A 4-week versus a 3-week schedule of gemcitabine monotherapy for advanced pancreatic cancer: a randomized phase II study to evaluate toxicity and dose intensity

Background

This randomized phase II study compared the efficacy and toxicity between 4-week and 3-week schedules of gemcitabine monotherapy in advanced pancreatic cancer.

Methods

Patients with advanced pancreatic cancer were randomly assigned to either a 4-week schedule (gemcitabine at 1000?mg/m2 as a 30-min infusion weekly for 3 consecutive weeks every 4?weeks) or a 3-week schedule (gemcitabine at 1000?mg/m2 as a 30-min infusion weekly for 2 consecutive weeks every 3?weeks). The primary endpoint was the compliance rate during the first 8?weeks between the two groups.

Results

A total of 90 patients were enrolled. The compliance rate during the first 8?weeks was the same (53.3%). For the 4- and 3-week schedules, the tumor response rates were 14.2 and 17.1% (p?=?0.92), median progression free survival was 112 and 114?days (p?=?0.82), and median overall survival was 206 and 250?days (p?=?0.84), respectively. Grade 3?? neutropenia was the major adverse event in both schedules: 37.7 and 35.5% (p?=?0.82). In contrast, thrombocytopenia (platelet count <70000/mm3) was significantly higher for the 4-week schedule: 26.6 and 4.4% (p?=?0.008). The mean received dose intensity was equal: 588 and 550?mg/m2/week (p?=?0.14).

Conclusions

The 3-week schedule of gemcitabine did not improve the compliance rate during 8?weeks compared with the 4-week schedule, but it attained a comparable efficacy with lower toxicity. Further investigation will be needed to introduce it into daily practice. Clinical trial registration number: UMIN ID 974.     

Impaired binding of thrombin to thrombomodulin is associated with risk of deep vein thrombosis

The complex of thrombin and thrombomodulin (TM) activates protein C, and impaired binding of thrombin to TM may be a risk factor for thrombosis. In this study, we evaluated the reactivity of thrombin to TM by determining the TM-bound thrombin (TMBTh) to total thrombin generation (t-Th) ratio (TMBT ratio). We also examined whether a decreased TMBT ratio is associated with increased risk of thrombosis. TMBTh was measured on TM-coated plates. Thrombin was generated by addition of prothrombin time reagent to plasma. Levels of t-Th and TMBTh were expressed as percentages of the levels in pooled normal plasma. The study included 124 patients with deep vein thrombosis and 150 age- and sex-matched healthy subjects. The TMBT ratio (TMBTh/t-Th) was significantly lower in patients than in control subjects (p < 0.05). Among the 124 patients, 43 (34.7%) showed TMBT ratios below the 5th percentile value of control subjects, and the odds ratio (OR) for development of deep vein thrombosis was 9.4 (95% confidence interval [CI], 4.6-19.1). When patients with a deficiency of natural anticoagulant (antithrombin III, protein C, or protein S) were excluded from analysis, the TMBT ratio in 37 (42.5%) of the remaining 87 patients was below this cutoff point, and the OR (13.1; 95% CI, 6.4-26.9) was increased compared to that in the total patient group. These results suggest that it is possible to evaluate the reactivity of thrombin to TM by determining the TMBT ratio, and this ratio may be a predictor of deep vein thrombosis.     

Effect of simple motor performance on regional dopamine release in the striatum in Parkinson disease patients and healthy subjects: a positron emission tomography study.

To investigate changes in dopamine release in the striatum during motor exercise in human subjects with and without striatal dopamine denervation, eight healthy subjects and eight patients with Parkinson disease (PD) were measured during unilateral foot extension/flexion movement using positron emission tomography with [11C]raclopride. Five subjects in each group were later scanned in the resting condition. Estimation of binding potential (k3/k4) of [11C]raclopride was based on Logan plot method. Significant reductions in [11C]raclopride k3/k4 were found in the dorsal putamen contralateral to the exercise side in the healthy group and ipsilaterally in the PD group. Spearman rank correlation analysis showed that [11C]raclopride k3/k4 correlated inversely with the decrease in performance (velocity and motion range) in the dorsal putamen contralaterally in the healthy group and ipsilaterally in the PD group. These results suggest that simple but laborious motor exercise (motor stimulation) generates significant dopamine release in the dorsal striatum contralateral to the motor execution in humans. Lack of the crossed pattern and ipsilateral increase in dopamine release in the dorsal striatum during the unilateral limb movement may reflect the pathophysiology for hypokinetic and insufficient coordinating movement in PD.     

Striatal D2 receptor availability after shunting in idiopathic normal pressure hydrocephalus.

Gait disturbance in idiopathic normal pressure hydrocephalus (iNPH) is reminiscent of parkinsonism. Our recent PET study showed reduction in postsynaptic D(2) receptor binding concomitant with a normality of presynaptic dopamine transporter binding. Here, we investigated the plasticity of D(2) receptor in treating iNPH patients with ventriculoperitoneal (VP) shunting using PET with (11)C-raclopride and discuss the contribution of D(2) receptor to the pathophysiology of iNPH. METHODS: Eight iNPH patients participated in this study. After evaluation of their neuropsychologic abilities, all patients underwent 3-dimensional MRI and quantitative PET measurements twice before and 1 mo after VP shunting. MRI-based morphometric analyses were performed to examine postoperative variations of the ventricles. Estimation of binding potential (BP) for (11)C-raclopride was based on Logan plot analysis. Region-of-interest analysis was used to examine changes in (11)C-raclopride BP in the striatum. A 2-tailed paired t test was used for evaluating changes in PET and MRI parameters between conditions, and correlation analysis was used to investigate clinicopathophysiologic relevance (clinical vs. in vivo findings). RESULTS: Clinical evaluation revealed significant recovery in a 5-m back-and-forth navigation test and an affect test and a mild increase in Mini-Mental State Examination scores after VP shunting. Significant postoperative increases in (11)C-raclopride BP were found in the nucleus accumbens and dorsal putamen, and the increases were significantly associated with emotional (Spearman rank r = 0.66, P < 0.05) and navigational improvement (r = 0.72, P < 0.05), respectively. The (11)C-raclopride BP increase in the striaum as a whole correlated significantly with improvement in general cognitive ability. There was a mild ventricular shrinkage after surgery, albeit there was no correlation of its size with clinical and PET parameters. CONCLUSION: Striatal upregulation of D(2) receptor after VP shunting is associated with amelioration of hypokinetic gait disturbance and anhedonic mentation in iNPH patients, indicating that the effect of VP shunting may reside in noninhibition of functionally suppressed D(2) receptor in the striatum. D(2) receptor responsiveness may indicate a mechanism for iNPH pathophysiology.     

Expansion of the spectral bandwidth by spatial and chemical shift selective saturation in high-speed magnetic resonance spectroscopic imaging

A new spectral bandwidth expansion technique for highspeed magnetic resonance spectroscopic imaging (MRSI) based on an echo-planar technique is presented. This expansion can be achieved by spatial and chemical shift selective saturation without increasing the total measurement time. In addition, displacement along the slice-select direction due to chemical-shift differences between the measured compounds is also suppressed. Experimental results are shown using a phantom consisting of benzene and acetone. High spatial resolution (1 × 1 mm²) and wide spectral bandwidth (1.5–1.8 kHz; the effective spectral bandwidth has been doubled) are obtained without the displacement along the slice-select direction.     

A case of non-curatively resected gastric cancer successfully treated over 3 years with biweekly paclitaxel therapy

We report a case of non-curatively resected gastric cancer successfully treated over 3 years with biweekly administration of paclitaxel. A 69-year-old man underwent non-curative resection with distal gastrectomy for advanced gastric cancer with remarkable lymph node metastasis on June 10, 2002. The metastatic lymph node (No. 8 a, 8 p and 12 a) linked up with the retroperitoneal node, making resection impossible. Postoperatively, he was initially treated with weekly administration of paclitaxel 100 mg/body (68 mg/m(2)) per week. However, due to grade 3 neutropenia in the first course, weekly administration was changed to biweekly administration with dose reduction to 60 mg/body (41 mg/m(2)), resulting in the continuation of paclitaxel therapy. Since then, no grade 3 or more severe adverse reactions have been observed. He has maintained NC for 3 years, and is still being treated on an outpatient basis at present. We believe that, in paclitaxel therapy for advanced gastric cancer, it is important for long-term survival to continue it perseveringly by dose reduction or change of schedule, when major adverse reactions are seen.     

An observation on the analysis of urinary calculi by infrared spectroscopy

The central nuclei of 500 urinary calculi in Japan, including 421 calculi of upper urinary tracts, 64 calculi of lower urinary tracts and 15 prostatic calculi, were analysed by infrared spectroscopy. The results of analysis revealed that 50.8% of calculi were composed of mixed calcium oxalate-calcium phosphate; 17.4%, simple calcium oxalate; 17.4%, magnesium ammonium phosphate mixed with calcium phosphate, and probably also with calcium carbonate; 4.4%, uric acid and urate with or without calcium phosphate or calcium oxalate; 3.2%, calcium phosphate; 1.0%, cystine; and 0.2% (one case) were composed of protein.Of 119 oxalate-phosphate calculi the ratios of calcium oxalate to calcium phosphate were measured on the chart of infrared spectra, and also the ratios of 53 cortices taken from these calculi were measured and compared to the ratios of these central nuclei. The results showed that the nuclei of oxalate-phosphate calculi contained greater amounts of calcium phosphate.

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Zusammenfassung In Japan wurden die zentralen Nuclei von 500 Nierensteinen mittels Infrarotspektroskopie untersucht. Es handelte sich dabei um 421 Steine aus den oberen Harnwegen, 64 Steine aus den unteren harnwegen und 15 Prostatasteine. Die Analysen ergaben folgende Resultate: 50,8% der Steine setzten sich aus einem Gemisch von Calciumoxalat und Calciumphosphat usammen; 17,4% enthielten nur Calciumoxalate; 17,4% bestanden aus einem Gemisch von Magnesiumammoniumphosphat mit Calciumphosphat und vermutlich auch Calciumcarbonat; 4,4% enthielten Harnsäure und Urate mit oder ohne Calciumphosphat oder Calciumoxalat; 3,2% bestanden aus Calciumphosphat; 1,0% aus Cystin und 0,2% (ein Fall) aus Protein.Bei 119 Phosphatoxalatsteinen wurde das Verhältnis von Calciumoxalat zu Calciumphosphat aus den Kurven der erhaltenen Infrarotspektra bestimmt. Dieses Verhältnis wurde ebenfalls für die äußere Schicht von 53 solcher Steine berechnet und mit dem Wert der zugehörigen zentralen Nuclei verglichen. Aus diesen Resultaten geht hervor, daß die Nuclei der Phosphatoxalatsteine größere Mengen von Calciumphosphat enthalten.

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Résumé Les noyaux centraux de 500 calculs urinaires, comportant 421 calculs des voies urinaires supérieures, 64 calculs des voies urinaires inférieures et 15 calculs de la prostate ont été analysés au Japon par spectroscopie infrarouge. Les résultats de cette analyse indiquent que 50,8% des calculs sont composés d'un mélange d'oxalate de calcium et phosphate de calcium: 17,4% d'oxalate de calcium simple; 17,4% de phosphate de magnésium ammoniaqué, mélangé au phosphate de calcium et probablement aussi au carbonate de calcium: 4,4% d'acide urique et d'urate avec ou sans phosphate de calcium ou d'oxalate de calcium: 3,2% de phosphate de calcium: 1,0% de cystine et 0,2% (un cas) constitué de protéine.Sur 119 calculs, constitués d'oxalate-phosphate, les rapports de l'oxalate de calcium et du phosphate de calcium sont mesurés á l'aide des spectres infra-rouges et les rapports de 53 régions corticales de ces calculs ont été déterminés et comparés è ceux des régions nucléaires centrales. Il apparait ainsi que le noyau des calculs d'oxalate phosphate contient de plus grandes quantités de phosphate de calcium.

     

Japanese guidelines for the management of intussusception in children, 2011

Background: The Japanese Society of Emergency Pediatrics has formulated evidence‐based guidelines for the management of intussusception in children in order to diagnose intussusceptions promptly, to initiate appropriate treatment as early as possible, and to protect intussuscepted children from death. Methods: Literature was collected systematically via the Internet using the key words “intussusception” and “children.” The evidence level of each paper was rated in accordance with the levels of evidence of the Oxford Center for Evidence‐based Medicine. The guidelines consisted of 50 clinical questions and the answers. Grades of recommendation were added to the procedures recommended on the basis of the strength of evidence levels. Results: Three criteria of “diagnostic criteria,”“severity assessment criteria,” and “criteria for patient transfer” were proposed aiming at an early diagnosis, selection of appropriate treatment, and patient transfer for referral to a tertiary hospital in severe cases. Barium is no longer recommended for enema reduction (recommendation D) because the patient becomes severely ill once perforation occurs. Use of other contrast media, such as water‐soluble iodinated contrast, normal saline, or air, is recommended under either fluoroscopic or sonographic guidance. Delayed repeat enema improves reduction success rate, and is recommended if the initial enema partially reduced the intussusception and if the patient condition is stable. Conclusions: The guidelines offer standards of management, but it is not necessarily the purpose of the guidelines to regulate clinical practices. One should judge each individual clinical situation in accordance with experiences, available devices, and the patient's condition.     

The presence of anti-phosphatidylserine/prothrombin antibodies as risk factor for both arterial and venous thrombosis in patients with systemic lupus erythematosus

In an effort to clarify the clinical significance of anti-phospholipid antibodies (aPL) detected by enzyme-linked immunosorbent assay (ELISA), we examined the prevalence of anti-cardiolipin antibodies (aCL), anti-beta2-glycoprotein I antibodies (anti-beta2-GPI), antiprothrombin antibodies (anti-PT), and anti-phosphatidylserine/prothrombin antibodies (anti-PS/PT) in 175 patients with systemic lupus erythematosus (SLE) comprising 67 patients with thrombotic complications. The present study showed that positive results of anti-beta2-GPI-ELISA and anti-PS/PT-ELISA could serve as markers of thrombotic complications in patients with SLE, whereas aCL and anti-PT are less reliable as markers of these complications. Furthermore, results of the anti-PS/PT-ELISA correlate best with the occurrence of both arterial and venous thrombosis in patients with SLE.