Alternative treatments of adenomyosis - an update in procedural management and clinical outcomes.

PURPOSE OF REVIEW: Adenomyosis is a common cause of abnormal uterine bleeding (AUB), dysmenorrhea, and pelvic pain. Definitive diagnosis and treatment have historically been by uterine histopathology at time of hysterectomy; however, advances in imaging have supported earlier diagnosis and subsequent conservative treatment. This review aims to update the evidence supporting the uterine-sparing, procedural management options with a focus on clinical outcomes. RECENT FINDINGS: Uterine artery embolization (UAE), radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), percutaneous microwave ablation (PMWA), and adenomyomectomy are minimally invasive interventions proven to be effective in reducing AUB and dysmenorrhea due to adenomyosis. Symptom improvement is associated with a decrease in uterine volume. Studies support the use of alternative treatment options given the overall low rates of symptom recurrence and reintervention. Combination therapy may be more effective than monotherapy. SUMMARY: This review provides the current evidence for use of alternative treatment options for adenomyosis. Access to ablative therapies in the USA is limited and primarily off label, given lack of FDA approval. High-quality prospective and randomized controlled trials are needed in order to further delineate treatment comparisons, efficacy, safety, and ideal patient selection for these treatments. More data are needed to assess safety and utility in those desiring future fertility.

ARID1A, BRG1, and INI1 deficiency in undifferentiated and dedifferentiated endometrial carcinoma: a clinicopathologic, immunohistochemical, and next-generation sequencing analysis of a case series from a single institution.

Undifferentiated/dedifferentiated endometrial carcinomas (UDEC and DDEC) are rare, aggressive uterine neoplasms, with no specific line of differentiation. A significant proportion of these cases feature mutations of SWI/SNF chromatin remodeling complex members, including ARID1A, SMARCA4, and SMARCB1 genes. To study these entities more comprehensively, we identified 10 UDECs and 10 DDECs from our pathology archives, obtained clinicopathologic findings and follow-up data, and performed immunohistochemical studies for ARID1A, BRG1 (SMARCA4), and INI1 (SMARCB1) proteins. In addition, we successfully conducted targeted next-generation sequencing for 23 samples, including 7 UDECs, and 7 undifferentiated and 9 well/moderately-differentiated components of DDECs. Cases consisted of 18 hysterectomies and 2 curettage/biopsy specimens. Patient age ranged from 47 to 77 years (median, 59 years), with a median tumor size of 8.0 cm (range, 2.5-13.0 cm). All cases demonstrated lymphovascular invasion and the majority (13/20) were FIGO stage III-IV. By immunohistochemistry, ARID1A loss was observed in 15 cases, BRG1 loss in 4, and all cases had intact INI1 expression. A trend for enrichment of the undifferentiated component of DDECs for ARID1A loss was seen, although not statistically significant. Sequencing revealed frequent pathogenic mutations in PTEN, PIK3CA, ARID1A, CTNNB1, and RNF43, a recurrent MAX pathogenic mutation, and MYC and 12p copy number gains. In DDECs, the undifferentiated component featured a higher tumor mutational burden compared to the well/moderately-differentiated component; however, the mutational landscape largely overlapped. Overall, our study provides deep insights into the mutational landscape of UDEC/DDEC, SWI/SNF chromatin remodeling complex member status, and their potential relationships with tumor features.

Structural and Genetic Studies Demonstrate Neurologic Dysfunction in Triosephosphate Isomerase Deficiency Is Associated with Impaired Synaptic Vesicle Dynamics.

Triosephosphate isomerase (TPI) deficiency is a poorly understood disease characterized by hemolytic anemia, cardiomyopathy, neurologic dysfunction, and early death. TPI deficiency is one of a group of diseases known as glycolytic enzymopathies, but is unique for its severe patient neuropathology and early mortality. The disease is caused by missense mutations and dysfunction in the glycolytic enzyme, TPI. Previous studies have detailed structural and catalytic changes elicited by disease-associated TPI substitutions, and samples of patient erythrocytes have yielded insight into patient hemolytic anemia; however, the neuropathophysiology of this disease remains a mystery. This study combines structural, biochemical, and genetic approaches to demonstrate that perturbations of the TPI dimer interface are sufficient to elicit TPI deficiency neuropathogenesis. The present study demonstrates that neurologic dysfunction resulting from TPI deficiency is characterized by synaptic vesicle dysfunction, and can be attenuated with catalytically inactive TPI. Collectively, our findings are the first to identify, to our knowledge, a functional synaptic defect in TPI deficiency derived from molecular changes in the TPI dimer interface.