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Douglas Tremblay,1 Nicole E Wagner,2 John Mascarenhas1 1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USACorrespondence: John Mascarenhas, Myeloproliferative Disorders Program, Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY, 10029, USA, Tel +1 212 241 3417, Fax +12128765276, Email john.mascarenhas@mssm.eduAbstract: Advanced systemic mastocytosis (AdvSM) is a rare hematologic malignancy with organ damage and compromised life expectancy arising from organ accumulation of neoplastic mast cells. Identification of the gain-of-function KITD816V in the majority of cases has accelerated pharmaceutical development culminating with the development of selective KIT inhibitors such as avapritinib. While the advent of these therapies has improved the quality and quantity of life in patients with AdvSM, current challenges remain in the management of this disease. In this review, we summarize the present and future therapeutics landscape of AdvSM, highlighting the development of novel KIT inhibitors including elenestinib and bezuclastinib. We also explore the continued role of additional treatment modalities including allogeneic stem cell transplantation before discussing unresolved clinical challenges in the management of AdvSM.Keywords: systemic mastocytosis, KITD816V, avapritinib, midostaurin

Suliman Al-Fayoumi,1 Taishi Hashiguchi,2 Yuka Shirakata,2 John Mascarenhas,3 Jack W Singer1 1CTI BioPharma, Seattle, WA, USA; 2SMC Laboratories, Tokyo, Japan; 3Tish Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA Background: Fibrotic diseases result from an exuberant response to chronic inflammation. Myelofibrosis is the end result of inflammation in bone, caused by an inflammatory process triggered by production of abnormal myeloid cells driven by mutations affecting the JAK–STAT pathway. Inflammatory cytokine overproduction leads to increased mesenchymal cell proliferation, culminating in fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow fibrosis in most patients. In two Phase III clinical trials, pacritinib, however, demonstrated improvements in platelet counts and hemoglobin and reductions in transfusion burden in some patients with baseline cytopenias, suggesting it may improve bone-marrow function. Unlike ruxolitinib, pacritinib suppresses signaling through IRAK1, a key control point for inflammatory and fibrotic signaling. Purpose: To investigate potential antifibrotic effects of pacritinib in an animal model of liver fibrosis relevant to the observed course of human disease.Methods: Pacritinib, negative control (vehicle), and positive control (the angiotensin 2-receptor antagonist and PPARγ partial agonist telmisartan) were assessed in the murine Stelic animal model, which mimics the clinically observed progression from hepatic steatosis to nonalcoholic steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Histopathological analysis used hematoxylin and eosin staining. Body and liver weight changes, nonalcoholic fatty-liver disease activity scores, and plasma cytokeratin 18 fragment levels (a biomarker of hepatic necrosis) were measured.Results: Pacritinib-treated mice had significantly (P

AimBacterial keratitis results in corneal scarring and subsequent visual impairment. The long-term evolution of corneal scars has not been well described. In this case series, we identified patients who had improvement in corneal scarring and visual acuity from a clinical trial for bacterial keratitis.MethodsWe searched the records of the Steroids for Corneal Ulcers Trial (SCUT) for patients who had improvement in vision between the 3-month and 12-month visits and reviewed their clinical photographs.ResultsOf the 500 patients enrolled in SCUT, five patients with large central corneal scars due to bacterial keratitis are presented. All experienced improvement in rigid contact lens-corrected visual acuity from months 3 to 12. All patients also had marked improvement in corneal opacity during the same time period. None of the patients opted to have penetrating keratoplasty.ConclusionsCorneal scars may continue to improve even many months after a bacterial corneal ulcer has healed. The corneal remodeling can be accompanied by considerable improvement in visual acuity, such that corneal transplantation may not be necessary.

PurposeTo analyse predictors of clinical outcome in fungal keratitis.MethodsData was collected during a prospective, randomized, controlled, double-masked clinical trial of treatment for fungal keratitis. Clinical features at presentation and demographics were collected at the enrollment visit for all patients. Pre-specified clinical outcomes included 3-month visual acuity and infiltrate/scar size, time to re-epithelialization, and corneal perforation. A separate multivariable model with each outcome as the dependent variable included all predictor variables.ResultsPredictors for worse 3-month visual acuity include older age (P=0.024), worse presentation visual acuity (P

Background: The Degenerative lumbar disc disease requires a multimodal therapeutic approach. Lumbar radiculopathy is a prevalent symptom that results from (a) mechanical pressure on nerve roots caused by a herniated disc (b) chemical irritation from inflammatory mediators1 and (c) compression of arteries supplying and veins draining the nerve roots. Given the complex pathophysiology of the degenerative cascade, an initial non-surgical management approach is necessary. Objectives: to determine the efficacy of Selective Nerve Root Block (SNRB) for pain relief. SNRB is an effective and less invasive intervention that is easy to administer and serves as an adjunct to non-operative treatment. Materials & Methods: A total of 46 patients who fulfilled these inclusion criteria were enrolled in the study. The duration of symptoms ranged from 4 to 24 weeks, and all patients were initially treated with analgesics, drugs for neuropathic pain, and physiotherapy, which failed to result in the resolution of radiculopathy. The nerve root block was performed in the operating theater with fluoroscopic guidance, using the technique described by Bogduk et al. under aseptic precautions. Pain Relief was measured periodically using Visual Analogue Scale. Results: Our study included a total of 46 patients with radiculopathy, consisting of 23 male and 23 female patients, with 1 patient having L3 radiculopathy, 36 patients having L5 radiculopathy, and nine patients having S1 radiculopathy. Immediate pain relief was observed in all 46 patients after the nerve root block procedure. Conclusion: Transforaminal epidural steroid injections may be used as part of a multimodal treatment regimen to provide pain relief in selected patients with radicular pain. Short-term (3 months) pain relief was very good, indicating that SNRB can be used to postpone surgery. However, long-term results require further follow-up. SNRB is therapeutically effective in relieving lumbar radiculopathy pain, easy to administer, costeffective, and has minimal complications. Therefore, it is recommended for initial non-surgical management. [ABSTRACT FROM AUTHOR]