Long-term Natural History of Pediatric Dominant and Recessive RYR1-Related Myopathy.

BACKGROUND AND OBJECTIVES: RYR1-related myopathies are the most common congenital myopathies, but long-term natural history data are still scarce. We aim to describe the natural history of dominant and recessive RYR1-related myopathies. METHODS: A cross-sectional and longitudinal retrospective data analysis of pediatric cases with RYR1-related myopathies seen between 1992-2019 in 2 large UK centers. Patients were identified, and data were collected from individual medical records. RESULTS: Sixty-nine patients were included in the study, 63 in both cross-sectional and longitudinal studies and 6 in the cross-sectional analysis only. Onset ranged from birth to 7 years. Twenty-nine patients had an autosomal dominant RYR1-related myopathy, 31 recessive, 6 de novo dominant, and 3 uncertain inheritance. Median age at the first and last appointment was 4.0 and 10.8 years, respectively. Fifteen% of patients older than 2 years never walked (5 recessive, 4 de novo dominant, and 1 dominant patient) and 7% lost ambulation during follow-up. Scoliosis and spinal rigidity were present in 30% and 17% of patients, respectively. Respiratory involvement was observed in 22% of patients, and 12% needed ventilatory support from a median age of 7 years. Feeding difficulties were present in 30% of patients, and 57% of those needed gastrostomy or tube feeding. There were no anesthetic-induced malignant hyperthermia episodes reported in this cohort. We observed a higher prevalence of prenatal/neonatal features in recessive patients, in particular hypotonia and respiratory difficulties. Clinical presentation, respiratory outcomes, and feeding outcomes were consistently more severe at presentation and in the recessive group. Conversely, longitudinal analysis suggested a less progressive course for motor and respiratory function in recessive patients. Annual change in forced vital capacity was -0.2%/year in recessive vs -1.4%/year in dominant patients. DISCUSSION: This clinical study provides long-term data on disease progression in RYR1-related myopathies that may inform management and provide essential milestones for future therapeutic interventions.

The case of encephalitis in a COVID-19 pediatric patient.

BACKGROUND: The COVID-19 pandemic, induced by the worldwide spreading of the SARS-CoV-2, is well known for its clinical picture consistent with respiratory symptoms. If pulmonary complications are the most common manifestation of the disease, neurological problems are also significantly present, with complications including acute cerebrovascular events, encephalitis, Guillain-Barré and Miller Fisher syndromes, acute necrotizing hemorrhagic encephalopathy and hemophagocytic lymphohistiocytosis. These medical signs can be considered direct effects of the virus on the nervous system, para-infectious or post-infectious immune-mediated diseases, and neurological complications of the systemic effects of the SARS-CoV-2. CASE: In the present article, the encephalitis case in a 5-year-old girl positive for COVID-19 admitted to the emergency department complaining of fever and swelling in the neck is described. At this time, her neurological examination was unremarkable. Over the next few days, the fever went down and she experienced acute behavioral changes, mild confusion, and drowsiness. The brain MRI and electroencephalography (EEG) showed CNS involvement, suggestive of encephalitis. CONCLUSION: The dramatic improvement of the symptoms after immunotherapy with corticosteroids reinforced the hypothesis of an immune-related mechanism.

Bone health in Duchenne muscular dystrophy: clinical and biochemical correlates.

PURPOSE: An increased fracture risk is commonly reported in Duchenne muscular dystrophy (DMD). Our aim was to investigate bone mineral density (BMD) and bone turnover, including sclerostin, and their association with markers of cardiac and respiratory performance in a cohort of DMD subjects. METHODS: In this single center, cross sectional observational study, lumbar spine (LS) BMD Z-scores, C-terminal telopeptide of procollagen type I (CTX) and osteocalcin (BGP), as bone resorption and formation markers, respectively, and sclerostin were assessed. Left ventricular ejection fraction (LVEF) and forced vital capacity (FVC) were evaluated. Clinical prevalent fractures were also recorded. RESULTS: Thirty-one patients [median age = 14 (12-21.5) years] were studied. Ambulant subjects had higher LS BMD Z-scores compared with non-ambulant ones and subjects with prevalent clinical fractures [n = 9 (29%)] showed lower LS BMD Z-scores compared with subjects without fractures. LS BMD Z-scores were positively correlated with FVC (r = 0.50; p = 0.01), but not with glucocorticoid use, and FVC was positively associated with BGP (r = 0.55; p = 0.02). In non-ambulant subjects, LS BMD Z-scores were associated with BMI (r = 0.54; p = 0.02) and sclerostin was associated with age (r = 0.44; p = 0.05). Age, BMI, FVC and sclerostin were independently associated with LS BMD Z-score in a stepwise multiple regression analysis. Older age, lower BMI, FVC and sclerostin were associated with lower LS BMD Z-scores. CONCLUSION: In a cohort of DMD patients, our data confirm low LS BMD Z-scores, mainly in non-ambulant subjects and irrespective of the glucocorticoid use, and suggest that FVC and sclerostin are independently associated with LS BMD Z-scores.

Pembrolizumab for advanced cervical cancer: safety and efficacy.

Introduction: Pembrolizumab is an immune checkpoint inhibitor with high specificity for binding to the programmed cell death 1 (PD-1) receptor. It has been approved by the FDA in patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express the programmed cell death ligand 1 (PD-L1).Areas covered: Clinical studies of pembrolizumab in cervical cancer were analyzed and discussed. Data were obtained by searching for English peer-reviewed articles on PubMed, clinical trials registered on clincaltrials.gov and related abstracts on the ASCO meeting library. The aim was to review the status of pembrolizumab, the published and ongoing trials, and its safety and efficacy.Expert opinion: Pembrolizumab may ultimately represent a treatment of choice for advanced cervical cancer with PD-L1 expression, both in metastatic and recurrent setting. However, it is essential to better identify and characterize patients that will benefit the most.

Effect of exercise on telomere length and telomere proteins expression in mdx mice.

In Duchenne muscular dystrophy (DMD), telomere shortening has been postulated to contribute to the failure of regenerative activity promoting the premature senescence of satellite cells. The aim of the present study was to investigate the telomere length and the expression of telomeric repeat-binding factor-1 (TRF1), poly (ADP-ribose) polymerase-1 (PARP1) and mouse telomerase reverse transcriptase (MTERT) in gastrocnemius, tibialis anterior and diaphragm muscles of the murine model of DMD, the mdx mouse and whether a chronic protocol of forced exercise impacts on them. Our results confirmed a telomere shortening in mdx muscles, more evident in the diaphragm, in which exercise induced a greater shortening than in wild-type mice. Moreover, we showed for the first time in mdx an increased TRF1 and PARP1 expression and an augmented activity of MTERT, further enhanced by exercise. These results reinforce the hypothesis that a deregulation of mechanisms involved in telomere length occurs and may pave the way for the test of compounds targeting proteins modulating telomere maintenance as a novel strategy to treat dystrophinopathies.

Trametinib response in heavily pretreated high-grade ovarian cancer: One step towards precision medicine.

Traditional treatment failure in recurrent ovarian cancer remains a challenge for clinicians. Tumor genetic testing is a promising tool which has been proved able to identify sensitivity profiles in patients affected by cancers. This may be helpful in choosing targeted systemic treatments, aiming to overcome histology boundaries and to avoid unnecessary toxicity. We describe the case of a patient affected by recurrent high-grade serous ovarian cancer responsive to MEK-inhibitors, who had undergone multiple lines of therapy. To our knowledge, this is the first reported case of recurrent high-grade ovarian cancer showing remarkable clinical, radiologic and biochemical response to trametinib. This report suggests that trametinib could be effective in high-grade serous ovarian cancer, although most of promising scientific data on this molecule have focused on low-grade ovarian cancer. Molecular profiling has gradually become part of care for patients affected by recurrent ovarian cancer, however further randomized studies are needed to prove its efficacy in everyday clinical practice.

Optimizing treatment in recurrent epithelial ovarian cancer.

INTRODUCTION: Optimal management of recurrent ovarian cancer (ROC) remains an area of uncertainty. An estimated 85% of patients with epithelial ovarian cancer who achieve a full remission following first-line therapy will develop recurrent disease and median survival for these patients' ranges from 12 months to 24 months. Many patients receive several lines of treatment following recurrence and, although each subsequent line of therapy is characterized by shorter disease-free intervals, decisions about the most appropriate treatment is complex. Areas covered: This review focuses on chemotherapy, surgery and emerging biologic agents that present a therapeutic option for patients with ROC. Expert commentary: Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. Patients with platinum-sensitive ovarian cancer should have their recurrence treated with a platinum-based agent. For patients whose cancer progresses after platinum retreatment and for those with platinum-resistant disease, numerous other non-platinum combination and targeted therapies have been shown to be effective in palliating cancer-related symptoms and extending life.

Health-related quality of life and functional changes in DMD: A 12-month longitudinal cohort study.

In Duchenne muscular dystrophy (DMD) little has been reported on the association between clinical outcome measures and patient health-related quality of life (HRQOL) tools. Our study evaluated the relationship between 12 month changes on the Generic Core Scales (GCS), the Multidimensional Fatigue Scale and the Neuromuscular Module of the PedsQL(TM) with several outcome measures (6 minute walk test, North Star Ambulatory Assessment and timed items) in ambulatory DMD. Ninety-eight ambulatory DMD in a multicentric setting were included in the study. At baseline, the PedsQL(TM) inventories correlated with almost all the functional measures On the Child Self-Report there was a significant decrease between baseline and 12 months on the PedsQL(TM) GCS and its first domain, in parallel with the decrement in the functional outcome measures. Correlation between the 12 month changes on the PedsQL(TM) inventories and functional measures were almost all negligible. Similar results were obtained on the Parent Proxy-Report. In conclusion, PedsQL(TM) correlates with the level of impairment at baseline, but this does not hold true when 12 month changes are considered. Further studies comparing different tools are needed to better elucidate the complexity of the relationship between HRQOL and functional performances.

Ovarian serous carcinoma presenting with mediastinal lymphadenopathy 20 months before the intraabdominal mass: role of immunohistochemistry.

INTRODUCTION: Metastatic involvement of the mediastinal lymph nodes is an extremely uncommon finding in epithelial ovarian cancers. CASE REPORT: A 63-year-old woman was admitted to hospital for dyspnoea due to an anterior mediastinal mass. The surgical biopsy showed a 6-cm metastatic lymph node with a papillary pattern, scattered psammomas and immunoreactivity for WT1, Cytokeratin 7, EMA and negative for E-cadherin, GCFDP-15, Thyroglobulin, Cytokeratin 20, Cytokeratin 5/6, CEA, Vimentin, Calretinin, TTF1. After 20 months a follow-up CT identified an ovarian mass with the same histological pattern and immunoreactivity of the mediastinal nodule. RESULTS: Immunohistochemistry, especially WT1, is useful in assessing the ovarian origin of an unusual metastasis particularly if it is the first presentation of the disease.

Prognostic role of the ratio between cyclooxygenase-2 in tumor and stroma compartments in cervical cancer.

PURPOSE: The aim of this study was to analyze the clinical role of cyclooxygenase (COX)-2 in a large series of 175 cervical cancer patients. EXPERIMENTAL DESIGN: Immunohistochemistry was performed on paraffin-embedded sections by using rabbit antiserum against COX-2. The tumor:stroma (T/S) ratio of COX-2 expression was used to define the overall COX-2 content in the tumor. RESULTS: The T/S COX-2 ratio values ranged from 0.03 to 48.2 (mean +/- SE, 3.7 +/- 0.5). A total of 95 of 175 patients (54.3%) were scored as having a high (>1) T/S COX-2 ratio. In locally advanced cervical cancer patients who underwent neoadjuvant treatment, the percentage of cases showing a high T/S COX-2 ratio was greater in patients who did not respond to treatment (26 of 29 patients, 89.7%) than in patients with a partial (32 of 50 patients, 64.0%) or complete (19 of 44 patients, 43.2%) response (P = 0.0003). When logistic regression was applied, International Federation of Gynecologists and Obstetricians (FIGO) stage (chi(2) = 11.3; P = 0.0008) and T/S COX-2 ratio (chi(2) = 5.3; P = 0.021) retained an independent role in predicting a poor chance of response. Cases with a high T/S COX-2 ratio had a shorter overall survival (OS) [2-year OS, 61%(95% confidence interval 750-83)] than cases with a low T/S COX-2 ratio (2-year OS, 90%; 95% confidence interval, 81-99; P = 0.0001). In multivariate analysis, the status of T/S COX-2 IDV ratio, together with advanced stage, retained an independent negative prognostic role for OS. CONCLUSIONS: The assessment of COX-2 status in both tumor and stroma compartment could provide valuable information to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant treatment and unfavorable prognosis.