Collapsin Response Mediator Protein 4 Expression is Associated with Liver Metastasis and Poor Survival in Pancreatic Cancer

Background

Pancreatic cancer is an aggressive malignancy with one of the worst mortality rates of all cancers. Recently, collapsin response mediator proteins (CRMPs) were reported to be associated with proliferation, apoptosis, differentiation, and invasion in several cancers. However, CRMP expression and their role in pancreatic cancer have not been investigated. This study aimed to clarify the clinical significance of CRMPs in pancreatic cancer.

Methods

Expression of crmp genes in 11 pairs of pancreatic cancer and corresponding noncancerous pancreas tissues were examined by real-time RT-PCR. Knockdown of CRMP4 expression using siRNA was examined in pancreatic cancer cell lines to determine whether CRMP4 regulates cell proliferation and invasion in vitro. Furthermore, CRMP4 protein levels in primary tumors of pancreatic cancer (n = 53) were examined by immunohistochemistry and compared with the clinicopathological features of the tumors.

Results

Of all the CRMPs, only CRMP4 was differentially expressed in pancreatic cancer tissues (p = 0.008). CRMP4 knockdown using siRNA reduced cellular invasion, but did not affect proliferation. The expression of CRMP4 was detected immunohistochemically in 34 (64.2 %) of the 53 pancreatic cancer samples, and CRMP4 expression was correlated with severe venous invasion (p = 0.044), stage (p = 0.019), and liver metastasis (p = 0.021). Multivariate analyses suggested that venous invasion and CRMP4 overexpression were prognostic factors for survival.

Conclusions

Our results suggested that CRMP4 is significantly associated with poor prognosis by promoting liver metastasis and can serve as a novel therapeutic target for pancreatic cancer.

     

Telomerase activity and Bcl-2 expression in gallbladders of pancreaticobiliary maljunction patients: a preliminary study

Background The congenital anomaly pancreaticobiliary maljunction (PBM) is considered to be a precancerous disease. PBM carcinogenesis is believed to be an accumulation of gene abnormalities, but the early events causing PBM carcinogenesis are still unclear. In the present study, telomerase activity and Bcl-2 expression in the gallbladder mucosa of PBM and non-PBM gallbladders were investigated.Methods The operative gallbladder materials were from five control cases, two cases of non-PBM gallbladder cancer, three of PBM gallbladder cancer, and three of non-neoplastic PBMs. Multiple sampling was performed from each gallbladder. The studies performed were: (1) immunohistochemistry of p53, Ki-67, and Bcl-2; (2) survey of k-ras point mutations; and (3) measurement of telomerase activity in each sample.Results In the cases of non-PBM cancer, abnormalities from the above studies were detected only in the cancerous lesions. Normal-appearing mucosa did not show Bcl-2 expression or telomerase activity. However, in the cases of PBM cancer, normal-appearing mucosa showed telomerase activity and Bcl-2 expression, but did not show p53, Ki-67, or k-ras abnormalities. In the non-neoplastic PBM, all samples showed Bcl-2 expression, and many showed telomerase activity.Conclusions Bcl-2 expression and activation of telomerase are probably early events causing carcinogenesis of the PBM gallbladder mucosa. They might be important factors causing carcinogenesis associated with chronic inflammation.     

Black (or brown) adrenal cortical adenoma: its characteristic features on computed tomography and endocrine data

Seventeen patients with adrenal adenoma causing Cushing's syndrome, eight patients with Cushing's disease due to hypersecretion of ACTH, and five patients with primary aldosteronism due to an aldosteronoma were studied for their computed tomographic (CT) patterns, hormonal profiles, and macroscopic and microscopic findings of the adrenal gland. Black (or brown) adrenal adenomas were found in 71% of the patients with Cushing's syndrome, but not in patients with aldosteronoma. The adrenal tissue of patients with Cushing's disease was predominantly yellow. The number of compact cells was larger in black or brown adenomas than in yellow tumors or hyperplastic adrenal tissue. In patients with Cushing's syndrome, urinary excretion of 17-ketosteroids (17-KS) and serum aldosterone concentrations were lower in those with black or brown adenomas than in those with yellow adenomas (P less than 0.05). Patients with Cushing's disease had even higher 17-KS and serum aldosterone levels. No difference was found in serum cortisol concentrations and dexamethasone suppressibility in two types of adenomas causing Cushing's syndrome. Visual estimation of radiological density of the adrenal tissue relative to the kidney on CT scan and quantitative measurement of it by CT number revealed a difference between the two types of adrenal tumors causing Cushing's syndrome. Adrenal tumors with decreased density on CT scan were yellow adenomas with predominantly clear cells, and those with equal or increased density were black or brown adenomas with predominantly compact cells. All aldosteronomas had decreased density and consisted of clear cells. It is suggested that black or brown adenomas of the adrenal gland have higher radiological density and accompanying lower serum aldosterone and urinary 17-KS levels than ordinary yellow tumors. The abundance of compact cells may have some significance for the development of this particular type of adrenal tumor.     

A case of acute renal failure after exercise with renal hypouricemia demonstrated compound heterozygous mutations of uric acid transporter 1

Familial renal hypouricemia is a hereditary disease characterized by extraordinary high renal uric acid (UA) clearance and is associated with acute renal failure (ARF). A 17-year-old Japanese male developed ARF after anerobic exercise. Renal function improved completely after approximately 2 weeks of hydration treatment. After remission, hypouricemia became evident (1.0 mg/dL) from the initial level of UA (4.8 mg/dL) and fractional excretion of uric acid (FEUA) was >50%. His parents showed normal levels of UA and FEUA. Polymerase chain reaction of a urate anion exchanger known to regulate UA level [SLC22A12 gene: UA transporter 1 (URAT1)] demonstrated compound heterozygous mutations (Q297X and R90H). Thus, we describe a Japanese male with hypouricemia complicated by anerobic exercise-induced ARF, with definite demonstration of a genetic abnormality in the responsible gene, URAT1.     

Intestinal obstruction caused by colonic metastasis from intrahepatic cholangiocarcinoma 6?years after removal of the primary tumor: report of a case

We report a case of intestinal obstruction caused by metastasis that manifested 6 years after surgery for intrahepatic cholangiocarcinoma (ICC). The patient, a 57-year-old man, had undergone resection of the hepatic left lobe, Spiegel lobe, and extrahepatic bile duct, following which histopathological examination had confirmed the diagnosis of ICC and that the resection margins were free from disease. There had been no signs of recurrence until an increase in the CA19-9 level was detected 6 years later. Colonoscopy revealed an ulcer-like lesion and stenosis at the level of the hepatic flexure. The patient was subsequently admitted to our hospital with abdominal pain and underwent right hemicolectomy with partial resection of hepatic segment V. Based on the immunohistological finding that the expression pattern of cytokeratins and mucins was consistent with ICC origin rather than colon cancer origin, we diagnosed colon metastasis from ICC.     

Excellent results with high-dose mizoribine combined with cyclosporine, corticosteroid, and basiliximab in renal transplant recipients: multicenter study in Japan

We performed a multicenter study in Japan to assess the efficacy and safety of immunosuppressive therapy with high-dose mizoribine (MZR; 6 mg/kg) combined with basiliximab (Bas), cyclosporine (CyA), and a corticosteroid in 90 patients. MZR was adjusted to maintain a target trough level of 1 to 2 μg/mL. CyA was started at 7 mg/kg to maintain blood levels in the target therapeutic range of 200 ng/mL (trough [C0]), 1200 ng/mL (2-hour post-dose [C2]), and 6000 ng · h/mL (area under the curve_0-9). Bas (20 mg/body weight) was administered on the day of transplantation and on postoperative day 4. Rejection was diagnosed by episode and protocol biopsies. Cytomegalovirus (CMV) antigenemia (direct immunological staining of leukocytes using peroxidase-labeled monoclonal antibody [C7-HRP]) levels were measured every 2 weeks for 6 months. At 12 months, all patients and grafts were surviving except for one death from infection: the 1-year patient and graft survival rate was 98.9%. The acute rejection rate was 21.1%. The mean serum creatinine level at 1 year was 1.51 ± 0.61 mg/dL. The incidence of CMV disease was 0% with 28.9%, CMV antigenemia and 5.6%, ganoyclovir treatment. The incidence of BK virus disease was 2.2%. The mean serum uric acid level was 7.15 ± 1.79 mg/dL at 1 month and 7.06 ± 1.78 mg/dL at 3 months. We observed that a high-dose MZR regimen in combination with CyA, Bas, and corticosteroid was safe and effective to reduce the frequency of CMV and BK virus-related events in renal transplant recipients.     

Sequential resection of lung metastasis following partial hepatectomy for colorectal cancer

BACKGROUND: Multiple organ metastases from colorectal carcinoma may be considered incurable, but long survival after both liver and lung resection for metastases has been reported. METHODS: A retrospective analysis of 48 patients who underwent lung resection for metastatic colorectal cancer between 1992 and 1999 was undertaken. Twenty-seven patients had lung metastasis alone, 15 had previous partial hepatectomy, and six had previous resection of local or lymph node recurrence. The relationship of clinical variables to survival was assessed. Survival was calculated from the time of first pulmonary resection. RESULTS: Five-year survival rates after resection of lung metastasis were 73 per cent in patients without preceding recurrence, 50 per cent following previous partial hepatectomy and zero after resection of previous local recurrence. Independent prognostic variables that significantly affected survival after thoracotomy were primary tumour histology and type of preceding recurrence. There was no significant difference in survival after lung resection between patients who had sequential liver and lung resection versus those who had lung resection alone. CONCLUSION: Sequential lung resection after partial hepatectomy for metastatic colorectal cancer may lead to long-term survival.     

Clinical significance of pulmonary metastases in stage D2 prostate cancer patients

Several prognostic factors such as the extent of bone metastases (EOD) in advanced prostate cancer (PCa) have been reported. Metastasis of the lung is rarely a significant clinical factor in the management of prostate cancer. The present study evaluates the clinical significance of lung metastases. We retrospectively reviewed the PCa database to identify patients with pulmonary metastases at initial diagnosis. The medical records of the patients were examined with respect to age, histologic grade, EOD score, marker response to endocrine therapy and clinical outcome. We then compared several potential clinical factors between patients with and without pulmonary metastases. Next, we retrospectively reviewed autopsy records of 60 Japanese patients who died of hormone-refractory metastatic PCa with particular focus upon metastatic profiles. A comparative study of stage D(2) patients with (n=20) and without (n=77) pulmonary metastases found no significant differences in EOD score, performance status, marker response and survival. Only tumor grade was better in the group with, than without pulmonary metastases (P=0.0120, chi-square analysis). In the series of autopsies, we found pulmonary metastases in 38 cases (63%), following metastases of the bone (57 cases, 95%) and lymph nodes (52 cases, 87%). A retrospective analysis of survival showed that patients with bone or lymph node metastases had a positive relative risk. In contrast, lung metastasis could be a positive prognostic indicator, although the findings were not statistically significant. These data suggest that the presence of pulmonary metastasis has no ominous impact on clinical course and disease outcome even in patients with disseminated prostate cancer.     

Differential diagnosis of kidney transplant rejection and cyclosporin/tacrolimus nephropathy using urine cytology

Abstract: A total of 9000 urine samples from 69 kidney transplant recipients were studied for differential diagnoses of transplant rejection and cyclosporin/tacrolimus toxicity. New–Sternheimer and Papanicolaou staining were used to differentiate cells in urine. We also employed an immunocytochemical technique for further identification of exfoliated cells. With New–Sternheimer and Papanicolaou staining, the predominance of proximal tubular cells was useful to differentiate cyclosporin/tacrolimus toxicity from acute rejection in cases of increased serum creatinine level. During rejection episodes, an increased number of mononuclear cells and renal epithelial cells were found. Immunocytochemical analysis showed a significant increase of CD2-, CD4- CD8-, CD25- and HLA-DR-positive cells with rejection. However, there was no relationship between Banff criteria rejection grade and the increase of mononuclear cells.     

Clinical significance of mucinous components in rectal cancer after preoperative chemoradiotherapy

Purpose

The clinical implications of mucinous components in rectal tumors, especially with regard to the efficacy of neoadjuvant chemoradiotherapy, remain unclear.

Methods

One hundred and thirty rectal cancer patients who received curative resection after neoadjuvant chemoradiotherapy were retrospectively reviewed. Patients were classified into 3 groups according to the proportion of extracellular mucin: low (<5 %), moderate (5–25 %), and high (>25 %).

Results

There were 82 (63.1 %), 26 (20.0 %), and 22 (16.9 %) patients in the low, moderate, and high mucin groups, respectively. Patients with a high mucinous tumor component were significantly more likely to have an advanced tumor stage (p = 0.010) and a shorter disease-free (p = 0.002) and distant recurrence-free survivals (p < 0.001), whereas the mucinous tumor component showed no correlation with local recurrence (p = 0.101). A high mucinous component was also an independent predictive factor for a shorter disease-free survival (p = 0.041, hazard ratio = 2.56) and distant recurrence-free survival (p = 0.001, hazard ratio = 5.74) according to a multivariate analysis.

Conclusions

Because the mucinous components showed little correlation with local recurrence, mucinous cancer should not be a determining factor for chemoradiotherapy. However, the frequent occurrence of metachronous distant metastasis among patients with a high mucin component makes this a possible indicator for more robust postoperative adjuvant treatment and close surveillance of recurrence.