Sustained partial remission of metastatic pancreatic cancer following systemic chemotherapy with gemcitabine and oxaliplatin plus adjunctive treatment with mistletoe extract.

BACKGROUND: The clinical prognosis of metastatic pancreatic cancer is very poor, with a median survival time of such patients ranging from 3 to 6 months. Current chemotherapy regimens include the combination of oxaliplatin and gemcitabine. CASE REPORT: A 43-year-old woman was diagnosed with pancreatic adenocarcinoma spreading into the regional lymph nodes and into multiple liver segments (pT3, pN1, pM1). Upon diagnosis, she underwent a pylorus-preserving pancreatic head resection, including dissection of regional lymph nodes and atypical resection of a single liver segment, followed by 9 cycles of palliative chemotherapy with gemcitabine and oxaliplatin. 37 weeks after surgery, the patient demonstrated a sustained partial remission, and the chemotherapy was stopped. Surprisingly, 10 months later, she still showed no evidence of tumor progression. Since the time of pancreatic surgery, the patient had taken mistletoe extracts and this adjunctive treatment has been continued until now. CONCLUSIONS: Cases of sustained long-term remission of metastatic pancreatic cancer are extremely rare. Although this single case observation does not allow for firm conclusions regarding potential mechanisms, the adjunctive therapy with mistletoe extracts might have played a role. Therefore, the clinical effects of such treatment in patients with pancreatic cancer warrant further investigation.

Selective amino acid deficiency in patients with impaired glucose tolerance and type 2 diabetes.

INTRODUCTION: Amino acids are important modulators of glucose metabolism, insulin secretion and insulin sensitivity. However, little is known about the changes in amino acid metabolism in patients with diabetes. PATIENTS AND METHODS: The circulating amino acid levels were determined in 17 patients with type 2 diabetes, 17 individuals with impaired glucose tolerance (IGT), and 14 control subjects. RESULTS: Total amino acid concentrations were 2850+/-57micromol/l in patients with type 2 diabetes, 2980+/-77micromol/l in individuals with IGT, and 2886+/-74micromol/l in control subjects (p=0.38). Patients with type 2 diabetes exhibited significant reductions in the concentrations of gamma-aminobutyric acid (GABA), arginine, glutamine and phosphoethanolamine (p<0.05), whereas valine levels were higher than in controls (p=0.008). In IGT subjects, GABA levels were reduced, while tyrosine concentrations were increased (p<0.05). The plasma levels of essential amino acids were positively related to fasting and post-challenge glucose levels, fasting C-peptide, HOMA insulin resistance and fasting glucagon levels (p<0.05). CONCLUSIONS: Total amino acid levels are similar in patients with diabetes, IGT subjects and controls, but the individual levels of several amino acids differ significantly between these groups. These alterations may contribute to the disturbances in insulin secretion and action in diabetic patients and may provide a rationale for offering specific amino acid supplementations to diabetic patients.

Amino acid malnutrition in patients with chronic pancreatitis and pancreatic carcinoma.

OBJECTIVES: Chronic pancreatitis (CP) and pancreatic cancer (CA) have been associated with intestinal malabsorption and inflammation. However, little is known about the changes in amino acid metabolism in such patients. METHODS: The circulating amino acid levels were determined in 12 patients with CP, 12 CA patients, and 12 controls. RESULTS: Total amino acid concentrations were 2850 +/- 71 micromol/L in controls, 2640 +/- 96 micromol/L in CP patients, and 2210 +/- 123 micromol/L in CA patients (P < 0.001). In CP patients, significant reductions in the concentrations of citrulline, gamma-aminobutyric acid, taurine, and aspartic acid were found (P < 0.05), whereas in CA patients, the levels of phosphoethanolamine, gamma-aminobutyric acid, aspartic acid, taurine, arginine, threonine, alanine, citrulline, and tryptophan were reduced. There was a significant inverse relationship between the total amino acid levels and the white blood cell counts (r = -0.44, P = 0.008). CONCLUSIONS: Both patients with CP and with CA exhibit alterations in amino acid levels. The mechanisms underlying these defects may involve intestinal malabsorption as well as systemic inflammation. Providing selective amino acid supplementation to such patients may minimize the excess morbidity and mortality associated with protein malnutrition.

Inhibition of human IAPP fibril formation does not prevent beta-cell death: evidence for distinct actions of oligomers and fibrils of human IAPP.

Type 2 diabetes mellitus (T2DM) is characterized by an approximately 60% deficit in beta-cell mass, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) forms oligomers, leading to either amyloid fibrils or toxic oligomers in an aqueous solution in vitro. Either application of hIAPP on or overexpression of hIAPP in cells induces apoptosis. It remains controversial whether the fibrils or smaller toxic oligomers induce beta-cell apoptosis. Rifampicin prevents hIAPP amyloid fibril formation and has been proposed as a potential target for prevention of T2DM. We examined the actions of rifampicin on hIAPP amyloid fibril and toxic oligomer formation as well as its ability to protect beta-cells from either application of hIAPP or endogenous overexpression of hIAPP (transgenic rats and adenovirus-transduced beta-cells). We report that rifampicin (Acocella G. Clin Pharmacokinet 3: 108-127, 1978) prevents hIAPP fibril formation, but not formation of toxic hIAPP oligomers (Bates G. Lancet 361: 1642-1644, 2003), and does not protect beta-cells from apoptosis induced by either overexpression or application of hIAPP. These data emphasize that toxic hIAPP oligomers, rather than hIAPP fibrils, initiate beta-cell apoptosis and that screening tools to identify inhibitors of amyloid fibril formation are likely to be less useful than those that identify inhibitors of toxic oligomer formation. Finally, rifampicin and related molecules do not appear to be useful as candidates for prevention of T2DM.