Clinical Characteristics of Patients with Autoimmune Pancreatitis with or without Mikulicz's Disease and Mikulicz's Disease Alone.

BACKGROUND/AIMS: The objective of this study was to compare the clinical characteristics of patients with autoimmune pancreatitis (AIP) with or without Mikulicz's disease (MD) and with MD alone. METHODS: We investigated the clinical findings in 15 AIP patients with MD (group A+M), 49 AIP only patients (group A), and 14 MD only patients (group M). RESULTS: The male-female ratio was significantly higher in group A+M (73%, p<0.05) and group A (78%, p<0.01) than group M (21%). Serum immunoglobulin G (IgG) levels were significantly higher in group A+M than in group A (p<0.01) and group M (p<0.05). Serum IgG4 levels were significantly higher in group A+M than in group A (p<0.01). Other organ involvement was observed in 73% (11/15) of patients in group A+M. The number of patients with diabetes mellitus was significantly higher in group A+M (66%, p<0.01) and group A (51%, p<0.05) than in group M (7%). All of the patients responded well to steroid therapy, but the relapse rate in group A+M (33%) was significantly higher than that in group A (3%, p<0.01). Salivary gland function was impaired in all groups compared with the control group, but the degree of dysfunction was less in group A compared with group A+M and group M. CONCLUSIONS: The relapse rate of AIP in MD patients was significantly higher than that of AIP in patients without MD.

Phase II study of cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) therapy for newly diagnosed patients with low- and low-intermediate risk, aggressive non-Hodgkin's lymphoma: final results of the Japan Clinical Oncology Group Study, JCOG9508.

The regimen of cyclophosphamide, doxorubicin, vincristine, and prednisolone, known as CHOP therapy, has been established as the standard treatment for aggressive non-Hodgkin's lymphoma (NHL). Although patients categorized as low (L) and low-intermediate (L-I) risk using the International Prognostic Index have favorable prognoses in Western countries, the efficacy and safety of CHOP therapy has not been prospectively evaluated in Japan. We conducted a phase II study of CHOP in L and L-I risk Japanese patients, evaluating overall survival (OS) as the primary endpoint. A total of 213 patients were enrolled and treated with eight courses of CHOP. Efficacy was evaluated in 168 eligible patients (L risk, 87; L-I risk, 81). Five-year OS rates in all eligible, L, and L-I risk patients were 68 % [95 % confidence interval (CI): 61-76 %], 73 % (95 % CI: 63-82 %), and 64 % (95 % CI: 53-74 %), respectively. The major toxicity observed was grade 4 neutropenia (64 %). Grade 4 non-hematological toxicities were observed as follows: one case each of paralytic ileus, convulsions, hypoxemia due to interstitial pneumonia, and reactivated fulminant hepatitis B. These results show reasonable efficacy and safety of the CHOP regimen in Japanese patients with lower risk aggressive NHL (UMIN-CTR Number C000000053).

[IgG4-related sclerosing disease, including its relation to carcinogenesis].

IgG4-related sclerosing disease is a systemic disease histologically characterized by extensive T lymphocytes and IgG4-positive plasma cell infiltration of various organs. Major clinical manifestations are apparent in the pancreas (autoimmune pancreatitis), bile duct (sclerosing cholangitis), gallbladder (sclerosing cholecystitis), salivary gland (sclerosing sialadenitis), and retroperitoneum (retroperitoneal fibrosis), in which tissue fibrosis with obliterative phlebitis is pathologically induced. Autoimmune pancreatitis is a pancreatic lesion and its extrapancreatic lesions are organs reflecting an IgG4-related sclerosing disease. In some cases, only one or two organs are clinically involved, while in others three or four organs are affected. The disease occurs predominantly in elderly males, is frequently associated with lymphadenopathy, and responds well to steroid therapy. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery. Some cases of autoimmune pancreatitis were reportedly associated with pancreatic cancer. Although no relationship between the two diseases is known, we showed frequent and significant K-ras mutations in the pancreas, the bile duct, and the gallbladder in autoimmune pancreatitis.

Serial changes of elevated serum IgG4 levels in IgG4-related systemic disease.

OBJECTIVE: Autoimmune pancreatitis (AIP) and Mikulicz's disease have recently been recognized as pancreatic or salivary gland lesions of IgG4-related systemic disease. These are frequently associated with elevated serum IgG4 levels. This study aimed to clarify clinical implications of serial changes of elevated serum IgG4 levels in IgG4-related systemic diseases. METHODS: Serial changes of elevated serum IgG4 levels were examined in patients with IgG4-related systemic diseases. Patients Serial changes of elevated serum IgG4 levels were examined in 44 patients: AIP (n=24), Mikulicz's disease (n=8), pancreatic cancer (n=5), bile duct cancer (n=1), sclerosing cholangitis (n=1), hypereosinophilic syndrome (n=1), chronic thyroiditis (n=1), hypophysitis (n=1), idiopathic pancreatitis (n=1), and Behcet's disease (n=1). RESULTS: The serum IgG4 levels decreased in all patients with AIP and Mikulicz's disease after steroid therapy. The serum IgG4 levels were normalized in 46% of AIP patients and 38% of Mikulicz's disease patients. The serum IgG4 levels were not normalized at remission in 3 of 4 relapsed AIP patients, and re-elevation of serum IgG4 levels was detected in all relapsed patients. Elevated serum IgG4 levels decreased in 3 patients with pancreatic cancer after resection or chemotherapy, and decreased in patients with hypereosinophilic syndrome, sclerosing cholangitis, and hypophysitis after steroid therapy. CONCLUSION: Measurement of serial serum IgG4 levels is useful to determine the disease activity of IgG4-related systemic diseases.

Serum IgG4-negative autoimmune pancreatitis.

BACKGROUND: Autoimmune pancreatitis (AIP) is considered to be a pancreatic lesion of IgG4-related systemic disease, but about 20% of AIP patients do not have elevated serum IgG4 levels. This study aimed to clarify the pathophysiology of AIP patients without elevated serum IgG4 levels. METHODS: Fifty-eight AIP patients were divided into 2 groups: those with elevated serum IgG4 levels (>135 mg/dl; SIgG4-positive AIP) and those without (SIgG4-negative AIP). The 2 groups' clinical, serological, radiological, and histological findings, as well as salivary and lacrimal gland function, were compared. RESULTS: Serum IgG4 levels were elevated in 45 AIP patients and normal in 13 patients. In SIgG4-negative AIP patients, the female ratio tended to be high; obstructive jaundice was less likely; abdominal pain and acute pancreatitis were more likely; segmental swelling of the pancreatic body and/or tail was more common; sclerosing extrapancreatic lesions, salivary and lacrimal gland dysfunction, and abundant infiltration of IgG4-positive plasma cells in the gastric mucosa were less likely; and conservative follow-up was sometimes implemented. Histological examination of the pancreas of SIgG4-negative AIP showed lymphoplasmacytic sclerosing pancreatitis (LPSP) rather confined to the pancreas (n = 4), inadequate material (n = 2), and pancreatic fibrosis showing infiltration of lymphocytes without infiltration of IgG4-positive cells or neutrophils (n = 2). CONCLUSIONS: Clinicopathological features of SIgG4-negative AIP differed from those of SIgG4-positive AIP. Some SIgG4-negative AIP cases are LPSP rather confined to the pancreas. SIgG4-negative AIP may include idiopathic duct-centric pancreatitis (IDCP) or sclerosing pancreatitis other than LPSP or IDCP, but further studies are needed to clarify this issue.

Phase II study of ABVd therapy for newly diagnosed clinical stage II-IV Hodgkin lymphoma: Japan Clinical Oncology Group study (JCOG 9305).

Although ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) therapy has been regarded as a standard of care for advanced-stage Hodgkin lymphoma (HL) since 1992, there has been no prospective data of ABVD therapy in Japan. To investigate the efficacy and safety of ABVd therapy with the lower dose of dacarbazine (250 mg/m(2)) in patients with newly diagnosed stage II-IV HL, Lymphoma Study Group of Japan Clinical Oncology Group conducted a phase II study. The primary endpoints were complete response rate (%CR) and progression-free survival (PFS). A total of 128 patients with age less than 70 years were enrolled and received 6-8 cycles of ABVd followed by radiation to initial bulky mass. The %CR in 118 eligible patients was 81.4% [95% confidence interval (CI) 73.1-87.9%]. Major toxicity was grade 4 neutropenia (45.3%). Grade 3 nausea/vomiting was the most frequent non-hematological toxicity (10.9%). Transient grade 4 constipation, infection (abscess), hypoxemia and hyperbilirubinemia were observed in 4 patients. No treatment-related death was observed. PFS and overall survival at 5 years were 78.4% (95% CI 70.9-85.9%) and 91.3% (95% CI 86.1-96.5%), respectively. In conclusion, ABVd is effective in Japanese patients with stage II-IV HL with acceptable toxicities (UMIN-CTR Number: C000000092).

[A case of small cell carcinoma arising in submandibular gland].

The patient was a 53-year-old male. He presented with swelling of the left submandibular region. Histopathological examination of a biopsy specimen showed small cell carcinoma. Computed tomography (CT) and bone scintigraphy revealed multiple liver, bone and lymph node metastases. He was diagnosed with small cell carcinoma of the submandibular gland with multiple metastases, Stage IV. Systemic chemotherapy consisting of CPT -11 plus CDDP as first-line and amrubicin as second-line therapy was given. Once CT showed a partial response of the tumors, but he passed away after about 10 months. Small cell carcinoma arising in the submandibular gland is extremely rare, and there are few clinical reports.

A new embryological theory of the pancreatic duct system.

BACKGROUND/AIMS: To clarify the anatomy of the pancreatic duct system and to investigate its embryology. METHODS: We reviewed pancreatograms of 256 patients with a normal pancreatic head and 36 cases of complete pancreas divisum. RESULTS: Accessory pancreatograms were divided into two patterns. The long-type accessory pancreatic duct (APD) forms a straight line and joins the main pancreatic duct (MPD) at the neck portion of the pancreas. The short-type APD joins the MPD near its first inferior branch. The short-type APD is less likely to have a long inferior branch arising from the APD. The length of the APD from the orifice to the first long inferior branch was similar in the short- and long-type APD. The first long inferior branch from the long-type APD passes through the MPD near the origin of the inferior branch from the MPD. Immunohistochemically, in the short-type APD, the MPD between the junction of the short-type APD and the neck portion originated from the ventral pancreas. CONCLUSION: The long-type APD represents a continuation of the main duct of the dorsal pancreatic bud. The short-type APD is very likely formed by the proximal main duct of the dorsal pancreatic bud and its long inferior branch, with the main duct of the dorsal pancreatic bud at the point of connection with the main duct of the ventral pancreatic bud being obliterated and replaced by this additional communication.

Autoimmune pancreatitis and IgG4-related sclerosing disease.

Autoimmune pancreatitis (AIP) is a unique form of pancreatitis in which the pathogenesis is suspected to involve autoimmune mechanisms. AIP sometimes mimics pancreatic cancer in its presentation, but as AIP responds dramatically to steroid therapy, accurate diagnosis is necessary. AIP is currently diagnosed on the basis of a combination of characteristic clinical, serological, morphological and histopathological features. However, its diagnosis remains a clinical challenge and there are no internationally agreed diagnostic criteria. Another type of AIP called 'idiopathic duct-centric chronic pancreatitis' or 'AIP with granulocytic epithelial lesion' has been reported in Western countries. IgG4-related sclerosing disease is a systemic disease in which IgG4-positive plasma cells and T lymphocytes extensively infiltrate various organs. Organs with tissue fibrosis and obliterative phlebitis, such as the pancreas, salivary gland and retroperitoneum, show clinical manifestations; AIP seems to represent one manifestation of IgG4-related sclerosing disease. As a mass is formed in most cases of IgG4-related sclerosing disease, a malignant tumor is frequently suspected on initial presentation. Clinicians should consider IgG4-related sclerosing disease in the differential diagnosis to avoid unnecessary surgery.

Differentiation of autoimmune pancreatitis from pancreatic cancer by diffusion-weighted MRI.

OBJECTIVES: We sought to clarify the clinical utility of diffusion-weighted magnetic resonance imaging (DWI) for differentiating autoimmune pancreatitis (AIP) from pancreatic cancer. METHODS: Thirteen AIP patients underwent DWI before therapy, and six of them underwent DWI after steroid therapy. The extent and shape of high-intensity areas were compared with those of 40 pancreatic cancer patients. Apparent diffusion coefficient (ADC) values were calculated in the AIP area before and after steroid therapy in pancreatic cancer patients and in a normal pancreatic body. RESULTS: On DWI, AIP and pancreatic cancer were detected as high-signal intensity areas. The high-intensity areas were diffuse (n=4), solitary (n=6), and multiple (n=3) in AIP patients, but all pancreatic cancer patients showed solitary areas (P<0.001). A nodular shape was significantly more frequent in pancreatic cancer, and a longitudinal shape was more frequently found in AIP (P=0.005). ADC values were significantly lower in AIP (1.012+/-0.112 x 10(-3) mm(2)/s) than in pancreatic cancer (1.249+/-0.113 x 10(-3) mm(2)/s) and normal pancreas (1.491+/-0.162 x 10(-3) mm(2)/s) (P<0.001). Receiver operating characteristic analysis yielded an optimal ADC cutoff value of 1.075 x 10(-3) mm(2)/s to distinguish AIP from pancreatic cancer. After steroid therapy, high-intensity areas on DWI disappeared or were markedly decreased, and the ADC values of the reduced pancreatic lesions increased almost to the values of normal pancreas. CONCLUSIONS: DWI is useful for detecting AIP and for evaluating the effect of steroid therapy. ADC values were significantly lower in AIP than in pancreatic cancer. An ADC cutoff value may be useful for distinguishing AIP from pancreatic cancer.

K-ras mutation in the major duodenal papilla and gastric and colonic mucosa in patients with autoimmune pancreatitis.

BACKGROUND: Pancreatic cancer occurs in some patients with autoimmune pancreatitis (AIP). Significant K-ras mutations are frequently detected in the pancreas of AIP patients. AIP may be a pancreatic lesion of IgG4-related systemic disease. Gastric and colonic cancer can occur during the follow up of AIP patients. We examined K-ras mutations in the major duodenal papilla and gastric and colonic mucosa of AIP patients. METHODS: K-ras analysis and/or immunohistochemical study was performed on the tissues of the major duodenal papilla (n = 8), gastric mucosa (n = 5), colonic mucosa (n = 3), pancreas (n = 5), common bile duct (n = 5), and gallbladder (n = 4) of 12 AIP patients. RESULTS: Significant K-ras mutations were detected in the major duodenal papilla of 4 of 8 cases [GAT (n = 4)], in the gastric mucosa of 2 of 4 cases [AGT (n = 2)], and in the colonic mucosa of 2 of 3 cases [GAT (n = 2)]. Significant K-ras mutations were detected in the pancreas of all 5 cases [GAT (n = 5), in the common bile duct of 4 cases (GAT (n = 2), TGT (n = 1), and GCT/TGT (n = 1)], and in the gallbladder epithelium of 3 cases [GAT (n = 1), GCT (n = 1), and GTT (n = 1)]. K-ras mutations were detected in the organs associated with IgG4-related fibroinflammation with abundant infiltration of T lymphocytes and forkhead box P3-positive cells. CONCLUSIONS: Significant K-ras mutations were frequently detected in the major duodenal papilla and gastric and colonic mucosa of AIP patients. AIP patients may have risk factors for gastric and colonic cancer, but the mechanisms of K-ras mutation and its clinical implications are not clear.

Phase II study of S-1 as first-line treatment for elderly patients over 75 years of age with advanced gastric cancer: the Tokyo Cooperative Oncology Group study.

PURPOSE: This prospective multicenter phase II study was carried out to investigate the efficacy, safety and pharmacokinetics of S-1 monotherapy in elderly patients over 75 years of age, with unresectable advanced or recurrent gastric cancer. METHODS: Patients had measurable or evaluable lesions according to the Japanese Classification of Gastric Carcinoma. S-1 (25-60 mg determined by the body surface area and creatinine clearance) was given orally, twice daily. A course of treatment consisted of 4-week administration followed by a 2-week rest period, and the patients received repeated courses. RESULTS: Thirty-three patients were enrolled. Pharmacokinetics of S-1 was studied in six patients, and the maximum plasma concentrations of respective metabolites after S-1 administration were found to be similar to those reported for younger cancer patients. The overall response rate in 33 patients was 21.2% (95% CI, 10.7-37.8%), and median progression-free survival was 3.9 months, with a median overall survival of 15.7 months. Frequently noted adverse events include leukopenia, neutropenia, anemia, anorexia, and fatigue. As for serious adverse events, relatively higher frequencies of anemia (9%) and anorexia (12%) of grade 3 severity were found, but there were no grade 4 episodes. CONCLUSIONS: The results suggest that S-1 monotherapy is safe and useful for elderly patients with unresectable advanced or recurrent gastric cancer when the dose is selected with caution, taking into account renal function.

Pancreaticobiliary maljunction.

Pancreaticobiliary maljunction (PBM) is a congenital anomaly defined as a junction of the pancreatic and bile ducts located outside the duodenal wall, usually forming a markedly long common channel. In PBM patients, this anomaly allows regurgitation between the pancreatobiliary and biliopancreatic tract. Since hydrostatic pressure within the pancreatic duct is usually higher than that in the common bile duct, pancreatic juice frequently refluxes into the bile duct. As a result, pancreatic enzyme levels are generally very high in the bile and there is a related high incidence of biliary cancer. PBM can be divided into PBM with biliary dilatation (congenital choledochal cyst [CCC]) and PBM without biliary dilatation (maximal diameter of the bile duct

Frequent and significant K-ras mutation in the pancreas, the bile duct, and the gallbladder in autoimmune pancreatitis.

OBJECTIVES: To assess the relationship between autoimmune pancreatitis (AIP) and pancreatic cancer, we analyzed K-ras mutation in the pancreatobiliary tissues of patients with AIP. METHODS: An analysis of K-ras mutation and an immunohistochemical study were performed on the pancreas of 8 patients with AIP and 10 patients with chronic alcoholic pancreatitis and on the common bile duct and the gallbladder of 9 patients with AIP. K-ras mutation was analyzed in the pure pancreatic juice from 3 patients with AIP. RESULTS: High-frequency K-ras mutation (2+ or 3+) was detected in the pancreas of all the 8 patients and in the pancreatic juice of the other 2 patients. The mutation in codon 12 of the ras gene was GAT in all the 10 patients. High-frequency K-ras mutation was detected in the common bile duct of 5 patients with AIP and in the gallbladder epithelium of 4 patients with AIP. The K-ras mutation was detected in the fibroinflammatory pancreas, the bile duct, and the gallbladder, with abundant infiltrating IgG4-positive plasma and Foxp3-positive cells of patients with AIP with elevated serum IgG4 levels. CONCLUSIONS: Significant K-ras mutation occurs most frequently in the pancreatobiliary regions of patients with AIP. Autoimmune pancreatitis may be a risk factor of pancreatobiliary cancer.

[A case of colon cancer with reversible posterior leukoencephalopathy syndrome following 5-FU and oxaliplatin (FOLFOX regime)].

We report a rare case of reversible posterior leukoencephalopathy syndrome (RPLS) induced by 5-FU and oxaliplatin (FOLFOX regime). A 35-year-old woman with ileus was diagnosed with sigmoid cancer Stage IV (T4N4M0P2H0), and excision of the sigmoid colon, and left ureteroureteral anastomosis was performed. Postoperative chemotherapy with FOLFOX4 was performed. Complications of hypertension were seen on day 6, and convulsions on day 11 after chemotherapy. Headache and visual disturbance were also complications. MRI of the brain revealed bilateral high signal intensities of posterior lobes on T2 weighted and FLAIR images without enhancement. The patient was treated with antihypertensive therapy and anticonvulsive therapy. Her symptoms entirely disappeared, including the bilateral posterior lesions on MRI after two weeks. This report would suggest that medical oncologists should be aware that multidrug chemotherapies may increase the risk of fatal neurological complications like RPLS.

Serum IgG4 concentrations and IgG4-related sclerosing disease.

BACKGROUND: Based on histological and immunohistochemical examinations of various organs of patients with autoimmune pancreatitis (AIP), a new clinicopathological entity, IgG4-related systemic disease, was proposed. This study aimed to clarify clinical utility of serum IgG4 levels in differentiating AIP from other pancreatobiliary diseases, clinical utility of serum IgG4 levels in differentiating Mikulicz's disease from other salivary gland disorders, as well as in identifying other IgG4-related diseases. METHODS: Serum IgG4 levels were measured in 468 patients. RESULTS: The median serum IgG4 level was significantly greater in AIP (301.5mg/dl) than in other pancreatobiliary diseases (p<0.01). Using the cutoff value of 119 mg/dl that was determined on the basis of this study's ROC curve data, the sensitivity and specificity to distinguish AIP from pancreatic cancer were 82.1% and 94.8%, respectively. The median serum IgG4 level was significantly greater in Mikulicz's disease (357.0mg/dl) than in other salivary gland diseases (p<0.01). Of 75 patients with elevated serum IgG4 levels, 15 had diseases other than pancreatobiliary and salivary gland diseases. CONCLUSIONS: Serum IgG4 levels were useful for diagnosing AIP and Mikulicz's disease. Some diseases with serum IgG4 level elevations may be lesions of IgG4-related systemic disease without manifestations of AIP and Mikulicz's disease.

Lacrimal gland function in autoimmune pancreatitis.

OBJECTIVE: Autoimmune pancreatitis (AIP) may be a pancreatic lesion of IgG4-related systemic disease. Lacrimal gland swelling is a rare extrapancreatic lesion of AIP. The aim of the present study was to investigate lacrimal gland function in AIP patients, and to determine changes after steroid therapy. PATIENTS AND METHODS: Schirmer's test and sialochemistry were done prospectively in 11 AIP patients. These tests were also performed after steroid therapy in 7 patients. RESULTS: Dysfunction of tear secretion was found in at least one eye in 7 (64%) patients. The average lower level in both eyes was 4.3+/-1.5 mm in the 7 patients with lacrimal gland dysfunction, which was significantly lower than the 8.2+/-2.4 mm in patients with normal lacrimal gland function (p=0.005). There were no significant differences between the two groups in age at diagnosis of AIP, sex ratio, and the presence of swelling of the lacrimal glands and the salivary glands. Although there was no significant difference, mean serum IgG4 levels and mean salivary Na+ and beta2 microglobulin levels were lower in patients with normal lacrimal gland function. After steroid therapy, lacrimal gland function improved in 3 of 5 patients with impaired lacrimal gland function, though the degree of improvement was not marked compared to the improvement of salivary gland function. CONCLUSION: Lacrimal gland function was frequently impaired in AIP patients, even when no lacrimal gland swelling was observed clinically. Lacrimal gland function impairment appears to be similar to impairment of salivary gland function in AIP patients.