A multi-center cooperative clinical trial was undertaken to evaluate the safety and efficacy of weekly taxol (TXL) therapy combined with short-premedication as a pretreatment in an effort to ...determine if TXL can be used in ambulatory treatment. TXL was administered at 60 mg/m2 to patients with advanced recurrent breast cancer once a week without a rest or with a rest for 1 week after treatment for 3 weeks. A total of 36 patients were finally enrolled. The site of recurrence was the local region in 8 patients, lung/pleura in 24, liver in 9, bone in 16, lymph nodes in 15, epicardium in 2, and brain metastasis in 2. The response was CR in 2, PR in 12, NC in 9, PD in 8, and NE in 5, with a response rate of 45.2%. Grade 4 anorexia was reported as non-hematotoxicity. All other adverse reactions, such as myalgia/arthralgia and peripheral neuropathy, were mild (grade 1 or 2). Hematotoxic effects observed in this study included only grade 3 leukopenia in 5 patients, neutropenia in 4, and decreases in hemoglobin in 1.
Background
IgG4-sclerosing cholangitis (IgG4-SC) patients have an increased level of serum IgG4, dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, and a ...good response to steroid therapy. However, it is not easy to distinguish IgG4-SC from primary sclerosing cholangitis, pancreatic cancer, and cholangiocarcinoma on the basis of cholangiographic findings alone because various cholangiographic features of IgG4-SC are similar to those of the above progressive or malignant diseases.
Methods
The Research Committee of IgG4-related Diseases and the Research Committee of Intractable Diseases of Liver and Biliary Tract in association with the Ministry of Health, Labor and Welfare, Japan and the Japan Biliary Association have set up a working group consisting of researchers specializing in IgG4-SC, and established the new clinical diagnostic criteria of IgG4-SC 2012.
Results
The diagnosis of IgG4-SC is based on the combination of the following 4 criteria: (1) characteristic biliary imaging findings, (2) elevation of serum IgG4 concentrations, (3) the coexistence of IgG4-related diseases except those of the biliary tract, and (4) characteristic histopathological features. Furthermore, the effectiveness of steroid therapy is an optional extra diagnostic criterion to confirm accurate diagnosis of IgG4-SC.
Conclusion
These diagnostic criteria for IgG4-SC are useful in practice for general physicians and other nonspecialists.
Background
The effect of maintenance steroid treatment (MST) in reducing the risk of relapse in patients with autoimmune pancreatitis (AIP) remains under debate. The aim of this study was to validate ...the effect of MST on AIP administered in accordance with the 2010 Japanese consensus guidelines.
Methods
The clinical data of patients with (
n
= 510) from 22 high-volume centers in Japan were studied. The primary endpoints were the relapse rates (RRs) in patients administered MST versus those not administered MST. The secondary endpoints were the optimal dose and duration of MST in terms of steroid toxicity and the predictors of relapse.
Results
The RRs were 10.0% within 1 year, 25.8% within 3 years and 35.1% within 5 years. The RR in the steroid therapy group reached a plateau at 42.7% at 7 years. In terms of the optimal dosage, the overall RR in the MST 5 mg/day group was 26.1%, which was significantly lower than that in the group which had discontinued steroid therapy (45.2%;
p
= 0.023) or was receiving MST at 2.5 mg/day (43.4%,
p
= 0.001). The RRs in the group receiving MST at ≥5 mg/day versus the patient group receiving MST at <5 mg/day were 10.6 vs. 10.3% within 1 year, 23.5 vs. 32.9% within 3 years and 32.2 vs. 41.3% within 5 years, respectively (log-rank,
p
= 0.028). The best cutoff value of the total steroid dose for serious steroid toxicity was 6405 mg, with a moderate accuracy of 0.717 determined using the area under the curve. Presence of diffuse pancreatic swelling odds ratio OR) 1.745;
p
= 0.008) and MST at >5 mg/day were identified as predictors of relapse (OR 0.483;
p
= 0.001).
Conclusions
The RR could continue to increase for 7 years even under MST. Based on our analysis of the side effects of steroid therapy, MST at 5 mg/day for 2 (total 4625 mg) to 3 (total 6425 mg) years might be a rational and safe therapeutic strategy in terms of keeping the RR to <30% while avoiding potential steroid toxicity.
Background
Sporadic autoimmune pancreatitis (AIP) cases showing remission without steroid treatment have been reported, however, the clinical course of these patients has not been clarified. This ...study sought to clarify the clinical course in AIP patients with hesitation for steroid treatment.
Methods
We collected clinical data for AIP patients from high‐volume centers in Japan. Data for AIP patients with and those without steroid treatment (steroid treatment vs. wait and see policy or W&S) were then compared. The primary point was the relapse‐free survival rate (RFS) in patients with and those without steroid treatment, as determined using Kaplan–Meier curve. The secondary point was the identification of predictors of remission and risks of relapse in AIP patients without steroid treatment.
Results
There were 510 AIP patients in the steroid treatment group and 97 patients in the W&S group. Overall, 55.7% (54/97) of type 1 AIP patients in the W&S group experienced transient remission without steroid treatment. The W&S group had a significantly higher patient age and significantly lower incidences of jaundice, diffuse pancreas swelling, proximal‐type sclerosing cholangitis, and stent placement and a lower remission rate than the steroid treatment group (each P < 0.05). The RFS reached a plateau at 10 years in both the W&S group (50%) and steroid treatment group (52.9%). As for the RFS (W&S vs. group with steroid), 89.4% vs. 74.4% within 3 years, 81.8% vs. 65.3% within 5 years, and 50% vs. 52.9% within 10 years (log‐rank, P = 0.064). Female gender (OR 0.340, P = 0.027) and stent placement for jaundice (OR 4.552, P = 0.008) were identified as predictors of transient remission in the W&S group. New‐onset diabetes mellitus (OR 8.333, P = 0.012) and the presence of extensive multi‐organ involvement (OR 35, P = 0.006) were identified as risks of relapse in the W&S group.
Conclusion
Some type 1 AIP patients without steroid treatment experience transient remission. These cases tend to have lower disease activities than AIP patients receiving steroids. Female gender and stent placement for jaundice may be predictors of transient remission among patients not receiving steroid treatment, however, relapses can occur in these patients with new‐onset diabetes mellitus and the presence of extensive multi‐organ involvement. Therefore, steroid treatment is still imperative for these patients.
Highlight
Some autoimmune pancreatitis patients exhibit transient remission without steroid treatment. In this retrospective multicenter study with long‐term follow‐up, Kubota and colleagues revealed that female gender and stent placement for jaundice may be predictors of remission in such patients. Patients with new‐onset diabetes mellitus and extensive multi‐organ involvement are prone to relapse.
Corticosteroid has been established as the standard therapy for autoimmune pancreatitis (AIP), but the requirement for maintenance corticosteroid therapy is controversial. We conducted a randomised ...controlled trial to clarify the efficacy of maintenance corticosteroid therapy in patients with AIP.
We conducted a multicentre, tertiary setting, randomised controlled trial. After the induction of remission with the initial oral prednisolone (PSL) treatment, maintenance therapy with PSL at 5-7.5 mg/day was continued for 3 years or withdrawn at 26 weeks. The primary endpoint was relapse-free survival over 3 years and the secondary endpoint was serious corticosteroid-related complications. All analyses were performed on an intention-to-treat basis.
Between April 2009 and March 2012, 49 patients with AIP were randomly assigned to the maintenance therapy group (n=30) or the cessation group (n=19). Baseline characteristics were not different between the two groups. Relapses occurred within 3 years in 11 out of 19 (57.9%) patients assigned to the cessation group, and in 7 of 30 (23.3%) patients in the maintenance therapy group. The relapse rate over 3 years was significantly lower in the maintenance therapy group than that in the cessation group (p=0.011). The relapse-free survival was significantly longer in the maintenance therapy group than that in the cessation group (p=0.007). No serious corticosteroid-related complications requiring discontinuation of PSL were observed.
Maintenance corticosteroid therapy for 3 years may decrease relapses in patients with AIP compared with those who discontinued the therapy at 26 weeks.
UMIN000001818; Results.
The standard treatment for autoimmune pancreatitis (AIP) is steroid therapy, although some patients improve spontaneously. Indications for steroid therapy in AIP patients are symptoms such as ...obstructive jaundice, abdominal pain, back pain, and the presence of symptomatic extrapancreatic lesions. Prior to steroid therapy, obstructive jaundice should be managed by biliary drainage, and blood glucose levels should be controlled in patients with diabetes mellitus. The recommended initial oral prednisolone dose for induction of remission is 0.6 mg/kg/day, which is administered for 2–4 weeks. The dose is then tapered by 5 mg every 1–2 weeks, based on changes in clinical manifestations, biochemical blood tests (such as liver enzymes and IgG or IgG4 levels), and repeated imaging findings (US, CT, MRCP, ERCP, etc.). The dose is tapered to a maintenance dose (2.5–5 mg/day) over a period of 2–3 months. Cessation of steroid therapy should be based on the disease activity in each case. Termination of maintenance therapy should be planned within 3 years in cases with radiological and serological improvement. Re-administration or dose-up of steroid is effective for treating AIP relapse. Application of immunomodulatory drugs is considered for AIP patients who prove resistant to steroid therapy. The prognosis of AIP appears to be good over the short-term with steroid therapy. The long-term outcome is less clear, as there are many unknown factors, such as relapse, pancreatic exocrine or endocrine dysfunction, and associated malignancy.
Background
In response to the proposal of the international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP) and the Japanese diagnostic criteria in 2011, the 2009 Japanese ...consensus guidelines for managing AIP required revision.
Methods
Three committees the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators were organized. Fifteen specialists for AIP extracted the specific clinical statements from 1,843 articles published between 1963 and 2012 (obtained from Pub Med and a secondary database, and developed the CQs and statements. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid.
Results
The professional committee created 13 CQs and statements for the current concept and diagnosis of AIP, 6 for extra-pancreatic lesions, 6 for differential diagnosis, and 11 for treatment.
Conclusion
After evaluation by the moderators, amendments to the Japanese consensus guidelines for AIP have been proposed for 2013.
The renin–angiotensin–aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin, the first and rate-limiting enzyme of the RAAS, is an attractive target for the treatment ...of hypertension and cardiovascular/renal diseases. Therefore, various direct renin inhibitors (DRIs) have been researched over recent decades; however, most exhibited poor pharmacokinetics and oral bioavailability due to the peptidomimetic or nonpeptidomimetic structures with a molecular weight (MW) of >600, and only aliskiren is approved. This study introduces a novel class of DRIs comprised of a 2-carbamoyl morpholine scaffold. These compounds have a nonpeptidomimetic structure and a MW of <500. The representative compound 26 was highly potent despite not occupying S1′–S2′ sites or the opened flap region used by other DRIs and exerted a significant antihypertensive efficacy via oral administration on double transgenic mice carrying both the human angiotensinogen and the human renin genes.
Autoimmune pancreatitis (AIP) has the potential to transform into chronic pancreatitis with pancreatic stone involvement. This retrospective investigation sought to clarify the risk factors for stone ...formation in type 1 AIP.
Questionnaires on patients with type 1 AIP were sent to 22 high-volume medical centers across Japan to compare the clinical features of patients with and without pancreatic stone formation.
Of the completed records on 624 type 1 AIP patients, 31 (5%) had experienced pancreatic stones. Median follow-up duration was 1853 days. Bentiromide test values at diagnosis were significantly lower, and hemoglobin A1c values after corticosteroid treatment were significantly higher in patients with pancreatic stones. Imaging results disclosed that pancreatic atrophy and hilar or intrahepatic bile duct stenosis were significantly more frequent in patients with pancreatic stone formation. Pancreatic head swelling tended to be more frequent in this group as well. On the other hand, a shorter follow-up period was associated with the nonformation of pancreatic stones.
The increased frequency of pancreatic head swelling in type 1 AIP patients exhibiting pancreatic stones indicated a propensity for pancreatic juice stasis with subsequent stone development and pancreatic dysfunction occurring over longer periods of disease duration.
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