Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to pathological pain syndromes of neuropathic or inflammatory origin. Drugs that enhance the activity of dorsal horn 2/3GABAARs normalize exaggerated nociceptive responses in rodents with neuropathic nerve lesions or peripheral inflammation but lack most of the typical side effects of less specific GABAergic drugs. It is however still unknown whether such drugs also reduce the clinically more relevant conscious perception of pain. Here, we investigated the effects of the 2/3GABAAR subtype-selective modulator TPA023B on the tonic aversive component of pain in mice with peripheral inflammation or neuropathy. In neuropathic mice with a chronic constriction injury of the sciatic nerve, TPA023B not only reversed hyperalgesia to tactile and heat stimuli but also was highly effective in the conditioned place preference test. In the formalin test, TPA023B not only reduced licking of the injected paw but also reversed facial pain expression scores in the mouse grimace scale assay. Taken together, our results demonstrate that 2/3GABAA receptor subtype-selective modulators not only reduce nociceptive withdrawal responses but also alleviate the tonic aversive components of chronic pain.

We report a retrospective analysis of 110 unselected pediatric patients with acute lymphoblastic leukemia (ALL) treated during 2015–2017 in a charity‐funded public institution in Cambodia with a reduced intensity ALL‐Moscow Berlin (MB)‐91 protocol. No patient abandoned treatment. Sixty‐three patients (57%) were high risk (HR). Seventy‐two patients (65.5%) reached complete remission (CR) on day 36. The 3‐year event‐free survival (EFS) and overall survival (OS) was 34.9% (50.5% for standard risk [SR]). Most deaths resulted from infections (40 [53.3%]) and bleeding (15 [20%]). With further selective reduction of treatment intensity and access to platelet infusion, leukemia therapy is justified in this setting.

Background. The treatment of childhood acute lymphoblastic leukemia (ALL) remains challenging in low-income countries. Here we evaluate the experience with a modified Berlin-Frankfurt-Münster (BFM) treatment protocol ALL-Moscow Berlin (MB)-91 at the Kantha Bopha hospitals, a charity-funded institution providing free pediatric care in Cambodia. Methods. This is a retrospective study including 110 unselected patients aged 9 months to 14 years diagnosed with ALL between 2015 and 2017. Patients were stratified in high- (HR) and standard-risk (SR) groups based on clinical criteria. The cumulative doses of anthracyclines were reduced to 120 mg/m2 for SR patients and consolidation was based on Capizzi methotrexate elements instead of cyclophosphamide, cytarabine and high dose methotrexate. Supportive empiric antibiotic treatment and whole blood transfusions were possible. Results. 63 patients (57 %) were HR, mostly based on high leukemia burden with hyperleukocytosis > 50 G/l, massive lymph node and hepato-splenic involvement, reflecting a high disease burden. 72 patients (65.5%) reached complete remission (CR) on day 36. The estimated 3-year overall survival (OS) was 34.9 %, 50.5 % for SR and 23.4 % for HR patients. Most events were due to severe infections (40 (53.3 %)) and bleeding (15 (20 %)), mostly during induction and consolidation. Relapse was confirmed in 13 cases (11.8 %). No patients abandoned treatment. Conclusion. ALL chemotherapy is feasible in a charity-funded public institution with results comparable to other low-middle income countries, but treatment-related mortality remains limiting. This will justify investments in diagnostics to stratify more patients for reduced intensity treatment and in supportive care.