Adoptive T cell therapy for solid tumors: current landscape and future challenges.

Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune response, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR) gene-modified T cells, and therapy with tumor-infiltrating lymphocytes (TILs). The outstanding results of CAR-T cells in some hematologic malignancies have launched the investigation of ACT in patients with refractory solid malignancies. However, certain characteristics of solid tumors, such as their antigenic heterogeneity and immunosuppressive microenvironment, hamper the efficacy of antigen-targeted treatments. Other ACT modalities, such as TIL therapy, have emerged as promising new strategies. TIL therapy has shown safety and promising activity in certain immunogenic cancers, mainly advanced melanoma, with an exciting rationale for its combination with immune checkpoint inhibitors. However, the implementation of TIL therapy in clinical practice is hindered by several biological, logistic, and economic challenges. In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell therapy in patients with solid tumors.

BRAF Inhibitors in Metastatic Colorectal Cancer and Mechanisms of Resistance: A Review of the Literature.

Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC. Current standard treatment for these tumors involves a combination of chemotherapy (CT) and VEGF inhibitors. Recently, targeted therapy against BRAF and immunotherapy (IT) for cases with microsatellite instability (MSI) have been integrated into clinical practice. While targeted therapy has shown promising results, resistance to treatment eventually develops in a significant portion of responsive patients. This article aims to review the available literature on mechanisms of resistance to BRAF inhibitors (BRAFis) and potential therapeutic strategies to overcome them.

Current Landscape of Immunotherapy for Advanced Sarcoma.

There is substantial heterogeneity between different subtypes of sarcoma regarding their biological behavior and microenvironment, which impacts their responsiveness to immunotherapy. Alveolar soft-part sarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma show higher immunogenicity and better responses to checkpoint inhibitors. Combination strategies adding immunotherapy to chemotherapy and/or tyrosine-kinase inhibitors globally seem superior to single-agent schemes. Therapeutic vaccines and different forms of adoptive cell therapy, mainly engineered TCRs, CAR-T cells and TIL therapy, are emerging as new forms of immunotherapy for advanced solid tumors. Tumor lymphocytic infiltration and other prognostic and predictive biomarkers are under research.

Maintained complete response to talazoparib in a BRCA-2 mutated metastatic luminal breast cancer: case report and review of literature.

PARP inhibitors are progressively becoming a part of our therapeutic arsenal against BRCA-defective tumors, because of their capacity to induce synthetic lethality in cells with a deficiency in the homologous recombination repair system. Olaparib and talazoparib have been approved for metastatic breast cancer in carriers of germline BRCA mutations, which are found in approximately 6% of patients with breast cancer. We report the case of a patient with metastatic breast cancer, carrier of a germline mutation in BRCA2, with a complete response to first-line treatment with talazoparib, maintained after 6 years. To the best of our knowledge, this is the longest response reported with a PARP inhibitor in a BRCA-mutated tumor. We have made a review of literature, regarding the rationale for PARP inhibitors in carriers of BRCA mutations and their clinical relevance in the management of advanced breast cancer, as well as their emerging role in early stage disease, alone and in combination with other systemic therapies.

Receptor Tyrosine Kinase Inhibitors for the Treatment of Recurrent and Unresectable Bone Sarcomas.

Bone sarcomas are a heterogeneous group of rare tumors with a predominance in the young population. Few options of systemic treatment are available once they become unresectable and resistant to conventional chemotherapy. A better knowledge of the key role that tyrosine kinase receptors (VEGFR, RET, MET, AXL, PDGFR, KIT, FGFR, IGF-1R) may play in the pathogenesis of these tumors has led to the development of multi-target inhibitors (TKIs) that are progressively being incorporated into our therapeutic arsenal. Osteosarcoma (OS) is the most frequent primary bone tumor and several TKIs have demonstrated clinical benefit in phase II clinical trials (cabozantinib, regorafenib, apatinib, sorafenib, and lenvatinib). Although the development of TKIs for other primary bone tumors is less advanced, preclinical data and early trials have begun to show their potential benefit in advanced Ewing sarcoma (ES) and rarer bone tumors (chondrosarcoma, chordoma, giant cell tumor of bone, and undifferentiated pleomorphic sarcoma). Previous reviews have mainly provided information on TKIs for OS and ES. We aim to summarize the existing knowledge regarding the use of TKIs in all bone sarcomas including the most recent studies as well as the potential synergistic effects of their combination with other systemic therapies.

Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates.

Metastatic urothelial cancer, associated with a poor prognosis, is still major cause of cancer-related death, with scarce options of effective treatment after progression to platinum-based chemotherapy and immunotherapy. The human epithelial growth factor receptor 2 (Her-2) has been identified as a new therapeutic target in medical oncology. However, despite the encouraging results in breast and gastric cancers, clinical trials with anti-Her-2 monoclonal antibodies and tyrosine-kinase inhibitors have shown limited efficacy of this strategy in urothelial tumors. Notably, more favorable data have been recently shown that antibody-drug conjugates are currently emerging as a novel promising approach for Her-2 targeted therapy in advanced urothelial cancer.

BRAF Mutated Colorectal Cancer: New Treatment Approaches.

Colon cancer is one of the most frequently diagnosed malignancies in adults, considering both its incidence and prevalence. Anatomically, the right colon is considered as being from the cecum to the splenic flexure, and the left colon is from the splenic flexure to the rectum. Sidedness is a surrogate of a wide spectrum of colorectal cancer (CRC) biology features (embryology, microbiome, methylation, microsatellite instability (MSI), BRAF, aging, KRAS, consensus molecular subtypes (CMS), etc.), which result in prognostic factors. Different molecular subtypes have been identified, according to genomic and transcriptomic criteria. A subgroup harboring a BRAF mutation has been described, and represents approximately 10% of the patients diagnosed with colon cancer. This subgroup has morphological, clinical, and therapeutic characteristics that differ substantially from patients who do not carry this genetic alteration. Unfortunately, there is no established standard of care for this particular cohort of patients. This manuscript aims to study the biology of this subgroup of colon cancer, to understand the current approach in clinical research.

Effectiveness of a primary care-based group educational intervention in the management of patients with migraine: a randomized controlled trial.

AIM: The aim of this study was to assess the effectiveness of a primary care-based group educational intervention about concepts of pain neuroscience for the management of migraine compared to the routine medical care delivered to patients with this condition. BACKGROUND: The way pain is understood has been radically changed in recent decades, thanks to developments in the field of neuroscience. Thus, migraine may develop as a result of an exaggerated perception of threat that activates the pain neuromatrix, which might be modifiable, from a learning perspective, by adjusting the beliefs and behaviours that favour the onset of an attack. METHODS: A randomised controlled trial was carried out in five primary care health centres of Vitoria-Gasteiz (Basque Country, Spain). The follow-up period was 12 months. The main outcome measure was the reduction in days lost due to migraine-related disability according to the Migraine Disability Assessment Test (MIDAS) score. Secondary outcome measures included the intensity and frequency of the pain and the number of analgesic drugs taken in the previous three months. A positive response to treatment was considered when the MIDAS score decreased by at least 50% from baseline. FINDINGS: Days lost due to migraine-related disability decreased by at least 50% in 68.9% (n = 37) of patients in the intervention group and 34.6% of patients in the control group (n = 18) (P < 0.001). The intensity of the headache [odds ratio (OR) 9.116; P = 0.005] and the medication intake (OR 13.267; P < 0.001) were also significantly reduced with the intervention. CONCLUSIONS: The provision of suitable information through a group educational intervention delivered in primary care appears to be effective in preventing migraine attacks. Moreover, the intervention could offer a new cost-effective management alternative that seems to reduce the need for pharmacological treatment in patients with migraine.

Targeting Angiogenesis in Pancreatic Neuroendocrine Tumors: Resistance Mechanisms.

Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.

Dioxins and furans legacy of lindane manufacture in Sabiñánigo (Spain). The Bailín landfill site case study.

Lindane (γ-hexachlorocyclohexane) manufacture in Spain generated nearly 200,000tonnes of HCH wastes; near 160,000tonnes were originated by the Inquinosa factory located in Sabiñánigo (northern Spain) and were deposited in unlined landfill sites. This study reports for the first time the content of polychlorinated dibenzo-p-dioxin/dibenzofuran (PCDD/Fs) in non-recycled HCH wastes that had been disposed in the Bailín landfill site in Sabiñánigo. Samples from solid HCH powder residues (white HCH and δ-paste wastes) and the dense non-aqueous phase liquids (DNAPLs), as well as landfill leachates, soil and sediments have been characterized. White HCH wastes exhibited a toxicity of 1488ngWHO-TEQ2005·kg-1 (Σ17 PCDD/Fs), while δ-paste wastes presented a noticeable higher toxicity (12,094ngWHO-TEQ2005·kg-1). Nevertheless, the maximum toxicity value was found for DNAPLs (37,353ngWHO-TEQ2005·L-1). Dioxins were predominant in the DNAPL waste whereas furans predominated in the landfill leachates, soil and sediments. However, in solid HCH wastes, PCDD and PCDFs contributed in a similar proportion. The PCDD/Fs congener profiles in landfill leachates, soil and sediments do not resemble the PCDD/Fs profiles found for the HCH wastes. These preliminary results will be of paramount importance in order to estimate the total quantities of PCDD/Fs disposed to the landfill site and to assess the potential mobility of PCDD/Fs, especially to groundwater and landfill leachates. Besides, this information is of great value to design periodical monitoring plans to evaluate the presence of PCDD/Fs in the impacted groundwater and leachates and finally, to evaluate the risk of PCDD/Fs for the environment and human health.

Structure, vibrational analysis, and insights into host-guest interactions in as-synthesized pure silica ITQ-12 zeolite by periodic B3LYP calculations.

As-made and calcined ITQ-12 zeolites are structurally characterized by means of the analysis of their vibrational modes. The experimental IR spectra made on high crystalline samples are compared with accurate B3LYP periodic calculations performed with the CRYSTAL06 code. The fair agreement between both sets of data allows us to make a reliable assignment of the IR modes. Thanks to the detailed information provided by the theoretical calculations, the analysis of the IR intensities, the Born dynamic charges, and the whole set of vibrational frequencies at Gamma-point shed light on several aspects of the host-guest interaction, structure-direction issues, including the role of fluoride anions in allowing the crystallization of silica structures with strained double-four rings, and the role played by the framework flexibility.

Ion hydration in nanopores and the molecular basis of selectivity.

Using a simple model, it is shown that the cost of constraining a hydrated potassium ion inside a narrow pore is smaller than the cost of constraining hydrated sodium or lithium ions in pores of radius around 1.5 A. The opposite is true for pores of radius around 2.5 A. The reason for the selectivity in the first region is that the potassium ion allows for a greater distortion of its hydration shell and can therefore maintain a better coordination, and the reason for the reverse selectivity in the second region is that the smaller ions retain their hydration shells in these pores. This is relevant to the molecular basis of ion selective channels, and since this mechanism does not depend on the molecular details of the pore, it could also operate in all sorts of nanotubes.

Umbral auditivo en mujeres que concurren a gomnasios con relación al ruido ambiente / Auditory threshold in woman with going to gymnastic with relation to development noise

El propósito general del trabajo fue establecer la relación entre umbral auditivo de las mujeres que concurrieron a gimnasia, el Nivel Sonoro de cuatro gimnasios ubicados en el radio céntrico de la ciudad de Rosario y factores favorecedores de riesgo auditivo. Es un estudio de tipo longitudinal ya que se evaluó el umbral auditivo en dos oportunidades. Para la realización del presente trabajo se seleccionaron 35 mujeres entre 22 y 30 años de edad que concurrieron a cuatro gimnasios; después de excluir por un cuestionario confeccionado especialmente para esta investigación, aquellas que presentaron alteraciones audiológicas que pudieran distorsionar los resultados y las que dejaron de concurrir al gimnasio en el tiempo que medió entre las dos evaluaciones. Se tomaron dos audiometrías tonales, la primera en el mes de mayo de 1996 y la segunda en el mes de octubre de 1996 en el consultorio de ORL de un establecimiento de salud. De esta forma la población quedó conformada por 23 mujeres. Posteriormnente se midió el Nivel Sonoro en los cuatro gimnasios, para ello se utilizó un decibelímetro Bruel & KJAER tipo 2230 que permitió efectuar las mediciones en RMS y en Pico. A partir de este trabajo de investigación se concluyó que: En los cuatro gimnasios el nivel sonoro fue alto (+85 dbA). En 5 mujeres (21,7 por ciento) que concurrían a gimnasia más de dos veces por semana y permanecían en el mismo una hora se observó descenso de sus umbrales auditivo, 3 de las 5 estaban expuestas a factores favorecedores de riesgo auditivo. A través de ésto se observó que la posibilidad de adquirir trastornos de audición, se encuentra relacionada con la frecuencia de asistencia y el Nivel Sonoro del lugar. Sería importante dar a conocer infoprmación sobre esta problemática, a fin de llamar la atención a las personas que concurren a gimnasia, sobre la acción del ruido sobre el órgano auditivo ya que no existe información al respecto

Umbral auditivo en mujeres que concurren a gomnasios con relación al ruido ambiente / Auditory threshold in woman with going to gymnastic with relation to development noise

El propósito general del trabajo fue establecer la relación entre umbral auditivo de las mujeres que concurrieron a gimnasia, el Nivel Sonoro de cuatro gimnasios ubicados en el radio céntrico de la ciudad de Rosario y factores favorecedores de riesgo auditivo. Es un estudio de tipo longitudinal ya que se evaluó el umbral auditivo en dos oportunidades. Para la realización del presente trabajo se seleccionaron 35 mujeres entre 22 y 30 años de edad que concurrieron a cuatro gimnasios; después de excluir por un cuestionario confeccionado especialmente para esta investigación, aquellas que presentaron alteraciones audiológicas que pudieran distorsionar los resultados y las que dejaron de concurrir al gimnasio en el tiempo que medió entre las dos evaluaciones. Se tomaron dos audiometrías tonales, la primera en el mes de mayo de 1996 y la segunda en el mes de octubre de 1996 en el consultorio de ORL de un establecimiento de salud. De esta forma la población quedó conformada por 23 mujeres. Posteriormnente se midió el Nivel Sonoro en los cuatro gimnasios, para ello se utilizó un decibelímetro Bruel & KJAER tipo 2230 que permitió efectuar las mediciones en RMS y en Pico. A partir de este trabajo de investigación se concluyó que: En los cuatro gimnasios el nivel sonoro fue alto (+85 dbA). En 5 mujeres (21,7 por ciento) que concurrían a gimnasia más de dos veces por semana y permanecían en el mismo una hora se observó descenso de sus umbrales auditivo, 3 de las 5 estaban expuestas a factores favorecedores de riesgo auditivo. A través de ésto se observó que la posibilidad de adquirir trastornos de audición, se encuentra relacionada con la frecuencia de asistencia y el Nivel Sonoro del lugar. Sería importante dar a conocer infoprmación sobre esta problemática, a fin de llamar la atención a las personas que concurren a gimnasia, sobre la acción del ruido sobre el órgano auditivo ya que no existe información al respecto(AU)

Umbral auditivo en mujeres que concurren a gomnasios con relación al ruido ambiente / Auditory threshold in woman with going to gymnastic with relation to development noise

El propósito general del trabajo fue establecer la relación entre umbral auditivo de las mujeres que concurrieron a gimnasia, el Nivel Sonoro de cuatro gimnasios ubicados en el radio céntrico de la ciudad de Rosario y factores favorecedores de riesgo auditivo. Es un estudio de tipo longitudinal ya que se evaluó el umbral auditivo en dos oportunidades. Para la realización del presente trabajo se seleccionaron 35 mujeres entre 22 y 30 años de edad que concurrieron a cuatro gimnasios; después de excluir por un cuestionario confeccionado especialmente para esta investigación, aquellas que presentaron alteraciones audiológicas que pudieran distorsionar los resultados y las que dejaron de concurrir al gimnasio en el tiempo que medió entre las dos evaluaciones. Se tomaron dos audiometrías tonales, la primera en el mes de mayo de 1996 y la segunda en el mes de octubre de 1996 en el consultorio de ORL de un establecimiento de salud. De esta forma la población quedó conformada por 23 mujeres. Posteriormnente se midió el Nivel Sonoro en los cuatro gimnasios, para ello se utilizó un decibelímetro Bruel & KJAER tipo 2230 que permitió efectuar las mediciones en RMS y en Pico. A partir de este trabajo de investigación se concluyó que: En los cuatro gimnasios el nivel sonoro fue alto (+85 dbA). En 5 mujeres (21,7 por ciento) que concurrían a gimnasia más de dos veces por semana y permanecían en el mismo una hora se observó descenso de sus umbrales auditivo, 3 de las 5 estaban expuestas a factores favorecedores de riesgo auditivo. A través de ésto se observó que la posibilidad de adquirir trastornos de audición, se encuentra relacionada con la frecuencia de asistencia y el Nivel Sonoro del lugar. Sería importante dar a conocer infoprmación sobre esta problemática, a fin de llamar la atención a las personas que concurren a gimnasia, sobre la acción del ruido sobre el órgano auditivo ya que no existe información al respecto(AU)

Umbral auditivo en mujeres que concurren a gomnasios con relación al ruido ambiente / Auditory threshold in woman with going to gymnastic with relation to development noise

El propósito general del trabajo fue establecer la relación entre umbral auditivo de las mujeres que concurrieron a gimnasia, el Nivel Sonoro de cuatro gimnasios ubicados en el radio céntrico de la ciudad de Rosario y factores favorecedores de riesgo auditivo. Es un estudio de tipo longitudinal ya que se evaluó el umbral auditivo en dos oportunidades. Para la realización del presente trabajo se seleccionaron 35 mujeres entre 22 y 30 años de edad que concurrieron a cuatro gimnasios; después de excluir por un cuestionario confeccionado especialmente para esta investigación, aquellas que presentaron alteraciones audiológicas que pudieran distorsionar los resultados y las que dejaron de concurrir al gimnasio en el tiempo que medió entre las dos evaluaciones. Se tomaron dos audiometrías tonales, la primera en el mes de mayo de 1996 y la segunda en el mes de octubre de 1996 en el consultorio de ORL de un establecimiento de salud. De esta forma la población quedó conformada por 23 mujeres. Posteriormnente se midió el Nivel Sonoro en los cuatro gimnasios, para ello se utilizó un decibelímetro Bruel & KJAER tipo 2230 que permitió efectuar las mediciones en RMS y en Pico. A partir de este trabajo de investigación se concluyó que: En los cuatro gimnasios el nivel sonoro fue alto (+85 dbA). En 5 mujeres (21,7 por ciento) que concurrían a gimnasia más de dos veces por semana y permanecían en el mismo una hora se observó descenso de sus umbrales auditivo, 3 de las 5 estaban expuestas a factores favorecedores de riesgo auditivo. A través de ésto se observó que la posibilidad de adquirir trastornos de audición, se encuentra relacionada con la frecuencia de asistencia y el Nivel Sonoro del lugar. Sería importante dar a conocer infoprmación sobre esta problemática, a fin de llamar la atención a las personas que concurren a gimnasia, sobre la acción del ruido sobre el órgano auditivo ya que no existe información al respecto(AU)

Mobiluncus SPP. en la vaginosis bacteriana: criterios diagnósticos / Mobilincus SPP. in the bacterial vaginosis: diagnostic criteria

Se evaluaron 30 pacientes remitidas al Servicio de Ginecología del hospital San Juan de Dios, 15 de ellas presentaban síntomas clínicos compatibles con vaginitis y 15 eran asintomáticas. De cada paciente se tomó una muestra de secreción vaginal, que se analizó microscópicamente a fresco y por tinción de Gram, se evaluó pH y se hizo la prueba de aminas. Dieciocho casos, incluyendo 3 asintomáticos, presentaron alteraciones de la flora vaginal, cuatro de los cuales fueron catalogados como vaginosis bacteriana. En tres de ellos se observaron bacterias similares a Mobiluncus, que se aisló de dos casos y se identificó como M. mulleris (AU)

Mobiluncus SPP. en la vaginosis bacteriana: criterios diagnósticos / Mobilincus SPP. in the bacterial vaginosis: diagnostic criteria

Se evaluaron 30 pacientes remitidas al Servicio de Ginecología del hospital San Juan de Dios, 15 de ellas presentaban síntomas clínicos compatibles con vaginitis y 15 eran asintomáticas. De cada paciente se tomó una muestra de secreción vaginal, que se analizó microscópicamente a fresco y por tinción de Gram, se evaluó pH y se hizo la prueba de aminas. Dieciocho casos, incluyendo 3 asintomáticos, presentaron alteraciones de la flora vaginal, cuatro de los cuales fueron catalogados como vaginosis bacteriana. En tres de ellos se observaron bacterias similares a Mobiluncus, que se aisló de dos casos y se identificó como M. mulleris