Molecular Genetics in the Diagnosis and Prognosis of Solid Pediatric Tumors

The field of molecular genetics continues to see an ever increasing number of applications to pediatric tumor analysis. Studies in pediatric tumors have identified novel genes and other genetic changes, a large number of which reflect one of the following mechanisms: (1) activation of proto-oncogenes; (2) loss of tumor suppressor genes; or (3) creation of novel fusion proteins. At least one of these mechanisms is operational in each of the following pediatric tumors: neuroblastoma, Ewing sarcoma and peripheral primitive neuroectodermal tumor (pPNET), intra-abdominal desmoplastic small-cell tumor, rhabdomyosarcoma, synovial sarcoma, and Wilms tumor. Out of this research has come not only an increased understanding of oncogenesis but also, for each of the tumors listed above, diagnostic and/or prognostic markers that can be used by the pathologist and oncologist to improve overall patient management. Received November 20, 1997; accepted April 20, 1998.     

The validity of continuous automated fluid monitoring during endometrial surgery: luxury or necessity?

Thirty-four consecutive women undergoing endometrial laser ablation, as a treatment of menorrhagia, were recruited to assess the validity of fluid absorption monitoring by a new continuous automated system (AquaSens). The same group of women also had monitoring of fluid absorption carried out by our standard technique of weighing. The intra-class correlation coefficient for the fluid deficit estimated by AquaSens compared to our standard technique of manually weighing the irrigation bags was 0.98 (95% CI 0.96–0.99). Aquasens therefore provides a valid and non-invasive method of continuously monitoring fluid deficit amongst patients undergoing operative hysteroscopy procedures, thereby reducing the risk of unexpected fluid absorption and its potentially fatal sequelae.     

Serial Transvaginal Ultrasonography Following McDonald Cerclage and Repeat Suture Insertion

Summary: The aim of this study was to explore the hypothesis that serial transvaginal ultrasonography identifies early evidence of suture failure and that repeat cerclage delays delivery. We undertook a review of our policy of transvaginal ultrasonographic cervical surveillance after McDonald cerclage and of repeat suture insertion if persistent cervical effacement developed. Data from 26 pregnancies in 26 women are analyzed. The women had had a total of 57 mid-trimester miscarriages with a median of 2 (1–6) mid-trimester losses per woman. Twelve (46%) of the 26 women developed cervical changes at scan and underwent repeat cerclage. All 14 women who had a single suture inserted progressed to live births but 1 of the 13 women who had repeat cerclage had a mid-trimester miscarriage (p>0.05). The median gestation at delivery for the women who had repeat cerclage was 35 (22–39) weeks compared with 38 (36–40) weeks for those who had a single suture (p>0.05). The median interval from the detection of cervical changes at scan to delivery was 13 (4–19) weeks. Serial transvaginal ultrasonography after cervical cerclage identifies a group of women who are more likely to deliver preterm, and provides an opportunity for intervention (repeat cerclage) which appears to delay delivery by an average of 7 weeks.     

Randomized trial of two intravenous schedules of the topoisomerase I inhibitor liposomal lurtotecan in women with relapsed epithelial ovarian cancer: a trial of the national cancer institute of Canada clinical trials group.

PURPOSE: Liposomal lurtotecan (OSI-211) is a liposomal formulation of the water-soluble topoisomerase I inhibitor lurtotecan (GI147211), which demonstrated superior levels of activity compared with topotecan in preclinical models. We studied two schedules of OSI-211 in a randomized design in relapsed ovarian cancer to identify the more promising of the two schedules for further study. PATIENTS AND METHODS: Eligible patients had measurable epithelial ovarian, fallopian, or primary peritoneal cancer that was recurrent after one or two prior regimens of chemotherapy. Patients were randomly assigned to receive either arm A (OSI-211 1.8 mg/m(2)/d administered by 30-minute intravenous infusion on days 1, 2, and 3 every 3 weeks) or arm B (OSI-211 2.4 mg/m(2)/d administered by 30-minute intravenous infusion on days 1 and 8 every 3 weeks). The primary outcome measure was objective response, which was confirmed by independent radiologic review, and a pick the winner statistical design was used to identify the schedule most likely to be superior. RESULTS: Eighty-one patients were randomized between October 2000 and September 2001. The hematologic toxic effects were greater on arm A than on arm B (grade 4 neutropenia, 51% v 22%, respectively), as was febrile neutropenia (26% v 2.4%, respectively). Of the 80 eligible patients, eight patients (10%) had objective responses; six responders (15.4%; 95% CI, 6% to 30%) were in arm A and two responders (4.9%; 95% CI, 1% to 17%) were in arm B. CONCLUSION: The OSI-211 daily for 3 days intravenous schedule met the statistical criteria to be declared the winner in terms of objective response. This schedule was also associated with more myelosuppression than the schedule of OSI-211 administered in arm B.     

The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication

Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disabling disease that can cause long-term severe arthritis. Since the last large CHIKV outbreak in 2015, the reemergence of the virus represents a serious public health concern. The morbidity associated with viral infection emphasizes the need for the development of specific anti-CHIKV drugs. Herein, we describe the development and characterization of a CHIKV reporter replicon cell line and its use in replicon-based screenings. We tested 960 compounds from MMV/DNDi Open Box libraries and identified four candidates with interesting antiviral activities, which were confirmed in viral infection assays employing CHIKV-nanoluc and BHK-21 cells. The most noteworthy compound identified was itraconazole (ITZ), an orally available, safe, and cheap antifungal, that showed high selectivity indexes of >312 and >294 in both replicon-based and viral infection assays, respectively. The antiviral activity of this molecule has been described against positive-sense single stranded RNA viruses (+ssRNA) and was related to cholesterol metabolism that could affect the formation of the replication organelles. Although its precise mechanism of action against CHIKV still needs to be elucidated, our results demonstrate that ITZ is a potent inhibitor of the viral replication that could be repurposed as a broad-spectrum antiviral.     

Risk assessment in COVID‐19: Prognostic importance of cardiovascular parameters

BackgroundCardiovascular risk factors and comorbidities are highly prevalent among COVID‐19 patients and are associated with worse outcomes.HypothesisWe therefore investigated if established cardiovascular risk assessment models could efficiently predict adverse outcomes in COVID‐19. Furthermore, we aimed to generate novel risk scores including various cardiovascular parameters for prediction of short‐ and midterm outcomes in COVID‐19.MethodsWe included 441 consecutive patients diagnosed with SARS‐CoV‐2 infection. Patients were followed‐up for 30 days after the hospital admission for all‐cause mortality (ACM), venous/arterial thromboembolism, and mechanical ventilation. We further followed up the patients for post‐COVID‐19 syndrome for 6 months and occurrence of myocarditis, heart failure, acute coronary syndrome (ACS), and rhythm events in a 12‐month follow‐up. Discrimination performance of DAPT, GRACE 2.0, PARIS‐CTE, PREDICT‐STABLE, CHA2‐DS2‐VASc, HAS‐BLED, PARIS‐MB, PRECISE‐DAPT scores for selected endpoints was evaluated by ROC‐analysis.ResultsOut of established risk assessment models, GRACE 2.0 score performed best in predicting combined endpoint and ACM. Risk assessment models including age, cardiovascular risk factors, echocardiographic parameters, and biomarkers, were generated and could successfully predict the combined endpoint, ACM, venous/arterial thromboembolism, need for mechanical ventilation, myocarditis, ACS, heart failure, and rhythm events. Prediction of post‐COVID‐19 syndrome was poor.ConclusionRisk assessment models including age, laboratory parameters, cardiovascular risk factors, and echocardiographic parameters showed good discrimination performance for adverse short‐ and midterm outcomes in COVID‐19 and outweighed discrimination performance of established cardiovascular risk assessment models.