Mitsuko Furuya

Marfan syndrome (MFS) is a hereditary connective tissue disorder characterized by cardiovascular and skeletal abnormalities. While cardiovascular pathology is well described, the microscopic features of peripheral vasculature remain poorly characterized. We report a case of perioperative pulmonary arterial rupture in a patient with FBN1 ‐related MFS. A 17‐year‐old woman underwent bullectomy for spontaneous pneumothorax. Although the procedure was initially uneventful, unexpected bleeding developed beneath the staple line immediately after reinflation for the post‐bullectomy air‐leak test, necessitating additional wedge resection. Histologically, a ruptured pulmonary arterial branch was identified adjacent to the staple line. Patchy foci of hyperacute vascular injury with hemostatic plugs were identified on the luminal surface, and the surrounding airspaces were filled with fresh blood. The affected arterial wall showed mucoid extracellular matrix accumulation and disorganization of smooth muscle bundles. Furthermore, the medial layer demonstrated an aberrant distribution of elastic fibers, deviating from the normal architecture of muscular arteries. These findings highlight previously underrecognized microscopic features of peripheral arterial involvement in FBN1 ‐related MFS, characterized by latent structural fragility associated with abnormal vascular patterning. Surgery‐associated hemodynamic changes, including perioperative reinflation for an air‐leak test, which would be tolerated under normal conditions, may precipitate vascular injury and rupture.

Hypersensitivity pneumonitis (HP) is classified into fibrotic and nonfibrotic phenotypes. Rarely, nonfibrotic HP presents radiologically with multiple cysts. Histologically, nonfibrotic HP is characterized by cellular interstitial pneumonia, cellular bronchiolitis, and poorly formed non-necrotizing granulomas; however, the histopathological features and mechanisms underlying cyst formation remain poorly understood. We report a rare case of cyst-predominant nonfibrotic HP. A 42-year-old woman underwent pulmonary surgery for enigmatic lung cysts complicated by spontaneous pneumothorax. Histological examination revealed subpleural cystic lesions mimicking those of Birt-Hogg-Dubé syndrome and an absence of cellular interstitial pneumonia, a feature considered mandatory in current HP guidelines. Despite this, the presence of cellular bronchiolitis, microgranulomas, and supportive clinical findings led to a diagnosis of nonfibrotic HP following multidisciplinary discussion. This case underscores a significant diagnostic pitfall, as cyst-predominant nonfibrotic HP may be overlooked by clinicians and pathologists and misdiagnosed as Birt-Hogg-Dubé syndrome or other cystic lung diseases.

Electron micrograph showing a glycogen-rich interstitial (PIG) cell beneath the alveolar epithelium. The PIG cell contains abundant β-particle glycogen and lacks an independent basal lamina, supporting a developmentally immature mesenchymal phenotype.

Table S3. Count data of RNA-seq analysis.

Figure S1. Doxycycline has no effect on HKO differentiation.

Table S1. Marker genes used for clustering cell subtypes.

Although kidney cancer arises from a variety of nephron cells with diverse characteristics and develops intratumor heterogeneity, a model to elucidate these complexities is incompletely developed. In this study, we report a genetically engineered human induced pluripotent stem cell–derived kidney organoid (HKO) model, which may recapitulate an early stage of renal tumorigenesis. When we overexpressed the VCL-ALK fusion gene, a renal oncogene, in HKO, tubular cells proliferated, and this proliferation was sustained under long-term culture or hypoxic conditions. In addition, the proliferating tubular cells migrated into the renal parenchyma of host mice upon transplantation. The deconvolution analysis and IHC revealed that the proliferating tubular cells could be arrested at an immature tubular progenitor stage with increased expressions of LIM homeobox protein 1 and jagged canonical Notch ligand 1, critical regulators of nephrogenesis. Our HKO model advances our understanding of renal tumorigenesis in the context of the trajectory of nephron development.Implications:Dysregulated nephron developmental machinery leads to aberrant cell proliferation of immature renal tubules.

Table S3. Count data of RNA-seq analysis.

Figure S3. VCL-ALK overexpressing HKO derived from HPS0381, another human iPSCs, exhibits proliferating tubular cells.

Figure S4. VCL-ALK fusion gene might drive proliferation of tubular cells in an early stage of nephrogenesis.