Neighboring macrophage-induced alteration in the phenotype of colorectal cancer cells in the tumor budding area.

BACKGROUND: A higher number of tumor buds in the invasive front of colorectal cancer (CRC) specimens has been shown to contribute to a poor prognosis in CRC patients. Because macrophages (Mφs) have been demonstrated to alter the phenotype of cancer cells, we hypothesized that the phenotype of CRC cells in the tumor budding (TB) area might be changed by the interaction between CRC cells and Mφs. METHODS: We assessed the expression of topoisomerase 1 in CRC cells to estimate the acquisition of chemoresistance in CRC. To demonstrate the tumor-stromal interaction between CRC cells and Mφs, we assessed two histological findings, the number of Mφs per single CRC cell and the proximity between CRC cells and Mφs by histological spatial analysis using HALO software. RESULTS: The expression levels of topoisomerase 1 in CRC cells were decreased in deeper areas, especially in the TB area, compared to the surface area. Our histological spatial analysis revealed that 2.6 Mφs located within 60 µm of a single CRC cell were required to alter the phenotype of the CRC cell. Double-immunofluorescence staining revealed that higher Mφs were positive for interleukin-6 (IL-6) in the TB area and that AE1/AE3-positive CRC cells were also positive for phospho-STAT3 (pSTAT3) in the TB area; thus, the IL-6 receptor (IL-6R)/STAT3 signaling pathway in CRC cells was upregulated by IL-6 derived from neighboring Mφs. CONCLUSION: IL-6 secreted from the neighboring Mφs would alter the phenotype of CRC cells via IL-6R/STAT3 signaling pathway.

Predicting anterior cruciate ligament degeneration using magnetic resonance imaging: Insights from histological evaluation.

BACKGROUND: Mucoid degeneration of the anterior cruciate ligament is a pathological condition that may impair knee mechanics and contribute to the symptomatology of osteoarthritis. This study aimed to evaluate whether preoperative magnetic resonance imaging can predict anterior cruciate ligament degeneration, specifically mucoid degeneration, and to elucidate the histopathological characteristics of mucoid degeneration in knee osteoarthritis patients. METHODS: We evaluated a total of 95 knees of osteoarthritis patients (23 males, 72 females; mean age: 72.7 ± 7.5) scheduled for total knee arthroplasty. The relationship between preoperative magnetic resonance imaging findings and the histopathological evidence of anterior cruciate ligament mucoid degeneration was examined. Immunohistochemical analysis was employed for collagen types (COL-I, COL-II), chondrogenesis (SOX9), and vascularity (CD31). RESULTS: High signal intensity on magnetic resonance imaging showed a positive correlation with Alcian Blue staining areas (rs = 0.59, p < 0.01) and the swelling index (rs = 0.62, p < 0.01), indicating advanced mucoid degeneration. The absence of synovial lining around the anterior cruciate ligament was associated with more severe degeneration. In the histological evaluations, advanced degeneration was characterized by an increase in chondroid metaplasia and collagen disorientation. The Alcian Blue and SOX9 correlation was positive (rs = 0.69, p < 0.01), but negative with COL-I (rs = -0.38, p = 0.03) and vascularity (CD31) (rs = -0.60, p < 0.01). CONCLUSIONS: Preoperative magnetic resonance imaging is an effective tool in assessing the severity of anterior cruciate ligament degeneration; it influences surgical decisions. High signal intensity on magnetic resonance images denotes advanced mucoid degeneration. The absence of synovial lining around the anterior cruciate ligament is associated with more severe degeneration and may accelerate degenerative changes. Chondroid metaplasia and collagen disorientation mark advanced degeneration. Magnetic resonance imaging can be used to gauge the degree of anterior cruciate ligament degeneration in osteoarthritis.

Pathogenesis of follicular thymic hyperplasia associated with rheumatoid arthritis.

Lymphoproliferative disorders may occur in patients with rheumatoid arthritis (RA) who are treated with methotrexate. However, follicular thymic hyperplasia (FTH) associated with RA (FTH-RA) is generally not considered a lymphoproliferative disorder. To investigate the pathogenesis of FTH-RA, we examined 12 cases of FTH involving thymic enlargement, four of FTH involving RA and eight of FTH involving myasthenia gravis (MG). Increased numbers and larger germinal center (GC) size were observed in FTH-RA group. The percentage of distorted GCs was 13.3% in FTH-RA group and 3.25% in FTH associated with MG (FTH-MG) group. A greater meshwork of follicular dendritic cells was observed in the GCs of FTH-RA group. Positive indices of CD27+ cells and PD-1+ cells per GC in FTH-RA group were significantly higher than those in FTH-MG group, though positive indices of CD68+ cells and CD163+ cells were similar. Myoid cell proliferation, as evaluated by α-SMA, tenascin-C, and l-caldesmon expression, was significantly increased in the FTH-RA group compared with the FTH-MG group. These results suggest that FTH should be considered in patients with RA treated with methotrexate. The pathogenesis of FTH-RA includes GC expansion and increased numbers of memory B cells, follicular helper T cells, and myoid cells, indicating humoral immunity activation.

Staging of osteochondritis dissecans of the elbow based on pathologic progression in the partially detached articular fragment.

BACKGROUND: Osteochondritis dissecans (OCD) is considered to show the following stages of pathologic progression: IA, nearly normal-cartilaginous; IB, deteriorated-cartilaginous; IIA, cartilage-ossifying; and IIB, cartilage-osteonecrotic. However, the validity of this pathologic staging for OCD has yet to be confirmed in a large number of cases. PURPOSE: The aim of the present study was to confirm the clinical validity of the proposed pathologic staging of OCD. METHODS: The subjects were 74 patients (mean age, 14.2 years; mean skeletal age score, 25.6 points) with capitellar OCD. Partially detached articular fragments were surgically removed and were examined histologically. The articular fragments were independently assessed by 5 observers, and the reliability of assessment was examined. The correlation between the pathologic stages and the clinical data was analyzed. RESULTS: The reliability of the assessment among 5 observers was almost perfect. OCD stages of IA, IB, IIA, and IIB were evident in 8, 36, 10, and 20 patients, respectively. OCD-I (cartilaginous) and OCD-II (osteochondral) corresponded significantly to radiographic stage I (radiolucency) and stage II (delayed ossification), respectively. The pathologic OCD stages were significantly correlated with the clinical data, including the period from symptom onset to surgery, patient age, and the skeletal age score (P < .01). CONCLUSION: Our results confirmed that the proposed pathologic staging of OCD corresponds to the observed clinical progression of OCD, thus validating the staging system. Our findings revealed that OCD begins with separation beneath the epiphyseal cartilage, which is programmed to be replaced with bone. When a stage IA articular fragment has remained partially detached for a prolonged period, the epiphyseal cartilage may be deteriorated and become degenerated, and subsequent ossification may not occur, as is evident in OCD-IB. In contrast, stage IA with a vascular supply through the fibrocartilaginous connection can progress to stage IIA. During the prolonged period in which the osteochondral articular fragment remains ununited, microtrauma can cause to disturb the blood supply to the bony fragment, resulting in osteonecrosis (stage IIB).

Progression of Epiphyseal Cartilage and Bone Pathology in Surgically Treated Cases of Osteochondritis Dissecans of the Elbow.

BACKGROUND: Although a variety of pathologic conditions associated with osteochondritis dissecans (OCD) have been reported, the pathological progression has remained unclear. HYPOTHESIS: Separation of the immature epiphyseal cartilage is an early event in OCD, and osteonecrosis in the articular fragment is a late event. STUDY DESIGN: Case Series; Level of evidence, 4. METHODS: The participants were 26 boys (mean age, 13.8 years; mean skeletal age score for the elbow, 24.6 points) with capitellar OCD who underwent osteochondral autograft transplantation. A total of 28 cylindrical osteochondral plugs, including the articular fragment, an intermediate layer, and proximal epiphyseal bone, were harvested from the central area of the capitellum and were examined histologically. The articular fragments of OCD were independently assessed by 5 observers and divided into 4 pathological variations: IA, nearly normal-cartilaginous; IB, deteriorated-cartilaginous; IIA, cartilage-ossifying; and IIB, cartilage-osteonecrotic. The reliability of assessment and the correlation of the pathological variations with the clinical data were examined. RESULTS: The reliability of the assessment among 5 observers was almost perfect (Cohen kappa value = 0.91). OCD variations of IA, IB, IIA, and IIB were evident in 5, 10, 5, and 6 patients, respectively. OCD-I (cartilaginous) and OCD-II (osteochondral) corresponded significantly to radiographic stage I (radiolucency or slight calcification with open physis) and stage II (delayed ossification or bony fragment), respectively (Cohen kappa value = 0.79; percentage agreement = 81%). The pathological OCD variations were significantly correlated with the clinical data, including the period from symptom onset to surgery, patient age, and the skeletal age score (P < .01, in each). CONCLUSION: The present study has revealed that the pathological variations correspond to the progression of OCD, thus proving our hypothesis. OCD-IA was shown to be an early lesion caused by separation of the immature epiphyseal cartilage. OCD-IB appeared to result from ossification arrest over a prolonged period from the onset of OCD-IA, whereas OCD-IIA showed delayed ossification in the epiphyseal cartilage where vascularization from the surrounding bone had been established. Osteonecrosis in OCD-IIB was shown to be a late pathological event caused by disruption of the vascular supply to OCD-IIA.