Hepatosplenic αß T-Cell Lymphoma as Second Malignancy in Young Adult Patient With Previously Undiagnosed Ataxia-Telangiectasia.

Ataxia-telangiectasia is a rare autosomal recessive neurodegenerative disease characterized by ataxia, radiosensitivity, telangiectases, and increased risk for hematologic malignancies. We present a case of a female individual diagnosed with T-cell acute lymphocytic leukemia at 13 years and subsequently with αß subtype of hepatosplenic T-cell lymphoma (HSTCL) at 20 years. During her diagnostic work up for HSTCL, paired tumor-germline sequencing identified a diagnosis of ataxia-telangiectasia. We also describe a very refractory clinical course of her αß HSTCL, including only a brief response to multiagent chemotherapy and an allogenic bone marrow transplant.

PD-1 inhibition in congenital pigment synthesizing metastatic melanoma.

A newborn female child was born with a congenital pigment synthesizing melanoma of the scalp. Further workup revealed metastatic disease within the liver, lungs, and left tibia. Whole exome sequencing was performed on multiple samples that revealed one somatic mutation, lysine methyltransferase 2C (KMT2C), at low allelic frequency but no v-Raf murine sarcoma viral oncogene homolog B (BRAF), NF-1 mutation. Programmed death ligand 1 was moderately expressed. Treatment was initiated with the programmed cell death protein 1 inhibitor nivolumab. The patient tolerated this treatment well with minimal toxicity. She is now over a year out from initial diagnosis, continuing on nivolumab, with stable disease.

Phase I study of bortezomib in combination with irinotecan in patients with relapsed/refractory high-risk neuroblastoma.

PURPOSE: Prognosis for relapsed/refractory high-risk neuroblastoma (HR-NBL) remains poor. Bortezomib, a proteasome inhibitor, has shown preclinical activity against NBL as a single agent and in combination with cytotoxic chemotherapy including irinotecan. PATIENTS AND METHODS: Eighteen HR-NBL patients with primary refractory (n = 8) or relapsed (n = 10) disease were enrolled in a Phase I study using modified Time To Event Continual Reassessment Method. Bortezomib (1.2 mg/m2 /day) was administered on days 1, 4, 8, and 11 intravenously (IV) and irinotecan was given IV on days 1-5 (35, 40, or 45 mg/m2 /day, on dose levels [DL] 1-3, respectively). The maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and response rate were examined. RESULTS: Eighteen NBL patients were evaluable for toxicity; 17 were evaluable for response assessment. A total of 142 courses were delivered (mean 8.2, median 2, range 1-48), with two patients receiving more than 40 courses of therapy. Two DLTs were reported, including a grade 4 thrombocytopenia (DL2) and a grade 3 irritability (DL3). MTD was estimated as DL3. Two of 17 (12%) evaluable patients showed objective responses (ORs) lasting more than 40 courses, including 1 partial remission and 1 complete remission. Four patients (23%) had prolonged stable disease (SD) lasting six or more courses, with a total of 35% study patients demonstrating clinical benefit in the form of prolonged OR or SD. CONCLUSION: The combination of bortezomib and irinotecan was well tolerated by patients with relapsed/refractory NBL with favorable toxicity profile. It also showed modest but promising clinical activity and merits further testing in Phase II studies.

Homozygous ATM mutation due to germline uniparental isodisomy in patient with T acute lymphoblastic leukemia and hepatosplenic T-cell lymphoma.

Uniparental disomy has long been recognized as a significant cause of genetic disease in imprinting-associated conditions. More recently, it has increasingly been implicated as a potentially significant cause of autosomal recessive disease. Here we report a case of a patient with a history of leukemia and αß hepatosplenic T-cell lymphoma who was diagnosed with ataxia telangiectasia via paired tumor-germline testing at age 20. Germline testing detected a homozygous pathogenic variant in the ATM gene. Parental testing identified this variant only in the mother, leading to suspicion for non-paternity or an atypical cause of autosomal recessive disease. Additional analysis of the proband's sample identified a 54 megabase region at chr11q13.4-q25 with alleles all derived from a single parent, consistent with uniparental isodisomy as causative of autosomal recessive ataxia telangiectasia in this case. This report provides further evidence that uniparental isodisomy should be considered in the potential etiology of autosomal recessive conditions, including in the setting of paired tumor-germline testing. Confirming the method of inheritance is particularly important in cases such as this one where being a heterozygous carrier has medical management implications for cancer screening for relatives as well as for cascade testing and family planning for relatives.

Novel natural withanolides induce apoptosis and inhibit migration of neuroblastoma cells through down regulation of N-myc and suppression of Akt/mTOR/NF-κB activation.

Despite recent advances in intensive chemotherapy treatments, long-term success is achieved in less than 30% of children with high-risk neuroblastoma (NB). Key regulatory pathways including the PI3K/Akt, mTOR and NF-κB are implicated in the pathogenesis of NB. Although drugs targeting these individual pathways are in clinical trials, they are not effective due to the activation of compensatory mechanisms. We have previously reported that natural novel withanolides from Physalis longifolia can potently inhibit these key regulatory pathways simultaneously. In the present study, we examined the efficacy and mechanisms through which novel withanolides and their acetate derivatives (WGA-TA and WGB-DA) from P.longifolia kill NB cells. The results from the study demonstrated that our novel acetate derivatives are highly effective in inhibiting the proliferation, shifting the cell cycle and inducing apoptosis in a dose dependent manner. Analysis of oncogenic pathway proteins targeted by withanolides indicated induction of heat shock response due to oxidative stress. Dose dependent decrease in clients of HSP90 chaperone function due to suppression of Akt, mTOR, and NF-κB pathways led to decrease in the expressions of target genes such as cyclin D1, N-myc and Survivin. Additionally, there was a dose dependent attenuation of the migration and invasion of NB cells. Furthermore, the lead compound WGA-TA showed significant reduction in tumor growth of NB xenografts. Taken together, these results suggest that withanolides are an effective therapeutic option against NBs.

Pediatric melanoma and aggressive Spitz tumors: a retrospective diagnostic, exposure and outcome analysis.

BACKGROUND: The diagnosis and management of pediatric melanomas is challenging given the presence of both melanomas and histologically aggressive Spitz tumors of undetermined biological significance (S-UBS) in this age group. Study objectives were to examine: factors leading to diagnostic delays, therapy side effects and patient outcomes in these diagnostic groups. METHODS: A retrospective case review was performed using The University of Michigan's pediatric oncology database over a 13-year timespan. Patients referred to our clinic for consideration of interferon therapy due to a diagnosis of a stage III melanoma or aggressive appearing S-UBS with significant lymph node involvement were included. RESULTS: We found two major causes of diagnosis delay: patients with amelanotic lesions misdiagnosed as having a wart and cases reviewed by non-expert pathologists upfront. The side effects from interferon therapy requiring dose adjustments included neutropenia, thrombocytopenia and mood disturbances. There was wide variability in surveillance scan utilization, therefore leading to variability in patient radiation exposure. Unlike melanoma patients, none of the S-UBS patients experienced disease progression or death. CONCLUSIONS: This study highlights the challenges with the initial clinical diagnosis and pathological sub-categorization of the pediatric S-UBS/melanoma spectrum of skin lesions and emphasizes the role of expert pathology review upfront. Further, education at the primary care level could improve accurate and timely diagnoses. Earlier diagnosis could spare patients from more extensive interventions, metastatic spread or adverse outcomes in this patient population. This study is limited due to its retrospective, single-institution perspective.