Gemcitabine and carboplatin treatment in patients with relapsing ovarian cancer.

Despite progress in primary treatment of patients with advanced ovarian cancer, the majority develop recurrence of the disease. A platinum salt treatment, either as monotherapy or in combination with another cytostatic agent, is indicated for patients who have relapsed 6 or more months after primary treatment and thus have platinum-sensitive relapse. Because repeated use of paclitaxel treatment may lead to substantial neurotoxicity, the combination of gemcitabine with carboplatin represents a suitable treatment option, which is widely used in common clinical practice in the Czech Republic and Slovakia. This non-interventional, prospective study observed the effectiveness and tolerability of second-line treatment with gemcitabine and carboplatin in patients with platinum-sensitive relapse of ovarian cancer in routine clinical practice. The primary endpoint was to evaluate the survival and secondary endpoints were to evaluate time to disease progression, objective tumor response rate, and treatment toxicity. Patients were enrolled to planned second-line treatment with gemcitabine and carboplatin (gemcitabine 1000 mg/m2 and carboplatin AUC 5 on Day 1, and gemcitabine 1000 mg/m2 on Day 8 of a 21-day cycle) for platinum-sensitive relapse of ovarian cancer as a part of routine clinical practice and followed for 12 months. The events (death, tumor progression), tumor response, and maximal grades of toxicity were recorded according to common clinical practice. Survival time (using Kaplan-Meier analysis) and objective tumor response rate were calculated using data forms, and a subgroup analysis was performed using log rank tests for time-to-event endpoints; p-values were also calculated. Response rates were calculated for the whole population; for the subgroups, the Fisher's exact test was performed and only p-values were calculated. Between January 2004 and June 2005, 53 patients were enrolled in the study. The median age was 57 years and 96% of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 and 1 at baseline. Approximately 91% of patients were originally diagnosed with stage III or IV; 60% of patients had disease free intervals (DFIs) of 12 or more months from previous therapy, and the additional 40% less than 12 months. The 1-year survival rate was 83%. Median survival time was not determined within the 12-month period following the start of the treatment study due to the limited duration of follow-up. Objective tumour response rate was 67.3%. Most common reasons for discontinuation of therapy were "Planned treatment completed" (53%) and "Tumor progression" (11%). Most common toxicities were leukopenia, anaemia, neutropenia, and thrombocytopenia; grades 3 and 4 of these toxicity types did not exceed 30%. Febrile neutropenia was recorded in two patients. Most common non-haematological toxicities were nausea and vomiting, fatigue, and neuropathy; grades 3 and 4 of these were below 6%. Results on time to disease progression are not published due to inconsistent statistical analysis of reported data. Based on this observation from routine clinical practice, which corresponds with previously published results from controlled clinical trials, the gemcitabine and carboplatin combination seems to be a suitable therapeutic option for patients with platinum-sensitive relapse of ovarian cancer.

Dynamic regulation of interregional cortical communication by slow brain oscillations during working memory.

Transiently storing information and mentally manipulating it is known as working memory. These operations are implemented by a distributed, fronto-parietal cognitive control network in the brain. The neural mechanisms controlling interactions within this network are yet to be determined. Here, we show that during a working memory task the brain uses an oscillatory mechanism for regulating access to prefrontal cognitive resources, dynamically controlling interactions between prefrontal cortex and remote neocortical areas. Combining EEG with non-invasive brain stimulation we show that fast rhythmical brain activity at posterior sites are nested into prefrontal slow brain waves. Depending on cognitive demand this high frequency activity is nested into different phases of the slow wave enabling dynamic coupling or de-coupling of the fronto-parietal control network adjusted to cognitive effort. This mechanism constitutes a basic principle of coordinating higher cognitive functions in the human brain.

Bacteremia and fungemia in cancer patients with venous catheters.

In 116 cancer patients with bacteremia and fungemia and neutropenia (71%) analysis for the cause was made with regard to the presence of venous catheter, previous therapy or prophylaxis, underlying disease and immunosuppression and etiology. The incidence of bacteremia in patients with catheter was 12x higher (8.25% vs. 0.76%) in comparison to those without catheter and the mortality in respective groups was 26.3% and 15%. Among 206 isolates, 128 (63%) were grampositive aerobes, 58 (27.5%) gramnegative aerobes and 20 (9.5%) fungi. The mortality was the highest in patients with catheter and fungemia (66.6%) and relatively higher in patients with catheter and gramnegative bacteremia.

Breakthrough bacteraemic and fungaemic episodes during antimicrobial prophylaxis and therapy in cancer patients: analysis of risk factors, etiology, therapy and outcome in 123 episodes.

One hundred twenty three breakthrough bacteraemias (BB) during 5 years in a National Cancer Institute, among 9986 admissions and 979 bacteraemic episodes were analysed. 123 BB were caused by 323 microbes, only 116 were resistant (31.5%) to currently administered antimicrobials. Sixty seven of 123 bacteraemic episodes were catheter associated confirmed by isolation of the same organisms from the blood and catheter tip. 77/123 BE were polymicrobial. The most frequently isolated strains were coagulase negative staphylococci (30.5%), Corynebacteria (10%), Ps. aeruginosa (10%), Str. faecalis (9%) and Viridans streptococci (8.5%). Gram-positive aerobes accounted for two-thirds of all organisms isolated during breakthrough bacteraemic and fungaemic episodes. Mixed polymicrobial breakthrough bacteraemic and fungaemic episodes were more frequently associated with vascular catheter insertion and neutropenia, and had a less favourable outcome in comparison to monomicrobial infections. The relapse was associated more frequently with catheter related bacteraemic and fungaemic episodes, but the overall mortality rate was similar independently from catheter insertion. Breakthrough bacteraemic and fungaemic episodes were associated more frequently with acute leukaemia. Polymicrobial breakthrough bacteraemic and fungaemic episodes were associated more frequently in neutropenic episodes and in venous catheters. Regarding the outcome, an extraction of the catheter with no dependence on variable and modification of antimicrobial therapy were essential for the improvement in the prognosis. (Tab. 5, Ref. 20.).

[Noninvasive evaluation of hemodynamics in changes in the atrioventricular interval in patients with dual-chamber pacemakers]. / Neinvazivní hodnocení hemodynamiky pri zmene sínokomorového intervalu u nemocných s dvoudutinovými stimulátory.

The authors evaluated in 19 patients with Dual Chamber pacemakers, using pulsed Doppler echocardiography, changes of the cardiac output after stimulation type DDD with an A-V interval of 100, 150, 175 and 200 ms. They evaluated also haemodynamic changes when changing the stimulation programme type DDD to ventricular stimulation type VVI. The group of patients was characterized by a left ventricular ejection fraction of 50.3 +/- 9.1%, a dimension of the left atrium of 37.1 +/- 5.6 mm and a end diastolic left ventricular dimension of 52.8 +/- 3.9 mm. The highest values of the cardiac output were recorded in 11 patients with an A-V interval of 175 ms, in 7 patients at 150 ms and in one patient at 200 ms. The difference of the cardiac output between the haemodynamically optimal and pessimal A-V interval assessed for individual patients during stimulation type DDD was 15.5 +/- 9.5%. The difference of the cardiac output during a change of stimulation type DDD with a haemodynamically optimal A-V interval to ventricular stimulation type VVI was 22.8 +/- 8.3%. Doppler echocardiography is a satisfactory non-invasive method for the evaluation of haemodynamic changes when assessing optimal parameters in patients with multiprogrammable dual chamber pacemakers.

[Interatrial and atrioventricular conduction in dual chamber stimulation]. / Interatriální a atrioventrikulární vedení u dvoudutinové stimulace.

SAMPLE AND METHODOLOGY: 111 patients (54 men) with atrioventricular stimulation of an average age 56.5 +/- 14.3 were examined. Permanent cardiostimulation was indicated in 56 patients for sick sinus syndrome and in 55 patients for complete AV blockade. Average LV EF was 52.1 +/- 5.7% and LA endsystolic dimension was 39.8 +/- 4.0 mm. All patients were done esophageal electrocardiography under synchronous atrioventricular stimulation regimen. Values of interatrial conduction were compared in relation to placement of stimulation electrode in atrium. RESULTS: Interatrial conduction in the whole sample was 79.8 +/- 19.5 (40-150) ms, for placement of an electrode in heart auricle, in lateral or in anteroseptal wall of the right atrium it was 79.9 +/- 17.9 ms, 108.3 +/- 16.3 ms, 61.5 +/- 16.2 ms. Difference between programmed AV interval and AV interval set up via esophageal electrocardiography was 40.9 +/- 19.7 (5-95) ms. Value of interatrial conduction in the monitored sample depended on placement of the electrode in atrium and the size of the left atrium (r = 0.24, p < 0.009). We did not prove relation of the interatrial conduction value to LV EF or indication diagnosis. CONCLUSION: Interatrial conduction affects value of the real AV interval in atrioventricular stimulation, depends on placement of stimulation electrode in atrium and on the size of the left atrium. Interatrial conduction can be assessed via esophageal electrocardiography.

[Testing the effectiveness of drug therapy in supraventricular dysrhythmias using diagnostic esophageal cardiac stimulation]. / Testování úcinnosti medikamentózní lécby supraventrikulárních dysrytmií pomocí diagnostické jícnové kardiostimulace.

The authors examined 33 patients aged 59.9 years with a new atrial fibrillation and 18 patients aged 45.6 years with attacks of supraventricular tachycardia. After medicamentous change to a sinus rhythm (in fibrillation after digoxin and verapamil i.v. and in supraventricular tachycardia after verapamil i.v.) the patients were changed to oral antiarrhythmic drugs. The method of diagnostic oesophageal stimulation was used after saturation with the oral form to test the effectiveness of long-term treatment. In the author's opinion the basic drug in atrial fibrillation is digoxin, possibly combined with verapamil or quinidine. In supraventricular tachycardia the basic drug is verapamil, in particular in case of a double AV node pathway. In the majority of patients combined treatment is indicated, selected individually by means of diagnostic oesophageal stimulation. The authors consider the described method due to its innocuous and repeatable character as the method of choice for optimization of antiarrhythmic treatment of supraventricular dysrhythmias.

[Long-term effect of drug therapy in supraventricular dysrhythmia evaluated by diagnostic esophageal cardiac pacing]. / Dlouhodobý efekt medikamentózní lécby supraventrikulárních dysrytmií stanovený pomocí diagnostické jícnové kardiostimulace.

The authors investigated the long-term therapeutic effect in 33 patients after a medicamentous reversal of recent atrial fibrillation and 18 patients after reversal of an attack of supraventricular tachycardia (SVT). None of the patients had signs of cardiac failure. A change to sinus rhythm was achieved in the group with atrial fibrillation by digoxin with verapamil, in the group with SVT by verapamil. Treatment was then adjusted, based on testing by means of diagnostic oesophageal pacing. The basic drug for long-term use in atrial fibrillation was digoxin either as monotherapy or in combination; the majority of patients with SVT had verapamil treatment. At the end of the period 24.5 +/- 8.4 (12-36) months after the reversal in the group with atrial fibrillation 8 (25.8%) had permanent atrial fibrillation or different therapy on account of atrial fibrillation; short-term attacks of palpitation were recorded during the investigation period in 16 (51.6%), and the remaining 7 patients (22.6%) had no complaints. In the group with SVT none of the patients was hospitalized on account of persisting dysrhythmia and it was not necessary to alter treatment. Testing treatment of supraventricular dysrhythmias by means of diagnostic oesophageal pacing is of prognostic importance and the authors consider it the method of choice.

[Non-invasive programmed transthoracic ventricular stimulation]. / Neinvazívní programovaná transtorakální stimulace komor.

In 10 healthy volunteers programmed transthoracic stimulation of the ventricles was performed using two commercially available non-invasive pacemakers. The connection of the oesophageal stimulator SP-5 with the transthoracic ventricular stimulator NP-4D made it possible to obtain a two-lead ECG tracing without artefacts. The quality of the obtained tracings (surface tracing and oesophageal tracing) made it possible to assess accurately the ventriculo-atrial conduction. The examinations performed indicate the practical use of combined oesophageal and transthoracic stimulation during non-invasive diagnosis.

A multicenter phase II study of the cryptophycin analog LY355703 in patients with platinum-resistant ovarian cancer.

LY355703 is a synthetic product structurally related to the cryptophycin family isolated from the blue-green algae, which exerts a potent destabilization of microtubules during mitosis. This study was performed to determine the activity of LY355703 in patients with platinum-resistant advanced ovarian cancer and to characterize its toxicity profile. Twenty-six patients were enrolled in this study. Resistant disease was defined as a platinum-free interval of <6 months from primary treatment or rechallenge. LY355703 (1.5 mg/m(2)) was administered intravenously on days 1 and 8, every 3 weeks, infused over 2 h. From 24 patients evaluable for response, three partial responses (12.5%) and seven disease stabilizations were registered (29.2%), for an overall clinical benefit of 41.7%. Fourteen patients (58.3%) experienced a progression of the disease during treatment. Among the 25 patients evaluable for toxicity, two episodes of grade 3 anemia (8%); one, grade 3 thrombocytopenia (4%); one, grade 4 elevation of creatinine (4%); and one, grade 3 hyperbilirubinemia (4%) were reported. LY355703 has a modest activity in patients with platinum-resistant advanced ovarian cancer. Nevertheless, the considerable rate of disease stabilization in the absence of serious adverse events in this poor-prognosis study population suggests that this novel cryptophycin may deserve further investigation in this setting.

A phase II study of gemcitabine plus carboplatin in platinum-sensitive, recurrent ovarian carcinoma.

OBJECTIVES: Gemcitabine and carboplatin each have demonstrated effectiveness without increased neurotoxicity in pretreated patients with ovarian cancer. We evaluated the efficacy and safety of gemcitabine plus carboplatin in patients with recurrent ovarian cancer in a multicenter phase II study. METHODS: Women with histologically proven measurable or evaluable epithelial ovarian cancer (any FIGO) who relapsed > or =6 months after discontinuation of first-line, platinum-containing therapy received gemcitabine 1000 mg/m(2) on days 1 and 8 and carboplatin AUC 4 on day 1 (after gemcitabine) every 21 days for up to six cycles. RESULTS: Of the 40 enrolled/evaluable patients, 6 (15%) had complete response and 19 (47.5%) had partial response (PR), including one patient with PR in nonmeasurable disease (PRNM), for an overall response rate of 62.5% (95% CI, 45.8-77.3%). The median duration of response was 7.8 months (95% CI, 6.7-10.0), the median time to progressive disease was 9.6 months (95% CI, 8.5-11.0), and the median time to treatment failure was 9.3 months (95% CI, 8.2-10.4). The main grade 3/4 toxicities were neutropenia (78% of patients), leukopenia (30%), thrombocytopenia (18%), and anemia (15%); no grade 4 nonhematologic toxicities occurred, and grade 3 nonhematologic toxicities were mild. CONCLUSIONS: The combination of gemcitabine and carboplatin is active and feasible in platinum-sensitive patients with recurrent ovarian cancer. This regimen is undergoing further evaluation in a large phase III trial.

Fluconazol plus ofloxacin in prophylaxis of infections in patients with acute leukemia: a comparative study.

In a retrospective study the incidence of infections, number of afebrile days, duration of antimicrobial chemotherapy, and cost of antibacterials and antimycotics were compared in two groups of patients. One was a group of 57 patients who received no prophylaxis during induction remission therapy of acute leukemia treated in 1989-1990, the second was a group of 22 patients treated in 1991 where prophylaxis with fluconazol and ofloxacin was administered. For ethical reasons pertaining since 1991, when prophylaxis became mandatory, the study was not randomized. A decrease in the number of febrile days, the cost of antimicrobials and the duration of treatment with antibiotics and antimycotics was observed in the group receiving fluconazol and ofloxacin.

Nosocomial bacterial and fungal meningitis in cancer patients.

Five cases of nosocomial meningitis are described that occurred within 5 years in a national cancer center in neutropenic cancer patients after cytotoxic chemotherapy: one caused by the yeast Aureobasidium mansoni and four caused by bacteria (two by Enterococcus faecalis and one by Salmonella enteritis and Arcanobacterium haemolyticus. Despite the severe symptoms, all cases were cured with appropriate antimicrobial therapy.