Browsing by Subject "melanoma"

Now showing 1 - 5 of 5
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    Endobronchial metastasis from primary anorectal melanoma.
    (The American journal of case reports, 2013-01) Heyman, Benjamin M; Chung, Matthew M; Lark, Amy L; Shofer, Scott
    PATIENT: Male, 64 FINAL DIAGNOSIS: Metastatic anorectal melanoma with endotracheal metastasis Symptoms: Fatigue • weight loss • hematochezia • cough MEDICATION: None Clinical Procedure: Biopsy of anal mass • rigid bronchoscopy Specialty: Internal medicine • oncology • pulmonology. OBJECTIVE: Rare disease. BACKGROUND: Anorectal melanoma is a rare cancer with a poor prognosis. The mean survival after diagnosis is 15-25 months. At the time of diagnosis, 61% of patients have local regional lymph node metastases, and 21% have distant metastases. The lungs are a common site for metastasis for all tumors including melanoma. However endobronchial metastasis is a rare phenomenon. Endotracheal metastases are even rarer, occurring in only 5% of patients with extrapulmonary endobronchial metastases. It is most commonly seen in breast, colorectal, and kidney cancers. It is extremely rare for cutaneous melanoma. The mean survival after diagnosis is only 15 months and treatment options are limited. CASE REPORT: We report the case of a 64 year-old gentleman with newly diagnosed metastatic anorectal melanoma. A 3 cm by 3 cm bluish-black, oval-shaped, exophytic mass protruding from his anus was found on physical exam. Endobronchial and endotracheal metastasis to the trachea were discovered on computed tomography and he was subsequently taken to the operating room for argon plasma coagulation laser recanalization of his trachea via rigid bronchoscopy, and resection of his anal mass. CONCLUSIONS: We have presented the first known case of anorectal melanoma with endobronchial metastasis. Palliative APC laser recanalization was used to prevent asphyxiation from the endotracheal mass. Endobronchial metastasis is uncommon and can be easily mistaken for primary bronchogenic carcinoma. It should always be considered when evaluating patients with new lung masses.
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    Integrated pathway and epistasis analysis reveals interactive effect of genetic variants at TERF1 and AFAP1L2 loci on melanoma risk.
    (Int J Cancer, 2015-10-15) Brossard, Myriam; Fang, Shenying; Vaysse, Amaury; Wei, Qingyi; Chen, Wei V; Mohamdi, Hamida; Maubec, Eve; Lavielle, Nolwenn; Galan, Pilar; Lathrop, Mark; Avril, Marie-Françoise; Lee, Jeffrey E; Amos, Christopher I; Demenais, Florence
    Genome-wide association studies (GWASs) have characterized 13 loci associated with melanoma, which only account for a small part of melanoma risk. To identify new genes with too small an effect to be detected individually but which collectively influence melanoma risk and/or show interactive effects, we used a two-step analysis strategy including pathway analysis of genome-wide SNP data, in a first step, and epistasis analysis within significant pathways, in a second step. Pathway analysis, using the gene-set enrichment analysis (GSEA) approach and the gene ontology (GO) database, was applied to the outcomes of MELARISK (3,976 subjects) and MDACC (2,827 subjects) GWASs. Cross-gene SNP-SNP interaction analysis within melanoma-associated GOs was performed using the INTERSNP software. Five GO categories were significantly enriched in genes associated with melanoma (false discovery rate ≤ 5% in both studies): response to light stimulus, regulation of mitotic cell cycle, induction of programmed cell death, cytokine activity and oxidative phosphorylation. Epistasis analysis, within each of the five significant GOs, showed significant evidence for interaction for one SNP pair at TERF1 and AFAP1L2 loci (pmeta-int  = 2.0 × 10(-7) , which met both the pathway and overall multiple-testing corrected thresholds that are equal to 9.8 × 10(-7) and 2.0 × 10(-7) , respectively) and suggestive evidence for another pair involving correlated SNPs at the same loci (pmeta-int  = 3.6 × 10(-6) ). This interaction has important biological relevance given the key role of TERF1 in telomere biology and the reported physical interaction between TERF1 and AFAP1L2 proteins. This finding brings a novel piece of evidence for the emerging role of telomere dysfunction into melanoma development.
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    Pharmacokinetics and tolerability of the dual TORC1/2 inhibitor sapanisertib in combination with the MEK inhibitor trametinib in dogs.
    (Frontiers in veterinary science, 2022-01) Wei, Bih-Rong; Peer, Cody J; Richardson, William J; Hewitt, Stephen M; Figg, William D; Simpson, R Mark
    Activation of one or both the Ras/MAPK and PI3K/Akt/mTOR signal transduction pathways are known to mediate oncogenicity of several canine and human cancers, including mucosal melanomas. Reciprocal cross activation between the two pathways can be a source of drug resistance. Consequently, oral dosing for plasma pharmacokinetic (PK) analysis and tolerability to a combination of sapanisertib, a dual TORC1/2 inhibitor, and trametinib, a MEK inhibitor, was evaluated in nontumor-bearing laboratory dogs for its potential application in parallel pathway targeting. Twelve dogs, divided into three equal cohorts, received either the combination or single agents. Animals were monitored for PK following single dose and 17-day repeat dosing, and by clinical observations, hematology, serum biochemistry, coagulation studies and urinalyses. A single trametinib dose (0.025 mg/kg), sulfated as dimethyl sulfoxide which enhanced its absorption, reached mean maximum concentration (Cmax) 0.64 ng/mL [18% coefficient of variation (CV)] at a median time to maximum concentration (Tmax) of 1.5 h (hr), and mean area under the concentration-time curve (AUC) 16.8 hr*ng/mL (14%CV), which were similar when given alone or in combination with sapanisertib. A prolonged half-life afforded 3-4-fold plasma accumulation of trametinib with daily dosing, analogous to humans. Trametinib PK mirrored previous regulatory data in dogs, while exposure approximated some published human values but generally not all patients. Sapanisertib-alone in canine plasma following single 0.1 mg/kg dose [mean Cmax 26.3 ng/mL (21%CV), median Tmax 2.0 hr, and mean AUC 248 hr*ng/mL (41%CV)] resembled levels in human therapeutic trials; whereas canine sapanisertib exposure was reduced when combined with trametinib, a known cytochrome P450 CYP3A4 inducer. Sex differences were not observed for either drug. Side effects upon repeat dosing with either or both drugs may include body weight loss, maldigestion, and cutaneous discoloration. The combination was tolerated without dose limiting toxicity, although clinical laboratory analyses revealed drug-induced acute-phase inflammation, proteinuria, and decreased blood reticulocytes, mild changes not necessitating intervention. Short-term results in dogs with this combination would appear to hold translational promise for clinical trial evaluation to target canine and possibly human melanoma, as well as other cancers having one or both signal transduction pathway activations.
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    The macrophage: Switches from a passenger to a driver during anticancer therapy
    (Oncoimmunology, 2015) Wang, T; Feldman, GM; Herlyn, M; Kaufman, RE
    We have recently discovered that BRAF inhibitors induce potent macrophage responses that confer melanoma resistance to therapy. Our studies lay a foundation for the hypothesis that macrophages switch their role from a passenger to a driver for tumor survival during therapeutic treatment, suggesting that agents that target macrophages can be an important component of "cocktail" anticancer therapy.
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    The relationship between blood IL-12p40 level and melanoma progression.
    (Int J Cancer, 2015-04-15) Fang, Shenying; Wang, Yuling; Chun, Yun Shin; Liu, Huey; Ross, Merrick I; Gershenwald, Jeffrey E; Cormier, Janice N; Royal, Richard E; Lucci, Anthony; Schacherer, Christopher W; Reveille, John D; Sui, Dawen; Bassett, Roland L; Wang, Li-E; Wei, Qingyi; Amos, Christopher I; Lee, Jeffrey E
    Cytokines such as Interleukin (IL)-12p70 ("IL-12") and IL-23 can influence tumor progression. We tested the hypothesis that blood levels of IL-12p40, the common subunit of both cytokines, are associated with melanoma progression. Blood from 2,048 white melanoma patients were collected at a single institution between March 1998 and March 2011. Plasma levels of IL-12p40 were determined for 573 patients (discovery), 249 patients (Validation 1) and 244 patients (Validation 2). Per 10-unit change of IL-12p40 level was used to investigate associations with melanoma patient outcome among all patients or among patients with early or advanced stage. Among stage I/II melanoma patients in the pooled data set, after adjustment for sex, age, stage and blood draw time from diagnosis, elevated IL-12p40 was associated with melanoma recurrence [hazard ratio (HR) = 1.04 per 10-unit increase in IL-12p40, 95% CI 1.02-1.06, p = 8.48 × 10(-5) ]; Elevated IL-12p40 was also associated with a poorer melanoma specific survival (HR = 1.06, 95% CI 1.03-1.09, p = 3.35 × 10(-5) ) and overall survival (HR = 1.05, 95% CI 1.03-1.08, p = 8.78×10(-7) ) in multivariate analysis. Among stage III/IV melanoma patients in the pooled data set, no significant association was detected between elevated IL-12p40 and overall survival, or with melanoma specific survival, with or without adjustment for the above covariates. Early stage melanoma patients with elevated IL-12p40 levels are more likely to develop disease recurrence and have a poorer survival. Further investigation with a larger sample size will be needed to determine the role of IL-12p40 in advanced stage melanoma patients.