Treatment strategy for synchronous metastases of colorectal cancer: is hepatic resection after an observation interval appropriate?

Background In cases of synchronous colorectal hepatic metastases, the primary colorectal cancer strongly influences on the metastases. Our treatment policy has been to conduct hepatic resection for the metastases at an interval of 3 months after colorectal resection. We examined the appropriateness of interval hepatic resection for synchronous hepatic metastasis. Materials and methods The subjects were 164 patients who underwent resection of hepatic metastasis of colorectal cancer (synchronous, 70 patients; metachronous, 94 patients). Background factors for hepatic metastasis and postoperative results were compared for synchronous and metachronous cases. Results The cumulative survival rate for 164 patients at 3, 5, and 10 years postoperatively was 71.9%, 51.8%, and 36.6%, and the post-resection recurrence rate in remnant livers was 26.8%. Interval resection for synchronous hepatic metastases was conducted in 49 cases after a mean interval of 131 days. No difference was seen in postoperative outcome between synchronous and metachronous cases. Conclusion The outcome was similarly favorable in cases of synchronous hepatic metastasis and in cases of metachronous metastasis. Delaying resection allows accurate understanding of the number and location of hepatic metastases, and is beneficial in determining candidates for surgery and in selecting surgical procedure.     

Phenotypic and genetic analyses of T-cell-mediated immunoregulation in patients with Type 1 diabetes.

AIMS: To investigate the contribution of regulatory T cells and co-stimulatory molecules in CD4(+) T cells to the development of Type 1 diabetes (T1D). METHODS: Twelve patients with T1D, nine patients with systemic lupus erythematosus (SLE), and 12 age-matched healthy control subjects participated. We analysed the proportions of CD25(+)CD4(+) T cells and natural killer T cells (NKT cells), and the expression levels of Foxp3, CTLA-4, CD28, ICOS, PD-1 and BTLA in peripheral blood mononuclear cells and purified CD4(+) T cells. RESULTS: There were no significant differences in the proportions of CD25(+) CD4(+) T cells or NKT cells among the three groups. PD-1 expression levels of peripheral CD4(+) T cells from T1D patients were significantly lower than those from healthy control subjects (P = 0.00066). In contrast, PD-1 expression levels were similar in SLE patients and healthy control subjects. The expression levels of Foxp3, CTLA-4, CD28, ICOS and BTLA were similar in the three groups. CONCLUSIONS: Decreased expression of the PD-1 gene in CD4(+) T cells may contribute to the development and/or maintenance of autoimmune T1D. As the population studied was small and heterogeneous, further studies are required to confirm the findings.     

Congenital pseudarthrosis of the tibia: analysis of the histology and the <Emphasis Type="Italic">NF1</Emphasis> gene

Background Congenital pseudarthrosis of the tibia (CPT) is frequently, but not always, associated with neurofibromatosis type 1 (NF1). Double inactivation of the NF1 gene has been reported to be the pathogenesis of CPT in NF1 cases. Methods We analyzed the loss of heterozygosity (LOH) of the NF1 gene in cases of CPT with NF1 to examine whether double inactivation was seen in the case. In addition to morphological analysis, immunoexpression of differentiation markers was examined. Results and discussion The tibia tapered with the zone phenomenon from mature to immature bone with osteoblastic rimming, resembling osteofibrous dysplasia. Osteosclerotic bowed bone with a small number of osteoclasts suggested dysfunction of bone remodeling. Fibrous tissue at the site of pseudarthrosis was associated with the periosteum and demonstrated myofibroblastic differentiation accompanied by massive cartilage formation, suggesting some misdirection during the differentiation of periosteum to myofibroblasts or chondrocytes. LOH of the NF1 gene locus was not seen in fibrous tissue. This result suggests that CPT is not accompanied by double inactivation in every NF1 case.     

Heterotopic transplantation of the failing rat heart as a model of left ventricular mechanical unloading toward recovery

The left ventricular assist device (LVAD) is usually used in patients with end-stage heart failure as a bridge to transplantation. Recently, some studies have reported functional recovery with the use of an LVAD, although the mechanisms responsible for recovery are not fully understood. We investigated the functional recovery of the infarcted, failing rat heart in response to mechanical unloading after heterotopic transplantation. Heart failure was induced in Lewis rats by ligating the left anterior descending artery. After 4 weeks, the infarcted hearts were harvested and heterotopically transplanted. The transplanted infarcted heart was removed after 2 weeks of unloading and examined for hypertrophy and fibrosis, as well as for mRNA levels encoding for brain natriuretic peptide, sarco(endo)plasmic reticulum Ca(2+)-ATPase2a (SERCA2a), and beta1- and beta2-adrenergic receptors. Normal and infarcted rats without transplantation served as control animals. The infarcted heart was hypertrophied as evidenced by an increase in heart weight and myocyte diameter. After unloading the infarcted heart for 2 weeks, there was a decrease in heart weight and myocyte diameter. However, the percentage of myocardial fibrosis increased after unloading. The mRNA expression of brain natriuretic peptide and the beta2-adrenergic receptor significantly improved after mechanical unloading. The levels of SERCA2a mRNA tended to increase after unloading. In conclusion, unloading the failing, infarcted heart can help normalize left ventricular hypertrophy and cardiac gene expression. This unloading model appears to partially mimic the conditions of hemodynamic support with an LVAD in heart failure patients and potentially offers insights into the mechanisms of functional recovery.     

Primary rhabdomyosarcoma of the iliac bone in an adult: A case mimicking fibrosarcoma

Primary rhabdomyosarcoma of bone is exceedingly rare. We present a case of rhabdomyosarcoma of the iliac bone in a 32-year-old male. Histologically, the tumour consisted mainly of a uniform proliferation of elongated spindle cells arranged in a herring bone pattern, simulating fibrosarcoma. Focally there was a conventional embryonal pattern with scattered rhabdomyoblasts possessing an eosinophilic cytoplasm. Immunohistochemical studies disclosed expression of muscle markers such as desmin and muscle-specific actin, in both the embryonal and spindle-cell areas and myoglobin only in the embryonal areas. Such histological features are unusual for classical embryonal rhabdomyosarcoma. The anatomical site and age of the patient are also atypical.     

Mechanisms of inactivation of the p16INK4a gene in leiomyosarcoma of soft tissue: decreased p16 expression correlates with promoter methylation and poor prognosis

The p16INK4a tumour suppressor gene, encoding p16 protein, plays a crucial role in regulation of the G1 cell-cycle phase. To investigate the potential role of p16 in soft tissue leiomyosarcoma (LMS), an immunohistochemical analysis was performed of 77 LMSs for p16 expression. Decreased expression of the p16 protein was identified in 25 of 77 LMSs (32%). Decreased expression of p16 correlated significantly with large tumour size (p=0.0038). In a univariate analysis, large tumour size and decreased expression of p16 were statistically significant adverse prognostic factors (p=0.025 and p=0.0021, respectively). In a multivariate analysis including conventional clinicopathological parameters, decreased expression of p16 protein was revealed as the only independent unfavourable prognostic factor (p=0.012). To elucidate the mechanisms of inactivation of the p16INK4a gene, 49 LMSs for which genomic DNA was available were examined; analysis for homozygous deletion, mutation, and promoter hypermethylation was conducted using differential PCR, PCR-SSCP, and methylation-specific PCR, respectively. Promoter hypermethylation was detected in 11 of 49 LMS cases (22%); homozygous deletion was detected in 3 of 49 cases (6%); and mutation was not recognized in any of the cases studied. Eight of 15 cases (53%) with decreased expression of p16 protein revealed methylation of the p16INK4a gene promoter. Promoter hypermethylation correlated closely with decreased expression and poor prognosis (p=0.0014 and p=0.0088, respectively). These results suggest that decreased expression of p16 protein can be considered as an independent reliable prognostic parameter in patients with soft tissue LMS. Furthermore, promoter methylation was more frequent than either homozygous deletion or mutation in this tumour, and promoter methylation was also shown to have a strong association with inactivation of the p16INK4a gene.     

Low-grade fibrosarcoma of the proximal humerus

We present the clinical, radiographical and pathological features of low-grade fibrosarcoma of the left proximal humerus in a 23-year-old man in whom it was necessary to distinguish the tumor from desmoplastic fibroma, malignant fibrous histiocytoma and intramedullary well-differentiated osteosarcoma. The patient presented with a 10-day history of pain in his left upper arm sustained when trying to break his fall with his left hand when slipping in the street. Plain radiography revealed an expanding multilobular osteolytic lesion from the proximal metaphysis to the diaphysis of his left humerus, accompanied by a pathological fracture at the distal portion of the lesion. Open biopsy of the lesion was performed twice; however, a conclusive diagnosis could not be obtained. The patient underwent wide excision and prosthetic replacement of the left proximal humerus. Histologically, the resected tumor was composed of both cellular areas and hypocellular areas. Cellular areas revealed a proliferation of bundles of uniform fibroblastic spindle-shaped cells with minimal cellular atypia, mixed with abundant intercellular collagenization. Mitotic figures were occasionally seen. Hypocellular areas showed myxoid features with loose bundles of collagen fibers. The patient demonstrates no evidence of disease 42 months after surgery. It is important to detect the scant atypical cells for the differential diagnosis of low-grade fibrosarcoma and desmoplastic fibroma of bone.