Tofacitinib is Effective in Treating Refractory Immune Checkpoint Inhibitor Hepatitis.

Immune checkpoint inhibitors (ICI) have improved metastatic melanoma outcomes; however, toxicities, such as hepatitis, can be dose-limiting or even fatal.1 Systemic glucocorticoids and antimetabolite immunosuppressive medications remain the mainstay of treatment for ICI-hepatitis, but options for patients refractory to these therapies are limited.2 Herein we present 3 cases of glucocorticoid-refractory ICI-hepatitis treated with tofacitinib, an inhibitor of Janus kinase (JAK) 1 and 3. These patients represent consecutive patients referred to the Massachusetts General Hospital Severe Immunotherapy Complications service who were determined by our experts to have treatment failure with systemic glucocorticoid and antimetabolite combination therapy between August 2022 and September 2023.3 These were the only 3 patients managed by the Severe Immunotherapy Complications service who were treated with tofacitinib for ICI-hepatitis during that time.

Clinical outcomes of adjuvant nivolumab in resected stage III melanoma: comparison of CheckMate 238 trial and real-world data.

OBJECTIVES: Nivolumab is approved as adjuvant therapy for resected stage III/IV melanoma based on the phase 3 CheckMate 238 trial. This analysis compared outcomes from CheckMate 238 with those from the real-world Flatiron Health electronic health record-derived de-identified database in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab. MATERIALS: Outcomes included baseline characteristics, overall survival (OS) in the CheckMate 238 cohort (randomization until death or last known alive), and real-world overall survival (rwOS) in the Flatiron Health cohort (nivolumab initiation until death or data cutoff). rwOS was compared with OS using unadjusted and adjusted Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was combined with the adjusted model to reduce baseline discrepancies. RESULTS: The CheckMate 238 and real-world cohorts included 369 and 452 patients, respectively (median age, 56.0 and 63.0 years; median follow-up, 61.4 vs. 25.5 months). rwOS was not different from OS in the unadjusted (hazard ratio [HR] 1.27; 95% CI 0.92-1.74), adjusted (HR 1.01; 95% CI 0.67-1.54), and adjusted IPTW (HR 1.07; 95% CI 0.70-1.63) analyses. In the adjusted analysis, 2-year OS and rwOS rates were 84%. Median OS and rwOS were not reached. After IPTW, OS and rwOS were not different (HR 1.07; 95% CI 0.70-1.64). CONCLUSIONS: In this comparative analysis, OS in the CheckMate 238 trial was similar to rwOS in the Flatiron Health database after adjustments in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab, validating the trial results.

First-in-class Microbial Ecosystem Therapeutic 4 (MET4) in combination with immune checkpoint inhibitors in patients with advanced solid tumors (MET4-IO trial).

BACKGROUND: The intestinal microbiome has been associated with response to immune checkpoint inhibitors (ICIs) in humans and causally implicated in ICI responsiveness in animal models. Two recent human trials demonstrated that fecal microbiota transplant (FMT) from ICI responders can rescue ICI responses in refractory melanoma, but FMT has specific limitations to scaled use. PATIENTS AND METHODS: We conducted an early-phase clinical trial of a cultivated, orally delivered 30-species microbial consortium (Microbial Ecosystem Therapeutic 4, MET4) designed for co-administration with ICIs as an alternative to FMT and assessed safety, tolerability and ecological responses in patients with advanced solid tumors. RESULTS: The trial achieved its primary safety and tolerability outcomes. There were no statistically significant differences in the primary ecological outcomes; however, differences in MET4 species relative abundance were evident after randomization that varied by patient and species. Increases in the relative abundance of several MET4 taxa, including Enterococcus and Bifidobacterium, taxa previously associated with ICI responsiveness, were observed and MET4 engraftment was associated with decreases in plasma and stool primary bile acids. CONCLUSIONS: This trial is the first report of the use of a microbial consortium as an alternative to FMT in advanced cancer patients receiving ICI and the results justify the further development of microbial consortia as a therapeutic co-intervention for ICI treatment in cancer.

A qualitative review of misinformation and conspiracy theories in skin cancer.

Misinformation on diseases and treatments is a worldwide threat and can lead to worse outcomes for patients with skin cancer. The aim of this study was to qualitatively assess the content of online misinformation related to skin cancer. Searches were performed via PubMed and Google using the terms 'skin cancer' OR 'melanoma' OR 'non-melanoma skin cancer' OR 'SCC' OR 'BCC' AND 'misinformation' OR 'disinformation' OR 'conspiracy theories'. The most common themes of misinformation related to skin cancer included assertions of the 'dangers' of using sunscreen and alternative sunscreen practices; promotion of tanning and Melanotan (an unlicensed and untested form of α-melanocyte-stimulating hormone) as safe practices; claims that risk of skin cancer are limited to people who are older or have fair skin; and assertions of alternative 'causes' and alternative 'cures' for skin cancer. Sunscreen was particularly vilified as being an ineffective prophylactic measure and a cause of skin cancer. Dermatologists should be aware of misinformation available online relating to skin cancer, and refute and rebut misleading health information.

Access to innovation through the national early access program and clinical trials for patients with malignant melanoma.

BACKGROUND: The arrival of immunotherapies and targeted therapies challenged the authorities to make them available as soon as possible. France has effective tools, such as clinical trials (CTs) and a national early access program (temporary authorizations for use [ATUs] and temporary recommendations for use [RTUs]), allowing the use of innovative drugs, whether or not they have been authorized or used off-label, for cases that have reached a therapeutic impasse. METHODS: The methodology involved real-time data collection from ATUs, RTUs (between September 1, 2009 and September 1, 2019), and CT authorizations (from December 1, 2017 to September 1, 2019) that were filed and reviewed by the French National Agency for Medicines for metastatic melanoma (MM). RESULTS: In total, 45 CTs were authorized for MM (51% early phase trials and 44% phase 2 and 3 trials), mainly for the metastatic line (86%) and with an industrial sponsor (73%). Immunotherapies and targeted therapies (63% and 24%, respectively) mostly were used in combination. Three RTUs were authorized for the adjuvant treatment of MM, whereas 13 drugs were available through nominal ATUs (nATUs), of which 5 were awarded a cohort ATU (cATU). This enabled the treatment of 6538 patients (28% through nATUs and 72% through cATUs). All of these drugs were granted marketing authorization and were included in the reimbursement list. CONCLUSIONS: Thanks to CTs and the national early access program, patients in France have been able to benefit from innovative MM treatments. LAY SUMMARY: Several tools allow the use of innovative drugs in France, even if they are not yet authorized or used off-label. From December 1, 2017 to September 1, 2019, 45 clinical trials have been authorized for metastatic melanoma, mostly using immunotherapy (63%) and targeted therapy (24%) at an early phase (51%). Since 2010, the national early access program has treated 6538 patients, including 28% under nominative temporary authorizations for use and 72% under cohort temporary authorizations for use. Fourteen drugs are available through nominative temporary authorizations for use, and 5 are available through cohort temporary authorizations for use, and all of these drugs were granted marketing authorization.

Course of Sars-CoV2 Infection in Patients with Cancer Treated with anti-PD-1: A Case Presentation and Review of the Literature.

The outbreak of COVID-19 pandemia is a major health worldwide concern. Patients with cancer might have a worse outcome, because of the immunosuppression determined by the tumor itself and anti-cancer treatments, including chemotherapy and radiotherapy. The impact and course of viral infection in patients receiving immunotherapy remains unknown. We report the case of a patient with metastatic melanoma, long responder to anti PD-1 blockade who got infected with Sars CoV-2, recovering without sequelae. A critical review of literature was performed. Limited data available in literature support the possibility to continue the immunotherapy in patients with cancer under control.

Interim [18F]FDG PET/CT can predict response to anti-PD-1 treatment in metastatic melanoma.

PURPOSE: In an attempt to identify biomarkers that can reliably predict long-term outcomes to immunotherapy in metastatic melanoma, we investigated the prognostic role of [18F]FDG PET/CT, performed at baseline and early during the course of anti-PD-1 treatment. METHODS: Twenty-five patients with stage IV melanoma, scheduled for treatment with PD-1 inhibitors, were enrolled in the study (pembrolizumab, n = 8 patients; nivolumab, n = 4 patients; nivolumab/ipilimumab, 13 patients). [18F]FDG PET/CT was performed before the start of treatment (baseline PET/CT) and after the initial two cycles of PD-1 blockade administration (interim PET/CT). Seventeen patients underwent also a third PET/CT scan after administration of four cycles of treatment. Evaluation of patients' response by means of PET/CT was performed after application of the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria and the PET Response Evaluation Criteria for IMmunoTherapy (PERCIMT). Response to treatment was classified into 4 categories: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). Patients were further grouped into two groups: those demonstrating metabolic benefit (MB), including patients with SMD, PMR, and CMR, and those demonstrating no MB (no-MB), including patients with PMD. Moreover, patterns of [18F]FDG uptake suggestive of radiologic immune-related adverse events (irAEs) were documented. Progression-free survival (PFS) was measured from the date of interim PET/CT until disease progression or death from any cause. RESULTS: Median follow-up from interim PET/CT was 24.2 months (19.3-41.7 months). According to the EORTC criteria, 14 patients showed MB (1 CMR, 6 PMR, and 7 SMD), while 11 patients showed no-MB (PMD). Respectively, the application of the PERCIMT criteria revealed that 19 patients had MB (1 CMR, 6 PMR, and 12 SMD), and 6 of them had no-MB (PMD). With regard to PFS, no significant difference was observed between patients with MB and no-MB on interim PET/CT according to the EORTC criteria (p = 0.088). In contrary, according to the PERCIMT criteria, patients demonstrating MB had a significantly longer PFS than those showing no-MB (p = 0.045). The emergence of radiologic irAEs (n = 11 patients) was not associated with a significant survival benefit. Regarding the sub-cohort undergoing also a third PET/CT, 14/17 patients (82%) showed concordant responses and 3/17 (18%) had a mismatch of response assessment between interim and late PET/CT. CONCLUSION: PET/CT-based response of metastatic melanoma to PD-1 blockade after application of the recently proposed PERCIMT criteria is significantly correlated with PFS. This highlights the potential ability of [18F]FDG PET/CT for early stratification of response to anti-PD-1 agents, a finding with possible significant clinical and financial implications. Further studies including larger numbers of patients are necessary to validate these results.

Impact of modern systemic therapies and clinical markers on treatment outcome for metastatic melanoma in a real-world setting.

BACKGROUND: The survival in metastatic melanoma has dramatically improved after the introduction of immune checkpoint- (ICIs) and MAPKinase inhibitors (MAPKis). OBJECTIVE: Our aim was to describe therapy response and survival in a real-world population as well as to assess the associations between clinical variables and therapy outcome for patients with metastatic melanoma receiving first-line ICIs or MAPKis. METHODS: A total of 252 patients with metastatic (stage IV) melanoma were prospectively followed between 1 January 2010 and 3 December 2017 with follow-up until 31 March 2019, at the Karolinska University Hospital, Sweden. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were analysed with Cox regression, and logistic regression was used to estimate odds ratios (ORs) for therapy response. RESULTS: Patients receiving ICIs (n = 138) experienced longer PFS compared to patients that received MAPKis (n = 114; median PFS for ICIs was 6.8 months, and median PFS for MAPKis was 5.3 months). In the multivariable analyses of clinical markers, increasing M-stage (OR 0.65; 95% CI 0.45-0.94; P = 0.022) and male sex (OR 0.41; 95% CI 0.19-0.90; P = 0.027) were significantly associated with lower response to ICIs. Lower baseline albumin levels (OR 0.90; 95% CI 0.83-0.98; P = 0.019) and male sex (OR 0.33; 95% CI 0.12-0.93; P = 0.036) were related with lower response to MAPKis. For ICIs, increasing M-stage (HR 1.34; 95% CI 1.07-1.68; P = 0.010), increasing LDH (HR 1.73; 95% CI 1.19-2.50; P = 0.004) and decreasing albumin (HR 1.06; 95% CI 1.01-1.10; P = 0.011) were significantly associated lower PFS in the adjusted model. The corresponding markers for MAPKis were increasing LDH (HR 1.44; 95% CI 1.08-1.92; P = 0.013) and decreasing albumin (HR 1.05; 95% CI 1.02-1.09; P = 0.005) for PFS. CONCLUSION: ICIs and MAPKis were effective in this real-world population, and we could confirm the importance of previously reported clinical prognostic markers. Albumin values may be associated with therapy outcome but need further validation.

[A Case of Thyroid Dysfunction and Isolated Adrenocorticotropin Deficiency after Nivolumab Therapy for Malignant Melanoma].

The patient was a 34-year-old woman. Surgical resection and chemotherapy had been performed on diagnosis of malignant melanoma in year X-9. Chronic thyroiditis was diagnosed in year X-8, but her thyroid function was normal. In November of the year X-1, the patient, who had metastasis to the left lung and the left main bronchus and radically unresectable metastases with distant metastases, was treated with the anti-PD-1 antibody nivolumab. In December X-1, we initiated levothyroxine sodium for hypothyroidism after the patient suffered indolent thyroiditis due to nivolumab. In March X, the nivolumab treatment was stopped because it proved to be ineffective, then in April, anorexia, fever, and general malaise were noted. Cortisol 5.0 and ACTH 17.5 were confirmed by blood test, and the patient was diagnosed with adrenal insufficiency and was admitted to the hospital. Head MRI showed no organic lesions, and a stress test showed abnormalities only in a CRH test (low response to both ACTH and cortisol). The patient was diagnosed with isolated ACTH deficiency due to nivolumab. Side effects of thyroid dysfunction due to nivolumab are frequently observed in Japan at a rate of 14.3%, and overseas at 5.9%. However, secondary adrenocortical dysfunction is observed in overseas clinical trials at a frequency of only about 0.3%. There are few reports of such complications, and we report this as a rare case.

Statins may reduce disease recurrence in patients with ulcerated primary melanoma.

BACKGROUND: Statins may restrict the cellular functions required for melanoma growth and metastasis. OBJECTIVES: To determine whether long-term statin use commenced before diagnosis of a primary melanoma is associated with reduced risk of melanoma recurrence. METHODS: We prospectively followed a cohort of patients newly diagnosed between 2010 and 2014 with localized tumour-stage T1b to T4b melanoma in Queensland, Australia. We used Cox regression analyses to examine associations between long-term statin use and melanoma recurrence for the entire cohort, and then separately by sex and by presence of ulceration, due to evidence of effect modification. RESULTS: Among 700 patients diagnosed with stage T1b to T4b primary melanoma (mean age 62 years, 59% male, 28% with ulcerated tumours), 94 patients (13%) developed melanoma recurrence within 2 years. Long-term statin users (n = 204, 29%) had a significantly lower risk of disease recurrence than nonusers [adjusted hazard ratio (HRadj ) 0·55, 95% confidence Interval (CI) 0·32-0·97] regardless of statin subtype or potency. Compared with nonusers of statins, risk of recurrence was significantly decreased in male statin users (HRadj 0·39, 95% CI 0·19-0·79) but not in female statin users (HRadj 0·82, 95% CI 0·29-2·27) and in statin users with ulcerated (HRadj 0·17, 95% CI 0·05-0·52) but not nonulcerated (HRadj 0·91, 95% CI 0·46-1·81) primary melanoma. CONCLUSIONS: Statins commenced before melanoma diagnosis may reduce the risk of melanoma recurrence, especially in men and in those with ulcerated tumours. Clinical trial evaluation of the potential role of statins in improving the prognosis of high-risk melanoma is warranted.

Associations between ultraviolet radiation, tree cover and adolescent sunburns.

BACKGROUND: Sunburn is the strongest risk factor for melanoma and non-melanoma skin cancers. Adolescent sunburns are related to higher risk of developing melanoma later in life. Little is known about the association of sunburns and shade, particularly tree cover, around adolescent homes and schools. This linkage study assessed associations of adolescent self-reported sunburns with ambient ultraviolet radiation (UV) and tree cover. METHODS: We analyzed a U.S. national sample of parent-child dyads (n = 1333) from the 2014 Family Life, Activity, Sun, Health, and Eating (FLASHE) study conducted by the National Cancer Institute. The outcome was adolescent sunburns reported for the previous 12 months. GIS buffers around geocoded home and school addresses were used to summarize UV and tree cover. A sensitivity analysis assessed different UV measures and tree cover buffer distances. Logistic regression models estimated the adjusted odds of any sunburns for five models: (1) no environmental variables; (2) spatial variables of latitude and longitude; (3) UV; (4) tree cover; and, (5) a combined model with UV and tree cover. Covariates included common sunburn-related items such as sun protective behaviors, socio-demographics, and latitude. Model residuals were assessed for spatial dependency and clustering. RESULTS: Overall, 44% of adolescents reported any sunburns in the previous 12 months. For the bivariate associations, lower categories of UV were associated with any reported sunburns (p-trend = 0.002). Home tree cover was not associated with any reported sunburns (p-trend = 0.08), whereas schools with lower categories of tree cover were associated with sunburns (p-trend = 0.008). The adjusted odds of any sunburns by UV tertiles, as a linear tread, was 0.89 (0.76-1.05) (p = 0.17); school tree cover was: 0.91 (0.78-1.07) (p = 0.25). Neither UV nor tree cover, in a combined model, were significant. Sensitivity analyses resulted in the optimal buffer size of 200 m for summarizing tree cover. Spatial dependence of residuals was not significant and clustering was significant for about 6% or less of the sample in each model. CONCLUSIONS: We did not find significant relationships between UV or tree cover and adolescent sunburns, when adjusted by sunburn-related covariates. Better contextual data about where sunburns occurred is needed to identify environmental correlates of sunburn.

The impact of new cancer drug therapies on site specialised cancer treatment activity in a UK cancer network 2014-2018.

INTRODUCTION: Drug treatment for cancer has changed dramatically over the past decade with many new drugs often with multiple applications. More recently, the detailed pathway for approval from the National Institute for Health and Care Excellence (NICE) in the UK has been simplified. To explore how these changes have impacted on systemic anti-cancer therapy tumour site-specific prescribing and workload activities, we have reviewed the prescribing records for 2014-2018 in a UK cancer network. METHODS: Information about the numbers of new systemic anti-cancer therapy drugs and NICE approvals were obtained from print editions of the British National Formulary (BNF) and the NICE website. Data on the numbers of new chemotherapy courses and individual treatment-related attendances were obtained from the cancer network Chemocare electronic prescribing system. RESULTS: During the five-year study period, there were 49 new systemic anti-cancer therapy drugs for all tumour types, and a total of 65 NICE technology approvals for solid tumour indications. Overall numbers of treatment courses increased by 40.7% and total treatment-related visits by 80.6%. There was a wide variation across tumour types with the highest number of increased visits seen for melanoma (349.3%) and prostate cancer (242.3%), but in contrast, no appreciable increases were seen for lower gastrointestinal cancers or small cell lung cancer. CONCLUSION: The study confirms the major impact of the arrival of new drug technology and positive NICE appraisals on increasing systemic anti-cancer therapy prescribing and chemotherapy unit activity. The data in this study may be of help in planning for future service delivery planning and workforce configurations.

Complete responses to two different anti-PD1 agents in a metastatic melanoma patient.

In the last decade, immune checkpoint inhibitors changed the landscape of metastatic melanoma. However, the optimal duration of treatment and treatment cessation in responders is largely unknown. Herein, we represent a heavily pretreated metastatic melanoma case who had a complete response to pembrolizumab and also a complete response with nivolumab after progression during drug-free follow-up. We think that reinduction with a different anti-PD1 antibody may be used in patients with metastatic melanoma responders. Clinical trials with prespecified sequential treatment protocols and large real-life data can further delineate this subject.

Potential use of melatonin in skin cancer treatment: A review of current biological evidence.

Skin cancer, particularly melanoma, is a leading cause of death worldwide. The therapeutic methods for this malignancy are not effective, and due to the side effects of these treatments, applying an appropriate alternative or complementary treatment is important. According to available data, melatonin as the main product of the pineal gland has oncostatic and antitumoral properties. Also, melatonin acts as an anti-inflammatory and reactive oxygen species inducer agent which suppresses the growth of tumors. It also has apoptosis induction characteristics through regulating signaling pathways, including heat shock protein 70, nuclear factor-erythroid 2 p45-related factor 2 and others. Thus, adding melatonin to chemo- and radiotherapy may have synergistic therapeutic effects and increase the survival time in patients with skin cancer. Few clinical studies have evaluated the efficacy of melatonin in skin cancer. Based on the related mechanisms, this review discusses about how melatonin may improve outcomes in skin cancer patients.

Patterns of response with talimogene laherparepvec in combination with ipilimumab or ipilimumab alone in metastatic unresectable melanoma.

Talimogene laherparepvec (T-VEC) has demonstrated efficacy for unresectable melanoma. We explored response patterns from a phase 2 study evaluating patients with unresectable stage IIIB-IVM1c malignant melanoma who received T-VEC plus ipilimumab or ipilimumab alone. Patients with objective response per modified irRC were evaluated for pseudo-progression (single ≥25% increase in tumour burden before response). Patients without pseudo-progression were classified by whether they responded within or after 6 months of treatment start; those with pseudo-progression were classified by whether pseudo-progression was due to increase in existing lesions or development of new lesions. Overall, 39% (n = 38/98) in the combination arm and 18% (n = 18/100) in the ipilimumab arm had an objective response. Eight responders (combination, n = 7 [18.4%]; ipilimumab, n = 1 [5.6%]) had pseudo-progression; most occurred by week 12 and were caused by an increase in existing lesions. These data reinforce use of T-VEC through initial progression when combined with checkpoint inhibitors.Trial Registration NCT01740297 (ClinicalTrials.gov; date of registration, December 4, 2012); 2012-000307-32 (ClinicalTrialsRegister.eu; date of registration, May 13, 2014).

Combined immune checkpoint inhibitor therapy with nivolumab and ipilimumab causing acute-onset type 1 diabetes mellitus following a single administration: two case reports.

BACKGROUND: The use of immune checkpoint inhibitor (ICI) therapy is becoming a standard of care for several cancers. Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand (PD-L1) cause a broad spectrum of autoimmune adverse events. ICI-induced type 1 diabetes mellitus (T1DM) is extremely rare (< 1%) but potentially life-threatening. It appears to be more common with PD-1 blockade (or combination immunotherapy) than with anti-CTLA-4 therapy, often during the first three to six months of therapy. CASES PRESENTATION: We report an acute onset T1DM with severe inaugural diabetic ketoacidosis (DKA) and remarkably elevated Glutamic Acid Decarboxylase antibody (GADA) titres following a single administration of combined ICI therapy with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in two adult patients with advanced metastatic melanoma. In these cases, the time to diabetes onset was remarkably short (two and five weeks), and one presented with fulminous T1DM in a previous long-standing type 2 diabetes mellitus. CONCLUSIONS: Oncological patients treated with combination therapy of anti-PD-1 and anti-CTLA-4 can develop a particular pattern of T1DM, with very rapid onset within a few weeks after starting ICI therapy, even in the presence of an existing type 2 diabetes. ICI-induced T1DM is a medical emergency in presence of severe inaugural DKA and requires a collaboration between specialists and primary care physicians, as well as patient education, for early diagnosis and supportive care.

[Enlarged mediastinal lymph nodes of a patient with malignant melanoma stage IV under pembrolizumab treatment]. / Mediastinale Lymphknotenvergrößerung bei einer Patientin mit malignem Melanom Stadium IV unter Therapie mit Pembrolizumab.

A 40-year-old patient with malignant melanoma pT4bN0M1a stage IV (AJCC classification 2017) was treated with the PD-1/PD-L1 antibody pembrolizumab. Three months after treatment initiation the patient developed enlarged mediastinal lymph nodes despite the partial response of the cutaneous metastases. An elective lymph node extirpation was performed. The histopathological result was consistent with a sarcoid-like reaction. Treatment was discontinued and a pulse therapy with systemic steroids led to a significant remission of the lymphadenopathy. This side effect can manifest both during PD-1/PD-L1 antibody and CTLA-4 antibody therapy and should be included in the differential diagnosis of mediastinal lymphadenopathy.

Pharmaceutical Topical Delivery of Poorly Soluble Polyphenols: Potential Role in Prevention and Treatment of Melanoma.

Melanoma is regarded as the fifth and sixth most common cancer in men and women, respectively, and it is estimated that one person dies from melanoma every hour in the USA. Unfortunately, the treatment of melanoma is difficult because of its aggressive metastasis and resistance to treatment. The treatment of melanoma continues to be a challenging issue due to the limitations of available treatments such as a low response rate, severe adverse reactions, and significant toxicity. Natural polyphenols have attracted considerable attention from the scientific community due to their chemopreventive and chemotherapeutic efficacy. It has been suggested that poorly soluble polyphenols such as curcumin, resveratrol, quercetin, coumarin, and epigallocatechin-3-gallate may have significant benefits in the treatment of melanoma due to their antioxidant, anti-inflammatory, antiproliferative, and chemoprotective efficacies. The major obstacles for the use of polyphenolic compounds are low stability and poor bioavailability. Numerous nanoformulations, including solid lipid nanoparticles, polymeric nanoparticles, micelles, and liposomes, have been formulated to enhance the bioavailability and stability, as well as the therapeutic efficacy of polyphenols. This review will provide an overview of poorly soluble polyphenols that have been reported to have antimetastatic efficacy in melanomas.

Can propranolol prevent progression of melanoma?

The worldwide incidence of melanoma has risen rapidly in the past 50 years and is a considerable public health burden in the United States, with significant financial implications. Studies have demonstrated the potential anticarcinogenic effects of antihypertensive agents, specifically beta-blockers, in patients with prostate cancer, breast cancer, and lately cutaneous malignant melanoma. This article explores the empirical clinical evidence of propranolol's anticarcinogenic effects on melanoma and the chemoprotective mechanisms of beta-blockers and other agents that have been used to modify melanoma progression.

Enhanced effect of checkpoint inhibitors when given after or together with IMM-101: significant responses in four advanced melanoma patients with no additional major toxicity.

BACKGROUND: The use of checkpoint inhibitors (ipilimumab, pembrolizumab, nivolumab) has revolutionised the treatment of metastatic melanoma. However still more than the half the patients do not respond to single-agent immunotherapy. This has led to the development of combining these agents in an attempt to enhance the anti-cancer activity. More than 300 different studies with 15 different drug doses are currently ongoing. Combining different checkpoint inhibitors (CPIs) does indeed lead to an increase in response rate, but this is associated with significant toxicity. IMM-101 is a heat killed Mycobacterium preparation which induces marked immune modulation and little systemic toxicity. It has been reported as having activity in melanoma as single agent and in pancreatic cancer in combination with gemcitabine, the latter in a randomised study. METHODS: Here we report the effect of adding CPIs to 3 patients who had previously been on IMM-101, either as a trial or a named patient programme and a patient who received the IMM-101 together with nivolumab. RESULTS: All 4 patients had rapid and very good responses, three of them maintained over 18 months with no significant additional toxicity. CONCLUSIONS: The rapid and complete clinical responses seen in these patients may suggest that IMM-101 is activating a complementary pathway which is synergistic with CPI treatment.