A rare case of chondroblastoma involving the distal phalanx of the ring finger.

Chondroblastoma, a rare benign bone tumor, is typically found in the epiphysis of long bones, with hand involvement being particularly uncommon. We present a case of an 11-year-old female with chondroblastoma involving the fourth distal phalanx of the hand. Imaging revealed a lytic, expansile lesion with sclerotic margins and no soft tissue component. A preoperative differential diagnosis included intraosseous glomus tumor, epidermal inclusion cyst, enchondroma, and chronic infection. The patient underwent open surgical biopsy and curettage for both diagnostic and treatment purpose. The final histopathologic diagnosis was chondroblastoma.

Findings on Chest CT Performed in the Emergency Department in Patients Receiving Immune Checkpoint Inhibitor Therapy: Single-Institution 8-Year Experience in 136 Patients.

BACKGROUND. Patients undergoing immune checkpoint inhibitor (ICI) therapy may present to the emergency department (ED) with a wide range of immune-related adverse events. OBJECTIVE. The purpose of our study was to evaluate chest CT findings in patients receiving ICI therapy presenting to the ED and to explore these findings' associations with clinical parameters. METHODS. This retrospective study included 136 patients (75 men, 61 women; mean age, 65 ± 12 [SD] years) receiving ICI therapy who underwent chest CT at 163 ED visits between 2011 and 2018. Two radiologists independently reviewed chest CT examinations for various findings and resolved discrepancies by consensus. Clinical parameters, including survival at last available follow-up, were recorded. Chest CT findings were summarized, and interreader agreement was evaluated using kappa coefficients. Associations between CT findings and clinical parameters were explored using Fisher exact, chi-square, Wilcoxon, and Kruskal-Wallis tests. RESULTS. A total of 62.5% of patients had primary lung cancer; 52.9% received nivolumab monotherapy, and 30.1% received pembrolizumab monotherapy. A total of 55.8% of ED visits occurred within 60 days after ICI initiation. The most common CT findings were worsening lung tumor burden (60.1%), new consolidation unrelated to tumor (30.1%), new or worsening pleural effusion (23.9%), and ICI-associated pneumonitis (12.9%). The most common CT pneumonitis pattern was radiation recall pneumonitis (6/21, 28.6%). A total of 78.5% of ED visits with chest CT resulted in hospitalization; 66.9% of patients subsequently died. Survival was worse for patients with, versus without, worsening tumor (72.2% vs 49.1% of patients deceased vs alive at follow-up, p = .006) and for patients with, versus without, pleural effusion (39.2% vs 17.5% of patients deceased vs alive at follow-up, p = .04). Kappa values for interreader agreement of evaluated chest CT findings ranged from 0.66 (worsening tumor burden) to 1.00 (numerous findings). CONCLUSION. Most ED chest CT examinations in patients receiving ICI therapy exhibited worsening lung tumor burden, which was associated with worse survival. New consolidation and ICI-associated pneumonitis (most commonly radiation recall pneumonitis) were also commonly detected in the ED setting. CLINICAL IMPACT. Understanding pathologies detected on chest CT in patients undergoing ICI therapy who present to the ED may guide radiologists in interpreting such imaging.

Imaging and clinical manifestations of immune checkpoint inhibitor-related colitis in cancer patients treated with monotherapy or combination therapy.

PURPOSE: To determine the frequency, imaging, and clinical manifestations of immune checkpoint inhibitor (ICI)-related colitis in cancer patients on monotherapy or combination therapy. METHODS: The electronic medical records of 1044 cancer patients who received ICIs were retrospectively reviewed to identify 48 patients who had a clinical diagnosis of immune-related colitis. Imaging studies were reviewed to identify patients with imaging manifestations of colitis. Demographic data, type of ICIs, symptoms, presence of other immune-related adverse events (irAEs), and management were recorded. RESULTS: There was imaging evidence of immune-related colitis in 34 patients (24 men; median age: 63.5 years). The median time to onset of colitis was 75 days (IQR 25-75, 49.5-216 days) in patients receiving monotherapy (group 1) and 78 days (IQR 25-75, 44.3-99.5 days) in patients undergoing combination therapy (group 2) following start of ICI. Symptoms included diarrhea (91.1% [31 of 34]), nausea/vomiting (52.9% [18 of 34]), and abdominal pain (52.9% [18 of 34]). The most common imaging findings were bowel wall thickening (97% [33 of 34]) and fluid-filled colon (82.3% [28 of 34]). Colitis was diffuse in 21 of 34 (61.8%) patients. Imaging manifestations did not differ between the two groups (p > 0.05). Steroids and antibiotics were used to treat colitis in 29 of 34 (85.2%) and 13 of 34 (38.2%) patients, respectively. No patients in group 1 experienced concurrent irAEs, but 5 of 18 (27.8%) of patients in group 2 had other irAEs (p = 0.046). CONCLUSION: Immune-related colitis occurred in 3.3% of patients receiving ICIs with bowel wall thickening, fluid-filled colon and pancolitis being the most common imaging manifestations. Imaging manifestations did not differ between patients receiving monotherapy or combination therapy. However, concurrent irAEs were significantly observed in patients undergoing combination therapy.

Context-Specific Transcription Factor Functions Regulate Epigenomic and Transcriptional Dynamics during Cardiac Reprogramming.

Ectopic expression of combinations of transcription factors (TFs) can drive direct lineage conversion, thereby reprogramming a somatic cell's identity. To determine the molecular mechanisms by which Gata4, Mef2c, and Tbx5 (GMT) induce conversion from a cardiac fibroblast toward an induced cardiomyocyte, we performed comprehensive transcriptomic, DNA-occupancy, and epigenomic interrogation throughout the reprogramming process. Integration of these datasets identified new TFs involved in cardiac reprogramming and revealed context-specific roles for GMT, including the ability of Mef2c and Tbx5 to independently promote chromatin remodeling at previously inaccessible sites. We also find evidence for cooperative facilitation and refinement of each TF's binding profile in a combinatorial setting. A reporter assay employing newly defined regulatory elements confirmed that binding of a single TF can be sufficient for gene activation, suggesting that co-binding events do not necessarily reflect synergy. These results shed light on fundamental mechanisms by which combinations of TFs direct lineage conversion.

Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration.

Human diseases are often caused by loss of somatic cells that are incapable of re-entering the cell cycle for regenerative repair. Here, we report a combination of cell-cycle regulators that induce stable cytokinesis in adult post-mitotic cells. We screened cell-cycle regulators expressed in proliferating fetal cardiomyocytes and found that overexpression of cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 efficiently induced cell division in post-mitotic mouse, rat, and human cardiomyocytes. Overexpression of the cell-cycle regulators was self-limiting through proteasome-mediated degradation of the protein products. In vivo lineage tracing revealed that 15%-20% of adult cardiomyocytes expressing the four factors underwent stable cell division, with significant improvement in cardiac function after acute or subacute myocardial infarction. Chemical inhibition of Tgf-ß and Wee1 made CDK1 and cyclin B dispensable. These findings reveal a discrete combination of genes that can efficiently unlock the proliferative potential in cells that have terminally exited the cell cycle.

Chemical Enhancement of In Vitro and In Vivo Direct Cardiac Reprogramming.

BACKGROUND: Reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells in situ represents a promising strategy for cardiac regeneration. A combination of 3 cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT), can convert fibroblasts into induced cardiomyocyte-like cells, albeit with low efficiency in vitro. METHODS: We screened 5500 compounds in primary cardiac fibroblasts to identify the pathways that can be modulated to enhance cardiomyocyte reprogramming. RESULTS: We found that a combination of the transforming growth factor-ß inhibitor SB431542 and the WNT inhibitor XAV939 increased reprogramming efficiency 8-fold when added to GMT-overexpressing cardiac fibroblasts. The small molecules also enhanced the speed and quality of cell conversion; we observed beating cells as early as 1 week after reprogramming compared with 6 to 8 weeks with GMT alone. In vivo, mice exposed to GMT, SB431542, and XAV939 for 2 weeks after myocardial infarction showed significantly improved reprogramming and cardiac function compared with those exposed to only GMT. Human cardiac reprogramming was similarly enhanced on transforming growth factor-ß and WNT inhibition and was achieved most efficiently with GMT plus myocardin. CONCLUSIONS: Transforming growth factor-ß and WNT inhibitors jointly enhance GMT-induced direct cardiac reprogramming from cardiac fibroblasts in vitro and in vivo and provide a more robust platform for cardiac regeneration.

Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis.

Mutation of highly conserved residues in transcription factors may affect protein-protein or protein-DNA interactions, leading to gene network dysregulation and human disease. Human mutations in GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects.