CSDE1 Intracellular Distribution as a Biomarker of Melanoma Prognosis

RNA-binding protein; Biomarker; MelanomaProteína de unión a ARN; Biomarcador; MelanomaProteïna d'unió a l'ARN; Biomarcador; MelanomaRNA-binding proteins are emerging as critical modulators of oncogenic cell transformation, malignancy and therapy resistance. We have previously found that the RNA-binding protein Cold Shock Domain containing protein E1 (CSDE1) promotes invasion and metastasis of melanoma, the deadliest form of skin cancer and also a highly heterogeneous disease in need of predictive biomarkers and druggable targets. Here, we design a monoclonal antibody useful for IHC in the clinical setting and use it to evaluate the prognosis potential of CSDE1 in an exploratory cohort of 149 whole tissue sections including benign nevi and primary tumors and metastasis from melanoma patients. Contrary to expectations for an oncoprotein, we observed a global decrease in CSDE1 levels with increasing malignancy. However, the CSDE1 cytoplasmic/nuclear ratio exhibited a positive correlation with adverse clinical features of primary tumors and emerged as a robust indicator of progression free survival in cutaneous melanoma, highlighting the potential of CSDE1 as a biomarker of prognosis. Our findings provide a novel feature for prognosis assessment and highlight the intricacies of RNA-binding protein dynamics in cancer progression.A.I. and P.E. were supported by PhD4MD fellowships from the CRG and the Emerald program (Marie Skłodowska-Curie grant agreement 101034290), respectively. This work was supported by the following grants to F.G.: PGC2018-099697-B-I00 and PID2021-127948NB-I00 from the Spanish Ministry of Science and Innovation (MCIN) funded by MCIN/ AEI /10.13039/501100011033/ and by ERDF; “la Caixa” Foundation (ID 100010434) under the Grant LCF/PR/HR17/52150016; the Catalan Agency for Research and Universities (SGR-Cat-2021-01215) and intramural funds from the CRG on emergent translational research. We acknowledge the support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI /10.13039/501100011033) and the Generalitat de Catalunya through the CERCA programme

Nivolumab-Induced Bullous Pemphigoid Managed without Drug Withdrawal

The widespread use of anti-programmed cell death receptor-1 (PD-1) agents has shed light to unusual immune-related adverse effects, especially affecting the skin. We report a case of bullous pemphigoid secondary to nivolumab therapy for metastatic renal carcinoma with a previously unreported complete response to clobetasol ointment alone. The autoimmune blistering disease was successfully treated without oral corticosteroids, and the anti-PD-1 agent could be maintained without recurrence of the skin lesions. Topical therapy remains a good option in selected, mild-to-moderate cases of induced bullous pemphigoid

Sentinel lymph node biopsy vs. Observation in thin melanoma: A multicenter propensity score matching study

The therapeutic value of sentinel lymph node biopsy (SLNB) in thin melanoma remains controversial. The aim of this study is to determine the role of SLNB in the survival of thin melanomas (≤1 mm). A multicenter retrospective observational study was designed. A propensity score matching was performed to compare patients who underwent SLNB vs. observation. A multivariate Cox regression was used. A total of 1438 patients were matched by propensity score. There were no significant differences in melanoma-specific survival (MSS) between the SLNB and observation groups. Predictors of MSS in the multivariate model were age, tumor thickness, ulceration, and interferon treatment. Results were similar for disease-free survival and overall survival. The 5- and 10-year MSS rates for SLN-negative and -positive patients were 98.5% vs. 77.3% (p < 0.001) and 97.3% vs. 68.7% (p < 0.001), respectively. SLNB does not improve MSS in patients with thin melanoma. It also had no impact on DSF or OS. However, a considerable difference in MSS, DFS, and OS between SLN-positive and -negative patients exists, confirming its value as a prognostic procedure and therefore we recommend discussing the option of SLNB with patients

Targeted therapy or immunotherapy in BRAF-mutated metastatic melanoma: a Spanish center’s decade of experience

BackgroundTargeted therapies and immunotherapy are currently considered the mainstay first-line treatment for advanced BRAF-mutated melanoma. However, the impact of treatment (targeted therapy and immunotherapy) and the prognostic factors are still not clear.Material and methodsMedical records of 140 patients diagnosed with advanced melanoma between 2011 and 2021 were retrospectively reviewed to extract demographic, BRAF status, treatment, performance status, and survival data. ORR, PFS, and OS were compared between patients diagnosed with advanced melanoma and treated with first-line IT or BRAF/MEKi. The prognostic factors were assessed using Cox regression models.ResultsIn all patients and those treated with immunotherapy, we did not find any effect of BRAF status on ORR, PFS, or OS. In patients with BRAF-mutated melanoma, ORR was 43.8% vs. 70% (P=0.04), PFS was 19.2 vs. 11.5 months (p=0.22), and OS was 33.4 vs. 16.4 months for the immunotherapy and targeted therapy groups, respectively (P=0.04). ECOG, presence of brain metastases, and high LDH level from initiation of first-line treatment were all associated with differences in PFS and OS.ConclusionPatients with advanced BRAF-mutated melanoma treated with first-line immunotherapy had a significantly longer PFS and OS than those treated with first-line BRAF/MEKi; however, first-line BRAF/MEKi treatment had a significantly higher ORR than first-line immunotherapy

Enhancement of Antiviral CD8 + T-Cell Responses and Complete Remission of Metastatic Melanoma in an HIV-1-Infected Subject Treated with Pembrolizumab

Background: Pembrolizumab is an immune checkpoint inhibitor against programmed cell death protein-1 (PD-1) approved for therapy in metastatic melanoma. PD-1 expression is associated with a diminished functionality in HIV-1 specific-CD8 + T cells. It is thought that PD-1 blockade could contribute to reinvigorate antiviral immunity and reduce the HIV-1 reservoir. Methods: Upon metastatic melanoma diagnosis, an HIV-1-infected individual on stable suppressive antiretroviral regimen was treated with pembrolizumab. A PET-CT was performed before and one year after pembrolizumab initiation. We monitored changes in the immunophenotype and HIV-1 specific-CD8 + T-cell responses during 36 weeks of treatment. Furthermore, we assessed changes in the viral reservoir by total HIV-1 DNA, cell-associated HIV-1 RNA, and ultrasensitive plasma viral load. Results: Complete metabolic response was achieved after pembrolizumab treatment of metastatic melanoma. Activated CD8 + T-cells expressing HLA-DR + /CD38 + transiently increased over the first nine weeks of treatment. Concomitantly, there was an augmented response of HIV-1 specific-CD8 + T cells with TNF production and poly-functionality, transitioning from TNF to an IL-2 profile. Furthermore, a transient reduction of 24% and 32% in total HIV-1 DNA was observed at weeks 3 and 27, respectively, without changes in other markers of viral persistence. Conclusions: These data demonstrate that pembrolizumab may enhance the HIV-1 specific-CD8 + T-cell response, marginally affecting the HIV-1 reservoir. A transient increase of CD8 + T-cell activation, TNF production, and poly-functionality resulted from PD-1 blockade. However, the lack of sustained changes in the viral reservoir suggests that viral reactivation is needed concomitantly with HIV-1-specific immune enhancement

Spaghetti Technique Versus Wide Local Excision for Lentigo Maligna Affecting the Head and Neck Regions: Surgical Outcome and Descriptive Analysis of 79 Cases From a Single Practice Cohort

Introduction: Lentigo maligna is a subtype of melanoma in situ that typically affects the head and neck region with an increasing incidence. Margin-controlled techniques, such as spaghetti technique (ST), have gained popularity over wide local excision (WLE) with a margin of 5 mm. Objectives: To evaluate the outcomes of lentigo maligna cases in the head and neck area treated by either WLE or ST in a tertiary referral hospital. The secondary goal was to describe the demographic and clinical characteristics of our series. Methods: Cohort study of patients diagnosed with lentigo maligna on the head and neck region between January 2014 and February 2022 in a tertiary hospital. Results: In total, 79 lentigo maligna were studied, corresponding to 77 patients. Fifty-three lesions (67%) were treated with WLE and 26 (33%) with ST. The mean age of the patients was 73 years and 58% were men. Most of the tumors were located on the cheek (50%) and mean lesion diameter was 2.2 cm for the ST group and 1.2 cm for the WLE group. Mean duration follow-up was 44 months. There were two local recurrences in the WLE group (2/53; 3.7%) and none in the ST group. Conclusions: Both WLE and ST are appropriate surgical approaches for lentigo maligna. ST offers an efficient alternative to Mohs surgery for treating lentigo maligna in the head and neck area, especially when guided by reflectance confocal microscopy

Contribuciones al manejo del melanoma mediante la biopsia selectiva del ganglio centinela

El valor clínic de la biòpsia selectiva del gangli sentinella (BSGS) en pacients amb melanoma gruixut (Breslow > 4 mm) no ha estat prou estudiada. L'objectiu principal d'quest treball és avaluar si la BSGS augmenta la supervivència en pacients amb melanoma gruixut i com a objectiu secundari, investigar la relació entre la supervivència i l'estat del gangli sentinella (GS). Altres objectius secundaris són identificar quines variables estan associades amb l'afectació de l'GS i analitzar el paper de la dissecció completa dels ganglis limfàtics en pacients amb una BSGS positiva. Es van incloure pacients amb melanomes gruixuts (> 4 mm) registrats en les bases de dades de melanoma dels hospitals participants entre 1997 i 2015. Els pacients van ser aparellats pel mètode de la puntuació de propensió segons el sexe, l'edat, la localització del tumor primari, les característiques histològiques del melanoma, l'any de diagnòstic, l'hospital i la realització de teràpia adjuvant amb interferó. Per identificar els factors associats amb l'afectació del GS, vam realitzar un estudi de cohorts retrospectiu multicèntric que va incloure a tots els pacients amb melanoma gruixut que s'havien sotmès a la BSGS. Per analitzar el paper de la limfadenectomia selectiva (LS) en pacients amb melanoma gruixut i una BSGS positiva, vàrem crear un model multivariat de riscos proporcionals de Cox per a la supervivència específica del melanoma (SEM) i la supervivència lliure de malaltia (SLM) i compararem els pacients que havien rebut LS i els que no. La BSGS enfront de l'observació es va associar amb una millor SLM (raó de risc ajustada [AHR], 0,74; interval de confiança [IC] de el 95%: 0,61-0,90); p = 0.002) i supervivència global (AHR, 0.75; IC 95%, 0,60-0,94; p = 0.013) però no SEM (AHR, 0.84; IC 95%, 0.65-1.08; p = 0,165). Els pacients amb BSGS negativa van tenir una millor SEM als 5 i 10 anys en comparació amb els pacients amb una BSGS positiva (65.4% vs 51.9% i 48.3% vs 38.8%; p = 0.01, respectivament). L'anàlisi de regressió logística va mostrar que l'edat, el subtipus histològic, la ulceració, les satelitosis microscòpiques i la invasió limfovascular es van associar amb l'afectació ganglionar. L'arbre de decisió CHAID (detecció automàtica d'interaccions mitjançant chi-quadrat) va mostrar que la ulceració és el predictor més important deafectació de l'GS. Per als melanomes no ulcerats, els subtipus histològics de melanoma lentigen maligne i altres subtipus poc freqüents es van associar amb una baixa taxa d'afectació de GS (4,3%). No es van observar diferències significatives per SLM i SEM entre els grups als quals s'havia realitzat LS i els que no. L'estat dels ganglis no sentinella en la LS es va associar amb diferències en les taxes de SLM i SEM. En conclusió, la biòpsia SLN es va associar a una millor SLM però no a una millor SEM, en pacients amb melanoma gruixut després de l'ajust per factors pronòstics clàssics. La BSGS és útil per estratificar aquests pacients en diferents grups de risc. Hi ha subgrups de pacients amb melanoma gruixut i una baixa probabilitat d'afectació de l'GS. La LS no ofereix beneficis de supervivència, però proporciona informació pronòstica.El valor clínico de la biopsia selectiva del ganglio linfático centinela (BSGC) en pacientes con melanoma grueso (Breslow> 4 mm) no ha sido suficientemente estudiada. El objetivo principal del trabajo es evaluar si la biopsia BSGC aumenta la supervivencia en pacientes con melanoma grueso y como objetivo secundario, investigar la relación entre la supervivencia y el estado del ganglio centinela (GC). Otros objetivos secundarios son identificar qué variables están asociadas con la afectación del GC y analizar el papel de la disección completa de ganglios linfáticos en pacientes con una BSGC positiva. Se incluyeron pacientes con melanomas gruesos (> 4 mm) registrados en las bases de datos de melanoma de los hospitales participantes entre 1997 y 2015. Los pacientes fueron emparejados por el método de la puntuación de propensión según el sexo, la edad, la localización del tumor primario, las características histológicas del melanoma, el año de diagnóstico, el hospital y la realización de terapia adyuvante con interferón. Para identificar los factores asociados con la afectación del GC, realizamos un estudio de cohorte retrospectivo multicéntrico que incluyó a todos los pacientes con melanoma grueso que se habían sometido a la BSGC. Para analizar el papel de la linfadenectomía selectiva (LS) en pacientes con melanoma grueso y una BSGC positiva, creamos un modelo multivariado de riesgos proporcionales de Cox para la supervivencia específica del melanoma (SEM) y la supervivencia libre de enfermedad (SLE) y comparamos a los pacientes que habían recibido LS y los que no. La BSGC frente a la observación se asoció con una mejor SLE (razón de riesgo ajustada [AHR], 0,74; intervalo de confianza [IC] del 95%: 0,61-0,90); p = 0.002) y supervivencia global (AHR, 0.75; IC 95%, 0.60-0.94; p = 0.013) pero no SEM (AHR, 0.84; IC 95%, 0.65-1.08; p = 0.165). Los pacientes con BSGC negativa tuvieron una mejor SEM de 5 y 10 años en comparación con los pacientes con BSGC positiva (65.4% vs. 51.9% y 48.3% vs 38.8%; p = 0.01, respectivamente). El análisis de regresión logística mostró que la edad, el subtipo histológico, la ulceración, la satelitosis microscópica y la invasión linfovascular se asociaron con la enfermedad ganglionar. El árbol de decisión CHAID (detección automática de interacciones mediante chi-cuadrado) mostró que la ulceración es el predictor más importante de afectación del GC. Para los melanomas no ulcerados, los subtipos histológicos de melanoma lentigo maligno y otros subtipos poco frecuentes se asociaron con una baja tasa de afectación de GC (4,3%). No se observaron diferencias significativas para SLE y SEM entre los grupos a los que se había realizado LS y los que no. El estado de los ganglios no centinela en la LS se asoció con diferencias en las tasas de SLE y SEM. En conclusión, la biopsia SLN se asoció con una mejor SLE pero no con una mejor SEM en pacientes con melanoma grueso después del ajuste por factores pronósticos clásicos. La BSGC es útil para estratificar a estos pacientes en diferentes grupos de pronóstico. Existen subgrupos de pacientes con melanoma grueso con una baja probabilidad de afectación del GC. La LS no ofrece beneficios de supervivencia, pero proporciona información pronóstica.The clinical value of sentinel lymph node (SLN) biopsy in thick melanoma patients (Breslow >4 mm) has not been sufficiently studied. The main aim of the study is to evaluate whether SLN biopsy increases survival in patients with thick cutaneous melanoma, and, as a secondary objective, to investigate correlations between survival and lymph node status. Other secondary objectives include the identification of variables associated with SLN involvement and analyze the role of complete lymph node dissection in patients with a positive SLN biopsy. Patients with thick melanomas (>4 mm) registered in the participating hospitals&#8217; melanoma databases between 1997 and 2015 were included. Patients were matchedinto pairs by propensity scores based on sex, age, tumor location, histologic features of melanoma, year of diagnosis, hospital, and adjuvant interferon therapy. To identify factors associated with SLN involvement in thick melanoma we performed a multicentric retrospective cohort study involving all patients with thick melanoma who had undergone SLN biopsy. To analyze the role of complete lymph node dissection (CLND) in thick melanoma patients with a positive SLN biopsy, we built a multivariate Cox proportional hazards model for melanoma-specific survival (MSS) and diseasefree survival (DFS) and compared patients who had undergone CLND with who had not. The SLN biopsy vs. observation was associated with better DFS (adjusted hazard ratio [AHR], 0.74; 95% confidence interval [CI] 0.61-0.90); p = 0.002) and OS (AHR, 0.75; 95% CI, 0.60-0.94; p = .013) but not MSS (AHR, 0.84; 95% CI, 0.65-1.08; p = 0.165). SLN-negative patients had better 5- and 10-year MSS compared to SLN-positive patients (65.4% vs. 51.9% and 48.3% vs 38.8%; p = 0.01, respectively). The logistic regression analysis showed that age, histologic subtype, ulceration, microscopic satellitosis, and lymphovascular invasion were associated with nodal disease. The CHAID (Chi-squared Automatic Interaction Detection) decision tree showed ulceration to be the most important predictor of lymphatic involvement. For nonulcerated melanomas, lentigo maligna melanoma and other rare histologic subtypes were associated with a low rate of SLN involvement (4.3%). No significant differences were observed for DFS and MSS between the CLND performed and not-performed groups. Nodal status on CLND was associated with differences in DFS and MSS rates. In conclusion, SLN biopsy was associated with better DFS but not MSS in thick melanoma patients after adjustment for classic prognostic factors. SLN biopsy is useful for stratifying these patients into different prognostic groups. We also identified subgroups of thick melanoma patients with a low likelihood of SLN involvement. CLND does not offer survival benefit, but provides prognostic information.Universitat Autònoma de Barcelona. Programa de Doctorat en Medicin

Mycophenolate mofetil-induced mouth ulcers in a kidney transplant patient: Case report and literature review

Mouth ulcers are a cutaneous complication that can often affect kidney transplant patients, mostly due to the effect of immunosuppressive treatment.Even so, before asserting that said complication is indeed secondary to drugs, it is very important to establish a differential diagnosis with other mouth ulcer causes, such as systemic diseases or viral infections, which are also common in these patients. Resumen: Las úlceras orales son una de las complicaciones cutáneas que pueden afectar con frecuencia a los pacientes trasplantados renales, debido muchas veces al efecto del tratamiento inmunosupresor.Aun así, es importante, antes de asegurar que dicha complicación es secundaria a los fármacos, establecer el diagnóstico diferencial con otras causas de úlceras orales como pueden ser enfermedades sistémicas o infecciones virales, también frecuentes en este tipo de pacientes. Keywords: Kidney transplant, Mycophenolate mofetil, Mouth ulcers, Cytomegalovirus, Palabras clave: Trasplante renal, Micofenolato mofetilo, Úlceras orales, Citomegaloviru