Molecular determinants of therapy response of venetoclax-based combinations in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous, highly malignant disease of the bone marrow. After decades of slow progress, recent years saw a surge of novel agents for its treatment. The most recent advancement is the registration of the Bcl-2 inhibitor ventoclax in combination with a hypomethylating agent (HMA) in the US and Europe for AML patients not eligible for intensive chemotherapy. Treatment of newly diagnosed AML patients with this combination results in remission rates that so far could only be achieved with intensive treatment. However, not all AML patients respond equally well, and some patients relapse early, while other patients experience longer periods of complete remission. A hallmark of AML is its remarkable genetic, molecular and clinical heterogeneity. Here, we review the current knowledge about molecular features of AML that help estimate the probability of response to venetoclax-containing therapies. In contrast to other newly developed AML therapies that target specific recurrent molecular alterations, it seems so far that responses are not specific for a certain subgroup. One exception is spliceosome mutations, where good response has been observed in clinical trials with venetoclax/azacitidine. These mutations are rather associated with a more unfavorable outcome with chemotherapy. In summary, venetoclax in combination with hypomethylating agents represents a significant novel option for AML patients with various molecular aberrations. Mechanisms of primary and secondary resistance seem to overlap with those towards chemotherapy.

An aggressive case of Warthin-like variant of papillary thyroid carcinoma (PTC)

Introduction/Objective Warthin-like variant of PTC is a rare subtype of PTC, characterized by papillary growth lined with oncocytic neoplastic cells and lymphocytic rich stroma in the stalks of the papillae. It is frequently associated with Hashimoto thyroiditis and has good prognosis due to lower risk of metastasis. An association with BRAF V600E mutation has been reported. Here we report an aggressive case of Warthin-like variant of PTC. Methods/Case Report A 33-year-old Hispanic female presented with a progressively expanding neck mass, difficulty swallowing, voice hoarseness, and neck pain. Ultrasound showed a 3.8 cm left thyroid nodule which on biopsy was positive for PTC. Laboratory tests were positive for anti-peroxidase and anti-thyroglobulin antibodies. A total thyroidectomy was performed. Grossly, the left thyroid lobe nodule was well-circumscribed, unencapsulated, and firm with solid homogenous gray-tan cut surface. Microscopically, the nodule consisted of large eosinophilic cells demonstrating characteristic PTC nuclear features, arranged in papillary structures with the cores packed with prominent lymphoplasmacytic infiltrate consistent with Warthin-like variant of PTC (figure). Separate sub-centimeter foci of PTC with similar features were identified in a background of chronic lymphocytic thyroiditis. Central and left neck dissection showed extensive lymph node metastasis which had features similar to the primary tumor but with less pronounced lymphoplasmacytic cores. The patient is currently 6-month post operation and is receiving iodine ablative therapy. Results (if a Case Study enter NA) NA Conclusion Molecular analysis of the tumor may aid in identifying molecular aberrations responsible for the aggressive nature in this case and potentially guide treatment.

Genetic and epigenetic basis of hepatoblastoma diversity

Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. Here, we perform an integrative genomic profiling of 163 pediatric liver tumors (154 HBs and nine hepatocellular carcinomas) based on the data acquired from a cohort study (JPLT-2). The total number of somatic mutations is precious low (0.52/Mb on exonic regions) but correlated with age at diagnosis. Telomerase reverse transcriptase (TERT) promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling reveals that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of IGF2 promoters, suggests their “cell of origin” derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach for understanding the epigenetic drivers of hepatoblast carcinogenesis and deriving clues for risk stratification.