Prognostic Value of the Neutrophil-to-lymphocyte Ratio, Platelet-to- lymphocyte Ratio and Monocyte-to-lymphocyte Ratio in Melanoma Patients: A Cohort Study.

The prognostic value of the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio in patients with melanoma has yielded controversial results in the literature. A retrospective single-centre cohort study was conducted from 1998 to 2020, including patients diagnosed with invasive melanoma. A total of 2,721 patients were included in the study. The median follow-up was 8.23 years (IQR 4.41-13.25). The median baseline neutrophil- lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio values increased significantly (p < 0.001) with the increasing American Joint Committee on Cancer stage. The optimal cut-off values for neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio were determined as 2.1, 184 and 0.2, respectively. In the multivariate analysis, high levels of neutrophil-lymphocyte ratio (≥ 2.1), platelet-lymphocyte ratio (≥ 184) and monocyte-lymphocyte ratio (≥ 0.2) were independently associated with significantly shorter melanoma-specific survival (neutrophil-lymphocyte ratio: HR 1.30, 95% CI 1.06-1.60, p = 0.013; platelet-lymphocyte ratio: HR 1.37, 95% CI 1.06-1.76, p = 0.014; monocyte- lymphocyte ratio: HR 1.29, 95% CI 1.05-1.58, p = 0.015) and overall survival (neutrophil-lymphocyte ratio: HR 1.39, 95% CI 1.19-1.64, p < 0.001; platelet- lymphocyte ratio: HR 1.44, 95% CI 1.19-1.74, p < 0.001; monocyte-lymphocyte ratio: HR 1.42, 95% CI 1.21-1.66, p < 0.001). High levels of neutrophil- lymphocyte ratio and monocyte-lymphocyte ratio were also associated with poor relapse-free survival, while platelet-lymphocyte ratio was not. In conclusion, baseline neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio were identified as independent predictors for the prognosis of melanoma.

Experimentally validated oxidative stress -associated prognostic signatures describe the immune landscape and predict the drug response and prognosis of SKCM.

Background: Skin Cutaneous Melanoma (SKCM) incidence is continually increasing, with chemotherapy and immunotherapy being among the most common cancer treatment modalities. This study aims to identify novel biomarkers for chemotherapy and immunotherapy response in SKCM and explore their association with oxidative stress. Methods: Utilizing TCGA-SKCM RNA-seq data, we employed Weighted Gene Co-expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) networks to identify six core genes. Gene co-expression analysis and immune-related analysis were conducted, and specific markers associated with oxidative stress were identified using Gene Set Variation Analysis (GSVA). Single-cell analysis revealed the expression patterns of Oxidative Stress-Associated Genes (OSAG) in the tumor microenvironment. TIDE analysis was employed to explore the association between immune therapy response and OSAG, while CIBERSORT was used to analyze the tumor immune microenvironment. The BEST database demonstrated the impact of the Oxidative Stress signaling pathway on chemotherapy drug resistance. Immunohistochemical staining and ROC curve evaluation were performed to assess the protein expression levels of core genes in SKCM and normal samples, with survival analysis utilized to determine their diagnostic value. Results: We identified six central genes associated with SKCM metastasis, among which the expression of DSC2 and DSC3 involved in the oxidative stress pathway was closely related to immune cell infiltration. DSC2 influenced drug resistance in SKMC patients. Furthermore, downregulation of DSC2 and DSC3 expression enhanced the response of SKCM patients to immunotherapy. Conclusion: This study identified two Oxidative Stress-Associated genes as novel biomarkers for SKCM. Additionally, targeting the oxidative stress pathway may serve as a new strategy in clinical practice to enhance SKCM chemotherapy and sensitivity.

Distinct presentation of melanoma in Black patients may inform strategies to improve outcomes.

INTRODUCTION: Melanoma guidelines stem largely from data on non-Hispanic White (NHW) patients. We aimed to identify features of melanoma within non-Hispanic Black (NHB) patients to inform strategies for earlier detection and treatment. METHODS: From 2004 to 2019 Surveillance, Epidemiology, and End Results (SEER) data, we identified nonmetastatic melanoma patients with known TN category and race. Kaplan-Meier cancer-specific survival (CSS) estimates and multivariable Cox proportional hazard modeling analyses were performed. RESULTS: Of 492 597 patients, 1499 (0.3%) were NHB, who were younger (21% vs. 17% age <50) and more commonly female (54% vs. 41%) than NHW, both p < 0.0005. For NHBs, lower extremity was the most common site (52% vs. 15% for NHWs, p < 0.0001), T category was higher (55% Tis-T1 vs. 82%; 27% T3-T4 vs. 8%, p < 0.0001) and stage at presentation was higher (19% Stage III, vs. 6%, p < 0.0001). Within the NHB cohort, males were older, and more often node-positive than females. Five-year Stage III CSS was 42% for NHB males versus 71% for females, adjusting for age and clinical nodal status (hazard ratio 2.48). CONCLUSIONS: NHB melanoma patients presented with distinct tumor characteristics. NHB males with Stage III disease had inferior CSS. Focus on this high-risk patient cohort to promote earlier detection and treatment may improve outcomes.

Avelumab in the Treatment of Advanced Merkel Cell Carcinoma: A Systematic Review.

BACKGROUND: Avelumab, a programmed death ligand-1 inhibitor, has shown success in providing durable responses for difficult-to-treat Merkel cell carcinomas (MCCs). OBJECTIVE: Evaluate the efficacy and safety of avelumab in the treatment of advanced MCC. METHODS: Studies reporting the use of avelumab as a monotherapy or in combination with other agents in the treatment of stage III or IV (advanced) MCC were included. The primary outcomes were overall response rate, overall survival (OS), and treatment-related adverse events. RESULTS: A total of 48 studies were included, involving 1,565 patients with advanced MCC. Most patients were male (1,051, 67.3%) with stage IV MCC (517, 97.0%). The overall response rate was 46.1% (partial response-25.4% and complete response-20.7%) after a mean follow-up period of 9.5 months. Kaplan-Meier survival curves for the pooled stage III and IV group demonstrated OS rates of 58% at 1 year, 47% at 2 years, and 28% at 5 years after completion of treatment with avelumab (median OS: 23.1 months). The most common treatment-related adverse events consisted of constitutional (44%), gastrointestinal (19%), and dermatologic (12%) symptoms. CONCLUSION: Avelumab monotherapy and combination therapy have shown success in the overall response rate and survival for patients with advanced MCC.

Cutaneous Squamous Cell Carcinoma Outcomes in Solid Organ Transplant Recipients: A Matched Retrospective Cohort Study.

BACKGROUND: Solid organ transplant recipients with cutaneous squamous cell carcinoma (CSCC) have an increased risk of poor outcomes. However, a recent study demonstrated that immunosuppression is not an independent risk factor for these poor outcomes after controlling for primary tumor stage. OBJECTIVE: To evaluate whether transplant status is an independent risk factor for poor outcomes in CSCC. MATERIALS AND METHODS: A database of CSCCs treated at an academic center over 10 years was used to perform a retrospective cohort study comparing the risk of poor outcomes (local recurrence, regional and distant metastases, and disease-specific death) in solid organ transplant recipients and controls. Subjects were matched on age, tumor stage, sex, tumor site, and time to poor outcome. RESULTS: There were 316 tumors from 78 transplant patients and 316 tumors from 262 controls. On multivariate analysis, tumor stage and location on the head and neck were predictive of poor outcomes. There was no significant difference in the risk of poor outcomes in the transplant group versus the control group. CONCLUSION: Transplant status was not an independent risk factor for poor squamous cell carcinoma outcomes after controlling for stage, age, sex, site, and time to poor outcome.

Global trends in cutaneous malignant melanoma incidence and mortality.

Mortality from cutaneous malignant melanoma (CMM) increased in the past, but trends have been favorable in more recent years in many high-income countries. However, incidence has been increasing in several countries. We provided an up-to-date overview of mortality trends from CMM. We analyzed death certification data from the WHO in selected countries worldwide from 1980 to the most recent available calendar years. We also reported incidence data derived from Cancer Incidence in Five Continents from 1990 to 2012. Separate analyses were performed for young adults aged 20-44 and middle-aged adults aged 45-64 years. Mortality from CMM in all age groups showed a favorable pattern in the majority of the countries considered. Mortality trends declined by 40 to 50% in Australia over the last decades, confirming the importance of prevention measures. Considering young adults aged 20-44, Australia, New Zealand and Northern Europe reported the highest death rates for both sexes (>0.90/100 000 in men and >0.60/100 000 in women) while Japan, the Philippines, and Latin America the lowest ones (<0.50/100 000 and <0.35/100 000 in men and women, respectively). Incidence trends were stable or upward in most countries, with higher rates among women. Our study highlights a global reduction of CMM mortality over the last three decades. The increasing awareness of risk factors, mainly related to UV exposure, along with early diagnosis and progress in treatment for advanced disease played pivotal roles in reducing CMM mortality, particularly in Australia.

Disparities in the Receipt of Systemic Treatment in Metastatic Melanoma.

BACKGROUND: In 2011, immunotherapy and targeted therapy revolutionized melanoma treatment. However, inequities in their use may limit the benefits seen by certain patients. METHODS: We performed a retrospective review of patients in the National Cancer Database for patients with stage IV melanoma from 2 time periods: 2004-2010 and 2016-2020, distinguishing between those who received systemic therapy and those who did not. We investigated the rates and factors associated with treatment omission. We employed Kaplan-Meier analysis to explore the impact of treatment on overall survival. RESULTS: A total of 19,961 patients met the inclusion criteria: 7621 patients were diagnosed in 2004-2010 and 12,340 patients in 2016-2020, of whom 54.9% and 28.3% did not receive systemic treatment, respectively. The rate of "no treatment" has decreased to a plateau of ∼25% in 2020. Median overall survival was improved with treatment in both time periods (2004-2010: 8.8 vs. 5.6 mo [ P <0.05]; and 2016-2020: 25.9 vs. 4.3 mo [ P <0.05]). Nonmedical factors associated with the omission of treatment in both periods included low socioeconomic status, Medicaid or no health insurance, and treatment at low-volume centers. In the period from 2016 to 2020, patients treated at nonacademic programs were also less likely to receive treatment. CONCLUSIONS: Systemic therapies significantly improve survival for patients with metastatic melanoma, but significant disparities exist with their receipt. Local efforts are needed to ensure all patients benefit from these revolutionary treatments.

Nodular type predominance of head and neck cutaneous malignant melanoma in Asian populations leads to poor outcome and low survival.

Cutaneous malignant melanomas of the head and neck (HNM) are proposed to have notable histological and clinical differences from those at other sites (other melanoma); however, HNMs among Asians have remained poorly understood. This study aimed to investigate the clinicopathological features and prognostic factors of HNM in Asians. Asian melanoma patients who underwent surgical treatment from January 2003 to December 2020 were retrospectively reviewed. The clinicopathological features and risk factors for local recurrence, lymph node metastasis, and distant metastasis were analyzed. Among 230 patients, 28 (12.2%) were diagnosed with HNM, and 202 (87.8%) with other melanoma. The histologic subtype significantly differed as the nodular type was predominant in HNM whereas the acral lentiginous type was predominant in other melanoma ( P  < 0.001). HNM was significantly associated with higher local recurrence ( P  = 0.045), lymph node metastasis ( P  = 0.048), distant metastasis ( P  = 0.023), and lower 5-year disease-free survival ( P  = 0.022) than other melanoma. Ulceration was the risk factor for lymph node metastasis based on multivariable analysis ( P  = 0.013). A high proportion of HNM present as the nodular subtype in Asians, leading to poor outcomes and low survival. Therefore, more cautious surveillance, evaluation, and aggressive treatment are required.

Lower limb cutaneous melanoma surgery: location matters.

The anatomical location of cutaneous melanoma is a relevant independent prognostic factor in melanoma. The aim of the study is to know the prognosis of lower limb cutaneous melanoma related to their location within the limb, regardless of the histological type, and if there are any other influencing variables. A real-world data observational study was developed. The lesions were divided depending on the location of the melanoma (thigh, leg and foot). Bivariate and multivariate analysis were performed, and melanoma-specific survival and disease-free survival rates were calculated. When these analysis were done, the results showed that, in melanomas of the lower limb, location on the foot presented a lower melanoma-specific survival rate compared to more proximal locations, and only the anatomical location presents statistical significance to discriminate cases with a higher mortality risk and a lower disease-free survival rate among distal melanomas (mainly on the foot). In conclusion, this study confirms that a more distal location of lower limb cutaneous melanoma is a relevant prognostic factor.Trial registration number NCT04625491 retrospectively registered.

SARS-CoV-2 infection in patients with melanoma: results of the Spanish Melanoma Group registry

Background The Spanish Melanoma Group (GEM) developed a national registry of patients with melanoma infected by SARS-CoV-2 (“GRAVID”). Methods The main objective was to describe the COVID-19 fatality rate in patients with melanoma throughout the pandemic, as well as to explore the effect of melanoma treatment and tumor stage on the risk of COVID-19 complications. These are the final data of the register, including cases from February 2020 to September 2021. Results One hundred-fifty cases were registered. Median age was 68 years (range 6–95), 61 (40%) patients were females, and 63 (42%) patients had stage IV. Thirty-nine (26%) were on treatment with immunotherapy, and 17 (11%) with BRAF-MEK inhibitors. COVID-19 was resolved in 119 cases, including 85 (57%) patients cured, 15 (10%) that died due to melanoma, and 20 (13%) that died due to COVID-19. Only age over 60 years, cardiovascular disorders, and diabetes mellitus increased the risk of death due to COVID-19, but not advanced melanoma stage nor melanoma systemic therapies. Three waves have been covered by the register: February–May 2020, August–November 2020, and December 2020–April 2021. The first wave had the highest number of registered cases and COVID-19 mortality. Conclusion Tumor stage or melanoma treatments are non-significant prognostic factors for COVID-19 mortality. During the pandemic in Spain there was a downward trend in the number of patients registered across the waves, as well as in the severity of the infection (AU)

Análisis de supervivencia en pacientes con micosis fungoide foliculotropa de un centro latinoamericano / Folliculotropic Mycosis Fungoides in a Latin American Hospital: Survival Analysis

Introducción La micosis fungoide foliculotropa es una variante de mal pronóstico y presentación clínica variada. Se ha planteado que la estadificación TNMB usada para esta neoplasia no es útil. En una propuesta reciente basada en aspectos clínicos e histológicos, se clasifica en enfermedad temprana y avanzada, encontrando diferencias pronósticas entre las 2categorías. El objetivo de este estudio fue comparar la supervivencia de estos 2 grupos en nuestra población. Materiales y métodos Se realizó un estudio observacional retrospectivo de serie de casos donde se evaluó la evolución clínica de los pacientes con micosis fungoide foliculotropa tratados en el Instituto Nacional de Cancerología entre el 2008 y el 2020, realizando un análisis comparativo de supervivencia entre aquellos que tienen enfermedad temprana y enfermedad avanzada. Resultados Se incluyó a un total de 21 pacientes, 11 de los cuales presentaban enfermedad temprana y 10 enfermedad avanzada. Se identificaron 7 decesos, todos ellos en los pacientes con enfermedad avanzada. La supervivencia global de la población total a 5 años fue del 62%, mientras que para la población con enfermedad avanzada fue del 40%. No hubo diferencias en la supervivencia según la estadificación TNMB. Conclusión La estadificación TNMB no es útil para los pacientes con una micosis fungoide foliculotropa. Por el contrario, la nueva clasificación clínico-patológica parece brindar información pronóstica fiable y permite tomar medidas terapéuticas acordes (AU)

Introduction Folliculotropic mycosis fungoides is a variant that has poor prognosis and a variable clinical presentation. Concerns have been expressed that the current TNMB staging of this tumor may not be useful. A recently developed classification system based on clinical and histologic variables classifies this tumor as early or advanced, a distinction found to correlate with prognosis. The aim of this study was to compare survival in FMF in Colombia between patients with early versus advanced tumors. Material and methods Retrospective, observational study of clinical course and outcomes in patients with FMF treated at the National Cancer Institute of Colombia between 2008 and 2020. Survival was compared between early and advanced disease. Results Twenty-one patients (11 with early FMF and 10 with advanced FMF) were studied. Seven patients, all with advanced disease, died. Survival at 5 years was 62% overall and 40% for patients with advanced FMF. No differences were observed when survival was analyzed according to TNMB stage. Conclusions TNMB staging is not useful in FMF. The new classification system based on clinicopathologic features appears to provide reliable information for assessing prognosis and guiding treatment decisions (AU)

[Translated article] Folliculotropic Mycosis Fungoides in a Latin American Hospital: Survival Analysis / Análisis de supervivencia en pacientes con micosis fungoide foliculotropa de un centro latinoamericano

Introduction Folliculotropic mycosis fungoides is a variant that has poor prognosis and a variable clinical presentation. Concerns have been expressed that the current TNMB staging of this tumor may not be useful. A recently developed classification system based on clinical and histologic variables classifies this tumor as early or advanced, a distinction found to correlate with prognosis. The aim of this study was to compare survival in FMF in Colombia between patients with early versus advanced tumors. Material and methods Retrospective, observational study of clinical course and outcomes in patients with FMF treated at the National Cancer Institute of Colombia between 2008 and 2020. Survival was compared between early and advanced disease. Results Twenty-one patients (11 with early FMF and 10 with advanced FMF) were studied. Seven patients, all with advanced disease, died. Survival at 5 years was 62% overall and 40% for patients with advanced FMF. No differences were observed when survival was analyzed according to TNMB stage. Conclusions TNMB staging is not useful in FMF. The new classification system based on clinicopathologic features appears to provide reliable information for assessing prognosis and guiding treatment decisions (AU)

Introducción La micosis fungoide foliculotropa es una variante de mal pronóstico y presentación clínica variada. Se ha planteado que la estadificación TNMB usada para esta neoplasia no es útil. En una propuesta reciente basada en aspectos clínicos e histológicos, se clasifica en enfermedad temprana y avanzada, encontrando diferencias pronósticas entre las 2categorías. El objetivo de este estudio fue comparar la supervivencia de estos 2 grupos en nuestra población. Materiales y métodos Se realizó un estudio observacional retrospectivo de serie de casos donde se evaluó la evolución clínica de los pacientes con micosis fungoide foliculotropa tratados en el Instituto Nacional de Cancerología entre el 2008 y el 2020, realizando un análisis comparativo de supervivencia entre aquellos que tienen enfermedad temprana y enfermedad avanzada. Resultados Se incluyó a un total de 21 pacientes, 11 de los cuales presentaban enfermedad temprana y 10 enfermedad avanzada. Se identificaron 7 decesos, todos ellos en los pacientes con enfermedad avanzada. La supervivencia global de la población total a 5 años fue del 62%, mientras que para la población con enfermedad avanzada fue del 40%. No hubo diferencias en la supervivencia según la estadificación TNMB. Conclusión La estadificación TNMB no es útil para los pacientes con una micosis fungoide foliculotropa. Por el contrario, la nueva clasificación clínico-patológica parece brindar información pronóstica fiable y permite tomar medidas terapéuticas acordes (AU)

Adjuvant nodal field radiation in resected Stage III melanoma: A single-centre retrospective study in Christchurch, New Zealand.

INTRODUCTION: Stage III melanoma is associated with poor outcomes. We studied the characteristics and outcomes of patients with resected Stage III melanoma before the routine use of adjuvant immunotherapy. Some of these patients received adjuvant nodal radiation with modern radiation techniques. METHODS: We retrieved data of patients with resected Stage III melanoma treated in Christchurch over 10 years. Overall survival (OS), melanoma-specific survival (MSS), recurrence-free survival (RFS) and nodal recurrence-free rate (NRFR) were determined, and the association of these outcomes with tumour and treatment factors was investigated. RESULTS: We identified 178 patients (110 male and 68 female), of whom 61 received adjuvant radiation. The median age was 66.6 years, and the median follow-up was 2.7 years. First recurrences occurred in 108 (61%) patients. There were 42 (24%) nodal field relapses and 103 (58%) distant relapses. One-half of nodal relapses in patients treated with adjuvant radiation were infield. The 5-year OS, RFS, MSS and NRFR were 46.4%, 26.8%, 53.7% and 69.6%, respectively. Adjuvant radiation was associated with improved RFS and no OS benefit. T4 disease and extranodal spread were associated with poorer OS, while extranodal spread and >3 involved nodes were associated with worse RFS. CONCLUSION: Patients treated with adjuvant radiation remain at moderate risk of regional and high risk of distant relapse, despite the use of modern radiation techniques. Adjuvant radiation was associated with improved local control but infield recurrence rates remained a problem. The role of combined adjuvant radiation and immunotherapy in improving these outcomes requires further investigation.

The Spectrum of Malignant Neoplasms among Liver Transplant Recipients: Sociodemographic Factors, Mortality, and Hospital Burden.

Objective: To determine the nationwide prevalence of malignant neoplasms (excluding hepatocellular carcinoma-HCC) in hospitalized liver transplant recipients and to study the hospital utilization, and mortality to the incidence of malignancies. To the best of our knowledge, few epidemiological studies addressed outcomes in post-liver transplant patients, such as the annual number of hospitalizations, mortality, patient characteristics regarding malignancies. Methods: NIS database was queried between 2016 and 2018 to retrieve records of patients admitted with a principal or secondary diagnosis of liver transplant following the International Classification of Diseases, tenth Revision (ICD-10). The population was divided into case and control groups according to the presence and absence of malignant neoplasm (MN) except for HCC. We also compared the incidence of MN in LTX patients and non-LTX matched cohort. Results: A total of 7.28% admissions were associated with malignant neoplasms (except HCC) in LTX patients. Lymphomas, respiratory, gastrointestinal (excluding HCC), leukemia, and head/neck were commonest cancers with estimated admission rates of 0.97%, 0.90%, 0.80%, 0.53%, and 0.49%, respectively. Lung cancer was the most frequent malignant neoplasm among White and Black racial/ethnic groups (15.78% and 14.8%), whereas lymphoma was pervasive among Hispanics (20.3%). Lung cancer had the highest in-hospital mortality (10.55%), followed by the cancer of the nervous system (9.09%). The LTX and non-LTX cohort comparison showed that LTX patients are at increased risk of head and neck cancers, skin cancers, lymphomas, tumors, and Myelodysplastic syndrome. According to a multivariate analysis, a statistically significant association existed between malignant neoplasms in LTX patients and the following factors: increasing age (P < .001), higher mortality (P < .001), females with 29% lesser odds than males (P < .001), Black race and Hispanic ethnicity with 20% and 26% lesser odds as compared to White (P < .05). Clinical factors included smoking, Alcoholic cirrhosis, Hepatitis B, and Hepatitis C, were statistically significant risk factors of post-liver transplantation malignancies. Conclusions: Malignancies were frequent among elderly patients and predominantly in males. Lymphoproliferative diseases were the most prevalent malignancy types, followed by respiratory/lung cancer- which showed the highest mortality risk of all cancers. LTX patients are at increased risk of head and neck cancers, skin cancers, lymphoma, tumors, and Myelodysplastic syndrome compared to non-LTX patients.

The clinical significance of adenomatous polyposis coli (APC) and catenin Beta 1 (CTNNB1) genetic aberrations in patients with melanoma.

BACKGROUND: Melanoma-intrinsic activated ß-catenin pathway, the product of the catenin beta 1 (CTNNB1) gene, has been associated with low/absent tumor-infiltrating lymphocytes, accelerated tumor growth, metastases development, and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. Little is known about the association between the adenomatous polyposis coli (APC) and CTNNB1 gene mutations in stage IV melanoma with immunotherapy response and overall survival (OS). METHODS: We examined the prognostic significance of somatic APC/CTNNB1 mutations in the Cancer Genome Atlas Project for Skin Cutaneous Melanoma (TCGA-SKCM) database. We assessed APC/CTNNB1 mutations as predictors of response to immunotherapies in a clinicopathologically annotated metastatic patient cohort from three US melanoma centers. RESULTS: In the TCGA-SKCM patient cohort (n = 434) presence of a somatic APC/CTNNB1 mutation was associated with a worse outcome only in stage IV melanoma (n = 82, median OS of APC/CTNNB1 mutants vs. wild-type was 8.15 vs. 22.8 months; log-rank hazard ratio 4.20, p = 0.011). APC/CTNNB1 mutation did not significantly affect lymphocyte distribution and density. In the 3-melanoma institution cohort, tumor tissues underwent targeted panel sequencing using two standards of care assays. We identified 55 patients with stage IV melanoma and APC/CTNNB1 genetic aberrations (mut) and 169 patients without (wt). At a median follow-up of more than 25 months for both groups, mut compared with wt patients had slightly more frequent (44% vs. 39%) and earlier (66% vs. 45% within six months from original diagnosis of stage IV melanoma) development of brain metastases. Nevertheless, time-to-development of brain metastases was not significantly different between the two groups. Fortunately, mut patients had similar clinical benefits from PD-1 inhibitor-based treatments compared to wt patients (median OS 26.1 months vs. 29.9 months, respectively, log-rank p = 0.23). Less frequent mutations in the NF1, RAC1, and PTEN genes were seen in the mut compared with wt patients from the 3-melanoma institution cohort. Analysis of brain melanoma tumor tissues from a separate craniotomy patient cohort (n = 55) showed that melanoma-specific, activated ß-catenin (i.e., nuclear localization) was infrequent (n = 3, 6%) and not prognostic in established brain metastases. CONCLUSIONS: APC/CTNNB1 mutations are associated with a worse outcome in stage IV melanoma and early brain metastases independent of tumor-infiltrating lymphocyte density. However, PD1 inhibitor-based treatments provide comparable benefits to both mut and wt patients with stage IV melanoma.

Maximizing response to intratumoral immunotherapy in mice by tuning local retention.

Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.

GPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models.

For many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.

Yeast-derived nanoparticles remodel the immunosuppressive microenvironment in tumor and tumor-draining lymph nodes to suppress tumor growth.

Microbe-based cancer immunotherapy has recently emerged as a hot topic for cancer treatment. However, serious limitations remain including infection associated side-effect and unsatisfactory outcomes in clinic trials. Here, we fabricate different sizes of nano-formulations derived from yeast cell wall (YCW NPs) by differential centrifugation. The induction of anticancer immunity of our formulations appears to inversely correlate with their size due to the ability to accumulate in tumor-draining lymph node (TDLN). Moreover, we use a percolation model to explain their distribution behavior toward TDLN. The abundance and functional orientation of each effector component are significantly improved not only in the microenvironment in tumor but also in the TDLN following small size YCW NPs treatment. In combination with programmed death-ligand 1 (PD-L1) blockade, we demonstrate anticancer efficiency in melanoma-challenged mice. We delineate potential strategy to target immunosuppressive microenvironment by microbe-based nanoparticles and highlight the role of size effect in microbe-based immune therapeutics.