Clinical Significance of Adjuvant Surgical Resection for Initially Unresectable Pancreatic Cancer Responsive to Arterial Infusion Chemotherapy.

BACKGROUND/AIMS: We have reported a clinically meaningful local-control effect and a hepatic metastatic tumor-regression effect of transcatheter peripancreatic arterial embolization-hepatic and splenic arterial infusion chemotherapy (TPPAE-HSAIC) for unresectable advanced pancreatic cancer. The aim of this study was to evaluate the clinical significance, of adjuvant surgical resection after TPPAE-HSAIC. METHODOLOGY: We assessed histopathological findings and outcomes of 6 patients who underwent surgical resection of tumors judged to be radically resectable after attaining tumor down-staging or long-term tumor control following TPPAE-HSAIC for pancreatic cancer initially diagnosed as unresectable. RESULTS: Clinical stage at the initial diagnosis was T4N0M0 Stage III in 4 patients and T4N0M1 Stage IV in 2 patients. The durations of TPPAE-HSAIC ranged from 5 to 46 months with a median of 19 months. An R0 resection was performed in 5 of the 6 patients (83%) and pathological down-staging, from the viewpoint of clinical stage, was observed in 4 patients. Of the 5 patients with R0 resection, one died from a postoperative complication at 7 months and another from pulmonary metastasis at 30 months post-operatively, while the other 3 patients have survived for 45 to 83 months to date. CONCLUSIONS: If surgical resection of pancreatic cancer initially diagnosed as unresectable can be carried out in patients responding favorably to TPPAE-HSAIC, the likelihood of long-term survival might be increased.

Essential role of protein kinase C zeta in transducing a motility signal induced by superoxide and a chemotactic peptide, fMLP.

Under various pathological conditions, including infection, malignancy, and autoimmune diseases, tissues are incessantly exposed to reactive oxygen species produced by infiltrating inflammatory cells. We show augmentation of motility associated with morphological changes of human squamous carcinoma SASH1 cells, human peripheral monocytes (hPMs), and murine macrophage-like cell line J774.1 by superoxide stimulation. We also disclose that motility of hPMs and J774.1 induced by a chemotactic peptide (N-formyl-methionyl-leucyl-phenylalanine [fMLP]) was inhibited by superoxide dismutase or N-acetylcystein, indicating stimulation of motility by superoxide generated by fMLP stimulation. In these cells, protein kinase C (PKC) zeta was activated to phosphorylate RhoGDI-1, which liberated RhoGTPases, leading to their activation. These events were inhibited by dominant-negative PKCzeta in SASH1 cells, myristoylated PKCzeta peptides in hPMs and J774.1, or a specific inhibitor of RhoGTPase in SASH1, hPMs, and J774.1. These results suggest a new approach for manipulation of inflammation as well as tumor cell invasion by targeting this novel signaling pathway.

[Reappearance of t(12;17)-positive primary myelofibrosis following Ph+ CML cell reduction by imatinib].

A 67-years old woman was referred to our hospital in October 1992 with thrombocytopenia and splenomegaly. A bone marrow biopsy revealed decreased cellularity, with moderately increased reticulin fibrosis and discrete dysmorphic megakaryocytes but no signs of dysplasia in the erythroid or the myeloid lineages. The karyotype of the bone marrow cells was t(12;17) (q24;q11). She was diagnosed as having agnogenic myeloid metaplasia. The patient received only blood transfusions until November 1998 when leukocytosis with immature cells started to appear. The bone marrow aspiration analysis showed increased cellularity and chromosomal analysis demonstrated the presence of t(9;22) (q34;q11) without any t(12;17) (q24;q11) abnormality. Because IFN therapy and oral administration of hydroxyurea did not show any cytological effect, administration of imatinib mesylate was started from December 2001. The Ph-positive cells as demonstrated by the FISH method had decreased to 7% by April 2003. But the t(12;17)(q24;q11) positive clones, which were observed on the first admission, again appeared in the peripheral blood, whereas Ph clones were detected in only one out of 24 cells examined. During the course of treatment with imatinib mesylate for chronic myelogenous leukemia which developed from agnogenic myeloid metaplasia accompanied with t(12;17)(q24;q11) translocation, the co-existence of two clones derived from, possibly, stem cells was identified.

[A case of intraductal papillary mucinous neoplasm with internal pancreatic fistula causing left ureteral obstruction].

A 75-year-old man had been admitted to another hospital because of left abdominal pain, and was given a diagnosis of left hydronephrosis and acute pancreatitis. After a JJ stent insertion and medication, he was transferred to our hospital for further examinations. US and EUS revealed a chronic pancreatitis-like pattern and multicystic lesion in the pancreas head and body. At that time enhanced CT findings showed an extrapancreatic low density area to be inflammatory change, extending from the pancreas body to the left crus of the diaphragm and posteriorly the spreading from the left crus of the diaphragm via the left urinary duct into the left iliopsoas muscle, in which MRI revealed partial high intensity. ERCP and MRCP showed focal irregular narrowing of the pancreatic duct of unknown cause, and we decided that an internal pancreatic fistula due to pancreatitis had induced left ureteral obstruction, caused by a protein plug or alcohol. Follow-up 6 months later showed that extrapancreatic spreading of the low density area had markedly regressed without any change in the ureteral obstruction.

[A case of primary carcinoma of the cystic duct with limy bile].

A 78-year-old man had been admitted to a previous hospital because of epigastralgia and a diagnosis of cholecystolithiasis had been made. He had been transferred to our institution for further examination. CT scan and US revealed chronic cholecystitis and gallstone, however, ERC revealed severe obstruction of the cystic duct and EUS revealed dilation of that duct and a solitary mass there. Carcinoma of the cystic duct was diagnosed, and we performed cholecystectomy and resection of the extrahepatic duct with two-field lymphadenectomy. The pathological specimen showed a round flat elevated mass localized in the cystic duct. Histopathologically, the diagnosis was well differentiated tubular adenocarcinoma of the cystic duct with limy bile and tiny gallstone.

[Evaluation of the endoprosthesis by metallic stent and tube stent for malignant biliary stenosis].

We evaluated the effect of biliary endoprotheses for 20 malignant stenosis patients by an expandable metallic stent and hydrophilic heparinized tube (H-PSD) connected to an implantable port (IP), which reduces bacterial adherence. Group A consisted of 6 patients of cholangiocarcinoma who underwent hepatic arterial infusion chemotherapy associated with radiotherapy. Groups B and C consisted of 8 and 6 patients of stage IVa and IVb pancreatic carcinoma, respectively, who underwent hepatic and splenic arterial infusion chemotherapy following transcatheter peripancreatic arterial embolization. The 50% patent time was 12 months, 6 months and 7 months in groups A, B and C and the 50% overall survival time was 16 months, 23 months and 13 months, respectively. There were two complications, 1 case of infection around the IP in which the IP was withdrawn, and 3 cases of cholangitis in which we had easy access to the bile duct via IP. This technique appears to offer significant benefit in selecting patients with this type of biliary obstruction.

[Intraperitoneal and intrapleural gemcitabine in patients with advanced pancreatic cancer].

We performed intraperitoneal and intrapleural dosing gemcitabine (GEM) to eight patients with advanced pancreatic cancer having peritoneal or pleural carcinomatosis and evaluated its actions and safety. GEM (500 mg/m2) was infused into the abdominal cavity or thoracic cavity after drainage of peritoneal or pleural effusion. We checked the change of serum GEM concentration and the side effects after the GEM administration. Then, we repeated the GEM administration observing their systematic symptoms and evaluated the alteration of peritoneal or pleural effusion and cytology. Plasma concentration of GEM by infusing into the abdominal cavity or thoracic cavity was lower than by intravenous injection. In three of the five cases of peritoneal carcinomatosis, intraperitoneal administration revealed a decrease of peritoneal effusion. In two of the three cases of pleural carcinomatosis, intrapleural administration revealed a decrease of pleural effusion. Four cases had leukocytopenia of grade 1/2, three cases had thrombocytopenia, and two cases had alopecia as side effects, although all of them were minor side effects. Intraperitoneal and intrapleural dosing GEM had minor side effects and could improve QOL for the patients with advanced pancreatic cancer associated with peritoneal or pleural carcinomatosis.

Mechanisms for increment of platelet associated IgG and platelet surface IgG and their implications in immune thrombocytopenia associated with chronic viral liver disease.

In addition to hypersplenism, immunological destruction of platelets by elevated platelet associated IgG (PAIgG) and platelet surface IgG (PSIgG) has been proposed as a causative factor for thrombocytopenia in chronic liver disease (CLD), although the implication of PAIgG may be debatable since recent investigations on idiopathic thrombocytopenic purpura disclosed the fact that PAIgG largely relates to the intra-platelet IgG in alpha-granules and not to PSIgG. Further, with regard to the elevated PSIgG of CLD, characterization as to whether it mainly represents anti-platelet glycoprotein (GP) antibodies or IgG contained in the immune complex has not been elucidated. Thirty-seven patients with chronic viral liver disease (CVLD); 31 hepatitis C and 6 hepatitis B were included in this study. First we monitored the changes in levels of PAIgG, alpha-granule IgG, PSIgG and mean platelet volume (MPV) during the course of partial splenic arterial embolization (PSE). The elevated level of PAIgG decreased after PSE, paralleling that of alpha-granule IgG, while PSIgG showed no change; MPV decreased reciprocally with the increase of platelet count. These results indicate that the increment of PAIgG in CVLD may be caused by accelerated destruction of platelets; this generally evokes hyperproduction of large-sized thrombocytes, which have an increased capability to uptake circulating IgG. To characterize PSIgG, we then tested CVLD patients for antiplatelet GP antibodies and found only a 5.4% positivity. It was also found that circulating immune complex levels in CVLD patients were clearly elevated, correlating with the levels of PSIgG. Thus, it was surmised that immune complexes bound to the platelet surface, and not platelet specific GP antibodies, may be playing a crucial role in platelet destruction of CVLD, possibly through phagocytosis by macrophages.

[Mixed warm and cold antibody-type autoimmune hemolytic anemia in a healthy pregnant woman with primary cytomegalovirus infection].

A 25-year-old previously healthy pregnant woman was admitted to our hospital because of severe anemia (Hb 6.7 g/dl), and diagnosed as having mixed-type autoimmune hemolytic anemia (AIHA) due to de novo cytomegalovirus (CMV) infection. After daily administration of prednisolone, the anemia gradually resolved and the patient delivered a healthy baby. This is the first report of a healthy person suffering from mixed-type AIHA due to de novo CMV infection.

[Adult-onset Still's disease accompanied by hemophagocytic syndrome at onset].

A 43-year-old woman was admitted for examination of fever, an elevated transaminase level, LDH, skin eruption, sore throat and bicytopenia. As bone marrow examination revealed an increased proportion of histiocytes and active phagocytosis, hemophagocytic syndrome (HPS) was diagnosed. After admission, the peripheral blood counts recovered spontaneously and the HPS subsided, but other symptoms persisted and the neutrophil count increased. At this time, we diagnosed the patient as having adult Still's disease. All the symptoms disappeared after administration of prednisolone. The markedly increased concentrations of TNF-alpha and IFN-gamma in the peripheral blood at the time of HPS declined gradually, and the IL-6 concentration increased at the time of diagnosis of Still's disease. However, all of these concentrations normalized after administration of prednisolone. As HPS and Still's disease have a common etiology, and each shows high concentrations of IFN-gamma, IL 6 and TNF-alpha, the symptoms are similar in both diseases. In particular, a relationship between HPS and high concentrations of TNF-alpha and IFN-gamma is suspected.

[Treatment of chronic myelogenous leukemia with imatinib mesylate resulting in hematological remission and marked regression of myelofibrosis].

We treated two chronic phase chronic myelogenous leukemia patients with imatinib mesylate. Hematological complete remission and significant regression of bone marrow fibrosis were observed in both patients. The large amount of TGF-beta produced by increased bone marrow megakaryocytes might have caused the myelofibrosis, and it was revealed that imatinib mesylate brought about regression of the myelofibrosis by reducing the number of megakaryocytes in both patients.

[Successful treatment with G-CSF and corticosteroid of adult idiopathic autoimmune neutropenia presenting as recurrent enterocolitis].

A 63-year-old woman had previously been admitted to another hospital due to fever, abdominal pain and diarrhea. She was treated with fasting, antibiotics and G-CSF administration because of the coexistence of neutropenia, and the symptoms improved. However, discontinuation of G-CSF administration resulted in a recurrence of the neutropenia accompanied with enterocolitis. After admission to our hospital, a diagnosis for idiopathic AIN was performed as she tested positive in both granulocyte immunofluorescence and granulocyte agglutination tests. Administration of corticosteroid following G-CSF resulted in a continuous increase in the neutrophil count and the disappearance of anti-neutrophil autoantibodies.

[A devised method of hepatic and splenic arterial infusion chemotherapy after transcatheter peripancreatic arterial embolization for patients with advanced pancreatic cancer].

We previously reported the clinical efficacy based on hepatic and splenic arterial infusion chemotherapy (HSAIC) for patients with advanced pancreatic cancer after transcatheter peripancreatic arterial embolization (TPPAE). However, this medical treatment pointed out a few problems in which the method had its complexity and a limited use of embolus micro-coil numbers. Then, we tried to improve the method in solving those problems. In order to reduce the embolus micro-coil numbers for TPPAE, we divided the micro-coil into several parts. We also devised the method of HSAIC. We used one catheter with a side hole, so that the catheter was able to supply a therapeutic drug for arterial infusion chemotherapy, both to the common hepatic artery and splenic artery. The effective rate for eleven cases was 72.7%, and there were no significant differences from the cases treated with the conventional method of TPPAE-HSAIC. Therefore, the devised treatment was considered to be an easy and useful method for TPPAE and HSAIC.

[A case of gastric carcinoma with multiple skin, bone, and bilateral ovary metastasis; effective treatment by chemotherapy].

A 40-year-old female visited our hospital with general malaise. She was diagnosed with gastric carcinoma with multiple skin, bone, and bilateral ovary metastases. Chemotherapy with 5-FU (1,000 mg/w) and cisplatin (10 mg/w) was performed in the outpatient clinic. Two years after the initial diagnosis, CEA was elevated. She then was given chemotherapy of CPT-11 (40 mg/w) in the outpatient clinic after 1 cycle of combined chemotherapy of CPT-11 and cisplatin. She died 38 months after the initial diagnosis. Weekly 5-FU/CDDP or low-dose CPT-11 appear to be effective for such a gastric carcinoma with systemic metastases without impairing quality of life.

Interleukin-2 gene transfer potentiates the alpha-galactosylceramide-stimulated antitumor effect by the induction of TRAIL in NKT and NK cells in mouse models of subcutaneous and metastatic carcinoma.

Alpha-Galactosylceramide (alpha-GalCer) is a potent CD1d ligand that activates natural killer like T-cells (NKT), leading to the production of helper T (Th) 1 and Th2 cytokines that mediate various immunemodulatory and antitumor effects. Here, we determined whether the administration of adenovirus-vector-encoding mouse interleukin-2 (AdmIL-2) can augment the antitumor effect of alpha-GalCer on subcutaneous and metastatic tumors in mice. Mice were intraperitoneally injected with alpha-GalCer on days 7, 10 and 13 after tumor inoculation, with or without intratumoral injection of AdmIL-2 on day 7. alpha-GalCer treatment increased the serum levels of interferon-gamma, while intratumoral injection of AdmIL-2 elevated serum IL-2 levels. A combination of alpha-GalCer and AdmIL-2 (alpha-GalCer/AdmIL-2) inhibited the in vivo tumor growth and improved the survival of tumor-bearing mice, as compared to the use of a single agent. Experiments on spontaneous metastasis models revealed that alpha-GalCer/AdmIL-2 reduced lung metastasis and prolonged survival, as compared to control groups. In addition, the splenic and liver mononuclear cells from mice treated with alpha-GalCer/AdmIL-2 showed enhanced cytolytic activity against NK-sensitive YAC-1 and NK-resistant 3LL tumors. Moreover, alpha-GalCer/AdmIL-2 treatment expanded the absolute numbers of lung and liver NK, NKT and T-cells as well as the TNF-related apoptosis-inducing ligand (TRAIL) expression of these cells. This study shows the efficacy of alpha-GalCer/AdmIL-2 immunomodulatory therapy, and provides a cellular mechanism on how it exerts the antitumor effects.

Donor cell derived acute myeloid leukemia after allogeneic cord blood transplantation in a patient with adult T-cell lymphoma.

We report a patient with adult T-cell lymphoma who developed acute myeloid leukemia (AML) after allogeneic cord blood transplantation (CBT). Fluorescence in situ hybridization (FISH) studies and molecular analysis using short tandem repeat (STR) sequences proved the AML to be of donor origin. Although 25 cases of donor cell leukemia (DCL) occurring after allogeneic bone marrow transplantation have previously been reported, there have been no reports of DCL after CBT. This case is the first-reported DCL patient after CBT.

Analysis of local control in patients with non-Hodgkin's lymphoma according to the WHO classification.

PURPOSE: To analyze the influence of radiotherapy doses, chemotherapy doses, and clinical parameters on in-field disease control to assess the optimal radiation doses for treatment of non-Hodgkin's lymphoma according to the newly proposed WHO classification. PATIENTS AND METHODS: Subjects consisted of 35 extranodal marginal-zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type, 75 diffuse large B-cell lymphomas (DLBCL), 14 follicular lymphomas, 17 extranodal natural killer (NK)/T-cell lymphomas, nasal type, eight unclassified peripheral T-cell lymphomas, four anaplastic large-cell lymphomas, T/null cell type, and five others. 59 patients received radiotherapy alone. 98 patients received CHOP, modified CHOP, or more intensive chemotherapy, and six patients were treated with other combination. RESULTS: No patients with MALT lymphoma had in-field local recurrence. There were no recurrences in DLBCL patients who received chemotherapy in which the doses of adriamycin were > 200 mg/m(2), nor in DLBCL patients who were treated with > 45 Gy. Only nine of 15 patients with T-cell lymphoma treated with < or = 50 Gy and three of five patients treated with > 50 Gy had local control. The dose of adriamycin had no influence on local control of T-cell lymphoma. CONCLUSION: T/NK-cell lymphomas were more radioresistant than B-cell lymphomas. The prognosis for peripheral T/NK-cell lymphomas is poor even when treated by irradiation combined with chemotherapy.

Enhanced expression of type IV collagen-binding protein (p29) in Fyn-transfected murine fibrosarcoma cells.

We investigated the mechanism of the enhancement of metastatic potential induced by transfection of the fyn gene, a member of the src family. We employed two murine fyn cDNA-transfected clones, ML-SN1 and ML-SN2, which were previously established from an ML-01 low-metastatic clone of Meth A sarcoma of BALB / c mice and were proven to have higher metastatic ability than ML-01 and the mock-transfected clone ML-MT-neo (Takayama et al., 1993). Our present investigation revealed that the two transfectants showed higher metastatic ability and higher rates of adherence to type IV collagen than ML-MT-neo. However, no difference was found in in vitro or in vivo growth rates, attachment to laminin or endothelial cells or cell motility through a reconstituted basement membrane. Analysis of surface membrane proteins labeled with (125)I on SDS-PAGE showed that a 29 kD band specifically bound to type IV collagen-coupled beads was more intense in ML-SN2 than in ML-MT-neo. Genistein, a protein tyrosine kinase inhibitor, dramatically reduced protein tyrosine kinase (PTK) activity of ML-SN2 in a dose-dependent fashion, corresponding to the reduction of adhesiveness to type IV collagen. The expression of the type IV collagen-binding protein (p29) of ML-SN2 was also reduced significantly by genistein treatment. These results suggested that the fyn product in Meth A cells augments the expression of a type IV collagen-binding protein through elevation of the PTK activity of the membrane fraction and thus facilitates the metastasis of Meth A.

Effect of Helicobacter pylori eradication on platelet recovery in Japanese patients with chronic idiopathic thrombocytopenic purpura and secondary autoimmune thrombocytopenic purpura.

The prevalence of Helicobacter pylori infection and the effect of its eradication on platelet count in 48 Japanese patients with autoimmune thrombocytopenic purpura (AITP), including 40 chronic idiopathic thrombocytopenic purpura (ITP) and eight secondary AITP, were investigated. H. pylori infection was found in 25 ITP patients (62.5%) and in two secondary AITP (25%). H.pylori eradication was obtained in 19 of 19 infected ITP patients (100%), who were not in remission (platelets < 100 x 109/l) at the time of infection assessment. During follow-up (median 14.8 months), 12 of 19 H. pylori-eradicated patients (63.2%) showed a significant increase in platelet count accompanied by a significant decrease of platelet-associated immunoglobulin G (IgG). This response was maintained in all responding patients throughout the follow-up period. However, two infected patients with secondary AITP did not show platelet increase after eradication. The assessment of H. pylori infection and its eradication should be attempted in ITP as this approach could be an effective strategy, at least for some of these patients.