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BackgroundMeaning-Centered Psychotherapy (MCP) is effective in improving meaning in life, hope, optimism, self-efficacy, well-being, and quality of life, and in reducing stress in people with cancer. However, all the studies on the application of MCP in cancer patients have been carried out in Anglo-Saxon samples. Therefore, it is necessary to adapt and verify the efficacy of MCP in populations that speak languages other than English, such as Spanish. Moreover, to expand the data supporting the efficacy of MCP for cancer patients, it would be necessary to compare MCP to other active therapies such as Cognitive Behavioral Therapy (CBT).MethodsThe aims of the proposed study are: the first objective is to verify the efficacy of the MCP intervention for Spanish participants with cancer in a randomized control trial (RCT) comparing it to CBT. The second objective is to analyze the feasibility and acceptance of MCP in Spanish participants with cancer. The third objective is to analyze whether the changes produced in the meaning in life dimensions (presence, search, comprehension, purpose, and mattering) will predict changes in anxiety, depression, quality of life, etc. Our research team adapted MCP for Spanish participants with cancer. This paper presents the study protocol. The study design consists of a two-arm RCT with two conditions: MCP and CBT, where participants will be randomized to one of the two groups. Eligible participants will be adults with stage I, II, and III cancer who were treated with curative intent and had completed their main medical treatment (surgery, radiotherapy, or chemotherapy). Participants will be assessed at pretreatment, post-treatment, and 6-month follow-up. The intention-to-treat principle will be used when analyzing data, using mixed-effects models with full information and maximum likelihood estimation.DiscussionThis study will provide results that confirm the efficacy of the MCP in Spanish participants with cancer.Trial RegistrationClinicalTrials.gov; https://register.clinicaltrials.gov/prs/app/template/Home.vm?uid=U0005WS9&ts=4&sid=S000BOTT&cx=bvr2ue, identifier NCT05197348

Resumen: El manejo del carcinoma de células escamosas cutáneo (cSCC) avanzado es complicado, siendo modesta la eficacia de muchos de los fármacos sistémicos disponibles. Cemiplimab ha demostrado su eficacia en el tratamiento del cSCC avanzado en ensayos clínicos, pero los datos del mundo real siguen siendo limitados. Con el objetivo de evaluar la eficacia de cemiplimab en un entorno clínico del mundo real, realizamos un estudio observacional prospectivo de 13 pacientes con cSCC avanzado. Seis pacientes (46%) tenían enfermedad localmente avanzada, mientras que 7 (54%) tenían enfermedad metastásica. Un total de 8 pacientes (62%) respondieron a cemiplimab, 5 (38%) mostraron una respuesta parcial y 3 (23%) mostraron una respuesta completa. Cuatro pacientes con respuesta parcial inicial presentaron una progresión de la enfermedad subsiguiente durante el seguimiento. Seis pacientes (46%) desarrollaron efectos secundarios, siendo leves la mayoría de los mismos (G1). La supervivencia libre de progresión fue de 5,9 meses, con un seguimiento medio de 9 meses. En conclusión, cemiplimab demostró su utilidad en el tratamiento del cSCC avanzado, con unas tasas de respuesta aceptables, un número destacable de respuestas completas y un perfil de seguridad muy bueno. Abstract: Management of advanced cSCC is challenging, and many available systemic medications have modest efficacy. Cemiplimab has demonstrated efficacy in the treatment of advanced cSCC in clinical trials, but real-world data are still limited. With the objective of evaluating the efficacy of cemiplimab in a real-world clinical setting, we conducted a prospective observational study of 13 patients with advanced cSCC. Six patients (46%) had locally advanced disease, while 7 (54%) had metastatic disease. A total of 8 patients (62%) responded to cemiplimab. Five (38%) showed a partial response, while 3 (23%) showed a complete response. Four patients with an initial partial response presented subsequent disease progression during follow-up. Six patients (46%) developed AEs, most of which were mild (G1). PFS was 5.9 months, with a median follow-up was 9 months. In conclusion, cemiplimab demonstrated its utility in the treatment of advanced cSCC, with acceptable response rates, a remarkable number of complete responses, and a very good safety profile.

Resumen: Sonidegib es un inhibidor del receptor transmembrana Smoothened (SMO), de la vía de señalización de Hedgehog, indicado para el tratamiento del carcinoma basocelular localmente avanzado (CBCla), no susceptible a cirugía curativa ni a radioterapia. Sonidegib ha demostrado su eficacia y seguridad en pacientes con CBCla en el ensayo de fase II (BOLT), donde el 61% (IC 95%: 48; 72) de los pacientes tratados con 200 mg de sonidegib tuvo una respuesta objetiva al tratamiento, con un tiempo medio hasta la respuesta de cuatro meses. La mediana de duración de respuesta fue de 26,1 meses y la mediana de supervivencia libre de progresión fue de 22,1 meses. Los eventos adversos más frecuentes fueron los espasmos musculares (54,4%), alopecia (49,4%) y disgeusia (44,3%), siendo principalmente de grado 1 y 2. Esta revisión proporciona un resumen sobre la eficacia, seguridad y tolerabilidad de sonidegib, así como consideraciones sobre su uso en el manejo de pacientes con CBCla. Abstract: Sonidegib is an antagonist of the transmembrane protein Smoothened in the Hedgehog signaling pathway. It is indicated for the treatment of locally advanced basal cell carcinoma (BCC) that is not amenable to curative surgery or radiotherapy. Sonidegib's efficacy and safety were demonstrated in the phase 2 BOLT trial, where 61% (95% CI, 48-72%) of patients with locally advanced BCC treated with sonidegib 200 mg achieved an objective response to treatment with a mean time to response of 4 months. The median duration of response was 26.1 months and the median progression-free survival was 22.1 months. The most common adverse events were muscle spasms (54.4%), hair loss (49.4%), and loss of taste (44.3%); most events were grade 1 or 2. In this review, we summarize the main findings on the efficacy, safety, and tolerability of sonidegib and discuss the management of locally advanced BCC with this drug.

Abstract Despite their recognised role in HER2-positive (HER2+) breast cancer (BC), the composition, localisation and functional orientation of immune cells within tumour microenvironment, as well as its dynamics during anti-HER2 treatment, is largely unknown. We here investigate changes in tumour-immune contexture, as assessed by stromal tumour-infiltrating lymphocytes (sTILs) and by multiplexed spatial cellular phenotyping, during treatment with lapatinib-trastuzumab in HER2+ BC patients (PAMELA trial). Moreover, we evaluate the relationship of tumour-immune contexture with hormone receptor status, intrinsic subtype and immune-related gene expression. sTIL levels increase after 2 weeks of HER2 blockade in HR-negative disease and HER2-enriched subtype. This is linked to a concomitant increase in cell density of all four immune subpopulations (CD3+, CD4+, CD8+, Foxp3+). Moreover, immune contexture analysis showed that immune cells spatially interacting with tumour cells have the strongest association with response to anti-HER2 treatment. Subsequently, sTILs consistently decrease at the surgery in patients achieving pathologic complete response, whereas most residual tumours at surgery remain inflamed, possibly reflecting a progressive loss of function of T cells. Understanding the features of the resulting tumour immunosuppressive microenvironment has crucial implications for the design of new strategies to de-escalate or escalate systemic therapy in early-stage HER2+ BC.

Intimal sarcomas (IS) are rare malignant mesenchymal tumors arising in large blood vessels of the systemic and pulmonary circulation and also in the heart. They are morphologically similar to other spindle cell, poorly differentiated sarcomas. The prognosis is poor and depends mainly on surgical options. Three cases of IS were collected from two institutions. Clinical data were retrieved and histological study was performed. A wide immunohistochemical panel was analyzed. FISH of MDM2 gene was performed, and a molecular study with NGS was implemented in all cases. The mean age of our cases was 54 years. Histologically, the tumors presented a diffuse growth pattern with heterogeneous atypical epithelioid or spindle cells and extensive thrombosed areas. All cases presented intense immunoexpression for MDM2, CDK4, CD117, c-myc, PDGFRA, and p16. PDGFRA, HTERT, and pan-TRK gained expression, while p16 lost intensity, being weaker in both the local recurrences and xenografts. The three cases showed amplification of MDM2 by FISH. NGS analysis revealed amplifications in the CDK4, PDGFRA, and KIT genes, together with BRAF mutation and KRAS amplification. P16 was expressed in all cases, losing intensity in local recurrence and xenografts. Two new alterations, a BRAF mutation and a KRAS amplification, were detected by NGS in different tumors, opening up new therapeutic options for these patients.

Background: The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [18Fluorine]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) and a pathological complete response-adapted strategy in HER2-positive (HER2+) early breast cancer (EBC). Herein, we present RESPONSE, a PHERGain substudy, where clinicopathological and molecular predictors of [18F]FDG-PET disease detection were evaluated. Methods: A total of 500 patients with HER2 + EBC screened in the PHERGain trial with a tumor size > 1.5 cm by magnetic resonance imaging (MRI) were included in the RESPONSE substudy. PET[−] criteria entailed the absence of ≥ 1 breast lesion with maximum standardized uptake value (SUVmax) ≥ 1.5 × SUVmean liver + 2 standard deviation. Among 75 PET[−] patients screened, 21 with SUVmax levels < 2.5 were randomly selected and matched with 21 PET[+] patients with SUVmax levels ≥ 2.5 based on patient characteristics associated with [18F]FDG-PET status. The association between baseline SUVmax and [18F]FDG-PET status ([−] or [+]) with clinicopathological characteristics was assessed. In addition, evaluation of stromal tumor-infiltrating lymphocytes (sTILs) and gene expression analysis using PAM50 and Vantage 3D™ Cancer Metabolism Panel were specifically compared in a matched cohort of excluded and enrolled patients based on the [18F]FDG-PET eligibility criteria. Results: Median SUVmax at baseline was 7.2 (range, 1–39.3). Among all analyzed patients, a higher SUVmax was associated with a higher tumor stage, larger tumor size, lymph node involvement, hormone receptor-negative status, higher HER2 protein expression, increased Ki67 proliferation index, and higher histological grade (p < 0.05). [18F]FDG-PET [−] criteria patients had smaller tumor size (p = 0.014) along with the absence of lymph node involvement and lower histological grade than [18F]FDG-PET [+] patients (p < 0.01). Although no difference in the levels of sTILs was found among 42 matched [18F]FDG-PET [−]/[+] criteria patients (p = 0.73), [18F]FDG-PET [−] criteria patients showed a decreased risk of recurrence (ROR) and a lower proportion of PAM50 HER2-enriched subtype than [18F]FDG-PET[+] patients (p < 0.05). Differences in the expression of genes involved in cancer metabolism were observed between [18F]FDG-PET [−] and [18F]FDG-PET[+] criteria patients. Conclusions: These results highlight the clinical, biological, and metabolic heterogeneity of HER2+ breast cancer, which may facilitate the selection of HER2+ EBC patients likely to benefit from [18F]FDG-PET imaging as a tool to guide therapy. Trial registration: Clinicaltrials.gov; NCT03161353; registration date: May 15, 2017. [ABSTRACT FROM AUTHOR]

Synovial sarcoma (SS) is a rare soft-tissue tumor characterized by a monomorphic blue spindle cell histology and variable epithelial differentiation. Morphologically, SSs may be confused with other sarcomas. Systemic treatment is more effective for patients with high-risk SSs, patients with advanced disease, and younger patients. However, further studies are required to find new prognostic biomarkers. Herein, we describe the morphological, molecular, and clinical findings, using a wide immunohistochemical panel, of a series of SS cases. We studied 52 cases confirmed as SSs by morphological diagnosis and/or molecular studies. Clinical data (gender, age, tumor size, tumor location, resection margins, adjuvant treatment, recurrences, metastasis, and survival) were also retrieved for each patient. All the available H&E slides were examined by four pathologists. Three tissue microarrays (TMAs) were constructed for each of the tumors, and a wide immunohistochemical panel was performed. For time-to-event variables, survival analysis was performed using Kaplan–Meier curves and log-rank testing, or Cox regression. Statistical significance was considered at p < 0.05. The mean age of our patients was 40.33, and the median was 40.5 years. We found a predominance of males versus females (1.7:1). The most frequent morphological subtype was monophasic. TRPS1, SS18-SSX, and SSX-C-terminus were positive in 96% of cases. GLI1 expression was strong in six and focal (cytoplasmic) in twenty patients. Moreover, BCOR was expressed in more than half of SSs. Positive expression of both proteins, BCOR and GLI1, was correlated with a worse prognosis. Multivariate analysis was also performed, but only BCOR expression appeared to be significant. The combination of GLI1 and BCOR antibodies can be used to group SSs into three risk groups (low, intermediate, and high risk). We hypothesize that these findings could identify which patients would benefit from receiving adjuvant treatment and which would not. Moreover, these markers could represent therapeutic targets in advanced stages. However, further, larger series of SSs and molecular studies are necessary to corroborate our present findings. [ABSTRACT FROM AUTHOR]

Speech given in the context of an Act of Recognition of the UAB for the academic career in defense of the rights of women and dissident groups, awarded by the Observatory for Equality, in commemoration of International Working Women's Day (8M). A narrative is constructed, the result of thirty-eight years of dedication to the UAB, which is organized around the beginnings, academic references, intergenerational family memory and links with research and teaching. It focuses on a work of articulation between Gender Studies and Mental Health, highlighting the theoretical-epistemological critique of the intersection, lived in one's own skin, between Gender, Power and Science, in relation to Science Psychology and implications of the scientific-cultural construction of Binary Sexual Identity in relation to the Science of Mental Health. Narrative built from a commitment to intersectional feminist thought and for an emancipatory and inclusive psychology. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic is the biggest global health problem in the last hundred years. The efficacy of the vaccine to protect against severe disease is estimated to be 70–95% according to the studies carried out, although there are aspects of the immune response to the vaccine that remain unclear. Methods: Humoral and cellular immunity after the administration of three doses of the Pfizer–BioNTech and Oxford AstraZeneca vaccines against SARS-CoV-2 over one year and the appearance of post-vaccination COVID-19 were studied. SARS-CoV-2 IgG and IgA antibodies, αβ and γδ T-cell subsets, and their differentiation stages and apoptosis were analyzed. Results: Anti-SARS-CoV-2 IgG and IgA antibodies showed a progressive increase throughout the duration of the study. This increase was the greatest after the third dose. The highest levels were observed in subjects who had anti-SARS-CoV-2 antibodies prior to vaccination. There was an increase in CD4+ αβ, CD8+ γδ and TEM CD8+ γδ T cells, and a decrease in apoptosis in CD4+ CD8+ and CD56+ αβ and γδ T cells. Post-vaccination SARS-CoV-2 infection was greater than 60%. The symptoms of COVID-19 were very mild and were related to a γδ T cell deficit, specifically CD8+ TEMRA and CD56+ γδ TEM, as well as lower pre-vaccine apoptosis levels. Conclusions: The results unveil the important role of γδ T cells in SARS-CoV-2-vaccine-mediated protection from the disease. [ABSTRACT FROM AUTHOR]

Abstract The progressive paradigm is a promising strategy to optimize network performance for speech enhancement purposes. Recent works have shown different strategies to improve the accuracy of speech enhancement solutions based on this mechanism. This paper studies the progressive speech enhancement using convolutional and residual neural network architectures and explores two criteria for loss function optimization: weighted and uniform progressive. This work carries out the evaluation on simulated and real speech samples with reverberation and added noise using REVERB and VoiceHome datasets. Experimental results show a variety of achievements among the loss function optimization criteria and the network architectures. Results show that the progressive design strengthens the model and increases the robustness to distortions due to reverberation and noise.

Melting and crystallization of ice close to the triple point is mediated by a thin liquid layer of water. Within an extended theoretical-numerical model, Sibley et al. capture both equilibrium properties and kinetic aspects of the film evolution to arrive at a broader perspective of how ice grows.

RESUMEN Introducción: La radioembolización transarterial (TARE) es una terapia alternativa para el tratamiento de tumores hepáticos no resecables. Método: Estudio retrospectivo y descriptivo en 27 pacientes sometidos a TARE con microesferas de resina cargadas con Ytrio-90. Se estudiaron las características basales, demográficas y clínicas, y se analizó la supervivencia global a 18 meses mediante el método de Kaplan-Meier. Resultados: La edad osciló entre 52-85 años, y el 81% de los pacientes fueron hombres. El 78% presentaron tumores hepáticos primarios, destacando el carcinoma hepatocelular estadio BCLC (Barcelona Clinic Liver Cancer) B (CHC BCLC B) (44%). El origen del tumor hepático secundario más frecuente fue adenocarcinoma colorrectal. El ECOG (Eastern Cooperative Oncology Group) fue 0 para el 78% de los pacientes y los antecedentes alcoholismo (41%) y hepatitis C (56%). La media de actividad administrada fue 1,8 GBq. El 34% recibieron más de un tratamiento previo: resección quirúrgica (11%), embolización o quimioembolización transarterial (48%), ablación por radiofrecuencia (22%), inhibidores multiquinasas (15%). El 33% recibieron tratamiento posterior con inhibidores multiquinasas. La supervivencia global a 18 meses fue del 58,9%. En pacientes con CHC BCLC B, la mediana de supervivencia fue de 15,6 meses. Conclusión: Los resultados de supervivencia concuerdan con los de otros estudios, aunque existen diferencias en algunas de las variables. Es necesario disponer de mayor número de pacientes y tiempo de seguimiento para analizar su influencia en la supervivencia.

Background: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. Patients and methods: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible. Results: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7–7.0) and the median overall survival was 19.0 months (95% CI 16.4–21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37–2.73, p

Primary Sjögren's syndrome (pSS) is an autoimmune disease triggered by a combination of environmental and host genetic factors, which results in the focal lymphocytic infiltration of exocrine glands causing eye and mouth dryness. Glandular infiltrates include T and B cell subsets positive for CD5 and/or CD6, two surface scavenger receptors involved in the fine-tuning of intracellular signals mediated by the antigen-specific receptor complex of T (TCR) and B (BCR) cells. Moreover, the epithelial cells of inflamed glands overexpress CD166/ALCAM, a CD6 ligand involved in homo and heterotypic cell adhesion interactions. All this, together with the reported association of functionally relevant single nucleotide polymorphisms (SNPs) of CD5, CD6, and CD166/ALCAM with the risk or prognosis of some immune-mediated inflammatory disorders, led us to investigate similar associations in a local cohort of patients with pSS. The logistic regression analyses of individual SNPs showed the association of CD5 rs2241002T with anti-Ro/La positivity, CD6 rs17824933C with neutropenia, and CD6 rs11230563T with increased leukopenia and neutropenia but decreased peripheral nervous system EULAR Sjögren's syndrome disease activity index (ESSDAI). Further analyses showed the association of haplotypes from CD5 (rs2241002T-rs2229177C) with anemia and thrombocytopenia, CD6 (rs17824933G-rs11230563C-rs12360861G) with cutaneous ESSDAI, and CD166/ALCAM (rs6437585C-rs579565A-rs1044243C and rs6437585C-rs579565G-rs1044243T) with disease susceptibility and several analytical parameters (anti-nuclear antibodies, neurological ESSDAI, and hematologic cytopenias). These results support the relevance of gene variation at loci coding for cell surface receptors involved in the modulation of T and B lymphocyte activation (CD5, CD6) and epithelial-immune cell adhesion (CD166/ALCAM) in modulating the clinical and analytical outcomes in patients with pSS.

Resumen La clasificación oficial de la Organización Mundial de la Salud de los tumores de tejidos hematopoyéticos y linfoides de 2016 introduce el concepto de policitemia vera (PV) enmascarada y revela que esta entidad ha sido infradiagnosticada en el pasado. Se presenta el caso de un varón de 49 años, fumador, intervenido de fractura de tobillo hace más de 15 años, remitido para valorar un posible proceso infeccioso asociado. Al no producirse separación previa de los hematíes por sedimentación durante el procedimiento de marcaje de leucocitos con 99mTc-exametazima se revisaron las causas de disminución de la velocidad de sedimentación globular. Entre ellas destacan la poliglobulia y el hábito tabáquico, ambas presentes en el paciente. Se recomendó realización de estudio hematológico que concluyó con el diagnóstico de PV. Las indicaciones del especialista en Radiofarmacia permitieron diagnosticar un caso no identificado hasta entonces, pese a que el paciente presentaba síntomas desde hacía años.

HER2-enriched breast cancers within the HER2-positive subtype are addicted to the HER2 pathway. Here, the authors analyse gene expression before, during, and after treatment with anti-HER2-based therapies in the phase II PAMELA clinical trial, finding phenotypic changes induced by treatment.

Summary: c-MYC controls global gene expression and regulates cell proliferation, cell differentiation, cell cycle, metabolism and apoptosis. According to some estimates, MYC is dysregulated in ≈70% of human cancers and strong evidence implicates aberrantly expressed MYC in both tumor initiation and maintenance. In vivo studies show that MYC inhibition elicits a prominent anti-proliferative effect and sustained tumor regression while any alteration on healthy tissue remains reversible. This opens an exploitable window for treatment that makes MYC one of the most appealing therapeutic targets for cancer drug development. This review describes the main functional and structural features of the protein structure of MYC and provides a general overview of the most relevant or recently identified interactors that modulate MYC oncogenic activity. This review also summarizes the different approaches aiming to abrogate MYC oncogenic function, with a particular focus on the prototype inhibitors designed for the direct and indirect targeting of MYC.

Summary: Background: Both clinical and genomic data independently predict survival and treatment response in early-stage HER2-positive breast cancer. Here we present the development and validation of a new HER2DX risk score, and a new HER2DX pathological complete response (pCR) score, both based on a 27-gene expression plus clinical feature-based classifier. Methods: HER2DX is a supervised learning algorithm incorporating tumour size, nodal staging, and 4 gene expression signatures tracking immune infiltration, tumour cell proliferation, luminal differentiation, and the expression of the HER2 amplicon, into a single score. 434 HER2-positive tumours from the Short-HER trial were used to train a prognostic risk model; 268 cases from an independent cohort were used to verify the accuracy of the HER2DX risk score. In addition, 116 cases treated with neoadjuvant anti-HER2-based chemotherapy were used to train a predictive model of pathological complete response (pCR); two independent cohorts of 91 and 67 cases were used to verify the accuracy of the HER2DX pCR likelihood score. Five publicly available independent datasets with >1,000 patients with early-stage HER2-positive disease were also analysed. Findings: In Short-HER, HER2DX variables were associated with good risk outcomes (i.e., immune, and luminal) and poor risk outcomes (i.e., proliferation, and tumour and nodal staging). In an independent cohort, continuous HER2DX risk score was significantly associated with disease-free survival (DFS) (p=0·002); the 5-year DFS in the low-risk group was 97·4% (94·4-100·0%). For the neoadjuvant pCR predictor training cohort, HER2DX variables were associated with pCR (i.e., immune, proliferation and HER2 amplicon) and non-pCR (i.e., luminal, and tumour and nodal staging). In both independent test set cohorts, continuous HER2DX pCR likelihood score was significantly associated with pCR (p