Programming parameters of subthalamic deep brain stimulators in Parkinson's disease from a controlled trial.

BACKGROUND: Programming algorithms have never been tested for outcome. The EARLYSTIM study showed superior outcomes of deep brain stimulation of the subthalamic nucleus (STN-DBS) over best medical treatment in early Parkinson's disease (PD). Patients were programmed according to common guidelines but customized for each patient. METHODS: Stimulation parameters were systematically documented at 1, 5, 12, and 24 month in the cohort of 114 patients who had bilateral STN-DBS at 24 month. We investigated the influence of atypical programming, changes of stimulated electrode contacts and stimulation energy delivered. Outcomes were the Unified Parkinson's Disease Rating Scale (UPDRS) motor and ADL-subscores, health-related quality of life (PDQ-39) summary index and mobility- and ADL-subscores. RESULTS: At 1/5/12/24 months follow up, mean amplitude (1.8/2.5/2.6/2.8 V), impedance (1107/1286/1229/1189 Ω) and TEED (33.7/69.0/84.4/93.0 V2*µs*Hz/Ω) mainly increased in the first 5 months, while mean pulse width (60.0/62.5/65.1/65.8 µs), frequency (130/137.7/139.1/142.7 Hz) remained relatively stable. Typical programming (single monopolar electrode contact) was used in 80.7% of electrodes. Double monopolar (11/114) and bipolar (2/114) stimulation was only rarely required. There was no significant difference in clinical outcomes between the patient groups requiring contact changes (n = 32/28.1%) nor between typical (n = 83/72.8%) versus non-typical programming. Energy used for STN-DBS was higher for the dominant side of PD. CONCLUSION: In the first 5 months an increase in amplitude is required to compensate for various factors. Monopolar stimulation is sufficient in 80% of patients at 24 months. Homogeneous stimulation strategies can account for the favorable outcomes reported in the Earlystim study.

Multicenter phase II trial to investigate safety and efficacy of gemcitabine combined with cetuximab as adjuvant therapy in pancreatic cancer (ATIP).

BACKGROUND: To investigate whether addition of cetuximab to standard adjuvant chemotherapy with gemcitabine improves outcome in pancreatic cancer, specifically whether the rate of disease-free survival (DFS) at 18 months (primary end point) exceeds the previously reported 35% of gemcitabine alone. PATIENTS AND METHODS: Prospective, open-label, multicenter, nonrandomized phase II study in 76 patients with R0- or R1-resected ductal adenocarcinoma of the pancreas included between October 2006 and November 2008. Gemcitabine and cetuximab were administered for 24 weeks. Secondary end points included overall survival (OS) and toxic effect. RESULTS: Seventy-three patients received cetuximab. Median DFS was 10.0 [95% confidence interval (CI) 8.9-13.6] months and the DFS rate at month 18 of 27.1% (16.7%-37.6%) was inferior to 35%. Median OS was 22.4 (18.2-27.9) months. Subgroup analyses revealed a nonsignificant increase in DFS for patients with versus without skin toxic effect ≥ grade 2 (median 14.7 versus 8.3 months, P = 0.073) and wild-type versus mutated K-Ras (median 11.5 versus 9.3 months, P = 0.57). Grade 3/4 toxic effects included neutropenia (11.0%), thrombopenia (7%), skin toxic effect (7%) and allergic reactions (7%). CONCLUSION: Addition of cetuximab to adjuvant gemcitabine does not seem to improve DFS or OS of unstratified pancreatic cancer patients. Trends for improved DFS in patients with wild-type K-Ras and skin toxic effect remain to be confirmed.

Neurostimulation for Parkinson's disease with early motor complications.

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS: Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).

[Assessing adverse reactions in clinical trials]. / Erfassung von Nebenwirkungen in der klinischen Forschung.

The intake of each drug represents an intervention into the complex human organism. In addition to the desired therapeutic effect, adverse reactions (AR) can occur. Package inserts should inform patients about the safety profile of drugs, but how reliable is this information and how are side effects determined? To explore this question, we reviewed data related to the ascertainment of adverse reactions in clinical research from 1977 to 2011. This article sums up the results of our literature research as well as own experiences in clinical research. It reveals very different methods of assessing side effects, discusses the obvious problems with inconsistent data collection and presents possible solutions. To create valid and comparable side effect profiles of drugs and thus ensure the safe use of medicine, a common European standard for the structured assessment of Adverse Reactions (AR) in clinical research, that does not exist yet, is required.

Randomised phase II study comparing topotecan/carboplatin administration for 5 versus 3 days in the treatment of extensive-stage small-cell lung cancer.

BACKGROUND: Topotecan is an active drug in small-cell lung cancer (SCLC). In our previous study, a combination of topotecan with cisplatin was associated with a median overall survival of 7.6 or 8.7 months, depending on the duration of treatment. We have replaced cisplatin by carboplatin in this trial, with the objective of creating a more convenient schedule for our patients. Furthermore, we have also compared the standard 5-day schedule with an experimental 3-day schedule. PATIENTS AND METHODS: A total of 100 patients with metastatic disease were included. Patients were randomly assigned to receive either topotecan 0.75 mg/m2, days 1-5, and carboplatin AUC 5, day 5 (arm A) or topotecan 1.25 mg/m2, days 1-3, and carboplatin AUC 5, day 3 (arm B). Six cycles were given at a 3-week interval. RESULTS: A total of 91 patients were assessable for response. The response during therapy was 86.9% in arm A and 80.0% in arm B. Median survival in arm A was 11.8 months and in arm B 11.6 months (P=0.37). CONCLUSIONS: The combination of topotecan and carboplatin is active in extensive-disease SCLC. Toxicity and median survival were comparable in both arms. Three days of treatment seems to be similar to the 5-day regimen.

Non-enrolment of ovarian cancer patients in clinical trials: reasons and background.

BACKGROUND: Some retrospective analyses have suggested that participation in clinical trials is associated with better outcome. However, it is not clear to what extent selection bias contributes to this observation. PATIENTS AND METHODS: We evaluated the reasons for non-enrolment of ovarian cancer patients in clinical trials. All patients with ovarian cancer not enrolled in clinical studies and treated in 2001 in the participating centres were documented retrospectively and compared with patients enrolled in clinical trials at the same institutions during the same time period. RESULTS: Two hundred and seventy-four patients with advanced ovarian cancer (FIGO stage IIB-IV) were included, of whom 139 (51%) and 135 (49%) patients were enrolled in this study and in prospective clinical trials, respectively. Ninety-four of 274 patients (34%) did not meet the inclusion criteria for clinical trials. Of 180 eligible patients, 28 (16%) refused participation and a further 17 patients (9%) were not recruited although they met the inclusion criteria. The non-study patients were older (66.7 versus 57.2 years; P <0.0001), underwent less radical surgery (hysterectomy, oophorectomy and omentectomy performed: 61.2% versus 80.7%; P = 0.001; rate of lymphadenectomy 30.9% versus 45.2%; P = 0.015) and more frequently had bulky residual disease (residual disease >2 cm: 36.2% versus 20%; P = 0.016). However, 62% of the non-study patients were treated with the same chemotherapy as in the standard arm of the respective clinical studies. CONCLUSIONS: Study patients differ substantially from non-study patients, thus hampering generalisation of study results. Our results suggest that at least some inclusion criteria for clinical trials should be modified to increase study participation without compromising safety.

Combination therapy with octreotide and alpha-interferon: effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors.

OBJECTIVE: We investigated the antiproliferative efficacy of the addition of alpha-interferon to the somatostatin analogue octreotide in patients with metastasized gastroenteropancreatic tumors unresponsive to octreotide monotherapy. METHODS: In an open prospective trial, 21 patients with metastasized neuroendocrine gastroenteropancreatic tumors (nine patients with carcinoid syndrome, eight with nonfunctioning tumors, four with gastrinoma) were treated with 5 x 10(6) IU alpha-interferon tiw in addition to 200 microg of octreotide tid. All patients, including 16 patients with preceding monotherapy with 200 microg of octreotide tid, had tumor progression documented by computed tomography before entering the study. Growth response (computed tomography documented) and biochemical response were assessed at 3-month intervals. RESULTS: Inhibition of tumor growth was observed in 14 patients (67%), 11 of whom had preceding octreotide monotherapy; complete regression was observed in one patient lasting for 49 months and stable disease (stand-still) in 13 patients lasting for 3 to 52 months (median, 12 months). Seven patients failing this combination therapy exhibited a significantly shorter overall survival (median, 23 months; range, 5 to 42 months) than the 14 patients responding to this regimen (median, 68 months; range, 12 to 112 months; p = 0.007). Two patients are still alive. Biochemical response was achieved in 69% of patients with functioning tumors: in three of four patients with gastrinoma and in six of nine patients with carcinoid syndrome. CONCLUSIONS: These data suggest that the addition of alpha-interferon to octreotide has antiproliferative efficacy in a subgroup of patients with advanced metastatic disease unresponsive to octreotide monotherapy. Prolonged survival was seen in the responder group.

Time-dependent protection by Na+/H+ exchange inhibition in a regionally ischemic, reperfused porcine heart preparation with low residual blood flow.

Inhibition of Na+/H+ exchange has been shown to protect the ischemic reperfused myocardium. This study investigated the time-dependent beneficial effect of the Na+/H+ exchange inhibitor HOE642 (4-isopropyl-3-methylsulphonylbenzoyl-guanedine methanesulphonite, cariporide). The left anterior descending coronary artery was ligated in 21 pigs (seven control animals) for 60 min and then reperfused for 24 h. An extracorporeal bypass system was used to achieve a constant residual blood flow of 3 ml/min within the ischemic myocardium. Cariporide (1 mg/kg) was injected intravenously in seven pigs after 15 min of ischemia (group A), and in another seven animals after 45 min of ischemia (group B). Histochemical (tetrazolium stain) and histologic infarct sizes were determined at the end of the experiments. Regional systolic shortening was determined by sonomicrometry. Mean calculated residual blood flows (ml/min/g of ischemic myocardium) amounted to 0.106 (group A), 0.093 (group B), and 0.117 (control group). Histochemical (32.9 +/- 21%) and histologic infarct sizes (36.7 +/- 17.7%) were significantly reduced in group A compared to both the control group (histochemical infarct size, 62.5 +/- 16.1%, P < 0.01; histologic infarct size. 67.8 +/- 16.3%, P = 0.013) and group B (histochemical infarct size 64.8 +/- 12.2%, P < 0.01; histologic infarct size 67.1 +/- 15.6%, P < 0.01). Infarct sizes of group B did not differ from control values. Recovery of regional systolic shortening after 24 h of reperfusion was insignificantly improved in group A compared to both other groups. In conclusion, inhibition of Na+/H+ exchange during early ischemia reduced cell death in an ischemic reperfused preparation with low residual blood flow.

In vivo study on the effectiveness of a lacquer containing CaF2/NaF in treating dentine hypersensitivity.

The purpose of this double-blind study was to evaluate the effectiveness of a commercially available fluoride lacquer (Bifluorid 12) containing CaF2 (6%) and NaF (6%) in reducing dentine hypersensitivity. A fluoride lacquer containing only NaF (6%) served as a control. Twenty-five adult patients complaining about at least two hypersensitive teeth participated in this study. In each patient and at each appointment, one tooth was treated with Bifluorid 12, while the other was treated with the control substance. Sensitivity levels were determined before and after the application of each lacquer at baseline as well as at 1, 2 and 3 weeks after the start of study. The final evaluation of hypersensitivity was performed at 4 weeks, and follow-ups were undertaken at 6 and 12 months. A reproducible air blast stimulus and a visual analogue scale were used for evaluation. Results demonstrated a distinct reduction of hypersensitivity after 1, 2 and 3 weeks in the Bifluorid 12 group. Initially, no obvious effects could be observed in the control group. However, a clear alleviation could be observed after 2 and 3 weeks with the control. After 4 weeks, the overall sensitivity scores were comparably low, without any significant differences between the two fluoride lacquers. In both groups, the effects of treatment were seen over the 12-month observation period. Bifluorid 12 was considered at least comparable to the control. It is concluded from this study that Bifluorid 12 is effective in the initial reduction of dentine hypersensitivity. The combination of CaF2/NaF can be recommended for clinical use.

Postmortem evaluation of four randomly selected automated biopsy devices for transthoracic lung biopsy.

PURPOSE: To evaluate four automated devices to achieve transthoracic lung biopsy. METHODS: Transthoracic lung biopsy specimens were obtained randomly from 21 human cadavers with unsuspicious lungs using Biopty (18- and 20-gauge), BIP (18 and 20-gauge), ASAP (18 gauge), and Autovac (18- and 20-gauge) devices. A total of 63 biopsies were carried out with each device and each needle diameter. The same devices and needles were then used randomly for biopsy of peripheral lung metastases. Specimens obtained during both parts of the study were analyzed for the area of tissue on the histologic section, adequacy of tissue for diagnosis, tissue preservation, and crush artifact. The examining pathologist was kept unaware of which procedure was used to obtain the specimens and the cadavers' clinical history. RESULTS: The Biopty 18-gauge device performed statistically better than any other of the evaluated systems for biopsy of normal lung parenchyma (p < 0.05). For biopsy of lung metastases, the differences between the devices and needle diameters were less, although the Biopty 18-gauge device performed better than the Autovac 18-gauge, BIP 18-gauge, and all 20-gauge devices for the area of tissue on the histologic section (p < 0.05). The results of the full-cut Autovac biopsy system were remarkable because of the large number of biopsies during which no tissue was obtained. CONCLUSION: Automated biopsy devices can obtain high quality lung specimens sufficient for definite histopathologic diagnosis. However, additional clinical studies on the use of automated biopsy devices for lung biopsy are mandatory.

Comparative study on the effects of intracoronary nicorandil and nitroglycerin in ischaemic, reperfused porcine hearts.

The direct cardioprotective properties of nitroglycerin and nicorandil were compared in regionally ischaemic (45 min), reperfused (24 h) porcine hearts. Intracoronary treatments, which were started 15 min prior to occlusion of the distal left anterior descending coronary artery (LAD), were continuously administered for 105 min. The following equi-hypotensive drug dosages were used in nine pigs each; nitroglycerin 6 micrograms.kg-1 x min before ischaemia and during 45 min of reperfusion, 0.6 microgram.kg-1 x min during ischaemia; nicorandil 5 micrograms.kg-1 x min before ischaemia and during 45 min of reperfusion, and 0.5 microgram.kg-1 x min during ischaemia. Nine control animals were treated with isotonic sodium hydrochloride solution (1 ml.min-1). Despite comparable effects on blood pressure, intracoronary nicorandil, in contrast to intracoronary nitroglycerin, did not increase heart rate. Although neither drug affected coronary blood flow significantly, nicorandil substantially reduced regional myocardial oxygen consumption before coronary artery occlusion (-37 +/- 22%, P = 0.003 vs control group, P = 0.01 vs nitroglycerin treatment). Infarct sizes (tetrazolium method) after 45 min of ischaemia and 24 h of reperfusion were significantly decreased by nicorandil (control group 76.9 +/- 19%, nicorandil group 49.3 +/- 24%, P = 0.012) whereas nitroglycerin exhibited a borderline effect (62.5 +/- 15%, P = 0.054). Both treatments resulted in improved regional systolic shortening of the reperfused segment at the end of the experiments but this was not significant. At these drug dosages the direct cardioprotective action of nicorandil is slightly superior to nitroglycerin. This may be ascribed to its K-channel opening property associated with reduced regional myocardial oxygen consumption before the onset of ischaemia.

Renal artery stenosis: grading with image-directed Doppler US evaluation of renal resistive index.

PURPOSE: To determine the role of intrarenal Doppler ultrasound (US) in detection of moderate to severe (> 50%) renal artery stenosis (RAS). MATERIALS AND METHODS: In 72 patients, 142 kidneys were examined with conventional angiography and color duplex US. Renal size, mean intrarenal-arterial resistive index (RI), and difference of mean RIs between both kidneys (delta RI) were determined and compared with severity of RAS as determined with quantitative angiography. RESULTS: In 32 patients, angiography showed mild RAS < or = 50% in 13, moderate RAS in 10, and severe RAS in nine. Both renal size and mean RI values were decreased significantly (P < .001) only for severe RAS compared with values in 40 control subjects. For delta RI, no significant difference was noted between controls and patients with mild RAS; highly significant differences, however, were noted for both moderate and severe RAS (P < .001). Sensitivity and specificity of a cutoff delta RI of > 5% were 82% and 92% for RAS > 50% and 100% and 94% for moderate RAS and RAS > 60%. CONCLUSION: Color Doppler US and analysis of intrarenal Doppler spectra are recommended as a useful method for noninvasive diagnosis and grading of RAS. In bilateral RAS > 50%, however, calculation of delta RI is potentially biased by undergrading of stenosis.

Postischemic cell death in reperfused porcine hearts is not attenuated by the spin trap agent PBN during early reperfusion.

Ischemic, reperfused porcine hearts were used to investigate whether the spin trap agent PBN (N-tert-butyl-alpha-phenylnitrone) attenuates postischemic cell death by scavenging of free radicals. The left anterior descending coronary artery (LAD) was ligated distally in 16 pigs for 45 min and then reperfused for 3 h. PBN (coronary concentration approximately 1 mM) was infused into the LAD of eight pigs during the first 45 min of reperfusion. Electron spin resonance spectroscopy (ESR) was performed to identify free radical adducts in the reperfused coronary venous blood. Regional systolic shortening (SS%) was determined by sonomicrometry. Infarct size was evaluated as the percentage of infarcted (tetrazolium stain) to ischemic (dye technique) myocardium. The transmural ultrastructural degree of myocardial injury as well as myocardial ATP levels were assessed at the end of the experiment. Intracoronary treatment with PBN during early reperfusion did not attenuate myocardial damage. Infarct sizes (control group 59 +/- 19%, treated group 55 +/- 14%), transmural ultrastructural alterations, myocardial ATP concentrations (control group 1.8 +/- 0.3 mumol/mg frozen weight, treated group 1.7 +/- 0.4 mumol/mg) and regional systolic shortening at the end of the experiments (control group -1 +/- 5%, treated group -2 +/- 6% did not differ significantly. Furthermore, under various experimental conditions of spin trapping, free radical adducts could not be identified in coronary venous blood during early reperfusion. The results suggest that the spin trap agent PBN (1 mM) does not affect postischemic cell death in porcine hearts.