Dysfunctional mitochondrial translation and combined oxidative phosphorylation deficiency in a mouse model of hepatoencephalopathy due to Gfm1 mutations.

Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 (COXPD1) is a recessive mitochondrial translation disorder caused by mutations in GFM1, a nuclear gene encoding mitochondrial elongation factor G1 (EFG1). Patients with COXPD1 typically present hepatoencephalopathy early after birth with rapid disease progression, and usually die within the first few weeks or years of life. We have generated two different mouse models: a Gfm1 knock-in (KI) harboring the p.R671C missense mutation, found in at least 10 patients who survived more than 1 year, and a Gfm1 knock-out (KO) model. Homozygous KO mice (Gfm1-/- ) were embryonically lethal, whereas homozygous KI (Gfm1R671C/R671C ) mice were viable and showed normal growth. R671C mutation in Gfm1 caused drastic reductions in the mitochondrial EFG1 protein content in different organs. Six- to eight-week-old Gfm1R671C/R671C mice showed partial reductions of in organello mitochondrial translation and respiratory complex IV enzyme activity in the liver. Compound heterozygous Gfm1R671C/- showed a more pronounced decrease of EFG1 protein in liver and brain mitochondria, as compared with Gfm1R671C/R671C mice. At 8 weeks of age, their mitochondrial translation rates were significantly reduced in both tissues. Additionally, Gfm1R671C/- mice showed combined oxidative phosphorylation deficiency (reduced complex I and IV enzyme activities in liver and brain), and blue native polyacrylamide gel electrophoresis analysis revealed lower amounts of both affected complexes. We conclude that the compound heterozygous Gfm1R671C/- mouse presents a clear dysfunctional molecular phenotype, showing impaired mitochondrial translation and combined respiratory chain dysfunction, making it a suitable animal model for the study of COXPD1.

Therapy Prospects for Mitochondrial DNA Maintenance Disorders.

Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional mitochondrial DNA (mtDNA) replication and maintenance. As is the case for many other mitochondrial diseases, the options for the treatment of these disorders are rather limited today. Some aggressive treatments such as liver transplantation or allogeneic stem cell transplantation are among the few available options for patients with some forms of MDDS. However, in recent years, significant advances in our knowledge of the biochemical pathomechanisms accounting for dysfunctional mtDNA replication have been achieved, which has opened new prospects for the treatment of these often fatal diseases. Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches to more complex treatments, such as lentiviral or adenoassociated vector-mediated gene therapy. Some of these experimental therapies have already reached the clinical phase with very promising results, however, they are hampered by the fact that these are all rare disorders and so the patient recruitment potential for clinical trials is very limited.

Why should radiation oncology do translational research? [corrected].

Radiological Oncology, like the rest of medical specialties, is beginning to provide can personalized therapies. The ongoing scientific advances enable a great degree of precision in diagnoses and therapies. To fight cancer, from a radiotherapy unit, requires up-to-date equipment, professionals with different specialties working in synchrony (doctors, physicists, biologists, etc.) and a lot of research. Some of the new therapeutic tendencies are immunotherapy, nanoparticles, gene therapy, biomarkers, artificial intelligence, etc. A new clinical paradigm in which new professional networks are inevitable is arising. The mission of translational research is to become a scientific engine in the clinical space.

Multi-institutional Analysis of Metastasis-directed Therapy with or Without Androgen Deprivation Therapy in Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND: Metastasis-directed therapy (MDT) is increasingly being used in oligometastatic castration-sensitive prostate cancer (omCSPC). However, it is currently unclear how to optimally integrate MDT with the standard of care of systemic hormonal therapy. OBJECTIVE: To report long-term outcomes of MDT alone versus MDT and a defined course of androgen deprivation therapy (ADT) in omCSPC. DESIGN, SETTING, AND PARTICIPANTS: Here, a multicenter, international retrospective cohort of omCSPC as defined by conventional imaging was reported. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical progression-free survival (bPFS), distant progression-free survival (dPFS), and combined biochemical or distant progression-free survival (cPFS) were evaluated with Kaplan-Meier and multivariable Cox proportional hazard regression models. RESULTS AND LIMITATIONS: A total of 263 patients were included, 105 with MDT + ADT and 158 with MDT alone. The majority of patients had metachronous disease (90.5%). Five-year bPFS, dPFS, and cPFS were, respectively, 24%, 41%, and 19% in patients treated with MDT + ADT and 11% (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.36-0.64), 29% (HR 0.56, 95% CI 0.40-0.78), and 9% (HR 0.50, 95% CI 0.38-0.67) in patients treated with MDT alone. On a multivariable analysis adjusting for pretreatment variables, the use of ADT was associated with improved bPFS (HR 0.43, p < 0.001), dPFS (HR 0.45, p = 0.002), and cPFS (HR 0.44, p < 0.001). CONCLUSIONS: In this large multi-institutional report, the addition of concurrent ADT to MDT appears to improve time to prostate-specific antigen progression and distant recurrence, noting that about 10% patients had durable control with MDT alone. Ongoing phase 3 studies will help further define treatment options for omCSPC. PATIENT SUMMARY: Here, we report a large retrospective review evaluating the outcomes of metastasis-directed therapy with or without a limited course of androgen deprivation for patients with oligometastatic castration-sensitive prostate cancer. This international multi-institutional review demonstrates that the addition of androgen deprivation therapy to metastasis-directed therapy (MDT) improves progression-free survival. While a proportion of patients appear to have long-term disease control with MDT alone, further work in biomarker discovery is required to better identify which patients would be appropriate for de-escalated therapy.

COVID-19: hypofractionation in the Radiation Oncology Department during the 'state of alarm': first 100 patients in a private hospital in Spain.

During the COVID-19 pandemic, Spain declared a 'state of alarm' on 14 March 2020. In our Radiation Oncology Department, experienced in administering hypofractionated treatments (partial irradiation in breast cancer, moderate hypofractionation in localized prostate cancer, etc), we have increased the hypofractionated treatment indications. We are only deferring the start of non-urgent treatments such as prostate tumours under androgen deprivation or benign brain tumours which are candidates for radiosurgery such as meningiomas or acoustic neuroma. In this hypofractionation era we find that we have decreased the number of sessions per patient and that we can evaluate the last years with the fractionation index (FI) (calculated by dividing the total number of fractions administered in the department by the total number of patients treated). We have gone from 14.4 in 2018 to 13.78 in 2019, excluding brachytherapy. We report the results of the first 100 patients who have experienced radiotherapy treatment since the state of alarm (66 women and 34 men). In these patients, the FI is 12.12-lower than previous years.

Short-Course Radiotherapy in Locally Advanced Rectal Cancer.

INTRODUCTION: To date, we do not know the best therapeutic scheme in locally advanced rectal cancer when patients are older or have comorbidities. METHODS: In 2009, we established a prospective treatment protocol that included short-course preoperative radiotherapy (RT) with standard surgery +/- chemotherapy in frail patients, mostly older than 80 years or with comorbidities. RESULTS: We included 87 patients; the mean follow-up was 43.5 months (0.66-106.3). Disease-specific survival and disease-free survival at 36 months were 86.3% and 82.8%; at 60 months, they were 78.2% and 78%, respectively, with a local recurrence rate of 2.5%. The rate of late radiotoxicity was 9% in the form of sacral insufficiency fracture and small bowel obstruction with one death. The interval before surgery varied according to the involvement of the mesorectal fascia, but it was less than 2 weeks in 45% of cases. The rate of R0 was 95%. Surgical complications included abdominal wound dehiscence (3.5%), anastomotic leak (2.4%), and reoperations (11.5%). Downstaging was observed in 51% of the cases, regardless of the interval before surgery. DISCUSSION: Therapeutic outcomes in our group of elderly patients and/or patients with comorbidities with neoadjuvant short-course RT are such as those of the general population treated with neoadjuvant RT-chemotherapy, all with acceptable toxicity. Therefore, this treatment scheme, with short-course preoperative RT, would be the most appropriate in this group of patients.

Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides.

BACKGROUND: Preclinical studies have shown that gene therapy is a feasible approach to treat mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the genetic murine model of the disease (Tymp/Upp1 double knockout, dKO) has a limited functional phenotype beyond the metabolic imbalances, and so the studies showing efficacy of gene therapy have relied almost exclusively on demonstrating correction of the biochemical phenotype. Chronic oral administration of thymidine (dThd) and deoxyuridine (dUrd) to dKO mice deteriorates the phenotype of the animals, providing a better model to test therapy approaches. METHODS: dKO mice were treated with both dThd and dUrd in drinking water from weaning until the end of the study. At 8 - 11 weeks of age, mice were treated with several doses of adeno-associated virus (AAV) serotype 8 vector carrying the human TYMP coding sequence under the control of different liver-specific promoters (TBG, AAT, or HLP). The biochemical profile and functional phenotype were studied over the life of the animals. FINDINGS: Nucleoside exposure resulted in 30-fold higher plasma nucleoside levels in dKO mice compared with non-exposed wild type mice. AAV-treatment provided elevated TP activity in liver and lowered systemic nucleoside levels in exposed dKO mice. Exposed dKO mice had enlarged brain ventricles (assessed by magnetic resonance imaging) and motor impairment (rotarod test); both were prevented by AAV treatment. Among all promoters tested, AAT showed the best efficacy. INTERPRETATION: Our results show that AAV-mediated gene therapy restores the biochemical homeostasis in the murine model of MNGIE and, for the first time, demonstrate that this treatment improves the functional phenotype. FUNDING: This work was funded in part by the Spanish Instituto de Salud Carlos III, and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Vacuna contra la COVID-19 y menstruación, desde el desconocimiento a la información: revisión sistemática / Vaccine against COVID-19 and menstruation, from ignorance to information: a systematic review

La creación de una vacuna para enfrentar la pandemia de COVID-19 conllevó un vacío de información sobre las posibles alteraciones del ciclo menstrual. El objetivo fue verificar las posibles alteraciones que se pudiesen haber generado en el ciclo menstrual de las mujeres posterior a la inoculación de la vacuna contra la COVID-19. Se realizó una revisión sistemática en las bases bibliografías Medline, Medline Complete, LILACS, CINAHL y ScIELO, utilizando los descriptores “Women”, “Woman”, “Fertile period”, “Vaccination”, “Mass vaccination”, “Immunization”, “COVID-19 vaccines”, “SARS-CoV-2 infection”, “COVID-19”, “Menstrual cycle”, “Menstruation”, “Endometrial cycle”, “Dysmenorrhea” y “Menstruation disturbances”. Mediante la utilización del protocolo PRISMA, de los 319 artículos localizados, 17 fueron incluidos en el análisis. La mayoría de los estudios incluyeron, principalmente, las vacunas Pfizer, Moderna, AstraZeneca y Johnson&Johnson/Janssen con una a tres dosis administradas. El porcentaje de ciclos menstruales alterados fue del 8,0% al 77,8%, y la alteración con mayor frecuencia referida fue la duración del ciclo menstrual, que fue desde 0,3 hasta 12 días de retraso de la menstruación. Todos los estudios refieren cambios en el ciclo menstrual con diversas prevalencias, con y sin significación estadística; sin embargo, también concluyen que estas alteraciones son reversibles y en un corto periodo de tiempo.

The creation of a vaccine to face the COVID-19 pandemic, led to an information gap on possible alterations of the menstrual cycle. The objective was to verify the possible alterations that could have been generated in the menstrual cycle of women, after the inoculation of the vaccine against COVID-19. A systematic review was carried out in the Medline, Medline Complete, LILACS, CINAHL and ScIELO bibliographic databases, using the descriptors “Women”, “Woman”, “Fertile period”, “Vaccination”, “Mass vaccination”, “Immunization”, “COVID-19 vaccines”, “SARS-CoV-2 infection”, “COVID-19”, “Menstrual cycle”, “Menstruation”, “Endometrial cycle”, “Dysmenorrhea” and “Menstruation disturbances”. Using the PRISMA protocol, of the 319 articles located, 17 were included in the analysis. Most of the studies mainly included the Pfizer, Moderna, AstraZeneca and Johnson&Johnson/Janssen vaccines with one to three doses administered. The percentage of altered menstrual cycles ranged from 8.0% to 77.8%, and the most frequently reported alteration was the length of the menstrual cycle, which occurred from 0.3 to 12 days late in menstruation. All the studies refer to changes in the menstrual cycle with different prevalences, with and without statistical significance; however, the same studies also conclude that these alterations are reversible and in a short period of time.