category of black tea consumption (≥5 versus ≤1 cups/day) were 0.75 (95% confidence interval: 0.59, 0.97) and 0.67 (95% confidence interval: 0.50, 0.91), respectively. No associations were observed for overall and nonadvanced prostate cancer. In conclusion, dietary flavonoid intake and black tea consumption were associated with a decreased risk of advanced stage prostate cancer.

  1. Leser-Trelat sign in metastasized malignant melanoma.

    PubMed

    Siedek, Vanessa; Schuh, Theda; Wollenberg, Andreas

    2009-02-01

    The Leser-Trelat sign is defined as the association of multiple, eruptive seborrheic keratoses with an internal malignancy of a usually advanced stage. We report the case of malignant melanoma in an 82-year-old man covered with hundreds of greyish-dark seborrheic keratoses resembling a Christmas tree pattern, who was diagnosed with metastasized malignant melanoma involving the parotid gland and lymph nodes. Though the pathogenesis of Leser-Trelat sign is still unknown, spontaneous regression of the seborrheic keratoses following tumor reduction described in some cases argues for a paraneoplastic origin of this highly instructive clinical entity. Physicians should consider a workup for internal malignancy in patients presenting with multiple eruptive seborrheic keratoses.

  2. Trp2 peptide vaccine adjuvanted with (R)-DOTAP inhibits tumor growth in an advanced melanoma model

    PubMed Central

    Vasievich, Elizabeth A.; Ramishetti, Srinivas; Zhang, Yuan; Huang, Leaf

    2012-01-01

    Previously we have shown cationic lipid (R)-DOTAP as the immunologically active enantiomer of the DOTAP racemic mixture, initiating complete tumor regression in an exogenous antigen model (murine cervical cancer model). Here, we investigate the use of (R)-DOTAP as an efficacious adjuvant delivering an endogenous antigen in an aggressive murine solid tumor melanoma model. (R)-DOTAP/Trp2 peptide complexes showed decreasing size and charge with increasing peptide concentration, taking a rod-shape at highest concentrations. The particles were stable for at 2 weeks at 4°C. A dose of 75nmol Trp2 (formulated in (R)-DOTAP) was able to show statistically significant tumor growth delay compared to lower doses of 5 and 25nmol which were no different than untreated tumors. (R)-DOTAP/Trp2 (75nmol) treated mice also showed increased T cell IFN-γ secretion after restimulation with Trp2, as well as CTL activity in vivo. This vaccination group also showed the highest population of functionally active tumor-infiltrating lymphocytes, indicated by IFN-γ secretion after restimulation with Trp2. Thus, (R)-DOTAP has shown the ability to break tolerance as an adjuvant. Its activity to enhance immunogenicity of other tumor associated antigens should be studied further. PMID:22142394

  3. Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment.

    PubMed

    Sustarsic, Elahu G; Junnila, Riia K; Kopchick, John J

    2013-11-01

    Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute's NCI60 panel includes 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation. Based on this data, GH could be a new therapeutic target in melanoma. PMID:24134847

  4. Advanced (stage D) heart failure: a statement from the Heart Failure Society of America Guidelines Committee.

    PubMed

    Fang, James C; Ewald, Gregory A; Allen, Larry A; Butler, Javed; Westlake Canary, Cheryl A; Colvin-Adams, Monica; Dickinson, Michael G; Levy, Phillip; Stough, Wendy Gattis; Sweitzer, Nancy K; Teerlink, John R; Whellan, David J; Albert, Nancy M; Krishnamani, Rajan; Rich, Michael W; Walsh, Mary N; Bonnell, Mark R; Carson, Peter E; Chan, Michael C; Dries, Daniel L; Hernandez, Adrian F; Hershberger, Ray E; Katz, Stuart D; Moore, Stephanie; Rodgers, Jo E; Rogers, Joseph G; Vest, Amanda R; Givertz, Michael M

    2015-06-01

    We propose that stage D advanced heart failure be defined as the presence of progressive and/or persistent severe signs and symptoms of heart failure despite optimized medical, surgical, and device therapy. Importantly, the progressive decline should be primarily driven by the heart failure syndrome. Formally defining advanced heart failure and specifying when medical and device therapies have failed is challenging, but signs and symptoms, hemodynamics, exercise testing, biomarkers, and risk prediction models are useful in this process. Identification of patients in stage D is a clinically important task because treatments are inherently limited, morbidity is typically progressive, and survival is often short. Age, frailty, and psychosocial issues affect both outcomes and selection of therapy for stage D patients. Heart transplant and mechanical circulatory support devices are potential treatment options in select patients. In addition to considering indications, contraindications, clinical status, and comorbidities, treatment selection for stage D patients involves incorporating the patient's wishes for survival versus quality of life, and palliative and hospice care should be integrated into care plans. More research is needed to determine optimal strategies for patient selection and medical decision making, with the ultimate goal of improving clinical and patient centered outcomes in patients with stage D heart failure.

  5. Reusable launch vehicles, enabling technology for the development of advanced upper stages and payloads

    NASA Astrophysics Data System (ADS)

    Metzger, John D.

    1998-01-01

    In the near future there will be classes of upper stages and payloads that will require initial operation at a high-earth orbit to reduce the probability of an inadvertent reentry that could result in a detrimental impact on humans and the biosphere. A nuclear propulsion system, such as was being developed under the Space Nuclear Thermal Propulsion (SNTP) Program, is an example of such a potential payload. This paper uses the results of a reusable launch vehicle (RLV) study to demonstrate the potential importance of a Reusable Launch Vehicle (RLV) to test and implement an advanced upper stage (AUS) or payload in a safe orbit and in a cost effective and reliable manner. The RLV is a horizontal takeoff and horizontal landing (HTHL), two-stage-to-orbit (TSTO) vehicle. The results of the study shows that an HTHL is cost effective because it implements airplane-like operation, infrastructure, and flight operations. The first stage of the TSTO is powered by Rocket-Based-Combined-Cycle (RBCC) engines, the second stage is powered by a LOX/LH rocket engine. The TSTO is used since it most effectively utilizes the capability of the RBCC engine. The analysis uses the NASA code POST (Program to Optimize Simulated Trajectories) to determine trajectories and weight in high-earth orbit for AUS/advanced payloads. Cost and reliability of an RLV versus current generation expandable launch vehicles are presented.

  6. Reusable launch vehicles, enabling technology for the development of advanced upper stages and payloads

    SciTech Connect

    Metzger, John D.

    1998-01-15

    In the near future there will be classes of upper stages and payloads that will require initial operation at a high-earth orbit to reduce the probability of an inadvertent reentry that could result in a detrimental impact on humans and the biosphere. A nuclear propulsion system, such as was being developed under the Space Nuclear Thermal Propulsion (SNTP) Program, is an example of such a potential payload. This paper uses the results of a reusable launch vehicle (RLV) study to demonstrate the potential importance of a Reusable Launch Vehicle (RLV) to test and implement an advanced upper stage (AUS) or payload in a safe orbit and in a cost effective and reliable manner. The RLV is a horizontal takeoff and horizontal landing (HTHL), two-stage-to-orbit (TSTO) vehicle. The results of the study shows that an HTHL is cost effective because it implements airplane-like operation, infrastructure, and flight operations. The first stage of the TSTO is powered by Rocket-Based-Combined-Cycle (RBCC) engines, the second stage is powered by a LOX/LH rocket engine. The TSTO is used since it most effectively utilizes the capability of the RBCC engine. The analysis uses the NASA code POST (Program to Optimize Simulated Trajectories) to determine trajectories and weight in high-earth orbit for AUS/advanced payloads. Cost and reliability of an RLV versus current generation expandable launch vehicles are presented.

  7. Staged Radiosurgical Ablation for Choroid Melanoma: A Case Report with Emphasis on the Role of Patient Preparation, Treatment Planning, and Precision of Delivery.

    PubMed

    Adamczyk, Marta; Janiga, Piotr

    2016-01-01

    The aim of reporting this case of choroid melanoma of the left eye is to introduce the in-house-designed treatment planning protocol for fractionated radiosurgical ablation of an intraocular lesion. This is a clinical case with emphasis on treatment preparation and delivery using the Accuray CyberKnife Robotic Radiosurgery System (Accuray, Sunnyvale, CA, USA) for a patient immobilized with a head mask and our in-house-made eye fixation system.

  8. Genetic Testing in the Multidisciplinary Management of Melanoma.

    PubMed

    Rashid, Omar M; Zager, Jonathan S

    2015-10-01

    Melanoma is increasing in incidence and represents an aggressive type of cancer. Efforts have focused on identifying genetic factors in melanoma carcinogenesis to guide prevention, screening, early detection, and targeted therapy. This article reviews the hereditary risk factors associated with melanoma and the known molecular pathways and genetic mutations associated with this disease. This article also explores the controversies associated with genetic testing and the latest advances in identifying genetic targets in melanoma, which offer promise for future application in the multidisciplinary management of melanoma.

  9. The Influence of Social Norms on Advancement Through Bystander Stages for Preventing Interpersonal Violence.

    PubMed

    Deitch-Stackhouse, Jacqueline; Kenneavy, Kristin; Thayer, Richard; Berkowitz, Alan; Mascari, Janine

    2015-10-01

    This research evaluates the impact of social norms on the advancement through the bystander stages toward prosocial (active) intervention in interpersonal violence (IPV): emotional abuse, physical violence, controlling behavior, sexual violence, and stalking. The influence of social norms on bystander behavior across stages and types of violence varies. Accurate social norms perceptions are associated with routine intervention, although social norms misperceptions are not always a strong deterrent to intervention. Interpretation of a violent situation as problematic predicts increased willingness to intervene. Implications for the development of social norms antiviolence campaigns and strategies for reducing barriers to prosocial intervention are discussed. PMID:26175519

  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. Adjuvant therapy of melanoma.

    PubMed

    Agarwala, S S; Kirkwood, J M

    1998-06-01

    Patients with AJCC Stage IIB and III melanoma have a poor 5-year survival rate which has been the driving force behind attempts to find an effective adjuvant therapy for this stage of disease that would effectively reduce relapse and improve survival. Immunotherapy with bacillus Calmette-Guerin (BCG), Corynebacterium parvum, and levamisole have not been successful in achieving this goal, nor have trials with chemotherapy in the adjuvant setting, including high-dose chemotherapy with autologous bone marrow transplantation. The recent Eastern Cooperative Oncology Group (ECOG) 1684 study showed significant improvement in relapse-free and overall survival with high doses of alpha interferon (IFNalpha) given for 1 year. Lower dosages of IFNalpha have to date been unsuccessful in impacting upon long-term survival. Recent data with vaccines have been encouraging, and the GM2-KLH vaccine is the focus of ongoing intergroup study comparing this treatment with IFNalpha in resected Stage IIB and III melanoma. The various regimens are reviewed in this article. PMID:9588723

  12. Arginine deprivation therapy for malignant melanoma

    PubMed Central

    Yoon, Jung-Ki; Frankel, Arthur E; Feun, Lynn G; Ekmekcioglu, Suhendan; Kim, Kevin B

    2013-01-01

    Despite recent development of promising immunotherapeutic and targeted drugs, prognosis in patients with advanced melanoma remains poor, and a cure for this disease remains elusive in most patients. The success of melanoma therapy depends on a better understanding of the biology of melanoma and development of drugs that effectively target the relevant genes or proteins essential for tumor cell survival. Melanoma cells frequently lack argininosuccinate synthetase, an essential enzyme for arginine synthesis, and as a result they become dependent on the availability of exogenous arginine. Accordingly, a therapeutic approach involving depletion of available arginine has been shown to be effective in preclinical studies. Early clinical studies have demonstrated sufficient antitumor activity to give rise to cautious optimism. In this article, the rationale for arginine deprivation therapy is discussed. Additionally, various strategies for depleting arginine are discussed and the preclinical and clinical investigations of arginine deprivation therapy in melanoma are reviewed. PMID:23293541

  13. Prospects in cancer immunotherapy: treating advanced stage disease or preventing tumor recurrence?

    PubMed

    Manjili, Masoud H; Payne, Kyle K

    2015-06-01

    Human vaccines against infectious agents are often effective in a prophylactic setting. However, they are usually not effective when used post-exposure. Rabies vaccine is one of the exceptions, which can be used post-exposure, but is effective only when used in combination with other treatments. Similar results have been obtained with cancer vaccines and immunotherapies. Cancer immunotherapies generally prolong patients' survival when they are used during advanced stage disease. The potential of immunotherapy to cure cancer could be revealed when it is applied in a prophylactic setting. This article provides a brief overview of cancer immunotherapeutics and suggests that immunotherapy can cure cancer if used at the right time against the right target; we suggest that targeting cancer during dormancy in order to prevent tumor recurrence as advanced stage disease is potentially curative.

  14. Hyperspectral imaging for melanoma screening

    NASA Astrophysics Data System (ADS)

    Martin, Justin; Krueger, James; Gareau, Daniel

    2014-03-01

    The 5-year survival rate for patients diagnosed with Melanoma, a deadly form of skin cancer, in its latest stages is about 15%, compared to over 90% for early detection and treatment. We present an imaging system and algorithm that can be used to automatically generate a melanoma risk score to aid clinicians in the early identification of this form of skin cancer. Our system images the patient's skin at a series of different wavelengths and then analyzes several key dermoscopic features to generate this risk score. We have found that shorter wavelengths of light are sensitive to information in the superficial areas of the skin while longer wavelengths can be used to gather information at greater depths. This accompanying diagnostic computer algorithm has demonstrated much higher sensitivity and specificity than the currently commercialized system in preliminary trials and has the potential to improve the early detection of melanoma.

  15. 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.

  16. 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

  17. Cutaneous Melanoma in Asians

    PubMed Central

    Kim, Sang Yub

    2016-01-01

    Malignant melanoma is a rare disease in Asians but potentially the most aggressive form of skin cancer worldwide. It can occur in any melanocyte-containing anatomic site. Four main cutaneous melanoma subtypes are recognized: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma (ALM), and nodular melanoma. Generally, excessive exposure to ultraviolet (UV) radiation increases the risk of melanoma. The exception is ALM, which is the most common melanoma subtype in Asians and is not associated with UV radiation. ALM presents as dark brownish to black, irregular maculopatches, nodules, or ulcers on the palms, soles, and nails. The lesions may be misdiagnosed as more benign lesions, such as warts, ulcers, hematomas, foreign bodies, or fungal infections, especially in amelanotic acral melanomas where black pigments are absent. The aim of this brief review is to improve understanding and the rate of early detection thereby reducing mortality, especially regarding cutaneous melanoma in Asians. PMID:27689028

  18. Nutrition and melanoma prevention.

    PubMed

    Jensen, J Daniel; Wing, Gregory J; Dellavalle, Robert P

    2010-01-01

    Melanoma has continued to rise in incidence despite public efforts to promote sun protection behaviors. Because sunscreen use does not completely prevent skin cancer induced by ultraviolet radiation, additional chemopreventive methods for protecting against and reversing the effects of ultraviolet photodamage need evaluation. Recent years have brought increased interest in dietary factors, such as natural botanicals and vitamins, for the prevention of melanoma. This contribution provides a narrative review of the relevant, nutrition-related literature found by searching the keywords "melanoma chemoprevention," "nutrition and melanoma," "dietary botanicals and melanoma prevention," "green tea and melanoma," "vitamin D and melanoma," and "vitamin E and melanoma" in the PubMed database. Although randomized controlled trials of humans are lacking, basic science and epidemiologic studies show promising benefits of many natural products in chemoprevention for melanoma. Future studies, hopefully, will yield concrete answers and clarify the role of commonly available dietary nutrients in melanoma chemoprevention.

  19. Cutaneous Melanoma in Asians.

    PubMed

    Kim, Sang Yub; Yun, Sook Jung

    2016-09-01

    Malignant melanoma is a rare disease in Asians but potentially the most aggressive form of skin cancer worldwide. It can occur in any melanocyte-containing anatomic site. Four main cutaneous melanoma subtypes are recognized: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma (ALM), and nodular melanoma. Generally, excessive exposure to ultraviolet (UV) radiation increases the risk of melanoma. The exception is ALM, which is the most common melanoma subtype in Asians and is not associated with UV radiation. ALM presents as dark brownish to black, irregular maculopatches, nodules, or ulcers on the palms, soles, and nails. The lesions may be misdiagnosed as more benign lesions, such as warts, ulcers, hematomas, foreign bodies, or fungal infections, especially in amelanotic acral melanomas where black pigments are absent. The aim of this brief review is to improve understanding and the rate of early detection thereby reducing mortality, especially regarding cutaneous melanoma in Asians. PMID:27689028

  20. Cutaneous Melanoma in Asians

    PubMed Central

    Kim, Sang Yub

    2016-01-01

    Malignant melanoma is a rare disease in Asians but potentially the most aggressive form of skin cancer worldwide. It can occur in any melanocyte-containing anatomic site. Four main cutaneous melanoma subtypes are recognized: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma (ALM), and nodular melanoma. Generally, excessive exposure to ultraviolet (UV) radiation increases the risk of melanoma. The exception is ALM, which is the most common melanoma subtype in Asians and is not associated with UV radiation. ALM presents as dark brownish to black, irregular maculopatches, nodules, or ulcers on the palms, soles, and nails. The lesions may be misdiagnosed as more benign lesions, such as warts, ulcers, hematomas, foreign bodies, or fungal infections, especially in amelanotic acral melanomas where black pigments are absent. The aim of this brief review is to improve understanding and the rate of early detection thereby reducing mortality, especially regarding cutaneous melanoma in Asians.

  1. The experience of living with advanced-stage cancer: a thematic synthesis of the literature.

    PubMed

    García-Rueda, N; Carvajal Valcárcel, A; Saracíbar-Razquin, M; Arantzamendi Solabarrieta, M

    2016-07-01

    The aim of the study was to understand the experience of people living with advanced-stage cancer through literature. The search included The Cochrane Library, PubMed, PsycInfo, CINAHL and Cuiden. Thirteen studies were included. A qualitative meta-synthesis was conducted. One thread emerged from the thematic synthesis: the desire to live as normally as possible, despite being aware of the proximity of death. Three themes also emerged: "a process that is unique" with its four sub-themes; "support network" and "health context," each of them having two sub-themes. This study concludes that living with advanced-stage cancer is a unique and complex process which has both positive and negative aspects. The review provides a comprehensive view of the experience, which considers the importance of the support network and the health context in which the person lives. In this study, "normalcy" is the adjustment to the new reality and living as closely as possible to the way one lived before the disease, while developing a new relationship with being finite and death. A better understanding of the experience of living with advanced-stage cancer will help health professionals to identify the needs of the patients in order to plan individual, high-quality care. PMID:27297131

  2. Physical activity in patients with advanced-stage cancer: a systematic review of the literature.

    PubMed

    Albrecht, Tara A; Taylor, Ann Gill

    2012-06-01

    The importance of physical activity for chronic disease prevention and management has become generally well accepted. The number of research interventions and publications examining the benefits of physical activity for patients with cancer has been rising steadily. However, much of that research has focused on the impact of physical activity either prior to or early in the cancer diagnosis, treatment, and survivorship process. Research focusing on the effects of physical activity, specifically for patients with advanced-stage cancer and poorer prognostic outcomes, has been addressed only recently. The purpose of this article is to examine the state of the science for physical activity in the advanced-stage disease subset of the cancer population. Exercise in a variety of intensities and forms, including yoga, walking, biking, and swimming, has many health benefits for people, including those diagnosed with cancer. Research has shown that, for people with cancer (including advanced-stage cancer), exercise can decrease anxiety, stress, and depression while improving levels of pain, fatigue, shortness of breath, constipation, and insomnia. People diagnosed with cancer should discuss with their oncologist safe, easy ways they can incorporate exercise into their daily lives. PMID:22641322

  3. Other targeted drugs in melanoma

    PubMed Central

    Rodón, Jordi; Karachaliou, Niki; Sánchez, Jesús; Santarpia, Mariacarmela; Viteri, Santiago; Pilotto, Sara; Teixidó, Cristina; Riso, Aldo; Rosell, Rafael

    2015-01-01

    Targeted therapy drugs are developed against specific molecular alterations on cancer cells. Because they are “targeted” to the tumor, these therapies are more effective and better tolerated than conventional therapies such as chemotherapy. In the last decade, great advances have been made in understanding of melanoma biology and identification of molecular mechanisms involved in malignant transformation of cells. The identification of oncogenic mutated kinases involved in this process provides an opportunity for development of new target therapies. The dependence of melanoma on BRAF-mutant kinase has provided an opportunity for development of mutation-specific inhibitors with high activity and excellent tolerance that are now being used in clinical practice. This marked a new era in the treatment of metastatic melanoma and much research is now ongoing to identify other “druggable” kinases and transduction signaling networking. It is expected that in the near future the spectrum of target drugs for melanoma treatment will increase. Herein, we review the most relevant potential novel drugs for melanoma treatment based on preclinical data and the results of early clinical trials. PMID:26605312

  4. Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

    PubMed

    Mangana, Joanna; Cheng, Phil F; Schindler, Katja; Weide, Benjamin; Held, Ulrike; Frauchiger, Anna L; Romano, Emanuella; Kähler, Katharina C; Rozati, Sima; Rechsteiner, Markus; Moch, Holger; Michielin, Olivier; Garbe, Claus; Hauschild, Axel; Hoeller, Christoph; Dummer, Reinhard; Goldinger, Simone M

    2015-01-01

    Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.

  5. [Laboratory markers of melanoma progression].

    PubMed

    Bánfalvi, Teodóra; Edesné, Mariann B; Gergye, Mária; Udvarhelyi, Nóra; Orosz, Zsolt; Gilde, Katalin; Kremmer, Tibor; Ottó, Szabolcs; Tímár, József

    2003-01-01

    Extracellular tumour markers may have potential role in the follow-up of patients with malignant melanoma, in therapy monitoring and in prediction of prognosis. In our article circulating tumour markers in melanoma (melanoma inhibitory activity, lipid bound sialic acid, neuron specific enolase, TA90 immune complex, S-100B protein, 5-S-cysteinyldopa, tyrosinase, cytokines, metalloproteinases, LDH) were reviewed. Among laboratory melanoma markers the S-100B protein is the most investigated. S-100B protein has high specificity, appropriate sensitivity and proved to be significant prognostic factor independent from stages. High serum values are associated with shorter survival. However, before S-100B monitoring immunohistochemistry for the detection of S-100B is required. In the case of malignant melanomas with low expression serum S-100B monitoring may not be sensitive enough to follow disease progression. Although the serum concentration of 5-S-cysteinyldopa did not prove to be independent prognostic factor in our previous studies comprising the highest patient number in the literature, the marker was suggested for therapy monitoring. The survival analysis indicated that the elevated 5-S-cysteinyldopa level predicts shorter survival. In spite of the calculated low correlation between the two markers, parallel elevation of S-100B protein and 5-S-cysteinyldopa indicated shorter survival. On the basis of the literature LDH is the most appropriate tumour marker in stage IV to predict prognosis, but its sensitivity and specificity could not achieve that of S-100B protein. S-100B and LDH proved to be similarly reliable in respect to the clinical outcome. Determination of serum concentration of MIA and tyrosinase are also reliable markers in malignant melanoma. The other investigated markers are not well known yet or do not provide useful information to the clinicians. PMID:12704461

  6. Treatment of Children with Advanced-Stage Lymphoblastic Lymphoma with Pegaspargase

    PubMed Central

    Yu-tong, Zhang; Li-hua, FENG; Xiao-dan, Zhong; Li-zhe, Wang; Jian, Chang

    2014-01-01

    Objective: To evaluate the feasibility of Pegaspargase instead of L-asparaginase to treat children with advanced-stage lymphoblastic lymphoma (LBL) on the Berlin-Frankfurt-Munster (BFM)-95 protocol. Methods: Fifty-four newly diagnosed patients with stage III or IV LBL and without any treatment were enrolled in this study. Pegaspargase took place of L-asparaginase in BFM-95. The complications and treatment responses of patients treated on the BFM-95 protocol and modified BFM-95 protocol were then evaluated respectively. Findings : For LBL patients treated with BFM-95 protocol or modified BFM-95 protocol, the complete response, event-free survival, overall survival were similar. Stage 4 myelosuppression was the most common complication in both groups. Besides that, among 31 patients receiving modified BFM-95 protocol, coagulation defects were the most common complication. In contrast, anaphylactic reaction was the most common complication in the other 23 patients receiving BFM-95 protocol. Conclusion: Modified BFM-95 protocol is available to children with advanced-stage LBL with an equal outcome and enhances its compliance and decreases the incidence of anaphylactic reaction, compared to BFM-95 protocol. Coagulation defects are the major complication and tolerable in modified one. PMID:25793049

  7. Update in genetic susceptibility in melanoma.

    PubMed

    Potrony, Miriam; Badenas, Celia; Aguilera, Paula; Puig-Butille, Joan Anton; Carrera, Cristina; Malvehy, Josep; Puig, Susana

    2015-09-01

    Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identification of new genes involved in melanoma susceptibility: Breast cancer 1 (BRCA1) associated protein 1 (BAP1), CXC genes, telomerase reverse transcriptase (TERT), protection of telomeres 1 (POT1), ACD and TERF2IP, the latter four being involved in telomere maintenance. Furthermore variants in melanocortin 1 receptor (MC1R) and microphthalmia-associated transcription factor (MITF) give a moderately increased risk to develop melanoma. Melanoma genetic counseling is offered to families in order to better understand the disease and the genetic susceptibility of developing it. Genetic counseling often implies genetic testing, although patients can benefit from genetic counseling even when they do not fulfill the criteria for these tests. Genetic testing for melanoma predisposition mutations can be used in clinical practice under adequate selection criteria and giving a valid test interpretation and genetic counseling to the individual.

  8. Update in genetic susceptibility in melanoma.

    PubMed

    Potrony, Miriam; Badenas, Celia; Aguilera, Paula; Puig-Butille, Joan Anton; Carrera, Cristina; Malvehy, Josep; Puig, Susana

    2015-09-01

    Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identification of new genes involved in melanoma susceptibility: Breast cancer 1 (BRCA1) associated protein 1 (BAP1), CXC genes, telomerase reverse transcriptase (TERT), protection of telomeres 1 (POT1), ACD and TERF2IP, the latter four being involved in telomere maintenance. Furthermore variants in melanocortin 1 receptor (MC1R) and microphthalmia-associated transcription factor (MITF) give a moderately increased risk to develop melanoma. Melanoma genetic counseling is offered to families in order to better understand the disease and the genetic susceptibility of developing it. Genetic counseling often implies genetic testing, although patients can benefit from genetic counseling even when they do not fulfill the criteria for these tests. Genetic testing for melanoma predisposition mutations can be used in clinical practice under adequate selection criteria and giving a valid test interpretation and genetic counseling to the individual. PMID:26488006

  9. Update in genetic susceptibility in melanoma

    PubMed Central

    Potrony, Miriam; Badenas, Celia; Aguilera, Paula; Puig-Butille, Joan Anton; Carrera, Cristina; Malvehy, Josep

    2015-01-01

    Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identification of new genes involved in melanoma susceptibility: Breast cancer 1 (BRCA1) associated protein 1 (BAP1), CXC genes, telomerase reverse transcriptase (TERT), protection of telomeres 1 (POT1), ACD and TERF2IP, the latter four being involved in telomere maintenance. Furthermore variants in melanocortin 1 receptor (MC1R) and microphthalmia-associated transcription factor (MITF) give a moderately increased risk to develop melanoma. Melanoma genetic counseling is offered to families in order to better understand the disease and the genetic susceptibility of developing it. Genetic counseling often implies genetic testing, although patients can benefit from genetic counseling even when they do not fulfill the criteria for these tests. Genetic testing for melanoma predisposition mutations can be used in clinical practice under adequate selection criteria and giving a valid test interpretation and genetic counseling to the individual. PMID:26488006

  10. Karnofsky Performance Status and Lactate Dehydrogenase Predict the Benefit of Palliative Whole-Brain Irradiation in Patients With Advanced Intra- and Extracranial Metastases From Malignant Melanoma

    SciTech Connect

    Partl, Richard; Richtig, Erika; Avian, Alexander; Berghold, Andrea; Kapp, Karin S.

    2013-03-01

    Purpose: To determine prognostic factors that allow the selection of melanoma patients with advanced intra- and extracerebral metastatic disease for palliative whole-brain radiation therapy (WBRT) or best supportive care. Methods and Materials: This was a retrospective study of 87 patients who underwent palliative WBRT between 1988 and 2009 for progressive or multiple cerebral metastases at presentation. Uni- and multivariate analysis took into account the following patient- and tumor-associated factors: gender and age, Karnofsky performance status (KPS), neurologic symptoms, serum lactate dehydrogenase (LDH) level, number of intracranial metastases, previous resection or stereotactic radiosurgery of brain metastases, number of extracranial metastasis sites, and local recurrences as well as regional lymph node metastases at the time of WBRT. Results: In univariate analysis, KPS, LDH, number of intracranial metastases, and neurologic symptoms had a significant influence on overall survival. In multivariate survival analysis, KPS and LDH remained as significant prognostic factors, with hazard ratios of 3.3 (95% confidence interval [CI] 1.6-6.5) and 2.8 (95% CI 1.6-4.9), respectively. Patients with KPS ≥70 and LDH ≤240 U/L had a median survival of 191 days; patients with KPS ≥70 and LDH >240 U/L, 96 days; patients with KPS <70 and LDH ≤240 U/L, 47 days; and patients with KPS <70 and LDH >240 U/L, only 34 days. Conclusions: Karnofsky performance status and serum LDH values indicate whether patients with advanced intra- and extracranial tumor manifestations are candidates for palliative WBRT or best supportive care.

  11. The European Medicines Agency review of ipilimumab (Yervoy) for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy: summary of the scientific assessment of the Committee for Medicinal Products for Human Use.

    PubMed

    Hanaizi, Zahra; van Zwieten-Boot, Barbara; Calvo, Gonzalo; Lopez, Arantxa Sancho; van Dartel, Maaike; Camarero, Jorge; Abadie, Eric; Pignatti, Francesco

    2012-01-01

    On 13 July 2011 the European Commission issued a marketing authorisation valid throughout the European Union (EU) for ipilimumab for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy. Ipilimumab is a monoclonal antibody that specifically blocks the inhibitory signal of cytotoxic T lymphocyte antigen 4 (CTLA-4), resulting in T cell activation, proliferation and lymphocyte infiltration into tumours, leading to tumour cell death. The recommended induction regimen of ipilimumab is 3mg/kg administered intravenously over a 90 min period every 3 weeks for a total of four doses. In a phase 3 trial in patients with advanced melanoma, median overall survival for ipilimumab was 10 months versus 6 months for gp100, an experimental melanoma vaccine (Hazard ratio (HR) 0.66; 95% confidence interval (CI): 0.51, 0.87; p = 0.0026). Ipilimumab was most commonly associated with adverse reactions resulting from increased or excessive immune activity. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of ipilimumab. The most common side-effects (affecting more than 10% of patients) were diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite and abdominal pain. The objective of this paper is to summarise the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics (SmPC), are available on the European Medicines Agency (EMA) website (www.ema.europa.eu).

  12. Intraepidermal epidermotropic metastatic melanoma: a clinical and histopathological mimicker of melanoma in situ occurring in multiplicity.

    PubMed

    Lestre, Sara; João, Alexandre; Ponte, Pedro; Peixoto, Ana; Vieira, Joana; Teixeira, Manuel R; Fidalgo, Ana

    2011-06-01

    The distinction between primary melanoma and melanoma metastatic to the skin has major prognostic implications. We report a case of a 67-year-old male with a diagnosis of a superficial spreading melanoma (stage IB) rendered 6 years earlier who presented clinically with an atypical nevus on his left thigh. Histopathological examination showed an intraepidermal melanocytic proliferation that was interpreted as melanoma in situ. Subsequently, 45 additional pigmented macules appeared in crops over a 9-month period. Clinically and dermoscopically, these lesions were extremely polymorphic. Histopathological findings were compatible with melanoma in situ, as each lesion consisted of a wholly intraepidermal proliferation of markedly atypical melanocytes arranged singly and in nests. A complete gastrointestinal study showed multiple pigmented metastatic lesions throughout the stomach and small bowel, which supported a diagnosis of metastatic melanoma with gastrointestinal and epidermotropic skin involvement. Monosomy of chromosome 9 and a BRAF V600E mutation were detected in the primary tumor sample and in macro-dissected secondary lesions. No CDKN2A or CDK4 germline mutations were found. Intraepidermal epidermotropic metastases of melanoma have been rarely described in literature. In this case, histopathology alone was insufficient to distinguish metastatic melanoma from multiple in situ melanomas. The recognition of epidermotropic metastases should be based on the correlation between clinical, dermoscopic, histopathological and molecular findings. PMID:21352266

  13. Staged Radiosurgical Ablation for Choroid Melanoma: A Case Report with Emphasis on the Role of Patient Preparation, Treatment Planning, and Precision of Delivery

    PubMed Central

    Janiga, Piotr

    2016-01-01

    The aim of reporting this case of choroid melanoma of the left eye is to introduce the in-house-designed treatment planning protocol for fractionated radiosurgical ablation of an intraocular lesion. This is a clinical case with emphasis on treatment preparation and delivery using the Accuray CyberKnife Robotic Radiosurgery System (Accuray, Sunnyvale, CA, USA) for a patient immobilized with a head mask and our in-house-made eye fixation system. PMID:27335716

  14. Melanoma risk perception and prevention behavior among African-Americans: the minority melanoma paradox

    PubMed Central

    Goldenberg, Alina; Vujic, Igor; Sanlorenzo, Martina; Ortiz-Urda, Susana

    2015-01-01

    Introduction Melanoma is the most deadly type of skin cancer with 75% of all skin cancer deaths within the US attributed to it. Risk factors for melanoma include ultraviolet exposure, genetic predisposition, and phenotypic characteristics (eg, fair skin and blond hair). Whites have a 27-fold higher incidence of melanoma than African-Americans (AA), but the 5-year survival is 17.8% lower for AA than Whites. It is reported continuously that AA have more advanced melanomas at diagnosis, and overall lower survival rates. This minority melanoma paradox is not well understood or studied. Objective To explore further, the possible explanations for the difference in melanoma severity and survival in AA within the US. Methods Qualitative review of the literature. Results Lack of minority-targeted public education campaigns, low self-risk perception, low self-skin examinations, intrinsic virulence, vitamin D differences, and physician mistrust may play a role in the melanoma survival disparity among AA. Conclusion Increases in public awareness of melanoma risk among AA through physician and media-guided education, higher index of suspicion among individuals and physicians, and policy changes can help to improve early detection and close the melanoma disparity gap in the future. PMID:26346576

  15. Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014.

    PubMed

    Ascierto, Paolo A; Atkins, Michael; Bifulco, Carlo; Botti, Gerardo; Cochran, Alistair; Davies, Michael; Demaria, Sandra; Dummer, Reinhard; Ferrone, Soldano; Formenti, Silvia; Gajewski, Thomas F; Garbe, Claus; Khleif, Samir; Kiessling, Rolf; Lo, Roger; Lorigan, Paul; Arthur, Grant Mc; Masucci, Giuseppe; Melero, Ignacio; Mihm, Martin; Palmieri, Giuseppe; Parmiani, Giorgio; Puzanov, Igor; Romero, Pedro; Schilling, Bastian; Seliger, Barbara; Stroncek, David; Taube, Janis; Tomei, Sara; Zarour, Hassane M; Testori, Alessandro; Wang, Ena; Galon, Jérôme; Ciliberto, Gennaro; Mozzillo, Nicola; Marincola, Francesco M; Thurin, Magdalena

    2015-11-30

    survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma.

  16. Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014.

    PubMed

    Ascierto, Paolo A; Atkins, Michael; Bifulco, Carlo; Botti, Gerardo; Cochran, Alistair; Davies, Michael; Demaria, Sandra; Dummer, Reinhard; Ferrone, Soldano; Formenti, Silvia; Gajewski, Thomas F; Garbe, Claus; Khleif, Samir; Kiessling, Rolf; Lo, Roger; Lorigan, Paul; Arthur, Grant Mc; Masucci, Giuseppe; Melero, Ignacio; Mihm, Martin; Palmieri, Giuseppe; Parmiani, Giorgio; Puzanov, Igor; Romero, Pedro; Schilling, Bastian; Seliger, Barbara; Stroncek, David; Taube, Janis; Tomei, Sara; Zarour, Hassane M; Testori, Alessandro; Wang, Ena; Galon, Jérôme; Ciliberto, Gennaro; Mozzillo, Nicola; Marincola, Francesco M; Thurin, Magdalena

    2015-01-01

    survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma. PMID:26619946

  17. Genetic Engineering of T cells to Target HERV-K, an Ancient Retrovirus on Melanoma

    PubMed Central

    Krishnamurthy, Janani; Rabinovich, Brian A.; Mi, Tiejuan; Switzer, Kirsten C.; Olivares, Simon; Maiti, Sourindra N.; Plummer, Joshua B.; Singh, Harjeet; Kumaresan, Pappanaicken R.; Huls, Helen M.; Wang-Johanning, Feng; Cooper, Laurence J.N.

    2015-01-01

    Purpose The human endogenous retrovirus (HERV-K) envelope (env) protein is a tumor- associated antigen expressed on melanoma, but not normal cells. This study was designed to engineer a chimeric antigen receptor (CAR) on T cell surface, such that they target tumors in advanced stages of melanoma. Experimental Design Expression of HERV-K protein was analyzed in 220 melanoma samples (with various stages of disease) and 139 normal organ donor tissues using immuno-histochemical (IHC) analysis. HERV-K env-specific CAR derived from mouse monoclonal antibody was introduced into T cells using the transposon-based Sleeping Beauty (SB) system. HERV-K env-specific CAR+ T cells were expanded ex vivo on activating and propagating cells (AaPC), and characterized for CAR expression and specificity. This includes evaluating the HERV-K-specific CAR+ T cells for their ability to kill A375-SM metastasized tumors in a mouse xenograft model. Results We detected HERV-K env protein on melanoma, but not in normal tissues. After electroporation of T cells and selection on HERV-K+ AaPC, over 95% of genetically-modified T cells expressed the CAR with an effector memory phenotype and lysed HERV-K env+ tumor targets in an antigen specific manner. Even though there is apparent shedding of this TAA from tumor cells which can be recognized by HERV-K env-specific CAR+ T cells, we observed a significant anti-tumor effect. Conclusion Adoptive cellular immunotherapy with HERV-K env-specific CAR+ T cells represents a clinically-appealing treatment strategy for advanced-stage melanoma and provides an approach for targeting this TAA on other solid tumors. PMID:25829402

  18. Differential oxidative status and immune characterization of the early and advanced stages of human breast cancer.

    PubMed

    Panis, C; Victorino, V J; Herrera, A C S A; Freitas, L F; De Rossi, T; Campos, F C; Simão, A N Colado; Barbosa, D S; Pinge-Filho, P; Cecchini, R; Cecchini, A L

    2012-06-01

    Breast cancer is the malignant neoplasia with the highest incidence in women worldwide. Chronic oxidative stress and inflammation have been indicated as major mediators during carcinogenesis and cancer progression. Human studies have not considered the complexity of tumor biology during the stages of cancer advance, limiting their clinical application. The purpose of this study was to characterize systemic oxidative stress and immune response parameters in early (ED; TNM I and II) and advanced disease (AD; TNM III and IV) of patients diagnosed with infiltrative ductal carcinoma breast cancer. Oxidative stress parameters were evaluated by plasmatic lipoperoxidation, carbonyl content, thiobarbituric reactive substances (TBARS), nitric oxide levels (NO), total radical antioxidant parameter (TRAP), superoxide dismutase, and catalase activities and GSH levels. Immune evaluation was determined by TNF-α, IL-1β, IL-12, and IL-10 levels and leukocytes oxidative burst evaluation by chemiluminescence. Tissue damage analysis included heart (total CK and CKMB), liver (AST, ALT, GGT), and renal (creatinine, urea, and uric acid) plasmatic markers. C-reactive protein (CRP) and iron metabolism were also evaluated. Analysis of the results verified different oxidative stress statuses occur at distinct cancer stages. ED was characterized by reduction in catalase, 8-isoprostanes, and GSH levels, with enhanced lipid peroxidation and TBARS levels. AD exhibited more pronounced oxidative status, with reduction in catalase activity and TRAP, intense lipid peroxidation and high levels of NO, TBARs, and carbonyl content. ED patients presented a Th2 immune pattern, while AD exhibited Th1 status. CRP levels and ferritin were increased in both stages of disease. Leukocytes burst impairment was observed in both the groups. Plasma iron levels were significantly elevated in AD. The data obtained indicated that oxidative stress enhancement and immune response impairment may be necessary to ensure

  19. Ares First Stage "Systemology" - Combining Advanced Systems Engineering and Planning Tools to Assure Mission Success

    NASA Technical Reports Server (NTRS)

    Seiler, James; Brasfield, Fred; Cannon, Scott

    2008-01-01

    Ares is an integral part of NASA s Constellation architecture that will provide crew and cargo access to the International Space Station as well as low earth orbit support for lunar missions. Ares replaces the Space Shuttle in the post 2010 time frame. Ares I is an in-line, two-stage rocket topped by the Orion Crew Exploration Vehicle, its service module, and a launch abort system. The Ares I first stage is a single, five-segment reusable solid rocket booster derived from the Space Shuttle Program's reusable solid rocket motor. The Ares second or upper stage is propelled by a J-2X main engine fueled with liquid oxygen and liquid hydrogen. This paper describes the advanced systems engineering and planning tools being utilized for the design, test, and qualification of the Ares I first stage element. Included are descriptions of the current first stage design, the milestone schedule requirements, and the marriage of systems engineering, detailed planning efforts, and roadmapping employed to achieve these goals.

  20. Association of Common Genetic Polymorphisms with Melanoma Patient IL-12p40 Blood Levels, Risk, and Outcomes

    PubMed Central

    Fang, Shenying; Wang, Yuling; Chun, Yun S; Liu, Huey; Ross, Merrick I; Gershenwald, Jeffrey E; Cormier, Janice N; Royal, Richard E; Lucci, Anthony; Schacherer, Christopher W; Reveille, John D; Chen, Wei; Sui, Dawen; Bassett, Roland L; Wang, Li-E; Wei, Qingyi; Amos, Christopher I; Lee, Jeffrey E

    2015-01-01

    Recent investigation has identified association of IL-12p40 blood levels with melanoma recurrence and patient survival. No studies have investigated associations of single-nucleotide polymorphisms (SNPs) with melanoma patient IL-12p40 blood levels or their potential contributions to melanoma susceptibility or patient outcome. In the current study, 818,237 SNPs were available for 1,804 melanoma cases and 1,026 controls. IL-12p40 blood levels were assessed among 573 cases (discovery), 249 cases (case validation), and 299 controls (control validation). SNPs were evaluated for association with log[IL-12p40] levels in the discovery data set and replicated in two validation data sets, and significant SNPs were assessed for association with melanoma susceptibility and patient outcomes. The most significant SNP associated with log[IL-12p40] was in the IL-12B gene region (rs6897260, combined P=9.26 × 10−38); this single variant explained 13.1% of variability in log[IL-12p40]. The most significant SNP in EBF1 was rs6895454 (combined P=2.24 × 10−9). A marker in IL12B was associated with melanoma susceptibility (rs3213119, multivariate P=0.0499; OR=1.50, 95% CI 1.00–2.24), whereas a marker in EBF1 was associated with melanoma-specific survival in advanced-stage patients (rs10515789, multivariate P=0.02; HR=1.93, 95% CI 1.11–3.35). Both EBF1 and IL12B strongly regulate IL-12p40 blood levels, and IL-12p40 polymorphisms may contribute to melanoma susceptibility and influence patient outcome. PMID:25848976

  1. Long-lasting multifunctional CD8+ T cell responses in end-stage melanoma patients can be induced by dendritic cell vaccination

    PubMed Central

    Wimmers, Florian; Aarntzen, Erik H. J. G.; Duiveman-deBoer, Tjitske; Figdor, Carl G.; Jacobs, Joannes F. M.; Tel, Jurjen; de Vries, I. Jolanda M.

    2016-01-01

    ABSTRACT Cytotoxic T cells are considered crucial for antitumor immunity and their induction is the aim of various immunotherapeutic strategies. High frequencies of tumor-specific CD8+ T cells alone, however, are no guarantee for long-term tumor control. Here, we analyzed the functionality of tumor-specific CD8+ T cells in melanoma patients upon dendritic cell vaccination by measuring multiple T cell effector functions considered crucial for anticancer immunity, including the expression of pro-inflammatory cytokines, chemokines and cytotoxic markers (IFNγ, TNFα, IL-2, CCL4, CD107a). We identified small numbers of multifunctional (polyfunctional) tumor-specific CD8+ T cells in several patients and dendritic cell therapy was able to improve the functionality of these pre-existing tumor-specific CD8+ T cells. Generated multifunctional CD8+ T cell responses could persist for up to ten years and within the same patient functionality could vary greatly for the different vaccination antigens. Importantly, after one cycle of DC vaccination highly functional CD8+ T cells were only detected in patients displaying prolonged overall survival. Our results shed light on the dynamics of multifunctional tumor-specific CD8+ T cells during metastatic melanoma and reveal a new feature of dendritic cell vaccination in vivo. PMID:26942087

  2. Two-stage, low noise advanced technology fan. 5: Acoustic final report

    NASA Technical Reports Server (NTRS)

    Sofrin, T. G.; Riloff, N., Jr.

    1975-01-01

    The NASA Q2S(quiet two-stage) fan is a 0.836m (32.9 in.) diameter model of the STF 433 engine fan, selected in a 1972 study for an Advanced Technology Transport (ATT) airplane. Noise-control features include: low tip speed, moderate stage pressure rise, large blade-vane spacings, no inlet guide vanes, and optimum blade and vane numbers. Tests were run on the baseline Q2S fan with standard inlet and discharge ducts. Further tests were made of a translating centerbody sonic inlet device and treated discharge ducts. Results were scaled to JT8D and JT3D engine fan size for comparison with current two-stage fans, and were also scaled to STF 433 fan size to compare calculated ATT flyover noise with FAR 36 limits. Baseline Q2S results scaled to JT8D and JT3D engine fan sizes showed substantial noise reductions. Calculated unsuppressed baseline ATT flyovers averaged about 2.5 EPNdB below FAR 36 limits. Using measured sonic inlet results, scaled baseline Q2S fan results, and calculated attenuations for a 1975 technology duct liner, projected flyover noise calculations for the ATT averaged about FAR 36 limits minus 10 EPNdB. Advances in suppression technology required to meet the 1985 goal of FAR 36 limits minus 20 EPNdB are discussed.

  3. Malignant melanoma and papillary thyroid carcinoma that were diagnosed concurrently and treated simultaneously: A case report.

    PubMed

    Ozgun, Alpaslan; Tuncel, Tolga; Emirzeoglu, Levent; Celik, Serkan; Bilgi, Oguz; Haholu, Abdullah; Urhan, Muammer; Karagoz, Bulent

    2015-01-01

    Malignant melanoma can be successfully treated when it is identified in its early stages, but the disease is associated with a poor prognosis when it is detected in an advanced stage. Papillary thyroid carcinoma is a thyroid cancer that has a good prognosis. The present study reports a rare case of malignant melanoma and papillary thyroid carcinoma that were diagnosed concurrently and treated simultaneously. The present patient was a 37-year-old male, in whom examination of a skin biopsy that was obtained from a lesion in the right retroauricular region revealed the lesion to be consistent with malignant melanoma. The patient underwent radical neck dissection upon the detection of malignant melanoma metastasis to the sentinel lymph node. Metastases of papillary thyroid carcinoma were detected in four out of 38 lymph nodes. The patient was then diagnosed with papillary thyroid carcinoma and underwent total thyroidectomy. The patient was administered with high-dose followed by moderate-dose interferon-α therapy for the treatment of malignant melanoma. The patient also received concurrent radioactive iodine therapy for the treatment of papillary thyroid carcinoma, at the same time as the interferon therapy. The two primary tumors of the patient were treated successfully. During therapy, no serious side-effects were observed, with the exception of fever caused by high-dose interferon therapy. Malignant melanoma and papillary thyroid carcinoma may occur concurrently, although this is rarely observed. The present study reports a rare case that demonstrates that the two tumors can be successfully treated simultaneously. PMID:25436010

  4. Incidence, Surgical Treatment, and Prognosis of Anorectal Melanoma From 1973 to 2011

    PubMed Central

    Chen, Haiyan; Cai, Yibo; Liu, Yue; He, Jinjie; Hu, Yeting; Xiao, Qian; Hu, Wangxiong; Ding, Kefeng

    2016-01-01

    Abstract Anorectal melanoma (AM) is a rare type of melanoma that accounts for 0.4% to 1.6% of total malignant melanomas. The incidence of AM increases over time, and it remains highly lethal, with a 5-year survival rate of 6% to 22%. Considering the rare nature of this disease, most studies on AM comprise isolated case reports and single-center trials, which could not provide comprehensive assessment of the disease. Therefore, we conducted a population-based study by using the Surveillance, Epidemiology, and End Results (SEER) program to provide the latest and best available evidence of AM. We extracted all cases of AM registered in the SEER database from 1973 to 2011 (April 2014 release) and calculated age-adjusted incidence. Only cases with active follow-up were included to predict factors associated with prognosis. Survival outcomes were also compared among different types of surgery. We identified 640 AM cases, which consisted of 265 rectal melanoma and 375 anal melanoma. The estimated annual incidence rates of AM per 1 million population were 0.259 in males and 0.407 in females, and it increased with advanced age and over time. Tumor stage and surgical treatment were independent predictors of survival. Results implied that surgery improved the prognosis of patients with local- and regional-stage AM but could not prolong the survival of patients with distant-stage AM. Moreover, the outcome of less extensive excision was not statistically different from that of more extensive excision. This study provides an up-to-date estimation of the incidence and prognosis of AM by using SEER data. The incidence of AM continuously increases over time, despite its rarity. This disease also exhibits poor prognosis. Thus, AM must be further investigated in future studies. We also recommend surgery as the optimal treatment for local- and regional-stage AM patients but not for those with distant metastasis. PMID:26886623

  5. Novel approaches in melanoma prevention and therapy.

    PubMed

    Grimaldi, Antonio M; Cassidy, Pamela B; Leachmann, Sancy; Ascierto, Paolo A

    2014-01-01

    The incidence of cutaneous melanoma has risen at a rate significantly higher than that for other malignancies. This increase persists despite efforts to educate the public about the dangers of excess exposure to UV radiation from both the sun and tanning beds. Melanoma affects a relatively younger population and is notorious for its propensity to metastasize and for its poor response to current therapeutic regimens. These factors make prevention an integral component to the goal of decreasing melanoma-related mortality. Transformation of melanocytes into malignant melanoma involves the interplay between genetic factors, UV exposure, and the tumor microenvironment. The roles of UV radiation in the etiology of melanoma are mediated by both direct damage of DNA through formation of photoproducts and production of reactive oxygen species (ROS). Many of the promising antioxidant agents under development for the prevention of melanoma are derived from foodstuffs. B-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases that plays a role in regulating the MAP kinase/ERKs signaling pathway. About 50 % of melanomas harbor activating BRAF mutations. BRAF mutations are found in 59 % of the melanomas arising in skin with intermittent sun exposure, such as trunk and arms, as compared with only 23 % of the acral melanomas, 11 % of mucosal melanomas, and 0 % of uveal melanomas. Two new agents, ipilimumab and vemurafenib, have been shown to improve outcome of advanced melanoma as presented at the plenary session of the 2011 annual meeting of the American Society of Clinical Oncology. Vemurafenib is the first personalized compound which demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) in metastatic melanoma harboring the BRAFV600 mutation and represents the first drug of a class that exerts its anti-proliferative activity through inhibition of a highly specific molecular target. GSK2118436 (dabrafenib), the

  6. A Two Stage Solution Procedure for Production Planning System with Advance Demand Information

    NASA Astrophysics Data System (ADS)

    Ueno, Nobuyuki; Kadomoto, Kiyotaka; Hasuike, Takashi; Okuhara, Koji

    We model for ‘Naiji System’ which is a unique corporation technique between a manufacturer and suppliers in Japan. We propose a two stage solution procedure for a production planning problem with advance demand information, which is called ‘Naiji’. Under demand uncertainty, this model is formulated as a nonlinear stochastic programming problem which minimizes the sum of production cost and inventory holding cost subject to a probabilistic constraint and some linear production constraints. By the convexity and the special structure of correlation matrix in the problem where inventory for different periods is not independent, we propose a solution procedure with two stages which are named Mass Customization Production Planning & Management System (MCPS) and Variable Mesh Neighborhood Search (VMNS) based on meta-heuristics. It is shown that the proposed solution procedure is available to get a near optimal solution efficiently and practical for making a good master production schedule in the suppliers.

  7. Long-Term Results of Concurrent Chemoradiotherapy for Advanced N2-3 Stage Nasopharyngeal Carcinoma

    PubMed Central

    Wang, Xue; Chen, Meng; Wu, Jing; Xu, Jian-Hua; Qian, Pu-Dong; Guo, Wen-Jie; Jiang, Xue-Song; Zhu, Huan-Feng; Gu, Jia-Jia; Wu, Jian-Feng; Zhang, Ye-wei; He, Xia

    2015-01-01

    Background N-stage is related to distant metastasis in nasopharyngeal carcinoma (NPC) patients. The purpose of this study was to evaluate the efficacy and toxicity of different nedaplatin-based chemotherapy regimens in advanced N2-3 stage NPC patients treated with intensity modulated radiation therapy (IMRT). Patients and Methods Between April 2005 and December 2009, a total of 128 patients with N2-3 advanced NPC were retrospectively analyzed. Patients were treated with IMRT concurrent with 2 cycles of chemotherapy consisting of either nedaplatin plus paclitaxel (NP group, n = 67) or nedaplatin plus fluorouracil and paclitaxel (NFP group, n = 61). Two to four cycles of adjuvant chemotherapy were then administered every 21 days following concurrent chemoradiotherapy. Results With a median follow-up of 60 months, the 5-year overall survival (OS), progression-free survival (PFS), local-regional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) for all patients were 81.4%, 71.5%, 87.8% and 82.0%, respectively. No significant difference in PFS (66.6% vs. 76.7%, P = 0.212) and LRRFS rates (89.0% vs. 86.3%, P = 0.664) was observed between the NP and NFP groups. The 5-year OS (75.4% vs. 88.5%, P = 0.046) and DMFS (75.1% vs. 89.0%, P = 0.042) rate were superior in the NFP group compared with the NP group. The NFP group had a higher incidence of grade 3–4 acute toxicities including bone marrow suppression (leukopenia: χ2 = 3.935, P = 0.047; anemia: χ2 = 9.760, P = 0.002; thrombocytopenia: χ2 = 8.821, P = 0.003), and both liver and renal dysfunction (χ2 = 5.206, P = 0.023) compared with the NP group. Late toxicities were moderate and no difference was observed between the two groups. Conclusion IMRT concurrent with nedaplatin-based chemotherapy is an advocated regimen for patients with advanced N2-3 stage NPC. Patients with advanced N2-3 stage may be better candidates for the NFP regimen although this regimen was associated with a high acute

  8. Emerging technologies for the detection of melanoma: achieving better outcomes

    PubMed Central

    Herman, Cila

    2012-01-01

    Every year around 2.5–3 million skin lesions are biopsied in the US, and a fraction of these – between 50,000 and 100,000 – are diagnosed as melanoma. Diagnostic instruments that allow early detection of melanoma are the key to improving survival rates and reducing the number of unnecessary biopsies, the associated morbidity, and the costs of care. Advances in technology over the past 2 decades have enabled the development of new, sophisticated test methods, which are currently undergoing laboratory and small-scale clinical testing. This review highlights and compares some of the emerging technologies that hold the promise of melanoma diagnosis at an early stage of the disease. The needs for detection at different levels (patient, primary care, specialized care) are discussed, and three broad classes of instruments are identified that are capable of satisfying these needs. Technical and clinical requirements on the diagnostic instruments are introduced to aid the comparison and evaluation of new technologies. White- and polarized-light imaging, spatial and spectroscopic multispectral methods, quantitative thermographic imaging, confocal microscopy, Optical Coherence Tomography (OCT), and Terahertz (THZ) imaging methods are highlighted in light of the criteria identified in the review. Based on the properties, possibilities, and limitations of individual methods, those best suited for a particular setting are identified. Challenges faced in development and wide-scale application of novel technologies are addressed. PMID:23204850

  9. AC-93253 triggers the downregulation of melanoma progression markers and the inhibition of melanoma cell proliferation.

    PubMed

    Karwaciak, Iwona; Gorzkiewicz, Michal; Ryba, Katarzyna; Dastych, Jaroslaw; Pulaski, Lukasz; Ratajewski, Marcin

    2015-07-01

    A major challenge in anti-melanoma therapy is to develop treatments that are effective for advanced melanoma patients. Unfortunately, the currently used regimens are not efficient and have unsatisfactory effects on disease progression, thus increasing the pressure to develop new, profitable drugs and to identify new molecular targets. Here, we show for the first time that AC-93253, a SIRT2 inhibitor, exerts a negative effect on the expression of a set of genes involved in the progression and chemoresistance (e.g., oncogenes, apoptosis-related genes, ABC transporter genes, and cell cycle control genes) of melanoma cells. Furthermore, melanoma cells exposed to AC-93253 and doxorubicin displayed altered biological responses, including apoptosis and proliferation, compared to cells exposed to single treatments. Taken together, we conclude that the usage of AC-93253 in combined therapy could be a promising strategy for melanoma patients.

  10. Immunotherapy for melanoma: the good, the bad, and the future.

    PubMed

    Poehlein, Christian H; Rüttinger, Dominik; Ma, Jun; Hu, Hong-Ming; Urba, Walter J; Fox, Bernard A

    2005-09-01

    The past 20 years have seen remarkable advances in our understanding of the molecular and cellular processes controlling the development of an anticancer immune response. These advances have spawned a renaissance in the field of cancer immunotherapy, the original targeted therapy, during which investigators have pushed the envelope and translated promising strategies into investigational therapeutics in patients with cancer. An approach that combined nonmyeloablative lymphodepleting chemotherapy with adoptive transfer of tumor-specific CD4 and CD8 T cells exhibited an initial objective response rate of 51% for patients with stage IV melanoma. Although this strategy is extremely challenging, one can expect technological advances that may simplify this approach and further improve outcome.

  11. Molecular Classification of Melanoma

    Cancer.gov

    Tissue-based analyses of precursors, melanoma tumors and metastases within existing study populations to further understanding of the heterogeneity of melanoma and determine a predictive pattern of progression for dysplastic nevi.

  12. General Information about Melanoma

    MedlinePlus

    ... Screening Research Melanoma Treatment (PDQ®)–Patient Version General Information About Melanoma Go to Health Professional Version Key ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  13. Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases

    PubMed Central

    Kraehn, G M; Utikal, J; Udart, M; Greulich, K M; Bezold, G; Kaskel, P; Leiter, U; Peter, R U

    2001-01-01

    Amplification and overexpression of the c-myc gene have been associated with neoplastic transformation in a plethora of malignant tumours. We applied interphase fluorescence in situ hybridization (FISH) with a locus-specific probe for the c-myc gene (8q24) in combination with a corresponding chromosome 8 α-satellite probe to evaluate genetic alterations in 8 primary melanomas and 33 advanced melanomas and compared it to 12 melanocytic nevi, 7 safety margins and 2 cases of normal skin. Additionally, in metaphase spreads of 7 melanoma cell lines a whole chromosome 8 paint probe was used. We investigated the functionality of the c-myc gene by detecting c-myc RNA expression with RT-PCR and c-myc protein by immunohistochemistry. 4/8 primary melanomas and 11/33 melanoma metastases showed additional c-myc signals relative to the centromere of chromosome 8 copy number. None of the nevi, safety margins or normal skin samples demonstrated this gain. In 2/7 melanoma cell lines (C32 and WM 266–4) isochromosome 8q formation with a relative gain of c-myc copies and a loss of 8p was observed. The highest c-myc gene expression compared to GAPDH was found in melanoma metastases (17.5%). Nevi (6.6%) and primary melanomas (5.0%) expressed the c-myc gene on a lower level. 72.7% of the patients with c-myc extra copies had visceral melanoma metastases (UICC IV), patients without c-myc gain in 35.0% only. The collective with additional c-myc copies also expressed the gene on a significantly higher level. These results indicate that a c-myc gain in relation to the centromere 8 copy number might be associated with advanced cutaneous melanoma. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11139316

  14. CTGF is a therapeutic target for metastatic melanoma.

    PubMed

    Finger, E C; Cheng, C-F; Williams, T R; Rankin, E B; Bedogni, B; Tachiki, L; Spong, S; Giaccia, A J; Powell, M B

    2014-02-27

    Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression.

  15. Selecting the best strategy of treatment in newly diagnosed advanced-stage ovarian cancer patients.

    PubMed

    Minig, Lucas; Zorrero, Cristina; Iserte, Pablo Padilla; Poveda, Andres

    2015-12-26

    Although it is assumed that the combination of chemotherapy and radical surgery should be indicated in all newly diagnosed advanced-stage ovarian cancer patients, one of the main raised questions is how to select the best strategy of initial treatment in this group of patients, neoadjuvant chemotherapy followed by interval debulking surgery or primary debulking surgery followed by adjuvant chemotherapy. The selection criteria to offer one strategy over the other as well as a stepwise patient selection for initial treatment are described. Selecting the best strategy of treatment in newly diagnosed advanced stage ovarian cancer patients is a multifactorial and multidisciplinary decision. Several factors should be taken into consideration: (1) the disease factor, related to the extension and localization of the disease as well as tumor biology; (2) the patient factor, associated with patient age, poor performance status, and co-morbidities; and (3) institutional infrastructure factor, related to the lack of prolonged operative time, an appropriate surgical armamentarium, as well as well-equipped intensive care units with well-trained personnel.

  16. High LIFr expression stimulates melanoma cell migration and is associated with unfavorable prognosis in melanoma.

    PubMed

    Guo, Hongwei; Cheng, Yabin; Martinka, Magdalena; McElwee, Kevin

    2015-09-22

    Increased or decreased expression of LIF receptor (LIFr) has been reported in several human cancers, including skin cancer, but its role in melanoma is unknown. In this study, we investigated the expression pattern of LIFr in melanoma and assessed its prognostic value. Using tissue microarrays consisting of 441 melanomas and 96 nevi, we found that no normal nevi showed high LIFr expression. LIFr staining was significantly increased in primary melanoma compared to dysplastic nevi (P = 0.0003) and further increased in metastatic melanoma (P = 0.0000). Kaplan-Meier survival curve and univariate Cox regression analyses showed that increased expression of LIFr was correlated with poorer 5-year patient survival (overall survival, P = 0.0000; disease-specific survival, P = 0.0000). Multivariate Cox regression analyses indicated that increased LIFr expression was an independent prognostic marker for primary melanoma (P = 0.036). LIFr knockdown inhibited melanoma cell migration in wound healing assays and reduced stress fiber formation. LIFr knockdown correlated with STAT3 suppression, but not YAP, suggesting that LIFr activation might stimulate melanoma cell migration through the STAT3 pathway. Our data indicate that strong LIFr expression identifies potentially highly malignant melanocytic lesions at an early stage and LIFr may be a potential target for the development of early intervention therapeutics. PMID:26329521

  17. Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome.

    PubMed

    Soura, Efthymia; Eliades, Philip J; Shannon, Kristen; Stratigos, Alexander J; Tsao, Hensin

    2016-03-01

    Malignant melanoma is considered the most lethal skin cancer if it is not detected and treated during its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (ie, unilateral lineage, multigenerational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. These patients have a high risk of developing multiple primary melanomas and internal organ malignancies, especially pancreatic cancer; therefore, a multidisciplinary approach is necessary in many cases. The value of dermoscopic examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first-degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. This must be performed with care, however, and only by qualified individuals trained in cancer risk analysis.

  18. Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome.

    PubMed

    Soura, Efthymia; Eliades, Philip J; Shannon, Kristen; Stratigos, Alexander J; Tsao, Hensin

    2016-03-01

    Malignant melanoma is considered the most lethal skin cancer if it is not detected and treated during its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (ie, unilateral lineage, multigenerational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. These patients have a high risk of developing multiple primary melanomas and internal organ malignancies, especially pancreatic cancer; therefore, a multidisciplinary approach is necessary in many cases. The value of dermoscopic examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first-degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. This must be performed with care, however, and only by qualified individuals trained in cancer risk analysis. PMID:26892650

  19. Melanoma to the heart

    PubMed Central

    Hall, James A.; Fidone, Erica J.; Mack, Ryan; Metting, Austin L.

    2016-01-01

    Malignant melanoma is the third most common skin cancer yet has the highest mortality rate due to its predilection for metastasis. While the diagnosis of antemortem melanoma with cardiac metastasis is relatively uncommon, diagnosing malignant melanoma itself by first identifying a cardiac metastasis is even more rare. This vignette describes an antemortem diagnosis of melanoma in a 50-year-old woman through identification of metastasis to multiple sites, including the tricuspid valve. PMID:27695188

  20. Melanoma to the heart

    PubMed Central

    Hall, James A.; Fidone, Erica J.; Mack, Ryan; Metting, Austin L.

    2016-01-01

    Malignant melanoma is the third most common skin cancer yet has the highest mortality rate due to its predilection for metastasis. While the diagnosis of antemortem melanoma with cardiac metastasis is relatively uncommon, diagnosing malignant melanoma itself by first identifying a cardiac metastasis is even more rare. This vignette describes an antemortem diagnosis of melanoma in a 50-year-old woman through identification of metastasis to multiple sites, including the tricuspid valve.

  1. Impact of underweight after treatment on prognosis of advanced-stage ovarian cancer.

    PubMed

    Kim, Se Ik; Kim, Hee Seung; Kim, Tae Hun; Suh, Dong Hoon; Kim, Kidong; No, Jae Hong; Chung, Hyun Hoon; Kim, Yong Beom; Song, Yong Sang

    2014-01-01

    This study aimed to investigate the impact of underweight status on the prognosis of advanced-stage ovarian cancer. A total of 360 patients with stage III-IV epithelial ovarian cancer were enrolled and divided into three groups by body mass indexes (BMIs): underweight (BMI < 18.5 kg/m(2)); normal weight to overweight (18.5 kg/m(2) BMI < 27.5 kg/m(2)); obesity (BMI ≥ 27.5 kg/m(2)). Progression-free survival (PFS), overall survival (OS), CA-125, and neutrophil to lymphocyte ratio (NLR) as a marker reflecting host inflammation and immunity were compared among the three groups according to the three treatment times: at diagnosis; after surgery; and after treatment. Only underweight status after treatment was associated with poor OS in comparison with normal weight to overweight or obesity (mean value, 44.9 versus 78.8 or 67.4 months; P = 0.05); it was also an unfavorable factor for OS (adjusted HR, 2.29; 95% CI, 1.08-4.85). Furthermore, NLR was higher in patients with underweight than in those with obesity after treatment (median value, 2.15 versus 1.47; P = 0.03), in spite of no difference in CA-125 among the three groups at the three treatment times. In conclusion, underweight status after treatment may be a poor prognostic factor in patients with advanced-stage ovarian cancer, which accompanies increased host inflammation and decreased immunity.

  2. 18F-FDG PET/CT Reveals Disease Remission in a Patient With Ipilimumab-Refractory Advanced Melanoma Treated With Pembrolizumab.

    PubMed

    Sachpekidis, Christos; Hassel, Jessica C; Dimitrakopoulou-Strauss, Antonia

    2016-02-01

    Pembrolizumab is an anti-programmed cell death receptor 1 (anti-PD-1) antibody, recently approved for the treatment of ipilimumab-refractory metastatic melanoma. We report on a 49-year-old patient with unresectable metastatic melanoma initially treated with 4 cycles of ipilimumab. Because of demonstration of progressive disease on PET/CT, the patient was enrolled into a clinical trial of pembrolizumab. After completion of 4 cycles of pembrolizumab, the follow-up PET/CT scans performed early after and 7 months after the end of treatment exhibited complete disease remission, reflecting the potential role of the modality in treatment response evaluation of melanoma patients receiving anti-PD-1 therapy.

  3. Two-stage, low noise advanced technology fan. Volume 2: Aerodynamic data

    NASA Technical Reports Server (NTRS)

    Harley, K. G.; Odegard, P. A.

    1975-01-01

    Aerodynamic data from static tests of a two-stage advanced technology fan designed to minimize noise are presented. Fan design conditions include delivery of 209.1kg/sec/sq m (42.85 lbm/sec/sq ft) specific corrected flow at an overall pressure ratio of 1.9 and an adiabatic efficiency of 85.3 percent. The 0.836m (2.74ft) diameter first stage rotor has a hub/tip ratio of 0.4 and 365.8m/sec (1200ft/sec) design tip speed. In addition to the moderate tip speed and pressure rise per stage, other noise control design features involve widely spaced blade rows and proper selection of blade-vane ratios. Aerodynamic data are presented for tests with unifrom and with hub and tip radially distorted inlet flow. Aerodynamic data are also presented for tests of this fan with acoustic treatments, including acoustically treated casing walls, a flowpath exit acoustic ring, and a translating centerbody sonic inlet device. A complete tabulation of the overall performance data, the blade element data, and the power spectral density information relating to turbulence levels generated by the sonic inlet obtained during these tests is included. For vol. 1, see N74-33789.

  4. [Malignant melanoma coexisting with pregnancy].

    PubMed

    Krasomski, G; Broniarczyk, D; Gładysiak, A

    1992-09-01

    An extremely rare case of melanoma amelanoticum coexisting with pregnancy has been discussed. Pregnant A. Ch., age 42, was admitted to the Polish Mother's Health Centre Memorial Hospital on the 22nd of August, 1990 with a diagnosis of the 5th pregnancy, the 2nd delivery, the 30th week of gestation, state after cesarean section. Suspected malignant melanoma. Stomach ulceration. Thrombophlebitis of left lower extremity. General condition--medium hard. For the last three days she did not report fetal movements, fetal heartbeat was not detected either. Us examination confirmed fetal death. On the 24th of August, 1990, spontaneous vaginal delivery terminated the pregnancy, giving a dead, macerated female fetus, body weight of 1500 g. On the 3rd day after delivery the patient died with growing circulation-respiratory insufficiency. Autopsy revealed melanoma malignum amelanoticum disseminatum. Neither an autopsy of the fetus nor histopathological examinations of the secundines were performed for the advanced maceration. The coexistence of pregnancy with malignant melanoma in this case brought a tragic end both for the mother and the fetus. PMID:1305602

  5. Gene signature of the metastatic potential of cutaneous melanoma: too much for too little?

    PubMed

    Tímár, József; Gyorffy, Balázs; Rásó, Erzsébet

    2010-08-01

    It was expected that with the advent of genomics, oncology may defeat the deadliest forms of cancer including malignant melanoma, but the past years have indicated that this is not the case. Despite the stunning success of genomics in defining markers or gene signatures for breast cancer prognosis and predicting therapies, there is virtually no progression in malignant melanoma. This is happening when experimental oncology or metastasis research is using several rodent and human melanoma models, when our knowledge on the metastatic cascade is actually derived from these models. Our critical analysis of these studies revealed several factors which might be responsible for this failure. First, it is evident, that these studies must be based on rigorous sample collection and basic pathological considerations, where divergent histological types of melanoma cannot be analysed universally. Secondly, without following basic consideration of metastasis biology, the majority of these studies were rarely based on primary tumors but frequently on various types of regional metastases. Third, successful expression profiling studies on other tumors such as breast cancer, provided evidences that the homogeneity of the patient cohort at least by clinicopathological stage is a critical element when defining prognostic signatures. Four studies attempted to define the prognostic signature of skin melanoma but only one based the study on the primary tumor resulting in heterogenous signatures with a minimal overlap (MCM3 and NFKBIZ). Four study attempted to define the invasiveness-signature in the primary tumor based on thickness or growth pattern discrimination identifying a 9-gene overlap which proved to be different from the prognostic signatures. On the other hand, seven studies analyzed various types of metastatic tissues (rarely visceral-, mostly cutaneous or lymphatic metastases) to define the metastasis-signatures, again with minimal overlap (AQP3, LGALS7 and SFN). Using seven

  6. Immunohistochemical Expression of Leptin in Non Melanoma Skin Cancer

    PubMed Central

    Farag, Azza G.A.; El-Dien, Marwa Mohammed Serag

    2016-01-01

    Introduction Obesity in adults is associated with numerous health disorders including some forms of cancer. Various epidemiological studies have found a link between excess adiposity and malignant melanoma; however, the association with non melanoma skin cancer is questionable. Leptin is a hormone produced mainly by the adipose tissue and its serum level may reflect body mass index. Leptin is reported to promote proliferation and angiogenesis and deregulate apoptosis, therefore facilitates the process of carcinogenesis. Aim The current study tried to assess leptin localization and expression in non melanoma skin cancer to verify its possible role in pathogenesis of this cancer. Materials and Methods This study was carried out on 13 Basal Cell Carcinoma (BCC) cases and 14 Squamous Cell Carcinoma (SCC) cases together with 19 normal skin biopsies as a control group using immunohistochemical method. Results Leptin was expressed in 52.6% of the normal epidermis with pure cytoplasmic and both cytoplasmic and nuclear staining patterns. All cases of SCC (100%) and two cases of BCC (15.4%) showed leptin expression in tumour cells whereas nuclear expression was in favour of SCC. Stromal expression of leptin was seen in both SCC (57.1%) and BCC (38.5%) without significant differences. Percentage of leptin expression by tumour cells in SCC showed positive linear correlation with tumour size (p=0.02) and microvessel density (p=0.000). Stromal expression of leptin in SCC was associated with large tumour size (p=0.04), advanced stage (p=0.01) and tumours arising in sites other than head and neck (p=0.01). Conclusion Leptin could have a more important role in pathogenesis of cutaneous SCC rather than BCC that may reflect the trivial role of obesity in induction of BCC. The expression of leptin by tumour and stromal cells of SCC could co-operate in its progression by promoting angiogenesis with subsequently acquiring large tumour size and then advanced stage. PMID:27656540

  7. Cutaneous malignant melanoma: update on diagnostic and prognostic biomarkers.

    PubMed

    Abbas, Ossama; Miller, Daniel D; Bhawan, Jag

    2014-05-01

    The incidence of cutaneous malignant melanoma has rapidly increased in recent years in all parts of the world, and melanoma is a leading cause of cancer death. As even relatively small melanomas may have metastatic potential, accurate assessment of progression is critical. Although diagnosis of cutaneous malignant melanoma is usually based on histopathologic criteria, these criteria may at times be inadequate in differentiating melanoma from certain types of benign nevi. As for prognosis, tumor (Breslow) thickness, mitotic rate, and ulceration have been considered the most important prognostic indicators among histopathologic criteria. However, there are cases of thin primary melanomas that have ultimately developed metastases despite complete excision. Given this, an accurate assessment of melanoma progression is critical, and development of molecular biomarkers that identify high-risk melanoma in its early phase is urgently needed. Large-scale genomic profiling has identified considerable heterogeneity in melanoma and suggests subgrouping of tumors by patterns of gene expression and mutation will ultimately be essential to accurate staging. This subgrouping in turn may allow for more targeted therapy. In this review, we aim to provide an update on the most promising new biomarkers that may help in the identification and prognostication of melanoma. PMID:24803061

  8. Melanoma never says die.

    PubMed

    Haass, Nikolas K; Schumacher, Udo

    2014-07-01

    Drug resistance in melanoma is commonly attributed to ineffective apoptotic pathways. Targeting apoptosis regulators is thus considered a promising approach to sensitizing melanoma to therapy. In the previous issue of Experimental Dermatology, Plötz and Eberle discuss the role that apoptosis plays in melanoma progression and drug resistance and the utility of apoptosis-inducing BH3-mimetics as targeted therapy. There are a number of compounds in clinical development and the field seems close to translating recent findings into benefits for patients with melanoma. Thus, this viewpoint is timely and achieves a valuable summary of the current state of apoptosis-inducing therapy of melanoma.

  9. Lymphadenectomy in locally advanced cervical cancer study (LiLACS): Phase III clinical trial comparing surgical with radiologic staging in patients with stages IB2-IVA cervical cancer.

    PubMed

    Frumovitz, Michael; Querleu, Denis; Gil-Moreno, Antonio; Morice, Philippe; Jhingran, Anuja; Munsell, Mark F; Macapinlac, Homer A; Leblanc, Eric; Martinez, Alejandra; Ramirez, Pedro T

    2014-01-01

    Radiation treatment planning for women with locally advanced cervical cancer (stages IB2-IVA) is often based on positron emission tomography (PET). PET, however, has poor sensitivity in detecting metastases in aortocaval nodes. We have initiated a study with the objective of determining whether pre-therapeutic laparoscopic surgical staging followed by tailored chemoradiation improves survival as compared with PET/computed tomography (CT) radiologic staging alone followed by chemoradiation. This international, multicenter phase III trial will enroll 600 women with stages IB2-IVA cervical cancer and PET/CT findings showing fluorodeoxyglucose-avid pelvic nodes and fluorodeoxyglucose-negative para-aortic nodes. Eligible patients will be randomized to undergo either pelvic radiotherapy with chemotherapy (standard-of-care arm) or surgical staging via a minimally invasive extraperitoneal approach followed by tailored radiotherapy with chemotherapy (experimental arm). The primary end point is overall survival. Secondary end points are disease-free survival, short- and long-term morbidity with pre-therapeutic surgical staging, and determination of anatomic locations of metastatic para-aortic nodes in relationship to the inferior mesenteric artery. We believe this study will show that tailored chemoradiation after pre-therapeutic surgical staging improves survival as compared with chemoradiation based on PET/CT in women with stages IB2-IVA cervical cancer.

  10. Pembrolizumab for the treatment of melanoma.

    PubMed

    Kumar, Sanjeev Srinivas; McNeil, Catriona Mairi

    2015-01-01

    The immune system plays a vital role in regulating tumor growth, and the oncology community has witnessed an exciting resurgence in clinical research to develop effective immunotherapeutic strategies. The utility of these strategies in advanced melanoma has been at the forefront of these developments. In particular, blockade of programmed cell death protein 1 (PD-1) in advanced melanoma has proven to be a most promising new anticancer strategy. Pembrolizumab is a humanized IgG4 anti-PD-1 antibody that exerts its anti-tumor effect through blocking the interaction of the immune inhibitory molecule PD-1 with its ligands. Its effect has been most convincingly demonstrated in the setting of advanced melanoma, with growing evidence of clinical responses across a broad spectrum of other solid and hematological malignancies.

  11. Genetics of familial melanoma: 20 years after CDKN2A.

    PubMed

    Aoude, Lauren G; Wadt, Karin A W; Pritchard, Antonia L; Hayward, Nicholas K

    2015-03-01

    Twenty years ago, the first familial melanoma susceptibility gene, CDKN2A, was identified. Two years later, another high-penetrance gene, CDK4, was found to be responsible for melanoma development in some families. Progress in identifying new familial melanoma genes was subsequently slow; however, with the advent of next-generation sequencing, a small number of new high-penetrance genes have recently been uncovered. This approach has identified the lineage-specific oncogene MITF as a susceptibility gene both in melanoma families and in the general population, as well as the discovery of telomere maintenance as a key pathway underlying melanoma predisposition. Given these rapid recent advances, this approach seems likely to continue to pay dividends. Here, we review the currently known familial melanoma genes, providing evidence that most additionally confer risk to other cancers, indicating that they are likely general tumour suppressor genes or oncogenes, which has significant implications for surveillance and screening. PMID:25431349

  12. Exome sequencing identifies early gastric carcinoma as an early stage of advanced gastric cancer.

    PubMed

    Kang, Guhyun; Hwang, Woo Cheol; Do, In-Gu; Wang, Kai; Kang, So Young; Lee, Jeeyun; Park, Se Hoon; Park, Joon Oh; Kang, Won Ki; Jang, Jiryeon; Choi, Min-Gew; Lee, Jun Ho; Sohn, Tae Sung; Bae, Jae Moon; Kim, Sung; Kim, Min Ji; Kim, Seonwoo; Park, Cheol Keun; Kim, Kyoung-Mee

    2013-01-01

    Gastric carcinoma is one of the major causes of cancer-related mortality worldwide. Early detection and treatment leads to an excellent prognosis in patients with early gastric cancer (EGC), whereas the prognosis of patients with advanced gastric cancer (AGC) remains poor. It is unclear whether EGCs and AGCs are distinct entities or whether EGCs are the beginning stages of AGCs. We performed whole exome sequencing of four samples from patients with EGC and compared the results with those from AGCs. In both EGCs and AGCs, a total of 268 genes were commonly mutated and independent mutations were additionally found in EGCs (516 genes) and AGCs (3104 genes). A higher frequency of C>G transitions was observed in intestinal-type compared to diffuse-type carcinomas (P = 0.010). The DYRK3, GPR116, MCM10, PCDH17, PCDHB1, RDH5 and UNC5C genes are recurrently mutated in EGCs and may be involved in early carcinogenesis.

  13. Identifying predictive factors in melanoma progression.

    PubMed

    Dabrowska, D M; Elashoff, R M; Ho, W; Morton, D L

    1998-01-01

    Identification of risk factors is a fundamental goal of melanoma studies. The current understanding of melanoma progression is based primarily on two-stage modeling. A multistate Markov chain process combined with Cox proportional hazard regression is used to model the melanoma progression. The model is applied to 3,434 patients initially diagnosed as AJCC stage I or stage II. Parameter estimates are obtained using Cox regression and supplemented by plots of survival probabilities. Age is associated with increased risk of progression from stage I, II to stage III and from stage III to stage IV. Males experienced an increased risk of stage I, II to stage III progression. Primary tumor located on extremities decreased the risk of all transitions. Clark's level of invasion >III and Breslow's depth >1 mm increased the risk of progression from stage I, II to stage III and stage IV. The following interactions among the prognostic factors were identified for the first time in this research: interaction of age and gender in progression from stage I, II to stage III; interactions of level and depth and site by gender were found in the progression from stage I, II to stage III; interaction of site and gender in progression from stage III to stage IV and stage IV to death. Also we identified primary site as a new prognostic factor for the progression from stage IV to death. The study employed a multistate model in order to identify prognostic factors relevant for disease progression. The unique feature is the modeling of interactions among the prognostic factors and their identification. PMID:9538154

  14. Single stage, low noise, advanced technology fan. Volume 5: Fan acoustics. Section 1: Results and analysis

    NASA Technical Reports Server (NTRS)

    Jutras, R. R.

    1976-01-01

    The acoustic tests and data analysis for a 0.508-scale fan vehicle of a 111,300 newton (25,000 pound) thrust, full-size engine, which would have application on an advanced transport aircraft, is described. The single-stage advanced technology fan was designed to a pressure ratio of 1.8 at a tip speed of 503 m/sec (1,650 ft/sec) to achieve the desired pressure ratio in a single-stage fan with low radius ratio (0.38), and to maintain adequate stall margin. The fan has 44 tip-shrouded rotor blades and 90 outlet guide vanes. The two basic approaches taken in the acoustic design were: (1) minimization of noise at the source, and (2) suppression of the generated noise in the inlet and bypass exhaust duct. Suppression of the generated noise was accomplished in the inlet through use of the hybrid concept (wall acoustic treatment plus airflow acceleration suppression) and in the exhaust duct with extensive acoustic treatment including a splitter. The goal of the design was attainment of twenty effective perceived noise decibels (20 EPNdB) below current Federal Air Regulation noise standards for a full-scale fan at the takeoff, cutback, and approach conditions. The suppression goal of FAR 36-20 was not reached, but improvements in the technology of both front and aft fan-noise suppression were realized. The suppressed fan noise was shown to be consistent with the proposed federal regulation on aircraft noise.

  15. MicroRNA-199a-5p inhibits tumor proliferation in melanoma by mediating HIF-1α.

    PubMed

    Yang, Xinghua; Lei, Shaorong; Long, Jianhong; Liu, Xiaojin; Wu, Qizhen

    2016-06-01

    The expression of hypoxia-inducible factor 1α (HIF-1α) is often abundant in human cancer and it is associated with poor prognosis. The present study aimed to investigate its regulation by microRNA (miRNA). The expression of miRNA-199a-5p (miR-199a-5p) in melanoma was detected by quantitative polymerase chain reaction on samples from 25 melanoma patients. The target of miR-199a-5p was predicted and demonstrated by a dual‑luciferase reporter system. The effects of miR-199a-5p on melanoma cells were assayed in B16 and HME1 melanoma cell lines. Furthermore, the potential of miR‑199a‑5p as a therapeutic target was illustrated in xenograft nude mice models. Low expression of miR‑199a‑5p in tumor melanoma tissue samples from patients was associated with high histological grade and advanced tumor stage. The 3'-untranslated region of HIF‑1α was identified as a target of miR‑199a‑5p by Targetscan software. The dual-luciferase reporter assay demonstrated that miR‑199a‑5p transfection of mimics decreased the luciferase activity significantly (P<0.05). In the B16 and HME1 cell lines, overexpression of miR‑199a‑5p suppressed cell proliferation and arrested the cell cycle in the G1 phase. In vivo overexpression of miR‑199a‑5p significantly suppressed xenograft growth and downregulated the expression of HIF‑1α (P<0.05). The results from the present study suggest that miR‑199a‑5p suppressed melanoma proliferation via HIF‑1α, suggesting it may be a potential therapeutic target for melanoma treatment. PMID:27122154

  16. Melanoma in Maori, Asian, and Pacific peoples in New Zealand.

    PubMed

    Sneyd, Mary Jane; Cox, Brian

    2009-06-01

    New Zealand Maori, Pacific, and Asian people develop melanoma less frequently than New Zealand Europeans, but little is known about melanomas that develop in these people. We examined the characteristics of melanoma in these minority ethnic groups in New Zealand. In 2007, all first primary melanomas diagnosed from January 1996 to December 2006 were extracted from the New Zealand Cancer Registry database. Melanoma was more commonly diagnosed in Maori than Asian or Pacific peoples. Age-adjusted incidence rates increased annually from 1996 to 2006 by 0.37 per 100,000 in the total population and 0.20 per 100,000 in Maori, a 12% (from 30.9 to 34.6) and 90% (from 2.3 to 4.3) increase, respectively, over the 11 years. Nodular melanoma occurred more often in Maori (15.9%) and Pacific peoples (17.1%) compared with Asians (8.7%) and New Zealand Europeans (10.5%). In Pacific peoples, acral lentiginous melanoma (22.9%) was the most common subtype. The median thickness of melanoma was 0.78 mm in New Zealand Europeans, 1.2 mm in Maori, 2.5 mm in Pacific peoples, and 0.73 mm in Asians (P < 0.001, difference in medians). Thirty-seven percent of melanomas in Pacific peoples were >4 mm thick compared with 7.9% in New Zealand Europeans. About 13% of Asians and 11% of Pacific peoples, compared with 4% of New Zealand Europeans with melanoma, were diagnosed by histology of metastases rather than the primary lesion. Minority ethnicities in New Zealand have a higher than expected risk of thick and more advanced melanoma, with poorer prognosis. Melanoma campaigns should include messages that incorporate the unique features of melanoma in minorities.

  17. Dual-Fuel Propulsion in Single-Stage Advanced Manned Launch System Vehicle

    NASA Technical Reports Server (NTRS)

    Lepsch, Roger A., Jr.; Stanley, Douglas O.; Unal, Resit

    1995-01-01

    As part of the United States Advanced Manned Launch System study to determine a follow-on, or complement, to the Space Shuttle, a reusable single-stage-to-orbit concept utilizing dual-fuel rocket propulsion has been examined. Several dual-fuel propulsion concepts were investigated. These include: a separate-engine concept combining Russian RD-170 kerosene-fueled engines with space shuttle main engine-derivative engines: the kerosene- and hydrogen-fueled Russian RD-701 engine; and a dual-fuel, dual-expander engine. Analysis to determine vehicle weight and size characteristics was performed using conceptual-level design techniques. A response-surface methodology for multidisciplinary design was utilized to optimize the dual-fuel vehicles with respect to several important propulsion-system and vehicle design parameters, in order to achieve minimum empty weight. The tools and methods employed in the analysis process are also summarized. In comparison with a reference hydrogen- fueled single-stage vehicle, results showed that the dual-fuel vehicles were from 10 to 30% lower in empty weight for the same payload capability, with the dual-expander engine types showing the greatest potential.

  18. Lymph node staging in colorectal cancer: Old controversies and recent advances

    PubMed Central

    Resch, Annika; Langner, Cord

    2013-01-01

    Outcome prediction based on tumor stage reflected by the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor node metastasis (TNM) system is currently regarded as the strongest prognostic parameter for patients with colorectal cancer. For affected patients, the indication for adjuvant therapy is mainly guided by the presence of regional lymph node metastasis. In addition to the extent of surgical lymph node removal and the thoroughness of the pathologist in dissecting the resection specimen, several parameters that are related to the pathological work-up of the dissected nodes may affect the clinical significance of lymph node staging. These include changing definitions of lymph nodes, involved lymph nodes, and tumor deposits in different editions of the AJCC/UICC TNM system as well as the minimum number of nodes to be dissected. Methods to increase the lymph node yield in the fatty tissue include methylene blue injection and acetone compression. Outcome prediction based on the lymph node ratio, defined as the number of positive lymph nodes divided by the total number of retrieved nodes, may be superior to the absolute numbers of involved nodes. Extracapsular invasion has been identified as additional prognostic factor. Adding step sectioning and immunohistochemistry to the pathological work-up may result in higher accuracy of histological diagnosis. The clinical value of more recent technical advances, such as sentinel lymph node biopsy and molecular analysis of lymph nodes tissue still remains to be defined. PMID:24379568

  19. Single stage, low noise, advanced technology fan. Volume 1: Aerodynamic design

    NASA Technical Reports Server (NTRS)

    Sullivan, T. J.; Younghans, J. L.; Little, D. R.

    1976-01-01

    The aerodynamic design for a half-scale fan vehicle, which would have application on an advanced transport aircraft, is described. The single stage advanced technology fan was designed to a pressure ratio of 1.8 at a tip speed of 503 m/sec 11,650 ft/sec). The fan and booster components are designed in a scale model flow size convenient for testing with existing facility and vehicle hardware. The design corrected flow per unit annulus area at the fan face is 215 kg/sec sq m (44.0 lb m/sec sq ft) with a hub-tip ratio of 0.38 at the leading edge of the fan rotor. This results in an inlet corrected airflow of 117.9 kg/sec (259.9 lb m/sec) for the selected rotor tip diameter if 90.37 cm (35.58 in.). The variable geometry inlet is designed utilizing a combination of high throat Mach number and acoustic treatment in the inlet diffuser for noise suppression (hybrid inlet). A variable fan exhaust nozzle was assumed in conjunction with the variable inlet throat area to limit the required area change of the inlet throat at approach and hence limit the overall diffusion and inlet length. The fan exit duct design was primarily influenced by acoustic requirements, including length of suppressor wall treatment; length, thickness and position on a duct splitter for additional suppressor treatment; and duct surface Mach numbers.

  20. Antineoplastic effects of Rhodiola crenulata treatment on B16-F10 melanoma.

    PubMed

    Dudek, Maxine C; Wong, Kaitlyn E; Bassa, Lotfi M; Mora, Maria Carmen; Ser-Dolansky, Jennifer; Henneberry, Jean M; Crisi, Giovanna M; Arenas, Richard B; Schneider, Sallie S

    2015-12-01

    Melanoma is an aggressive form of skin cancer with limited treatment options for advanced stage disease. Early detection and wide surgical excision remain the initial mode of treatment for primary tumors thus preventing metastases and leading to improved prognosis. Through this work, we have evaluated the antineoplastic effects of Rhodiola crenulata (R. crenulata) root extracts on the B16-F10 melanoma cell line, both in vitro and in vivo. We observed that R. crenulata treatment resulted in increased cell death as well as a reduction in tumor cell proliferation and migration in vitro. Additionally, we observed that R. crenulata decreased the expression of integrin β1 and vimentin and increased the expression of E-cadherin. Further, in mice treated with a topical R. crenulata-based cream therapy, tumors were more likely to have a radial growth pattern, a reduction in mitotic activity, and an increase in tumor necrosis. We also observed that mice drinking water supplemented with R. crenulata displayed a reduction of metastatic foci in disseminated models of melanoma. Collectively, these findings suggest that R. crenulata exhibits striking antitumorigenic and antimetastatic properties and that this extract may harbor potential novel adjuvant therapy for the treatment of melanoma. PMID:26159852

  1. Unexpected reduction of mortality rates from melanoma in males living in central Italy.

    PubMed

    Crocetti, E; Carli, Paolo

    2003-04-01

    A registry-based study has been carried out in central Italy to investigate cutaneous melanoma incidence and mortality trends. The incidence of invasive (1492 cases analysed) and in situ (224 cases) cutaneous melanomas increased significantly from 1985 to 1997, in both genders. The increase of invasive tumours was mainly due to 'thin' (stage at diagnosis was worse for males than females at the beginning of the analysed period, therefore the former had more possibilities for improvement than females. This may partially explain this finding since mortality rates among females were also quite low during the late 1980s. However, the stable incidence rates of the thick forms of melanoma make this finding largely unexpected, and difficult to understand assuming that in the last decade no 'clear-cut' improvements in survival have been documented as a result of new treatments in advanced melanomas.

  2. Generation and analysis of zebrafish melanoma models.

    PubMed

    Wojciechowska, S; van Rooijen, E; Ceol, C; Patton, E E; White, R M

    2016-01-01

    The rapid emergence of the zebrafish as a cancer model has been aided by advances in genetic, chemical, and imaging technologies. Melanoma in particular highlights both the power and challenges associated with cancer modeling in zebrafish. This chapter focuses on the lessons that have emerged from the melanoma models as paradigmatic of what will apply to nearly all cancer models in the zebrafish system. We specifically focus on methodologies related to germline and mosaic transgenic melanoma generation, and how these can be used to deeply interrogate additional cooperating oncogenes or tumor suppressors. These transgenic tumors can in turn be used to generate zebrafish-specific, stable melanoma cell lines which can be fluorescently labeled, modified by cDNA/CRISPR techniques, and used for detailed in vivo imaging of cancer progression in real time. These zebrafish melanoma models are beginning to elucidate both cell intrinsic and microenvironmental factors in melanoma that have broader implications for human disease. We envision that nearly all of the techniques described here can be applied to other zebrafish cancer models, and likely expanded beyond what we describe here. PMID:27312504

  3. The E3 ligase APC/C(Cdh1) promotes ubiquitylation-mediated proteolysis of PAX3 to suppress melanocyte proliferation and melanoma growth.

    PubMed

    Cao, Juxiang; Dai, Xiangpeng; Wan, Lixin; Wang, Hongshen; Zhang, Jinfang; Goff, Philip S; Sviderskaya, Elena V; Xuan, Zhenyu; Xu, Zhixiang; Xu, Xiaowei; Hinds, Philip; Flaherty, Keith T; Faller, Douglas V; Goding, Colin R; Wang, Yongjun; Wei, Wenyi; Cui, Rutao

    2015-09-01

    The anaphase-promoting complex or cyclosome with the subunit Cdh1 (APC/C(Cdh1)) is an E3 ubiquitin ligase involved in the control of the cell cycle. Here, we identified sporadic mutations occurring in the genes encoding APC components, including Cdh1, in human melanoma samples and found that loss of APC/C(Cdh1) may promote melanoma development and progression, but not by affecting cell cycle regulatory targets of APC/C. Most of the mutations we found in CDH1 were those associated with ultraviolet light (UV)-induced melanomagenesis. Compared with normal human skin tissue and human or mouse melanocytes, the abundance of Cdh1 was decreased and that of the transcription factor PAX3 was increased in human melanoma tissue and human or mouse melanoma cell lines, respectively; Cdh1 abundance was further decreased with advanced stages of human melanoma. PAX3 was a substrate of APC/C(Cdh1) in melanocytes, and APC/C(Cdh1)-mediated ubiquitylation marked PAX3 for proteolytic degradation in a manner dependent on the D-box motif in PAX3. Either mutating the D-box in PAX3 or knocking down Cdh1 prevented the ubiquitylation and degradation of PAX3 and increased proliferation and melanin production in melanocytes. Knocking down Cdh1 in melanoma cells in culture or before implantation in mice promoted doxorubicin resistance, whereas reexpressing wild-type Cdh1, but not E3 ligase-deficient Cdh1 or a mutant that could not interact with PAX3, restored doxorubicin sensitivity in melanoma cells both in culture and in xenografts. Thus, our findings suggest a tumor suppressor role for APC/C(Cdh1) in melanocytes and that targeting PAX3 may be a strategy for treating melanoma. PMID:26329581

  4. Incidence, Surgical Treatment, and Prognosis of Anorectal Melanoma From 1973 to 2011: A Population-Based SEER Analysis.

    PubMed

    Chen, Haiyan; Cai, Yibo; Liu, Yue; He, Jinjie; Hu, Yeting; Xiao, Qian; Hu, Wangxiong; Ding, Kefeng

    2016-02-01

    Anorectal melanoma (AM) is a rare type of melanoma that accounts for 0.4% to 1.6% of total malignant melanomas. The incidence of AM increases over time, and it remains highly lethal, with a 5-year survival rate of 6% to 22%. Considering the rare nature of this disease, most studies on AM comprise isolated case reports and single-center trials, which could not provide comprehensive assessment of the disease. Therefore, we conducted a population-based study by using the Surveillance, Epidemiology, and End Results (SEER) program to provide the latest and best available evidence of AM.We extracted all cases of AM registered in the SEER database from 1973 to 2011 (April 2014 release) and calculated age-adjusted incidence. Only cases with active follow-up were included to predict factors associated with prognosis. Survival outcomes were also compared among different types of surgery.We identified 640 AM cases, which consisted of 265 rectal melanoma and 375 anal melanoma. The estimated annual incidence rates of AM per 1 million population were 0.259 in males and 0.407 in females, and it increased with advanced age and over time. Tumor stage and surgical treatment were independent predictors of survival. Results implied that surgery improved the prognosis of patients with local- and regional-stage AM but could not prolong the survival of patients with distant-stage AM. Moreover, the outcome of less extensive excision was not statistically different from that of more extensive excision.This study provides an up-to-date estimation of the incidence and prognosis of AM by using SEER data. The incidence of AM continuously increases over time, despite its rarity. This disease also exhibits poor prognosis. Thus, AM must be further investigated in future studies. We also recommend surgery as the optimal treatment for local- and regional-stage AM patients but not for those with distant metastasis.

  5. Incidence, Surgical Treatment, and Prognosis of Anorectal Melanoma From 1973 to 2011: A Population-Based SEER Analysis.

    PubMed

    Chen, Haiyan; Cai, Yibo; Liu, Yue; He, Jinjie; Hu, Yeting; Xiao, Qian; Hu, Wangxiong; Ding, Kefeng

    2016-02-01

    Anorectal melanoma (AM) is a rare type of melanoma that accounts for 0.4% to 1.6% of total malignant melanomas. The incidence of AM increases over time, and it remains highly lethal, with a 5-year survival rate of 6% to 22%. Considering the rare nature of this disease, most studies on AM comprise isolated case reports and single-center trials, which could not provide comprehensive assessment of the disease. Therefore, we conducted a population-based study by using the Surveillance, Epidemiology, and End Results (SEER) program to provide the latest and best available evidence of AM.We extracted all cases of AM registered in the SEER database from 1973 to 2011 (April 2014 release) and calculated age-adjusted incidence. Only cases with active follow-up were included to predict factors associated with prognosis. Survival outcomes were also compared among different types of surgery.We identified 640 AM cases, which consisted of 265 rectal melanoma and 375 anal melanoma. The estimated annual incidence rates of AM per 1 million population were 0.259 in males and 0.407 in females, and it increased with advanced age and over time. Tumor stage and surgical treatment were independent predictors of survival. Results implied that surgery improved the prognosis of patients with local- and regional-stage AM but could not prolong the survival of patients with distant-stage AM. Moreover, the outcome of less extensive excision was not statistically different from that of more extensive excision.This study provides an up-to-date estimation of the incidence and prognosis of AM by using SEER data. The incidence of AM continuously increases over time, despite its rarity. This disease also exhibits poor prognosis. Thus, AM must be further investigated in future studies. We also recommend surgery as the optimal treatment for local- and regional-stage AM patients but not for those with distant metastasis. PMID:26886623

  6. Primary malignant melanoma

    PubMed Central

    Mısır, A. Ferhat; Durmuşlar, Mustafa C.; Zerener, Tamer; Gün, Banu D.

    2016-01-01

    Malignant melanomas (MM) of the oral cavity are extremely rare, accounting for 0.2% to 8.0% of all malignant melanomas. Malignant melanomas is more frequently seen at the level of the hard palate and gingiva. Early diagnosis and treatment are important for reducing morbidity. Malignant melanoma cells stain positively with antibodies to human melanoma black 45, S-100 protein, and vimentin; therefore, immunohistochemistry can play an important role in evaluating the depth of invasion and the location of metastases. A 76-year-old man developed an oral malignant melanoma, which was originally diagnosed as a bluish reactive denture hyperplasia caused by an ill-fitting lower denture. The tumor was removed surgically, and histopathological examination revealed a nodular-type MM. There was no evidence of recurrence over a 4-year follow-up period. PMID:27052289

  7. Serpine2, a potential novel target for combating melanoma metastasis

    PubMed Central

    Wu, Qi Wei

    2016-01-01

    Early stages of melanoma can be treated by surgical resection of tumor, but there is still no effective treatment once it is progressed to metastatic phases. Although growing family of both metastasis promoting and metastasis suppressor genes have been reported, the molecular mechanisms governing melanoma metastatic cascade are still not completely understood. Therefore, defining the molecules that govern melanoma metastasis may aid the development of more effective therapeutic strategies for combating cancer. In the present study, we found that Serpin Peptidase Inhibitor 2, Serpine2 was involved in the metastasis of melanoma cells. The requirement of Serpine2 in the migration of melanoma cells was confirmed by gene silencing and over-expression in vitro. Moreover, down-regulation of Serpine2 expression strikingly inhibited melanoma cellular metastasis in vivo. Finally, we found that Serpine2 promotes melanoma metastasis through the glycogen synthesis kinase 3β, GSK-3β signaling pathway. To conclude, our findings suggested a novel mechanism underlying the metastasis of melanoma cells which might serve as a new intervention target for the treatment of melanoma. PMID:27347308

  8. Oxidized low-density lipoprotein is associated with advanced-stage prostate cancer.

    PubMed

    Wan, Fangning; Qin, Xiaojian; Zhang, Guiming; Lu, Xiaolin; Zhu, Yao; Zhang, Hailiang; Dai, Bo; Shi, Guohai; Ye, Dingwei

    2015-05-01

    Clinical and epidemiological data suggest coronary artery disease shares etiology with prostate cancer (PCa). The aim of this work was to assess the effects of several serum markers reported in cardiovascular disease on PCa. Serum markers (oxidized low-density lipoprotein [ox-LDL], apolipoprotein [apo] B100, and apoB48) in peripheral blood samples from 50 patients from Fudan University Shanghai Cancer Center (FUSCC) with localized or lymph node metastatic PCa were investigated in this study. Twenty-five samples from normal individuals were set as controls. We first conducted enzyme-linked immunosorbent assay analysis to select candidate markers that were significantly different between these patients and controls. Then, the clinical relevance between OLR1 (the ox-LDL receptor) expression and PCa was analyzed in The Cancer Genome Atlas (TCGA) cohort. We also investigated the function of ox-LDL in PCa cell lines in vitro. Phosphorylation protein chips were used to analyze cell signaling pathways in ox-LDL-treated PC-3 cells. The ox-LDL level was found to be significantly correlated with N stage of prostate cancer. OLR1 expression was correlated with lymph node metastasis in the TCGA cohort. In vitro, ox-LDL stimulated the proliferation, migration, and invasion of LNCaP and PC-3 in a dose-dependent manner. The results of phosphoprotein microarray illustrated that ox-LDL could influence multiple signaling pathways of PC-3. Activation of proliferation promoting signaling pathways (including β-catenin, cMyc, NF-κB, STAT1, STAT3) as well as apoptosis-associating signaling pathways (including p27, caspase-3) demonstrated that ox-LDL had complicated effects on prostate cancer. Increased serum ox-LDL level and OLR1 expression may indicate advanced-stage PCa and lymph node metastasis. Moreover, ox-LDL could stimulate PCa proliferation, migration, and invasion in vitro.

  9. Results of two different surgical techniques in the treatment of advanced-stage Freiberg's disease

    PubMed Central

    Özkul, Emin; Gem, Mehmet; Alemdar, Celil; Arslan, Hüseyin; Boğatekin, Ferit; Kişin, Bülent

    2016-01-01

    Background: Freiberg's disease is an osteochondrosis most commonly seen in adolescent women and characterized by pain, swelling and motion restriction in the second metatarsal. The early stages of this disease can be managed with semirigid orthoses, metatarsal bars and short leg walking cast. Number of operative methods are suggested which can be used depending on the pathophysiology of the disease, including abnormal biomechanics, joint congruence and degenerative process. We evaluated the outcomes of the patients with Freiberg's disease who were treated with dorsal closing-wedge osteotomy and resection of the metatarsal head. Patients and Methods: 16 patients (11 female, 5 male) with a mean age of 24.5 (range 13–49 years) years who underwent dorsal closing wedge osteotomy or resection of the metatarsal head were included in this retrospective study. Second metatarsal was affected in 13 and third metatarsal in three patients. According to the Smillie's classification system, ten patients had type IV osteonecrosis and six patients had type V. The results of the patients were evaluated using the lesser metatarsophalangeal-interphalangeal (LMPI) scale. Results: According to the LMPI scale, the postoperative scores for the osteotomy and excision groups were 86 (range 64–100) and 72.6 (range 60–85), respectively. In the osteotomy group, mean passive flexion restriction was 18° (range 0°–35°) and mean passive extension restriction was 12° (range 0°–25°). Mean metatarsal shortening was 2.2 mm (range 2–4 mm) in the osteotomy group as opposed to 9.8 mm (range 7–14 mm) in the excision group. Significant pain relief was obtained in both groups following the surgery. Conclusions: The decision of performing osteotomy or resection arthroplasty in the patients with advanced-stage Freiberg's disease should be based on the joint injury and the patients should be informed about the cosmetic problems like shortening which may arise from resection. PMID:26955180

  10. The role of neoadjuvant chemotherapy in patients with advanced (stage IIIC) epithelial ovarian cancer

    PubMed Central

    Škof, Erik; Merlo, Sebastjan; Pilko, Gasper

    2016-01-01

    Abstract Background Primary treatment of patients with advanced epithelial ovarian cancer consists of chemotherapy either before (neoadjuvant chemotherapy, NACT) or after primary surgery (adjuvant chemotherapy). The goal of primary treatment is no residual disease after surgery (R0 resection) what is associated with an improvement in survival of patients. There is, however, no evidence of survival benefits in patients with R0 resections after prior NACT. Methods We retrospectively reviewed the records of patients who were treated with diagnosis of epithelial ovarian cancer at Institute of Oncology Ljubljana in the years 2005–2007. The differences in the rates of R0 resections, progression free survival (PFS), overall survival (OS) and in five-year and eight-year survival rates between patients treated with NACT and patients who had primary surgery were compared. Results Overall 160 patients had stage IIIC epithelial ovarian cancer. Eighty patients had NACT and eighty patients had primary surgery. Patients in NACT group had higher rates of R0 resection (42% vs. 20%; p = 0.011) than patients after primary surgery. PFS was 14.1 months in NACT group and 17.7 months after primary surgery (p = 0.213). OS was 24.8 months in NACT group and 31.6 months after primary surgery (p = 0.012). In patients with R0 resections five-year and eight-year survival rates were 20.6% and 17.6% in NACT group compared to 62.5% and 62.5% after primary surgery (p < 0.0001), respectively. Conclusions Despite higher rates of R0 resections achieved by NACT, survival of patients treated with NACT was inferior to survival of patients who underwent primary surgery. NACT should only be offered to patients with advanced epithelial cancer who are not candidates for primary surgery. PMID:27679552

  11. The role of neoadjuvant chemotherapy in patients with advanced (stage IIIC) epithelial ovarian cancer

    PubMed Central

    Škof, Erik; Merlo, Sebastjan; Pilko, Gasper

    2016-01-01

    Abstract Background Primary treatment of patients with advanced epithelial ovarian cancer consists of chemotherapy either before (neoadjuvant chemotherapy, NACT) or after primary surgery (adjuvant chemotherapy). The goal of primary treatment is no residual disease after surgery (R0 resection) what is associated with an improvement in survival of patients. There is, however, no evidence of survival benefits in patients with R0 resections after prior NACT. Methods We retrospectively reviewed the records of patients who were treated with diagnosis of epithelial ovarian cancer at Institute of Oncology Ljubljana in the years 2005–2007. The differences in the rates of R0 resections, progression free survival (PFS), overall survival (OS) and in five-year and eight-year survival rates between patients treated with NACT and patients who had primary surgery were compared. Results Overall 160 patients had stage IIIC epithelial ovarian cancer. Eighty patients had NACT and eighty patients had primary surgery. Patients in NACT group had higher rates of R0 resection (42% vs. 20%; p = 0.011) than patients after primary surgery. PFS was 14.1 months in NACT group and 17.7 months after primary surgery (p = 0.213). OS was 24.8 months in NACT group and 31.6 months after primary surgery (p = 0.012). In patients with R0 resections five-year and eight-year survival rates were 20.6% and 17.6% in NACT group compared to 62.5% and 62.5% after primary surgery (p < 0.0001), respectively. Conclusions Despite higher rates of R0 resections achieved by NACT, survival of patients treated with NACT was inferior to survival of patients who underwent primary surgery. NACT should only be offered to patients with advanced epithelial cancer who are not candidates for primary surgery.

  12. MicroRNA dysregulation in melanoma.

    PubMed

    Latchana, Nicholas; Ganju, Akaansha; Howard, J Harrison; Carson, William E

    2016-09-01

    Melanoma is the deadliest form of skin cancer. Current challenges facing the management of melanoma include accurate prediction of individuals who will respond to adjuvant therapies as well as early detection of recurrences. These and other challenges have prompted investigation into biomarkers that could be used as diagnostic, prognostic and therapeutic aids. MicroRNAs (miRs) are small 19-22 nucleotide RNA inhibitors of protein translation. Over 800 different miRs are present within cells and importantly miR expression profiles may vary across different cells types and stages of malignancy. Unique expression profiles have been described for malignant melanoma; however, this work has yet to be translated into routine clinical practice. We highlight pertinent studies involving common miRs implicated in the oncogenesis of melanoma including miR-21, miR-125b, miR-150, miR-155, miR-205, and miR-211. In particular, emphasis is placed upon differential expression across different stages of melanoma progression, prognostic implications and potential mechanistic involvement. Focused efforts on inhibition of these miRs could be the most efficient method of translating preclinical endeavors into clinically meaningful applications. PMID:27566021

  13. Hereditary melanoma: Update on syndromes and management: Emerging melanoma cancer complexes and genetic counseling.

    PubMed

    Soura, Efthymia; Eliades, Philip J; Shannon, Kristen; Stratigos, Alexander J; Tsao, Hensin

    2016-03-01

    Recent advances in cancer genomics have enabled the discovery of many cancer-predisposing genes that are being used to classify new familial melanoma/cancer syndromes. In addition to CDKN2A and CDK4, germline variants in TERT, MITF, and BAP1 have been added to the list of genes harboring melanoma-predisposing mutations. These newer entities may have escaped earlier description in part because of more advanced technologies now being used and in part because of their mixed cancer phenotype as opposed to a melanoma-focused syndrome. Dermatologists should be aware of (and be able to recognize) the clinical signs in high-risk patients in different contexts. Personal and family histories of cancer should always be sought in patients with multiple nevi or a positive history for melanoma, and should be updated annually. Various features that are unique to specific disorders, such as the appearance of melanocytic BAP1-mutated atypical intradermal tumors in cases of BAP1 melanoma syndrome, should also be recognized early. These patients should be offered regular screenings with the use of dermoscopy and total body photography, as needed. More importantly, referral to other specialists may be needed if a risk for internal malignancy is suspected. It is important to have in mind that these patients tend to develop multiple melanomas, along with various internal organ malignancies, often at younger ages; a multidisciplinary approach to their cancer screening and treatment is ideal.

  14. Hereditary melanoma: Update on syndromes and management: Emerging melanoma cancer complexes and genetic counseling.

    PubMed

    Soura, Efthymia; Eliades, Philip J; Shannon, Kristen; Stratigos, Alexander J; Tsao, Hensin

    2016-03-01

    Recent advances in cancer genomics have enabled the discovery of many cancer-predisposing genes that are being used to classify new familial melanoma/cancer syndromes. In addition to CDKN2A and CDK4, germline variants in TERT, MITF, and BAP1 have been added to the list of genes harboring melanoma-predisposing mutations. These newer entities may have escaped earlier description in part because of more advanced technologies now being used and in part because of their mixed cancer phenotype as opposed to a melanoma-focused syndrome. Dermatologists should be aware of (and be able to recognize) the clinical signs in high-risk patients in different contexts. Personal and family histories of cancer should always be sought in patients with multiple nevi or a positive history for melanoma, and should be updated annually. Various features that are unique to specific disorders, such as the appearance of melanocytic BAP1-mutated atypical intradermal tumors in cases of BAP1 melanoma syndrome, should also be recognized early. These patients should be offered regular screenings with the use of dermoscopy and total body photography, as needed. More importantly, referral to other specialists may be needed if a risk for internal malignancy is suspected. It is important to have in mind that these patients tend to develop multiple melanomas, along with various internal organ malignancies, often at younger ages; a multidisciplinary approach to their cancer screening and treatment is ideal. PMID:26892651

  15. Evolving Pharmacotherapies for the Treatment of Metastatic Melanoma

    PubMed Central

    Salama, April K.S.

    2013-01-01

    Metastatic melanoma remains a difficult disease to treat, and long term survivors are rare. Over the past few years, however, breakthroughs in both immunotherapy as well as targeted agents have had a tremendous impact on patients diagnosed with this disease. This review summarizes recent advances in systemic therapies for melanoma, including immune modulators directed against cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), as well as a number of targeted agents. These approaches hold great promise as the landscape of therapeutic options for advanced melanoma continues to evolve. PMID:23843723

  16. Improving Goals of Care Discussion in Advanced Cancer Patients

    ClinicalTrials.gov

    2016-06-30

    Primary Stage IV Hepatobiliary; Esophageal; Colorectal Cancer; Glioblastoma; Cancer of Stomach; Cancer of Pancreas; Melanoma; Head or Neck Cancer; Stage III; Stage IV; Lung Cancers; Pancreatic Cancers

  17. Future perspectives in melanoma research: meeting report from the "Melanoma Bridge", Napoli, December 5th-8th 2013.

    PubMed

    Ascierto, Paolo A; Grimaldi, Antonio M; Anderson, Ana Carrizosa; Bifulco, Carlo; Cochran, Alistair; Garbe, Claus; Eggermont, Alexander M; Faries, Mark; Ferrone, Soldano; Gershenwald, Jeffrey E; Gajewski, Thomas F; Halaban, Ruth; Hodi, F Stephen; Kefford, Richard; Kirkwood, John M; Larkin, James; Leachman, Sancy; Maio, Michele; Marais, Richard; Masucci, Giuseppe; Melero, Ignacio; Palmieri, Giuseppe; Puzanov, Igor; Ribas, Antoni; Saenger, Yvonne; Schilling, Bastian; Seliger, Barbara; Stroncek, David; Sullivan, Ryan; Testori, Alessandro; Wang, Ena; Ciliberto, Gennaro; Mozzillo, Nicola; Marincola, Francesco M; Thurin, Magdalena

    2014-10-28

    The fourth "Melanoma Bridge Meeting" took place in Naples, December 5 to 8th, 2013. The four topics discussed at this meeting were: Diagnosis and New Procedures, Molecular Advances and Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers.

  18. Advanced Imaging and Receipt of Guideline Concordant Care in Women with Early Stage Breast Cancer

    PubMed Central

    Buist, Diana S. M.; Gold, Laura S.; Zeliadt, Steven; Hunter Merrill, Rachel; Etzioni, Ruth; Ramsey, Scott D.; Sullivan, Sean D.; Kessler, Larry

    2016-01-01

    Objective. It is unknown whether advanced imaging (AI) is associated with higher quality breast cancer (BC) care. Materials and Methods. Claims and Surveillance Epidemiology and End Results data were linked for women diagnosed with incident stage I-III BC between 2002 and 2008 in western Washington State. We examined receipt of preoperative breast magnetic resonance imaging (MRI) or AI (defined as computed tomography [CT]/positron emission tomography [PET]/PET/CT) versus mammogram and/or ultrasound (M-US) alone and receipt of guideline concordant care (GCC) using multivariable logistic regression. Results. Of 5247 women, 67% received M-US, 23% MRI, 8% CT, and 3% PET/PET-CT. In 2002, 5% received MRI and 5% AI compared to 45% and 12%, respectively, in 2008. 79% received GCC, but GCC declined over time and was associated with younger age, urban residence, less comorbidity, shorter time from diagnosis to surgery, and earlier year of diagnosis. Breast MRI was associated with GCC for lumpectomy plus radiation therapy (RT) (OR 1.55, 95% CI 1.08–2.26, and p = 0.02) and AI was associated with GCC for adjuvant chemotherapy for estrogen-receptor positive (ER+) BC (OR 1.74, 95% CI 1.17–2.59, and p = 0.01). Conclusion. GCC was associated with prior receipt of breast MRI and AI for lumpectomy plus RT and adjuvant chemotherapy for ER+ BC, respectively. PMID:27525122

  19. HLA-G Expression and Role in Advanced-Stage Classical Hodgkin Lymphoma

    PubMed Central

    Caocci, G.; Greco, M.; Fanni, D.; Senes, G.; Littera, R.; Lai, S.; Risso, P.; Carcassi, C.; Faa, G.; La Nasa, G.

    2016-01-01

    Non-classical human leucocyte antigen (HLA)-G class I molecules have an important role in tumor immune escape mechanisms. We investigated HLA-G expression in lymphonode biopsies taken from 8 controls and 20 patients with advanced-stage classical Hodgkin lymphoma (cHL), in relationship to clinical outcomes and the HLA-G 14-basepair (14-bp) deletion-insertion (del-ins) polymorphism. Lymphnode tissue sections were stained using a specific murine monoclonal HLA-G antibody. HLA-G protein expression was higher in cHL patients than controls. In the group of PET-2 positive (positron emission tomography carried out after 2 cycles of standard chemotherapy) patients with a 2-year progression-free survival rate (PFS) of 40%, we observed high HLA-G protein expression within the tumor microenvironment with low expression on Hodgkin and Reed-Sternberg (HRS) cells. Conversely, PET-2 negative patients with a PFS of 86% had higher HLA-G protein expression levels on HRS cells compared to the microenvironment. Lower expression on HRS cells was significantly associated with the HLA-G 14-bp ins/ins genotype. These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2. PMID:27349312

  20. Advanced Imaging and Receipt of Guideline Concordant Care in Women with Early Stage Breast Cancer.

    PubMed

    Loggers, Elizabeth Trice; Buist, Diana S M; Gold, Laura S; Zeliadt, Steven; Hunter Merrill, Rachel; Etzioni, Ruth; Ramsey, Scott D; Sullivan, Sean D; Kessler, Larry

    2016-01-01

    Objective. It is unknown whether advanced imaging (AI) is associated with higher quality breast cancer (BC) care. Materials and Methods. Claims and Surveillance Epidemiology and End Results data were linked for women diagnosed with incident stage I-III BC between 2002 and 2008 in western Washington State. We examined receipt of preoperative breast magnetic resonance imaging (MRI) or AI (defined as computed tomography [CT]/positron emission tomography [PET]/PET/CT) versus mammogram and/or ultrasound (M-US) alone and receipt of guideline concordant care (GCC) using multivariable logistic regression. Results. Of 5247 women, 67% received M-US, 23% MRI, 8% CT, and 3% PET/PET-CT. In 2002, 5% received MRI and 5% AI compared to 45% and 12%, respectively, in 2008. 79% received GCC, but GCC declined over time and was associated with younger age, urban residence, less comorbidity, shorter time from diagnosis to surgery, and earlier year of diagnosis. Breast MRI was associated with GCC for lumpectomy plus radiation therapy (RT) (OR 1.55, 95% CI 1.08-2.26, and p = 0.02) and AI was associated with GCC for adjuvant chemotherapy for estrogen-receptor positive (ER+) BC (OR 1.74, 95% CI 1.17-2.59, and p = 0.01). Conclusion. GCC was associated with prior receipt of breast MRI and AI for lumpectomy plus RT and adjuvant chemotherapy for ER+ BC, respectively. PMID:27525122

  1. A Positive Prospective Trial of Antibiotic Therapy in Advanced Stage, Non-Bulky Indolent Lymphoma

    PubMed Central

    Portlock, Carol S; Hamlin, Paul A; Gerecitano, John F; Noy, Ariela; Palomba, Maria Lia; Walkley, Janelle; Corcoran, Stacie; Migliacci, Jocelyn; Schoder, Heiko; Papanicolaou, Genovefa; Markowitz, Arnold J

    2016-01-01

    Background We have prospectively studied a three month course of clarithromycin (substituted by Prevpac®, lansoprazole/ amoxicillin/ clarithromycin, in the first two wks when stool H pylori+) for non-bulky, advanced stage indolent lymphoma. These patients are often candidates for expectant monitoring and it is during this period that a window of opportunity may exist to identify and treat associated infections. Methods All previously untreated patients with a new diagnosis of indolent lymphoma (FL and non-FL) meeting GELF criteria were treated with 12 weeks of clarithromycin. There were 32 evaluable patients, 4 of whom had stool H pylori. Results At one month post-antibiotic therapy, we have observed lymphoma responses in 7 of 32 patients (21.9%). Two additional patients had objective response during followup (28.1% overall response). The median treatment free survival for antibiotic responders is 69.9 months and for non-responders, 30.6 months (p = 0.019). Conclusion Three response patterns have been noted, perhaps suggestive of an immune-mediated response -- prompt PET negative; flair with delayed PET negative response; and gradual continuous improvement. This prospective study appears promising, may be a step toward developing a lymphoma prevention strategy by reducing “antigen drive,” and deserves further clinical/biological study. http://clinicaltrials.gov/show/NCT00461084 PMID:26798624

  2. Cost-utility analysis of imatinib mesilate for the treatment of advanced stage chronic myeloid leukaemia.

    PubMed

    Gordois, A; Scuffham, P; Warren, E; Ward, S

    2003-08-18

    Imatinib mesilate (Glivec), Novartis Pharmaceuticals) is a novel therapy for the treatment of chronic myeloid leukaemia (CML). We evaluated the cost-effectiveness of imatinib (600 mg daily) when used for the treatment of patients in advanced stages of CML (accelerated phase and blast crisis) against conventional therapies of combination chemotherapy (DAT) and palliative care in hospital or at home. A Markov model simulated the transitions of hypothetical patient cohorts and outcomes were modelled for 5 years from the start of treatment. Costs were estimated from the perspective of the UK National Health Service. Over 5 years, a patient in accelerated phase will, on average, accrue an additional 2.09 QALYs with imatinib compared to conventional therapies, while patients in blast crisis will accrue an additional 0.58 quality-adjusted life-years (QALYs) with imatinib compared to conventional therapies. The costs per additional QALY gained from treatment with imatinib compared with conventional therapies were pound 29344 (accelerated phase) and pound 42239 (blast crisis). The results were particularly sensitive to the price of imatinib, improvements in quality of life, and the duration of haematological responses. We conclude that treatment of CML with imatinib confers considerably greater survival and quality of life than conventional treatments but at a cost. PMID:12915870

  3. Malignant melanoma of the lacrimal sac.

    PubMed

    Yamade, S; Kitagawa, A

    1978-01-01

    A case of malignant melanoma of the lacrimal sac in a 41-year-old woman is reported, which is propably the 12th one in the world literature. Dacryocystectomy is advisable at a localized stage. The importance of early diagnosis is discussed. PMID:714368

  4. First Oncolytic Viral Therapy for Melanoma.

    PubMed

    Poh, Alissa

    2016-01-01

    The FDA has approved talimogene laherparepvec, or T-VEC, to treat surgically unresectable skin and lymph node lesions in patients with advanced melanoma. T-VEC is the first oncolytic viral therapy to gain regulatory endorsement, based on data from the OPTiM study.

  5. Tumor-Infiltrating Lymphocyte Grade in Primary Melanomas Is Independently Associated With Melanoma-Specific Survival in the Population-Based Genes, Environment and Melanoma Study

    PubMed Central

    Thomas, Nancy E.; Busam, Klaus J.; From, Lynn; Kricker, Anne; Armstrong, Bruce K.; Anton-Culver, Hoda; Gruber, Stephen B.; Gallagher, Richard P.; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Venn, Alison; Kanetsky, Peter A.; Groben, Pamela A.; Hao, Honglin; Orlow, Irene; Reiner, Anne S.; Luo, Li; Paine, Susan; Ollila, David W.; Wilcox, Homer; Begg, Colin B.; Berwick, Marianne

    2013-01-01

    Purpose Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas. Patients and Methods On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined. Results Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (Ptrend < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage. Conclusion At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions. PMID:24127443

  6. The potential role of bevacizumab in early stages and locally advanced non-small cell lung cancer

    PubMed Central

    Schettino, Clorinda; Bareschino, Maria Anna; Rossi, Antonio; Maione, Paolo; Castaldo, Vincenzo; Mazzeo, Nicole; Sacco, Paola Claudia; Ferrara, Marianna Luciana; Palazzolo, Giovanni; Ciardiello, Fortunato; Gridelli, Cesare

    2009-01-01

    Improving outcomes for early-stage non-small cell lung cancer (NSCLC) is a major research area considering that a significant percentage of such patients develop recurrent disease within 5 years of complete lung resection. Adjuvant chemotherapy prolongs survival, with an absolute improvement in 5-year overall survival of about 5% with drawbacks such as treatment toxicity. Approximately, one third of patients with newly diagnosed NSCLC have locally advanced disease not amenable for surgical resection – in this setting of patients concurrent chemoradiation is the standard of therapy. However, the treatment of locally advanced NSCLC is still controversial and clinical outcomes are disappointing, and so new approaches are required to improve the clinical benefit in this setting of patients. Vascular endothelial growth factor (VEGF) is a key angiogenic factor implicated in tumor blood vessels formation and permeability, and tumor VEGF overexpression in patients with early stage lung cancer has been associated with worse relapse free and overall survival. Several agents have been developed that inhibit VEGF or its receptor signalling system. Bevacizumab is the first recombinant humanized monoclonal antibody binding VEGF to demonstrate clinical benefit or rather a survival prolongation in combination with chemotherapy in the treatment of non-squamous advanced NSCLC patients. These positive results led to a large number of clinical trials to evaluate bevacizumab in combination with other targeted agents in advanced disease, and to define the role of this agent in early stage NSCLC such as the impact of bevacizumab integration in chemoradiotherapy strategy for locally advanced disease. PMID:21789109

  7. The potential role of bevacizumab in early stages and locally advanced non-small cell lung cancer.

    PubMed

    Schettino, Clorinda; Bareschino, Maria Anna; Rossi, Antonio; Maione, Paolo; Castaldo, Vincenzo; Mazzeo, Nicole; Sacco, Paola Claudia; Ferrara, Marianna Luciana; Palazzolo, Giovanni; Ciardiello, Fortunato; Gridelli, Cesare

    2009-07-01

    Improving outcomes for early-stage non-small cell lung cancer (NSCLC) is a major research area considering that a significant percentage of such patients develop recurrent disease within 5 years of complete lung resection. Adjuvant chemotherapy prolongs survival, with an absolute improvement in 5-year overall survival of about 5% with drawbacks such as treatment toxicity. Approximately, one third of patients with newly diagnosed NSCLC have locally advanced disease not amenable for surgical resection - in this setting of patients concurrent chemoradiation is the standard of therapy. However, the treatment of locally advanced NSCLC is still controversial and clinical outcomes are disappointing, and so new approaches are required to improve the clinical benefit in this setting of patients. Vascular endothelial growth factor (VEGF) is a key angiogenic factor implicated in tumor blood vessels formation and permeability, and tumor VEGF overexpression in patients with early stage lung cancer has been associated with worse relapse free and overall survival. Several agents have been developed that inhibit VEGF or its receptor signalling system. Bevacizumab is the first recombinant humanized monoclonal antibody binding VEGF to demonstrate clinical benefit or rather a survival prolongation in combination with chemotherapy in the treatment of non-squamous advanced NSCLC patients. These positive results led to a large number of clinical trials to evaluate bevacizumab in combination with other targeted agents in advanced disease, and to define the role of this agent in early stage NSCLC such as the impact of bevacizumab integration in chemoradiotherapy strategy for locally advanced disease.

  8. Antibody-drug conjugates: targeting melanoma with cisplatin encapsulated in protein-cage nanoparticles based on human ferritin

    NASA Astrophysics Data System (ADS)

    Falvo, Elisabetta; Tremante, Elisa; Fraioli, Rocco; Leonetti, Carlo; Zamparelli, Carlotta; Boffi, Alberto; Morea, Veronica; Ceci, Pierpaolo; Giacomini, Patrizio

    2013-11-01

    A novel antibody-drug conjugate (ADC) was synthesized incorporating ferritin-based nanoparticles. An average of three molecules of monoclonal antibody (mAb) Ep1 to the human melanoma-specific antigen CSPG4 were conjugated to a single ferritin cage encapsulating about 50 cisplatin molecules (HFt-Pt-Ep1). The HFt-Pt-Ep1 nanoparticle had an estimated molecular size of about 900 kD and 33 nm, and flow cytometry demonstrated specific binding to a CSPG4+ melanoma cell line, but not to a CSPG4- breast carcinoma cell line. As compared to the cisplatin-containing ferritin nanoparticle alone (HFt-Pt), which inhibited thymidine incorporation more efficiently in breast carcinoma than melanoma cells, the mAb-derivatized HFt-Pt-Ep1 nanoparticle had a 25-fold preference for the latter. A similar preference for melanoma was observed upon systemic intravenous administration of HFt-Pt-Ep1 to nude mice xenotransplanted with pre-established, palpable melanoma and breast carcinoma tumors. Thus, we have been able to determine precise combinations and stoichiometric relationships between mAbs and nanoparticle protein cages, whereby the latter lose their tropism for ubiquitously distributed cellular receptors, and acquire instead remarkably lineage-selective binding. HFt-Pt-Ep1 is therefore an interesting model to improve the therapeutic index of antiblastic therapy in a tumor such as melanoma, which at its advanced stages is totally refractory to mono- and combination-chemotherapy.A novel antibody-drug conjugate (ADC) was synthesized incorporating ferritin-based nanoparticles. An average of three molecules of monoclonal antibody (mAb) Ep1 to the human melanoma-specific antigen CSPG4 were conjugated to a single ferritin cage encapsulating about 50 cisplatin molecules (HFt-Pt-Ep1). The HFt-Pt-Ep1 nanoparticle had an estimated molecular size of about 900 kD and 33 nm, and flow cytometry demonstrated specific binding to a CSPG4+ melanoma cell line, but not to a CSPG4- breast carcinoma cell

  9. Melanoma with gastric metastases

    PubMed Central

    Wong, Katherine; Serafi, Sam W.; Bhatia, Abhijit S.; Ibarra, Irene; Allen, Elizabeth A.

    2016-01-01

    An 81-year-old woman with a history of malignant melanoma who presented with dyspnea and fatigue was found to have metastases to the stomach detected on endoscopy. Primary cutaneous malignant melanoma with gastric metastases is a rare occurrence, and it is often not detected until autopsy because of its non-specific manifestations. PMID:27609722

  10. Melanoma with gastric metastases.

    PubMed

    Wong, Katherine; Serafi, Sam W; Bhatia, Abhijit S; Ibarra, Irene; Allen, Elizabeth A

    2016-01-01

    An 81-year-old woman with a history of malignant melanoma who presented with dyspnea and fatigue was found to have metastases to the stomach detected on endoscopy. Primary cutaneous malignant melanoma with gastric metastases is a rare occurrence, and it is often not detected until autopsy because of its non-specific manifestations. PMID:27609722

  11. Pembrolizumab and Ziv-aflibercept in Treating Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2016-09-09

    Adult Solid Neoplasm; Metastatic Melanoma; Metastatic Renal Cell Cancer; Recurrent Colorectal Carcinoma; Recurrent Melanoma; Recurrent Ovarian Carcinoma; Recurrent Renal Cell Carcinoma; Stage IV Ovarian Cancer; Stage IVA Colorectal Cancer; Stage IVB Colorectal Cancer

  12. Utility of BRAF V600E Immunohistochemistry Expression Pattern as a Surrogate of BRAF Mutation Status in 154 Patients with Advanced Melanoma.

    PubMed

    Tetzlaff, Michael T; Pattanaprichakul, Penvadee; Wargo, Jennifer; Fox, Patricia S; Patel, Keyur P; Estrella, Jeannelyn S; Broaddus, Russell R; Williams, Michelle D; Davies, Michael A; Routbort, Mark J; Lazar, Alexander J; Woodman, Scott E; Hwu, Wen-Jen; Gershenwald, Jeffrey E; Prieto, Victor G; Torres-Cabala, Carlos A; Curry, Jonathan L

    2015-08-01

    Successful BRAF inhibitor therapy depends on the accurate assessment of the mutation status of the BRAF V600 residue in tissue samples. In melanoma, immunohistochemical (IHC) analysis with monoclonal anti-BRAF V600E has emerged as a sensitive and specific surrogate of BRAF V600E mutation, particularly when BRAF V600E protein expression is homogeneous and strong. A subset of melanomas exhibit heterogeneous labeling for BRAF V600E, but our understanding of the significance of heterogeneous BRAF V600E IHC expression is limited. We used next-generation sequencing to compare BRAF V600E IHC staining patterns in 154 melanomas: 79 BRAF(WT) and 75 BRAF (including 53 V600E) mutants. Agreement among dermatopathologists on tumor morphology, IHC expression, and intensity was excellent (ρ = 0.99). A predominantly epithelioid cell phenotype significantly correlated with the BRAF V600E mutation (P = .0085). Tumors demonstrating either heterogeneous or homogeneous IHC expression were significantly associated with the BRAF V600E mutation (P < .0001), as was increased intensity of staining (P < .0001). The positive predictive value was 98% for homogenous IHC expression compared with 70% for heterogeneous labeling. Inclusion of both heterogeneous and homogeneous BRAF V600E IHC expression as a positive test significantly improved IHC test sensitivity from 85% to 98%. However, this reduced BRAF V600E IHC test specificity from 99% to 96%. Cautious evaluation of heterogeneous BRAF V600E IHC expression is warranted and comparison with sequencing results is critical, given its reduced test specificity and positive predictive value for detecting the BRAF V600E mutation.

  13. [Update on surgical treatment of primary and metastatic cutaneous melanoma].

    PubMed

    Zuluaga-Sepúlveda, María Alejandra; Arellano-Mendoza, Ivonne; Ocampo-Candiani, Jorge

    2016-01-01

    Melanoma is a common cutaneous tumour. It is of great importance due to its increasing incidence and aggressive behaviour, with metastasis to lymph nodes and internal organs. When suspecting melanoma, excisional biopsy should be performed to obtain complete histological information in order to determine the adverse factors such as ulceration, mitosis rate, and Breslow depth, which influence preoperative staging and provide data for sentinel lymph biopsy decision making. The indicated management for melanoma is wide local excision, observing recommended and well-established excision margins, depending on Breslow depth and anatomical location of the tumour. Therapeutic lymphadenectomy is recommended for patients with clinically or radiologically positive lymph nodes. This article reviews surgical treatment of melanoma, adverse histological factors, sentinel lymph node biopsy, and radical lymphadenectomy. Details are presented on special situations in which management of melanoma is different due to the anatomical location (plantar, subungual, lentigo maligna), or pregnancy.

  14. Time-resolved fluorescence lifetime for cutaneous melanoma detection

    PubMed Central

    Pires, Layla; Nogueira, Marcelo Saito; Pratavieira, Sebastião; Moriyama, Lilian Tan; Kurachi, Cristina

    2014-01-01

    Melanoma is the most aggressive skin cancer type. It is characterized by pigmented lesions with high tissue invasion and metastatic potential. The early detection of melanoma is extremely important to improve patient prognosis and survival rate, since it can progress to the deadly metastatic stage. Presently, the melanoma diagnosis is based on the clinical analysis of the macroscopic lesion characteristics such as shape, color, borders following the ABCD rules. The aim of this study is to evaluate the time-resolved fluorescence lifetime of NADH and FAD molecules to detect cutaneous melanoma in an experimental in vivo model. Forty-two lesions were analyzed and the data was classified using linear discriminant analysis, a sensitivity of 99.4%, specificity of 97.4% and accuracy of 98.4% were achieved. These results show the potential of this fluorescence spectroscopy for melanoma detection. PMID:25401022

  15. Effects of amifostine in a patient with an advanced-stage myelodysplastic syndrome.

    PubMed

    Yilmaz, A; Kaufmann, C C; Binder, C; Wörmann, B; Haase, D

    2001-01-01

    We report on a 63-year-old man with myelodysplastic syndrome at the stage of a refractory anemia with an excess of blasts in transformation (MDS-RAEB-T), first diagnosed in December 1996. After a period of stability, with no need for transfusions, the MDS progressed into acute myeloid leukemia (AML) in August 1998 with the emergence of a cytogenetic abnormality (11q-). Two courses of chemotherapy were given, resulting in prolonged pancytopenia; however, no clearance of bone marrow (BM) blasts was achieved. At that time, severe infections and daily epistaxis occurred. Frequent transfusions of packed red blood cells (RBC) and platelets (2-3/week) were necessary. After 2 months of persisting severe pancytopenia, we started a therapy with amifostine: 4 x 250 mg intravenously (i.v.) weekly for 1 month, followed by a maintenance therapy with 500 mg once weekly. After 2 weeks of amifostine therapy, hematopoiesis began to improve. In the subsequent 2 months, the patient became completely independent of the platelet transfusions; the transfusion frequency of RBC was permanently reduced (2 RBC transfusions/month) and a significant decrease of BM blasts was achieved. After 30 weeks of amifostine therapy, the morphology of the MDS switched to a chronic myelomonocytic leukemia (CMML)-like appearance, with continuously increasing leukocytes, so that we discontinued amifostine therapy for 1 month to exclude a possible side effect of amifostine. At that time, leukocytes further increased to 74,000/microl; thus, we decided to perform a cytoreductive chemotherapy (hydroxycarbamide) and continued weekly amifostine infusions. During 1 year of amifostine therapy, the patient had a good quality of life, with no need for hospitalization and a complete cytogenetic remission. We conclude that, in this case, amifostine had two effects: a significant improvement of impaired hematopoiesis and a slowing down of disease progression. Thus, amifostine might be a therapeutic option in older

  16. HLA-G expression and role in advanced-stage classical Hodgkin lymphoma.

    PubMed

    Caocci, G; Greco, M; Fanni, D; Senes, G; Littera, R; Lai, S; Risso, P; Carcassi, C; Faa, G; La Nasa, G

    2016-01-01

    Non-classical human leucocyte antigen (HLA)-G class I molecules have an important role in tumor immune escape mechanisms. We investigated HLA-G expression in lymphonode biopsies taken from 8 controls and 20 patients with advanced-stage classical Hodgkin lymphoma (cHL), in relationship to clinical outcomes and the HLA-G 14-basepair (14-bp) deletion-insertion (del-ins) polymorphism. Lymphnode tissue sections were stained using a specific murine monoclonal HLA-G antibody. HLA-G protein expression was higher in cHL patients than controls. In the group of PET-2 positive (positron emission tomography carried out after 2 cycles of standard chemotherapy) patients with a 2-year progression-free survival rate (PFS) of 40%, we observed high HLA-G protein expression within the tumor microenvironment with low expression on Hodgkin and Reed-Sternberg (HRS) cells. Conversely, PET-2 negative patients with a PFS of 86% had higher HLA-G protein expression levels on HRS cells compared to the microenvironment. Lower expression on HRS cells was significantly associated with the HLA-G 14-bp ins/ins genotype. These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2.These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2. PMID:27349312

  17. Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy.

    PubMed

    Lee, Nayoung; Zakka, Labib R; Mihm, Martin C; Schatton, Tobias

    2016-02-01

    The field of systemic cancer therapy for metastatic disease has entered an exciting era with the advent of novel immunomodulatory strategies targeting immune checkpoints. At the heart of these promising efforts are the tumour-infiltrating lymphocytes (TILs). As the reports demonstrating efficacy of modulating TIL effector function in patients with advanced stage cancer continue to accrue, it has become essential to better understand TIL immunobiology in order to further improve clinical outcome. In addition to providing an overview of the current immunotherapies available for metastatic melanoma, this review will briefly introduce the history and classification of TILs. Moreover, we will dissect the multifaceted roles of TILs in tumour-specific immunity and melanoma immune escape. The significance of TILs in melanoma prognosis and cancer immunotherapy will also be discussed, with a particular focus on their potential utility as biomarkers of patient response. The goal of personalised medicine appears to be in realistic sight, as new immunomodulatory techniques and technological innovations continue to advance the field of cancer immunotherapy. In light of recent studies highlighting the possible utility of TILs in determining therapeutic outcome, further characterisation of TIL phenotype and function has the potential to help translate individualised care into current medical practice.

  18. Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy.

    PubMed

    Lee, Nayoung; Zakka, Labib R; Mihm, Martin C; Schatton, Tobias

    2016-02-01

    The field of systemic cancer therapy for metastatic disease has entered an exciting era with the advent of novel immunomodulatory strategies targeting immune checkpoints. At the heart of these promising efforts are the tumour-infiltrating lymphocytes (TILs). As the reports demonstrating efficacy of modulating TIL effector function in patients with advanced stage cancer continue to accrue, it has become essential to better understand TIL immunobiology in order to further improve clinical outcome. In addition to providing an overview of the current immunotherapies available for metastatic melanoma, this review will briefly introduce the history and classification of TILs. Moreover, we will dissect the multifaceted roles of TILs in tumour-specific immunity and melanoma immune escape. The significance of TILs in melanoma prognosis and cancer immunotherapy will also be discussed, with a particular focus on their potential utility as biomarkers of patient response. The goal of personalised medicine appears to be in realistic sight, as new immunomodulatory techniques and technological innovations continue to advance the field of cancer immunotherapy. In light of recent studies highlighting the possible utility of TILs in determining therapeutic outcome, further characterisation of TIL phenotype and function has the potential to help translate individualised care into current medical practice. PMID:27020390

  19. Targeted therapies and immune checkpoint inhibitors in the treatment of metastatic melanoma patients: a guide and update for pathologists.

    PubMed

    Kakavand, Hojabr; Wilmott, James S; Long, Georgina V; Scolyer, Richard A

    2016-02-01

    The previously dismal prospects for patients with advanced stage metastatic melanoma have greatly improved in recent years. Enhanced understanding of both the pathogenesis of melanoma and its molecular drivers, as well as the importance and regulation of anti-tumour immune responses, have provided new therapeutic opportunities for melanoma patients. There are two major distinct categories of systemic treatments with activity for patients with metastatic melanoma: (1) targeted therapies, which act to inhibit the oncogenes that drive the aberrant growth and dissemination of the tumour; and (2) immune checkpoint inhibitor therapies, which act to enhance anti-tumour immune responses by blocking negative regulators of immunity. Pathologists play a critical and expanding role in the selection of the most appropriate treatment for individual metastatic melanoma patients in the modern era of personalised/precision medicine. The molecular pathology testing of melanoma tumour tissue for the presence of targetable oncogenic mutations is already part of routine practice in many institutions. In addition, other potential oncogenic therapeutic targets continue to be identified and pathology testing techniques must readily adapt to this rapidly changing field. Recent research findings suggest that pathological assessment of tumour associated immune cells and immunosuppressive ligand expression of the tumour are likely to be important in identifying patients most likely to benefit from immune checkpoint inhibitors. Similarly, pathological and molecular observations of on-treatment tumour tissue biopsies taken from patients on targeted therapies have provided new insights into the mechanisms of action of targeted molecular therapies, have contributed to the identification of resistance mechanisms to these novel therapies and may be of higher value for selecting patients most likely to benefit from therapies. These data have already provided a rational biological basis for the

  20. A Matrix Metalloproteinase-1/Protease Activated Receptor-1 signaling axis promotes melanoma invasion and metastasis

    PubMed Central

    Blackburn, Jessica S.; Liu, Ingrid; Coon, Charles I.; Brinckerhoff, Constance E.

    2009-01-01

    Hallmarks of malignant melanoma are its propensity to metastasize and its resistance to treatment, giving patients with advanced disease a poor prognosis. The transition of melanoma from non-invasive radial growth phase (RGP) to invasive and metastatically competent vertical growth phase (VGP) is a major step in tumor progression, yet the mechanisms governing this transformation are unknown. Matrix Metalloproteinase-1 (MMP-1) is highly expressed by VGP melanomas, and is thought to contribute to melanoma progression by degrading type I collagen within the skin to facilitate melanoma invasion. Protease activated receptor-1 (PAR-1) is activated by MMP-1, and is also expressed by VGP melanomas. However, the effects MMP-1 signaling through PAR-1 have not been examined in melanoma. Here, we demonstrate that an MMP-1/PAR-1 signaling axis exists in VGP melanoma, and is necessary for melanoma invasion. Introduction of MMP-1 into RGP melanoma cells induced gene expression associated with tumor progression and promoted invasion in vitro, and enhanced tumor growth and conferred metastatic capability in vivo. This study demonstrates that both the type I collagenase and PAR-1 activating functions of MMP-1 are required for melanoma progression, and suggests that MMP-1 may be a major contributor to the transformation of melanoma from non-invasive to malignant disease. PMID:19734937

  1. Genetic determinants of cutaneous melanoma predisposition.

    PubMed

    Udayakumar, Durga; Mahato, Bisundev; Gabree, Michele; Tsao, Hensin

    2010-09-01

    In the last 2 decades, advances in genomic technologies and molecular biology have accelerated the identification of multiple genetic loci that confer risk for cutaneous melanoma. The risk alleles range from rarely occurring, high-risk variants with a strong familial predisposition to low-risk to moderate-risk variants with modest melanoma association. Although the high-risk alleles are limited to the CDKN2A and CDK4 loci, the authors of recent genome-wide association studies have uncovered a set of variants in pigmentation loci that contribute to low risk. A biological validation of these new findings would provide greater understanding of the disease. In this review we describe some of the important risk loci and their association to risk of developing cutaneous melanoma and also address the current clinical challenges in CDKN2A genetic testing. PMID:21051013

  2. Circulating melanoma cells as a predictive biomarker.

    PubMed

    Karakousis, Giorgos; Yang, Ruifeng; Xu, Xiaowei

    2013-06-01

    The prognosis of patients with metastatic melanoma has improved significantly with targeted therapeutic agents and immunotherapies. Detection of early melanoma recurrence after treatment will be beneficial to switch patients who fail on one therapy to different modalities. Circulating tumor cells (CTCs) are cancer cells released by a tumor into the peripheral blood. These cells hold potential as prognostic, predictive, and pharmacodynamic biomarkers for treatment. In this issue, Khoja et al. report that melanoma CTCs can be detected using Melcam and high molecular weight melanoma-associated antibody. They found that in 101 stage IV melanoma patients, CTC numbers ranged between 0 and 36/7.5 ml blood; 26% of the patients had ≥ 2 CTCs at baseline. The CTC number (≥ 2 CTCs) at baseline was significantly prognostic for median overall survival (OS) in univariate and multivariate analysis. Patients receiving treatment where CTC numbers remained ≥ 2 CTCs during their treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, hazard ratio 0.34, 95% confidence interval 0.14-0.81, log-rank test P=0.015). The implications of this work are substantial in counseling patients about their prognosis and in helping to assess responses to systemic therapies. PMID:23673501

  3. Tissue prognostic biomarkers in primary cutaneous melanoma.

    PubMed

    Mandalà, Mario; Massi, Daniela

    2014-03-01

    Cutaneous melanoma (CM) causes the greatest number of skin cancer-related deaths worldwide. Predicting CM prognosis is important to determine the need for further investigation, counseling of patients, to guide appropriate management (particularly the need for postoperative adjuvant therapy), and for assignment of risk status in groups of patients entering clinical trials. Since recurrence rate is largely independent from stages defined by morphological and morphometric criteria, there is a strong need for identification of additional robust prognostic factors to support decision-making processes. Most data on prognostic biomarkers in melanoma have been evaluated in tumor tissue samples by conventional morphology and immunohistochemistry (IHC) as well as DNA and RNA analyses. In the present review, we critically summarize main high-quality studies investigating IHC-based protein biomarkers of melanoma outcome according to Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK)-derived criteria. Pathways have been classified and conveyed in the "biologic road" previously described by Hanahan and Weinberg. Data derived from genomic and transcriptomic technologies have been critically reviewed to better understand if any of investigated proteins or gene signatures should be incorporated into clinical practice or still remain a field of melanoma research. Despite a wide body of research, no molecular prognostic biomarker has yet been translated into clinical practice. Conventional tissue biomarkers, such as Breslow thickness, ulceration, mitotic rate and lymph node positivity, remain the backbone prognostic indicators in melanoma.

  4. Efficacy of short-term nivolumab treatment in a Chinese patient with relapsed advanced-stage lung squamous cell carcinoma

    PubMed Central

    Pi, Guoliang; He, Hanping; Bi, Jianping; Li, Ying; Li, Yanping; Zhang, Yong; Wang, Mingwei; Han, Guang; Lin, Chi

    2016-01-01

    Abstract Introduction: Currently, the options are limited for the treatment of patients who have failed 2 lines of chemotherapy for advanced lung squamous cell carcinoma (SCC). Recently, nivolumab, a fully human IgG4 programmed death 1 immune checkpoint inhibitor antibody, was approved to treat patients with advanced stage, relapsed/refractory lung SCC. Although nivolumab has demonstrated antitumor activity with survival benefit in Caucasian patients, its efficacy in Asian patients is unknown. Case Report: In this report, we describe a Chinese patient with relapsed advanced stage lung SCC who had an excellent response to nivolumab after only 2 doses without any adverse effects. Immunohistochemical analysis indicated the tumor was stained positive for programmed death-ligand 1. Conclusion: To our knowledge, this is the first report of satisfactory efficacy of short-term nivolumab treatment in a Chinese patient with relapsed advanced-stage lung SCC. Further clinical trials in Asian countries are needed to test whether nivolumab immunotherapy is a safe and effective treatment for Asian patients with lung SCC. PMID:27749580

  5. Advanced Launch Vehicle Upper Stages Using Liquid Propulsion and Metallized Propellants

    NASA Technical Reports Server (NTRS)

    Palaszewski, Bryan A.

    1990-01-01

    Metallized propellants are liquid propellants with a metal additive suspended in a gelled fuel or oxidizer. Typically, aluminum (Al) particles are the metal additive. These propellants provide increase in the density and/or the specific impulse of the propulsion system. Using metallized propellant for volume-and mass-constrained upper stages can deliver modest increases in performance for low earth orbit to geosynchronous earth orbit (LEO-GEO) and other earth orbital transfer missions. Metallized propellants, however, can enable very fast planetary missions with a single-stage upper stage system. Trade studies comparing metallized propellant stage performance with non-metallized upper stages and the Inertial Upper Stage (IUS) are presented. These upper stages are both one- and two-stage vehicles that provide the added energy to send payloads to altitudes and onto trajectories that are unattainable with only the launch vehicle. The stage designs are controlled by the volume and the mass constraints of the Space Transportation System (STS) and Space Transportation System-Cargo (STS-C) launch vehicles. The influences of the density and specific impulse increases enabled by metallized propellants are examined for a variety of different stage and propellant combinations.

  6. Advanced launch vehicle upper stages using liquid propulsion and metallized propellants

    NASA Technical Reports Server (NTRS)

    Palaszewski, B. A.

    1990-01-01

    Metallized propellants are liquid propellants with a metal additive suspended in a gelled fuel or oxidizer. Typically, aluminum particles are the metal additives. These propellants provide increase in the density and/or the specific impulse of the propulsion system. Using metallized propellants for volume- and mass-constrained upper stages can deliver modest increases in performance for Low Earth Orbit to Geosynchronous Earth Orbit and other Earth orbital transfer missions. Metallized propellants, however, can enable very fast planetary missions with a single-stage upper stage system. Trade studies comparing metallized propellant stage performance with non-metallized upper stages and the Inertial Upper Stage are presented. These upper stages are both one- and two-stage vehicles that provide the added energy to send payloads to altitudes and onto trajectories that are unattainable with only the launch vehicle. The stage designs are controlled by the volume and the mass constraints of the Space Transportation System and Space Transportation System-Cargo launch vehicles. The influences of the density and specific impulse increases enabled by metallized propellants are examined for a variety of different stage and propellant combinations.

  7. Immunotherapy for Melanoma: Current Status and Perspectives

    PubMed Central

    Alexandrescu, Doru T.; Ichim, Thomas E.; Riordan, Neil H.; Marincola, Francesco M.; Nardo, Anna Di; Kabigting, Filamer D.; Dasanu, Constantin A.

    2012-01-01

    Summary Immunotherapy is an important modality in the therapy of patients with malignant melanoma. As our knowledge about this disease continues to expand, so does the immunotherapeutic armamentarium. Nevertheless, successful preclinical models do not always translate into clinically meaningful results. The authors give a comprehensive analysis of most recent advances in the immune anti-melanoma therapy, including interleukins, interferons, other cytokines, adoptive immunotherapy, biochemotherapy, as well as the use of different vaccines. We also present the fundamental concepts behind various immune enhancement strategies, passive immunotherapy, as well as the use of immune adjuvants. This review brings into discussion the results of newer and older clinical trials, as well as potential limitations and drawbacks seen with the utilization of various immune therapies in malignant melanoma. Development of novel therapeutic approaches, along with optimization of existing therapies, continues to hold a great promise in the field of melanoma therapy research. Use of anti-CTLA4 and anti-PD1 antibodies, realization of the importance of co-stimulatory signals, which translated into the use of agonist CD40 monoclonal antibodies, as well as activation of innate immunity through enhanced expression of co-stimulatory molecules on the surface of dendritic cells by TLR agonists are only a few items on the list of recent advances in the treatment of melanoma. The need to engineer better immune interactions and to boost positive feedback loops appear crucial for the future of melanoma therapy, which ultimately resides in our understanding of the complexity of immune responses in this disease. PMID:20551839

  8. Is uniportal thoracoscopic surgery a feasible approach for advanced stages of non-small cell lung cancer?

    PubMed Central

    Fieira, Eva; Delgado, Maria; Mendez, Lucía; Fernandez, Ricardo; de la Torre, Mercedes

    2014-01-01

    Objectives Conventional video-assisted thoracoscopic (VATS) lobectomy for advanced lung cancer is a feasible and safe surgery in experienced centers. The aim of this study is to assess the feasibility of uniportal VATS approach in the treatment of advanced non-small cell lung cancer (NSCLC) and compare the perioperative outcomes and survival with those in early-stage tumors operated through the uniportal approach. Methods From June 2010 to December 2012, we performed 163 uniportal VATS major pulmonary resections. Only NSCLC cases were included in this study (130 cases). Patients were divided into two groups: (A) early stage and (B) advanced cases (>5 cm, T3 or T4, or tumors requiring neoadjuvant treatment). A descriptive and retrospective study was performed, comparing perioperative outcomes and survival obtained in both groups. A survival analysis was performed with Kaplan-Meier curves and the log-rank test was used to compare survival between patients with early and advanced stages. Results A total of 130 cases were included in the study: 87 (A) vs. 43 (B) patients (conversion rate 1.1 vs. 6.5%, P=0.119). Mean global age was 64.9 years and 73.8% were men. The patient demographic data was similar in both groups. Upper lobectomies (A, 52 vs. B, 21 patients) and anatomic segmentectomies (A, 4 vs. B, 0) were more frequent in group A while pneumonectomy was more frequent in B (A, 1 vs. B, 6 patients). Surgical time was longer (144.9±41.3 vs. 183.2±48.9, P<0.001), and median number of lymph nodes (14 vs. 16, P=0.004) were statistically higher in advanced cases. Median number of nodal stations (5 vs. 5, P=0.165), days of chest tube (2 vs. 2, P=0.098), HOS (3 vs. 3, P=0.072), and rate of complications (17.2% vs. 14%, P=0.075) were similar in both groups. One patient died on the 58th postoperative day. The 30-month survival rate was 90% for the early stage group and 74% for advanced cases Conclusions Uniportal VATS lobectomy for advanced cases of NSCLC is a safe and

  9. Ginsenoside Rg3 Inhibits Melanoma Cell Proliferation through Down-Regulation of Histone Deacetylase 3 (HDAC3) and Increase of p53 Acetylation

    PubMed Central

    Shan, Xiu; Fu, Yuan-Shan; Aziz, Faisal; Wang, Xiao-Qi; Yan, Qiu; Liu, Ji-Wei

    2014-01-01

    Malignant melanoma is an aggressive and deadly form of skin cancer, and despite recent advances in available therapies, is still lacking in completely effective treatments. Rg3, a monomer extracted from ginseng roots, has been attempted for the treatment of many cancers. It is reported that the expressions of histone deacetylase 3 (HDAC3) and p53 acetylation correlate with tumor cell growth. However, the antitumor effect of Rg3 on melanoma and the mechanism by which it regulates HDAC3 expression and p53 acetylation remain unknown. We found high expression of HDAC3 in human melanoma tissues to be significantly correlated to lymph node metastasis and clinical stage of disease (p<0.05). In melanoma cells, Rg3 inhibited cell proliferation and induced G0/G1 cell cycle arrest. Rg3 also decreased the expression of HDAC3 and increased the acetylation of p53 on lysine (k373/k382). Moreover, suppression of HDAC3 by either siRNA or a potent HDAC3 inhibitor (MS-275) inhibited cell proliferation, increased p53 acetylation and transcription activity. In A375 melanoma xenograft studies, we demonstrated that Rg3 and HDAC3 short hairpin RNA (shHDAC3) inhibited the growth of xenograft tumors with down-regulation of HDAC3 expression and up-regulation of p53 acetylation. In conclusion, Rg3 has antiproliferative activity against melanoma by decreasing HDAC3 and increasing acetylation of p53 both in vitro and in vivo. Thus, Rg3 serves as a potential therapeutic agent for the treatment of melanoma. PMID:25521755

  10. [Melanoma secondary prevention].

    PubMed

    Suppa, M; Daxhelet, M; del Marmol, V

    2015-09-01

    Melanoma represents a major public health problem. Its incidence is constantly rising and the mortality rate can be frightfully important if the diagnosis is delayed. Melanoma also exerts a significant economical burden on the society. Therefore there is a need of concrete and pragmatic public health strategies in order to enhance melanoma prevention. Primary prevention of melanoma consists in avoiding excessive exposure to ultraviolet rays,'which represent the main risk factor for the disease occurrence. Secondary prevention is a synonym of melanoma early diagnosis and can be obtained by means of two methods : patients' self-examination and medical examination. Both these examinations must be routinely and thoroughly performed, must be based on the ABCDE rule and the ugly duckling sign, and ideally must be aided by the use of total-body photography. Current international guidelines suggest that all cutaneous screenings should be performed using dermoscopy, a non-invasive imaging technique that allows improving considerably the diagnostic performance. More sophisticated imaging techniques, such as confocal microscopy, are also available in specialised centres. The current scientific evidence supports the efficacy of melanoma primary and secondary prevention programs as a tool to decrease melanoma mortality. Many skin cancer prevention campaigns have been organised worldwide. The most famous and successful in Europe is Euromelanoma.

  11. [Issues around melanoma].

    PubMed

    Haanen, John

    2011-01-01

    Over the past 30 years little progress has been made in the treatment of patients with a metastatic melanoma. Recently there have been two new developments. One of these is ipilimumab, a monoclonal antibody that blocks the function of the protein cytotoxic T lymphocyte-associated antigen 4 (CTLA4) which inhibits activated T lymphocytes. This gives the immune system a chance to build up an immune response to the melanoma. The other development is vemurafenib, a small molecule that inhibits a mutated protein (BRAF) that occurs in many melanomas. The BRAF mutation leads to uninhibited proliferation.

  12. Intraoral malignant melanoma

    PubMed Central

    Babburi, Suresh; Subramanyam, R. V.; Aparna, V.; Sowjanya, P.

    2013-01-01

    Primary oral mucosal melanoma is a rare aggressive neoplasm and accounts for only 0.2-8% of all reported melanomas. It is a malignant neoplasm of melanocytes that may arise from a benign melanocytic lesion or de novo from melanocytes within normal skin or mucosa. It is considered to be the most deadly and biologically unpredictable of all human neoplasms, having the worst prognosis. In this article, we report a case of oral melanoma in a 52-year-old female patient with a chief complaint of black discolouration of the maxillary gingiva and palate. PMID:24249959

  13. Lymphangiogenesis and Anti-lymphangiogenesis in Cutaneous Melanoma.

    PubMed

    Raica, Marius; Jitariu, Adriana-Andreea; Cimpean, Anca Maria

    2016-09-01

    Cutaneous malignant melanoma is an aggressive tumor characterized by early lymph node metastasis and bad prognosis. Although the spread of tumor cells in the regional lymph nodes is very important in the staging, prognosis and therapeutic strategy of malignant melanoma, the mechanism(s) of initial lymphatic vessels invasion is are) not completely understood. In the present review, we analyze the main factors involved in melanoma-associated lymphangiogenesis, based on existing available evidence. Currently, there are no anti-lymphangiogenic drugs approved for clinical trials. On the other hand, inhibition of lymph node metastasis has been demonstrated in experimental models by inhibiting tumor-associated lymphangiogenesis. PMID:27630278

  14. Proton Beam Radiotherapy for Uveal Melanomas at Nice Teaching Hospital: 16 Years' Experience

    SciTech Connect

    Caujolle, Jean-Pierre; Mammar, Hamid; Chamorey, Emmanuel Phar; Pinon, Fabien; Herault, Joel; Gastaud, Pierre

    2010-09-01

    Purpose: To present the results of uveal melanomas treated at Nice Teaching Hospital. Methods and Materials: This retrospective study included 886 consecutive patients referred to our clinic for the treatment of uveal melanomas by proton beam radiotherapy from June 1991 to December 2007. Survival rates were determined by using Kaplan-Meier estimates, and prognostic factors were evaluated using the log-rank test or Cox model. Results: The number (percent total) of subjects staged according to the TNM classification system (6th edition) of malignant tumors included 39 stage T1 (4.4%), 420 stage T2 (47.40%), 409 stage T3 (46.16%), and 18 stage T4 (2.03%) patients. The median follow-up was 63.7 months. The Kaplan-Meier overall survival rate at 5 years according to the sixth edition TNM classification was 92% for T1, 89% for T2, 67% for T3, and 62% for T4; and at 10 years, 86% for T1, 78% for T2, 43% for T3, and 41% for T4. Five factors were found to be associated with an increased death rate: advanced age, tumor thickness, largest tumor basal diameter, tumor volume, and tumor volume-to-eyeball volume ratio. The metastasis-free survival rates were 88.3 % at 5 years and 76.4 % at 10 years. The local control rates were 93.9% at 5 years and 92.1% at 10 years. The ocular conservation rates were 91.1% at 5 years and 87.3% at 10 years. Conclusions: We report the results of a large series of patients treated for uveal melanomas with a very long follow-up. Despite the large tumor volume treated, our results were similar to previously published findings relating to proton beam therapy.

  15. Method and apparatus for advanced staged combustion utilizing forced internal recirculation

    DOEpatents

    Rabovitser, Iosif K.; Knight, Richard A.; Cygan, David F.; Nester, Serguei; Abbasi, Hamid A.

    2003-12-16

    A method and apparatus for combustion of a fuel in which a first-stage fuel and a first-stage oxidant are introduced into a combustion chamber and ignited, forming a primary combustion zone. At least about 5% of the total heat output produced by combustion of the first-stage fuel and the first-stage oxidant is removed from the primary combustion zone, forming cooled first-stage combustion products. A portion of the cooled first-stage combustion products from a downstream region of the primary combustion zone is recirculated to an upstream region of primary combustion zone. A second-stage fuel is introduced into the combustion chamber downstream of the primary combustion zone and ignited, forming a secondary combustion zone. At least about 5% of the heat from the secondary combustion zone is removed. In accordance with one embodiment, a third-stage oxidant is introduced into the combustion chamber downstream of the secondary combustion zone, forming a tertiary combustion zone.

  16. Long-term Results of Carbon Ion Radiation Therapy for Locally Advanced or Unfavorably Located Choroidal Melanoma: Usefulness of CT-based 2-Port Orthogonal Therapy for Reducing the Incidence of Neovascular Glaucoma

    SciTech Connect

    Toyama, Shingo; Tsuji, Hiroshi; Mizoguchi, Nobutaka; Nomiya, Takuma; Kamada, Tadashi; Tokumaru, Sunao; Mizota, Atsushi; Ohnishi, Yoshitaka; Tsujii, Hirohiko

    2013-06-01

    Purpose: To determine the long-term results of carbon ion radiation therapy (C-ion RT) in patients with choroidal melanoma, and to assess the usefulness of CT-based 2-port irradiation in reducing the risk of neovascular glaucoma (NVG). Methods and Materials: Between January 2001 and February 2012, a total of 116 patients with locally advanced or unfavorably located choroidal melanoma received CT-based C-ion RT. Of these patients, 114 were followed up for more than 6 months and their data analyzed. The numbers of T3 and T2 patients (International Union Against Cancer [UICC], 5th edition) were 106 and 8, respectively. The total dose of C-ion RT varied from 60 to 85 GyE, with each dose given in 5 fractions. Since October 2005, 2-port therapy (51 patients) has been used in an attempt to reduce the risk of NVG. A dose-volume histogram analysis was also performed in 106 patients. Results: The median follow-up was 4.6 years (range, 0.5-10.6 years). The 5-year overall survival, cause-specific survival, local control, distant metastasis-free survival, and eye retention rates were 80.4% (95% confidence interval 89.0%-71.8%), 82.2% (90.6%-73.8%), 92.8% (98.5%-87.1%), 72.1% (81.9%-62.3%), and 92.8% (98.1%-87.5%), respectively. The overall 5-year NVG incidence rate was 35.9% (25.9%-45.9%) and that of 1-port group and 2-port group were 41.6% (29.3%-54.0%) and 13.9% (3.2%-24.6%) with statistically significant difference (P<.001). The dose-volume histogram analysis showed that the average irradiated volume of the iris-ciliary body was significantly lower in the non-NVG group than in the NVG group at all dose levels, and significantly lower in the 2-port group than in the 1-port group at high dose levels. Conclusions: The long-term results of C-ion RT for choroidal melanoma are satisfactory. CT-based 2-port C-ion RT can be used to reduce the high-dose irradiated volume of the iris-ciliary body and the resulting risk of NVG.

  17. A Phase 1 Study of a Vaccine Targeting Preferentially Expressed Antigen in Melanoma and Prostate-specific Membrane Antigen in Patients With Advanced Solid Tumors

    PubMed Central

    Weber, Jeffrey S.; Vogelzang, Nicholas J.; Ernstoff, Marc S.; Goodman, Oscar B.; Cranmer, Lee D.; Marshall, John L.; Miles, Sabrina; Rosario, Dar; Diamond, David C.; Qiu, Zhiyong; Obrocea, Mihail; Bot, Adrian

    2013-01-01

    Summary Preferentially expressed antigen in melanoma (PRAME) and prostate-specific membrane antigen (PSMA) are tumor-associated antigens implicated in cellular differentiation, genetic stability, and angiogenesis. MKC1106-PP is an immunotherapeutic regimen cotargeting PRAME and PSMA, comprised of a recombinant plasmid (pPRA-PSM encoding fragments derived from both antigens) and 2 peptides (E-PRA and E-PSM derived from PRAME and PSMA, respectively). This multicenter study evaluated MKC1106-PP with a fixed plasmid dose and 2 different peptide doses, administered by intralymph node injection in a prime-boost sequence in human leukocyte antigen-A*0201 and tumor-antigen-positive patients with progressing metastatic solid tumors who had failed standard therapy. Immune monitoring was done by tetramer and enzymatic-linked immune spot analysis. The treatment was well tolerated, with no significant differences in safety, immune response, and clinical outcome relative to peptide doses. Fifteen of 24 evaluable patients showed an immune response, as defined by the expansion of PRAME-specific or PSMA-specific T cells in the blood. There were no partial or complete responses by the Response Evaluation Criteria in Solid Tumors. Seven patients showed stable disease (SD) for 6 months or longer, or prostate specific antigen decline: 4 of 10 with prostate carcinoma, 2 of 2 with renal clear cell carcinoma, and 1 of 10 with metastatic melanoma. In addition, there was an association between the induction and persistence of antigen-specific T cells in blood above baseline levels and disease control, defined as SD for 6 months or longer. These results support further development of MKC1106-PP in specific clinical indications. PMID:21760528

  18. Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate.

    PubMed

    Salcedo, Margarita; Bercovici, Nadège; Taylor, Rachel; Vereecken, Pierre; Massicard, Séverine; Duriau, Dominique; Vernel-Pauillac, Frédérique; Boyer, Aurélie; Baron-Bodo, Véronique; Mallard, Eric; Bartholeyns, Jacques; Goxe, Béatrice; Latour, Nathalie; Leroy, Sophie; Prigent, Didier; Martiat, Philippe; Sales, François; Laporte, Marianne; Bruyns, Catherine; Romet-Lemonne, Jean-Loup; Abastado, Jean-Pierre; Lehmann, Frédéric; Velu, Thierry

    2006-07-01

    The aim of the present phase I/II study was to evaluate the safety, immune responses and clinical activity of a vaccine based on autologous dendritic cells (DC) loaded with an allogeneic tumor cell lysate in advanced melanoma patients. DC derived from monocytes were generated in serum-free medium containing GM-CSF and IL-13 according to Good Manufacturing Practices. Fifteen patients with metastatic melanoma (stage III or IV) received four subcutaneous, intradermal, and intranodal vaccinations of both DC loaded with tumor cell lysate and DC loaded with hepatitis B surface protein (HBs) and/or tetanus toxoid (TT). No grade 3 or 4 adverse events related to the vaccination were observed. Enhanced immunity to the allogeneic tumor cell lysate and to TAA-derived peptides were documented, as well as immune responses to HBs/TT antigens. Four out of nine patients who received the full treatment survived for more than 20 months. Two patients showed signs of clinical response and received 3 additional doses of vaccine: one patient showed regression of in-transit metastases leading to complete remission. Eighteen months later, the patient was still free of disease. The second patient experienced stabilization of lung metastases for approximately 10 months. Overall, our results show that vaccination with DC loaded with an allogeneic melanoma cell lysate was feasible in large-scale and well-tolerated in this group of advanced melanoma patients. Immune responses to tumor-related antigens documented in some treated patients support further investigations to optimize the vaccine formulation.

  19. Optimization of two-stage production/inventory systems under order base stock policy with advance demand information

    NASA Astrophysics Data System (ADS)

    Nakade, Koichi; Yokozawa, Shiori

    2016-08-01

    It is important to share demand information among the members in supply chains. In recent years, production and inventory systems with advance demand information (ADI) have been discussed, where advance demand information means the information of demand which the decision maker obtains before the corresponding actual demand arrives. Appropriate production and inventory control using demand information leads to the decrease of inventory and backlog costs. For a single stage system, the optimal base stock and release lead time have been discussed in the literature. In practical production systems the manufacturing system has multiple processes. The multiple stage production and inventory system with ADI, however, has been analyzed by simulation or assuming exponential processing time. That is, their theoretical analysis and optimization of release lead time and base stock level have little been obtained because of its difficulty. In this paper, theoretical analysis of a two-stage production inventory system with advance demand information is developed, where the processing time is assumed deterministic and identical; demand arrival process is Poisson, and an order base stock policy is adopted. Using the analytical results, optimal release lead time and optimal base stock levels for minimizing the average cost on the holding and backlog costs are explicitly derived.

  20. Melanoma International Foundation

    MedlinePlus

    ... Exam Card Download a Patient Navigation Card Events, Webinars & Videos Events, Webinars & Videos Patient Experience Video Events Host an Event Past Webinars Upcoming Webinars Volunteer Blog Blog Melanoma? The Doctor ...

  1. Melanoma Epidemiology and Prevention.

    PubMed

    Berwick, Marianne; Buller, David B; Cust, Anne; Gallagher, Richard; Lee, Tim K; Meyskens, Frank; Pandey, Shaily; Thomas, Nancy E; Veierød, Marit B; Ward, Sarah

    2016-01-01

    The epidemiology of melanoma is complex, and individual risk depends on sun exposure, host factors, and genetic factors, and in their interactions as well. Sun exposure can be classified as intermittent, chronic, or cumulative (overall) exposure, and each appears to have a different effect on type of melanoma. Other environmental factors, such as chemical exposures-either through occupation, atmosphere, or food-may increase risk for melanoma, and this area warrants further study. Host factors that are well known to be important are the numbers and types of nevi and the skin phenotype. Genetic factors are classified as high-penetrant genes, moderate-risk genes, or low-risk genetic polymorphisms. Subtypes of tumors, such as BRAF-mutated tumors, have different risk factors as well as different therapies. Prevention of melanoma has been attempted using various strategies in specific subpopulations, but to date optimal interventions to reduce incidence have not emerged. PMID:26601858

  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. Melanoma and Hawaii's youth.

    PubMed

    Williams, Laura

    2004-03-01

    Hawaii's sandy beaches, warm crystal waters, and mild climate attract tourists and residents alike to enjoy hours of outdoor activities under the sun. As frequent participants of these sun related activities, Hawaii's youth are exposed to high levels and duration of ultraviolet radiation throughout their early lives. This study aims to define occurrence trends of cutaneous malignant melanoma in Hawaii in correlation to increased childhood ultraviolet exposure. This paper addresses trends in melanoma incidence during 1979-2002 for Hawaii residents < 25 years of age. Data obtained from this review were analyzed by age group and ethnicity. Results show that although the incidence of melanoma is increasing for Hawaii residents over 25 years of age, the rate of melanoma occurrence in Hawaii's youth (< 25 years) is not increasing. PMID:15124743

  4. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer.

    PubMed

    Eberhardt, W E E; De Ruysscher, D; Weder, W; Le Péchoux, C; De Leyn, P; Hoffmann, H; Westeel, V; Stahel, R; Felip, E; Peters, S

    2015-08-01

    To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on locally advanced disease.

  5. Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations

    PubMed Central

    Apollo, Alessandro; Pescucci, Chiara; Licastro, Danilo; Urso, Carmelo; Gerlini, Gianni; Borgognoni, Lorenzo; Luzzatto, Lucio; Stecca, Barbara

    2016-01-01

    Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression. PMID:27095580

  6. Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations.

    PubMed

    Montagnani, Valentina; Benelli, Matteo; Apollo, Alessandro; Pescucci, Chiara; Licastro, Danilo; Urso, Carmelo; Gerlini, Gianni; Borgognoni, Lorenzo; Luzzatto, Lucio; Stecca, Barbara

    2016-05-24

    Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression.

  7. Familial cutaneous melanoma.

    PubMed

    Hansson, Johan

    2010-01-01

    Approximately 5-10 % of all cutaneous melanomas occur in families with hereditary melanoma predisposition. Worldwide, approximately 20-40% of kindreds with familial elanoma harbor germline mutations in the CDKN2A gene, located on chromosome 9p21, which encodes two different proteins, p16INK4 and p14ARF, both involved in regulation of cell cycle progression and induction of senescence. In different populations several recurring CDKN2A founder mutations have been described. The risk of melanoma in CDKN2A mutations carriers varies between populations and is higher in regions with high sun exposure and high incidence of melanoma in the general population. Some CDKN2A mutations have been associated not only with melanoma but also with increased risk of other malignancies--most notably pancreatic carcinoma. A much smaller number of families have germline mutations in the CDK4 gene on chromosome 12q14, encoding a cyclin dependent kinase which normally interacts with p16INK4A. The management of families with hereditary melanoma is discussed. PMID:20687502

  8. Delayed type hypersensitivity response to recall antigens does not accurately reflect immune competence in advanced stage breast cancer patients.

    PubMed

    Schiffman, Kathy; Rinn, Kristine; Disis, Mary L

    2002-07-01

    The development of delayed-type hypersensitivity (DTH) response to recall antigens has long been utilized as a measure of immune competence. It is assumed that because patients with advanced stage cancers exhibit multiple immune system defects they may not be responsive to immunization. We pre-selected patients with advanced HER-2/neu (HER2) overexpressing breast and ovarian cancers for enrolment into a phase I trial designed to evaluate the immunogenicity of a HER2 peptide vaccine based on the patient's immune competence as assessed by DTH skin testing to common recall antigens (Multitest CMI, Institut Merieux, Lyon, France). At the time of a positive DTH response to tetanus toxoid (tt) peripheral blood was obtained to measure T cell responses to tt. Of 53 patients evaluated, 38 (72%) were not anergic. Among the 15 (28%) who were, seven patients with advanced stage breast cancer were re-tested a median of 26 days (range 12-150 days) after receiving a tt bopster vaccination. Five of the seven had positive DTH responses when re-challenged with tt and six had peripheral blood tetanus specific T cell response with stimulation index >2.0. Thus, the majority of patients studied with advanced stage breast or ovarian cancer were able to mount a DTH response to common recall antigens. Moreover, a negative response by DTH testing to a battery of common recall antigens was not a reflection of the breast cancer patient's ability to mount a cell-mediated immune response to a vaccinated antigen, tt.

  9. Neoadjuvant chemotherapy in early-stage and locally advanced small bulk squamous cell carcinoma of the oral cavity and oropharynx.

    PubMed

    Tichler, T; Ramon, Y; Rath, P; Hendler, S; Brenner, H J

    1988-01-01

    Thirty patients with Stages I, II and III squamous cell carcinoma of the oral cavity and oropharynx (6, 12 and 12 patients, respectively) were entered into a combined modality protocol using preoperative chemotherapy, followed by resection with or without radical neck dissection and radiotherapy. None of the patients received prior treatment and all had good performance status. Primary sites included alveolar ridge (in nine patients), buccal mucosa (in eight), tongue (in six), floor of mouth (in five), and hard palate and tonsillar fossa in one each. Chemotherapy was given as a neoadjuvant debulking procedure using two courses of the Price-Hill regimen (5FU, methotrexate with citrovorum rescue, vincristine, bleomycin, and hydrocortisone) followed in 10 to 14 days by local resection for Stage I-II patients and radical neck dissection plus radiotherapy for Stage III patients. Response to chemotherapy alone was observed in 70% (21 of 30), with 17% (5 of 30) complete responders. Responses were seen in 100% of Stage I, 75% of Stage II, and 50% of Stage III patients. Age greater than 80 years was a poor prognostic indicator. Both men and women responded equally well. Of the 25 patients not entering CR with chemotherapy, a further 75% (11 of 15) did so after local resection and 50% (5 of 10) after local resection, radical neck dissection, and radiotherapy. Overall salvage rate post chemotherapy was 64% (16 of 25). All five patients in CR with chemotherapy alone are alive at a median follow-up time of greater than or equal to 43 months; full survival data are discussed. Toxicity was minimal and did not affect change in treatment course in any patient. These results show that further investigations on the use of neoadjuvant chemotherapy in early-stage and locally advanced squamous cell carcinoma of the oral cavity and oropharynx are indicated.

  10. Could S6K1 immunopositivity be used to distinguish early and advanced stages of endometrioid endometrial adenocarcinoma?

    PubMed Central

    Gün, İsmet; Özdamar, Özkan; Küçükodacı, Zafer; Muhçu, Murat; Demirel, Dilaver

    2016-01-01

    Objective To assess whether the immunopositivity of S6K1, a crucial effector of the mTOR signaling pathway, varies between early-stage low-grade and advanced-stage high-grade endometrial endometrioid adenocarcinoma (EEA) as well as to discuss its prognostic significance. Material and Methods A total of 22 normal endometrial tissue samples (Control group) and 41 EEA specimens (Study group) were enrolled in the study, and all the samples underwent immunohistochemical staining for S6 kinase alpha (S6K1). The study group was further evaluated in two subgroups; stage 1A, grade 1 (Group 1) and stage ≥1A, grade 2 or 3 (Group 2). Group 2 patients were considered as a poor prognosis for EEA. The samples were examined by two independent pathologists. Statistical analyses were performed using the Student’s t-test for continuous variables, the Chi-square test for categorical variables, and one-way analysis of variance for the comparison of multiple variables. Results The immunopositivity rate for all the included EEA patients was 56.1%, whereas none of the 22 normal endometrial tissue samples revealed immunoreactivity for S6K1. The immunopositivity rates were significantly different between Groups 1 and 2 [38.1% (8/21) and 75.0% (15/20), respectively, p=0.039]. When S6K1 positivity was used as a criterion of poor prognosis in EEA, the sensitivity, specificity, positive predictive value, and negative predictive value were calculated to be 62%, 75%, 72%, and 65%, respectively (OR: 4.9 and 95% CI: 1.3–18.7). Conclusion S6K1 was positive in the majority of EEAs and malignancies at an advanced stage. Higher grade disease had a significantly higher rate of S6K1 positivity. S6K1 immunopositivity appears to be a promising method to predict poor prognosis in EEA.

  11. Could S6K1 immunopositivity be used to distinguish early and advanced stages of endometrioid endometrial adenocarcinoma?

    PubMed Central

    Gün, İsmet; Özdamar, Özkan; Küçükodacı, Zafer; Muhçu, Murat; Demirel, Dilaver

    2016-01-01

    Objective To assess whether the immunopositivity of S6K1, a crucial effector of the mTOR signaling pathway, varies between early-stage low-grade and advanced-stage high-grade endometrial endometrioid adenocarcinoma (EEA) as well as to discuss its prognostic significance. Material and Methods A total of 22 normal endometrial tissue samples (Control group) and 41 EEA specimens (Study group) were enrolled in the study, and all the samples underwent immunohistochemical staining for S6 kinase alpha (S6K1). The study group was further evaluated in two subgroups; stage 1A, grade 1 (Group 1) and stage ≥1A, grade 2 or 3 (Group 2). Group 2 patients were considered as a poor prognosis for EEA. The samples were examined by two independent pathologists. Statistical analyses were performed using the Student’s t-test for continuous variables, the Chi-square test for categorical variables, and one-way analysis of variance for the comparison of multiple variables. Results The immunopositivity rate for all the included EEA patients was 56.1%, whereas none of the 22 normal endometrial tissue samples revealed immunoreactivity for S6K1. The immunopositivity rates were significantly different between Groups 1 and 2 [38.1% (8/21) and 75.0% (15/20), respectively, p=0.039]. When S6K1 positivity was used as a criterion of poor prognosis in EEA, the sensitivity, specificity, positive predictive value, and negative predictive value were calculated to be 62%, 75%, 72%, and 65%, respectively (OR: 4.9 and 95% CI: 1.3–18.7). Conclusion S6K1 was positive in the majority of EEAs and malignancies at an advanced stage. Higher grade disease had a significantly higher rate of S6K1 positivity. S6K1 immunopositivity appears to be a promising method to predict poor prognosis in EEA. PMID:27651726

  12. Efficacy Comparison Between Total Laryngectomy and Nonsurgical Organ-Preservation Modalities in Treatment of Advanced Stage Laryngeal Cancer

    PubMed Central

    Fu, Xiaoyuan; Zhou, Qi; Zhang, Xianquan

    2016-01-01

    Abstract It remains unclear whether the efficacy of nonsurgical organ-preservation modalities (NOP) in the treatment of advanced-stage laryngeal cancer was noninferiority compared with that of total laryngectomy (TL). The objective of this study was to compare the curative effects between TL and NOP in the treatment of advanced-stage laryngeal cancer through a meta-analysis. Clinical studies were retrieved from the electronic databases of PubMed, Embase, Wanfang, and Chinese National Knowledge infrastructure. A meta-analysis was performed to investigate the differences in the curative efficacy of advanced-stage laryngeal cancer between TL and the nonsurgical method. Two reviewers screened all titles and abstracts, and independently assessed all articles. All identified studies were retrospective. Sixteen retrospective studies involving 8308 patients (4478 in the TL group and 3701 in the nonsurgical group) were included in this meta-analysis. The analysis results displayed the advantage of TL for 2-year and 5-year overall survival (OS)(OR 2.79, 95% CI 1.85–4.23 and OR 1.52, 95% CI 1.09–2.14) as well as in 5-year disease-specific survival (DSS)(OR 1.79, 95% CI 1.61–1.98), but no significant difference in 2-year DSS was detected between the 2 groups (OR = 2.09,95% CI0.69–6.40). Additionally, there were no significant differences between TL and NOP for 5-year local control (LC) either (OR = 1.75, 95% CI 0.87–3.53). When we carried out subgroup analyses, the advantage of TL was especially obvious in T4 subgroups, but not in T3 subgroups. This is the first study to compare the curative effects on advanced-stage laryngeal cancer using meta-analytic methodology. Although there was a trend in favor of TL for OS and DSS, there is no clear difference in oncologic outcome between TL and NOP. Therefore, other factors such as tumor T-stage and size, lymph node metastasis, and physical condition are also important indicators for treatment choice. PMID:27057837

  13. Modeling of an advanced concept of a double stage Hall effect thruster

    SciTech Connect

    Garrigues, L.; Boniface, C.; Hagelaar, G. J. M.; Boeuf, J. P.

    2008-11-15

    We present a study of the principle and operation of a two-stage Hall effect thruster, the SPT-MAG, using a two-dimensional quasineutral hybrid model coupled with a Monte Carlo simulation of electron transport. The purpose of the two-stage design is the separation of ion production and acceleration in two separate chambers, the ionization stage and the acceleration stage, with separate control of acceleration voltage and total ionization. The originality of the SPT-MAG lies in the magnetic field configuration in the ionization chamber. Electrons are confined by this magnetic field while ions are supposed to be trapped in the electric potential well supposedly resulting from the magnetic configuration, and guided toward the acceleration stage. The acceleration stage is similar to the channel of a conventional Hall effect thruster. The purpose of this paper is to clarify the physics of the SPT-MAG and to understand the formation of the positive ion trap in the ionization chamber. Using a hybrid model and a Monte Carlo simulation we show that under typical operating conditions most of the ionization in the chamber is due to high energy electrons accelerated in the channel and entering the chamber rather than to electrons accelerated by the voltage applied in the ionization chamber. We also raise the question of the possible role of an additional emissive cathode inside the ionization chamber. The model predicts that an electric potential well guiding the ions to the channel entrance forms in the chamber only if the intermediate electrode inside the chamber is an emissive cathode (which is not the case in recent configurations used for this thruster)

  14. Prognosis and Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase (IDH) Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma

    PubMed Central

    Goyal, Lipika; Govindan, Aparna; Sheth, Rahul A.; Nardi, Valentina; Blaszkowsky, Lawrence S.; Faris, Jason E.; Clark, Jeffrey W.; Ryan, David P.; Kwak, Eunice L.; Allen, Jill N.; Murphy, Janet E.; Saha, Supriya K.; Hong, Theodore S.; Wo, Jennifer Y.; Ferrone, Cristina R.; Tanabe, Kenneth K.; Chong, Dawn Q.; Deshpande, Vikram; Borger, Darrell R.; Iafrate, A. John; Bardeesy, Nabeel; Zheng, Hui

    2015-01-01

    Background. Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase (IDH) mutation in intrahepatic cholangiocarcinoma (ICC), and limited data exist in patients with advanced-stage disease. Similarly, the clinical phenotype of patients with advanced IDH mutant (IDHm) ICC has not been characterized. In this study, we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC. Methods. Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated. Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild-type (IDHwt) ICC. Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging. Results. Of the 104 patients with ICC who were evaluated, 30 (28.8%) had an IDH mutation (25.0% IDH1, 3.8% IDH2). The median overall survival did not differ significantly between IDHm and IDHwt patients (15.0 vs. 20.1 months, respectively; p = .17). The pretreatment serum carbohydrate antigen 19-9 (CA19-9) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL, respectively (p = .04). Age at diagnosis, sex, histologic grade, and pattern of metastasis did not differ significantly by IDH mutation status. Conclusion. The IDH mutation was not associated with prognosis in patients with advanced ICC. The clinical phenotypes of advanced IDHm and IDHwt ICC were similar, but patients with IDHm ICC had a lower median serum CA19-9 level at presentation. Implications for Practice: Previous studies assessing the prognostic impact of the isocitrate dehydrogenase (IDH) gene mutation in intrahepatic cholangiocarcinoma (ICC) mainly focused on patients with early-stage disease who have undergone resection. These studies offer conflicting results. The target population for clinical trials of IDH inhibitors is patients with

  15. Contemporary surgical management of advanced end stage emphysema: an evidence based review.

    PubMed

    Sachithanandan, Anand; Badmanaban, Balaji

    2012-06-01

    Emphysema is a progressive unrelenting component of chronic obstructive pulmonary disease and a major source of mortality and morbidity globally. The prevalence of moderate to severe emphysema is approximately 5% in Malaysia and likely to increase in the future. Hence advanced emphysema will emerge as a leading cause of hospital admission and a major consumer of healthcare resources in this country in the future. Patients with advanced disease have a poor quality of life and reduced survival. Medical therapy has been largely ineffective for many patients however certain subgroups have disease amenable to surgical palliation. Effective surgical therapies include lung volume reduction surgery, lung transplantation and bullectomy. This article is a comprehensive evidence based review of the literature evaluating the rationale, efficacy, safety and limitations of surgery for advanced emphysema highlighting the importance of meticulous patient selection and local factors relevant to Malaysia.

  16. What Is Melanoma Skin Cancer?

    MedlinePlus

    ... that can become melanoma. They make a brown pigment called melanin , which gives the skin its tan ... to the sun, melanocytes make more of the pigment, causing the skin to tan or darken. Melanoma ...

  17. 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.

  18. Animal Models of Uveal Melanoma: Methods, Applicability, and Limitations.

    PubMed

    Stei, Marta M; Loeffler, Karin U; Holz, Frank G; Herwig, Martina C

    2016-01-01

    Animal models serve as powerful tools for investigating the pathobiology of cancer, identifying relevant pathways, and developing novel therapeutic agents. They have facilitated rapid scientific progress in many tumor entities. However, for establishing a powerful animal model of uveal melanoma fundamental challenges remain. To date, no animal model offers specific genetic attributes as well as histologic, immunologic, and metastatic features of uveal melanoma. Syngeneic models with intraocular injection of cutaneous melanoma cells may suit best for investigating immunologic/tumor biology aspects. However, differences between cutaneous and uveal melanoma regarding genetics and metastasis remain problematic. Human xenograft models are widely used for evaluating novel therapeutics but require immunosuppression to allow tumor growth. New approaches aim to establish transgenic mouse models of spontaneous uveal melanoma which recently provided preliminary promising results. Each model provides certain benefits and may render them suitable for answering a respective scientific question. However, all existing models also exhibit relevant limitations which may have led to delayed research progress. Despite refined therapeutic options for the primary ocular tumor, patients' prognosis has not improved since the 1970s. Basic research needs to further focus on a refinement of a potent animal model which mimics uveal melanoma specific mechanisms of progression and metastasis. This review will summarise and interpret existing animal models of uveal melanoma including recent advances in the field. PMID:27366747

  19. Animal Models of Uveal Melanoma: Methods, Applicability, and Limitations

    PubMed Central

    Stei, Marta M.; Loeffler, Karin U.; Holz, Frank G.; Herwig, Martina C.

    2016-01-01

    Animal models serve as powerful tools for investigating the pathobiology of cancer, identifying relevant pathways, and developing novel therapeutic agents. They have facilitated rapid scientific progress in many tumor entities. However, for establishing a powerful animal model of uveal melanoma fundamental challenges remain. To date, no animal model offers specific genetic attributes as well as histologic, immunologic, and metastatic features of uveal melanoma. Syngeneic models with intraocular injection of cutaneous melanoma cells may suit best for investigating immunologic/tumor biology aspects. However, differences between cutaneous and uveal melanoma regarding genetics and metastasis remain problematic. Human xenograft models are widely used for evaluating novel therapeutics but require immunosuppression to allow tumor growth. New approaches aim to establish transgenic mouse models of spontaneous uveal melanoma which recently provided preliminary promising results. Each model provides certain benefits and may render them suitable for answering a respective scientific question. However, all existing models also exhibit relevant limitations which may have led to delayed research progress. Despite refined therapeutic options for the primary ocular tumor, patients' prognosis has not improved since the 1970s. Basic research needs to further focus on a refinement of a potent animal model which mimics uveal melanoma specific mechanisms of progression and metastasis. This review will summarise and interpret existing animal models of uveal melanoma including recent advances in the field. PMID:27366747

  20. A population-based study of prognosis in advanced stage follicular lymphoma managed by watch and wait.

    PubMed

    El-Galaly, Tarec Christoffer; Bilgrau, Anders E; de Nully Brown, Peter; Mylam, Karen J; Ahmad, Syed A; Pedersen, Lars M; Gang, Anne O; Bentzen, Hans H; Juul, Maja B; Bergmann, Olav J; Pedersen, Robert S; Nielsen, Berit J; Johnsen, Hans E; Dybkaer, Karen; Bøgsted, Martin; Hutchings, Martin

    2015-05-01

    Watch and wait (WAW) is a common approach for asymptomatic, advanced stage follicular lymphoma (FL), but single-agent rituximab is an alternative for these patients. In this nationwide study we describe the outcome of patients selected for WAW. A cohort of 286 out of 849 (34%) stage III-IVA FL patients seen between 2000 and 2011, were managed expectantly and included. The 5-year progression-free survival (PFS) was 35% [95% confidence interval (CI) 29-42]. The 10-year overall survival (OS) was 65% (95%CI 54-78), and the cumulative risk of dying from lymphoma within 10 years of diagnosis was 13% (95%CI 7-20). Elevated lactate dehydrogenase and > four nodal regions involved were associated with a higher risk of lymphoma treatment and death from lymphoma. The WAW patients and a matched background population had similar OS during the first 50 months after diagnosis (P = 0·7), but WAW patients had increased risk of death after 50 months (P < 0·001). The estimated loss of residual life after 10 years was 6·8 months. The 10-year cumulative risk of histological transformation was 22% (95%CI 15-29) and the 3-year OS after transformation was 71% (95%CI 58-87%). In conclusion, advanced stage FL managed by WAW had a favourable outcome and abandoning this strategy could lead to overtreatment in some patients.

  1. A heartrending burden of gynaecological cancers in advance stage at nuclear institute of medicine and radiotherapy Jamshoro Sindh

    PubMed Central

    Bibi, Seema; Ashfaque, Sanober; Laghari, Naeem Ahmed

    2016-01-01

    Objectives: In Pakistan gynaecological cancers are among the leading causes of women’s morbidity and mortality posing huge financial burden on families, communities and state. Due to lack of national cancer registry exact facts and figures are unknown therefore this study was planned to find out prevalence, age, site and stage of presentation of gynaecological cancers at Nuclear Institute of Medicine and Radiotherapy (NIMRA), Jamshoro. Methods: A retrospective, cross sectional study was conducted from 1st January 2011 to 31st December 2011 at NIMRA Jamshoro. All cases of genital tract cancers were evaluated, required data was entered on predesigned performa and results were analyzed manually. Results: Out of 2401 total registered cancer cases, 231 (9.6%) patients were suffering from gynaecological cancer making it third most common cancer. Ovary was commonest site followed by cervix and uterus. More than 60% cases presented in advanced stage, mostly during 4th and 5th decade of life. Conclusion: Gynecological cancer was among top three cancers at one of the busiest public sector cancer institute in Sindh province and significant number presented in advance stage making treatment difficult and expensive. There is urgent need for development and implementation of an effective health policy regarding cancer prevention and treatment. PMID:27022358

  2. “EXHALE”: exercise as a strategy for rehabilitation in advanced stage lung cancer patients: a randomized clinical trial comparing the effects of 12 weeks supervised exercise intervention versus usual care for advanced stage lung cancer patients

    PubMed Central

    2013-01-01

    Background Lung cancer is the leading cause of cancer death in North America and Western Europe. Patients with lung cancer in general have reduced physical capacity, functional capacity, poor quality of life and increased levels of anxiety and depression. Intervention studies indicate that physical training can address these issues. However, there is a lack of decisive evidence regarding the effect of physical exercise in patients with advanced lung cancer. The aim of this study is to evaluate the effects of a twelve weeks, twice weekly program consisting of: supervised, structured training in a group of advanced lung cancer patients (cardiovascular and strength training, relaxation). Methods/Design A randomized controlled trial will test the effects of the exercise intervention in 216 patients with advanced lung cancer (non-small cell lung cancer (NSCLC) stage IIIb - IV and small cell lung cancer (SCLC) extensive disease (ED)). Primary outcome is maximal oxygen uptake (VO2peak). Secondary outcomes are muscle strength (1RM), functional capacity (6MWD), lung capacity (Fev1) and patient reported outcome (including anxiety, depression (HADS) and quality of life (HRQOL)). Discussion The present randomized controlled study will provide data on the effectiveness of a supervised exercise intervention in patients receiving systemic therapy for advanced lung cancer. It is hoped that the intervention can improve physical capacity and functional level, during rehabilitation of cancer patients with complex symptom burden and help them to maintain independent function for as long as possible. Trial registration http://ClinicalTrials.gov, NCT01881906 PMID:24124893

  3. Comparison of weight changes following unilateral and staged bilateral STN DBS for advanced PD

    PubMed Central

    Lee, Eric M; Kurundkar, Ashish; Cutter, Gary R; Huang, He; Guthrie, Barton L; Watts, Ray L; Walker, Harrison C

    2011-01-01

    Unilateral and bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) result in weight gain in the initial postoperative months, but little is known about the changes in weight following unilateral and staged bilateral STN DBS over longer time intervals. A case–control comparison evaluated weight changes over 2 years in 43 consecutive unilateral STN DBS patients, among whom 25 elected to undergo staged bilateral STN DBS, and 21 age-matched and disease severity matched PD controls without DBS. Regression analyses incorporating age, gender, and baseline weight in case or control were conducted to assess weight changes 2 years after the initial unilateral surgery. Unilateral STN DBS and staged bilateral STN DBS patients gained 3.9 ± 2.0 kg and 5.6 ± 2.1 kg versus their preoperative baseline weight (P < 0.001, respectively) while PD controls without DBS lost 0.8 ± 1.1 kg. Although bilateral STN DBS patients gained 1.7 kg more than unilateral STN DBS patients at 2 years, this difference was not statistically significant (P = 0.885). Although there was a trend toward greater weight gain in staged bilateral STN DBS patients versus unilateral patients, we found no evidence for an equivalent or synergistic increase in body weight following placement of the second DBS electrode. PMID:22398977

  4. Pathways and therapeutic targets in melanoma

    PubMed Central

    Shtivelman, Emma; Davies, Michael A.; Hwu, Patrick; Yang, James; Lotem, Michal; Oren, Moshe; Flaherty, Keith T.; Fisher, David E.

    2014-01-01

    This review aims to summarize the current knowledge of molecular pathways and their clinical relevance in melanoma. Metastatic melanoma was a grim diagnosis, but in recent years tremendous advances have been made in treatments. Chemotherapy provided little benefit in these patients, but development of targeted and new immune approaches made radical changes in prognosis. This would not have happened without remarkable advances in understanding the biology of disease and tremendous progress in the genomic (and other “omics”) scale analyses of tumors. The big problems facing the field are no longer focused exclusively on the development of new treatment modalities, though this is a very busy area of clinical research. The focus shifted now to understanding and overcoming resistance to targeted therapies, and understanding the underlying causes of the heterogeneous responses to immune therapy. PMID:24743024

  5. Ipilimumab-Induced Neutropenia in Melanoma

    PubMed Central

    Ban-Hoefen, Makiko; Burack, Richard; Sievert, Lynn; Sahasrabudhe, Deepak

    2016-01-01

    Ipilimumab is a human monoclonal IgG1 antibody against CTLA-4 that has been shown to prolong the overall survival of advanced melanoma. The most common adverse events associated with ipilimumab are immune-related. Severe hematological toxicity is rare. We report a case of severe neutropenia following ipilimumab therapy that fully resolved after the administration of prednisone, cyclosporine, and anti-thymocyte globulin therapies. PMID:27570779

  6. Ipilimumab-Induced Neutropenia in Melanoma.

    PubMed

    Ban-Hoefen, Makiko; Burack, Richard; Sievert, Lynn; Sahasrabudhe, Deepak

    2016-01-01

    Ipilimumab is a human monoclonal IgG1 antibody against CTLA-4 that has been shown to prolong the overall survival of advanced melanoma. The most common adverse events associated with ipilimumab are immune-related. Severe hematological toxicity is rare. We report a case of severe neutropenia following ipilimumab therapy that fully resolved after the administration of prednisone, cyclosporine, and anti-thymocyte globulin therapies. PMID:27570779

  7. Culturing Uveal Melanoma Cells.

    PubMed

    Angi, Martina; Versluis, Mieke; Kalirai, Helen

    2015-04-01

    A major challenge in cancer research is the use of appropriate models with which to study a specific biological question. Cell lines have long been used to study cellular processes and the effects of individual molecules because they are easy to use, grow rapidly, produce reproducible results and have a strong track record in research. In uveal melanoma in particular, the absence of animal models that faithfully replicate the behavior of the human disease has propagated the generation and use of numerous cell lines by individual research groups. This in itself, however, can be viewed as a problem due to the lack of standardization when characterizing these entities to determine how closely they reflect the genetic and phenotypic characteristics of this disease. The alternative is to use in vitro primary cultures of cells obtained directly from uveal melanoma patient samples, but this too has its difficulties. Primary cell cultures are difficult to use, hard to obtain and can show considerable heterogeneity. In this article, we review the following: (1) the uveal melanoma cell lines that are currently available, discussing the importance of establishing a bank of those that represent the molecular heterogeneity of uveal melanoma; (2) the methods used to isolate and perform short-term cultures of primary uveal melanoma cells, and (3) the establishment of 3D tissue culture models that bridge the gap between 2D in vitro systems and in vivo models with which to dissect cancer biology and perform therapeutic screens. PMID:27171555

  8. Cutaneous melanoma mortality among the socioeconomically disadvantaged in Massachusetts.

    PubMed Central

    Geller, A C; Miller, D R; Lew, R A; Clapp, R W; Wenneker, M B; Koh, H K

    1996-01-01

    OBJECTIVES: To identify groups for melanoma prevention and early detection programs, this study explored the hypothesis that survival with cutaneous melanoma is disproportionately lower for persons of lower socioeconomic status. METHODS: Massachusetts Cancer Registry and Registry of Vital Records and Statistics data (1982 through 1987) on 3288 incident cases and 1023 deaths from cutaneous melanoma were analyzed. Mortality/incidence ratios were calculated and compared, predictors of late stage disease were examined with logistic regression analysis, and a proportional hazards regression analysis that used death registration as the outcome measure for incident cases was performed. RESULTS: Lower socioeconomic status was associated with a higher mortality/incidence ratio after adjustment for age and sex. For education, the mortality/incidence ratio was 0.37 in the lower group vs 0.25 in the higher group (rate ratio = 1.48, 95% confidence interval [CI] = 1.08, 2.03). Late stage disease was independently associated with lower income (rate ratio for lowest vs highest tertile = 1.64, 95% CI = 1.20, 2.25), and melanoma mortality among case patients was associated with lower education (rate ratio = 1.52, 95% CI = 1.09, 213). CONCLUSIONS: Melanoma patients of lower socioeconomic status may be more likely to die from their melanoma than patients of higher socioeconomic status. Low- SES communities may be appropriate intervention targets. PMID:8604786

  9. Two stage low noise advanced technology fan. 1: Aerodynamic, structural, and acoustic design

    NASA Technical Reports Server (NTRS)

    Messenger, H. E.; Ruschak, J. T.; Sofrin, T. G.

    1974-01-01

    A two-stage fan was designed to reduce noise 20 db below current requirements. The first-stage rotor has a design tip speed of 365.8 m/sec and a hub/tip ratio of 0.4. The fan was designed to deliver a pressure ratio of 1.9 with an adiabatic efficiency of 85.3 percent at a specific inlet corrected flow of 209.2kg/sec/sq m. Noise reduction devices include acoustically treated casing walls, a flowpath exit acoustic splitter, a translating centerbody sonic inlet device, widely spaced blade rows, and the proper ratio of blades and vanes. Multiple-circular-arc rotor airfoils, resettable stators, split outer casings, and capability to go to close blade-row spacing are also included.

  10. Advancements in Estimating Crop Growth Stages Using RADARSAT-2 and Terrasar-X Polarimetric Data

    NASA Astrophysics Data System (ADS)

    Lampropoulos, G.; Li, Y.; Liu, T.

    2015-04-01

    This paper uses RADARSAT-2 quad Polarimetric Synthetic Aperture Radar (PolSAR) and TerraSAR-X dual polarimetric SAR data to monitor agriculture crop growth stages. Two RADARSAT-2 Fine Quad Wide (FQW) beam modes FQ2W and FQ10W, each with 5 sets of data and 13 sets of Stripmap TerraSAR-X data were used in the study. Both RADARSAT-2 POLSAR data and TerraSARX data were acquired in summer 2012 outside Winnipeg, Manitoba, Canada. The study was carried out to two crop types: canola and wheat, each contains 5 regions of interest from ground truth crop classification map in the image scene. Polarimetric features such as differential reflectivity bands ratio, entropy, anisotropy, alpha angle, lambda, scattering diversity and polarization index were evaluated for two crop types. The results from both RADARSAT-2 and TerraSAR-X data were compared and they demonstrated clear relationships between crop growth stages and polarimetric parameters. It is observed that entropy, lambda and differential reflectivity from both data have similar responses to crop growth stages in their common coverage period. The results were also validated using ground truth information.

  11. Melanoma proliferation and chemoresistance controlled by the DEK oncogene

    PubMed Central

    Khodadoust, Michael S.; Verhaegen, Monique; Kappes, Ferdinand; Riveiro-Falkenbach, Erica; Cigudosa, Juan C.; Kim, David S.L.; Chinnaiyan, Arul M.; Markovitz, David M.; Soengas, María S.

    2009-01-01

    Gain of chromosome 6p is a consistent feature of advanced melanomas. However, the identity of putative oncogene(s) associated with this amplification has remained elusive. The chromatin remodeling factor DEK is an attractive candidate as it maps to 6p (i.e. within common melanoma-amplified loci). Moreover, DEK expression is increased in metastatic melanomas, although the functional relevance of this induction remains unclear. Importantly, in other tumor types, DEK can display various tumorigenic effects, in part through its ability to promote proliferation and inhibit p53-dependent apoptosis. Here, we report a generalized upregulation of DEK protein in cells from aggressive melanomas. In addition, we provide genetic and mechanistic evidence to support a key role of DEK in the maintenance of malignant phenotypes of melanoma cells. Specifically, we show that long-term DEK downregulation by independent shRNAs resulted in premature senescence of a variety of melanoma cell lines. Short-term abrogation of DEK expression was also functionally relevant, as it attenuated the traditional resistance of melanomas to DNA damaging agents. Unexpectedly, DEK shRNA had no impact on p53 levels or p53-dependent apoptosis. Instead, we identified a new role for DEK in the transcriptional activation of the antiapoptotic MCL-1. Other MCL-1 related factors such as BCL-2 or BCL-xL were unaffected by changes in the endogenous levels of DEK, indicating a selective impact of this gene on the apoptotic machinery of melanoma cells. These results provide support for DEK as a long sought-after oncogene mapping at chromosome 6, with novel functions in melanoma proliferation and chemoresistance. PMID:19679545

  12. New Perspectives of “omics” Applications in Melanoma Research

    PubMed Central

    Rodríguez-Cerdeira, Carmen; Molares-Vila, Alberto

    2011-01-01

    Background: Oncoproteomics is the study of proteins and their interactions in a cancer cell by proteomic technologies and has the potential to revolutionize clinical practice, including cancer diagnosis. Recent technological advances in the analysis of the human genome have opened the door to improving our primitive understanding of the gene expression patterns in cancer. The examination of the phenotypic and (epi) genetic changes in cutaneous melanoma has identified several genes deemed central to the development and progression of melanoma. Methods: A review of the literature was performed to determine the role of epigenetic modifications in human melanoma. The role of array-based high-throughput gene expression analysis in understanding the specific genes involved as well as the pathways and the comparative gene expression patterns of primary and metastatic melanoma. The development and clinical application of selective pharmacologic agents are also discussed. Results: We identified several articles that have extensively studied the role of epigenetics in melanoma, further elucidating the complex processes involved in gene regulation and expression. Other studies utilizing gene microarray analysis and other whole genome approaches reveal a wide array of genes and expression patterns in human melanoma. Several genes have been identified as potential prognostic markers of tumor progression and overall clinical outcome. Conclusions: High-throughput gene expression analysis has had a major impact in melanoma research. Several gene expression platforms have provided insight into the gene expression patterns in melanoma. Such data will provide foundations for the future development of prognostic markers and improved targeted therapies for patients with melanoma. PMID:22253648

  13. A Case of Metastatic Melanoma in the Ureter

    PubMed Central

    Hossack, Tania

    2016-01-01

    Advances in the treatment of melanoma are resulting in patients living for extended periods after being diagnosed with metastatic disease. Metastases to the ureter are rare, but they have been described in the literature on a number of occasions. In this case report, we describe a patient with established metastatic melanoma who, whilst taking and responding to immunomodulatory therapy, was found to have an obstructive mass in the middle of his left ureter. Rather than performing either a nephroureterectomy or partial resection of the ureter, we opted to perform an endoscopic resection of the melanoma. Follow-up imaging at 12 months shows no evidence of local disease recurrence. We submit that primary endoscopic management of metastatic melanoma in the ureter is a viable alternative to a radical approach.

  14. Technology requirements for advanced earth-orbital transportation systems: Summary report. [single stage to orbit vehicles

    NASA Technical Reports Server (NTRS)

    Haefeli, R. C.; Littler, E. G.; Hurley, J. B.; Winter, M. G.

    1977-01-01

    Areas of advanced technology that are either critical or offer significant benefits to the development of future Earth-orbit transportation systems were identified. Technology assessment was based on the application of these technologies to fully reusable, single-state-to-orbit (SSTO) vehicle concepts with horizontal landing capability. Study guidelines included mission requirements similar to space shuttle, an operational capability beginning in 1995, and main propulsion to be advanced hydrogen-fueled rocket engines. The technical and economic feasibility of this class of SSTO concepts were evaluated as well as the comparative features of three operational take-off modes, which were vertical boost, horizontal sled launch, and horizontal take-off with subsequent inflight fueling. Projections of both normal and accelerated technology growth were made. Figures of merit were derived to provide relative rankings of technology areas. The influence of selected accelerated areas on vehicle design and program costs was analyzed by developing near-optimum point designs.

  15. C-Reactive Protein As a Marker of Melanoma Progression

    PubMed Central

    Fang, Shenying; Wang, Yuling; Sui, Dawen; Liu, Huey; Ross, Merrick I.; Gershenwald, Jeffrey E.; Cormier, Janice N.; Royal, Richard E.; Lucci, Anthony; Schacherer, Christopher W.; Gardner, Julie M.; Reveille, John D.; Bassett, Roland L.; Wang, Li-E; Wei, Qingyi; Amos, Christopher I.; Lee, Jeffrey E.

    2015-01-01

    Purpose To investigate the association between blood levels of C-reactive protein (CRP) in patients with melanoma and overall survival (OS), melanoma-specific survival (MSS), and disease-free survival. Patients and Methods Two independent sets of plasma samples from a total of 1,144 patients with melanoma (587 initial and 557 confirmatory) were available for CRP determination. Kaplan-Meier method and Cox regression were used to evaluate the relationship between CRP and clinical outcome. Among 115 patients who underwent sequential blood draws, we evaluated the relationship between change in disease status and change in CRP using nonparametric tests. Results Elevated CRP level was associated with poorer OS and MSS in the initial, confirmatory, and combined data sets (combined data set: OS hazard ratio, 1.44 per unit increase of logarithmic CRP; 95% CI, 1.30 to 1.59; P < .001; MSS hazard ratio, 1.51 per unit increase of logarithmic CRP; 95% CI, 1.36 to 1.68; P < .001). These findings persisted after multivariable adjustment. As compared with CRP < 10 mg/L, CRP ≥ 10 mg/L conferred poorer OS in patients with any-stage, stage I/II, or stage III/IV disease and poorer disease-free survival in those with stage I/II disease. In patients who underwent sequential evaluation of CRP, an association was identified between an increase in CRP and melanoma disease progression. Conclusion CRP is an independent prognostic marker in patients with melanoma. CRP measurement should be considered for incorporation into prospective studies of outcome in patients with melanoma and clinical trials of systemic therapies for those with melanoma. PMID:25779565

  16. Proteomic Analysis of Laser Microdissected Melanoma Cells from Skin Organ Cultures

    PubMed Central

    Hood, Brian L.; Grahovac, Jelena; Flint, Melanie S.; Sun, Mai; Charro, Nuno; Becker, Dorothea; Wells, Alan; Conrads, Thomas P

    2010-01-01

    Gaining insights into the molecular events that govern the progression from melanoma in situ to advanced melanoma, and understanding how the local microenvironment at the melanoma site influences this progression, are two clinically pivotal aspects that to date are largely unexplored. In an effort to identify key regulators of the crosstalk between melanoma cells and the melanoma-skin microenvironment, primary and metastatic human melanoma cells were seeded into skin organ cultures (SOCs), and grown for two weeks. Melanoma cells were recovered from SOCs by laser microdissection and whole-cell tryptic digests analyzed by nanoflow liquid chromatography-tandem mass spectrometry with an LTQ-Orbitrap. The differential protein abundances were calculated by spectral counting, the results of which provides evidence that cell-matrix and cell-adhesion molecules that are upregulated in the presence of these melanoma cells recapitulate proteomic data obtained from comparative analysis of human biopsies of invasive melanoma and a tissue sample of adjacent, non-involved skin. This concordance demonstrates the value of SOCs for conducting proteomic investigations of the melanoma microenvironment. PMID:20459140

  17. Melanoma Stem Cells and Metastasis: Mimicking Hematopoietic Cell Trafficking?

    PubMed Central

    Lee, Nayoung; Barthel, Steven R.; Schatton, Tobias

    2014-01-01

    Malignant melanoma is a highly metastatic cancer that bears responsibility for the majority of skin cancer-related deaths. Amidst the research efforts to better understand melanoma progression, there has been increasing evidence that hints at a role for a subpopulation of virulent cancer cells, termed malignant melanoma stem or initiating cells (MMICs), in metastasis formation. MMICs are characterized by their preferential ability to initiate and propagate tumor growth and their selective capacity for self-renewal and differentiation into less tumorigenic melanoma cells. The frequency of MMICs has been shown to correlate with poor clinical prognosis in melanoma. Additionally, MMICs are enriched among circulating tumor cells (CTCs) in the peripheral blood of cancer patients, suggesting that MMICs may be a critical player in the metastatic cascade. Although these links exist between MMICs and metastatic disease, the mechanisms by which MMICs may advance metastatic progression are only beginning to be elucidated. Recent studies have shown that MMICs express molecules critical for hematopoietic cell maintenance and trafficking, providing a possible explanation for how circulating MMICs could drive melanoma dissemination. We therefore propose that MMICs might fuel melanoma metastasis by exploiting homing mechanisms commonly utilized by hematopoietic cells. Here we review the biological properties of MMICs and the existing literature on their metastatic potential. We will discuss possible mechanisms by which MMICs might initiate metastases in the context of established knowledge of cancer stem cells (CSCs) in other cancers and of hematopoietic homing molecules, with a particular focus on selectins, integrins, chemokines, and chemokine receptors known to be expressed by melanoma cells. Biological understanding of how these molecules might be utilized by MMICs to propel the metastatic cascade could critically impact the development of more effective therapies for advanced

  18. Metastasis of Ciliary Body Melanoma to the Contralateral Eye: A Case Report and Review of Uveal Melanoma Literature

    PubMed Central

    Torossian, Nouritza M.; Wallace, Roy T.; Hwu, Wen-Jen; Bedikian, Agop Y.

    2015-01-01

    Many types of cancers metastasize to the eye. However, uveal melanoma metastasizing to the contralateral choroid is very rare. We report the case of a 68-year-old man with history of treated uveal melanoma of the right eye that developed metastasis to the liver and the choroid of the left eye. Ten years earlier, he was diagnosed to have uveal melanoma of the right eye and was initially treated with plaque radiotherapy. Two years later, upon progression of the disease in the right eye he had enucleation of the eye. We describe the patient's clinical history, the diagnosis of recurrent disease in the contralateral eye, therapy of the left eye, and systemic metastasis. In addition, we reviewed the published medical literature and described the recent advances in the management of uveal melanoma. PMID:25874144

  19. 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

  20. Targeting KIT in Melanoma: A Paradigm of Molecular Medicine and Targeted Therapeutics

    PubMed Central

    Woodman, Scott E.; Davies, Michael A.

    2014-01-01

    Despite multiple clinical trials utilizing a spectrum of therapeutic modalities, melanoma remains a disease with dismal outcomes in patients with advanced disease. However, it is now clear that melanoma is not a single entity, but can be molecularly divided into subtypes that generally correspond to the anatomical location of the primary melanoma. Melanomas from acral lentiginous, mucosal, and chronic sun-damaged sites frequently harbor activating mutations and/or increased copy number in the KIT tyrosine kinase receptor gene, which are very rare in the more common cutaneous tumors. Multiple case reports and early observations from clinical trials suggest that targeting mutant KIT with tyrosine kinase inhibitors is efficacious in KIT mutant melanoma. This review recounts what is known about the role of KIT in melanocyte maturation, our current understanding of KIT genetic aberrations in melanoma, and how this knowledge is being translated into clinical oncology. PMID:20457136

  1. Two-Stage Axial Compressor Rig Designed To Develop and Validate Advanced Aerodynamic Technologies

    NASA Technical Reports Server (NTRS)

    Larosiliere, Louis M.

    2003-01-01

    Future aeropropulsion gas turbine engines must be affordable in addition to being energy efficient and environmentally benign. Progress in aerodynamic design capability is required not only to maximize the specific thrust of next-generation engines without sacrificing fuel consumption, but also to reduce parts count by increasing the aerodynamic loading of the compression system. To meet future compressor requirements, the NASA Glenn Research Center is investigating advanced aerodynamic design concepts that will lead to more compact, higher efficiency, and wider operability configurations than are currently in operation.

  2. Effect of nivolumab on health-related quality of life in patients with treatment-naïve advanced melanoma: results from the phase III CheckMate 066 study

    PubMed Central

    Long, G. V.; Atkinson, V.; Ascierto, P. A.; Robert, C.; Hassel, J. C.; Rutkowski, P.; Savage, K. J.; Taylor, F.; Coon, C.; Gilloteau, I.; Dastani, H. B.; Waxman, I. M.; Abernethy, A. P.

    2016-01-01

    in patients with advanced melanoma. PMID:27405322

  3. Image Guided Hypofractionated 3-Dimensional Radiation Therapy in Patients With Inoperable Advanced Stage Non-Small Cell Lung Cancer

    SciTech Connect

    Osti, Mattia Falchetto; Agolli, Linda; Valeriani, Maurizio; Falco, Teresa; Bracci, Stefano; De Sanctis, Vitaliana; Enrici, Riccardo Maurizi

    2013-03-01

    Purpose: Hypofractionated radiation therapy (HypoRT) can potentially improve local control with a higher biological effect and shorter overall treatment time. Response, local control, toxicity rates, and survival rates were evaluated in patients affected by inoperable advanced stage non-small cell lung cancer (NSCLC) who received HypoRT. Methods and Materials: Thirty patients with advanced NSCLC were enrolled; 27% had stage IIIA, 50% had stage IIIB, and 23% had stage IV disease. All patients underwent HypoRT with a prescribed total dose of 60 Gy in 20 fractions of 3 Gy each. Radiation treatment was delivered using an image guided radiation therapy technique to verify correct position. Toxicities were graded according to Radiation Therapy Oncology Group morbidity score. Survival rates were estimated using the Kaplan-Meier method. Results: The median follow-up was 13 months (range, 4-56 months). All patients completed radiation therapy and received the total dose of 60 Gy to the primary tumor and positive lymph nodes. The overall response rate after radiation therapy was 83% (3 patients with complete response and 22 patients with partial response). The 2-year overall survival and progression-free survival rates were 38.1% and 36%, respectively. Locoregional recurrence/persistence occurred in 11 (37%) patients. Distant metastasis occurred in 17 (57%) patients. Acute toxicities occurred consisting of grade 1 to 2 hematological toxicity in 5 patients (17%) and grade 3 in 1 patient; grade 1 to 2 esophagitis in 12 patients (40%) and grade 3 in 1 patient; and grade 1 to 2 pneumonitis in 6 patients (20%) and grade 3 in 2 patients (7%). Thirty-three percent of patients developed grade 1 to 2 late toxicities. Only 3 patients developed grade 3 late adverse effects: esophagitis in 1 patient and pneumonitis in 2 patients. Conclusions: Hypofractionated curative radiation therapy is a feasible and well-tolerated treatment for patients with locally advanced NSCLC. Randomized

  4. A Decade of Experience in Developing Preclinical Models of Advanced- or Early-Stage Spontaneous Metastasis to Study Antiangiogenic Drugs, Metronomic Chemotherapy, and the Tumor Microenvironment.

    PubMed

    Kerbel, Robert S

    2015-01-01

    The clinical circumstance of treating spontaneous metastatic disease, after resection of primary tumors, whether advanced/overt or microscopic in nature, is seldom modeled in mice and may be a major factor in explaining the frequent discordance between preclinical and clinical therapeutic outcomes where the trend is "overprediction" of positive results in preclinical mouse model studies. To evaluate this hypothesis, a research program was initiated a decade ago to develop multiple models of metastasis in mice, using variants of human tumor cell lines selected in vivo for enhanced spontaneous metastatic aggressiveness after surgical resection of established orthotopic primary tumors. These models have included breast, renal, and colorectal carcinomas; ovarian cancer (but without prior surgery); and malignant melanoma. They have been used primarily for experimental therapeutic investigations involving various antiangiogenic drugs alone or with chemotherapy, especially "metronomic" low-dose chemotherapy. The various translational studies undertaken have revealed a number of clinically relevant findings. These include the following: (i) the potential of metronomic chemotherapy, especially when combined with a vascular endothelial growth factor pathway targeting drug to successfully treat advanced metastatic disease; (ii) the development of relapsed spontaneous brain metastases in mice with melanoma or breast cancer whose systemic metastatic disease is successfully controlled for a period with a given therapy; (iii) foreshadowing the failure of adjuvant antiangiogenic drug-based phase III trials; (iv) recapitulating the failure of oral antiangiogenic tyrosine kinase inhibitors plus standard chemotherapy in contrast to the modest successes of antiangiogenic antibodies plus chemotherapy in metastatic breast cancer; and (v) revealing "vessel co-option" and absence of angiogenesis as a determinant of intrinsic resistance or minimal responsiveness to antiangiogenic therapy

  5. [Diagnosis and treatment of depression in the advanced stage of cancer].

    PubMed

    Ronson, A

    2002-10-01

    The diagnosis of depression in patients with advanced cancer is a particularly complex task. The lack of diagnostic tools specifically developed for this patient population, the difficulty of interpreting neurovegetative symptoms of depression--which can result from the neoplastic disease--and the "normal and understandable" nature of many symptoms or signs of psychological distress are among the main obstacles to a clear-cut diagnosis of depression. Things go even more complex when it comes about to discuss whether one should treat patients displaying psychological distress that does not meet established criteria for the diagnosis of a depressive illness. When the indication to treat is finally acknowledged, the choice of the optimal antidepressant will depend upon a series of parameters including survival expectancy, tolerance profile and drug interactions. Though we currently lack prospective data about the efficacy and safety of antidepressants in depressed patients with advanced cancer, extrapolation of data available from other patient populations with severe medical conditions and clinical experience allow to draw guidelines aimed at helping healthcare professionals faced with those problems to improve the quality of life of their patients. These elements are presented and discussed in this paper in the light of the recent developments resulting from the growing interest of the medical community to the care to patients with terminal illness. PMID:12474322

  6. Basic and clinical aspects of malignant melanoma

    SciTech Connect

    Nathanson, L. )

    1987-01-01

    This book contains the following 10 chapters: The role of oncogenes in the pathogenesis of malignant melanoma; Laminin and fibronectin modulate the metastatic activity of melanoma cells; Structure, function and biosynthesis of ganglioside antigens associated with human tumors derived from the neuroectoderm; Epidemiology of ocular melanoma; Malignant melanoma: Prognostic factors; Endocrine influences on the natural history of human malignant melanoma; Psychosocial factors associated with prognostic indicators, progression, psychophysiology, and tumor-host response in cutaneous malignant melanoma; Central nervous system metastases in malignant melanoma; Interferon trials in the management of malignant melanoma and other neoplasms: an overview; and The treatment of malignant melanoma by fast neutrons.

  7. Long-term Survival of Patients With Invasive Ultra-thin Cutaneous Melanoma

    PubMed Central

    Vecchiato, Antonella; Zonta, Elisa; Campana, Luca; Dal Bello, Giacomo; Rastrelli, Marco; Rossi, Carlo Riccardo; Alaibac, Mauro

    2016-01-01

    Abstract The incidence of cutaneous melanoma is increasing worldwide, especially for thin melanoma (Breslow ≤1 mm). Thin cutaneous melanoma has a favorable prognosis but there are few data about the prognosis of patients with ultra-thin cutaneous melanoma (Breslow ≤ 0.5 mm). Our aim was to investigate the disease-free survival among patients with invasive cutaneous melanoma with Breslow ≤ 0.5 mm after 10 years from the initial diagnosis. A retrospective review of 240 cutaneous melanoma patients with Breslow ≤ 0.5 mm was performed. Recurrence, death from cutaneous melanoma, and disease-free survival were all identified. In the whole group of patients, we observed only 2 deaths from cutaneous melanoma. Median follow-up was 13, 11 years. Among all 240 patients, 221 were alive and disease free, 2 died of cutaneous melanoma, 11 died of other non-neoplastic diseases, 5 died of other neoplastic diseases different from melanoma, and 1 patient had a local recurrence; therefore the 10-year melanoma survival rate was 99.6%. Our data indicate that death from cutaneous melanoma in the group of patients with Breslow ≤0.5 mm was a very rare event and that diagnosis at this stage dramatically decreases the risk of developing metastatic tumors to a <0.5% also after a 10-year period of follow-up. Limitation of the study includes the fact that other risk factors for melanoma, notably ulceration, and mitotic rate, were not evaluated. PMID:26765437

  8. Non-albuminuric renal disease among subjects with advanced stages of chronic kidney failure related to type 2 diabetes mellitus.

    PubMed

    Boronat, Mauro; García-Cantón, César; Quevedo, Virginia; Lorenzo, Dionisio L; López-Ríos, Laura; Batista, Fátima; Riaño, Marta; Saavedra, Pedro; Checa, María D

    2014-03-01

    Urinary albumin excretion has been consistently found to be normal in a significant number of subjects with early stages of diabetic kidney disease. This study was aimed to estimate the prevalence and characteristics of non-albuminuric chronic kidney disease associated with type 2 diabetes mellitus among subjects who reach advanced stages of renal failure. Study population was composed of incident patients with advanced chronic kidney disease (glomerular filtration rate <30 mL/min) related to type 2 diabetes in a tertiary hospital from Gran Canaria (Spain) during a period of 2 years. Subjects were classified as normoalbuminuric (urinary albumin-to-creatine ratio [UACR] <30 mg/g), microalbuminuric (UACR ≥30 and <300 mg/g), or proteinuric (UACR ≥300 mg/g). Of 78 eligible patients, 21.8% had normoalbuminuria, 20.5% had microalbuminuria, and 57.7% had proteinuria. Individuals with normoalbuminuria were mostly women and had a lower prevalence of smoking and polyneuropathy than subjects with microalbuminuria or proteinuria. They also presented greater measures of body mass index and waist circumference, higher values of total and LDL cholesterol, and lower values of HbA1c and serum creatinine than subjects with microalbuminuria or proteinuria. Multivariate analysis demonstrated that female sex (positively) and HbA1c and polyneuropathy (negatively) were independently associated with absence of albuminuria. In conclusion, around 20% of subjects with diabetes-related advanced chronic kidney disease, characteristically women, have normal urinary albumin excretion. HbA1c and polyneuropathy are inversely related to this non-albuminuric form of nephropathy.

  9. Sulfur removal in advanced two-stage fluidized-bed combustion. [Quarterly] technical report, December 1, 1993--February 28, 1994

    SciTech Connect

    Abbasian, J.; Hill, A.H.; Wangerow, J.R.; Rue, D.M.

    1994-06-01

    The objective of this study is to obtain data on the rates of reaction between, hydrogen sulfide (H{sub 2}S) and uncalcined calcium-based sorbents under operating conditions relevant to first stage (carbonizer) of Advanced Two-Stage Pressurized Fluidized-Bed Combustors (PFBC). In these systems the CO{sub 2} partial pressure in the first stage generally exceeds the equilibrium value for calcium carbonate decomposition. Therefore, removal of sulfur compounds takes place through the reaction between H{sub 2}S and calcium carbonate. To achieve this objective the rates of reaction between hydrogen sulfide and uncalcined calcium-based sorbents will be determined by conducting tests in pressurized thermogravimetric analyzer (TGA) and high-pressure/high-temperature fluidized-bed reactor (HPTR) units. The effects of sorbent type, sorbent particle size, reactor temperature and pressure, and CO{sub 2} and H{sub 2}S partial pressures on the sulfidation reaction rate will be determined. During this quarter, the high-pressure thermogravimetric analyzer (HPTGA) unit was installed and the shakedown process was completed. Several tests were conducted in the HPTGA unit to establish the operating procedure and the repeatability of the experimental results. Sulfidation by conducting the baseline sulfidation tests. The results are currently being analyzed.

  10. Sulfur removal in advanced two-staged pressurized fluidized-bed combustion; [Quarterly] report, September 1--November 1993

    SciTech Connect

    Abbasian, J.; Hill, A.H.; Wangerow, J.R.; Rue, D.M.

    1994-03-01

    The objective of this study is to obtain data on the rates of reaction between hydrogen sulfide (H{sub 2}S) and uncalcined calcium-based sorbents under operating conditions relevant to first stage (carbonizer) of Advanced Two-Stage Pressurized Fluidized-Bed Combustors (PFBC). In these systems the CO{sub 2} partial pressure in the first stage generally exceeds the equilibrium value for calcium carbonate decomposition. Therefore, removal of sulfur compounds takes place through the reaction between H{sub 2}S and calcium carbonate. To achieve this objective, the rates of reaction between hydrogen sulfide and uncalcined calcium-based sorbents will be determined by conducting tests in pressurized thermogravimetric analyzer (TGA) and high-pressure/high-temperature fluidized-bed reactor (HPTR) units. The effects of sorbent type, sorbent particle size, reactor temperature and pressure, and CO{sub 2} and H{sub 2}S partial pressures on the sulfidation reaction rate will be determined. A pressurized TGA unit has been purchased by IGT for use in this project.

  11. Advanced Stage Mucinous Adenocarcinoma of the Ovary is both Rare and Highly Lethal: A Gynecologic Oncology Group Study

    PubMed Central

    Zaino, Richard J.; Brady, Mark F.; Lele, Subodh M.; Michael, Helen; Greer, Benjamin; Bookman, Michael A.

    2010-01-01

    Background Primary mucinous adenocarcinomas of the ovary are uncommon and their biologic behavior uncertain. Retrospective studies suggest that many mucinous carcinomas diagnosed as primary to the ovary were actually metastatic from another site. A prospective randomized trial provided an opportunity to estimate the frequency of mucinous tumors, diagnostic reproducibility, and clinical outcomes. Methods A phase III trial enrolled 4000 women with stage III or IV ovarian carcinoma, treated by surgical staging and debulking, with randomization to one of five chemotherapeutic arms. Slides and pathology reports classified as primary mucinous carcinoma were reviewed independently by three pathologists. Cases were re-classified as primary or metastatic to the ovary according to two methods. Overall survival (OS) of reclassified groups was compared with each other and with that of patients with serous carcinomas. Results Forty-four cases were classified as mucinous adenocarcinoma at review. Using either method, only about one third were interpreted by the three reviewers as primary mucinous carcinomas. Reproducibility of interpretations among the reviewers was high with unanimity of opinion in 30 of the 44 (68%) cases. The median survival (MS) did not differ significantly between the groups interpreted as primary or metastatic, but the OS was significantly less than that for women with serous carcinoma (14 vs 42 months, p<0.001). Conclusion Advanced stage mucinous carcinoma of the ovary is very rare and is associated with poor OS. Many mucinous adenocarcinomas that are diagnosed as primary ovarian neoplasms appear to be metastatic to the ovary. PMID:20862744

  12. Investigation of FOXM1 as a Potential New Target for Melanoma

    PubMed Central

    Miyashita, Azusa; Fukushima, Satoshi; Nakahara, Satoshi; Yamashita, Junji; Tokuzumi, Aki; Aoi, Jun; Ichihara, Asako; Kanemaru, Hisashi; Jinnin, Masatoshi; Ihn, Hironobu

    2015-01-01

    Recent studies have shown that immunotherapies and molecular targeted therapies are effective for advanced melanoma. Non-antigen-specific immunotherapies such as immunocheckpoint blockades have been shown to be effective in the treatment of advanced melanoma. However, the response rates remain low. To improve their efficacy, they should be combined with antigen-specific immunotherapy. Elevated expression of the transcription factor, Forkhead box M1 (FOXM1), has been reported in various human cancers, and it has been shown to have potential as a target for immunotherapy. The purpose of this study was to investigate the FOXM1 expression in human melanoma samples and cell lines, to evaluate the relationship between the FOXM1 expression and the clinical features of melanoma patients and to investigate the association between the FOXM1 and MAPK and PI3K/AKT pathways in melanoma cell lines. We conducted the quantitative reverse transcription PCR (qRT-PCR) and Western blotting analyses of melanoma cell lines, and investigated melanoma and nevus tissue samples by qRT-PCR and immunohistochemistry. We performed MEK siRNA and PI3K/AKT inhibitor studies and FOXM1 siRNA studies in melanoma cell lines. We found that FOXM1 was expressed in all of the melanoma cell lines, and was expressed in 49% of primary melanomas, 67% of metastatic melanomas and 10% of nevi by performing immunohistochemical staining. Metastatic melanoma samples exhibited significantly higher mRNA levels of FOXM1 (p = 0.004). Primary melanomas thicker than 2 mm were also more likely to express FOXM1. Patients whose primary melanoma expressed FOXM1 had a significantly poorer overall survival compared to patients without FOXM1 expression (p = 0.024). Downregulation of FOXM1 by siRNA significantly inhibited the proliferation of melanoma cells, and blockade of the MAPK and PI3K/AKT pathways decreased the FOXM1 expression in melanoma cell lines. In conclusion, FOXM1 is considered to be a new therapeutic target for

  13. Design and development of an advanced two-stage centrifugal compressor

    SciTech Connect

    Palmer, D.L.; Waterman, W.F.

    1995-04-01

    Small turboshaft engines require high-pressure-ratio, high-efficiency compressors to provide low engine fuel consumption. This paper describes the aeromechanical design and development of a 3.3 kg/s (7.3 lb/sec), 14:1 pressure ratio two-stage centrifugal compressor, which is used in the T800-LHT-800 helicopter engine. The design employs highly nonradial, splitter bladed impellers with swept leading edges and compact vaned diffusers to achieve high performance in a small and robust configuration. The development effort quantified the effects of impeller diffusion and passive inducer shroud bleed on surge margin as well as the effects of impeller loading on tip clearance sensitivity and the impact of sand erosion and shroud roughness on performance. The developed compressor exceeded its performance objectives with a minimum of 23% surge margin without variable geometry. The compressor provides a high-performance, rugged, low-cost configuration ideally suited for helicopter applications.

  14. Melanoma risk and survival among organ transplant recipients

    PubMed Central

    Robbins, Hilary A.; Clarke, Christina A.; Arron, Sarah T.; Tatalovich, Zaria; Kahn, Amy R.; Hernandez, Brenda Y.; Paddock, Lisa; Yanik, Elizabeth L.; Lynch, Charles F.; Kasiske, Bertram L.; Snyder, Jon; Engels, Eric A.

    2015-01-01

    Solid organ transplant recipients, who are medically immunosuppressed to prevent graft rejection, have increased melanoma risk, but risk factors and outcomes are incompletely documented. We evaluated melanoma incidence among 139,991 non-Hispanic white transplants using linked U.S. transplant-cancer registry data (1987–2010). We used standardized incidence ratios (SIRs) to compare incidence to the general population, and incidence rate ratios (IRRs) from multivariable Poisson models to assess risk factors. Separately, we compared post-melanoma survival among transplant recipients (N=182) and non-recipients (N=131,358) using multivariable Cox models. Among transplant recipients, risk of invasive melanoma (N=519) was elevated (SIR=2.20, 95%CI 2.01-2.39), especially for regional stage tumors (SIR=4.11, 95%CI 3.27–5.09). Risk of localized tumors was stable over time after transplantation, but higher with azathioprine maintenance therapy (IRR=1.35, 95%CI 1.03–1.77). Risk of regional/distant stage tumors peaked within 4 years following transplantation and increased with polyclonal antibody induction therapy (IRR=1.65, 95%CI 1.02–2.67). Melanoma-specific mortality was higher among transplant recipients than non-recipients (HR 2.98, 95%CI 2.26–3.93). Melanoma exhibits increased incidence and aggressive behavior under transplant-related immunosuppression. Some localized melanomas may result from azathioprine, which acts synergistically with ultraviolet radiation, while T-cell depleting induction therapies may promote late stage tumors. Our findings support sun safety practices and skin screening for transplant recipients. PMID:26270022

  15. Raman spectroscopy detects melanoma and the tissue surrounding melanoma using tissue-engineered melanoma models

    PubMed Central

    Yorucu, Ceyla; Lau, Katherine; Mittar, Shweta; Green, Nicola H.; Raza, Ahtasham; Rehman, Ihtesham Ur; MacNeil, Sheila

    2016-01-01

    ABSTRACT Invasion of melanoma cells from the primary tumor involves interaction with adjacent tissues and extracellular matrix. The extent of this interaction is not fully understood. In this study Raman spectroscopy was applied to cryo-sections of established 3D models of melanoma in human skin. Principal component analysis was used to investigate differences between the tumor and normal tissue and between the peri-tumor area and the normal skin. Two human melanoma cells lines A375SM and C8161 were investigated and compared in 3D melanoma models. Changes were found in protein conformations and tryptophan configurations across the entire melanoma samples, in tyrosine orientation and in more fluid lipid packing only in tumor dense areas, and in increased glycogen content in the peri-tumor areas of melanoma. Raman spectroscopy revealed changes around the perimeter of a melanoma tumor as well as detecting differences between the tumor and the normal tissue. PMID:27158185

  16. Melanoma of the Skin

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 76,380 % of All New Cancer Cases 4.5% Estimated Deaths in 2016 10,130 % of All Cancer ... of This Cancer : In 2013, there were an estimated 1,034,460 people living with melanoma of ...

  17. Spice Blocks Melanoma Growth

    ERIC Educational Resources Information Center

    Science Teacher, 2005

    2005-01-01

    Curcumin, the pungent yellow spice found in both turmeric and curry powders, blocks a key biological pathway needed for development of melanoma and other cancers, according to a study that appears in the journal Cancer. Researchers from The University of Texas M. D. Anderson Cancer Center demonstrate how curcumin stops laboratory strains of…

  18. Melanoma Risk Prediction Models

    Cancer.gov

    Developing statistical models that estimate the probability of developing melanoma cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  19. Survival analysis of patients with advanced-stage nasopharyngeal carcinoma according to the Epstein-Barr virus status

    PubMed Central

    Peng, Hao; Chen, Lei; Zhang, Yuan; Guo, Rui; Li, Wen-Fei; Mao, Yan-Ping; Tan, Ling-Long; Sun, Ying; Zhang, Fan; Liu, Li-Zhi; Tian, Li; Lin, Ai-Hua; Ma, Jun

    2016-01-01

    Purpose The main aim of this study is to analyze the prognostic differences in nasopharyngeal carcinoma (NPC) patients who are positive and negative for Epstein-Barr virus (EBV). Results Of the 1106 patients, 248 (22.4%) had undetectable pre-treatment plasma EBV DNA levels. The total distant metastasis rate for EBV-negative group vs. EBV-positive group were 3.6% (9/248) vs. 15.0% (128/858) (P < 0.001). The estimated 4-year disease-free survival (DFS), overall survival (OS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) for EBV-negative group vs. EBV-positive group were 88.9% vs. 76.9% (P < 0.001), 93.6% vs. 85.9% (P = 0.001), 96.7% vs. 84.8% (P < 0.001) and 94.1% vs. 90.0% (P = 0.1), respectively. Multivariate analysis revealed that the EBV status was an independent prognostic factor for DFS (HR, 1.813; 95% CI, 1.219-2.695; P = 0.003), OS (HR, 1.828; 95% CI, 1.075-3.107; P = 0.026) and DMFS (HR, 3.678; 95% CI, 1.859-7.277; P <0.001), and overall stage still remained the most important prognostic factor in patients with stage III-IVB NPC. Methods and Materials Data on 1106 patients with non-metastatic, histologically proven advanced-stage (III-IVB) NPC who underwent intensity-modulated radiotherapy (IMRT) were retrospectively reviewed. Patient survival between different EBV status groups were compared. Conclusions EBV status was an independent prognostic factor for patients with stage III–IVB NPC. Neoadjuvant chemotherapy (NCT) plus concurrent chemoradiotherapy (CCRT) should be better treatment regimen for EBV-positive patients since distant metastasis was the main failure pattern, and CCRT may be enough for EBV-negative patients. PMID:27008701

  20. Primary Tumor Site as a Predictor of Treatment Outcome for Definitive Radiotherapy of Advanced-Stage Oral Cavity Cancers

    SciTech Connect

    Lin, Chien-Yu; Wang, Hung-Ming; Kang, Chung-Jan; Lee, Li-Yu; Huang, Shiang-Fu; Fan, Kang-Hsing; Chen, Eric Yen-Chao

    2010-11-15

    Purpose: To evaluate the outcome of definitive radiotherapy (RT) for oral cavity cancers and to assess prognostic factors. Methods and Materials: Definitive RT was performed on 115 patients with oral cavity cancers at Stages III, IVA, and IVB, with a distribution of 6%, 47%, and 47%, respectively. The median dose of RT was 72Gy (range, 62-76Gy). Cisplatin-based chemotherapy was administered to 95% of the patients. Eleven patients underwent salvage surgery after RT failure. Results: Eight-eight (76.5%) patients responded partially and 23 (20%) completely; of the patients who responded, 18% and 57%, respectively, experienced a durable effect of treatment. The 3-year overall survival, disease-specific survival, and progression-free survival were 22%, 27%, and 25%, respectively. The 3-year PFS rates based on the primary tumor sites were as follows: Group I (buccal, mouth floor, and gum) 51%, Group II (retromolar and hard palate) 18%, and Group III (tongue and lip) 6% (p < 0.0001). The 3-year progression-free survival was 41% for N0 patients and 19% for patients with N+ disease (p = 0.012). The T stage and RT technique did not affect survival. The patients who underwent salvage surgery demonstrated better 3-year overall survival and disease-specific survival (53% vs. 19%, p = 0.015 and 53% vs. 24%, p = 0.029, respectively). Subsite group, N+, and salvage surgery were the only significant prognostic factors for survival after multivariate analysis. Conclusion: The primary tumor site and neck stage are prognostic predictors in advanced-stage oral cancer patients who received radical RT. The primary tumor extension and RT technique did not influence survival.

  1. Objective and subjective stressors and the psychological adjustment of melanoma survivors.

    PubMed

    Hamama-Raz, Y; Solomon, Z; Schachter, J; Azizi, E

    2007-04-01

    This study of 300 melanoma survivors examines the relative contributions of objective illness-related factors (stage of illness at diagnosis, time since diagnosis, and change in physical condition) and of subjective factors (cognitive appraisal) to their psychological adjustment. The findings show that lower appraisal of their situation as a threat, higher appraisal of it as a challenge, and higher appraisal of their subjective ability to cope with it all increased their well-being, while lower threat appraisal and higher appraisal of subjective ability to cope also reduced their distress. These findings, which are consistent with Lazarus and Folkman's stress coping theory, suggest that subjective factors may be more important than objective medical factors in predicting patients' adjustment. With this, more advanced stage at diagnosis contributed to reducing distress, while being married contributed both to higher well-being and reduced distress.

  2. Trousseau’s syndrome in a patient with advanced stage gastric cancer

    PubMed Central

    Chien, Tai-Long; Rau, Kung-Ming; Chung, Wen-Jung; Tai, Wei-Chen; Wang, Shih-Ho; Chiu, Yi-Chun; Wu, Keng-Liang; Chou, Yeh-Pin; Wu, Chia-Che; Chen, Yen-Hao; Chuah, Seng-Kee

    2015-01-01

    Patients with cancer are at high risk for thrombotic events, which are known collectively as Trousseau’s syndrome. Herein, we report a 66-year-old male patient who was diagnosed with terminal stage gastric cancer and liver metastasis and who had an initial clinical presentation of upper gastrointestinal bleeding. Acute ischemia of the left lower leg that resulted in gangrenous changes occurred during admission. Subsequent angiography of the left lower limb was then performed. This procedure revealed arterial thrombosis of the left common iliac artery with extension to the external iliac artery, the left common iliac artery, the posterior tibial artery, and the peroneal artery, which were occluded by thrombi. Aspiration of the thrombi demonstrated that these were not tumor thrombi. The interesting aspect of our case was that the disease it presented as arterial thrombotic events, which may correlate with gastric adenocarcinoma. In summary, we suggested that the unexplained thrombotic events might be one of the initial presentations of occult malignancy and that thromboprophylaxis should always be considered. PMID:26379411

  3. Dynamic contrast-enhanced MRI of ocular melanoma.

    PubMed

    Jiang, Xuyuan; Asbach, Patrick; Willerding, Gregor; Dulce, Miriam; Xu, Ke; Taupitz, Matthias; Hamm, Bernd; Erb-Eigner, Katharina

    2015-04-01

    Dynamic contrast-enhanced MRI is used for the assessment of microvasculature in several tumours. We aimed to assess the contrast signal enhancement characteristics of ocular melanoma. Forty patients with ocular melanoma were prospectively investigated with ocular MRI including dynamic contrast-enhanced sequences over a 13-month period. A region-of-interest analysis of the images was carried out to calculate signal enhancement characteristics after a contrast injection. Clinical follow-up data such as extraocular spread and development of liver metastasis were compared with the signal enhancement characteristics of the ocular melanoma. In 39 patients (98%), the ocular melanomas showed an early strong signal enhancement after contrast injection, resulting in a mean time of maximum enhancement of 49 s. Clinical follow-up was available in 28 patients (70%) and indicated that the peak signal intensity was significantly increased (P=0.039) in patients who developed extraocular spread or liver metastasis at a later stage. Ocular melanoma shows signal enhancement characteristics of hypervascular neoplasms. This study provides baseline curve pattern data that may be useful for assessing changes in vascularity, for example during therapy response. Furthermore, the study showed that a strong signal enhancement of the ocular melanoma might be linked to a less favourable prognosis.

  4. Socioeconomic and lifestyle factors and melanoma: a systematic review.

    PubMed

    Jiang, A J; Rambhatla, P V; Eide, M J

    2015-04-01

    Evidence of social determinants of disease and awareness of the impact of these factors on outcomes continues to increase. Social determinants include both socioeconomic and lifestyle factors. This review examines the interface between socioeconomic status (SES) and lifestyle and their effects on melanoma incidence and mortality. Lifestyle factors including occupation, occupational exposures, body mass index, marital status, smoking, recreational sun exposure and tanning were explored as they have a known relationship with melanoma. A remarkable association of SES with melanoma incidence and prognosis has been acknowledged worldwide. Melanoma incidence is increased in populations of higher SES, especially among the highly educated, while lower SES populations present with later-stage disease at time of diagnosis and display greater mortality. The aforementioned lifestyle factors are also related to SES, and have been shown internationally to affect melanoma incidence and mortality. This comprehensive systematic review suggests that lifestyle factors including occupation, occupational exposure, obesity, recreational sun exposure and tanning may explain the relationship between SES and melanoma.

  5. Expression of Phosphatase and Tensin Homologue, phospho-Akt, and p53 in Acral Benign and Malignant Melanocytic Neoplasms (Benign Nevi, Dysplastic Nevi, and Acral Melanomas)

    PubMed Central

    Lyu, So Min; Wu, Ju Yeon; Byun, Ji Yeon; Choi, Hae Young; Park, Sang Hee

    2016-01-01

    Background The role of the phosphatidylinositol-3 kinase signaling pathway in the development of acral melanoma has recently gained evidence. Phosphatase and tensin homologue (PTEN), one of the key molecules in the pathway, acts as a tumor suppressor through either an Akt-dependent or Akt-independent pathway. Akt accelerates degradation of p53. Objective We assessed the expression of PTEN, phospho-Akt (p-Akt), and p53 by immunohistochemistry in benign acral nevi, acral dysplastic nevi, and acral melanomas in the radial growth phase and with a vertical growth component. Methods Ten specimens in each group were included. Paraffin-embedded specimens were immunostained with antibodies for PTEN, p-Akt, and p53. We scored both the staining intensity and the proportion of positive cells. The final score was calculated by multiplying the intensity score by the proportion score. Results All specimens of benign acral nevi except one showed some degree of PTEN-negative cells. The numbers of p-Akt and p53-positive cells were higher in acral dysplastic nevi and melanoma than in benign nevi. P-Akt scores were 1.7, 1.8, 2.6, and 4.4, and p53 scores were 2.0, 2.1, 3.8, and 4.1 in each group. PTEN and p-Akt scores in advanced acral melanoma were higher than in the other neoplasms. Conclusion The expression of PTEN was decreased and the expression of p-Akt was increased in acral melanoma, especially in advanced cases. The PTEN-induced pathway appears to affect the late stage of melanomagenesis. Altered expression of p-Akt is thought to be due to secondary changes following the loss of PTEN. PMID:27746632

  6. Upcoming translational challenges for uveal melanoma.

    PubMed

    Amirouchene-Angelozzi, Nabil; Schoumacher, Marie; Stern, Marc-Henri; Cassoux, Nathalie; Desjardins, Laurence; Piperno-Neumann, Sophie; Lantz, Olivier; Roman-Roman, Sergio

    2015-11-01

    The past few years have witnessed major advances in the understanding of the molecular landscape of uveal melanoma (UM). The discovery of a mutational background that is completely different from the one of skin melanoma has granted to UM a stand-alone status. The absence of effective therapy for metastatic disease offers now a chessboard for targeted therapy but at the same time urges preclinical science to develop accordingly, to guide the use of economical resources to the best profit of patients. This review describes the current knowledge on the biology of this disease and discusses the challenges that must be undertaken to translate this knowledge into real benefit for patients. PMID:26505679

  7. Upcoming translational challenges for uveal melanoma

    PubMed Central

    Nabil, Amirouchene-Angelozzi; Marie, Schoumacher; Marc-Henri, Stern; Nathalie, Cassoux; Laurence, Desjardins; Sophie, Piperno-Neumann; Olivier, Lantz; Sergio, Roman-Roman

    2015-01-01

    The past few years have witnessed major advances in the understanding of the molecular landscape of uveal melanoma (UM). The discovery of a mutational background that is completely different from the one of skin melanoma has granted to UM a stand-alone status. The absence of effective therapy for metastatic disease offers now a chessboard for targeted therapy but at the same time urges preclinical science to develop accordingly, to guide the use of economical resources to the best profit of patients. This review describes the current knowledge on the biology of this disease and discusses the challenges that must be undertaken to translate this knowledge into real benefit for patients. PMID:26505679

  8. Proteomics of Uveal Melanoma: A Minireview

    PubMed Central

    Abildgaard, Søren K. O.; Vorum, Henrik

    2013-01-01

    Uveal melanoma (UM) continues to be associated with a high mortality rate of up to 50% due to metastatic spread primarily to the liver. Currently there are relatively effective treatments for the primary tumor, though the management of the metastatic disease remains inadequate. Conventional diagnostic tools have a low sensitivity for detecting metastasis, and early detection of metastatic spread would allow more treatment options that could ultimately increase survival of UM patients. Advanced proteomic methods have already helped to find potential biomarkers associated with UM pathogenesis and metastasis. In the present review we discuss the field of proteomics in relation to studies elucidating biomarkers of UM, where proteins such as S-100β, osteopontin (OPN), and melanoma inhibitory activity (MIA) have been shown to be associated with metastasis. PMID:24078811

  9. Radiation Therapy and MK-3475 for Patients With Recurrent/Metastatic Head and Neck Cancer, Renal Cell Cancer, Melanoma, and Lung Cancer

    ClinicalTrials.gov

    2016-10-18

    Head and Neck Squamous Cell Carcinoma; Metastatic Renal Cell Cancer; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IV Lung Cancer; Stage IV Skin Melanoma

  10. [A Case of HER2-Positive Stage IV Advanced Gastric Cancer Treated with Chemotherapy Combined with Trastuzumab].

    PubMed

    Takaya, Kai; Takahashi, Ryosuke; Honma, Satoru; Horii, Shinichiro; Takahashi, Hirokazu; Hagiwara, Motohisa; Chin, Masahiro; Hashizume, Eiji

    2016-09-01

    We report a case of human epidermal growth factor receptor(HER)2 positive stage IV advanced gastric cancer successfully treated with chemotherapy combined with trastuzumab. A 50-year-old man was diagnosed with type 3 gastric cancer complicated by liver and lymph node metastases. Owing to a HER2 immunohistochemistry tumor score of 3+, we initiated capecitabine plus CDDP plus trastuzumab chemotherapy. After 6 chemotherapy courses, computed tomography showed the liver metastasis had disappeared and the paraaortic lymph nodes had shrunk. We continued the capecitabine plus trastuzumab chemotherapy, which resulted in a progression free survival of 31 months. After 38 chemotherapy courses, the primary tumor progressed; therefore, the patient underwent surgery. Chemotherapy combined with trastuzumab can allow for resec- tion of the primary tumor. PMID:27628555

  11. FUTURE PERSPECTIVES IN MELANOMA RESEARCH. Meeting report from the “Melanoma Research: a bridge from Naples to the World. Napoli, December 5th–6 th2011”

    PubMed Central

    2012-01-01

    After more than 30 years, landmark progress has been made in the treatment of cancer, and melanoma in particular, with the success of new molecules such as ipilimumab, vemurafenib and active specific immunization. After the first congress in December 2010, the second edition of “Melanoma Research: a bridge from Naples to the World” meeting, organized by Paolo A. Ascierto (INT, Naples, Italy), Francesco M. Marincola (NIH, Bethesda, USA), and Nicola Mozzillo (INT, Naples, Italy) took place in Naples, on 5–6 December 2011. We have identified four new topics of discussion: Innovative Approaches in Prevention, Diagnosis and Surgical Treatment, New Pathways and Targets in Melanoma: An Update about Immunotherapy, and Combination Strategies. This international congress gathered more than 30 international faculty members and was focused on recent advances in melanoma molecular biology, immunology and therapy, and created an interactive atmosphere which stimulated discussion of new approaches and strategies in the field of melanoma. PMID:22551296

  12. Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24): Novel gene therapeutic for metastatic melanoma

    SciTech Connect

    Fisher, Paul B. Sarkar, Devanand; Lebedeva, Irina V.; Emdad, Luni; Gupta, Pankaj; Sauane, Moira; Su Zaozhong; Grant, Steven; Dent, Paul; Curiel, David T.; Senzer, Neil; Nemunaitis, John

    2007-11-01

    A potentially less toxic approach for cancer therapy comprises induction of tumor cells to lose growth potential irreversibly and terminally differentiate. Combining this scheme termed 'differentiation therapy of cancer' with subtraction hybridization to human melanoma cells resulted in the cloning of melanoma differentiation associated (mda) genes displaying elevated expression as a consequence of induction of terminal differentiation. One originally novel gene, mda-7, was found to display elevated expression in normal melanocytes and nevi with progressive loss of expression as a consequence of melanoma development and progression to metastasis. Based on structure, biochemical properties and chromosomal location, mda-7 has now been reclassified as interleukin (IL)-24, a member of the expanding IL-10 family of cytokines. In vitro cell culture and in vivo animal studies indicate that mda-7/IL-24 selectively induces programmed cell death (apoptosis) in multiple human cancers (including melanomas), without harming normal cells, and promotes profound anti-tumor activity in nude mice containing human tumor xenografts. Based on these remarkable properties, a Phase I clinical trial was conducted to test the safety of administration of mda-7/IL-24 by a replication incompetent adenovirus (Ad.mda-7; INGN 241) in patients with advanced solid cancers including melanoma. mda-7/IL-24 was found to be safe and to promote significant clinical activity, particularly in the context of patients with metastatic melanoma. These results provide an impetus for further clinical studies and document a central paradigm of cancer therapy, namely translation of basic science from the 'bench to the bedside.'.

  13. 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.

  14. Understanding the Racial and Ethnic Differences in Cost and Mortality Among Advanced Stage Prostate Cancer Patients (STROBE).

    PubMed

    Chhatre, Sumedha; Bruce Malkowicz, Stanley; Sanford Schwartz, J; Jayadevappa, Ravishankar

    2015-08-01

    The aims of the study were to understand the racial/ethnic differences in cost of care and mortality in Medicare elderly with advanced stage prostate cancer.This retrospective, observational study used SEER-Medicare data. Cohort consisted of 10,509 men aged 66 or older and diagnosed with advanced-stage prostate cancer between 2001and 2004. The cohort was followed retrospectively up to 2009. Racial/ethnic variation in cost was analyzed using 2 part-models and quantile regression. Step-wise GLM log-link and Cox regression was used to study the association between race/ethnicity and cost and mortality. Propensity score approach was used to minimize selection bias.Pattern of cost and mortality varies between racial/ethnic groups. Compared with other racial/ethnic groups, non-Hispanic white patients had higher unadjusted costs in treatment and follow-up phases. Quintile regression results indicated that in treatment phase, Hispanics had higher costs in the 95th quantile and non-Hispanic blacks had lower cost in the 95th quantile, compared with non-Hispanic white men. In terminal phase non-Hispanic blacks and Hispanics had higher cost. After controlling for treatment, all-cause and prostate cancer-specific mortality was not significant for non-Hispanic black men, compared with non-Hispanic white men. However, for Asians, mortality remained significantly lower compared with non-Hispanic white men.In conclusion, relationship between race/ethnicity, cost of care, and mortality is intricate. For non-Hispanic black men, disparity in mortality can be attributed to treatment differences. To reduce racial/ethnic disparities in prostate cancer care and outcomes, tailored policies to address underuse, overuse, and misuse of treatment and health services are necessary. PMID:26266389

  15. The Modern Role of Radiation Therapy in Treating Advanced-Stage Retinoblastoma: Long-Term Outcomes and Racial Differences

    SciTech Connect

    Orman, Amber; Koru-Sengul, Tulay; Miao, Feng; Markoe, Arnold; Panoff, Joseph E.

    2014-12-01

    Purpose/Objective(s): To evaluate the effects of various patient characteristics and radiation therapy treatment variables on outcomes in advanced-stage retinoblastoma. Methods and Materials: This was a retrospective review of 41 eyes of 30 patients treated with external beam radiation therapy between June 1, 1992, and March 31, 2012, with a median follow-up time of 133 months (11 years). Outcome measures included overall survival, progression-free survival, local control, eye preservation rate, and toxicity. Results: Over 90% of the eyes were stage V. Definitive external beam radiation therapy (EBRT) was delivered in 43.9% of eyes, adjuvant EBRT in 22% of eyes, and second-line/salvage EBRT in 34.1% of eyes. A relative lens sparing (RLS) technique was used in 68.3% of eyes and modified lens sparing (MLS) in 24.4% of eyes. Three eyes were treated with other techniques. Doses ≥45 Gy were used in 68.3% of eyes. Chemotherapy was a component of treatment in 53.7% of eyes. The 10-year overall survival was 87.7%, progression-free survival was 80.5%, and local control was 87.8%. White patients had significantly better overall survival than did African-American patients in univariate analysis (hazard ratio 0.09; 95% confidence interval 0.01-0.84; P=.035). Toxicity was seen in 68.3% of eyes, including 24.3% with isolated acute dermatitis. Conclusions: External beam radiation therapy continues to be an effective treatment modality for advanced retinoblastoma, achieving excellent long-term local control and survival with low rates of treatment-related toxicity and secondary malignancy.

  16. Endoscopic ultrasound for the characterization and staging of rectal cancer. Current state of the method. Technological advances and perspectives.

    PubMed

    Gersak, Mariana M; Badea, Radu; Graur, Florin; Hajja, Nadim Al; Furcea, Luminita; Dudea, Sorin M

    2015-06-01

    Endoscopic ultrasound is the most accurate type of examination for the assessment of rectal tumors. Over the years, the method has advanced from gray-scale examination to intravenous contrast media administration and to different types of elastography. The multimodal approach of tumors (transrectal, transvaginal) is adapted to each case. 3D ultrasound is useful for spatial representation and precise measurement of tumor formations, using CT/MR image reconstruction; color elastography is useful for tumor characterization and staging; endoscopic ultrasound using intravenous contrast agents can help study the amount of contrast agent targeted at the level of the tumor formations and contrast wash-in/wash-out time, based on the curves displayed on the device. The transvaginal approach often allows better visualization of the tumor than the transrectal approach. Performing the procedure with the rectal ampulla distended with contrast agent may be seen as an optimization of the examination methodology. All these aspects are additional methods for gray-scale endoscopic ultrasound, capable of increasing diagnostic accuracy. This paper aims at reviewing the progress of transrectal and transvaginal ultrasound, generically called endoscopic ultrasound, for rectal tumor diagnosis and staging, with emphasis on the current state of the method and its development trends.

  17. Sulfur removal in advanced two stage pressurized fluidized bed combustion. Technical report, March 1--May 31, 1995

    SciTech Connect

    Abbasian, J.

    1995-12-31

    The objective of this study is to obtain data on the rates and the extent of sulfation reactions involving partially sulfided calcium-based sorbents, and oxygen as well as sulfur dioxide, at operating conditions closely simulating those prevailing in the second stage (combustor) of Advanced Two-Stage Pressurized Fluidized-Bed Combustors. In these systems the CO{sub 2} partial pressure generally exceeds the equilibrium value for calcium carbonate decomposition. Therefore, calcium sulfate is produced through the reactions between SO{sub 2} and calcium carbonate as well as the reaction between calcium sulfide and oxygen. To achieve this objective, the rates of reaction involving SO{sub 2} and oxygen, calcium sulfide and calcium carbonate will be determined by conducting tests in a pressurized thermogravimetric analyzer unit. The sulfate tests conducted during this quarter, focused on the determination of the rate of sulfation reaction involving partially sulfided half-calcined dolomite and oxygen. The test parameters included CO{sub 2} and O{sub 2} concentrations, reaction temperature and pressure, as well as the sorbent particle size. The results obtained during this quarter suggest that the rate of sulfation reaction involving partially sulfided half-calcined dolomite and oxygen is very fast at temperatures above 850 C which rapidly increases with increasing temperature, achieving more than 85% conversion in less than a few minutes. The reaction appears to continue to completion, however, above 85% conversion, the rate of reaction appears to be low, requiring long residence time to reach complete conversion.

  18. Sulfur removal in advanced two stage pressurized fluidized bed combustion. Technical report, December 1, 1994--February 28, 1995

    SciTech Connect

    Abbasian, J.

    1996-03-01

    The objective of this study is to obtain data on the rates and the extent of sulfation reactions involving partially sulfided calcium-based sorbents, and oxygen as well as sulfur dioxide, at operating conditions closely simulating those prevailing in the second stage (combustor) of Advanced Two-Stage Pressurized Fluidized-Bed Combustors (PFBC). In these systems the CO{sub 2} partial pressure generally exceeds the equilibrium value for calcium carbonate decomposition. Therefore, calcium sulfate is produced through the reactions between SO{sub 2} and calcium carbonate as well as the reaction between calcium sulfide and oxygen. To achieve this objective, the rates of reaction involving SO{sub 2} and oxygen (gaseous reactant); and calcium sulfide and calcium carbonate (solid reactants), will be determined by conducting tests in a pressurized thermogravimetric analyzer (HPTGA) unit. The effects of sorbent type, sorbent particle size, reactor temperature and pressure; and O{sub 2} as well as SO{sub 2} partial pressures on the sulfation reactions rate will be determined. During this quarter, samples of the selected limestone and dolomite, sulfided in the fluidized-bed reactor during last quarter, were analyzed. The extent of sulfidation in these samples was in the range of 20 to 50%, which represent carbonizer discharge material at different operating conditions. The high pressure thermogravimetric analyzer (BPTGA) unit has been modified and a new pressure control system was installed to eliminate pressure fluctuation during the sulfation tests.

  19. Sulfur removal in advanced two stage pressurized fluidized bed combustion. Technical report, September 1--November 30, 1994

    SciTech Connect

    Abbasian, J.; Hill, A.; Wangerow, J.R.

    1994-12-31

    The objective of this study is to obtain data on the rates and the extent of sulfation reactions involving partially sulfided calcium-based sorbents, and oxygen as well as sulfur dioxide, at operating conditions closely simulating those prevailing in the second stage (combustor) of Advanced Two-Stage Pressurized Fluidized-Bed Combustors (PFBC). In these systems the CO{sub 2} partial pressure generally exceeds the equilibrium value for calcium carbonate decomposition. Therefore, calcium sulfate is produced through the reactions between SO{sub 2} and calcium carbonate as well as the reaction between calcium sulfide and oxygen. To achieve this objective, the rates of reaction involving SO{sub 2} and oxygen (gaseous reactant); and calcium sulfide and calcium carbonate (solid reactants), will be determined by conducting tests in a pressurized thermogravimetric analyzer (HPTGA) unit. The effects of sorbent type, sorbent particle size, reactor temperature and pressure; and O{sub 2} as well as SO{sub 2} partial pressures on the sulfation reactions rate will be determined. During this quarter, samples of the selected limestone and dolomite were sulfided in the fluidized-bed reactor. These tests were conducted in both calcining and non-calcining operating conditions to produce partially-sulfided sorbents containing calcium oxide and calcium carbonate, respectively. These samples which represent the carbonizer discharge material, will be used as the feed material in the sulfation tests to be conducted in the HPTGA unit during the next quarter.

  20. Results of Two-Stage Light-Gas Gun Development Efforts and Hypervelocity Impact Tests of Advanced Thermal Protection Materials

    NASA Technical Reports Server (NTRS)

    Cornelison, C. J.; Watts, Eric T.

    1998-01-01

    Gun development efforts to increase the launching capabilities of the NASA Ames 0.5-inch two-stage light-gas gun have been investigated. A gun performance simulation code was used to guide initial parametric variations and hardware modifications, in order to increase the projectile impact velocity capability to 8 km/s, while maintaining acceptable levels of gun barrel erosion and gun component stresses. Concurrent with this facility development effort, a hypervelocity impact testing series in support of the X-33/RLV program was performed in collaboration with Rockwell International. Specifically, advanced thermal protection system materials were impacted with aluminum spheres to simulate impacts with on-orbit space debris. Materials tested included AETB-8, AETB-12, AETB-20, and SIRCA-25 tiles, tailorable advanced blanket insulation (TABI), and high temperature AFRSI (HTA). The ballistic limit for several Thermal Protection System (TPS) configurations was investigated to determine particle sizes which cause threshold TPS/structure penetration. Crater depth in tiles was measured as a function of impact particle size. The relationship between coating type and crater morphology was also explored. Data obtained during this test series was used to perform a preliminary analysis of the risks to a typical orbital vehicle from the meteoroid and space debris environment.

  1. 4-methylcatechol-Induced Oxidative Stress Induces Intrinsic Apoptotic Pathway in Metastatic Melanoma Cells

    PubMed Central

    Payton, Florastina; Bose, Rumu; Alworth, William L; Kumar, Addanki P; Ghosh, Rita

    2011-01-01

    There has been a steady rise in fatalities associated with thick melanomas (>4mm). Although understanding of the biology of the disease has improved, effective treatment strategies for patients with advanced metastatic melanoma remain elusive. Therefore, more intensive testing of agents with therapeutic potential are needed to improve survival of patients with metastatic malignant melanoma. We have tested the ability of 4-methylcatechol, a metabolite of quercetin; a naturally occurring compound that is commonly found in a variety of fruits for its potential as an anti-melanoma agent. Our results show that 4-methylcatechol inhibits proliferation of melanoma cells in culture while not affecting the growth of normal human epidermal melanocytes. Further, the ability of metastatic melanoma cells to form colonies on soft agar was also inhibited. 4-methylcatechol caused the accumulation of cells in G2/M phase of the cell cycle and induced apoptosis. There was an increase in reactive oxygen species following treatment with 4-methylcatechol that led to apoptosis through the intrinsic mitochondrial pathway. Treatment also inhibited cell survival mediated by Akt, a key player in melanoma cell survival. Taken together our results suggest that 4-methylcatechol exhibits cytotoxicity towards metastatic malignant melanoma cells while sparing normal melanocytes and should be tested further as a potential drug candidate for malignant melanoma. PMID:21419106

  2. Sulfur removal in advanced two stage pressurized fluidized bed combustion. Technical report, 1 March--31 May 1994

    SciTech Connect

    Abbasian, J.; Chowdiah, P.; Hill, A.H.; Rue, D.M.

    1994-09-01

    The objective of this study is to obtain data on the rates of reaction between hydrogen sulfide (H{sub 2}S) and uncalcined calcium-based sorbents under operating conditions relevant to first stage (carbonizer) of Advanced Two-Stage Pressurized Fluidized-Bed Combustors (PFBC). In these systems the CO{sub 2} partial pressure in the first stage generally exceeds the equilibrium value for calcium carbonate decomposition. Therefore, removal of sulfur compounds takes place through the reaction between H{sub 2}S and calcium carbonate. To achieve this objective, the rates of reaction between hydrogen sulfide and uncalcined calcium-based sorbents will be determined by conducting tests in pressurized thermogravimetric analyzer (TGA) and high-pressure/high-temperature fluidized-bed reactor (HPTR) units. The effects of sorbent type, sorbent particle size, reactor temperature and pressure, and CO{sub 2} and H{sub 2}S partial pressures on the sulfidation reaction rate will be determined. During this quarter a series of sulfidation tests were conducted in the high-pressure/high-temperature fluidized-bed reactor (HPTR) units. The effects of sorbent type, sorbent particle size, reactor temperature and pressure, and CO{sub 2} and H{sub 2}S partial pressures on the sulfidation reaction rate will be determined. During this quarter a series of sulfidation tests were conducted in the high-pressure high-temperature thermogravimetric analyzer (HPTGA unit) using limestone and dolomite. The results suggest that half-calcined dolomite is much more reactive than uncalcined limestone. Also, temperature in the range of 800 to 950 C did not significantly affect the sulfidation reaction rates for both limestone and dolomite.

  3. Targeting BRAF in melanoma: biological and clinical challenges.

    PubMed

    Mandalà, Mario; Voit, Christiane

    2013-09-01

    Melanoma is an aggressive form of skin cancer that causes the greatest number of skin cancer-related deaths worldwide. In its early stages malignant melanoma can be cured by surgical resection, but once it has progressed to the metastatic stage it is extremely difficult to treat and does not respond to current therapies. A majority of cutaneous melanomas show activating mutations in the NRAS or BRAF proto-oncogenes, components of the Ras-Raf-Mek-Erk (MAPK) signal transduction pathway. The discovery of activating BRAF mutations in ∼50% of all melanomas has proved to be a turning point in the therapeutic management of the disseminated disease. This review summarizes the critical role of BRAF in melanoma pathophysiology, the clinical and pathological determinants of BRAF mutation status and finally addresses the current state of the art of BRAF inhibitors. We further outline the most recent findings on the mechanisms that underlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing preclinical and clinical studies designed to delay or abrogate the onset of therapeutic escape.

  4. Low podoplanin expression in pretreatment biopsy material predicts poor prognosis in advanced-stage squamous cell carcinoma of the uterine cervix treated by primary radiation.

    PubMed

    Dumoff, Kimberly L; Chu, Christina S; Harris, Eleanor E; Holtz, David; Xu, Xiaowei; Zhang, Paul J; Acs, Geza

    2006-05-01

    Lymphatic invasion and nodal metastasis are predictors of poor outcome in cervix carcinoma. We have recently found that low podoplanin immunoreactivity in cervix carcinoma correlated with the presence of lymphatic invasion and nodal metastasis. In the current study, we examined whether podoplanin expression in pretreatment cervical biopsies can predict the presence lymphatic invasion, nodal metastasis, and outcome in advanced-stage tumors treated by nonsurgical means. Podoplanin expression was analyzed by immunohistochemistry in 48 cervical biopsies and corresponding hysterectomy specimens of early-stage invasive squamous cell carcinoma and in 74 pretreatment biopsies from advanced-stage tumors treated with primary radiation. We found a highly significant correlation between podoplanin expression obtained in biopsy and corresponding hysterectomy materials (r = 0.8962, P < 0.0001). Low podoplanin expression showed a significant correlation with lymphatic invasion (P < 0.0001) and nodal metastasis (P = 0.0058). Low podoplanin expression in pretreatment biopsy material showed a significant correlation with poor disease-free (P = 0.0009) and overall (P = 0.0002) survival in advanced-stage tumors. Our results suggest that in advanced-stage cervix carcinomas treated by radiation, when traditional prognostic indicators are not available and treatment decisions are based on biopsy material and clinical staging parameters, examination of podoplanin expression in pretreatment biopsy material may be a useful marker to predict lymphatic metastasis and patient outcome. Prospective studies involving larger numbers of patients are needed to further evaluate the clinical utility of examination of podoplanin expression in patients with cervix carcinoma.

  5. Primary pineal malignant melanoma

    PubMed Central

    Cedeño Diaz, Oderay Mabel; Leal, Roberto García; La Cruz Pelea, Cesar

    2011-01-01

    Primary pineal malignant melanoma is a rare entity, with only thirteen cases reported in the world literature to date. We report a case of a 70-year-old man, who consulted with gait disturbance of six months duration, associated in the last month with dizziness, visual abnormalities and diplopia. No other additional melanocytic lesions were found elsewhere. The magnetic resonance showed a 25 mm expansive mass in the pineal gland that was associated with hydrocephaly, ventricular and transependimary oedema. The lesion was partially excised by a supracerebellar infratentorial approach. The histological examination revealed a melanoma. The patient received radiation therapy, but died of disease 16 weeks later. We herein review the literature on this rare tumour and comment on its clinical, radiological and histopathological features and differential diagnosis. PMID:24765293

  6. The Role of Intralesional Therapies in Melanoma.

    PubMed

    Agarwala, Sanjiv S

    2016-05-01

    The US Food and Drug Administration has been rapidly approving new checkpoint inhibitors and targeted therapies for melanoma and other tumors. Recently, it approved the first intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of metastatic melanoma lesions in the skin and lymph nodes. Several other intralesional therapies (PV-10, interleukin-12 electroporation, coxsackievirus A21 [CVA21]) are entering later-stage testing. Locally injected agents have clearly shown their ability to produce local responses that can be durable. The possibility that they also stimulate a regional and even systemic immune response is exciting, as this potential effect may have utility in combination regimens; such regimens are an area of active research. Favorable responses with minimal toxicities in monotherapy trials have led to the first melanoma studies of T-VEC in combination with the cytotoxic T-lymphocyte-associated antigen 4 inhibitor ipilimumab and, separately, with the programmed death 1-blocking antibody pembrolizumab. Studies of PV-10 with pembrolizumab and of CVA21 with pembrolizumab are also being initiated. Preliminary analyses of the results of the first combination trials, which show higher response rates than with either agent alone, offer some optimism that these locoregional therapies will find application--as treatment for patients who cannot tolerate systemic immunotherapies, to alleviate locoregional morbidity, and perhaps even to "prime" the immune system.

  7. Update and Review on the Surgical Management of Primary Cutaneous Melanoma.

    PubMed

    Leilabadi, Solmaz Niknam; Chen, Amie; Tsai, Stacy; Soundararajan, Vinaya; Silberman, Howard; Wong, Alex K

    2014-06-10

    The surgical management of malignant melanoma historically called for wide excision of skin and subcutaneous tissue for any given lesion, but has evolved to be rationally-based on pathological staging. Breslow and Clark independently described level and thickness as determinant in prognosis and margin of excision. The American Joint Committee of Cancer (AJCC) in 1988 combined features from each of these histologic classifications, generating a new system, which is continuously updated and improved. The National Comprehensive Cancer Network (NCCN) has also combined several large randomized prospective trials to generate current guidelines for melanoma excision as well. In this article, we reviewed: (1) Breslow and Clark classifications, AJCC and NCCN guidelines, the World Health Organization's 1988 study, and the Intergroup Melanoma Surgical Trial; (2) Experimental use of Mohs surgery for in situ melanoma; and (3) Surgical margins and utility and indications for sentinel lymph node biopsy (SLNB) and lymphadenectomy. Current guidelines for the surgical management of a primary melanoma of the skin is based on Breslow microstaging and call for cutaneous margins of resection of 0.5 cm for MIS, 1.0 cm for melanomas ≤1.0 mm thick, 1-2 cm for melanoma thickness of 1.01-2 mm, 2 cm margins for melanoma thickness of 2.01-4 mm, and 2 cm margins for melanomas >4 mm thick. Although the role of SLNB, CLND, and TLND continue to be studied, current recommendations include SLNB for Stage IB (includes T1b lesions ≤1.0 with the adverse features of ulceration or ≥1 mitoses/mm²) and Stage II melanomas. CLND is recommended when sentinel nodes contain metastatic deposits.

  8. The gene expression signatures of melanoma progression

    PubMed Central

    Haqq, Christopher; Nosrati, Mehdi; Sudilovsky, Daniel; Crothers, Julia; Khodabakhsh, Daniel; Pulliam, Brian L.; Federman, Scot; Miller, James R.; Allen, Robert E.; Singer, Mark I.; Leong, Stanley P. L.; Ljung, Britt-Marie; Sagebiel, Richard W.; Kashani-Sabet, Mohammed

    2005-01-01

    Because of the paucity of available tissue, little information has previously been available regarding the gene expression profiles of primary melanomas. To understand the molecular basis of melanoma progression, we compared the gene expression profiles of a series of nevi, primary melanomas, and melanoma metastases. We found that metastatic melanomas exhibit two dichotomous patterns of gene expression, which unexpectedly reflect gene expression differences already apparent in comparing laser-capture microdissected radial and vertical phases of a large primary melanoma. Unsupervised hierarchical clustering accurately separated nevi and primary melanomas. Multiclass significance analysis of microarrays comparing normal skin, nevi, primary melanomas, and the two types of metastatic melanoma identified 2,602 transcripts that significantly correlated with sample class. These results suggest that melanoma pathogenesis can be understood as a series of distinct molecular events. The gene expression signatures identified here provide the basis for developing new diagnostics and targeting therapies for patients with malignant melanoma. PMID:15833814

  9. Of Mice and Melanoma: PDX System for Modeling Personalized Medicine.

    PubMed

    Hartsough, Edward J; Aplin, Andrew E

    2016-04-01

    Targeted therapies have advanced the treatment options for cutaneous melanoma, but many patients will progress on drug. Patient-derived xenografts (PDX) can be used to recapitulate therapy-resistant tumors. Furthermore, PDX modeling can be utilized in combination with targeted sequencing and phosphoproteomic platforms, providing preclinical basis for second-line targeted inhibitor strategies. See related article by Krepler et al., p. 1592.

  10. Identification of cells initiating human melanomas

    PubMed Central

    Schatton, Tobias; Murphy, George F.; Frank, Natasha Y.; Yamaura, Kazuhiro; Waaga-Gasser, Ana Maria; Gasser, Martin; Zhan, Qian; Jordan, Stefan; Duncan, Lyn M.; Weishaupt, Carsten; Fuhlbrigge, Robert C.; Kupper, Thomas S.; Sayegh, Mohamed H.; Frank, Markus H.

    2012-01-01

    Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies1,2 and solid cancers3–6. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5− bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ sub-populations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5− progeny, whereas ABCB5− tumour populations give rise, at lower rates, exclusively to ABCB5− cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy. PMID:18202660

  11. 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.

  12. Tail-flick test response in 3×Tg-AD mice at early and advanced stages of disease.

    PubMed

    Baeta-Corral, Raquel; Defrin, Ruti; Pick, Chagi G; Giménez-Llort, Lydia

    2015-07-23

    Despite the impact of pain in cognitive dysfunctions and affective disorders has been largely studied, the research that examines pain dimensions in cognitive impairment or dementia is still scarce. In patients with Alzheimer's disease (AD) and related dementias, management of pain is challenging. While the sensory-discriminative dimension of pain is preserved, the cognitive-evaluative and the affective-motivational pain dimensions are affected. Due to the complexity of the disease and the poor self-reports, pain is underdiagnosed and undertreated. In confluence with an impaired thermoregulatory behavior, the patients' ability to confront environmental stressors such as cold temperature can put them at risk of fatal accidental hypothermia. Here, 3xTg-AD mice demonstrate that the sensorial-discriminative threshold to a noxious cold stimulus, as measured by the latency of tail-flicking, was preserved at early and advances stages of disease (7 and 11 month-old, respectively) as compared to age-matched (adulthood and middle aged, respectively) non-transgenic mice (NTg). In both genotypes, the sensory deterioration and poor thermoregulatory behavior associated to age was observed as an increase of tail-flick response and poor sensorimotor performance. At both stages studied, 3xTg-AD mice exhibited BPSD (Behavioral and Psychological Symptoms of Dementia)-like alterations in the corner, open-field, dark-light box and the T-maze tests. In the adult NTg mice, this nociceptive withdrawal response was correlated with copying with stress-related behaviors. This integrative behavioral profile was lost in both groups of 3xTg-AD mice and middle aged controls, suggesting derangements in their subjacent networks and the complex interplay between the pain dimensions in the elderly with dementia. PMID:26091881

  13. Recruitment of natural killer cells in advanced stages of endogenously arising B-cell lymphoma: implications for therapeutic cell transfer.

    PubMed

    Przewoznik, Margarethe; Hömberg, Nadine; Naujoks, Marcella; Pötzl, Johann; Münchmeier, Niklas; Brenner, Christoph D; Anz, David; Bourquin, Carole; Nelson, Peter J; Röcken, Martin; Mocikat, Ralph

    2012-04-01

    During inflammation and in transplantable tumor models, natural killer (NK) cells are recruited to pathologic tissues and activated to produce proinflammatory cytokines favoring adaptive immune responses of the T-helper type 1 (Th1) type. Interferon (IFN)-γ is needed to induce chemokines that attract NK cells in transplanted tumors. Nothing, however, is known on NK-cell migration in spontaneous tumors. As effective recruitment is a prerequisite for therapeutic NK-cell transfer, we investigated the cytokine milieu and the mechanisms that are instrumental for NK-cell accumulation in an endogenous tumor model. We make use of λ-myc transgenic mice that harbor the c-myc oncogene and develop spontaneous B-cell lymphoma. In contrast to lymphomas induced by tumor cell injection, virtually no IFN-γ produced by NK or by other cells was present in the tumor environment, particularly in advanced stages. Dendritic cells showed an impaired expression of interleukin-12, which is suggestive of deficient Th1 priming. The IFN-γ-dependent chemokines CXCL9 and CXCL10 were pivotal for NK-cell migration in the endogenous lymphoma model. Although IFN-γ was absent in late tumor stages, there was still expression of CXCL9 and CXCL10 with an ongoing influx of NK cells. The results demonstrate that transplantable tumor models do not reflect the situation as found in endogenously arising neoplasia, because in the latter, effective Th1 and cytotoxic T-lymphocyte responses are presumably not induced because of impaired IFN-γ production. The data also suggest that CXCL9 and CXCL10 production and NK-cell migration become independent of IFN-γ during tumor progression, and therefore support approaches of adoptive NK-cell transfer that hold promise for treatment of cancer. PMID:22421939

  14. Immunobiology of primary murine melanomas.

    PubMed

    Donawho, C; Evans, R; Kripke, M L

    1992-10-01

    Primary cutaneous melanomas can be induced in inbred mice by applying a dose of dimethylbenz[a]anthracene to the skin of 4-day-old mice, and then applying repeated doses of a tumor promoter to the same site over a long period of time. Preliminary experiments suggest that the final incidence of melanomas is strongly influenced by the age at which the initiating dose of carcinogen is applied. Melanomas induced by this method in C3H mice are immunogenic and exhibit a high degree of cross-reactivity when tested by immunization and challenge in vivo. Exposing the mice to ultraviolet (UV) radiation during carcinogenesis dramatically accelerates the appearance of melanoma. We are attempting to determine how UV radiation potentiates melanoma induction by studying the growth of melanoma cells transplanted into UV-irradiated skin. Our studies suggest that UV irradiation accelerates the outgrowth of melanoma cells by means of a local, immunosuppressive effect on the skin. However, this effect is distinct from the ability of UV irradiation to alter epidermal Langerhans cells and interfere with the induction of contact hypersensitivity responses. We postulate that UV irradiation augments melanoma development by interfering with the efferent arm of the immune response in the UV-irradiated site. PMID:1445809

  15. Advanced glycation end products, carotid atherosclerosis, and circulating endothelial progenitor cells in patients with end-stage renal disease.

    PubMed

    Ueno, Hiroki; Koyama, Hidenori; Fukumoto, Shinya; Tanaka, Shinji; Shoji, Takuhito; Shoji, Tetsuo; Emoto, Masanori; Tahara, Hideki; Inaba, Masaaki; Kakiya, Ryusuke; Tabata, Tsutomu; Miyata, Toshio; Nishizawa, Yoshiki

    2011-04-01

    Numbers of endothelial progenitor cells (EPCs) have been shown to be decreased in subjects with end-stage renal disease (ESRD), the mechanism of which remained poorly understood. In this study, mutual association among circulating EPC levels, carotid atherosclerosis, serum pentosidine, and skin autofluorescence, a recently established noninvasive measure of advanced glycation end products accumulation, was examined in 212 ESRD subjects undergoing hemodialysis. Numbers of circulating EPCs were measured as CD34+ CD133+ CD45(low) VEGFR2+ cells and progenitor cells as CD34+ CD133+ CD45(low) fraction by flow cytometry. Skin autofluorescence was assessed by the autofluorescence reader; and serum pentosidine, by enzyme-linked immunosorbent assay. Carotid atherosclerosis was determined as intimal-medial thickness (IMT) measured by ultrasound. Circulating EPCs were significantly and inversely correlated with skin autofluorescence in ESRD subjects (R = -0.216, P = .002), but not with serum pentosidine (R = -0.079, P = .25). Circulating EPCs tended to be inversely associated with IMT (R = -0.125, P = .069). Intimal-medial thickness was also tended to be correlated positively with skin autofluorescence (R = 0.133, P = .054) and significantly with serum pentosidine (R = 0.159, P = .019). Stepwise multiple regression analyses reveal that skin autofluorescence, but not serum pentosidine and IMT, was independently associated with low circulating EPCs. Of note, skin autofluorescence was also inversely and independently associated with circulating progenitor cells. Thus, tissue accumulated, but not circulating, advanced glycation end products may be a determinant of a decrease in circulating EPCs in ESRD subjects.

  16. Advanced glycation end products, carotid atherosclerosis, and circulating endothelial progenitor cells in patients with end-stage renal disease.

    PubMed

    Ueno, Hiroki; Koyama, Hidenori; Fukumoto, Shinya; Tanaka, Shinji; Shoji, Takuhito; Shoji, Tetsuo; Emoto, Masanori; Tahara, Hideki; Inaba, Masaaki; Kakiya, Ryusuke; Tabata, Tsutomu; Miyata, Toshio; Nishizawa, Yoshiki

    2011-04-01

    Numbers of endothelial progenitor cells (EPCs) have been shown to be decreased in subjects with end-stage renal disease (ESRD), the mechanism of which remained poorly understood. In this study, mutual association among circulating EPC levels, carotid atherosclerosis, serum pentosidine, and skin autofluorescence, a recently established noninvasive measure of advanced glycation end products accumulation, was examined in 212 ESRD subjects undergoing hemodialysis. Numbers of circulating EPCs were measured as CD34+ CD133+ CD45(low) VEGFR2+ cells and progenitor cells as CD34+ CD133+ CD45(low) fraction by flow cytometry. Skin autofluorescence was assessed by the autofluorescence reader; and serum pentosidine, by enzyme-linked immunosorbent assay. Carotid atherosclerosis was determined as intimal-medial thickness (IMT) measured by ultrasound. Circulating EPCs were significantly and inversely correlated with skin autofluorescence in ESRD subjects (R = -0.216, P = .002), but not with serum pentosidine (R = -0.079, P = .25). Circulating EPCs tended to be inversely associated with IMT (R = -0.125, P = .069). Intimal-medial thickness was also tended to be correlated positively with skin autofluorescence (R = 0.133, P = .054) and significantly with serum pentosidine (R = 0.159, P = .019). Stepwise multiple regression analyses reveal that skin autofluorescence, but not serum pentosidine and IMT, was independently associated with low circulating EPCs. Of note, skin autofluorescence was also inversely and independently associated with circulating progenitor cells. Thus, tissue accumulated, but not circulating, advanced glycation end products may be a determinant of a decrease in circulating EPCs in ESRD subjects. PMID:20494372

  17. Bioinformatics Analysis Reveals Distinct Molecular Characteristics of Hepatitis B-Related Hepatocellular Carcinomas from Very Early to Advanced Barcelona Clinic Liver Cancer Stages.

    PubMed

    Kong, Fan-Yun; Wei, Xiao; Zhou, Kai; Hu, Wei; Kou, Yan-Bo; You, Hong-Juan; Liu, Xiao-Mei; Zheng, Kui-Yang; Tang, Ren-Xian

    2016-01-01

    Hepatocellular carcinoma (HCC)is the fifth most common malignancy associated with high mortality. One of the risk factors for HCC is chronic hepatitis B virus (HBV) infection. The treatment strategy for the disease is dependent on the stage of HCC, and the Barcelona clinic liver cancer (BCLC) staging system is used in most HCC cases. However, the molecular characteristics of HBV-related HCC in different BCLC stages are still unknown. Using GSE14520 microarray data from HBV-related HCC cases with BCLC stages from 0 (very early stage) to C (advanced stage) in the gene expression omnibus (GEO) database, differentially expressed genes (DEGs), including common DEGs and unique DEGs in different BCLC stages, were identified. These DEGs were located on different chromosomes. The molecular functions and biology pathways of DEGs were identified by gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and the interactome networks of DEGs were constructed using the NetVenn online tool. The results revealed that both common DEGs and stage-specific DEGs were associated with various molecular functions and were involved in special biological pathways. In addition, several hub genes were found in the interactome networks of DEGs. The identified DEGs and hub genes promote our understanding of the molecular mechanisms underlying the development of HBV-related HCC through the different BCLC stages, and might be used as staging biomarkers or molecular targets for the treatment of HCC with HBV infection. PMID:27454179

  18. Bioinformatics Analysis Reveals Distinct Molecular Characteristics of Hepatitis B-Related Hepatocellular Carcinomas from Very Early to Advanced Barcelona Clinic Liver Cancer Stages

    PubMed Central

    Hu, Wei; Kou, Yan-Bo; You, Hong-Juan; Liu, Xiao-Mei; Zheng, Kui-Yang; Tang, Ren-Xian

    2016-01-01

    Hepatocellular carcinoma (HCC)is the fifth most common malignancy associated with high mortality. One of the risk factors for HCC is chronic hepatitis B virus (HBV) infection. The treatment strategy for the disease is dependent on the stage of HCC, and the Barcelona clinic liver cancer (BCLC) staging system is used in most HCC cases. However, the molecular characteristics of HBV-related HCC in different BCLC stages are still unknown. Using GSE14520 microarray data from HBV-related HCC cases with BCLC stages from 0 (very early stage) to C (advanced stage) in the gene expression omnibus (GEO) database, differentially expressed genes (DEGs), including common DEGs and unique DEGs in different BCLC stages, were identified. These DEGs were located on different chromosomes. The molecular functions and biology pathways of DEGs were identified by gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and the interactome networks of DEGs were constructed using the NetVenn online tool. The results revealed that both common DEGs and stage-specific DEGs were associated with various molecular functions and were involved in special biological pathways. In addition, several hub genes were found in the interactome networks of DEGs. The identified DEGs and hub genes promote our understanding of the molecular mechanisms underlying the development of HBV-related HCC through the different BCLC stages, and might be used as staging biomarkers or molecular targets for the treatment of HCC with HBV infection. PMID:27454179

  19. Management of conjunctival malignant melanoma: a review and update

    PubMed Central

    Wong, James R.; Nanji, Afshan A.; Galor, Anat; Karp, Carol L.

    2014-01-01

    Conjunctival malignant melanoma is a pigmented lesion of the ocular surface. It is an uncommon but potentially devastating tumor that may invade the local tissues of the eye, spread systemically through lymphatic drainage and hematogenous spread, and recur in spite of treatment. Despite its severity, the rarity of available cases has limited the evidence for diagnosis and management. This review will provide an overview of the epidemiology, presentation, diagnosis, management, and surveillance of conjunctival melanoma, with an emphasis on recent advances in biological therapies to treat this disease. PMID:25580155

  20. Risk of malignant melanoma in men with prostate cancer: Nationwide, population-based cohort study.

    PubMed

    Thomsen, Frederik B; Folkvaljon, Yasin; Garmo, Hans; Robinson, David; Loeb, Stacy; Ingvar, Christian; Lambe, Mats; Stattin, Pär

    2016-05-01

    An increased risk of malignant melanoma has been observed in men with prostate cancer. To assess potential shared risk factors and confounding factors, we analysed risk of melanoma in men with prostate cancer including information on tumor characteristics and demographics including socioeconomic status. In The Prostate Cancer data Base Sweden, risk of melanoma was assessed in a cohort of men with prostate cancer and in a comparison cohort of prostate-cancer free men. Data on prostate cancer risk category, melanoma stage, basal cell carcinoma, location of residency, and socioeconomic status were obtained from nationwide registers. Melanoma was diagnosed in 830/108,145 (0.78%) men with prostate cancer and in 3,699/556,792 (0.66%) prostate cancer-free men. In multivariable Cox regression models, men with prostate cancer had a significantly increased risk of melanoma (HR 1.18, 95% CI 1.09-1.27), and so had married men, men with high education and income, and men residing in southern Sweden. The strongest associations were observed for stage 0 melanoma in men with low-risk prostate cancer (HR 1.45, 1.14-1.86), high education (HR 1.87, 1.60-2.18) and top income (HR 1.61, 1.34-1.93), respectively, whereas there was no association between these factors and late-stage melanoma. Men with prostate cancer also had an increased risk of basal cell carcinoma (HR 1.18, 1.15-1.22). In conclusion, men with low-risk prostate cancer, high education, high income and residency in southern Sweden had an increased risk of early-stage melanoma.

  1. Vemurafenib beyond progression in a patient with metastatic melanoma: a case report.

    PubMed

    Grimaldi, Antonio M; Simeone, Ester; Palla, Marco; Festino, Lucia; Caracò, Corrado; Mozzillo, Nicola; Petrillo, Antonella; Muto, Paolo; Ascierto, Paolo A

    2015-04-01

    The prognosis of metastatic melanoma has changed markedly in recent years because of the advent of newer targeted therapies such as BRAF inhibitors. However, the response to BRAF inhibitor therapy is frequently nondurable in patients with advanced melanoma. Novel approaches are thus needed to overcome resistance to these agents and to improve the management of advanced melanoma patients after disease progression. Here, we present the case of a 44-year-old man diagnosed with advanced melanoma in July 2010, harboring a BRAF mutation. Melanoma progressed during first-line chemotherapy with dacarbazine, but showed significant benefit after the initiation of vemurafenib on August 2011. Six months later, the patient experienced disease progression in left-obturator lymphadenopathy; still, anti-BRAF treatment was continued together with stereotactic radiotherapy, and was interrupted only shortly for intestinal occlusion secondary to melanoma metastasis of the bowel. When his conditions were stable, after 1 month of vemurafenib treatment discontinuation, anti-BRAF therapy was reinitiated, with a positive outcome. Vemurafenib treatment was definitively discontinued for disease progression in the brain, peritoneum, lymph node, intestine, and skin in March 2013, after about 20 months from initiation, and the patient died a few weeks later. The clinical case presented here shows that treatment beyond progression with vemurafenib can yield a survival benefit in melanoma patients whose disease progresses in a few sites, which can be treated with locoregional therapies. This clinical strategy needs further validation in prospective clinical trials. PMID:25622086

  2. Stage-by-Stage and Parallel Flow Path Compressor Modeling for a Variable Cycle Engine, NASA Advanced Air Vehicles Program - Commercial Supersonic Technology Project - AeroServoElasticity

    NASA Technical Reports Server (NTRS)

    Kopasakis, George; Connolly, Joseph W.; Cheng, Larry

    2015-01-01

    This paper covers the development of stage-by-stage and parallel flow path compressor modeling approaches for a Variable Cycle Engine. The stage-by-stage compressor modeling approach is an extension of a technique for lumped volume dynamics and performance characteristic modeling. It was developed to improve the accuracy of axial compressor dynamics over lumped volume dynamics modeling. The stage-by-stage compressor model presented here is formulated into a parallel flow path model that includes both axial and rotational dynamics. This is done to enable the study of compressor and propulsion system dynamic performance under flow distortion conditions. The approaches utilized here are generic and should be applicable for the modeling of any axial flow compressor design accurate time domain simulations. The objective of this work is as follows. Given the parameters describing the conditions of atmospheric disturbances, and utilizing the derived formulations, directly compute the transfer function poles and zeros describing these disturbances for acoustic velocity, temperature, pressure, and density. Time domain simulations of representative atmospheric turbulence can then be developed by utilizing these computed transfer functions together with the disturbance frequencies of interest.

  3. Melanoma and naevi: Incidence, interrelationships and implications

    SciTech Connect

    Elwood, J.M.

    1988-01-01

    This book contains 11 chapters. Some of the chapter titles are: Trend with Time of the Incidence of Malignant Melanoma of Skin in White Populations; Classical and Molecular Genetics of Malignant Melanoma and Dysplastic Naevi; Individuals at High Risk of Melanoma (with 1 color plate); Control of Melanoma in High-Risk Populations; and Frequency of Benign Pigmented Naevi in the General Population.

  4. Herpetic viruses and spontaneous recovery in melanoma.

    PubMed

    Motofei, I G

    1996-08-01

    The malignant melanoma may display extremely variable forms of development, from clinical forms with a lethal course to the unforeseeable situations of spontaneous cures. The basic immunotherapeutic procedures, as well as hypotheses regarding the mechanisms involved in courses towards spontaneous regressions, are presented. Since viruses of the herpes genus are involved in the mechanisms assumed to be at the basis of spontaneous regressions, it is suggested that these viruses (selected strains) be used in the clinic, in order to check the advanced hypothesis, an opportunity which could permit to study also the very probable therapeutic alternative offered by this virus, namely the association of the well-known immunotherapeutic methods. PMID:8869920

  5. Thermographic evaluation of early melanoma within the vascularized skin using combined non-Newtonian blood flow and bioheat models.

    PubMed

    Bhowmik, Arka; Repaka, Ramjee; Mishra, Subhash C

    2014-10-01

    A theoretical study on vascularized skin model to predict the thermal evaluation criteria of early melanoma using the dynamic thermal imaging technique is presented in this article. Thermographic evaluation of melanoma has been carried out during the thermal recovery of skin from undercooled condition. During thermal recovery, the skin has been exposed to natural convection, radiation, and evaporation. The thermal responses of melanoma have been evaluated by integrating the bioheat model for multi-layered skin with the momentum as well as energy conservation equations for blood flow. Differential changes in the surface thermal response of various melanoma stages except that of the early stage have been determined. It has been predicted that the thermal response due to subsurface blood flow overpowers the response of early melanoma. Hence, the study suggests that the quantification of early melanoma diagnosis using thermography has not reached a matured stage yet. Therefore, the study presents a systematic analysis of various intermediate melanoma stages to determine the thermal evaluation criteria of early melanoma. The comprehensive modeling effort made in this work supports the prediction of the disease outcome and relates the thermal response with the variation in patho-physiological, thermal and geometrical parameters.

  6. Prognostic factors and disease-specific survival among immigrants diagnosed with cutaneous malignant melanoma in Sweden.

    PubMed

    Simberg-Danell, Caroline; Lyth, Johan; Månsson-Brahme, Eva; Frohm-Nilsson, Margareta; Carstensen, John; Hansson, Johan; Eriksson, Hanna

    2016-08-01

    Little is known about cutaneous malignant melanoma (CMM) among immigrants in Europe. We aimed to investigate clinical characteristics and disease-specific survival among first- and second-generation immigrants in Sweden. This nationwide population-based study included 27,235 patients from the Swedish Melanoma Register diagnosed with primary invasive CMM, 1990-2007. Data were linked to nationwide, population-based registers followed up through 2013. Logistic regression and Cox regression models were used to determine the association between immigrant status, stage and CMM prognosis, respectively. After adjustments for confounders, first generation immigrants from Southern Europe were associated with significantly more advanced stages of disease compared to Swedish-born patients [Stage II vs. I: Odds ratio (OR) = 2.37, 95% CI = 1.61-3.50. Stage III-IV vs I: OR = 2.40, 95% CI = 1.08-5.37]. The ORs of stage II-IV versus stage I disease were increased among men (OR = 1.9; 95% CI = 1.1-3.3; p = 0.020), and women (OR = 4.8; 95% CI = 2.6-9.1; p < 0.001) in a subgroup of immigrants from former Yugoslavia compared to Swedish-born patients. The CMM-specific survival was significantly decreased among women from former Yugoslavia versus Swedish-born women [hazard ratio (HR)=2.2; 95% CI = 1.1-4.2; p = 0.043]. After additional adjustments including stage, the survival difference was no longer significant. No survival difference between the second generation immigrant group and Swedish-born patients were observed. In conclusion, a worse CMM-specific survival in women from former Yugoslavia was associated with more advanced stages of CMM at diagnosis. Secondary prevention efforts focusing on specific groups may be needed to further improve the CMM prognosis. PMID:27004457

  7. Sox4 Mediated Dicer Expression is Critical for Suppression of Melanoma Cell Invasion

    PubMed Central

    Jafarnejad, Seyed Mehdi; Ardekani, Gholamreza Safaee; Ghaffari, Mazyar; Martinka, Magdalena; Li, Gang

    2016-01-01

    We previously reported reduced expression of Sox4 in metastatic melanoma and its role in suppression of cell migration and invasion through inhibition of NF-κB p50. Sox4 can also bind to the promoter sequence of Dicer, a miRNA biogenesis factor. Interestingly, altered expression of Dicer was also observed in cancers. However, the potential mechanisms which regulate Dicer expression and its potential significance in melanoma progression are unknown. Here we studied the regulation of Dicer expression by Sox4 and its role in suppression of melanoma invasion. Our data showed that Sox4 positively regulates Dicer expression by binding to its promoter sequences and enhancing its activity. We found that knockdown of Dicer enhances the matrigel invasion of melanoma cells by at least 2-fold. In addition, we revealed that overexpression of exogenous Dicer reverts the enhanced melanoma cell invasion upon Sox4 knockdown. Furthermore, we examined the expression of Dicer protein in a large set of melanocytic lesions (n=504) at different stages by tissue microarray and found that Dicer expression is inversely correlated with melanoma progression (P < 0.0001). Consistently, reduced Dicer expression was correlated with a poorer overall and disease-specific 5-year survival of patients (P = 0.015 and 0.0029, respectively). In addition, we found a significant correlation between expression of Sox4 and Dicer proteins in melanoma biopsies (P = 0.009), further indicating the regulation of Dicer expression by Sox4. Finally, we revealed that knockdown of Sox4 induces a major change in the expression pattern of miRNAs in melanoma cells, mainly due to reduced expression of Dicer. Our results pinpoint the regulation of Dicer expression by Sox4 in melanoma and the critical role of Dicer in suppression of melanoma invasion. Our findings on Sox4 regulated miRNA biogenesis pathway may aid toward the development of novel targeted therapeutic approaches for melanoma. PMID:22689055

  8. Gamma-probe-guided lymph node localization in malignant melanoma.

    PubMed

    Alex, J C; Weaver, D L; Fairbank, J T; Rankin, B S; Krag, D N

    1993-10-01

    The initial draining lymph node (sentinel node) has been successfully localized using intraoperative vital dye mapping and reportedly is predictive of regional nodal metastases in Clinical- Stage 1 melanoma. In an animal model, we previously established the technique of gamma-probe-guided localization of the technetium-99 sulfur colloid labelled sentinel node and found its sensitivity equal to vital dye mapping. We now report our initial experience using gamma-probe-guided localization to identify and then surgically remove the first draining lymph node(s) in 10 malignant melanoma patients. Lymphoscintigraphy was used to confirm localization. We conclude that this technique: (a) reliably localizes the sentinel node draining the site of a primary melanoma, (b) allows the lymphatic bed to be checked intraoperatively verifying complete sentinel node biopsy, and (c) is relatively simple and can be performed under local anaesthesia.

  9. Skin lesion image segmentation using Delaunay Triangulation for melanoma detection.

    PubMed

    Pennisi, Andrea; Bloisi, Domenico D; Nardi, Daniele; Giampetruzzi, Anna Rita; Mondino, Chiara; Facchiano, Antonio

    2016-09-01

    Developing automatic diagnostic tools for the early detection of skin cancer lesions in dermoscopic images can help to reduce melanoma-induced mortality. Image segmentation is a key step in the automated skin lesion diagnosis pipeline. In this paper, a fast and fully-automatic algorithm for skin lesion segmentation in dermoscopic images is presented. Delaunay Triangulation is used to extract a binary mask of the lesion region, without the need of any training stage. A quantitative experimental evaluation has been conducted on a publicly available database, by taking into account six well-known state-of-the-art segmentation methods for comparison. The results of the experimental analysis demonstrate that the proposed approach is highly accurate when dealing with benign lesions, while the segmentation accuracy significantly decreases when melanoma images are processed. This behavior led us to consider geometrical and color features extracted from the binary masks generated by our algorithm for classification, achieving promising results for melanoma detection.

  10. An Association Between Glatiramer Acetate and Malignant Melanoma.

    PubMed

    Walker, John; Smylie, AnneLiese; Smylie, Michael

    2016-09-01

    A 43-year-old female receiving immunomodulatory therapy with glatiramer acetate (copaxone, GA) for relapsing, remitting multiple sclerosis was diagnosed with stage IIIB melanoma that recurred <7 months after resection and lymphadenectomy. In preparation for systemic therapy the patient discontinued GA, and shortly thereafter experienced spontaneous and complete clinical and radiographic resolution of her disease. The development and subsequent regression of melanoma in this patient may be due to the use and subsequent discontinuation of GA, and our discussion of the case includes the potential immunologic mechanisms that may provide an explanation for our findings. To the best of our knowledge, this case represents the first reported association between the immunomodulatory agent GA and malignant melanoma. PMID:27404942

  11. Skin lesion image segmentation using Delaunay Triangulation for melanoma detection.

    PubMed

    Pennisi, Andrea; Bloisi, Domenico D; Nardi, Daniele; Giampetruzzi, Anna Rita; Mondino, Chiara; Facchiano, Antonio

    2016-09-01

    Developing automatic diagnostic tools for the early detection of skin cancer lesions in dermoscopic images can help to reduce melanoma-induced mortality. Image segmentation is a key step in the automated skin lesion diagnosis pipeline. In this paper, a fast and fully-automatic algorithm for skin lesion segmentation in dermoscopic images is presented. Delaunay Triangulation is used to extract a binary mask of the lesion region, without the need of any training stage. A quantitative experimental evaluation has been conducted on a publicly available database, by taking into account six well-known state-of-the-art segmentation methods for comparison. The results of the experimental analysis demonstrate that the proposed approach is highly accurate when dealing with benign lesions, while the segmentation accuracy significantly decreases when melanoma images are processed. This behavior led us to consider geometrical and color features extracted from the binary masks generated by our algorithm for classification, achieving promising results for melanoma detection. PMID:27215953

  12. Clinical systemic lupeol administration for canine oral malignant melanoma

    PubMed Central

    YOKOE, INORU; AZUMA, KAZUO; HATA, KEISHI; MUKAIYAMA, TOSHIYUKI; GOTO, TAKAHIRO; TSUKA, TAKESHI; IMAGAWA, TOMOHIRO; ITOH, NORIHIKO; MURAHATA, YUSUKE; OSAKI, TOMOHIRO; MINAMI, SABURO; OKAMOTO, YOSHIHARU

    2015-01-01

    Canine oral malignant melanoma (COMM) is the most aggressive malignant tumor in dogs. Lupeol is a triterpene extracted from various fruits and vegetables that reportedly inhibits melanoma cell proliferation in vitro and in vivo. In this study, the efficacy of subcutaneous lupeol for spontaneous COMM was evaluated. A total of 11 dogs (3, 5 and 3 dogs diagnosed with clinical stage I, II and III melanoma, respectively) were evaluated. Subcutaneous lupeol (10 mg/kg) was administered postoperatively at various time points to treat these 11 COMM cases. Of the 11 subjects, 7 exhibited no local recurrence 180 days postoperatively and no severe adverse effects were observed in any of the cases. Furthermore, no distant metastasis was observed during the experimental period. Therefore, systemic lupeol may prevent local tumor progression and distant metastasis and may be a novel adjuvant treatment for the treatment of COMM. PMID:25469276

  13. Fully Regressive Melanoma: A Case Without Metastasis.

    PubMed

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

    2016-08-01

    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

  14. Genomic investigations of posterior uveal melanoma.

    PubMed

    Hovland, Peter G; Trempe, Clement

    2005-01-01

    The specific genetic mechanisms responsible for the malignant behavior of uveal melanoma are not known. Unlike cutaneous melanoma, epidemiologic studies have not demonstrated a definitive germline form of uveal melanoma, though familial melanoma and racial predilections occur. Molecular cytogenetic characterization of uveal melanoma suggests that somatic deletions of chromosome 3 are associated with a worse prognosis. Microarray technology has been used to characterize uveal melanoma gene expression and may provide tests useful for determining prognosis. As an improved understanding of the cellular mechanisms used by uveal melanoma is gained, new opportunities to adapt or design therapeutic approaches may emerge.

  15. NM23 deficiency promotes metastasis in a UV radiation-induced mouse model of human melanoma.

    PubMed

    Jarrett, Stuart G; Novak, Marian; Harris, Nathan; Merlino, Glenn; Slominski, Andrezj; Kaetzel, David M

    2013-01-01

    Cutaneous malignant melanoma is the most lethal form of skin cancer, with 5-year survival rates of <5 % for patients presenting with metastatic disease. Mechanisms underlying metastatic spread of UVR-induced melanoma are not well understood, in part due to a paucity of animal models that accurately recapitulate the disease in its advanced forms. We have employed a transgenic mouse strain harboring a tandem deletion of the nm23-m1 and nm23-m2 genes to assess the combined contribution of these genes to suppression of melanoma metastasis. Crossing of the nm23-h1/nm23-h2 knockout in hemizygous-null form ([m1m2](+/-)) to a transgenic mouse strain (hepatocyte growth factor/scatter factor-overexpressing, or HGF(+) strain) vulnerable to poorly-metastatic, UVR-induced melanomas resulted in UVR-induced melanomas with high metastatic potential. Metastasis to draining lymph nodes was seen in almost all cases of back skin melanomas, while aggressive metastasis to lung, thoracic cavity, liver and bone also occurred. Interestingly, no differences were observed in the invasive characteristics of primary melanomas of HGF(+) and HGF(+) × [m1m2](+/-) strains, with both exhibiting invasion into the dermis and subcutis, indicating factors other than simple invasive activity were responsible for metastasis of HGF(+) × [m1m2](+/-) melanomas. Stable cell lines were established from the primary and metastatic melanoma lesions from these mice, with HGF(+) × [m1m2](+/-) lines exhibiting increased single cell migration and genomic instability. These studies demonstrate for the first time in vivo a potent metastasis suppressor activity of NM23 in UVR-induced melanoma, and have provided new tools for identifying molecular mechanisms that underlie melanoma metastasis.

  16. Design and overall performance of four highly loaded, high speed inlet stages for an advanced high-pressure-ratio core compressor

    NASA Technical Reports Server (NTRS)

    Reid, L.; Moore, R. D.

    1978-01-01

    The detailed design and overall performances of four inlet stages for an advanced core compressor are presented. These four stages represent two levels of design total pressure ratio (1.82 and 2.05), two levels of rotor aspect ratio (1.19 and 1.63), and two levels of stator aspect ratio (1.26 and 1.78). The individual stages were tested over the stable operating flow range at 70, 90, and 100 percent of design speeds. The performances of the low aspect ratio configurations were substantially better than those of the high aspect ratio configurations. The two low aspect ratio configurations achieved peak efficiencies of 0.876 and 0.872 and corresponding stage efficiencies of 0.845 and 0.840. The high aspect ratio configurations achieved peak ratio efficiencies of 0.851 and 0.849 and corresponding stage efficiencies of 0.821 and 0.831.

  17. An electrochemical immunosensing method for detecting melanoma cells.

    PubMed

    Seenivasan, Rajesh; Maddodi, Nityanand; Setaluri, Vijaysaradhi; Gunasekaran, Sundaram

    2015-06-15

    An electrochemical immunosensing method was developed to detect melanoma cells based on the affinity between cell surface melanocortin 1 receptor (MC1R) antigen and anti-MC1R antibody (MC1R-Ab). The MC1R-Abs were immobilized in amino-functionalized silica nanoparticles (n-SiNPs)-polypyrrole (PPy) nanocomposite modified on working electrode surface of screen-printed electrode (SPE). Cyclic voltammetry was employed, with the help of redox mediator ([Fe(CN)6](3-)), to measure the change in anodic oxidation peak current arising due to the specific interaction between MC1R antigens and MC1R-Abs when the target melanoma cells are present in the sample. Various factors affecting the sensor performance, such as the amount of MC1R-Abs loaded, incubation time with the target melanoma cells, the presence of interfering non-melanoma cells, were tested and optimized over different expected melanoma cell loads in the range of 50-7500 cells/2.5 mL. The immunosensor is highly sensitive (20 cells/mL), specific, and reproducible, and the antibody-loaded electrode in ready-to-use stage is stable over two weeks. Thus, in conjunction with a microfluidic lab-on-a-chip device our electrochemical immunosensing approach may be suitable for highly sensitive, selective, and rapid detection of circulating tumor cells (CTCs) in blood samples.

  18. [The reevaluation of neoangiogenesis indices in cutaneous melanoma].

    PubMed

    Marasà, S; Sciancalepore, G; Marasà, L

    2007-02-01

    The melanoma today represents one of more diffuse malignant neoplasm and known, object of numerous studies and you debate yourself, topic more and more puts into effect them, observed and estimated under more it varies aspects to you. Our study has been lead taking in consideration the process of neoangiogenesis, fundamental stage in the progression graduates them of the malignant melanoma, than it comes true through the release of VEGF and many other angiogenic molecules from part of the same neoplastic cells. The evolution of such process represents a critical moment for the development of whichever neoplasm, but in particular way in the melanoma it is in charge of the transition from the phase of horizontal increase to that one of vertical increase. We have therefore place the attention on the appraisal of objective indices of the vascularization as factor I prognosticate of the melanoma; particularly way we have correlated the indices of vascularisation in 54 cases of melanomas, all to III the level of Clark, and have obtained of turns out to you that confirm the possibility to insert between the prognostic factors determinants also those.

  19. An electrochemical immunosensing method for detecting melanoma cells

    PubMed Central

    Seenivasan, Rajesh; Maddodi, Nityanand; Setaluri, Vijaysaradhi; Gunasekaran, Sundaram

    2015-01-01

    An electrochemical immunosensing method was developed to detect melanoma cells based on the affinity between cell surface melanocortin 1 receptor (MC1R) antigen and anti-MC1R antibody (MC1R-Ab). The MC1R-Abs were immobilized in amino-functionalized silica nanoparticles (n-SiNPs)-polypyrrole (PPy) nanocomposite modified on working electrode surface of screen-printed electrode (SPE). Cyclic voltammetry was employed, with the help of redox mediator ([Fe(CN)6]3−), to measure the change in anodic oxidation peak current arising due to the specific interaction between MC1R antigens and MC1R-Abs when the target melanoma cells are present in the sample. Various factors affecting the sensor performance, such as the amount of MC1R-Abs loaded, incubation time with the target melanoma cells, the presence of interfering non-melanoma cells, were tested and optimized over different expected melanoma cell loads in the range of 50–7500 cells/2.5 mL. The immunosensor is highly sensitive (20 cells/mL), specific, and reproducible, and the antibody-loaded electrode in ready-to-use stage is stable over two weeks. Thus, in conjunction with a microfluidic lab-on-a-chip device our electrochemical immunosensing approach may be suitable for highly sensitive, selective, and rapid detection of circulating tumor cells (CTCs) in blood samples. PMID:25636023

  20. A Case of Choroidal Melanoma Metastatic to the Breast

    PubMed Central

    Taran-Munteanu, L.; Hartkopf, A.; Eigentler, T. K.; Vogel, U.; Brucker, S.; Taran, F. A.

    2016-01-01

    A 61-year-old woman developed blurred vision in her left eye in December 2006. A clinical diagnosis of choroidal melanoma was made. The patient underwent excision of the left lens, followed by vitrectomy and stereotactic radiotherapy. She remained systemically healthy until 50 months later when, during a CT scan done for staging purposes, a newly visible lump was noted in the lower quadrant of her left breast. Core needle biopsy of the lesion in the left breast was performed, and histologic examination revealed metastasis from the choroidal melanoma. The patient underwent breast-conserving surgery of the left breast. Definitive histological examination showed clear tumor margins in the resected specimen and one sentinel lymph node without evidence of metastatic cells. Twenty-nine months after surgery, a similar nodule was detected in the upper quadrant of the left breast. Core biopsy again showed metastatic melanoma, and similar breast-conserving surgery was performed. Systemic examination, including magnetic resonance imaging of the head and computed tomography of the pelvis, abdomen, and chest, was done regularly and revealed no significant findings. Solitary breast metastases from choroidal melanoma are extremely rare. Nevertheless, clinicians should be aware of this rare form of metastasis when treating patients with suspicious breast lesions and a history of choroidal melanoma. If solitary metastasis is confirmed, then breast-conserving surgery may be recommended. PMID:27239068

  1. ‘Proteolytic switching’: opposite patterns of regulation of gelatinase B and its inhibitor TIMP-1 during human melanoma progression and consequences of gelatinase B overexpression

    PubMed Central

    MacDougall, J R; Bani, M R; Lin, Y; Muschel, R J; Kerbel, R S

    1999-01-01

    Although it is generally accepted that proteolytic degradation is an important mechanism used by malignant cells in the process of metastasis, comparatively little is known about the regulation of molecules responsible for proteolysis and how they become de-regulated during human tumour progression. Using a genetically related pair of human melanoma cell lines, derived from the same patient at different stages of disease, we analysed differences in the cytokine-mediated regulation of gelatinase B (MMP-9), an enzyme thought to play an important role in cellular invasiveness, and TIMP-1, a physiological inhibitor of this enzyme. Whereas the advanced stage (i.e. metastatic) partner of this pair (WM 239) could produce gelatinase B upon induction with interleukin (IL)-1β or tumour necrosis factor alpha (TNF-α), the early stage (i.e. primary) partner (WM 115) could not. In sharp contrast, we found that TIMP-1 displayed an opposite pattern of induction in these cell lines. Specifically, the early stage cell line, WM 115, demonstrated a marked increase in the production of TIMP-1 when treated with IL-1β or TNF-α whereas the advanced cell line, WM 239, showed no such increase. Treatment with the DNA demethylating agent, 2-deoxy-5-azacytidine, resulted in a marked up-regulation of both gelatinase B and TIMP-1 in both cell lines. It was further found that constitutive overexpression of gelatinase B in WM 239 cells and an additional melanoma cell line (MeWo), derived from a metastatic lesion, was able to greatly enhance lung colonization in an experimental metastasis assay while we did not observe differences in tumorigenicity. From these results we conclude that an altered responsiveness of gelatinase B and TIMP-1 to induction by similar agents is associated with disease progression in human melanoma and that this altered responsiveness can have consequences to the aggressive nature of the disease. © 1999 Cancer Research Campaign PMID:10408860

  2. Results of an Advanced Fan Stage Operating Over a Wide Range of Speed and Bypass Ratio. Part 1; Fan Stage Design and Experimental Results

    NASA Technical Reports Server (NTRS)

    Suder, Kenneth L.; Prahst, Patricia S.; Thorp, Scott A.

    2011-01-01

    NASA s Fundamental Aeronautics Program is investigating turbine-based combined cycle (TBCC) propulsion systems for access to space because it provides the potential for aircraft-like, space-launch operations that may significantly reduce launch costs and improve safety. To this end, National Aeronautics and Space Administration (NASA) and General Electric (GE) teamed to design a Mach 4 variable cycle turbofan/ramjet engine for access to space. To enable the wide operating range of a Mach 4+ variable cycle turbofan ramjet required the development of a unique fan stage design capable of multi-point operation to accommodate variations in bypass ratio (10 ), fan speed (7 ), inlet mass flow (3.5 ), inlet pressure (8 ), and inlet temperature (3 ). In this paper, NASA has set out to characterize a TBCC engine fan stage aerodynamic performance and stability limits over a wide operating range including power-on and hypersonic-unique "windmill" operation. Herein, we will present the fan stage design, and the experimental test results of the fan stage operating from 15 to 100 percent corrected design speed. Whereas, in the companion paper, we will provide an assessment of NASA s APNASA code s ability to predict the fan stage performance and operability over a wide range of speed and bypass ratio.

  3. Uveal Melanoma: Current Trends in Diagnosis and Management

    PubMed Central

    Tarlan, Berçin; Kıratlı, Hayyam

    2016-01-01

    Uveal melanoma, which is the most common primary intraocular malignancy in adults, arises from melanocytes within the iris, ciliary body and choroid. The diagnosis is based principally on clinical examination of the tumor with biomicroscopy and indirect ophthalmoscopy and confirmed by diagnostic techniques such as ultrasonography, fundus fluorescein angiography and optical coherence tomography. The clinical diagnosis of posterior uveal melanomas can be made when the classical appearance of a pigmented dome-shaped mass is detected on dilated fundus exam. Uveal melanomas classically show low to medium reflectivity on A-scan ultrasonography and on B-scan ultrasonography the tumor appears as a hyperechoic, acoustically hollow intraocular mass. Management of a suspicious pigmented lesion is determined by its risk factors of transforming into a choroidal melanoma, such as documentation of growth, thickness greater than 2 mm, presence of subretinal fluid, symptoms and orange pigment, margin within 3 mm of the optic disc, and absence of halo and drusen. Advances in the diagnosis and local and systemic treatment of uveal melanoma have caused a shift from enucleation to eye-conserving treatment modalities including transpupillary thermotherapy and radiotherapy over the past few decades. Prognosis can be most accurately predicted by genetic profiling of fine needle aspiration biopsy of the tumor before the treatment, and high-risk patients can now be identified for clinical trials that may lead to target-based therapies for metastatic disease and adjuvant therapy which aims to prevent metastatic disease. PMID:27800275

  4. Proteomic Findings in Melanoma

    PubMed Central

    Sengupta, Deepanwita; Tackett, Alan J

    2016-01-01

    Although the emergence of proteomics as an independent branch of science is fairly recent, within a short period of time it has contributed substantially in various disciplines. The tool of mass spectrometry has become indispensable in the analysis of complex biological samples. Clinical applications of proteomics include detection of predictive and diagnostic markers, understanding mechanism of action of drugs as well as resistance mechanisms against them and assessment of therapeutic efficacy and toxicity of drugs in patients. Here, we have summarized the major contributions of proteomics towards the study of melanoma, which is a deadly variety of skin cancer with a high mortality rate. PMID:27274624

  5. The embryonic morphogen, Nodal, is associated with channel-like structures in human malignant melanoma xenografts.

    PubMed

    McAllister, Josephine C; Zhan, Qian; Weishaupt, Carsten; Hsu, Mei-Yu; Murphy, George F

    2010-04-01

    Formation of channel-like structures, also termed vasculogenic mimicry (VM), describes the ability of aggressive melanoma cells to form PAS-positive anastomosing structures that correlate with tumor virulence. This phenomenon may indicate differentiation plasticity, a feature