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1.
Front Pediatr ; 11: 1067131, 2023.
Article in English | MEDLINE | ID: mdl-36937957

ABSTRACT

Background: Germline Checkpoint Kinase 2 gene (CHEK2) mutations can increase the risk of solid tumors. Recently, they have been identified as risk factors for hematologic malignancies. However, to the best of our knowledge, B-acute lymphoblastic leukemia (B-ALL) has never been described as a presenting manifestation of germline CHEK2 mutation. Chimeric antigen receptor-T (CAR-T) cell therapy directed against CD19 antigen (tisagenlecleucel) is a novel cellular therapy for treatment of relapsed/refractory (R/R) B-ALL. The use of tisagenlecleucel has not been described in patients with CHEK2 mutation. Case Presentation: We describe a case of a pediatric patient with a heterozygous pathogenic germline CHEK2 mutation (c.1100delC; p.Thr367Metfs*15) successfully treated with tisagenlecleucel for relapsed B-ALL to avoid hematopoietic cell transplant (HCT). The twelve-year-old boy was diagnosed with National Cancer Institute (NCI) high-risk B-ALL (white blood cell count >50,000/mcL), with no extramedullary disease. Cytogenetic analysis revealed normal karyotype but fluorescent in situ hybridization (FISH) showed 93% positivity for CRLF2::P2RY8 rearrangement. He was treated as per Children's Oncology Group (COG) AALL1131 therapy and achieved a complete remission. Seven months after diagnosis, he was found to have papillary thyroid carcinoma with no evidence of metastatic disease. The patient underwent a total thyroidectomy with central lymph node biopsy and radioactive iodine therapy. The patient's biological mother and fraternal twin brother carry the same germline CHEK2 mutation with no history of malignancy. The biological father tested negative for the familial mutation. The patient's genetic panel also identified three variants of unclear significance: CDKN2A (c.37 °C > T; p.Arg124Cys), FLCN (c.62G > A; p.Cys21Tyr) and SDHAF2 (c.139A > G; p.Met47Val). Extended family history also revealed a diagnosis of anaplastic thyroid cancer in maternal uncle at the age of 44 years. Fifteen months after diagnosis the patient had a relapse of B-ALL (both medullary and extramedullary with blasts in CSF), which was successfully treated with tisagenlecleucel. The patient remains in remission 3 years after receiving tisagenlecleucel. Conclusion: As conventional chemotherapy and radiation can potentially increase the risk of DNA damage and development of secondary malignancies, CD19 CAR-T therapy (tisagenlecleucel) can be used as a substitute for intensive re-induction chemotherapy and HCT in patients with a germline CHEK2 mutation.

2.
Expert Opin Orphan Drugs ; 9(11-12): 265-272, 2022 Mar 01.
Article in English | MEDLINE | ID: mdl-35548705

ABSTRACT

Background: The Orphan Drug Act was created to stimulate the development of drugs and biologics for rare diseases. Investigating products that have received orphan drug designation provide a greater understanding of rare disease drug development, as well as the repositioning business models of developers. Research design and methods: We used a dataset containing all orphan drug designations between 1983 and 2019. To analyze the orphan products, we constructed a variable, 'unique product,' that allowed for the standardization of generic names of drugs and biologics. Additional analysis was performed on the most frequently designated unique products and their repositioning strategies. Results: We found 5,099 orphan drug designations representing 3,269 unique products, of which 508 had an orphan-designated approval from FDA. Unique products with only a single designation represented 2,448 (75%) of the total products and 26 (1%) products had 10 or more designations. Over 60% of these unique products with 10 or more designations were antineoplastics or immunomodulators. Conclusions: The most designated unique products revealed a continuum of repositioning strategies, from the repurposing of approved drugs to parallel indication development programs for recently developed drugs. The fact that over 3,000 unique products have been studied for rare diseases indicates that future repositioning opportunities may become increasingly available.

3.
Indian J Ophthalmol ; 63(6): 524-7, 2015 Jun.
Article in English | MEDLINE | ID: mdl-23571244

ABSTRACT

A seventy-year-old male presented with dense asteroid hyalosis in both eyes. He had undergone cataract extraction in one eye 3 years ago, and the other eye had immature cataract. Both the autorefractor and dilated streak retinoscopy did not give readings and subjective visual improvement could not be achieved. Immediately following YAG posterior capsulotomy and anterior vitreous asteroid disruption, the vision improved to 20/20 with recordable auto refractor and streak retinoscopy values. Our initial experience indicates that the treatment is simple, safe and effective but needs controlled and prospective studies to confirm its long-term safety.


Subject(s)
Capsule Opacification/surgery , Laser Therapy/methods , Lasers, Solid-State/therapeutic use , Phacoemulsification/adverse effects , Posterior Capsule of the Lens/surgery , Posterior Capsulotomy/methods , Aged , Capsule Opacification/etiology , Capsule Opacification/pathology , Humans , Male , Posterior Capsule of the Lens/pathology
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