Role of immunoproteasomes and thymoproteasomes in health and disease

The proteasome is a multisubunit protease that degrades intracellular proteins into small peptides. Besides playing a pivotal role in many cellular processes indispensable for survival, it is involved in the production of peptides presented by major histocompatibility complex class I molecules. In addition to the standard proteasome shared in all eukaryotes, jawed vertebrates have two specialized forms of proteasome known as immunoproteasomes and thymoproteasomes. The immunoproteasome, which contains cytokine-inducible catalytic subunits with distinct cleavage specificities, produces peptides presented by class I molecules more efficiently than the standard proteasome. The thymoproteasome, which contains a unique catalytic subunit β5t, is a tissue-specific proteasome expressed exclusively in cortical thymic epithelial cells. It plays a critical role in CD8⁺ cytotoxic T cell development via positive selection. This review provides a brief overview on the structure and function of these specialized forms of proteasome and their involvement in human disease.     

Does Radiographic Coxa Profunda Indicate Increased Acetabular Coverage or Depth in Hip Dysplasia?

Background

Although radiographic coxa profunda has been considered an indicator of acetabular overcoverage, recent studies suggest that radiographic coxa profunda is a nonspecific finding seen even in hip dysplasia. The morphologic features of coxa profunda in hip dysplasia and the frequency with which the two overlap are not well defined.

Questions/purposes

We determined (1) the prevalence of radiographic coxa profunda in patients with hip dysplasia; (2) the morphologic differences of the acetabulum and pelvis between patients with hip dysplasia and control subjects; and (3) the morphologic differences between hip dysplasia with and without coxa profunda.

Methods

We retrospectively reviewed the pelvic radiographs and CT scans of 70 patients (70 hips) with hip dysplasia. Forty normal hips were used as controls. Normal hips were defined as those with a lateral center-edge angle between 25° and 40°. Coxa profunda was defined as present when the acetabular fossa was observed to touch or was medial to the ilioischial line on an AP pelvic radiograph. CT measurements included acetabular version, acetabular coverage, acetabular depth, and rotational alignment of the innominate bone.

Results

The prevalence of coxa profunda was 44% (31 of 70 hips) in dysplastic hips and 73% (29 of 40 hips) in the control hips (odds ratio, 3.32; 95% CI, 1.43–7.68). Dysplastic hips had a more anteverted and globally shallow acetabulum with inwardly rotated innominate bone compared with the control hips (p < 0.001). Dysplastic hips with coxa profunda had a more anteverted acetabulum (p < 0.001) and inwardly rotated innominate bone (p < 0.002) compared with those without coxa profunda, whereas the acetabular coverage and depth did not differ between the two groups, with the numbers available.

Conclusions

Radiographic coxa profunda was not a sign of increased acetabular coverage and depth in patients with hip dysplasia, but rather indicates classic acetabular dysplasia, defined by an anteverted acetabulum with anterolateral acetabular deficiency and an inwardly rotated pelvis. Thus, the presence of coxa profunda does not indicate a disease in addition to hip dysplasia, and the conventional maneuvers during periacetabular osteotomy are adequate for these patients.

Level of Evidence

Level IV, diagnostic study.     

Spontaneous rupture of metastatic α-fetoprotein-producing gastric cancer of the liver

An 80-year-old man was admitted to our hospital because of the rupture of the liver. Laboratory data showed iron-deficiency anemia, although there was no liver dysfunction. A computed tomography scan showed large liver tumor with intraperitoneal hemorrhage, and since a serum level of α-fetoprotein (AFP) was extremely high, we initially suspected a rupture of hepatocellular carcinoma (HCC). Transarterial embolization was performed to stop bleeding from the tumor, followed by an endoscopic examination that revealed advanced gastric cancer. Histological analysis revealed that both the gastric and the hepatic tumors were moderately to poorly differentiated adenocarcinoma, as well as that both tumors were immunohistochemically positive for AFP. Finally, we diagnosed AFP-producing gastric cancer associated with liver metastasis. Rupture of metastatic liver cancer is rare, and accordingly, distinction from HCC is important, particularly for the cases of AFP-producing gastric cancer.     

Colonoscopic Stigmata of 1 mm or Deeper Submucosal Invasion in Colorectal Cancer

Purpose  This study was designed to identify colonoscopic stigmata, indicating substantial invasion into the submucosa by T1 colorectal cancer with sessile morphology, including both flat and protruded types. Methods  A total of 111 Tis or T1 colorectal cancers were studied retrospectively. The lesions were divided into two groups: Group A (n = 83), Tis or T1 cancers with <1 mm submucosal invasion; and Group B (n = 28), T1 cancers with a ≥1 mm submucosal invasion. Printed photographs of the lesions were reviewed by five experienced colonoscopists who were blinded to histology. Deep depression, irregular surface, ulceration or erosion, fold convergence, and spontaneous bleeding were independently evaluated. Findings considered present by three or more reviewers were defined as positive. Kappa analysis was used to measure inter/intraobserver variability. Results  Positive rates of four findings but not fold convergence were significantly higher in Group B than in Group A. Irregular surface and spontaneous bleeding were significant independent predictors of ≥1 mm submucosal invasion, with diagnostic accuracies of 85.6 and 76.6 percent, respectively. Kappa analysis demonstrated fair-to-good inter/intraobserver agreement for spontaneous bleeding and fair-to-good intraobserver agreement for irregular surface. Conclusions  Irregular surface and spontaneous bleeding were colonoscopic stigmata, indicating ≥1 mm submucosal invasion in T1 colorectal cancer.     

Congenital Hypoplasia of the Dorsal Pancreas: With Special Reference to Duodenal Papillary Dysfunction

We report a case of dorsal pancreatic hypoplasia complicated with atresia of the vagina, type-A chronic atrophic gastritis, duodenal papillary dysfunction, and insulin-requiring diabetes mellitus, in a 32-yr-old woman. The laboratory data showed elevated hepatobiliary enzymes. Endoscopic retrograde cholangiopancreatography (ERCP) revealed a slightly dilated common bile duct and a short major pancreatic duct connected with a minor pancreatic duct. Ultrasonography and computerized tomography could not identify any pancreatic tissue in the region of the body or tail of the pancreas. The pancreatic tissue weight calculated by the serial thin slice of computerized tomography was 43.1 g, approximately 45% of the standard Japanese adult pancreas. Reevaluated pancreatic exocrine function based on this weight showed a hypersecretory state. The pancreatic ductal pressure was slightly increased, and the motility of the sphincter of Oddi (SO) was abnormal when measured with a 4Fr. microtransducer inserted through a duodenoscope. These findings suggest that dysfunction of the sphincter of Oddi may play some role in the pathophysiology in the hypoplasia of the dorsal pancreas and pancreaticobiliary diseases associated with it.     

Differential diagnosis of benign versus malignant nonfunctioning islet cell tumors of the pancreas: the roles of EUS and ERCP.

BACKGROUND: Differentiation between benign and malignant nonfunctioning islet cell tumors of the pancreas before surgery is often difficult. The roles of EUS and ERCP were evaluated in the differential diagnosis of these tumors. METHODS: Seven patients with histologically confirmed nonfunctioning islet cell tumors (4 benign, 3 malignant) underwent EUS and ERCP. OBSERVATIONS: EUS demonstrated a homogeneous hypoechoic mass or a hypoechoic mass with a regular central echogenic area in the 4 cases of benign tumor, and a hypoechoic mass with an irregular central echogenic area in all 3 cases of malignant tumor. The irregular central echogenic area corresponded to severe hemorrhage, necrosis, or fibrosis with hyalinosis (hyaline degeneration) on pathologic examination. ERCP demonstrated displacement or complete obstruction (because of ductal invasion) of the main pancreatic duct in 2 patients with malignant tumors and no abnormalities in the other 5 cases. CONCLUSIONS: In patients with nonfunctioning islet cell tumors, a hypoechoic mass with an irregular central echogenic area on EUS or complete obstruction of the main pancreatic duct on ERCP suggests malignancy.