Trabectedin and low-dose radiation therapy in patients with advanced leiomyosarcoma.

Background and objectives: Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin, achieved an overall response rate (ORR) of less than 10%. This fact potentially hinders the options for fast symptomatic relief or surgical rescue. The combination of trabectedin plus low-dose radiation therapy (T-XRT) demonstrated a response rate of 60% in phase I/II trial, while real-life data achieved 32.5% ORR, probably due to a more relaxed timing between treatments. These results were obtained in progressing and advanced STS. In this study, the merged databases (trial plus real life) have been analyzed, with a special focus on leiomyosarcoma patients. Design and methods: As responses were seen in a wide range of sarcoma histologies (11), this study planned to analyze whether leiomyosarcoma, the largest subtype with 26 cases (30.6%) in this series, exhibited a better clinical outcome with this therapeutic strategy. In addition, four advanced and progressing leiomyosarcoma patients, all with extraordinarily long progression-free survival of over 18 months, were collected. Results: A total of 847 cycles of trabectedin were administered to 85 patients, with the median number of cycles per patient being 7 (1-45+). A trend toward a longer progression-free survival (PFS) was observed in leiomyosarcoma patients with median PFS (mPFS) of 9.9 months [95% confidence interval (CI): 1.1-18.7] versus 5.6 months (95% CI: 3.2-7.9) for the remaining histologies, p = 0.25. When leiomyosarcoma and liposarcoma were grouped, this difference reached statistical significance, probably due to the special sensitivity of myxoid liposarcoma. The mPFS for L-sarcomas was 12.7 months (95% CI: 7-18.5) versus 4.3 months (95% CI: 3.3-5.3) for the remaining histologies, p = 0.001. Cases with long-lasting disease control are detected among leiomyosarcoma patients. Conclusion: Even when extraordinarily long-lasting responses do exist among leiomyosarcoma patients treated with T-XR, we were unable to demonstrate a significant difference favoring leiomyosarcoma patients in clinical outcomes.

Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis.

In this study, we have evaluated whether 57 genome-wide association studies (GWAS)-identified common variants for type 2 diabetes (T2D) influence the risk of developing prostate cancer (PCa) in a population of 304 Caucasian PCa patients and 686 controls. The association of selected single nucleotide polymorphisms (SNPs) with the risk of PCa was validated through meta-analysis of our data with those from the UKBiobank and FinnGen cohorts, but also previously published genetic studies. We also evaluated whether T2D SNPs associated with PCa risk could influence host immune responses by analysing their correlation with absolute numbers of 91 blood-derived cell populations and circulating levels of 103 immunological proteins and 7 steroid hormones. We also investigated the correlation of the most interesting SNPs with cytokine levels after in vitro stimulation of whole blood, peripheral mononuclear cells (PBMCs), and monocyte-derived macrophages with LPS, PHA, Pam3Cys, and Staphylococcus Aureus. The meta-analysis of our data with those from six large cohorts confirmed that each copy of the FTOrs9939609A, HNF1Brs7501939T, HNF1Brs757210T, HNF1Brs4430796G, and JAZF1rs10486567A alleles significantly decreased risk of developing PCa (p = 3.70 × 10-5, p = 9.39 × 10-54, p = 5.04 × 10-54, p = 1.19 × 10-71, and p = 1.66 × 10-18, respectively). Although it was not statistically significant after correction for multiple testing, we also found that the NOTCH2rs10923931T and RBMS1rs7593730 SNPs associated with the risk of developing PCa (p = 8.49 × 10-4 and 0.004). Interestingly, we found that the protective effect attributed to the HFN1B locus could be mediated by the SULT1A1 protein (p = 0.00030), an arylsulfotransferase that catalyzes the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. In addition to these results, eQTL analysis revealed that the HNF1Brs7501939, HNF1Brs757210, HNF1Brs4430796, NOTCH2rs10923931, and RBMS1rs7593730 SNPs influence the risk of PCa through the modulation of mRNA levels of their respective genes in whole blood and/or liver. These results confirm that functional TD2-related variants influence the risk of developing PCa, but also highlight the need of additional experiments to validate our functional results in a tumoral tissue context.

Prospective Real-World Gynaecological Cancer Clinical Registry with Associated Biospecimens: A Collaborative Model to Promote Translational Research between GEICO and the Spanish Biobank Network.

Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated with biobanks for the collection of real-world data and biological samples of gynaecological cancer patients. This collaborative project aims to promote research by providing broad access to high-quality clinical data and biospecimens for future research according to the needs of investigators and to increase diagnostic and therapeutic opportunities for gynaecological cancer patients in Spain. The VCR will include the participation of more than 60 Spanish hospitals entering relevant clinical information in harmonised electronic case report forms (eCRFs) in four different cohorts: ovarian, endometrial, cervical, and rare gynaecological cancers (gestational trophoblastic disease). Initial data for the cases included till December 2021 are presented. The model described herein establishes a real-world win-win collaboration between multicentre structures, promoted and supported by GEICO, that will contribute to the success of translational research in gynaecological cancer.

Predicting dynamic response to neoadjuvant chemotherapy in breast cancer: a novel metabolomics approach.

Neoadjuvant chemotherapy (NACT) outcomes vary according to breast cancer (BC) subtype. Since pathologic complete response is one of the most important target endpoints of NACT, further investigation of NACT outcomes in BC is crucial. Thus, identifying sensitive and specific predictors of treatment response for each phenotype would enable early detection of chemoresistance and residual disease, decreasing exposures to ineffective therapies and enhancing overall survival rates. We used liquid chromatography-high-resolution mass spectrometry (LC-HRMS)-based untargeted metabolomics to detect molecular changes in plasma of three different BC subtypes following the same NACT regimen, with the aim of searching for potential predictors of response. The metabolomics data set was analyzed by combining univariate and multivariate statistical strategies. By using ANOVA-simultaneous component analysis (ASCA), we were able to determine the prognostic value of potential biomarker candidates of response to NACT in the triple-negative (TN) subtype. Higher concentrations of docosahexaenoic acid and secondary bile acids were found at basal and presurgery samples, respectively, in the responders group. In addition, the glycohyocholic and glycodeoxycholic acids were able to classify TN patients according to response to treatment and overall survival with an area under the curve model > 0.77. In relation to luminal B (LB) and HER2+ subjects, it should be noted that significant differences were related to time and individual factors. Specifically, tryptophan was identified to be decreased over time in HER2+ patients, whereas LysoPE (22:6) appeared to be increased, but could not be associated with response to NACT. Therefore, the combination of untargeted-based metabolomics along with longitudinal statistical approaches may represent a very useful tool for the improvement of treatment and in administering a more personalized BC follow-up in the clinical practice.

Early use of tocilizumab in patients with severe pneumonia secondary to severe acute respiratory syndrome coronavirus 2 infection and poor prognostic criteria: Impact on mortality rate and intensive care unit admission.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, keeps spreading globally. Evidence suggests that a subgroup of patients with severe symptomatology might have cytokine storms, which increases mortality. The use of interleukin-6 (IL-6) inhibitors may help in controlling the pathological immune response to the virus. Tocilizumab, a monoclonal antibody against IL-6, stands as an optional treatment for COVID-19 patients presenting this inflammatory hyper-response.We conducted a retrospective, observational, cohort study including 50 patients affected by COVID-19 with severe pneumonia and poor prognosis criteria, who have also undergone standard treatment; 36 of these patients additionally received tocilizumab in an early stage. The need for intensive care unit (ICU) admission, mortality, recovery of respiratory function, and improvement of biochemical and hematological parameters were compared between cohorts.Most patients were men, non-smokers and the most frequently reported comorbidities were hypertension and diabetes. Recurrent symptoms were fever, cough, and dyspnoea. 54.8% of patients from the tocilizumab group needed intubation, while in the control group 85.7% needed it. Treatment with tocilizumab significatively increased IL-6 levels, (554.45; CI 95% 186.69, 1032.93; P < .05) while C-reactive protein mean levels were reduced (-108.19; CI 95% -140.15, -75.33; P < .05), but no significant difference was found between cohorts. In comparison with the controls, tocilizumab reduced mortality (25.0% vs 42.9%, P = .021) and the number of ICU admissions (63.9% vs 100.0%, P = .021). 44.1% of patients treated with tocilizumab showed favorable radiological evolution, when compared with 15.4% of patients from the control group.Tocilizumab may improve clinical symptoms and mitigate deterioration observed in severe COVID-19 patients, and could be considered as an effective therapeutic option in subjects experiencing a significant inflammatory response to the disease.

Angiosarcoma radioinducido de mama. Revisión bibliográfica a propósito de dos casos en nuestro centro / Radiotherapy-related angiosarcoma of the breast. A literature review apropos of two cases treated in our hospital

Objetivo Revisión bibliográfica del diagnóstico y tratamiento actual del angiosarcoma radioinducido de mama. Pacientes Presentamos dos casos de angiosarcoma radioinducido de mama comentándose los aspectos clínicos, diagnósticos y terapéuticos de interés. Conclusión El angiosarcoma de mama radioinducido es un tumor infrecuente que se presenta como complicación tardía en pacientes sometidas a tratamiento conservador del cáncer de mama mediante cirugía y radioterapia. La cirugía es el único tratamiento curativo, aunque su elevada tasa de recaída local requiere de tratamiento multimodal para optimizar los resultados de control local. (AU)

Objective Literature review of the diagnosis and treatment of radiotherapy related angiosarcoma of the breast. Case reportWe present two cases of radiotherapy-related angiosarcoma of the breast treated in our hospital and describe the clinical, diagnostic, and therapeutic features. Conclusion Radiotherapy-related angiosarcoma of the breast is an uncommon tumour that usually presents as a late complication in patients who have undergone surgery and radiotherapy as conservative treatment for breast cancer. Surgery is the only curative treatment. However, because of its high rate of local recurrence, multimodal therapy is required to optimise prevention of recurrence. (AU)

Human Plasma Metabolomics for Biomarker Discovery: Targeting the Molecular Subtypes in Breast Cancer.

PURPOSE: The aim of this study is to identify differential metabolomic signatures in plasma samples of distinct subtypes of breast cancer patients that could be used in clinical practice as diagnostic biomarkers for these molecular phenotypes and to provide a more individualized and accurate therapeutic procedure. METHODS: Untargeted LC-HRMS metabolomics approach in positive and negative electrospray ionization mode was used to analyze plasma samples from LA, LB, HER2+ and TN breast cancer patients and healthy controls in order to determine specific metabolomic profiles through univariate and multivariate statistical data analysis. RESULTS: We tentatively identified altered metabolites displaying concentration variations among the four breast cancer molecular subtypes. We found a biomarker panel of 5 candidates in LA, 7 in LB, 5 in HER2 and 3 in TN that were able to discriminate each breast cancer subtype with a false discovery range corrected p-value < 0.05 and a fold-change cutoff value > 1.3. The model clinical value was evaluated with the AUROC, providing diagnostic capacities above 0.85. CONCLUSION: Our study identifies metabolic profiling differences in molecular phenotypes of breast cancer. This may represent a key step towards therapy improvement in personalized medicine and prioritization of tailored therapeutic intervention strategies.