Relapsed Acute Lymphoblastic Leukemia.

Outcomes for children with acute lymphoblastic leukemia (ALL) have improved worldwide to >85%. For those who relapse, outcomes have remained static at ~50% making relapsed acute lymphoblastic leukemia one of the leading causes of death in childhood cancers. Those relapsing within 18 mo in the bone marrow have a particularly dismal outcome. The mainstay of treatment is chemotherapy, local radiotherapy with or without hematopoietic stem cell transplantation (HSCT). Improved biological understanding of mechanisms of relapse and drug resistance, use of innovative strategies to identify the most effective and least toxic treatment regimens and global partnerships are needed to improve outcomes in these patients. Over the last decade, new therapeutic options and strategies have been developed for relapsed ALL including immunotherapies and cellular therapies. It is imperative to understand how and when to use these newer approaches in relapsed ALL. Increasingly, integrated precision oncology strategies are being used to individualize treatment of patients with relapsed ALL, especially in patients with poor response disease.

MSC.sensor: Capturing cancer cell interactions with stroma for functional profiling.

Mesenchymal stromal cells (MSCs) contribute to the microenvironment regulating normal and malignant hematopoiesis, and thus may support subpopulations of cancer cells to escape therapeutic pressure. Here, we engineered bone marrow MSCs to express a synthetic CD19-sensor receptor to detect and display interacting primary CD19+ leukemia cells in coculture. This implementation provides a versatile platform facilitating ex vivo drug response profiling of primary CD19+ leukemia cells in coculture with high-sensitivity and scalability.

Activity and toxicity of intramuscular 1000 iu/m2 polyethylene glycol-E. coli L-asparaginase in the UKALL 2003 and UKALL 2011 clinical trials.

In successive UK clinical trials (UKALL 2003, UKALL 2011) for paediatric acute lymphoblastic leukaemia (ALL), polyethylene glycol-conjugated E. coli L-asparaginase (PEG-EcASNase) 1000 iu/m2 was administered intramuscularly with risk-stratified treatment. In induction, patients received two PEG-EcASNase doses, 14 days apart. Post-induction, non-high-risk patients (Regimens A, B) received 1-2 doses in delayed intensification (DI) while high-risk Regimen C patients received 6-10 PEG-EcASNase doses, including two in DI. Trial substudies monitored asparaginase (ASNase) activity, ASNase-related toxicity and ASNase-associated antibodies (total, 1112 patients). Median (interquartile range) trough plasma ASNase activity (14 ± 2 days post dose) following first and second induction doses and first DI dose was respectively 217 iu/l (144-307 iu/l), 265 iu/l (165-401 iu/l) and 292 iu/l (194-386 iu/l); 15% (138/910) samples showed subthreshold ASNase activity (<100 iu/l) at any trough time point. Older age was associated with lower (regression coefficient -9.5; p < 0.0001) and DI time point with higher ASNase activity (regression coefficient 29.9; p < 0.0001). Clinical hypersensitivity was observed in 3.8% (UKALL 2003) and 6% (UKALL 2011) of patients, and in 90% or more in Regimen C. A 7% (10/149) silent inactivation rate was observed in UKALL 2003. PEG-EcASNase schedule in UKALL paediatric trials is associated with low toxicity but wide interpatient variability. Therapeutic drug monitoring potentially permits optimisation through individualised asparaginase dosing.

Unsatisfactory quality of E. coli asparaginase biogenerics in India: Implications for clinical outcomes in acute lymphoblastic leukaemia.

BACKGROUND: The biotherapeutic asparaginase is a cornerstone of therapy in acute lymphoblastic leukaemia (ALL). With limited access to the original native Escherichia coli-derived asparaginase (EcASNase), a variety of EcASNase biogenerics are used in low-middle-income countries (LMICs). The variable quality of these biogenerics potentially influences clinical outcomes. PROCEDURE: Seven biogeneric EcASNases (P1-P7) marketed widely in India were evaluated, with P2 as an exemplar for in vivo monitoring. Therapeutic activity of P2 (10,000 IU/m2 /dose, intramuscular, every 72 hours) was monitored during induction therapy, and drug-related toxicities recorded. Molecular identity, purity and in vitro drug activity of seven biogenerics were characterised using multimodal analyses, and findings compared with reference EcASNase (R). RESULTS: In patients (N = 62) receiving P2, subtherapeutic asparaginase activity (<100 U/L) was observed in 66% (46/70) of trough timepoints (72 hours postdose) during induction. Twelve patients (19%), 11 with high-risk ALL, developed hypersensitivity. Isoforms of EcASNase were identified in all seven biogenerics. All generic products contained impurities with batch-to-batch variability. These included high levels of protein aggregates and host cell protein contamination. In vitro assays of EcASNase activity and leukaemia cell line cytotoxicity were not discriminatory. CONCLUSIONS: Our findings confirm widespread concerns over the unsatisfactory quality and therapeutic activity of native EcASNase biogenerics marketed in LMICs. Appropriate use of these products requires monitored studies to identify clinical suitability and determine appropriate dosing and schedule. For large parts of the world, assured access to high-quality asparaginases remains an unmet therapeutic need.

Total intravenous versus inhaled anesthesia in transsphenoidal tumor surgery.

PURPOSE: Visualization of the surgical field is essential for patient safety during endoscopic transsphenoidal tumor surgery. In this retrospective chart review and data analysis of patients undergoing endoscopic transsphenoidal resection of pituitary tumors under general anesthesia we sought to determine if total intravenous anesthesia with propofol and remifentanil leads to decreased bleeding, surgical duration, time to extubation and/or length of stay in the recovery room compared to inhaled anesthesia with sevoflurane or desflurane. METHODS: After IRB approval, chart reviews of 193 American Society of Anesthesiologists class 1 to 3 patients were conducted who had undergone transsphenoidal, endonasal resections of pituitary tumors under total intravenous or inhaled anesthesia at an academic teaching hospital in the United States over a seven-year time period. One hundred four patients fulfilled the inclusion criteria and were further reviewed. Primary outcome was intraoperative blood loss; secondary outcomes were surgical duration, time to extubation and length of stay in the recovery room. RESULTS: Gender, age, and Lund-Mackay-Scores were equally distributed between the two anesthetic groups. We found no significant effect of the anesthetic technique, age, gender, or Lund Mackay score on any of the primary or secondary outcomes. The only significant predictor for recovery room length of stay was intraoperative blood loss. CONCLUSION: Our study shows no evidence that total intravenous anesthesia is superior to inhaled anesthesia or vice versa during endoscopic transsphenoidal sinus surgery with regard to relevant clinical outcome parameters.

Maternal and Neonatal Tetanus: A Journey into Oblivion.

India was declared free of maternal and neonatal tetanus on 15th May, 2015. The journey towards its elimination from India has not been easy, and sustained efforts will be required to maintain this status. As the schedule of tetanus vaccination during pregnancy has been same across various health programs by the Government of India, we deliberated to find out other factors that contributed to a decline in maternal and neonatal tetanus in India. The emphasis on augmenting antenatal care services, increasing institutional deliveries and improving routine vaccination coverage are factors that might have led to a reduction in cases of neonatal tetanus.

Acute Disseminated Encephalomyelitis After Plasmodium Vivax Infection: Case Report and Review of Literature.

Acute demyelinating encephalomyelitis (ADEM) usually occurs after viral infections or vaccination. Its occurrence after Plasmodium vivax infection is extremely uncommon. We report the case of an 8-year-old girl who had choreo-athetoid movements and ataxia after recovery from P.vivax infection. Diagnosis of ADEM was made on the basis of magnetic resonance imaging findings. The child responded to corticosteroids with complete neurological recovery.

Advanced trauma life support radiographic trauma series: Part 3--The pelvis radiograph.

Pelvic fractures are often high energy injuries and are associated with a high morbidity and mortality. The plain antero-posterior pelvis radiograph is part of the advanced trauma life support radiographic trauma series and is used as a screening test. The main limitation of plain anteroposterior pelvic radiographs is the difficulty in identification of some fractures, in particular posterior fractures, therefore radiographic findings should be considered in conjunction with clinical assessment.

Advanced trauma life support radiographic trauma series: part 1--The cervical spine radiograph.

Plain cervical spine radiographs are the first line investigation in trauma patients to exclude cervical spine fractures and dislocations. Adequate views are essential to reduce the risk of missing diagnoses. Injuries may however not be visible on plain cervical spine radiographs despite adequate views. Additional imaging such as computer tomography scanning is indicated in the event of a normal plain radiograph if there is any clinical suspicion of injury.

Advanced trauma life support radiographic trauma series: part 2--the chest radiograph.

The chest radiograph is used as a screening test to exclude significant thoracic injuries in cases of major trauma. A systematic approach to reviewing chest radiographs is necessary for accurate interpretation. Radiographic findings should be considered together with clinical assessment.