Haruo Iguchi

Increased incidence of bone metastases in hepatocellular carcinoma

Objectives Recently, we often encounter hepatocellular carcinoma patients with bone metastases. We therefore examined the changes in the incidence of bone metastases in hepatocellular carcinoma from 1978 to 1997 and tried to identify the characteristic clinical features. We also discuss the reasons for the increased incidence of bone metastasis in hepatocellular carcinoma. Methods A total of 673 patients with hepatocellular carcinoma during the period 1978–1997 were studied. Bone metastasis was screened by bone scintigraphy, and bone lesions were confirmed by plain radiography, computed tomography and/or magnetic resonance imaging. The serum levels of the C-terminal telopeptide of type 1 collagen, which represent osteoclastic bone resorption, were also measured. Results The incidence of bone metastasis during the decade 1988–1997 was significantly higher than that during the period 1978–1987. The median survival time of patients with hepatocellular carcinoma during 1988–1997 was also significantly longer than that during 1978–1987. Portal thrombus was found in about half of the patients with bone metastases. The most common site of bone metastases was the vertebra followed by the pelvis, rib and skull in that order. All bone lesions depicted by plain radiograph, computed tomography and/or magnetic resonance imaging were of the osteolytic type, and the serum levels of C-terminal telopeptide of type 1 collagen were significantly elevated in the patients with bone metastases. Conclusions The increased incidence of bone metastasis in hepatocellular carcinoma in the decade 1988–1997 is first attributed to the prolonged survival rate of hepatocellular carcinoma patients due to recent progress in both the diagnosis and treatment of the disease. Dissemination of hepatocellular carcinoma cells to the vertebra through the portal vein–vertebral vein plexuses due to the presence of portal thrombus and/or portal hypertension may be related to a higher incidence of bone metastasis in hepatocellular carcinoma. Both an early diagnosis and timely treatment of bone metastases are thus called for in the follow-up of hepatocellular carcinoma patients.

Tissue Distribution and Molecular Forms of a Novel Pituitary Protein in the Rat

A sensitive and specific radioimmunoassay (RIA) was developed for a novel pituitary protein that we recently isolated from human and porcine pituitary gland and designated 7B2. By employing this RIA, we were able to detect and assay this novel protein in different rat tissue extracts. The concentrations of 7B2 in rat anterior pituitary lobe, neurointermediate lobe, hypothalamus, adrenal medulla and thyroid gland were 10,400 +/- 804; 6,190 +/- 908; 773 +/- 50; 697 +/- 83 and 1,368 +/- 116 pg/mg tissue (wet weight, n = 10, mean +/- SEM), respectively. However, the concentrations of 7B2 were lower than 30 pg/mg tissue in extracts of pancreas, ileum and colon, and were below the sensitivity of the RIA in extracts of liver, kidney, spleen, lung, adrenal cortex and testis. Gel permeation chromatography of extracts of anterior pituitary lobe, neurointermediate lobe, hypothalamus, adrenal medulla and thyroid gland on Sephadex G-100 revealed that most of the immunoreactive (Ir)-7B2 has an apparent molecular weight of 45,000-50,000. Subsequent dissociation of this Ir-7B2 by polyacrylamide gel electrophoresis containing sodium dodecyl sulfate (SDS) yielded an Ir-7B2 with an apparent molecular weight of around 19,000. In addition, high K+ concentration (50 mM) induced the release of Ir-7B2 from cultured cells of both rat anterior pituitary and neurointermediate lobe. Finally, Ir-7B2 was detected in the neurosecretory granule fraction prepared from porcine neurointermediate lobe. These results indicate that 7B2 may be a novel secretory protein in the pituitary gland.

Utility of Contrast-Enhanced FDG-PET/CT in the Clinical Management of Pancreatic Cancer: Impact on Diagnosis, Staging, Evaluation of Treatment Response, and Detection of Recurrence

Objectives Fluorodeoxyglucose (FDG)–positron emission tomography/contrast-enhanced computed tomography (PET/CE-CT) involving whole-body scanning first by non–CE-CT and FDG-PET followed by CE-CT has been used for detailed examination of pancreatic lesions. We evaluated PET/CE-CT images with regard to differential diagnosis, staging, treatment response, and postoperative recurrence in pancreatic cancer. Methods Positron emission tomography/CE-CT was conducted in 108 patients with pancreatic cancer and in 41 patients with other pancreatic tumor diseases. Results The maximum standardized uptake value (SUVmax) overlapped in benign and malignant cases, suggesting that differential diagnosis of pancreatic tumors based on the SUVmax is difficult. In the evaluation of staging in 31 resectable pancreatic cancer by PET/CE-CT, the diagnostic accuracy rate was more than 80% for most factors concerning local invasion and 94% for distant metastasis but only 42% for lymph node metastasis. Significant positive correlations were found between the SUVmax and tumor size/markers, suggesting that SUVmax may be a useful indicator for the treatment response. Regarding the diagnosis of the postoperative recurrence, PET/CE-CT correctly detected local recurrence in all the 11 cases of recurrence, whereas abdominal CE-CT detected only 7 of 11 cases, suggesting that PET/CE-CT is superior in this context. Conclusions Positron emission tomography/CE-CT is useful for the clinical management of pancreatic cancer.

Phase II study of erlotinib plus gemcitabine in Japanese patients with unresectable pancreatic cancer

Erlotinib combined with gemcitabine has not been evaluated in Japanese patients with unresectable pancreatic cancer. This two‐step phase II study assessed the safety and pharmacokinetics of erlotinib 100 mg/day (oral) plus gemcitabine 1000 mg/m2 (i.v. days 1, 8, 15) in a 28‐day cycle in the first step, and efficacy and safety in the second step. The primary end‐point was safety. One hundred and seven patients were enrolled (first step, n = 6; second step, n = 101). The most common adverse event was RASH (compiled using the preferred terms rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash) in 93.4% of patients. One treatment‐related death occurred. While interstitial lung disease‐like events were reported in nine patients (8.5%; grade 1/2/3, 3.8/2.8/1.9%), all patients recovered or improved. The median overall survival, the 1‐year survival rate and median progression‐free survival were 9.23 months, 33.0% and 3.48 months, respectively. The overall response and disease control rates were 20.3% and 50.0%, respectively. In Japanese patients with unresectable pancreatic cancer, erlotinib plus gemcitabine had acceptable toxicity and efficacy that was not inferior to that seen in Western patients. (Cancer Sci 2011; 102: 425–431)

Clinical observations of pancreatic diabetes caused by pancreatic carcinoma, and survival period

AbstractBackground. Pancreatic carcinoma is often associated with diabetes mellitus. The interrelationship between them is very interesting and important for clinical examination and treatment. Methods. We examined diabetes mellitus in our patients with pancreatic carcinoma, especially those with invasive ductal pancreatic carcinoma, who were admitted to the National Kyushu Cancer Center between 1972 and 1998, in relation to secondary (pancreatic) diabetes, obstructive pancreatitis, angiopathies, treatment, and prognosis. Results. Diabetes mellitus was found at a high frequency (53.1%) in patients with invasive ductal pancreatic carcinoma and was mostly thought to be secondary diabetes (45.9%), caused, in part, by obstructive pancreatitis following pancreatic tumor recognized on the first admission. Control of blood glucose with insulin was sometimes difficult, but was indispensable for the treatment of pancreatic carcinoma. Diabetic angiopathies are usually not seen in patients with pancreatic diabetes caused by pancreatic carcinoma, because the survival period of patients with pancreatic carcinoma has been limited. Furthermore, in spite of the absence of angiopathies, the survival period was significantly lower in pancreatic carcinoma patients with diabetes than in those without diabetes. Conclusion. Diabetes in patients with invasive ductal pancreatic carcinoma is usually secondary diabetes, occurring in part as a consequence of obstructive pancreatitis shown at the beginning of the clinical course. The duration of diabetes is too short for marked diabetic angiopathies to develop, and the survival period in patients with invasive ductal pancreatic carcinoma with diabetes is also short compared with that of those patients without diabetes.

Clinical assessment of pancreatic diabetes caused by chronic pancreatitis

Abstract: Despite the high prevalence of diabetes mellitus in patients with chronic pancreatitis, few studies of pancreatic diabetes have been reported. We investigated 154 patients with chronic pancreatitis, of whom 50% were diabetics, with special reference to the features and clinical course of pancreatic diabetes. We arrived to clarify the features of pancreatic diabetes by comparing pancreatic exocrine function in 112 patients with primary diabetes with findings in a separate group of 80 patients with chronic pancreatitis. Pancreatic diabetes is proposed as a type of diabetes in which exocrine pancreatic function is markedly decreased. Progressive and fatal angiopathies were found in patients with pancreatic diabetes after a long duration of diabetes. The present investigation suggests that treatment of malnutrition is necessary in patients with pancreatic diabetes and that control of blood glucose is often difficult in these patients because of the high incidence of insulin-induced hypoglycemic episodes.

Acute lymphocytic leukemia in adolescence with multiple osteolytic lesions and hypercalcemia mediated by lymphoblast-producing parathyroid hormone-related peptide: A case report and review of the literature

Osteopathy is one of the common initial symptoms of acute lymphocytic leukemia (ALL) in children and adolescents, but multiple osteolysis accompanied by hypercalcemia is rarely observed.

Chromogranin B (secretogranin I), a neuroendocrine-regulated secretory protein, is sorted to exocrine secretory granules in transgenic mice

Chromogranin B (CgB, secretogranin I) is a secretory granule matrix protein expressed in a wide variety of endocrine cells and neurons. Here we generated transgenic mice expressing CgB under the control of the human cytomegalovirus promoter. Northern and immunoblot analyses, in situ hybridization and immunocytochemistry revealed that the exocrine pancreas was the tissue with the highest level of ectopic CgB expression. Upon subcellular fractionation of the exocrine pancreas, the distribution of CgB in the various fractions was indistinguishable from that of amylase, an endogenous constituent of zymogen granules. Immunogold electron microscopy of pancreatic acinar cells showed co‐localization of CgB with zymogens in Golgi cisternae, condensing vacuoles/immature granules and mature zymogen granules; the ratio of immunoreactivity of CgB to zymogens being highest in condensing vacuoles/immature granules. CgB isolated from zymogen granules of the pancreas of the transgenic mice aggregated in a mildly acidic (pH 5.5) milieu in vitro, suggesting that low pH‐induced aggregation contributed to the observed concentration of CgB in condensing vacuoles. Our results show that a neuroendocrine‐regulated secretory protein can be sorted to exocrine secretory granules in vivo, and imply that a key feature of CgB sorting in the trans‐Golgi network of neuroendocrine cells, i.e. its aggregation‐mediated concentration in the course of immature secretory granule formation, also occurs in exocrine cells although secretory protein sorting in these cells is thought to occur largely in the course of secretory granule maturation.

Highly sensitive determination of N-terminal prolyl dipeptides, proline and hydroxyproline in urine by high-performance liquid chromatography using a new fluorescent labelling reagent, 4-(5,6-dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride

A highly sensitive pre-column HPLC method for simultaneous determination of prolyl dipeptides, Pro and Hyp in urine was developed. The analytes were labelled with 4-(5,6-dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride at 70 degrees C for 20 min. The derivatives separated on tandem reversed-phase columns by a gradient elution and were monitored with fluorescence detection at 318 nm (excitation) and 392 nm (emission). The detection limits for prolyl dipeptides, Pro and Hyp were 1-5 fmol/injection (S/N = 3). Urine samples were treated with o-phthalaldehyde, followed by purification on a Bond Elut C18 column before conducting the labelling reaction. Pro-Hyp, Pro-Gly and Pro-Pro were identified as prolyl dipeptides in urine. The within-day and between-day relative standard deviations were 1.5-4.8 and 1.7-5.8%, respectively. The concentrations of Pro-Hyp, Pro-Gly, Pro-Pro, Pro and Hyp in normal human urine were 97.6 +/- 28.2, 2.74 +/- 1.48, 2.08 +/- 1.13, 6.71 +/- 3.34 and 2.30 +/- 1.59 nmol/mg creatinine, respectively.

Direct interaction between metastasis-associated protein 1 and endophilin 3.

The yeast two‐hybrid system was used to search for partners of mouse metastasis‐associated protein 1 (Mta1). Screening of a cDNA library prepared from mouse embryo yielded positive clones coding for endophilin 3. The site of interaction was suggested to be the SH‐3‐binding domain of Mta1 and SH‐3 domain of endophilin 3. This interaction was confirmed by GST pull‐down assay in vitro and immunoprecipitation in vivo. The Mta1 and endophilin 3 transcripts were highly expressed in testis and brain. But, Mta1 localized mainly in nucleus and to a lesser extent in cytoplasm while endophilin 3 localized mainly in cytoplasm. If Mta1 functions in cytoplasm, it might be involved in the regulation of endocytosis mediated by endophilin 3.