Ossama M. Maher

Histone deacetylase inhibitor for NUT midline carcinoma

NUT Midline carcinoma (NMC) is a rare and invariably fatal poorly differentiated carcinoma characterized by chromosomal rearrangement involving the nuclear protein of the testis (NUT) gene. Current approaches do not provide durable response. We report a case of widely metastatic NMC in a 17‐year‐old female who, following an initial response to combination chemotherapy developed rapid disease progression. Treatment with vorinostat, a histone deacetylase inhibitor (HDACi) resulted in an objective response, yet she died in less than one year from initial diagnosis. This report shows a potentially promising activity of HDACi in the treatment of NMC that needs further exploration. Pediatr Blood Cancer 2015;62:715–717.

The genetic landscape of ganglioglioma

Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas. Thirty-six harbored mutations predicted to activate the MAP kinase signaling pathway, including 18 with BRAF p.V600E mutation, 5 with variant BRAF mutation (including 4 cases with novel in-frame insertions at p.R506 in the β3-αC loop of the kinase domain), 4 with BRAF fusion, 2 with KRAS mutation, 1 with RAF1 fusion, 1 with biallelic NF1 mutation, and 5 with FGFR1/2 alterations. Three gangliogliomas with BRAF p.V600E mutation had concurrent CDKN2A homozygous deletion and one additionally harbored a subclonal mutation in PTEN. Otherwise, no additional pathogenic mutations, fusions, amplifications, or deletions were identified in any of the other tumors. Amongst the 4 gangliogliomas without canonical MAP kinase pathway alterations identified, one epilepsy-associated tumor in the temporal lobe of a young child was found to harbor a novel ABL2-GAB2 gene fusion. The underlying genetic alterations did not show significant association with patient age or disease progression/recurrence in this cohort. Together, this study highlights that ganglioglioma is characterized by genetic alterations that activate the MAP kinase pathway, with only a small subset of cases that harbor additional pathogenic alterations such as CDKN2A deletion.

Characterization of metastatic angiomatoid fibrous histiocytoma.

Angiomatoid fibrous histiocytoma (AFH) is a soft-tissue tumor of low-grade malignancy and uncommon metastatic behavior. In this study, we describe the clinical findings of a metastatic case of AFH in the pelvis. In addition, we characterize 16 patients in the literature with AFH who metastasized over the last 4 decades. The time of appearance of metastases varied substantially and was reported 5 months to 16 years after primary tumor resection. Nine patients metastasized to lymph nodes. Excision of metastatic lymph nodes was usually curative. Pulmonary metastases were associated with fatal outcome. Long-term monitoring should be considered in patients with AFH.

Outcomes of children, adolescents, and young adults following allogeneic stem cell transplantation for secondary acute myeloid leukemia and myelodysplastic syndromes—The MD Anderson Cancer Center experience

We conducted a retrospective analysis of outcomes for children and young adults with sAML/sMDS who underwent HSCT at our institution. Thirty‐two patients (median age 20 years) with sAML (n=24) and sMDS (n=8) received HSCT between 1990 and 2013. The median time from sAML/sMDS diagnosis to HSCT was 4.1 months (range: 1.2‐27.2 months). The transplant regimens were primarily busulfan based (n=19). BM was the primary donor source (n=15). Eleven recipients were transplanted with residual disease. At a median follow‐up of 62.3 months (range: 0.4‐250.9 months), 14 patients had disease recurrence. Acute GVHD, grade III/IV, occurred in three patients. Causes of death were as follows: disease relapse (n=12), infection (n=2), pneumonia (n=1), pulmonary hemorrhage (n=1), acute GVHD (n=1), and graft failure (n=1). A PS of ≥90% at the time of HSCT had a significant impact on PFS (P=.02). Patients achieving pretransplant primary CR (n=8) and those with sMDS and RA (n=6) had prolonged PFS (P=.04). On multivariate analysis, shorter time to transplantation (≤6 months from diagnosis of sAML/sMDS) was associated with superior OS (P=.0018) and PFS (P=.0005).

Etiologies and impact of readmission rates in the first 180 days after hematopoietic stem cell transplantation in children, adolescents, and young adults

Introduction: High rates of patients require readmission to the hospital within 6 months of hematopoietic stem cell transplantation (HSCT). We investigated the relationship between readmission rates and outcomes after HSCT in children, adolescents, and young adults (CAYA). Materials and Methods: A retrospective analysis of patients (26 years or younger) treated with HSCT was conducted. Results: A chart review of 435 CAYA who underwent HSCT from 2008 to 2015 revealed that 171 patients (39%) had at least 1 hospital readmission within 180 days of transplant; 87% received allogeneic and 13% received autologous HSCT. A total of 312 readmission events were reported. The median follow-up time was 31 months. Documented infection (n=99) and graft-versus-host disease complications (n=60) were the most common causes. Higher than 2 readmission rates were associated with lower overall survival (OS) (P=0.001) and disease-free survival (P<0.001) in patients who received allogeneic HSCT. These findings were not found in the autologous HSCT. In a multivariate analysis of those who received allogeneic HSCT, prior treatment with ≥2 chemotherapy regimens (P=0.03) was independent predictor of lower OS. There were also trends noted toward lower OS for patients with documented infections at index admission or subsequent readmissions (P=0.09). Conclusions: More than 2 hospital readmissions within 6 months of allogeneic HSCT in CAYA, who are either heavily pretreated or had documented infections at index admission or subsequent readmissions adversely affected the outcomes.

Prognostic Analysis of Absolute Lymphocyte and Monocyte Counts after Autologous Stem Cell Transplantation in Children, Adolescents, and Young Adults with Refractory or Relapsed Hodgkin Lymphoma

Previous studies in adults have shown that peripheral blood absolute lymphocyte and monocyte count ratio (ALC/AMC) after autologous stem cell transplantation (ASCT) can predict outcome in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). We retrospectively reviewed all of our children, adolescent, and young adult (CAYA) patients (age ≤26) who underwent transplantation for R/R HL between 2004 and 2015. Seventy-six patients (median age, 21; range, 10 to 26 years) who reached day 100 disease free were analyzed; 33% of them had positron emission tomography (PET)-positive tumors before ASCT. Patients received high-dose carmustine, etoposide, cytarabine, and melphalan (n = 40) or gemcitabine/busulfan/melphalan (n = 36). Median follow-up after day 100 was 3.9 years (95% confidence interval [CI], 2.8 to 4.9). A day 100 ALC/AMC ratio >2.1 correlated with lower risk of relapse (hazard ratio,  .097; 95% CI, .03 to .29; P <.0001). Patients with day 100 ALC/AMC ratios >2.1 and ≤2.1 had 4-year relapse-free survival rates of 93% and 33%, respectively (P = .0001) and 4-year overall survival rates of 96% and 76%, respectively (P = .0001). In addition, an ALC/AMC ratio increase >1.8 from day 15 to day 100 correlated with lower risk of relapse (hazard ratio, .24; 95% CI, .08 to 0.73; P = .01). Likewise, an ALC/AMC ratio change >.26 from day 30 to day 100 also correlated with a lower likelihood of relapse (hazard ratio, .20; 95% CI,  .081 to .51; P = .0007). Multivariate analysis showed that a positive PET scan at ASCT, day 100 ALC/AMC ratio ≤ 2.1, and an ALC/AMC ratio change either ≤1.8 from day 15 to day 100 or ≤.26 from day 30 to day 100 were independent adverse predictors. In conclusion, our analysis confirms in CAYA patients prior observations in adults indicating a major prognostic effect of peripheral lymphocyte and monocyte counts at day 100 and earlier post-ASCT time points in R/R HL.

Fanconi Anemia and Fanconi Syndrome: Time to Correct the Misnomers.

Guido Fanconi is a Swiss pediatrician who is regarded as one of the forefathers of modern pediatrics with several medical disorders bearing his name. In 1927, he described hereditary panmyelopathy with short stature and hyperpigmentation, currently known as Fanconi anemia.1 In contrast, Fanconi syndrome is a defect in the proximal renal tubules due to a variety of hereditary and acquired disorders, which ironically was first described in 1903 by an investigator named Abdelhalden in 1903. Fanconi himself did not report a similar case until 1931, then revealed similarities in 7 additional cases by 1936.2 He originally named the disease “nephrotic-glucosuric dwarfism with hyposphosphatemic rickets”. With an increased number of cases being diagnosed, however, the disease eventually came to be known as Fanconi syndrome. With the advent of medicine, we know that both diseases are actually misnomers, as they are not an accurate reflection of their etiopathology and clinical presentations. Fanconi anemia approximately affects 3 per million and is inherited as an autosomal recessive disease.3 It is characterized by physical abnormalities, bone marrow failure, and an increased risk of malignancies. Anemia is actually not a hallmark of the disease, and rather an increase in chromosomal breakage is what underlies the pathogenesis of the multisystems dysfunction that we see.3,4 Progressive bone marrow failure typically presents in the first decade, with a peak cumulative incidence by the age of 40 to 50 years. Physical abnormalities affect multiple organs (including short stature; abnormal skin pigmentation; malformations of extremities, eyes, urinary tract, ears, heart, gastrointestinal system, central nervous system; hypogonadism; and developmental delay) and are present in 60% to 70% of patients. Also, there is an increased incidence of hematologic and nonhematologic malignancies that affect almost one third of these patients at a later age.5 Fanconi syndrome on the contrary is due to proximal renal tubular defects. The age of onset varies with the etiology, with the inherited type being predominately autosomal recessive.6 This entity is well described in the oncology field following exposure to high cumulative doses of ifosfamide.7,8 The pathophysiology of the disease results from diminished absorption of solutes by the proximal tubules, with features of the syndrome including polyuria, glycosuria, acidosis, secondary growth failure, and hypophosphatemic rickets/osteomalacia.6 Numerous manifestations of Fanconi syndrome occur secondary to renal dysfunction, compared to Fanconi anemia, in which the disease is actually a constellation of the several systems which are involved. The history tends to lend itself to protecting this erroneous nomenclature, even if for most of us, the terminology is incorrect. We, as a young generation of physicians, suggest a consideration to address these prominent misnomers after almost nine decades since both diseases were initially discovered. Fanconi anemia could very well be named “Fanconi syndrome”, whereas Fanconi syndrome could be better described as “renal Fanconi disease”.

Metachronous Medulloblastoma in a Child With Successfully Treated Neuroblastoma: Case Report and Novel Findings of DNA Sequencing

Metachronous neoplasms have rarely been reported in patients with neuroblastoma. This report presents the clinical case of a 23-month-old child who was diagnosed with an anaplastic medulloblastoma 5 months after completing treatment for stage IV neuroblastoma. The patient was treated with complete surgical resection and adjuvant chemoradiation followed by maintenance chemotherapy at an outside institution and came to our institution for further management. A pathologic diagnosis and review of both the suprarenal and posterior fossa masses were performed, as well as a genetic analysis of both cerebellar tumor tissue and blood using next-generation gene sequencing. At our institution, the patient was submitted to induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation and remains free of disease 2 years after completion of treatment. Genetic analysis revealed multiple somatic copy number variations with most deleted genes located in 2q37, a region which harbors genes involved in epigenetic regulation and tumor suppression. A homozygous deletion was found in the TSC2 gene, which is a clinically actionable gene, and patients with activating deletions in TSC2 can potentially be eligible for basket clinical trials with mTOR inhibitors. Germline single nucleotide variants were also identified in multiple genes involved in cancer (ALK, FGFR3, FLT3/4, HNF1A, NCOR1, and NOTCH2/3), cancer predisposition (TP53, TSC1, and BRCA1/2), and genes involved in DNA repair (MSH6, PMS2, POLE, and ATM). Metachronous neoplasms are rare and challenging to treat, hence genetic analysis and referral are needed to exclude hereditary cause. DNA sequencing of the tumor and germline can help identify alterations that increase predisposition or can be used to guide treatment decisions on recurrence and when standard options fail.

Retroperitoneal ganglioneuroma and reversible posterior leukoencephalopathy in a child with acute lymphoblastic leukemia.

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