Makio Kawakami

CD147 and matrix metalloproteinase-2 protein expression as significant prognostic factors in esophageal squamous cell carcinoma.

The authors investigated whether the presence of matrix metalloproteinase‐2 (MMP‐2) and its inducer, CD147, in cancerous esophageal lesions and surrounding tissue might help to predict patient prognosis.

Angiogenesis in pancreatic carcinoma

Recently, the usefulness of intratumoral microvessel density (IMD) and expression of several angiogenic factors as prognostic indicators have been demonstrated in several human solid tumors.

Expression of progastrin-releasing peptide and gastrin-releasing peptide receptor mRNA transcripts in tumor cells of patients with small cell lung cancer.

Abstract Purpose. Small cell lung cancer (SCLC) is a rapidly growing neoplasm accounting for approximately 20% of patients with lung cancer. Progastrin-releasing peptide (proGRP) is produced in about two-thirds of SCLC tumors and is used as a specific marker for SCLC. Although GRP is known to have a variety of biological functions, only limited information is available concerning expression of proGRP mRNA and protein, and that of the receptor for GRP (GRPR) in SCLC tumors. Methods. In individuals with SCLC, the levels of serum proGRP(31–98) were measured by enzyme-linked immunosorbent assay. Expression of proGRP as well as GRPR mRNA in SCLC tumor tissues was investigated by reverse transcription-nested polymerase chain reaction (PCR) amplification. The proportions of alternatively spliced proGRP mRNA transcripts were analyzed in proGRP-producing tumors by nested and competitive PCR amplification. Finally, production of proGRP protein in SCLC tumor was evaluated by using immunohistochemical staining with a polyclonal human anti-proGRP antibody. Results. ProGRP mRNA transcripts could be detected only in tumor tissues recovered from individuals with high serum proGRP levels. The proportions of mRNA subtypes in each case were nearly the same, revealing type I of 55.4±7.6%, type II with 21-b deletion of 1.8±3.6%, and type III with 19-b deletion of 42.8±4.3%, respectively. ProGRP protein production was demonstrated in tumor tissues exclusively from individuals exhibiting high serum proGRP levels. In contrast, GRPR mRNA transcripts were detectable in cancer cells from two of five proGRP-expressing tumor tissues. Conclusions. ProGRP mRNA expression is closely related with the synthesis of proGRP protein which is eventually released into the blood. It is suggested GRP may function as an autocrine growth factor for cancer cells in a subgroup of SCLC patients through, at least in part, upregulation of GRPR expression.

Cardiac expression of urocortin (Ucn) in diseased heart; preliminary results on possible involvement of Ucn in pathophysiology of cardiac diseases

Recently, several studies reported that urocortin (Ucn) had beneficial effects on cardiovascular system and was expressed both in the normal heart and in the heart of dilated cardiomyopathy (DCM), yet the relationship between high expression of Ucn and pathophysiology of Ucn in diseased heart has been discussed. Thus, the present study was designed to elucidate the expression of Ucn in the diseased heart by immunohistochemical approach using endomyocardial biopsy specimens. The involvement of immunoreactive Ucn in pathophysiology of cardiac disease was evaluated using endomyocardial biopsy specimens obtained from the patients with some heart diseases, including DCM and hypertrophic cardiomyopathy (HCM). Ucn was detected in all endomyocardial biopsy specimens of ventricular tissue obtained from the patients with such cardiac diseases, a specimens of atrial tissue, and normal heart specimens obtained from autopsy cases. In DCM patients, left ventricular end-diastolic pressure significantly elevated in severely stained group. On the contrary, in HCM patients, left ventricular ejection fraction was higher in the severely stained group. Ucn was expressed more abundantly in the diseased heart, especially in HCM and DCM, than in the normal heart. In conclusion, such close relationship between Ucn expression in the heart and cardiac function indicated that clinical features of Ucn resembled those of norepinephrine and Ucn could play a certain pathophysiological roles in the cardiac diseases.

Prognostic significance of vascular endothelial growth factor D in gastric carcinoma.

The angiogenic factor called vascular endothelial growth factor (VEGF)-D is a ligand for VEGF receptor-2 (VEGFR-2/KDR) and receptor-3 (VEGFR-3/Flt-4). It is implicated in the development of lymphatic vessels and promotion of lymphatic metastasis. The purpose of this study was to investigate the prognostic significance of VEGF-D expression in patients with gastric carcinoma. We assessed the expression of VEGF-D in gastric carcinoma by immunohistochemistry on 143 consecutive patients’ stored sections and evaluated the lymphatic vessel count (LVC) in tumors using the novel selective lymphatic endothelium marker D2-40. VEGF-D expression was observed in 55 (39%) tumor sections. The expression of VEGF-D correlated significantly with tumor size, T of the TNM classification, lymphatic and venous system invasion, LVC, lymph node metastasis, M of TNM, and pTNM stage. Multivariate analysis indicated that VEGF-D expression was an independent prognostic factor for both relapse-free survival (RFS) and overall survival (OS). Our data indicate the involvement of VEGF-D in tumor progression via lymphoangiogenic pathways. Practically, VEGF-D expression can be useful for predicting RFS and OS in patients with gastric carcinoma.

Clinicopathologic Study of Angiogenesis in Japanese Patients with Breast Cancer

Abstract. To evaluate the clinicopathologic significance of angiogenesis as a prognostic factor and the objective methods for evaluating angiogenesis, we immunohistochemically stained a representative section of breast tumors with factor VIII-related antigen staining. There were 109 patients with primary breast cancer from 1971 to 1979. The two methods of identifying angiogenesis were the average microvessel count per square millimeter (AMC) and the highest microvessel count per square millimeter (HMC). There was no relation between microvessel count (AMC or HMC) or age, menopausal status, clinical tumor size (T), histologic classification, nuclear grade, node status, histologic grade (HG), mitosis index, or lymphatic invasion (LI). There was a relation between microvessel count and blood vessel invasion (BVI) (HMC:p = 0.0007) and tumor necrosis (TN) (HMC:p = 0.0050). Univariate analysis showed that AMC or HMC was a statistically significant predictor of overall survival in all patients (p = 0.0086 andp = 0.0307, respectively). Multivariate analysis showed that AMC was an independent predictor of node status when we fitted a model with node status, BVI, and either AMC or HMC; but HMC was not independent. However, when we fitted a model including all 11 of the other indicators and AMC or HMC, the node status, HG, and LI were independent predictors, but AMC and HMC were not. Although AMC was a better method than HMC for evaluating angiogenesis, we cannot confirm angiogenesis as a significant independent prognostic factor associated with long-term survival in Japanese breast cancer patients.

Comparison Between the Pathology of Encapsulating Sclerosis and Simple Sclerosis of the Peritoneal Membrane in Chronic Peritoneal Dialysis

Abstract:  Reports analyzing the histopathological differences between encapsulating peritoneal sclerosis (EPS) and simple peritoneal sclerosis (non‐EPS) and those comparing the pathology of early and late EPS are limited. We present pathological comparisons between EPS and non‐EPS, also between the early and late EPS stages. We compared peritoneal membrane (PM) samples (Group B) of 12 EPS patients (Group A) and 23 non‐EPS cases regarding; mesothelial loss, submesothelial compact zone degenerated layer and compact zone thicknesses, densities of total and diseased vessels, fibrin stain, new membrane formation and degenerative changes. Group A was subdivided into 7 early (group A1) and 8 late (group A2) EPS cases; we compared both subgroups in the same manner and finally compared groups A1, A2, and B. No differences were found between groups A and B in the incidences of mesothelial detachment, new membrane formation and compact zone degenerative changes between the two groups. Furthermore, there were no differences in compact zone thickness, and vascular densities in the compact zone of respective vascular grade. Whereas, fibrin deposition and thickness of the submesothelial degenerated layer were significantly higher in group A than group B (P = 0.01 and 0.05, respectively), and the thickness of the compact zone was less in group A1 than in group A2 (P = 0.03). Positive fibrin stains and thick degenerative compact zone layers are important pathological findings in EPS. Angiogenesis, vasculopathy, new membrane formation, fibrosis and degenerative changes of the compact zone are not unique characteristics for EPS. Larger size studies are recommended to verify this issue.

Aicardi syndrome: Postmortem findings

A 2-month-old infant with the typical clinical features of Aicardi syndrome (i.e., infantile spasms, chorioretinal lacunae, and agenesis of the corpus callosum) is reported. At 5 years of age, pathologic examination revealed cortical heterotopias, rostral agenesis of the corpus callosum, hypoplasia of the unilateral optic nerve, and bilateral cerebellar hemispheres. Cavum septum pellucidum was present. A literature review of 5 autopsied patients with this syndrome is included.

Metastasis to the orbit from transitional cell carcinoma of the bladder

PurposeTo demonstrate the pathological features of the extremely rare metastatic transitional cell carcinoma (TCC) from the bladder to the orbit, and to review the literature on metastatic TCC to the orbit.MethodsA 74-year-old man experienced 2 weeks of red eye, proptosis, diplopia, pain, and visual loss in the right eye. Three years previous to the current presentation, the patient had undergone a transurethral resection for superficial and moderately differentiated TCC of the bladder. A transseptal anterior orbitotomy was performed.ResultsHistopathological examination of the orbital lesion revealed nests of carcinomatous cells. Atypical pleomorphic cells with vacuolated cytoplasm were evident. The cellular morphology of the orbital lesion was identical to that of the primary TCC. There have been 12 previously reported cases of metastases to the orbit from TCC of the bladder, with the time from onset of primary TCC to observation of ocular symptoms ranging from 3 weeks to 11 years. Mean survival after orbital metastasis developed from TCC was 3.0 months.ConclusionThis study presents a detailed description of the pathological features of metastatic TCC in the orbit. In cases of orbital metastasis from TCC, patient prognosis is very poor. Jpn J Ophthalmol 2006;50:469–473

Pseudo-Gaucher Cell Proliferation Associated with Myelodysplastic Syndrome

We report an extremely rare case of pseudo-Gaucher cell proliferation with myelodysplastic syndrome (MDS). A 77-year-old Japanese man was referred to our hospital with splenomegaly and thrombocytopenia, and subsequent bone marrow aspiration revealed infiltrates of foamy vacuolated macrophages without any evidence of other morphologic abnormalities. A karyotype analysis showed the presence of 46,XY,del(20)(q11) in 20 of 20 examined bone marrow cells. We performed a splenectomy, and the resulting pathologic findings revealed massive infiltration of foamy vacuolated macrophages, which were morphologically compatible with Gaucher cells. The activities of β-glucosidase and acid sphingomyelinase were within normal ranges; therefore, the foamy vacuolated macrophages were considered pseudo-Gaucher cells. A diagnosis of MDS, subclassified as refractory anemia, was then made according to World Health Organization classification guidelines. Pseudo-Gaucher cell proliferation and infiltration might therefore be observed in other patients presenting with MDS.