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.

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.

Neurologic Toxicity of Immune Checkpoint Inhibitors: A Review of Literature.

Immune checkpoint inhibitors have entailed a change of paradigm in the management of multiple malignant diseases and are acquiring a key role in an increasing number of clinical sceneries. However, since their mechanism of action is not limited to the tumor microenvironment, their systemic activity may lead to a wide spectrum of immune-related side effects. Although neurological adverse events are much less frequent than gastrointestinal, hepatic, or lung toxicity, with an incidence of <5%, their potential severity and consequent interruptions to cancer treatment make them of particular importance. Despite them mainly implying peripheral neuropathies, immunotherapy has also been associated with an increased risk of encephalitis and paraneoplastic disorders affecting the central nervous system, often appearing in a clinical context where the appropriate diagnosis and early management of neuropsychiatric symptoms can be challenging. Although the pathogenesis of these complications is not fully understood yet, the blockade of tumoral inhibitory signals, and therefore the elicitation of cytotoxic T-cell-mediated response, seems to play a decisive role. The aim of this review was to summarize the current knowledge about the pathogenic mechanisms, clinical manifestations, and therapeutic recommendations regarding the main forms of neurotoxicity related to checkpoint inhibitors.

Complicaciones postoperatorias del manejo quirúrgico de escoliosis / Post-operative complications after surgical management of scoliosis

Introducción La tasa de complicaciones en cirugía de escoliosis sigue siendo alta. Lo que buscamos con este estudio es saber que características de los pacientes se relacionan con la presentación de complicaciones perioperatorias y poder usar esta informacion para la toma de medidas preventivas. Materiales y métodos Estudio descriptivo de corte transversal retrospectivo. Se incluyeron pacientes con escoliosis llevados a cirugía para corrección de su deformidad, obteniendo 230 pacientes y 318 procedimientos. Variables sociodemográficas fueron evaluadas con medidas de tendencia central, posteriormente se realizó un análisis bivariado y finalmente un análisis de regresión logística multinomial. Resultados Con una p<0,005 se encontró por diagnostico: escoliosis neuromuscular y sindromática un 28,8 y 16,66% de neumonías y una prevalencia de 15,87 y 33,33% de derrame pleural respectivamente. Escoliosis Congénita 1,88% tuvo Infección de vías urinarias. Se realizó un modelo de regresión logística obteniendo a la edad como principal predictor para presentación de complicaciones, siendo más frecuentes en los pacientes más jóvenes (p<0,000). Discusión Se encontró que a menor edad mas frecuente era la presentación de complicaciones, resultado no reportado previamente, pero que sirve para respaldar la conducta conservadora en pacientes con escoliosis de inicio temprano. Las complicaciones mas comunes fueron las pulmonares. Escoliosis neuromuscular es el diagnostico que mas complicaciones reportó. Datos comparables con la literatura que se deben tener en cuenta para tomar medidas de prevención y el desarrollo de planes de mejoramiento.

Background The rate of complications in scoliosis surgery remains high. This study intends to determine the characteristics of the patients that are related to the presentation of perioperative complications, and to be able to use this information to take preventive measures. Material and Method Descriptive cross-sectional retrospective study, including 230 patients and 318 procedures, was conducted on patients with scoliosis who underwent surgery to correct their deformity. Socio-demographic variables were evaluated using measures of central tendency measurements, followed by a bivariate analysis, and finally a multinomial logistic regression analysis. Results A significance of P<.005 was found for diagnosis: neuromuscular and syndromic scoliosis presented with 28.8 and 16.66% of pneumonias, and a prevalence of 15.87 and 33.33% for pleural effusion, respectively. A urinary tract infection (1.88%) was observed in Congenital Scoliosis. A logistic regression model was performed, observing age as the main predictor for presenting with complications, and being more frequent in younger patients (P<.000). Discussion It was found that more complications were present in younger patients. This outcome has not been previously reported, but can be used to support conservative behaviour in patients with early-onset scoliosis. The most common complication was pulmonary, with neuromuscular scoliosis being the diagnosis with more complications reported. These data are comparable with those in the literature, and should be taken into account when taking preventive measures and for the development of improvement plans.

Outcomes and complications of S2 alar iliac fixation technique in patients with neuromuscular scoliosis: experience in a third level pediatric hospital.

BACKGROUND: Multiple techniques are utilized for distal fixation in patients with neuromuscular scoliosis. Although there is evidence of benefit with S2 alar iliac (S2AI) fixation, this remains controversial. The objective of this study is to evaluate the radiological outcomes and complications associated with this surgical technique in a pediatric population. METHODS: An observational retrospective case series study was performed. All pediatric patients between January 2011 and February 2014 diagnosed with neuromuscular scoliosis associated with pelvic obliquity, which required surgery with fixation unto S2AI, were included. Clinical, radiological findings, and adverse events were presented with measures of central tendency. Comparison of deformity correction was carried out using a non-parametric analysis for related samples (Wilcoxon signed-rank test). Significance was set at P<0.05. RESULTS: A total of 31 patients diagnosed with neuromuscular scoliosis that met inclusion criteria were analyzed. The leading cause of neuromuscular scoliosis in 23 (74.2%) patients was spastic cerebral palsy (CP). The correction of pelvic obliquity in the immediate postoperative period was of 76%, which is statistically significant. The extent of correction that patients maintained at the end of the follow-up was analyzed, and it was found that there were no significant differences in this magnitude, compared with the immediate postoperative pelvic obliquity. The mean follow-up time was 9±7 months. Regarding postoperative adverse events, occurred in 64.5% of patients, the most common outcome was pneumonia (14.8%). The overall rate of complications related to instrumentation was low (1.9%), which corresponds to one patient with an intra-articular screw in the left hip that required repositioning. CONCLUSIONS: S2AI fixation for the treatment of neuromuscular scoliosis is a safe alternative, in which the onset of adverse events is related to the comorbidities of patients instead of the surgical procedure itself. An approximate correction of 76% of pelvic obliquity is maintained during the follow-up.