Citations

AbstractThe detection of recurrent genetic abnormalities in B‐lymphoblastic leukemia (B‐ALL) is critical for risk stratification and therapy‐related decisions. Near‐haploidy (24‐30 chromosomes), a subgroup of hypodiploidy (<46 chromosomes), and BCR/ABL1 gene fusions are both recurrent genetic abnormalities in B‐ALL and are considered adverse prognostic findings, although outcomes in BCR/ABL1‐positive patients have improved with tyrosine kinase inhibitor therapy. While near‐haploid clones are primarily observed in children and rarely harbor structural abnormalities, BCR/ABL1‐positive B‐ALL is primarily observed in adults. Importantly, recurrent genetic abnormalities are considered mutually exclusive and rarely exist within the same neoplastic clone. We report only the second case to our knowledge of a near‐haploid clone that harbors a BCR/ABL1 fusion in an adult with newly diagnosed B‐ALL. Conventional chromosome studies revealed a near‐haploid clone (27 chromosomes) along with a der(22)t(9;22)(q34.1;q11.2) in 17 of 20 metaphases analyzed. Our B‐ALL fluorescence in situ hybridization (FISH) panel confirmed the BCR/ABL1 fusion and monosomies consistent with chromosome studies in approximately 95% of interphase nuclei. Moreover, no evidence of a “doubled” near‐haploid clone was observed by chromosome or FISH studies. This highly unusual case illustrates that while rare, recurrent genetic abnormalities in B‐ALL can exist within the same neoplastic clone.

Key Clinical MessageWe report a patient with developmental delay, autism, epilepsy, macrocephaly, facial dysmorphism, gastrointestinal, and behavioral issues due to EXT2 compound heterozygous likely pathogenic variants. This case report expands the EXT2 gene mutation database and the clinical spectrum of patients with deficiencies in the heparan sulfate pathway.

Background . Hypertriglyceridemia and hyperglycemia coexist in 30-60% of patients with diabetes. The impact of hypertriglyceridemia regarding HbA1c assay reliability remains uncertain. Therefore, we conducted a prospective in vivo controlled study with the aim of defining the association between triglyceride levels and HbA1c. Methods . A total of 44 patients with an index-hospital admission diagnosis of diabetic ketoacidosis or hypertriglyceridemia-induced pancreatitis, as a model for acute elevation of triglycerides, were recruited. Blood samples were drawn for the measurement of HbA1c, triglycerides, glucose, and hemoglobin at baseline and subsequently 24 and 48 hours after admission. HbA1c analysis was performed with high-performance liquid chromatography Bio-Rad D10 (NGSP approved). Results . All patients completed the study protocol. A difference between mean triglycerides from day 0 (baseline) to day 2 of 1567.2 mg/dL was observed. We found a difference between mean serum HbA1c from days 0 to 2 of 0.09% [1 mmol/mol] ( p = 0.004 ). Moreover, a weak correlation between the mean difference of HbA1c and triglycerides from baseline to day 2 was found to be statistically significant ( r = 0.256 , p = 0.015 ). None of these findings, however, are clinically significant. Conclusion . Triglycerides do not impair the interpretation of HbA1c assay. Patients and clinicians can now be confident that hypertriglyceridemia is not an important factor when interpreting HbA1c results.

DDX3X (Xp11.4) encodes a DEAD‐box RNA helicase that escapes X chromosome inactivation. Pathogenic variants in DDX3X have been shown to cause X‐linked intellectual disability (ID) (MRX102, MIM: 300958). The phenotypes associated with DDX3X variants are heterogeneous and include brain and behavioral abnormalities, microcephaly, hypotonia, and movement disorders and/or spasticity. The majority of DDX3X variants described are de novo mutations in females with ID. In contrast, most male DDX3X variants are inherited from an unaffected mother, with one documented exception being a recently identified de novo splice site variant. It has been suggested, therefore, that DDX3X exerts its effects through haploinsufficiency in females, and that affected males carry hypomorphic alleles that retain partial function. Given the lack of male de novo DDX3X variants, loss‐of‐function variants in this gene are suspected to be male lethal. Through whole‐exome sequencing, we identified three unrelated males with hemizygous missense DDX3X variants and ID. All three variants were confirmed by Sanger sequencing, with two established as de novo. In silico analyses were supportive of pathogenicity. We report the male phenotypes and compare them to phenotypes observed in previously reported male and female patients. In conclusion, we propose that de novo DDX3X variants are not necessarily male lethal and should be considered as a cause of syndromic ID in both males and females.

ABSTRACTThe MLLT10 (formerly AF10) gene is the fourth most common KMT2A fusion partner across all acute leukemias and requires at least 3 breaks to form an in‐frame KMT2A/MLLT10 fusion due to the opposite orientation of each gene. A 10‐year retrospective review was performed to identify individuals from all age groups that harbor KMT2A/MLLT10 fusion obtained by our KMT2A/MLLT10 dual‐color dual‐fusion fluorescence in situ hybridization (D‐FISH) assay. Of the 60 unique individuals identified, 31 were male and 29 were female (M:F ratio, 1.1:1) with ages ranging from 3 days to 86 years (mean 21.5 years, median 5.5 years). The diagnoses included acute myeloid leukemia (AML) (49 patients, 82%), B‐ or T‐lymphoblastic leukemia/lymphoma (7 patients, 12%), myeloid sarcoma (3 patients, 5%), and a single case (2%) of undifferentiated leukemia. Twenty‐seven of 49 patients (55%) with AML were in the infant or pediatric age group. Fifty‐three of 60 patients (88%) had KMT2A/MLLT10 D‐FISH signal patterns mostly consisting of single fusions. In addition, 10 (26%) of 38 patients with conventional chromosome studies had “normal” (5 patients) or abnormal (5 patients) chromosome studies that lacked structural or numeric abnormalities involving chromosomes 10 or 11, implying cryptic cytogenetic mechanisms for KMT2A/MLLT10 fusion. Lastly, mate‐pair sequencing was performed on 4 AML cases, 2 of which had “normal” chromosome studies and cryptic KMT2A/MLLT10 fusion as detected by KMT2A/MLLT10 D‐FISH studies, and verified the multiple breaks required to generate KMT2A/MLLT10 fusion.

321 Background: G3 NENs are aggressive, and optimal systemic treatment is unclear. Temozolomide (TEM)-based regimens have been used to treat grade 1-2 NETs, but their efficacy in G3 NENs (Ki-67 > 20%) remains undetermined. Aims: To assess the clinical efficacy of TEM-containing regimens in advanced grade III gastroenteropancreatic NENs (GEPNENs). Methods: A multicentre retrospective review (2008-2017) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports without formal RECIST criteria. Results: 118 patients in six centers were included (median age 55, 65% male, 15% functional, 75% pancreatic NEN). 57% were well-differentiated, 35% poorly-differentiated, and 18% unknown based on local pathology reports. The regimen used was CAPTEM in 93% and TEM in 7%. Best radiological responses were: complete response (1%), partial response (39%), stable disease (22%), progressive disease (31%), unknown (7%) not by RECIST. Median TTF was 150 days and median overall survival (OS) 18.0 months. Fifteen patients (14%) required dose reductions/discontinuation due to adverse events. TTF was shorter for patients on TEM alone (p = 0.02, Table 1). Well-differentiated NENs had better response rate (52% vs 26%, p = 0.02) and overall survival (30.1 vs 12.0 mo, p = 0.008) compared to poorly-differentiated NEN. Conclusions: This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NET centers. 40% of patients showed some degree of response, and treatment was generally well-tolerated. TEM-based regimens should be considered a viable treatment option in this setting. Prospective confirmatory trials (such as EA2142) may face difficulties in accrual due to disease rarity. [Table: see text]

BackgroundOlfactory nerve fibers are at risk of injury during transnasal endoscopic skull‐base approaches. Olfactory outcomes for various techniques have not been thoroughly investigated. This study aims to report long‐term olfactory outcomes when a cold knife upper septal limb incision technique is used compared to monopolar cautery.MethodsA prospective cohort study was performed at a tertiary referral center. Adult patients undergoing endoscopic approaches with septal incisions were randomized to cold knife or monopolar cautery groups. Patient demographics, clinical history, surgical data, and outcomes were collected. Preoperative, 3‐month, and 12‐month postoperative scores on the University of Pennsylvania Smell Inventory Test (UPSIT) and 22‐item Sino‐Nasal Outcome Test (SNOT‐22) were measured. Fisher's exact tests were performed for categorical variables and t tests were performed for continuous variables.ResultsTwenty‐two (22) patients (10 cold knife, 12 cautery) were enrolled between March 2016 and August 2017. The average age ± standard deviation was 50.2 ± 14.0 years (p = 0.59), 54% (p = 0.69) were female, and the primary pathology was pituitary adenoma (73%, p = 1.00). Preoperative, 3‐month, and 12‐month postoperative UPSIT scores were similar between the cold knife and cautery groups (32.8 vs 32.4, p = 0.80; 33.1 vs 33.0, p = 0.96; 33.6 vs 33.3, p = 0.84). On the “sense of smell/taste” question of the SNOT‐22, there was also no difference at all time points (p > 0.22).ConclusionThere was no significant change in patient UPSIT scores 1 year after transnasal skull‐base approaches, and no short‐term or long‐term differences between cold knife and cautery upper septal limb incision techniques. Our study supports an individualized approach based on surgeon preference.