A phase II study of the 5-lipoxygenase inhibitor, CV6504, in advanced pancreatic cancer: correlation of clinical data with pharmacokinetic and pharmacodynamic endpoints.

PURPOSE: Primary objective was to determine response rate of patients with advanced pancreatic cancer to a novel lipoxygenase and thromboxane A2 synthetase inhibitor (CV6504); secondary objectives included estimation of pharmacokinetics of CV6504, target-enzyme inhibition, safety and tolerance, quality of life and survival. PATIENTS AND METHODS: Thirty-one patients with advanced pancreatic cancer were planned to receive CV6504, 100 mg TDS, orally for three months, at which point CT scans were performed to assess therapeutic response rates. Steady state concentrations of CV6504 and thromboxane B2 (an indirect measure of thromboxane A2 synthetase (TA2S) inhibition) were made. Of the 31 patients entered into the study, 23 were considered fully evaluable for response. RESULTS: The drug was well tolerated with few side effects; no partial or complete responses were seen, but 10 patients had stable disease at 3 months; quality of life was maintained during therapy; mean CV6504 steady state plasma concentrations of 14 +/- 6 ng/ml resulting in 75 +/- 18% inhibition of TA2S were achieved; median-survival time for all patients considered eligible for assessment of efficacy was 36.6 weeks after the initial dose of study medication. The actuarial one-year survival was approximately 25%. CONCLUSION: CV6504 inhibits its target enzyme in vivo, maintains stable disease in 32% of evaluable patients and is well tolerated.

Can pharmacokinetic monitoring improve clinical use of fluorouracil?

Fluorouracil is used clinically against a variety of solid tumors. It is a prodrug that undergoes a series of intracellular conversions to active cytotoxic species. There is wide interindividual variability in fluorouracil metabolism; furthermore, it has nonlinear kinetics that make it relatively more difficult to predict plasma concentrations after brief infusions compared with prolonged infusions. There is an increasing body of evidence that relates plasma fluorouracil concentrations to toxicity and effectiveness, and consequently there may be a definable mathematical relationship that describes a 'therapeutic window'. Dose nomograms and pharmacokinetic models based on limited sampling strategies have been developed, as have empirical dose escalation schedules based on multivariate analysis of the determinants of toxicity, The utility of these approaches should be tested in properly powered, prospective, randomised trials.

Relapsing thrombotic thrombocytopenic purpura in association with recurrent pancreatitis.

We report the case of a 28-year-old woman who presented with two episodes of acute pancreatitis 3 years apart both of which were complicated by the development of thrombotic thrombocytopenic purpura (TTP). On each occasion the TTP was successfully managed with plasmapheresis. Although TTP has been reported as causing acute pancreatitis, the induction of TTP by pancreatitis is rare. As far as we are aware this is the first reported case of recurrent TTP in association with acute pancreatitis. It is possible that circulating pancreatic proteases may have induced the TTP by modifying von Willebrand factor enabling spontaneous platelet membrane receptor binding resulting in intravascular platelet aggregation.

Are serial measurements of CA19-9 useful in predicting response to chemotherapy in patients with inoperable adenocarcinoma of the pancreas?

Thirty-nine patients with inoperable adenocarcinoma of the pancreas were studied (27 male, 12 female; median age 60 years, range 39-75 years). All patients received chemotherapy with continuous infusion 5-fluorouracil with intravenous bolus epirubicin followed by cisplatin, repeated every 21 days for a total of six cycles and were evaluable for response. Serum CA19-9 concentrations were obtained at baseline and before each cycle. A rise or fall in the tumour marker was defined as a greater than 15% increase or decrease in the marker on two consecutive occasions 3 weeks apart. A plateau in the tumour marker was defined as a less than 15% decrease or increase on two occasions. Changes in marker expression were compared with serial computerized tomography scanning before treatment and after the third and sixth cycle of chemotherapy. Thirty-five of 39 patients had an elevated CA19-9 (87.9%). Thirteen (36.2%) exhibited a decrease, seven (19.4%) a plateau and 16 (44.4%) patients had a progressive rise in serum CA19-9. The sensitivity of CA19-9 was 67% for predicting a partial response and 86% for progressive disease. The median survival for the 13 patients exhibiting a reduction was 333 days, for the seven patients exhibiting a plateau 253 days and for those who had a progressive rise 185 days. The difference in median survival between the group of patients with > 15% decrease and those with > 15% increase of CA19-9 was significant (P = 0.001). In the cohort of patients who exhibited a reduction in CA19-9, no tumour progression was seen, and the reduction occurred during the first three cycles of treatment. Thus, interval scanning may be avoided in this group of patients.

Priapism in a patient with protein C deficiency.

We present the case of a patient with classical protein C deficiency presenting with acute priapism during warfarinization for thrombophlebitis. Priapism is a well-recognized complication of a number of conditions including sickle cell disease and haematological malignancies, but to our knowledge it has not previously been reported in association with protein C deficiency. This case highlights the potential dangers of initiating oral anticoagulant therapy using conventional loading dose regimens in patients with protein C deficiency.

Spontaneous pneumothorax associated with expectoration of a lump of metastatic renal cancer.

The case report of a patient known to have metastatic renal cancer and right main bronchus obstruction is presented. During an episode of haemoptysis, the patient expectorated a large fragment of tissue, which proved to be metastatic renal cell cancer. This event produced a right-sided hydropneumothorax with partial re-expansion of the previously collapsed right lung. A chest tube was inserted producing a full re-expansion, following which pleurodesis with tetracycline was performed. To our knowledge, this is the first ever description of spontaneous clearance of a malignant bronchial obstruction.

Plasma proinflammatory cytokine concentrations, Acute Physiology and Chronic Health Evaluation (APACHE) III scores and survival in patients in an intensive care unit.

OBJECTIVE: To more clearly define the relationships between plasma proinflammatory cytokine concentrations, physiologic disturbance, and survival in severely ill patients. DESIGN: Prospective, longitudinal, cohort analytic study. SETTING: Teaching hospital intensive care unit (ICU). PATIENTS: Two hundred fifty-one consecutive nonselected patients admitted to the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Daily Acute Physiology and Chronic Health Evaluation (APACHE) III scores were calculated from clinical and laboratory data. In concurrent blood samples, plasma concentrations were measured of four proinflammatory cytokines (tumor necrosis factor-[TNF] alpha, interleukin [IL]-1 beta, IL-6, and IL-8), all of which are believed to be of central importance in host proinflammatory and immune responses. Plasma TNF concentrations were increased in 42 patients, plasma IL-1 beta in 15 patients, IL-6 in 194 patients, and IL-8 in 52 patients at presentation. Although admission plasma IL-1 beta, IL-6, and IL-8 concentrations were higher in patients who died in the ICU compared with survivors (n = 33; p < .02, p < .01, p < .02, respectively), only admission plasma IL-8 concentrations were higher in patients with a fatal outcome if all in-hospital deaths were considered (n = 53; p = .05). APACHE III score was the best predictor of mortality (odds ratio 11.41; p = .003). Detection, but not the absolute level, of TNF bioactivity in plasma was a weak independent predictor of death (odds ratio 3.17; p = .02). There was no relationship between bacteremia or presence of the systemic inflammatory response syndrome and plasma cytokine concentrations. Nineteen patients were in the ICU for > or = 10 days, and of these 19 patients, 16 patients had prolonged increases of plasma cytokines. Two patients with persistently increased plasma TNF concentrations died. Otherwise, persistently increased plasma cytokine concentrations had a variable relation to daily APACHE scores and to mortality. CONCLUSIONS: Plasma cytokine concentrations fluctuate in serious illness and have a poor correlation with derangement of whole body physiology in seriously ill patients. Only the presence of bioactive TNF in plasma was an independent predictor of mortality. Daily measurement of plasma proinflammatory cytokine concentrations is unlikely to have clinical application in the ICU setting, except possibly in specific subgroups of patients.