G protein-coupled receptor signaling in human ductal pancreatic cancer cells: neurotensin responsiveness and mitogenic stimulation.

Neuropeptides and their corresponding G protein-coupled receptors (GPCRs) are increasingly implicated in the autocrine/paracrine stimulation of growth of human cancers. We report that neurotensin induced rapid Ca2+ mobilization from intracellular stores followed by Ca2+ influx in five human ductal pancreatic cancer cell lines: HPAF-II, Capan-1, Capan-2, PANC-1, and MIA PaCa-2. In addition, most cell lines exhibited Ca2+ responses to multiple neuropeptides including bombesin, bradykinin, cholecystokinin, and vasopressin and to bioactive lipids, including lysophosphatidic acid (LPA), that also act via GPCRs. The well-differentiated line HPAF-II responded to at least seven independent GPCR agonists. The concentrations of neurotensin required to induce half-maximal effects (EC50) in HPAF-II and PANC-1 cells were 5 and 8nM, respectively. Digital fluorescence image analysis to measure Ca2+ responses in single cells revealed that 90% or more of HPAF-II and PANC-1 cells responded to 10nM neurotensin. Addition of neurotensin to PANC-1 cells also induced rapid and dose-dependent extracellular-regulated protein kinase (ERK-1 and ERK-2) activation and subsequently, stimulated DNA synthesis. The signaling complexity of GPCRs uncovered by these studies reveals a new aspect in the biology of human pancreatic cancer and could offer the basis for new approaches to the treatment of this disease.

Muscle abnormalities in juvenile dermatomyositis patients: P-31 magnetic resonance spectroscopy studies.

OBJECTIVE: To characterize metabolic abnormalities in the muscles of children with the juvenile variant of dermatomyositis (JDM) by the use of noninvasive P-31 magnetic resonance spectroscopy (MRS). METHODS: Thirteen patients with JDM (ages 4-16 years) were studied. Biochemical status was evaluated with P-31 MRS by determining the concentrations of the high-energy phosphate compounds, ATP and phosphocreatine (PCr), ratios of inorganic phosphate (Pi) to PCr (Pi:PCr ratio), levels of free cytosolic ADP, and phosphorylation potentials (PPs) during rest, exercise, and recovery. RESULTS: Significant metabolic abnormalities were observed in the thigh muscles of 10 severely affected patients during rest, 2 graded levels of exercise, and recovery. Mean ATP and PCr levels in the muscles of JDM patients were 35-40% below the normal control values (P < 0.003). These data, along with elevated Pi:PCr ratios, higher ADP levels, and abnormal values for PPs, indicated defective oxidative phosphorylation in the mitochondria of diseased JDM muscles. MRS findings were normal in 2 additional patients who had improved with prednisone treatment and in 1 patient who had no muscle weakness (amyopathic variant of JDM). CONCLUSION: JDM patients can be monitored with noninvasive P-31 MRS without sedation. Biochemical defects in energy metabolism are concordant with the weakness and fatigue reported by JDM patients. Quantitative MRS data are useful for evaluating patients and optimizing drug treatment regimens.

Primary duodenal adenocarcinoma: a 40-year experience.

HYPOTHESIS: In patients with duodenal adenocarcinoma, certain pathologic features of the tumor will have prognostic significance. DESIGN: Retrospective case series. PATIENTS: Forty-nine patients diagnosed with duodenal adenocarcinoma between 1957 and 1998. RESULTS: The tumors of 31 (63%) of the 49 patients underwent resection, 18 (37%) had surgical palliation or underwent biopsy. Mean (+/- SEM) survival for all patients was 49 +/- 9 months. The patients whose tumors were resected had longer survival than those who underwent palliation (mean +/- SEM, 66 +/- 13 months vs 18 +/- 6 months, P =.02). Multivariate analysis revealed large tumor size (P =.01), transmural invasion (P =.004), and moderate to poor tumor grade (P =.03) were negatively correlated with survival. Lymph node status did not influence survival. CONCLUSIONS: Our 40-year experience with duodenal adenocarcinoma demonstrates that large tumor size, advanced histological grade, and transmural invasion are associated with decreased survival. These results underscore the importance of early diagnosis, and suggest the presence of nodal spread is not a contraindication to resection.

Pancreatic surgery.

Several important advances in pancreatic surgery have been made over the past year. As in other areas of general surgery, laparoscopic techniques are being used with increasing frequency, but their real value remains to be determined. Methods to stage pancreatic cancer, perform palliative bypass, relieve pain, and perform distal pancreatic resections have been described. Using more conventional surgical approaches, data continue to accumulate about pylorus preserving pancreaticoduodenectomy as an alternative to the standard operation. The survival benefit of extended pancreatic resection for pancreatic cancer remains dubious. Studies continue to demonstrate lower morbidity and mortality rates for pancreaticoduodenectomy performed at high-volume centers. In the arena of chronic pancreatitis, pain relief is still the most common reason for surgical treatment, and the efficacy of various operations has been assessed by some new studies. Data continue to show that aggressive surgical treatment for infected necrosis leads to improved survival in patients with severe acute pancreatitis.

Magnetic resonance imaging and P-31 magnetic resonance spectroscopy provide unique quantitative data useful in the longitudinal management of patients with dermatomyositis.

OBJECTIVE: To evaluate the utility of magnetic resonance imaging (MRI) and P-31 magnetic resonance spectroscopy (MRS) in the longitudinal management of patients with dermatomyositis (DM). METHODS: The study group consisted of 11 patients, including 3 children, all of whom had a clinical diagnosis of DM. A control group of 8 subjects was studied simultaneously. MRI included images as well as calculations of T1 and T2 relaxation times. The P-31 MRS protocol evaluated metabolic status (i.e., inorganic phosphate/phosphocreatine ratios and phosphocreatine and ATP levels) during rest, exercise, and recovery. RESULTS: T2-weighted images of the thigh muscles showed inflammation even when serum creatine phosphokinase levels were in the normal range. Metabolic abnormalities, which were accentuated with exercise, were found in 10 patients. In some individuals, bioenergetic defects preceded other changes and persisted after resolution of inflammation. In general, clinical impressions correlated with MRI/MRS data. CONCLUSION: MRI and MRS provide unique data which are quantitative and which cannot be obtained from routine laboratory tests. These MR evaluations appear to be of value in assessing the status of DM patients during treatment with steroids and immunosuppressive drugs.