A case of a 22-year-old man with primary synovial sarcoma of the parapharyngeal space with an AR somatic mutation: A case report and review of the literature.

This case report describes a 22-year-old man with a pharyngeal foreign body sensation arising from the left side of the postpharyngeal wall. Histological examination showed a biphasic pattern of epithelioid and spindle cells including glandular differentiation. The tumour was positive for vimentin and SS18-SSX, and the spindle cells were positive for bcl-2; in contrast, the epithelioid tumour cells were positive for pan-cytokeratin, epithelial membrane antigen and CD99. There was no INI-loss in tumour cells. Then, the presence of the SYT-SSX gene fusion was demonstrated by fluorescence in situ hybridization. In addition, androgen receptor gene somatic mutations were detected by next-generation sequencing. However, 6 months postoperatively, the patient had neither developed a recurrence nor received adjuvant radiotherapy and chemotherapy. Accurate diagnosis depends on morphological and immunohistochemical examination and a proper molecular analysis, and novel technologies can detect a wide variety of genetic alterations. Although androgen receptor somatic mutations cannot provide addition treatment at present, surgical resection with a clean margin and follow-up is an appropriate approach.

Phenotypic and biochemical characteristics and molecular basis in 36 Chinese patients with androgen receptor variants.

BACKGROUND: Androgen insensitive syndrome (AIS) is a rare genetic disease resulting from androgen receptor (AR) mutations and one of the causes of 46, XY disorder of sexual development (DSD). This study aimed to describe the clinical features and molecular defects of 36 Chinese patients with AR variants and investigate the functional alterations of novel variants in vitro. MATERIAL AND METHODS: Subjects with AR variants were identified from 150 Chinese 46, XY DSD patients using targeted next-generation sequencing. In-silico and functional assays were performed to evaluate the transcriptional activity and nuclear localization of novel AR variants. RESULTS: Eight novel and fifteen reported AR variants were identified. 30.6% (11/36) of patients harbored additional variants other than AR. Mutations in the Arg841 residue were found in 7 unrelated patients. Postpubertal serum gonadotropin levels were significantly elevated in patients with complete AIS (CAIS) compared with those in patients with partial AIS (PAIS) (P < 0.05). All the novel variants initially predicted to be uncertain significance by in-silico analyses were reclassified as likely pathogenic for defective AR transcriptional activity in vitro, except p.L295P, which was found in an atypical patient with oligogenic mutations and reclassified as likely benign. c.368_369 ins T was observed to interfere with nuclear translocation. CONCLUSIONS: Compared with PAIS patients, postpubertal CAIS patients had higher gonadotropin levels. Arg841 was disclosed as the location of recurrent mutations in Chinese AIS patients. Functional assays are important for reclassifying the novel AR variants and re-examining the diagnosis of AIS in specific patients with oligogenic mutations, instead of in-silico analysis.

Moving Towards Precision Urologic Oncology: Targeting Enzalutamide-resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Novel Inhibitor Darolutamide (ODM-201).

Darolutamide (ODM-201) is a novel androgen receptor (AR) antagonist with a chemical structure distinctly different from currently approved AR antagonists that targets both wild-type and mutated ligand binding domain variants to inhibit AR nuclear translocation. Here, we evaluate the activity of darolutamide in enzalutamide-resistant castration resistant prostate cancer (CRPC) as well as in AR mutants detected in patients after treatment with enzalutamide, abiraterone, or bicalutamide. Darolutamide significantly inhibited cell growth and AR transcriptional activity in enzalutamide-resistant MR49F cells in vitro, and led to decreased tumor volume and serum prostate-specific antigen levels in vivo, prolonging survival in mice bearing enzalutamide-resistant MR49F xenografts. Moreover, darolutamide inhibited the transcriptional activity of AR mutants identified in the plasma of CRPC patients progressing on traditional therapies. In particular, darolutamide significantly inhibited the transcriptional activity of the F877L, H875Y/T878A, F877L/T878A, and the previously unreported T878G AR mutants, that transform enzalutamide into a partial agonist. In silico cheminformatics computer modeling provided atomic level insights confirming darolutamide antagonist effect in F877L and T878G AR mutants. In conclusion, our results provide a rationale for further clinical evaluation of darolutamide in enzalutamide-resistant CRPC, in particular in combination with circulating tumor DNA assays that detect AR mutants sensitive to darolutamide, in a precision oncology setting. PATIENT SUMMARY: In this study we evaluated the novel drug darolutamide in preclinical models of prostate cancer. We found that darolutamide delays growth of enzalutamide-resistant prostate cancer, in particular in cells with mutated forms of the androgen receptor after previous treatment. Our data supports further evaluation of darolutamide in clinical trials.

Clinical features of Kennedy's disease without sensory nerve involvement: a report of 5 cases / 中国神经精神疾病杂志

Objective To analyze the clinical feature,serum examination,EMG of Kennedy'Disease to reduce misdiagnosis of Kennedy's Disease.Methods Five cases of Kennedy's disease were confirmed by genetic test.The clinical data was analyzed including clinical features,laboratory findings,EMG characteristics and determination of AR gene exon 1 CAG repeat sequence.Results These cases were male without an obvious positive family history.The average age of onset was 39.8 ±7.2 years old and the average duration from onset to diagnosis was 9 ±5.2 years.Onset symptoms included Lower limbs weakness in 3 cases,facial fasciculationin 1 cases and gynecomastia in 1 case.The most prominent clinical manifestations were tongue muscle atrophy,tongue muscle fibrillation and proximal limb muscle weakness.In addition,these 5 cases did not have clinical manifestation of sensation loss nor EMG evidence of abnormal sensation.Conclusion Kennedy's disease is a neurodegenerative disease characterized by lower motor neuron damage.The clinical features of these 5 cases are approximately the same as those reported in previous literatures.Although the patients have been reported to have abnormal sensation,the present study indicates that some patients with Kennedy's disease may not present with abnormal sensation and that the diagnosis of Kennedy's disease depends on the genetic test.

Clinical features of Kennedy's disease without sensory nerve involvement: a report of 5 cases / 中国神经精神疾病杂志

Objective To analyze the clinical feature,serum examination,EMG of Kennedy'Disease to reduce misdiagnosis of Kennedy's Disease.Methods Five cases of Kennedy's disease were confirmed by genetic test.The clinical data was analyzed including clinical features,laboratory findings,EMG characteristics and determination of AR gene exon 1 CAG repeat sequence.Results These cases were male without an obvious positive family history.The average age of onset was 39.8 ±7.2 years old and the average duration from onset to diagnosis was 9 ±5.2 years.Onset symptoms included Lower limbs weakness in 3 cases,facial fasciculationin 1 cases and gynecomastia in 1 case.The most prominent clinical manifestations were tongue muscle atrophy,tongue muscle fibrillation and proximal limb muscle weakness.In addition,these 5 cases did not have clinical manifestation of sensation loss nor EMG evidence of abnormal sensation.Conclusion Kennedy's disease is a neurodegenerative disease characterized by lower motor neuron damage.The clinical features of these 5 cases are approximately the same as those reported in previous literatures.Although the patients have been reported to have abnormal sensation,the present study indicates that some patients with Kennedy's disease may not present with abnormal sensation and that the diagnosis of Kennedy's disease depends on the genetic test.