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Abstract: Immunotherapy has recently emerged as the central pillar of metastatic melanoma therapy. The response rate in 30% after monotherapy with PD1 inhibitors is below 30%, though the risk of combined PD1+CTLA-4 inhibitors is 60% but in 50% patients is associated with high-grade toxicities. We've found that adrenergic receptor blockade blocking blockade with propranolol can raises anti-tumor activity of PD1 inhibition in a mouse model. We designed a phase Ib/II clinical trial to raise the effectiveness of pesoolizumab in combination with PRO at various doses recruiting 3 pts at each dose. BID 100 mg daily, 3 pts of metastatic melanoma were treated with P 200 mg every 3 weeks + PRO 10 mg BID. The PRO dose, according to Biomarkers' review, should be tested in phase II. Results: Trends point to an increase in CD8+T cell and MDSC subsets with a decrease in above ratios was observed. The 30 wk value of CD8+T cell/m-MDSC was also much lower than the baseline compared to baseline. The inverse association of high-I-10 and shrinking CD8+/MDSC and TReg populations, as well as declining CD8+/Treg populations, could indicate the contribution of IFN-u03b3 and trafficking of CD8+ T-cells into tumor/tissue. In patients with metastatic melanoma treated with peeloid derived suppressor cells, T regulatory cells, CD8+ and CD4+T-cells, and cytokines/chemokines, measurements of myeloid derived suppressor cells, T regulatory cells, CD8+T-cells, and cytokines/chemokines are missing [abstract]. Cancer Res 2019; 4057, a Abstract nr 4057.
Source link: https://doi.org/10.1158/1538-7445.am2019-4057
Methods: Metastatic melanoma and CDKN2A loss patients were treated for 14 days on BRAF V600 mutation and CDKN2A loss patients, which were followed by seven days off dosing schedule of Palbo + continuous bid dosing of VM. Population PK was estimated using a non linear mixed effect model approach by determining the maximum likelihood estimator of the parameters without any approximation of the model. In 236 and 275 blood samples respectively, VM and palbo plasma concentrations were determined. PPK parameters for the experimental model were as follows: Ka = 0. 791 h-1, CL/F=76. 0L/h, and F=2830 L. Albuminemia had a major effect on palbo CL. According to an allometric scaling rule, body weight was the highest size descriptor when VM CL and V terms were normalized to a mean BW of 70 Kg. Conclusions: The PPK analysis derived the plasma Plabo and VM time-concentration curves in patients in a convincing manner. Palbo and VM have no reported results for drug-drug PK interaction. [abstract]: With BRAF V600 mutated and CDKN2A loss & expression of Rb [abstract], a phase I-III pharmaceutical drug-drug interaction analysis of oral palbociclib in conjunction with vemurafenib in patients suffering metastatic melanoma with a BRAF V600 mutated and CDKN2A [abstract]. Philadelphia, GA; Cancer Res 2019;3895;Abstract nr 3895; the American Association for Cancer Research Annual Meeting (APr 2019) (WWRC) Proceedings; 2019 Mar 29-Apr 3; AACR; Cancer Res 2019;3995; Abstract nr 3895.
Source link: https://doi.org/10.1158/1538-7445.am2019-3895
Abstract Background: There is no comparable diagnostic test to predict response to programmed cell death 1 axis immune checkpoint inhibitor therapy in melanoma. After undergoing chemotherapy with ICI in metastatic melanoma patients, we try only the prototype mRNA expression profile on the GeneXpert closed system using real-time quantitative reverse transcription polymerase chain reaction for association with clinical benefit. Methods: Pretreatment Formalin-fixed paraffin-embedded tissue sections from melanoma patients treated with anti-PD-1 therapy between 2011-17 were obtained from the Yale Pathology archives, and Pretreatment is a pretreatment. To identify high versus low mRNA or protein expression groups, median values for each marker were used. Inter-transcript regression was found among all four markers with R2 ranging from 0. 20 to 0. 51. Transcript levels were significantly higher in CR/PR/SD than in PD for CD8A and IRF1. Similar results were found for OS with elevated CD274, CD8A, and IRF1 mRNA expression. Multivariate analyses revealed that multivariate analyses showed a similar PFS relationship with CD8A and IRF1 parameters. Between transcript and protein levels for CD8A and IRF1 was found in a nonlinear exponential relationship. Conclusions: Although we were only testing in a single melanoma patient, CD274, CD8A, and IRF1 mRNA measurements indicate promising correlations with outcome. In a closed system RT-qPCR panel and immunotherapy result in metastatic melanoma [abstract], A CD274, PDCD1LG2, CD8A, and IRF1 multiplex were among the numerousx in a closed system RT-qPCR panel and immunotherapy findings in metastatic melanoma [abstract]. 2019 Mar 29-Apr 3142; Cancer Res 2019;39:Abstract nr 3142. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3142; Philadelphia, GA; Cancer Res 2019; 3142.
Source link: https://doi.org/10.1158/1538-7445.am2019-3142
Abstract Background: The gut microbiome is increasingly being recognized as a key modulator of anti-PD1-based cancer immunotherapy, as shown by the gut microbiome. Methods: We assembled a cohort of patients with metastatic melanoma who have received CICB. According to NCI CTCAE 4. 0 criteria, all patients were classified as R or NR based on RECIST v1. 1, and as having a grade 3 or higher incidence of an immune related adverse event. Baseline stool samples were characterized by 16S rRNA sequencing. Correspondent investigations of peripheral immune cell populations by flow cytometry and circulating T cell genome by TCR-sequencing were done on matched pre-treatment blood samples. Results: The overall gut microbial landscape in these patients was characterized by a large number of Bacteroidales and Clostridiales, with a high concentration of Bacteroidales and Clostridiales. A lack of clustering by subtype of primary tumor with no apparent correlation to the tumor histology was seen in the ordination of beta-diversity distances, according to the initiation of beta-diversity distances, despite no evidence of a relationship between the tumor histology. The order Clostridiales' median relative abundance was also higher in R versus NR, in keeping with our previous findings. NR was still higher than NR, but not in R versus NR. Conclusion: These results expand on our previous research and support the belief that there is a close correlation between the gut microbiome and therapeutic outcomes to checkpoint blockade therapy. The gut microbiome influences therapeutic efficacy and tolerability of combined immune checkpoint blockade in metastatic melanoma patients. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; Mar 29-Apr 3; Atlanta, GA; Cancer Res 2019; 1493 Abstract nr 1493.
Source link: https://doi.org/10.1158/1538-7445.am2019-1493
Abstract Uveal melanoma is the most common primary intraocular disease in adults with a life expectancy of less than a year for patients with metastases. We reviewed the biodistribution and anti-cancer activity of arylsulfonamide KCN1, a lead compound in a novel class of hypoxia-inducible factor pathway in UM models, in this research. KCN1 preferentially localizes to the eye and liver, the organ in which UM preferentially metastasizes, according to 11C-labeled KCN1. UM cells were transplanted into the suprachoroidal space of the right murine eye using a transscleral technique, and the eye was enucleated 7-9 days post-inoculation. Prolyl-4-hydroxylases P4HA1 and 2 were among the most consistently HIF-inhibited genes that modify the tumor microenvironment's physical characteristics by post-translationally altering collagen. P4HA1 and 2 expression in UM patients with metastatic disease is significantly elevated in UM patients with metastatic disease, and high levels of expression correlates with poor prognosis. In summary, our findings show that KCN1 has anti-UM activity by inhibiting the primary tumor formation, reducing vascular density in the primary tumor, and the number and size of the hepatic metastases; KCN1 has therefore therapeutic potential for treating UM and further clinical growth. AACR; Cancer Res 2019; 79:Abstract nr 1296, Philadelphia, Ga.
Source link: https://doi.org/10.1158/1538-7445.am2019-1296
 if baseline PD-1 serum levels were prognostic for survival in the specific treatment arms was randomized during a randomized phase 2 trial, to determine  if baseline PD-1 serum levels were predictive of survival benefit both in the acute and treatment arms, and  if changes in PD-1 serum values were predictive of survival benefit overall and treatment. Patients with metastatic melanoma were included in a randomized phase 2 clinical trial comparing chemotherapy with autologous dendritic cell vaccines that were produced from autologous tumor antigens obtained from short-term autologous cell cultures [Dillman et al. ] Patients with metastatic melanoma were enrolled in a randomized phase 2 clinical trial comparing treatment with autologous dendritic cell vaccines containing autologous tumor antigens DCV had longer OS than TCV, both in patients with baseline PD1 of 1. 2 ng/ml and > 1. 2 ng/ml. Patients with TCV induced Tissue-lowering were more likely to live 4 years than those with a decrease in PD-1, but this was not present in patients treated with TCV. baseline serum PD1 levels were not prognostic for survival in patients treated with DCV, but they were predictive of survival benefits in patients treated with DCV, as well as a decrease in PD1 level following three weekly DCV vaccinations. CONCLUSONS: [abstract]: Serum levels of programmed cell death molecule-1 as a biomarker in metastatic melanoma patients randomized for treatment with autologous dendritic cell or tumor cell vaccines are not available [abstract].
Source link: https://doi.org/10.1158/1538-7445.am2019-1357
Abstract Metastatic melanoma is the deadliest form of skin cancer in the United States, with one person dying from the disease every hour. Cells from the primary tumor cells migrate and multiply at local and distant organ sites, causing metastasis. The lymph nodes, bone, brain, and lung are the most common sites of melanoma metastasis. Current models of metastatic disease in immunocompetent animals must be improved in order to produce new and highly effective agents that can effectively eliminate MM. Many in vivo studies focus on injecting tumor cells directly into the circulation via the tail vein to prevent lesions from developing within the lungs. Primary tumors can spontaneously metastasize because of subcutaneous tumor inoculation. Other MM models use subcutaneous tumor inoculation to encourage primary tumors to spontaneously metastasize. B16F10 melanoma cells that expressed firefly luciferase were inoculated on the dorsal ear of C57BL/6 mice in this model. Metastatic tumor formation in the draining lymph node and at distant locations was demonstrated by using the IVIS Lumina imaging device and gross examination of target organs after euthanasia. Metastatic lesions developed in the draining lymph node about 8. 8 weeks after inoculation and distant metastasis were reported. Metastatic melanoma, ear to lymph node, and beyond [abstract]. Cancer Res 2019;4906; Abstract nr 4606; The American Association for Cancer Research Annual Meeting (Apr 3; Atlanta, GA.
Source link: https://doi.org/10.1158/1538-7445.am2019-4606
Because of the high cost and potential toxicity of ipilimumab, it is of utmost importance to find biomarkers that can be used to select patients who will benefit from CTLA-4 blockade therapy. We hypothesize that patients who do not respond to therapy with ipilimumab have lower drug levels in tumor tissues as compared to patients with a positive reaction to therapy. We predict that the drug levels in potentially affected tissues will rise at the second injection as irAEs generally occur about 6-8 weeks after the first injection of ipilimumab. Experimental techniques To determine in vivo localization of ipilimumab in patients treated with metastatic melanoma, 37 MBq, 10 mg 89Zr-labeled ipilimumab in patients with metastatic melanoma, 37 MBq, 37 MBq, 10 mg 89Zr-labeled ipilimumab, 10 mg 89Zr-labeled ipi 89Zr-labeled iab in patients diagnosed with ipimab i ib mela, 37 mela, 37 mela, 37 mela, 37 ir-labeled i ib, 10 mg 89Zr-labeledo a, 37 ma, 37 89Zr-labeled ib, 10 mg 89Zr-labeled ib 89Zr-labeled 89Z This technique was repeated three weeks later at the second ipilimumab cycle and was obtained at 2h, 72h, and 144h post injection. 89Zr-labeled ipilimumab's blood test revealed a pattern consistent with 89Zr-labeled antibodies, liver and spleen, as well as increased circulating antibody in the bloodstream corresponding to ipilimumab's pharmacokinetics. The uptake of 89Zr-labeled ipilimumab in 5/12 evaluable tumor lesions was visible at both first and second injections of ipilimumab, according to a visual analysis. There were no significant differences in tumor uptake between the first and second doses of ipilimumab. 89Zirconium-labeled ipilimumab in patients with metastatic melanoma during ipilimumab therapy [abstract].
Source link: https://doi.org/10.1158/1538-7445.am2019-1136
The percentage of B16F10 cells expressing the IL-2R gene on the cell surface and at the mRNA level was found to rise after a B16F10 cell culture treated with the u03b1-subunit of IL-2R gene on the cell surface and at the mRNA level. The resistance of CsA-treated B16F10 cells to NK lysis was not apparent, but no significant differences were observed in the resistance of CsA-treated B16F10 cells to NK lysis. These findings show that CsA may have an effect on B16F10 cells' metastatic progression of the B16F10 melanoma by modulation of cytokines and MHC antigen expression.
Source link: https://doi.org/10.1159/000024505
Metastatic tumors are the most common heart tumors, with melanoma metastasis being the most common. If a cardiac tamponade or a low cardiac output syndrome due to the location of the tumor, it may lead to an acute life-threatening disease for the patient. Case report: We report a case of a successfully treated metastatic cardiac melanoma in a life-saving cardiac surgery. After cardiac surgery, the patient was well on follow-up tests for 4 months, revealing ascites and melanosis of the entire skin with ascites and melanosis of the entire skin followed by lethal results five months after. Conclusion: In the case of solitary metastasis, surgical reconstruction of metastatic cardiac melanoma can be safe and effective in an emergency situation.
Source link: https://doi.org/10.1532/hsf.3097
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