Larotrectinib in a Patient With Advanced Pleomorphic Liposarcoma of the Uterus.

Pleomorphic liposarcoma of the uterus (PLU) is an extremely rare disease with poor prognosis. Limited treatment options exist for these patients, and disease recurrence usually occurs rapidly within months of initial diagnosis. Few case reports of metastatic PLU are available in the literature. We describe a 70-year-old woman who presented with a large uterus and ovarian mass on imaging and negative serum tumor markers and endometrial biopsy. Staging revealed localized disease. Surgical resection revealed PLU on pathology. Immunohistochemistry was negative for smooth muscle actin (SMA), S100, and MDM2, and positive for CD10 and cyclin-D1. She was treated with adjuvant therapy and experienced disease recurrence in the liver at 15 months from surgery. Genetic testing of the metastasis showed IQGAP-NTRK3 gene fusion. She was given entrectinib but continued to show progression in the liver. Right partial hepatectomy was performed, showing positivity for CD10, BCL-1, MDM2, and SMA on tumor staining. Treatment was switched to pazopanib with disease progression in the neck. She was treated with larotrectinib last, showing no disease progression and adequate tolerance of therapy after 18 months of this treatment. This is the first case in the literature of metastatic PLU with NRTK3 fusion treated with sequential first-generation NRTK inhibitors. More case reports are needed to identify commonalities and therapeutic options. Genetic testing in all PLU cases is needed for targeted therapy approaches.

Efficacy of an Integrated Hands-On Thyroid Ultrasound Session for Medical Student Education.

As ultrasound has gained popularity with improving technology and ease-of-use, a push has been made to integrate ultrasound into the medical school curriculum. Many institutions are reporting one- to four-year integrated ultrasound curricula to augment anatomy and pathophysiology teaching. Our goal was to integrate a thyroid ultrasound scanning session into the endocrinology block of our institution's medical school curriculum to enhance medical student understanding of thyroid anatomy and pathophysiology. We conducted a prospective, single-center cohort (pre-experimental) study to evaluate student performance and knowledge acquisition using a pretest-posttest design. These multimodal sessions, consisting of a didactic, hands-on scanning sessions, and knowledge integration tests, covered ultrasound technique and thyroid evaluation and advanced to diagnosing an abnormal thyroid and working up a thyroid nodule. There were 26 to 27 second-year medical students per session who rotated between three stations proctored by credentialled physicians. Students participated in hands-on scanning of patients with or without thyroid pathology at each station. Out of the 209 students who participated in the ultrasound sessions, 114 (54.5%) consented to participate in the research project and completed both the pretest and posttest. Test data from the 114 students showed a mean pretest score of 57.5% ± 14.6% and the mean posttest score of 73.9% ± 17.4%. They had a 16.5% ± 19.6% (p < 0.001) increase in score between the two tests. Our study demonstrates that a multimodal thyroid ultrasound scanning session is an effective tool to augment the medical school endocrinology curriculum and to improve students' knowledge of thyroid anatomy, pathophysiology, and diagnostic workup of thyroid nodules.

Transcriptional targeting of oncogene addiction in medullary thyroid cancer.

Metastatic medullary thyroid cancer (MTC) is incurable and FDA-approved kinase inhibitors that include oncogenic RET as a target do not result in complete responses. Association studies of human MTCs and murine models suggest that the CDK/RB pathway may be an alternative target. The objective of this study was to determine if CDKs represent therapeutic targets for MTC and to define mechanisms of activity. Using human MTC cells that are either sensitive or resistant to vandetanib, we demonstrate that palbociclib (CDK4/6 inhibitor) is not cytotoxic to MTC cells but that they are highly sensitive to dinaciclib (CDK1/2/5/9 inhibitor) accompanied by reduced CDK9 and RET protein and mRNA levels. CDK9 protein was highly expressed in 83 of 83 human MTCs and array-comparative genomic hybridization had copy number gain in 11 of 30 tumors. RNA sequencing demonstrated that RNA polymerase II-dependent transcription was markedly reduced by dinaciclib. The CDK7 inhibitor THZ1 also demonstrated high potency and reduced RET and CDK9 levels. ChIP-sequencing using H3K27Ac antibody identified a superenhancer in intron 1 of RET. Finally, combined inhibition of dinaciclib with a RET kinase inhibitor was synergistic. In summary, we have identified what we believe is a novel mechanism of RET transcription regulation that potentially can be exploited to improve RET therapeutic targeting.

Reduced Retinoblastoma Protein Expression Is Associated with Decreased Patient Survival in Medullary Thyroid Cancer.

BACKGROUND: The retinoblastoma (RB) transcriptional corepressor 1 protein functions to slow cell-cycle progression. Inactivation of RB by reduced expression and/or hyperphosphorylation allow for enhanced progression through the cell cycle. Murine models develop medullary thyroid carcinoma (MTC) after generalized loss of RB. However, RB expression in MTC has only been evaluated in a small number of tumors, with differing results. The objective of this study was to determine whether reduced expression of RB and/or overexpression of hyperphosphorylated RB predict MTC aggressive behavior. METHODS: Formalin-fixed, paraffin-embedded primary thyroid tumors and lymph node metastases from MTC patients were evaluated for calcitonin, RB, and phosphorylated RB (pRB) expression by immunohistochemistry. Two expert pathologists evaluated the slides in a blinded manner, and the immunohistochemistry results were compared to disease-specific survival as a primary endpoint. RESULTS: Seventy-four MTC samples from 56 patients were analyzed in this study, including 51 primary tumors and 23 lymph node metastases. The median follow-up time was 6.75 years after surgery (range 0.64-24.30 years), and the median primary tumor size was 30 mm (range 6-96 mm). Sixty-six percent of cases were classified as stage IV. RB nuclear expression was diffusely present in 88% of primary tumors and 78% of lymph node metastases. Nuclear pRB expression was present in 22% of primary tumors and 22% of lymph node metastases. On univariate analysis, reduced RB (<75% tumor cell staining) trended with lower MTC-specific survival for primary tumor and metastatic nodes (primary tumor hazard ratio = 3.54 [confidence interval 0.81-15.47], p = 0.08; and lymph node hazard ratio = 4.35 [confidence interval 0.87-21.83], p = 0.05). For primary tumors, multivariable analysis showed that low nuclear RB expression was independently associated with worse disease-specific (p = 0.01) and overall (p = 0.02) survival. pRB levels were not associated with survival for either primary tumor or lymph node metastases. CONCLUSIONS: Reduced RB expression is associated with decreased patient survival in univariate and multivariable analyses, independent from patient age at surgery or advanced TNM stage. Future studies involving larger MTC patient populations are warranted to determine if lower RB expression levels may serve as a biomarker for aggressive disease in patients with MTC.

Comparison of dietary supplementation with lutein diacetate and lutein: a pilot study of the effects on serum and macular pigment.

UNLABELLED: The responses of subjects taking a 20 mg/day lutein diacetate supplement were compared with that for a 20 mg/day crystalline lutein or a placebo. Ten subjects, assigned to each of three groups, lutein diacetate (group 1), lutein (group 2), and a placebo (group 3), were supplemented for 24 weeks. Groups 1 and 2 consumed a dose equivalent to 20 mg per day of free lutein. Serum samples, collected at baseline, and at weeks 6, 12, 18, and 24 were analyzed by HPLC. Macular Pigment Optical Density (MPOD) was obtained by heterochromatic flicker photometry at baseline and weeks 6, 12, 18 and 24. RESULTS: The average serum lutein concentrations for weeks 6 to 24 expressed as a ratio to the baseline value (±S.D.) were 5.52 ± 2.88 for group 1, 4.43 ± 1.61 for group 2, and 1.03 ± 0.25 for group 3. The median rate of macular pigment increase (milli-absorbance units/week) for groups 1, 2, and 3 were 2.35, 1.55, and 0.19 mAU/wk, respectively. P-values for these serum and MPOD increases are both highly significant when compared to placebo. The average serum response was about 25% higher for group 1 compared with group 2 and, the median MPOD response was 52% higher for group 1 than group 2. P-values calculated for the differences in these increases were, p = 0.066, marginally significant, for serum, and p = 0.09 approaching significance, for MPOD.