Access to systemic treatment of non-melanoma skin cancer in Spain: a survey analysis.

BACKGROUND: Novel and highly effective drugs for non-melanoma skin cancer (NMSC) improve patient outcomes, but their high cost strains healthcare systems. Spain's decentralized public health system, managed by 17 autonomous communities (AaCc), raises concerns about equitable access. METHODS: A cross-sectional survey (July-September 2023) was sent to Spanish Multidisciplinary Melanoma Group (GEM Group) members to assess access to new drugs. FINDINGS: Fifty physicians from 15 Spanish AaCc responded to the survey. Access for drug with approved public reimbursement, Hedgehog inhibitors in basal-cell carcinoma and anti PD-L1 antibody in Merkel carcinoma, was observed in 84% and 86% of centers, respectively. For other EMA-approved treatments, but without reimbursement in Spain access decreased to 78% of centers. Heterogeneity in access was mainly observed intra regions. CONCLUSION: Unequal financial support for drugs for NMSC with creates a patchwork of access across Spanish hospitals, with variations even within the same AaCc.

Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study).

BACKGROUND: Encorafenib plus binimetinib (EB) is a standard of care treatment for advanced BRAFV600-mutant melanoma. We assessed efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response. METHODS: E-BRAIN/GEM1802 was a prospective, multicenter, single arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression.Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%. RESULTS: The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After two months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial PFS and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grade 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%). CONCLUSION: Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.

KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination.

BACKGROUND: KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. METHODS: Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. RESULTS: Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. CONCLUSIONS: We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.

Access to melanoma drugs in Spain: a cross-sectional survey.

BACKGROUND: The development of highly active drugs has improved the survival of melanoma patients, but elevated drug prices place a significant burden on health care systems. In Spain, the public health care system is transferred to the 17 autonomous communities (AACC). The objective of this study is to describe the situation of drug access for melanoma patients in Spain and how this decentralized system is affecting equity. METHODS: From July to September 2023, a cross-sectional survey was sent to members of the Spanish Multidisciplinary Melanoma Group (GEM Group). The questionnaire consulted about the real access to new drugs in each hospital. The responses were collected anonymously and analyzed according to several variables, including the AACC. RESULTS: The survey was answered by 50 physicians in 15 AACC. No major differences on access between AACC were observed for indications that are reimbursed by the Spanish Health Care System (adjuvant immunotherapy for stage IIIC-IIID and resected stage IV melanoma). Important differences in drug access were observed among AACC and among centers within the same AACC, for most of the EMA indications that are not reimbursed (adjuvant immunotherapy for stages IIB-IIC-IIIA-IIIB) or that are not fully reimbursed (ipilimumab plus nivolumab in advanced stage). Homogeneously, access to adjuvant targeted drugs, TIL therapy and T-VEC, is extremely low or non-existing in all AACC. CONCLUSIONS: For most indications that reimbursement is restricted out of the EMA indication, a great diversity on access was found throughout the different hospitals in Spain, including heterogeneity intra-AACC.

HMGB1 Expression Levels Correlate with Response to Immunotherapy in Non-Small Cell Lung Cancer.

Purpose: High-mobility group box 1 protein (HMGB1) is subject to exportin 1 (XPO1)-dependent nuclear export, and it is involved in functions implicated in resistance to immunotherapy. We investigated whether HMGB1 mRNA expression was associated with response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). Patients and Methods: RNA was isolated from pretreatment biopsies of patients with advanced NSCLC treated with ICI. Gene expression analysis of several genes, including HMGB1, was conducted using the NanoString Counter analysis system (PanCancer Immune Profiling Panel). Western blotting analysis and cell viability assays in EGFR and KRAS mutant cell lines were carried out. Evaluation of the antitumoral effect of ICI in combination with XPO1 blocker (selinexor) and trametinib was determined in a murine Lewis lung carcinoma model. Results: HMGB1 mRNA levels in NSCLC patients treated with ICI correlated with progression-free survival (PFS) (median PFS 9.0 versus 18.0 months, P=0.008, hazard ratio=0.30 in high versus low HMGB1). After TNF-α stimulation, HMGB1 accumulates in the cytoplasm of PC9 cells, but this accumulation can be prevented by using selinexor or antiretroviral drugs. Erlotinib or osimertinib with selinexor in EGFR-mutant cells and trametinib plus selinexor in KRAS mutant abolish tumor cell proliferation. Selinexor with a PD-1 inhibitor with or without trametinib abrogates the tumor growth in the murine Lewis lung cancer model. Conclusion: An in-depth exploration of the functions of HMGB1 mRNA and protein is expected to uncover new potential targets and provide a basis for treating metastatic NSCLC in combination with ICI.

Anti-PD-L1 Immunotherapy of Chronic Virus Infection Improves Virus Control without Augmenting Tissue Damage by Fibrosis.

Immunotherapy with checkpoint inhibitors, albeit commonly used against tumors, is still at its infancy against chronic virus infections. It relies on the reinvigoration of exhausted T lymphocytes to eliminate virus-infected cells. Since T cell exhaustion is a physiological process to reduce immunopathology, the reinvigoration of these cells might be associated with an augmentation of pathological changes. To test this possibility, we here analyzed in the model system of chronic lymphocytic choriomeningitis virus (LCMV)-infected mice whether treatment with the checkpoint inhibitor anti-PD-L1 antibody would increase CD8 T cell-dependent fibrosis. We show that pre-existing spleen fibrosis did not worsen under conditions that increase CD8 T cell functionality and reduce virus loads suggesting that the CD8 T cell functionality increase remained below its pathogenicity threshold. These promising findings should further encourage immunotherapeutic trials against chronic virus infections.

Converging and evolving immuno-genomic routes toward immune escape in breast cancer.

The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions.

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)

Respuesta patológica a la quimioterapia neoadyuvante: correlación entre 2 sistemas de gradación histológica / Pathologic response to neoadjuvant chemotherapy: Correlation between 2 histologic grading systems

Objetivo. Determinar la variabilidad entre 2 sistemas de gradación a la hora de catalogar la respuesta patológica a la quimioterapia neoadyuvante en una misma lesión. Material y métodos. En 8 años se han estudiado 51 pacientes con cáncer infiltrante de la mama sometidas a quimioterapia neoadyuvante de forma consecutiva. Se ha establecido la respuesta patológica de cada caso siguiendo el sistema de Miller y Payne (MyP) y el de la carga tumoral residual (RCB) correlacionando los resultados de ambos sistemas en la misma lesión. Resultados. Según el sistema de gradación de MyP las lesiones se clasificaron en grado 1 (6%), 2 (25%), 3 (27%), 4 (27%) y 5 (14%). La clase RCB fue 0 (13%), I (13%), II (54%) y III (20%). La correlación entre MyP 5 y RCB 0, entre MyP 4 y RCB I, y entre MyP 2 y RCB III fue buena. Se detectaron más discrepancias entre MyP 1, 2, 3 y RCB II. Conclusión. La correlación en la respuesta completa es buena entre los 2 sistemas de gradación. Hay discrepancias en la clasificación en la ausencia de respuesta entre ambos sistemas. Estas discrepancias pueden ser debidas a la inclusión del estado ganglionar en el sistema RCB(AU)

Objective. To determine the variability between 2 grading systems in the classification of pathologic response to neoadjuvant chemotherapy in the same lesion. Material and methods. Fifty-one patients with invasive breast cancer were consecutively treated with neoadjuvant chemotherapy in an 8-year period. Pathologic response in each patient was established according to the Miller and Payne (MP) and the residual cancer burden (RCB) systems and the results were correlated. Results. In the MP system, the lesions were classified in grade 1 (6%), 2 (25%), 3 (27%), 4 (27%) and 5 (14%). RCB class was 0 (13%), I (13%), II (54%) and III (20%). The correlation between MP 5 and RCB 0, between MP 4 and RCB I, and between MP 2 and RCB III was good. There were more discrepancies between MP 1, 2, 3 and RCB II. Conclusions. The correlation between the 2 grading systems is good. There are discrepancies in the assessment of lack of response between the 2 systems. This disagreement could be due to the inclusion of lymph node status in the RCB system(AU)

Quimioterapia neoadyuvante en cáncer de mama precoz / Neoadjuvant chemotherapy in early-stage breast cancer

Objetivos. La quimioterapia neoadyuvante (QNA) es el tratamiento de elección en las pacientes con cáncer de mama localmente avanzado. El objetivo de este estudio es evaluar la utilidad de QNA en tumores pequeños pero con factores pronósticos desfavorables. Material y métodos. Se compara la respuesta a la QNA en pacientes con tamaño tumoral T3-T4 frente a T1c-T2. Desde enero de 2000 a enero de 2011, 110 pacientes han recibido QNA. Se han revisado los datos demográficos, el tamaño tumoral, los factores pronósticos, la respuesta radiológica y anatomopatológica a la QNA, según la clasificación de Miller y Payne (MP), y la supervivencia en ambos grupos. Resultados. Se revisaron 76 casos en el grupo T1c-T2 y 34 en el T3-T4. En el grupo T3-T4 se observó en mayor porcentaje tumores con factores pronósticos desfavorables (afectación ganglionar, receptores hormonales negativos y Her2Neu positivo). En el grupo T1c-T2, 23 casos (30,3%) recibieron antraciclinas y 53 (69,7%) antraciclinas y taxanos, mientras que en el grupo T3-T4, 10 (29,4%) y 24 (70,6%) casos recibieron dichas pautas, respectivamente. En el grupo T1c-T2 se observó en mayor porcentaje el subtipo tumoral receptores hormonales positivos frente a tumores Her2Neu positivos en los T3-T4. En relación con la respuesta a la QNA no se observaron diferencias estadísticamente significativas en la valoración radiológica o anatomopatológica, 38 pacientes (50%) T1c-T2 presentaron MP 4/5 frente a 16 (47,1%) en T3-T4. Conclusiones. En las pacientes con cáncer de mama precoz existe la misma respuesta anatomopatológica a la QNA que en el grupo T3-T4. En nuestro estudio, el único factor independiente asociado a la respuesta patológica tumoral es el subtipo tumoral, presentando los tumores Her2Neu positivos mejor respuesta(AU)

Aims. In locally advanced breast tumors, neoadjuvant chemotherapy (NC) is the standard treatment. The aim of this study was to analyze the utility of NC in small tumors with unfavorable prognostic factors. Material and methods. We compared the response to NC in patients with T3-T4 tumors versus those with T1c-T2 tumors. From January 2000 to January 2011, 110 patients received NC. Demographic data, tumor size, prognostic factors, radiological and histopathological response according to the Miller-Payne classification and survival were reviewed. Results. We reviewed 76 patients in the T1c-T2 group and 34 in the T3-T4 groups. Tumors with poorer prognostic factors (negative hormone receptors, positive Her2Neu and metastatic nodal involvement) were observed in the T3-T4 group. In the T1c-T2 group, 23 patients (30.3%) received anthracyclines and 53 (69.7%) received anthracyclines plus taxanes. In the T3-T4 group, 10 (29.4%) and 24 (70.6%) patients received these chemotherapy regimens respectively. A higher percentage of the hormone receptor-positive tumor subtype was observed in the T1c-T2 group compared with Her2Neu-positive tumors in the T3-T4 group. No statistically significant differences in radiologic or histopathologic assessment were found: Miller-Payne grades 4/5 were found in 38 patients (50%) in the T1c-T2 group versus 16 (47.1%) in the T3-T4 group. Conclusions. Pathologic response to NC is the same in early-stage tumors as in locally-advanced breast cancer. In this study, the only independent factor associated with pathological tumor response was the tumor subtype, with the greatest response being found in Her2Neu-positive tumors(AU)

Ileal carcinoid tumor with liver metastases and cardiac involvement treated with intraarterial liposomal doxorubicin and valve replacement

Unless carcinoid are in general slow-growing tumors,some cases could be frankly malignant. Thecommonest cause of death in patients suffering acarcinoid tumor is liver failure due to tumor progression.When tumors have a fast evolution a multidisciplinaryapproach must be perform. This casereport is an example of this specific situation

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Biochemotherapy with low doses of subcutaneous interleukin-2 in patients with melanoma: results of a phase II trial

Introduction. Metastatic melanoma has an ominous prognosis. Bio-chemotherapy regimens can increase the response rate but with a high degree of toxicity due, mainly, to the use of high-dose intravenous interleukin-2. Objectives. To test the feasibility and activity profile of a bio-chemotherapy regimen of low-dose subcutaneous interleukin-2. Material and methods. Administration scheme: dacarbazine at 200 mg/m²/d on days 1-4, cisplatin at 20 mg/m²/d intravenous on days 1-4, vinblastine at 1.5 mg/m²/d on days 1-4, IL-2 at 4.5 MUI/m²/d subcutaneous on days 5-8, IFN-alpha at 5 MU subcutaneous on days 5-9, 11, 13, 15 of every 21-day cycle. Results. Objective response was obtained in 11 patients (39.3%; 95%CI: 21-59) including 4 with complete response (14.3%; 95%CI: 4-33). With an extended follow-up of 49 months and 60 months, respectively, 2 patients continue with complete response. The main toxicities were haematological: grade 3-4 neutropenia in 8.2% of cycles, thrombocytopenia in 1.2% and anaemia in 3.2%. Conclusions. The regimen is safe and has a good activity profile. The presence of long-term survivors, despite the use of lower doses and subcutaneous IL-2, is encouraging