Deoxycoformycin-containing combination chemotherapy for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study (JCOG9109)

Aggressive adult T-cell leukemia-lymphoma (ATL) generally has a very poor prognosis. Deoxycoformycin (DCF, pentostatin), an inhibitor of adenosine deaminase, has shown promising therapeutic efficacy for ATL. To develop a new effective therapy against aggressive ATL, we carried out a multicenter phase II study of DCF-containing combination chemotherapy. Sixty-two previously untreated patients with ATL (34, 21, and 7 patients with diseases of the acute, lymphoma, and unfavorable chronic types, respectively) were enrolled, but 2 were ineligible because they were judged to be favorable chronic types. A regimen of 1 mg/m2 vincristine intravenously on days 1 and 8, 40 mg/m2 doxorubicin intravenously on day 1, 100 mg/m2 etoposide intravenously on days 1 through 3, 40 mg/m2 prednisolone orally on days 1 and 2, and 5 mg/m2 DCF intravenously on days 8, 15, and 22 was administered every 28 days for 10 cycles unless disease progression or toxic complications occurred. Fifty-two percent of 60 eligible patients responded (95% confidence interval [CI], 38%-65%), with 17 patients (28%) achieving a complete response (CR) (95% CI, 17%-41%) and 14 achieving a partial response. The CR rate was inferior to those of both the previous Japan Clinical Oncology Group (JCOG) study (JCOG8701, 43%), a 9-drug combination chemotherapy of the second generation, and the subsequent JCOG9303 study (35%), a granulocyte colony-stimulating factor-supported, dose-intensified, 9-drug regimen. The median survival time of the 60 eligible patients in JCOG9109 was 7.4 months, and the estimated 2-year survival rate was 15.5%; these results were identical with those of JCOG8701 but inferior to those of JCOG9303. Grade 4 neutropenia and infection of grade 3 or greater were frequent (67% and 22%, respectively), and treatment-related death was observed in 4 patients (7%), septicemia in 2, and cytomegalovirus pneumonia in 2. We conclude that DCF-containing combination chemotherapy is not a promising regimen against aggressive ATL.     

Endoscopic sphincterotomy and endoscopic papillary balloon dilatation for bile duct stones: A prospective randomized controlled multicenter trial

BACKGROUND: Endoscopic papillary balloon dilatation may be an alternative to endoscopic sphincterotomy in the treatment of bile duct stones. However, there is a controversy as to the effectiveness and safety of endoscopic papillary balloon dilatation. METHODS: Two hundred eighty-two patients with bile duct stones were enrolled and randomized to an endoscopic sphincterotomy or endoscopic papillary balloon dilatation group. The success rate for duct clearance as well as the frequency and types of complications were evaluated prospectively. Endoscopic sphincterotomy was performed in a standard manner. Endoscopic papillary balloon dilatation was carried out with gradual inflation of a 4-, 6-, or 8-mm diameter balloon. RESULTS: Complete duct clearance was achieved in 100% in the endoscopic sphincterotomy group and 99.3% in the endoscopic papillary balloon dilatation group (not significant). Complications occurred in 11.8% of patients in the endoscopic sphincterotomy group and 14.5% of those in the endoscopic papillary balloon dilatation group (not significant). No complication was severe; there was no mortality. The frequency of acute pancreatitis was higher in the endoscopic papillary balloon dilatation group than the endoscopic sphincterotomy group (respectively, 10.9% vs. 2.8%; p < 0.045). Hemorrhage occurred only in the endoscopic sphincterotomy group. CONCLUSIONS: Endoscopic sphincterotomy and endoscopic papillary balloon dilatation were approximately equal in terms of successful clearance of bile duct stones. They were also similar with respect to overall complications. Endoscopic papillary balloon dilatation is an alternative to endoscopic sphincterotomy as a treatment of bile duct stones.     

The Usefulness of Endoscopic Retrograde Cholangiopancreatography in Infants and Small Children

We performed endoscopic retrograde cholangiopancreatography (ERCP) on nine infants and small children over a period of 7 yr from 1985 to 1991. In three infants, diagnosis on admission was congenital biliary atresia or neonatal hepatitis. In one, congenital biliary atresia was diagnosed by ERCP. In the other six cases, diagnosis on admission was congenital biliary dilation, acute cholangitis, or acute pancreatitis. In five, we diagnosed the anomalous arrangement of the pancreaticobiliary ductal system by ERCP. ERCP is a relatively easy and safe technique when applied to infants and small children. It is also a useful procedure when making morphologic diagnosis of organic disorders around the biliary and pancreatic ductal system, such as biliary atresia, intra-hepatic cholestasis, and the anomalous arrangement of the pancreaticobiliary ductal system. It enables us to determine the surgical procedure and to investigate the residual bile duct after surgical treatment. Therefore, ERCP should be conducted on infants and small children who may be suffering from disorders of the pancreaticobiliary system.     

Carcinoma of donor origin after allogeneic peripheral blood stem cell transplantation

Secondary cancers developing after allogeneic hematopoietic stem cell transplantation generally originate from recipient-derived cells. In this study, we analyzed the tumor cell origin of 5 epithelial malignant tumors (esophageal squamous cell carcinoma, lung adenocarcinoma, gastric adenocarcinoma, pharyngeal squamous cell carcinoma, and thyroid papillary carcinoma) that developed after allogeneic peripheral blood stem cell transplantation using anti-AE1/3 immunofluorescence with fluorescence in situ hybridization analysis for sex chromosomes and/or short-tandem repeat microsatellite analysis of laser-microdissected tumor cells. The results revealed that 1 of these 5 cancers was derived from donor cells. In this case, transfused pluripotent cells, which include both mesenchymal stem cells and hematopoietic stem cells, might have given rise to epithelial malignant cells. Our observations suggest that transfused peripheral blood cells may be involved in the development of cancers after allogeneic peripheral blood stem cell transplantation.     

Relationship between the shape and the patency of Santorini's accessory pancreatic duct revealed by a balloon endoscopic retrograde pancreatography compression study

Background: Pancreatic juice flows into the duodenum via two pancreatic ducts including Wirsung's duct (main pancreatic duct) and Santorini's duct (accessory pancreatic duct). In contrast to Wirsung's duct, the precise anatomy and functions of Santorini's duct are still obscure. Methods: We clinically examined the shape and the patency of Santorini's duct using a balloon endoscopic retrograde pancreatography compression study (balloon ERP‐CS) and analyzed 178 cases out of a total of 683 of balloon ERP‐CS cases according to our criteria. Results: We found the total patency ratio of Santorini's duct to be 78.1% (139 of 178 cases). The shape of Santorini's duct, as examined by balloon ERP‐CS, was classified into four types. The most common types were the Rod type (44%) and the Spindle type (25%). The Branch type comprised 22%. The most rare type was the Cystic type (9%). The Rod type and Spindle type showed a high patency ratio (more than 95%), but the Cystic type and Branch type showed lower levels (36 and 31%, respectively). Conclusions: Most cases with a poor flow of Santorini's duct were observed, especially in the Cystic and Branch types. In such cases, Santorini's duct could not function as a safety valve when a Wirsung's obstruction occurred in association with stones, tumors or edema in the papilla of Vater.     

Ghrelin directly regulates bone formation.

To clarify the role of ghrelin in bone metabolism, we examined the effect of ghrelin in vitro and in vivo. Ghrelin and its receptor, GHS-R1a, were identified in osteoblasts, and ghrelin promoted both proliferation and differentiation. Furthermore, ghrelin increased BMD in rats. Our results show that ghrelin directly affects bone formation. INTRODUCTION: Ghrelin is a gut peptide involved in growth hormone (GH) secretion and energy homeostasis. Recently, it has been reported that the adipocyte-derived hormone leptin, which also regulates energy homeostasis and opposes ghrelin's actions in energy homeostasis, plays a significant role in bone metabolism. This evidence implies that ghrelin may modulate bone metabolism; however, it has not been clarified. To study the role of ghrelin in skeletal integrity, we examined its effects on bone metabolism both in vitro and in vivo. MATERIALS AND METHODS: We measured the expression of ghrelin and growth hormone secretagogue receptor 1a (GHS-R1a) in rat osteoblasts using RT-PCR and immunohistochemistry (IHC). The effect of ghrelin on primary osteoblast-like cell proliferation was examined by recording changes in cell number and the level of DNA synthesis. Osteoblast differentiation markers (Runx2, collagen alpha1 type I [COLI], alkaline phosphatase [ALP], osteocalcin [OCN]) were analyzed using quantitative RT-PCR. We also examined calcium accumulation and ALP activity in osteoblast-like cells induced by ghrelin. Finally, to address the in vivo effects of ghrelin on bone metabolism, we examined the BMD of Sprague-Dawley (SD) rats and genetically GH-deficient, spontaneous dwarf rats (SDR). RESULTS: Ghrelin and GHS-R1a were identified in osteoblast-like cells. Ghrelin significantly increased osteoblast-like cell numbers and DNA synthesis in a dose-dependent manner. The proliferative effects of ghrelin were suppressed by [D-Lys(3)]-GHRP-6, an antagonist of GHS-R1a, in a dose-dependent manner. Furthermore, ghrelin increased the expression of osteoblast differentiation markers, ALP activity, and calcium accumulation in the matrix. Finally, ghrelin definitely increased BMD of both SD rats and SDRs. CONCLUSIONS: These observations show that ghrelin directly stimulates bone formation.     

Advances in Management of Retinoblastoma

Retinobiastoma is a highly malignant intraocular tumor of children that requires accurate diagnosis to prompt treatment. This article reviewed clinical, pathological and follow-up data on 1 147 cases of retinobiastoma registered in Japan from 1975 to 1982. It is obvious that the prognosis of children with retinobiastoma has improved remarkably in recent years. The current advances in the management of the retinobiastoma were discussed.     

Multidrug Resistance in Cultured Human Leukemia and Lymphoma Cell Lines Detected by a Monoclonal Antibody, MRK16

Forty cultured human leukemia and lymphoma cell lines never exposed to anticancer agents in culture, apart from doxorubicin (ADM)-resistant K562/ADM, were examined for reactivity with a monoclonal antibody, MRK16 in F(ab')₂ form [MRK16-F(ab')₂], which recognizes P-glycoprotein (P-gp). The relative resistance index to various drugs was calculated by dividing the 50% growth inhibitory concentration (IC₅₀) of the test cell line by IC₅₀ of K562, which was the negative control in the antibody experiment. MRK16-F(ab')₂ reacted with four cell lines, K562/ADM, KYO-1, HEL and CMK, which had relative resistance index values of 2 or more to vincristine (VCR), vindesine, vinblastine, ADM, daunorubicin, mitoxantrone (MIT), etoposide (VP-16) and actinomycin-D (ACT-D). The level of resistance to VCR and ADM in these cell lines decreased significantly in the presence of 10 μ M verapamil in vitro . Significant expression of mRNA of P-gp gene was also detected in K562/ADM, KYO-1 and HEL. MRK16-F(ab')₂ did not react with 36 other cell lines. Among them, three cell lines, PL-21, P31/FUJ and KOPM-28, had relative resistance index values of 2 or more to anthracyclines, MIT and VP-16, but not to vinca alkaloids or ACT-D. The level of ADM-resistance in these cell lines did not decrease significantly in the presence of 10 μ M verapamil. Five cell lines, ATL-1K, HL-60, KMOE-2, ML-1 and U266, had relative resistance index values of 2 or more to some of the drugs, but not to the others, and 19 other cell lines did not. These results indicate that the reactivity of MRK16-F(ab')₂ correlates with a relative resistance index of 2 or more to all these drugs in cultured human leukemia and lymphoma cell lines.     

Immunohistochemical detection of carcinoembryonic antigen in benign hyperplasia and adenocarcinoma of the prostate with monoclonal antibody

Immunoperoxidase localization of carcinoembryonic antigen was done on tissue sections of benign hyperplasia and adenocarcinoma of the prostate using murine monoclonal antibody against carcinoembryonic antigen. The study was done to determine whether carcinoembryonic antigen would be a tissue marker of prostatic malignancy. Of 30 benign lesions 25 (83 per cent) were negative and 5 had focally weak staining, while of 36 adenocarcinomas 31 (86 per cent) had diffusely positive staining and 5 were negative. Diffusely moderate or strong staining was noted in 5 of 10 grade I (50 per cent), 11 of 12 (92 per cent) grade II and 13 of 14 (93 per cent) grade III tumors, as well as 14 of 15 (93 per cent) tumors from patients with bone metastasis. These findings suggested that extensive immunostaining for carcinoembryonic antigen in prostatic glandular lesions might be a potentially important prognostic marker of malignancy. Further studies are warranted to extend and confirm these results.     

Concurrent Adult T-Cell Leukemia and Acute Myeloblastic Leukemia

A 49-year-old man developed adult T-cell leukemia (ATL) andacute myeloblastic leukemia (AML) at the same time. Using Southernblotting analysis, the leukemic cells of the ATL were foundto contain the human T-cdl leukemia virus type I (HTLV-I) proviralgenome, whereas those of the AML did not, indicating the HTLV-Inot to be associated with the AML oncogenesis. At the initialpresentation, the serum anti-HTLV-I antibody was judged on screeningby a routine particle-agglutination (PA) test and an indirectimmunofluorescence assay (IF) to be negative. By Western blottinganalysis, however, the serum was proved to be positive for anti-HTLV-Iantibody. These results indicate that a routine PA-test andan IF way show false negative reactions on very rare occasionsof low antibody titer. This is the first report of a coincidenceof ATL with another type of leukemia.