Real-world treatment patterns and outcomes in patients with primary hemophagocytic lymphohistiocytosis treated with emapalumab.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome. Emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon-gamma, is approved in the United States to treat primary HLH (pHLH) in patients with refractory, recurrent, progressive disease or intolerance with conventional HLH. REAL-HLH, a retrospective study, conducted across 33 US hospitals, evaluated real-world treatment patterns and outcomes in patients treated with ≥1 dose of emapalumab between November 20, 2018, and October 31, 2021. Forty-six patients met the pHLH classification criteria. Median (range) age at diagnosis was 1.0 (0.3-21.0) year. Emapalumab was initiated for treating refractory (19/46), recurrent (14/46), or progressive (7/46) pHLH. At initiation, 15/46 patients were in the intensive care unit and 35/46 had received prior HLH-related therapies. Emapalumab treatment resulted in normalization of key laboratory parameters, including chemokine ligand 9 (CXCL9) (24/33; 72.7%), ferritin (20/45; 44.4%), fibrinogen (37/38; 97.4%), platelets (39/46; 84.8%), and absolute neutrophil count (40/45; 88.9%). Forty-two (91.3%) patients were considered eligible for transplant. Pre-transplant survival was 38/42 (90.5%). Thirty-one (73.8%) transplant-eligible patients proceeded to transplant and 23/31 (74.2%) of those transplanted were alive at the end of the follow-up period. Twelve-month survival probability from emapalumab initiation for the entire cohort (n=46) was 73.1%. There were no discontinuations due to adverse events. In conclusion, results from the REAL-HLH study, which describes treatment patterns, effectiveness, and outcomes in patients with pHLH treated with emapalumab in real-world settings, are consistent with the emapalumab pivotal phase 2/3 pHLH trial.

Vagus nerve stimulation primes platelets and reduces bleeding in hemophilia A male mice.

Deficiency of coagulation factor VIII in hemophilia A disrupts clotting and prolongs bleeding. While the current mainstay of therapy is infusion of factor VIII concentrates, inhibitor antibodies often render these ineffective. Because preclinical evidence shows electrical vagus nerve stimulation accelerates clotting to reduce hemorrhage without precipitating systemic thrombosis, we reasoned it might reduce bleeding in hemophilia A. Using two different male murine hemorrhage and thrombosis models, we show vagus nerve stimulation bypasses the factor VIII deficiency of hemophilia A to decrease bleeding and accelerate clotting. Vagus nerve stimulation targets acetylcholine-producing T lymphocytes in spleen and α7 nicotinic acetylcholine receptors (α7nAChR) on platelets to increase calcium uptake and enhance alpha granule release. Splenectomy or genetic deletion of T cells or α7nAChR abolishes vagal control of platelet activation, thrombus formation, and bleeding in male mice. Vagus nerve stimulation warrants clinical study as a therapy for coagulation disorders and surgical or traumatic bleeding.

The Use of Hyperbaric Oxygen Therapy in the Management of Severe Radiation-Induced Hemorrhagic Gastritis in a Pediatric Patient.

Radiation-induced hemorrhagic gastritis is a serious and rare complication of radiation therapy. Optimal therapies in the pediatric population are not well established. We report a 2-year-old female diagnosed with rhabdomyosarcoma who developed hemorrhagic gastritis following chemotherapy and radiation therapy. The patient presented with acute onset anemia, hematemesis, and melena. Endoscopies revealed circumferential ulceration at the pylorus with spontaneous oozing that failed to respond effectively with multimodal medical and endoscopic therapies. Following hemodynamic stabilization, the patient was treated with hyperbaric oxygen therapy with excellent clinical response of the bleeding. Further research on the benefit of hyperbaric oxygen therapy is warranted to determine if this treatment can reduce the incidence of gastrointestinal complications in patients who have received radiation therapy.

Primary thromboprophylaxis to prevent thrombotic events in pediatric oncology patients with a malignant mediastinal mass.

Children with malignant mediastinal masses have increased thrombotic events (TE). Eligible subjects with malignant mediastinal masses between January 2000 and December 2017 were evaluated for TE, with 19 among 76 subjects receiving enoxaparin thromboprophylaxis. There were 13 TEs among 76 subjects for an incidence of 17.1%. Mediastinal compression directly led to TE in 9.2% of subjects who also had statistically significant superior vena cava compression at diagnosis. Primary thromboprophylaxis did not significantly affect TE occurrence; however, larger studies are warranted to consider strategic thromboprophylaxis guided by radiological monitoring of dynamic vascular compression to improve TE outcomes.

Data on optimization of microprojectile bombardment parameters in development of salinity tolerant transgenic lines.

This data deals with the optimization of microprojectile bombardment particles for efficient genetic transformation in an indica rice involving AmSOD gene for development of salinity tolerant transgenic lines [1]. In this study, various parameters such as effect of genotypes, helium pressure, osmoticum, explants, flight distance, particle size, particle volume, vacuum, carrier DNA and stopping screen properties have been evaluated to determine their role in transformation of indica rice involving AmSOD gene for development of salinity tolerant Pusa Basmati 1 rice variety. To perform the transformation process, plasmid vector pCAMBIA 1305.2 was used, which harbours GUS Plus™ gene, intron from the castor bean catalase gene, pBR322 ori, kanamycin resistant gene and Xho I site. The transformants have been confirmed using slot blot, polymerase chain reaction and Southern hybridization techniques.

Hb Adana (HBA2 or HBA1: c.179G > A) and alpha thalassemia: Genotype-phenotype correlation.

Alpha thalassemia due to nondeletional mutations usually leads to more severe disease than that caused by deletional mutations. Devastating outcomes such as hydrops fetalis can occur with two nondeletional mutations, therefore warranting DNA-based workup for suspected carriers with subtle hematological abnormalities for family counseling purposes. We describe three cases with hemoglobin (Hb) Adana, a nondeletional alpha chain mutation, compounded with an alpha globin gene deletion resulting in thalassemia intermedia. We review the literature, draw genotype-phenotype correlations from published cases of Hb Adana, and propose that this correlation can be used by clinicians to help direct diagnostic studies and urge hematologists to thoroughly workup high-risk patients.

Bleeding Disorders in Congenital Syndromes.

Pediatricians provide a medical home for children with congenital syndromes who often need complex multidisciplinary care. There are some syndromes associated with thrombocytopenia, inherited platelet disorders, factor deficiencies, connective tissue disorders, and vascular abnormalities, which pose a real risk of bleeding in affected children associated with trauma or surgeries. The risk of bleeding is not often an obvious feature of the syndrome and not well documented in the literature. This makes it especially hard for pediatricians who may care for a handful of children with these rare congenital syndromes in their lifetime. This review provides an overview of the etiology of bleeding in the different congenital syndromes along with a concise review of the hematologic and nonhematologic clinical manifestations. It also highlights the need and timing of diagnostic evaluation to uncover the bleeding risk in these syndromes emphasizing a primary care approach.

An unusual presentation of autonomic dysreflexia in a patient with cold abscess of cervical spine for anterolateral decompression.

A young female having complaints of quadriparesis along with bladder and bowel involvement, diagnosed to have osseous destruction of C4, C6, C7, T2 vertebral bodies with pre- and para-vertebral abscess, was taken up for anterolateral decompression and fusion of cervical spine. She presented with anxiety, agitation, sweating and headache and was in hypertensive crisis which was refractory to antihypertensives, anxiolytics and analgesics but showed a reasonable response to intravenous dexmedetomidine and finally responded dramatically to rectal evacuation. Autonomic dysreflexia was suspected with stimulus arising from distended rectum as all other causes of hypertension were ruled out.

The homozygous VHL(D126N) missense mutation is associated with dramatically elevated erythropoietin levels, consequent polycythemia, and early onset severe pulmonary hypertension.

von Hippel-Lindau (VHL) protein is the principal negative regulator of hypoxia sensing mediated by transcription factors. Mutations in exon 3 of the VHL gene lead to Chuvash (VHL(R200W)) and Croatian (VHL(H191D)) polycythemias. Here, we describe an infant of Bangladesh ethnicity with a novel homozygous VHL(D126N) mutation with congenital polycythemia and dramatically elevated erythropoietin (EPO) levels, who developed severe fatal pulmonary hypertension. In contrast to Chuvash polycythemia, erythroid progenitors (BFU-Es) did not reveal a marked EPO hypersensitivity. Further, NF-E2 and RUNX1 transcripts that correlate with BFU-Es EPO hypersensitivity in polycythemic mutations were not elevated.