Backgrounds A multicenter phase II trial was initiated in order to evaluate the weekly, high-dose... more Backgrounds A multicenter phase II trial was initiated in order to evaluate the weekly, high-dose 24-hour infusion of 5-fluorouracil (5-FU) plus folinic acid (FA) in patients with unresectable colorectal cancer hepatic metastases. £aii£nts_and_meih£L(hj A weekly hepatic arterial infusion (HAI) of FA 500 mg/m 2 followed by a 24-hour infusion of 5-FU 2,600 mg/m 2 (later reduced to 2,200 mg/m 2) was given via a surgically implanted intra-arterial port system. One treatment cycle consisted of six weekly applications followed by a two-week rest period. Toxicity was assessed according to the WHO criteria. Chemotherapy was continued until disease progression or complete response occured. Results: A total of 50 patients (40 chemonaive, 10 pretreated) entered this trial. An objective tumor response occurred in 28 patients (56%), while 13 patients (26%) had stable disease. The median progression free survival was 12 months, and the median survival 22.3 months. Due to a high rate of gastrointestinal side-effects in the initial phase of the trial, the dosage of 5-FU was reduced to 2,200 mg/m 2 for all subsequent patients. Diarrhea and nausea led to a dose reduction in 40% of applications and 24% of patients, respectively. One patient died of cardiac insufficiency unrelated to chemotherapy before response evaluation. Conchtsiamsj. This HAI approach using high-dose 5-FU was relatively well tolerated when 2,200 mg/m 2 instead of 2,600 mg/m 2 was used. The activity of this regimen is promising and warrants further evaluation and modification. \
The role of arthroscopy in patients with persistent hip pain after total hip arthroplasty
Technology and health care : official journal of the European Society for Engineering and Medicine, 2013
Total hip arthroplasty (THA) is a safe and successful procedure for the treatment of osteoarthrit... more Total hip arthroplasty (THA) is a safe and successful procedure for the treatment of osteoarthritis. One of the most common postoperative problems remains persistent hip pain. The arthroscopic evaluation of persistent hip pain following THA can be a valuable diagnostic tool in a select number of patients when carried out by experts in this technique. Indication for arthroscopy was persistent pain after THA. Inclusion criteria were an absence of radiological loosening and a sterile aspiration 6 weeks before arthroscopy. Hip joint function and pain were evaluated pre- and postoperatively using the visual analogue scale (VAS) and the Hip Outcome Score (HOS), which scored the activities of daily living (ADL), and a sports subscale. 5 patients (3 female, 2 male) with an average age of 60.2 ± 4.27 years (range 51-72 years) were included in the study. Arthroscopy with biopsy, adhesiolysis and psoas tendon release was performed 21.0 ± 21.97 months (range 6-57 months) after primary hip repla...
Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has recently been approved for the sym... more Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has recently been approved for the symptomatic treatment of arthritis. In some clinical studies, doses of 400 and 800 mg/day provided somewhat less efficacy compared with 200 mg/day, which suggests an early ceiling effect. Using the zymosan-induced inflammation model in rats, we show that celecoxib significantly reduces paw swelling at 50 mg/kg but completely loses its anti-inflammatory efficacy at doses ≥100 mg/kg. To evaluate the underlying mechanisms, we used rat renal mesangial cells as a cell culture model. In these cells, celecoxib (50 µM) increased the interleukin Iβ stimulated nuclear translocation and DNA binding of NF-κB and facilitated the degradation of I-κB. Consequently, COX-DQG WXPRU QHFURVLV IDFWRU. 71)-α) expression were increased. The up-regulation of COX-2 and TNF-α also occurred in the spinal cord of rats treated with celecoxib (≥100 mg/kg), indicating that in vitro mechanisms were relevant in vivo. Clinically, the overexpression of COX-2 might be less important because celecoxib inhibits COX-2 enzymatically. However, the up-regulation of TNF-α and possibly other NF-κB regulated proinflammatory genes might worsen the pathophysiological processes underlying chronic arthritis.
Background: Due to the intraoperative catecholamine secretion with hemodynamic changes, a larger ... more Background: Due to the intraoperative catecholamine secretion with hemodynamic changes, a larger tumor size and marked neovascularization, as compared with other adrenal pathologies, endoscopic adrenalectomy for pheochromocytoma represents a particular challenge involving a more difficult and morbid procedure. The aim of this study was to identify the optimal surgical approach for endoscopic adrenalectomy in patients with pheochromocytoma. Methods: Over a period of 10 years (February 1994 to June 2004), 38 consecutive patients underwent endoscopic adrenalectomy for pheochromocytoma. As three patients underwent a bilateral procedure, a total of 41 adrenalectomies were performed. The transperitoneal approach was carried out in 23 patients, whereas 18 patients underwent a retroperitoneal adrenalectomy by a single operative team. Perioperative parameters were prospectively followed. Results: There was no conversion to the open procedure. Intraoperative hypertensive episodes occurred in 21 patients (55.3%) and were controlled by antihypertensive agents. In 11 patients (28.9%), blood pressure values rose to above 200 mmHg (>1 min). A comparison between the retroperitoneal and transperitoneal procedures did not show a significant difference between the maximum intraoperative systolic (p = 0.730) and diastolic (p = 0.663) blood pressure values although intraoperative blood pressure peaks were seen more frequently during retroperitoneal adrenalectomy. The operative time was shorter for the patients who had transperitoneal adrenalectomy than compared to for those who had retroperitoneal adrenalectomy, although the difference was not significant. The intraoperative blood loss, perioperative morbidity, and length of postoperative hospital stay did not differ significantly between the surgical techniques (p > 0.05). Conclusion: After adequate preparation, endoscopic adrenalectomy may be performed in patients with pheochromocytoma via both the retroperitoneal and the transperitoneal approaches. The shorter operating time, less frequent intraoperative blood pressure peaks, and the better overview of the operating field recommend the transperitoneal approach with the patient placed in a lateral position as the preferred operative procedure.
Peripheral tissue injury and in¯ammation may result in a facilitated spinal nociceptive transmiss... more Peripheral tissue injury and in¯ammation may result in a facilitated spinal nociceptive transmission and central sensitization. Particularly, nitric oxide (NO) and prostaglandins (PGs) have been shown to be key mediators involved in the induction and maintenance of this state. By means of spinal cord microdialysis we have determined interstitial glutamate, NO (NO 2 2 /NO 3 2), PGE 2 , glycerol, glucose and lactate concentrations in the dorsal horns of the spinal cord following peripheral nociceptive stimulation to gain further insight into the link between excitatory neurotransmitters and metabolic functions in the spinal cord during nociception. Formalin and zymosan injection into one hind paw evoked a biphasic release of glutamate and NO with the glutamate peaks preceding those of NO. Moreover, zymosan induced a biphasic increase of interstitial glycerol concentrations accompanied by an increase of interstitial lactate indicating metabolic disturbances. In contrast, formalin injection led to an elevation of dialysate glucose concentrations which may be interpreted as an indication of enhanced metabolic activity. The sequential release of glutamate and NO in the dorsal horns of the spinal cord in response to peripheral nociceptive stimulation supports the theory that NO may act as a retrograde transmitter. The metabolic changes observed after formalin and zymosan injection suggest that an intense peripheral nociceptive stimulation may not only activate but also disturb metabolic activity and possibly membrane integrity in the spinal cord.
In light of a recent demonstration that probenecid enhanced the central nervous system (CNS) upta... more In light of a recent demonstration that probenecid enhanced the central nervous system (CNS) uptake of morphine-3glucuronide (M3G), we investigated the consequences of probenecid co-administration for the spinal cord concentrations and antinociceptive effects of morphine-6-glucuronide (M6G) in rats. Spinal cord tissue concentrations of M6G were assessed by in-vivo microdialysis. Ten rats were administered M6G by intravenous infusion for 8 h, five of them additionally received an infusion of probenecid. Antinociceptive effects of M6G were assessed by means of formalin tests during the 8th h of the M6G infusion in another five rats that received M6G together with probenecid. Five additional rats per groups received probenecid only, M6G only and placebo. The inhibition of probenecid-sensitive transporters caused a raise in both plasma (statistically significant) and spinal cord tissue (not statistically significant) concentrations of M6G by a factor of 1.3, without affecting the tissue to plasma concentration ratio of M6G (0.0812^0.034 for M6G alone, 0.0824^0.021 for M6G plus probenecid). Co-administration of probenecid with M6G resulted in a significant reduction of the number of flinches by a factor of 2.5 as compared to M6G alone. The study showed that probenecid sensitive transporters play a role for the CNS concentrations of M6G via an increase of its plasma concentrations, but the effect of probenecid co-administration is small as compared to the reported effects on the CNS concentrations of M3G in rats.
Background: Excellent results after resection of colorectal liver metastases are associated with ... more Background: Excellent results after resection of colorectal liver metastases are associated with a high rate of recurrence. Influenced by positive results of palliative and adjuvant treatment in advanced cancer, various chemotherapy regimens were evaluated to improve long-term results. Methods: The databases Medline and Cancerlit (1982-1998) gave information about 675 patients who were treated either by means of systemic, intra-arterial, intraportal or intraperitoneal administration before or after liver resection. Results: In general, the feasibility of an adjuvant treatment was tested. Proof has been furnished for the practicability of systemic and arterial therapy and for immunotherapy after liver resection whereas, for peritoneal and portal treatment, further studies are necessary. In a few non-randomised trials, it has been possible to discern a trend towards an improvement due to adjuvant postoperative therapy using historical or matched-pair control groups. Until now, only one of five randomised studies has been published. Six months of postoperative adjuvant intra-arterial treatment using 5-fluorouracil (1000 mg/m 2 for 5 days every 28 days) and folinic acid (200 mg/m 2 for 5 days every 28 days) was compared with observation only. Neither in the intention-totreat nor in the as-treated analysis was median survival time (34.5 months versus 40.8 months and 39.7 months versus 44.8 months, respectively) significantly increased. As neoadjuvant treatment was successful in primary non-resectable patients, this approach is now being tested in resectable patients. Conclusion: Despite several theoretical reasons for post-or preoperative treatment in resectable patients, every approach should be tested using of controlled studies.
Morphine-6-glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms an outward tran... more Morphine-6-glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms an outward transporter at the bloodbrain barrier. Inhibition of P-gp may therefore be expected to cause increased CNS uptake of M6G. We directly assessed the spinal concentrations of M6G and its antinociceptive effects in rats following pharmacological inhibition of P-gp. Spinal cord tissue concentrations of M6G were assessed by microdialysis with probes transversally implanted through the dorsal horns of the spinal cord at level L4. Ten rats received M6G intravenously (0.018 mg/kg loading dose plus 0.00115 mg/kg/min for an 8-h infusion), five of them together with PSC833 to inhibit P-gp (32-h infusion, starting 24 h before the addition of M6G). Antinociceptive effects were explored by means of formalin tests. After having obtained evidence for enhanced CNS uptake and antinociception of M6G in the presence of PSC833, additional behavioural experiments were performed in another 32 rats to assess the dose dependency of the antinociceptive effects of M6G either with or without PSC833 in comparison with both PSC833 alone and placebo. Inhibition of P-gp increased the M6G concentrations in the spinal cord approximately threefold whereas the plasma concentrations were increased only by a factor of 1.4, which resulted in a more than doubled spinal cord/plasma concentration ratio (from 0.08 ± 0.03 for M6G alone to 0.17 ± 0.08 for M6G plus PSC833). Antinociceptive effects of M6G were significantly enhanced by inhibition of P-gp. Inhibition of P-gp alters the transport of M6G across the blood-brain barrier, resulting in enhanced spinal cord uptake and enhanced antinociception.
Effects of selective COX-1 and -2 inhibition on formalin-evoked nociceptive behaviour and prostaglandin E2 release in the spinal cord
Journal of Neurochemistry, 2008
Nociception evoked prostaglandin (PG) release in the spinal cord considerably contributes to the ... more Nociception evoked prostaglandin (PG) release in the spinal cord considerably contributes to the induction of hyperalgesia and allodynia. To evaluate the relative contribution of cyclooxygenase-1 (COX-1) and COX-2 in this process we assessed the effects of the selective COX-1 inhibitor SC560 and the selective COX-2 inhibitor celecoxib on formalin-evoked nociceptive behaviour and spinal PGE(2) release. SC560 (10 and 20 mg/kg) significantly reduced the nociceptive response and completely abolished the formalin-evoked PGE(2) raise. In contrast, celecoxib (10 and 20 mg/kg) was ineffective in both regards, i.e. the flinching behaviour was largely unaltered and the formalin-induced PGE(2) raise as assessed using microdialysis was only slightly, not significantly reduced. This suggests that the formalin-evoked rapid PG release was primarily caused by COX-1 and was independent of COX-2. Mean free spinal cord concentrations of celecoxib during the formalin assay were 32.0 +/- 4.5 nM, thus considerably higher than the reported IC50 for COX-2 (3-7 nM). Therefore, the lack of efficacy of celecoxib is most likely not to be a result of poor tissue distribution. COX-2 mRNA and protein expression in the spinal cord were not affected by microdialysis alone but the mRNA rapidly increased following formalin injection and reached a maximum at 2 h. COX-2 protein was unaltered up to 4 h after formalin injection. The time course of COX-2 up-regulation suggests that the formalin-induced nociceptive response precedes COX-2 protein de novo synthesis and may therefore be unresponsive to COX-2 inhibition. Considering the results obtained with the formalin model it may be hypothesized that the efficacy of celecoxib in early injury evoked pain may be less than that of unselective NSAIDs.
Inhibition of Noxious Stimulus-Induced Spinal Prostaglandin E2 Release by Flurbiprofen Enantiomers
Journal of Neurochemistry, 2008
Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E2 release at the site of... more Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E2 release at the site of inflammation and in the spinal cord. The antiinflammatory and antinociceptive effects of cyclooxygenase-inhibiting drugs are thought to depend on the inhibition of PG synthesis. R-Flurbiprofen, however, does not inhibit cyclooxygenase activity in vitro but still produces antinociceptive effects. To find out whether R-flurbiprofen acts via inhibition of spinal PG release, concentrations of PGE2 and flurbiprofen in spinal cord tissue were assessed by microdialysis. The catheter was transversally implanted through the dorsal horns of the spinal cord at level L4. R- and S-flurbiprofen (9 and 27 mg kg(-1), respectively) were administered intravenously 10-15 min before subcutaneous injection of formalin into the dorsal surface of one hindpaw. Flurbiprofen was rapidly distributed into the spinal cord with maximal concentrations after 30-45 min. Baseline PGE2 dialysate concentrations were 100.6 +/- 6.4 pg ml(-1) (mean +/- SEM). After formalin injection they rose about threefold with a maximum of 299.4 +/- 68.4 pg ml(-1) at 7.5 min. After approximately 1 h PGE2 levels returned to baseline. Both flurbiprofen enantiomers completely prevented the formalin-induced increase of spinal PGE2 release and reduced PGE2 concentrations below basal levels. S- and R-flurbiprofen at 9 mg kg(-1) produced a minimum of 15.8 +/- 5.2 and 27.7 +/- 14.9 pg ml(-1), respectively, and 27 mg kg(-1) S- and R-flurbiprofen resulted in 11.7 +/- 1.7 and 9.3 +/- 4.7 pg ml(-1), respectively. PGE2 levels remained at the minimum up to the end of the observation period at 5 h. When 27 mg kg(-1) R-flurbiprofen was injected intravenously without subsequent formalin challenge, baseline immunoreactive PGE2 concentrations were not affected. S-Flurbiprofen (27 mg kg(-1)), however, led to a moderate reduction (approximately 40%). The data suggest that antinociception produced by R-flurbiprofen is mediated at least in part by inhibition of stimulated spinal PGE2 release and support the current view that increased spinal PGE2 release significantly contributes to nociceptive processing.
Purpose This study was designed to evaluate whether the mechanical axis deviation (MAD) of the le... more Purpose This study was designed to evaluate whether the mechanical axis deviation (MAD) of the leg correlates with an increased hip alpha angle as described by Nötzli, which is associated with femoroacetabular impingement (FAI). Methods In a retrospective analysis, standing full-length anteroposterior radiographs were analysed in patients who suffered from symptomatic leg alignment. The study included 85 radiographs of 80 patients with an average age of 43.11 years (range 18-60 years). Five patients underwent a bilateral longleg X-ray examination. All radiographs were transferred as Digital Imaging and Communications in Medicine data files from the Picture Archiving and Communications System into the OrthoPlanner software version 2.3.2. The radiographs were measured by one orthopaedic surgeon and one independent radiologist. Results The mean value of the alpha angle of Nötzli was 61.43°(49.07-74.04°). A total of 57 (67 %) radiographs showed a varus deviation, 25 (29.5 %) had a valgus malalignment and three (3.5 %) a straight leg axis. Of 82 radiographs, 40 (48.8 %) had a moderate axis deviation with a MAD <15 or >−15 mm and a mean alpha angle of 57.81°, and 42 (51.2 %) with extended axis deviation of a MAD>15 or <−15 mm had a mean alpha angle of 62.93°; 40 (95.2 %) of these 42 showed an alpha angle >55°. The alpha angle was significantly increased in extended axis deviation compared to moderate axis deviation (P =0.001). Conclusions This study confirmed that increased alpha angles were found significantly at higher degrees of axis deviation on the full-length radiograph. In cases of a MAD >15 or <−15 mm and symptomatic coxalgia, diagnostic tests must be pursued for FAI.
Background: Preoperative bowel preparation is still routinely used prior to colorectal surgery. T... more Background: Preoperative bowel preparation is still routinely used prior to colorectal surgery. This concept is based on traditional and personal empiricism and usually not evidence based. The objective of the present review was to reassess this dogma against the background of the highest level of evidence published thus far. Methods: The Medline database was searched using the search terms ‘preoperative’, ‘bowel’ and ‘preparation’ limited to ‘randomized controlled trials’ and ‘meta-analyses’. Ten randomised controlled trials and seven meta-analyses comparing orthograde bowel cleansing to no preoperative bowel preparation were considered for rates of anastomotic leakages, surgical infections and other types of complications, reoperations and mortality. Results: All the most recent meta-analyses showed a significant increase of anastomotic dehiscences in patients with preoperative orthograde bowel cleansing. Additionally, a trend towards higher rates of surgical infectious complicati...
Die Stellung der regionalen Langzeitchemotherapie bei Lebermetastasen
Der Chirurg, 1999
Summary. In numerous tumors, metastasis can be limited to the liver. In non-resectable patients... more Summary. In numerous tumors, metastasis can be limited to the liver. In non-resectable patients, regional treatment modalities, especially arterial cytostatic infusion, are favored in contrast to systemic chemotherapy, whereas intraportal or intraperitoneal application is not successful. Improved results with high response rates have been reported after development of intra-arterial (i.a.) long-term regimens with FUdR in patients with colorectal liver metastases
Is the Kinect system suitable for evaluation of the hip joint range of motion and as a screening tool for femoroacetabular impingement (FAI)?
Technology and health care : official journal of the European Society for Engineering and Medicine, 2015
In the clinical evaluation of femoroacetabular impingement (FAI), there is a lack of quantitative... more In the clinical evaluation of femoroacetabular impingement (FAI), there is a lack of quantitative, reliable and informative assessment methods for the overall functional capability of an individual. We compared clinical and radiological measurements of the hip joint with a new methodology based on the concept of 3-dimensional reachable workspace using Microsoft Kinect. We assessed the correlation between the alpha angle of Nötzli on full-length radiographs and the clinical internal rotation. We evaluated the accuracy of joint positions and angles of the hip between the Kinect system and clinical examination including range of motion (ROM). The results of our clinical trial with 24 study participants showed a significant difference between normal internal rotation (> 21°) and reduced internal rotation (⩽ 21°) in comparison to the radiological alpha angle of Nötzli (P=0.026). The acquired reachable Kinect data demonstrated a moderate agreement between the Kinect and clinical examin...
Backgrounds A multicenter phase II trial was initiated in order to evaluate the weekly, high-dose... more Backgrounds A multicenter phase II trial was initiated in order to evaluate the weekly, high-dose 24-hour infusion of 5-fluorouracil (5-FU) plus folinic acid (FA) in patients with unresectable colorectal cancer hepatic metastases. £aii£nts_and_meih£L(hj A weekly hepatic arterial infusion (HAI) of FA 500 mg/m 2 followed by a 24-hour infusion of 5-FU 2,600 mg/m 2 (later reduced to 2,200 mg/m 2) was given via a surgically implanted intra-arterial port system. One treatment cycle consisted of six weekly applications followed by a two-week rest period. Toxicity was assessed according to the WHO criteria. Chemotherapy was continued until disease progression or complete response occured. Results: A total of 50 patients (40 chemonaive, 10 pretreated) entered this trial. An objective tumor response occurred in 28 patients (56%), while 13 patients (26%) had stable disease. The median progression free survival was 12 months, and the median survival 22.3 months. Due to a high rate of gastrointestinal side-effects in the initial phase of the trial, the dosage of 5-FU was reduced to 2,200 mg/m 2 for all subsequent patients. Diarrhea and nausea led to a dose reduction in 40% of applications and 24% of patients, respectively. One patient died of cardiac insufficiency unrelated to chemotherapy before response evaluation. Conchtsiamsj. This HAI approach using high-dose 5-FU was relatively well tolerated when 2,200 mg/m 2 instead of 2,600 mg/m 2 was used. The activity of this regimen is promising and warrants further evaluation and modification. \
The role of arthroscopy in patients with persistent hip pain after total hip arthroplasty
Technology and health care : official journal of the European Society for Engineering and Medicine, 2013
Total hip arthroplasty (THA) is a safe and successful procedure for the treatment of osteoarthrit... more Total hip arthroplasty (THA) is a safe and successful procedure for the treatment of osteoarthritis. One of the most common postoperative problems remains persistent hip pain. The arthroscopic evaluation of persistent hip pain following THA can be a valuable diagnostic tool in a select number of patients when carried out by experts in this technique. Indication for arthroscopy was persistent pain after THA. Inclusion criteria were an absence of radiological loosening and a sterile aspiration 6 weeks before arthroscopy. Hip joint function and pain were evaluated pre- and postoperatively using the visual analogue scale (VAS) and the Hip Outcome Score (HOS), which scored the activities of daily living (ADL), and a sports subscale. 5 patients (3 female, 2 male) with an average age of 60.2 ± 4.27 years (range 51-72 years) were included in the study. Arthroscopy with biopsy, adhesiolysis and psoas tendon release was performed 21.0 ± 21.97 months (range 6-57 months) after primary hip repla...
Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has recently been approved for the sym... more Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has recently been approved for the symptomatic treatment of arthritis. In some clinical studies, doses of 400 and 800 mg/day provided somewhat less efficacy compared with 200 mg/day, which suggests an early ceiling effect. Using the zymosan-induced inflammation model in rats, we show that celecoxib significantly reduces paw swelling at 50 mg/kg but completely loses its anti-inflammatory efficacy at doses ≥100 mg/kg. To evaluate the underlying mechanisms, we used rat renal mesangial cells as a cell culture model. In these cells, celecoxib (50 µM) increased the interleukin Iβ stimulated nuclear translocation and DNA binding of NF-κB and facilitated the degradation of I-κB. Consequently, COX-DQG WXPRU QHFURVLV IDFWRU. 71)-α) expression were increased. The up-regulation of COX-2 and TNF-α also occurred in the spinal cord of rats treated with celecoxib (≥100 mg/kg), indicating that in vitro mechanisms were relevant in vivo. Clinically, the overexpression of COX-2 might be less important because celecoxib inhibits COX-2 enzymatically. However, the up-regulation of TNF-α and possibly other NF-κB regulated proinflammatory genes might worsen the pathophysiological processes underlying chronic arthritis.
Background: Due to the intraoperative catecholamine secretion with hemodynamic changes, a larger ... more Background: Due to the intraoperative catecholamine secretion with hemodynamic changes, a larger tumor size and marked neovascularization, as compared with other adrenal pathologies, endoscopic adrenalectomy for pheochromocytoma represents a particular challenge involving a more difficult and morbid procedure. The aim of this study was to identify the optimal surgical approach for endoscopic adrenalectomy in patients with pheochromocytoma. Methods: Over a period of 10 years (February 1994 to June 2004), 38 consecutive patients underwent endoscopic adrenalectomy for pheochromocytoma. As three patients underwent a bilateral procedure, a total of 41 adrenalectomies were performed. The transperitoneal approach was carried out in 23 patients, whereas 18 patients underwent a retroperitoneal adrenalectomy by a single operative team. Perioperative parameters were prospectively followed. Results: There was no conversion to the open procedure. Intraoperative hypertensive episodes occurred in 21 patients (55.3%) and were controlled by antihypertensive agents. In 11 patients (28.9%), blood pressure values rose to above 200 mmHg (>1 min). A comparison between the retroperitoneal and transperitoneal procedures did not show a significant difference between the maximum intraoperative systolic (p = 0.730) and diastolic (p = 0.663) blood pressure values although intraoperative blood pressure peaks were seen more frequently during retroperitoneal adrenalectomy. The operative time was shorter for the patients who had transperitoneal adrenalectomy than compared to for those who had retroperitoneal adrenalectomy, although the difference was not significant. The intraoperative blood loss, perioperative morbidity, and length of postoperative hospital stay did not differ significantly between the surgical techniques (p > 0.05). Conclusion: After adequate preparation, endoscopic adrenalectomy may be performed in patients with pheochromocytoma via both the retroperitoneal and the transperitoneal approaches. The shorter operating time, less frequent intraoperative blood pressure peaks, and the better overview of the operating field recommend the transperitoneal approach with the patient placed in a lateral position as the preferred operative procedure.
Peripheral tissue injury and in¯ammation may result in a facilitated spinal nociceptive transmiss... more Peripheral tissue injury and in¯ammation may result in a facilitated spinal nociceptive transmission and central sensitization. Particularly, nitric oxide (NO) and prostaglandins (PGs) have been shown to be key mediators involved in the induction and maintenance of this state. By means of spinal cord microdialysis we have determined interstitial glutamate, NO (NO 2 2 /NO 3 2), PGE 2 , glycerol, glucose and lactate concentrations in the dorsal horns of the spinal cord following peripheral nociceptive stimulation to gain further insight into the link between excitatory neurotransmitters and metabolic functions in the spinal cord during nociception. Formalin and zymosan injection into one hind paw evoked a biphasic release of glutamate and NO with the glutamate peaks preceding those of NO. Moreover, zymosan induced a biphasic increase of interstitial glycerol concentrations accompanied by an increase of interstitial lactate indicating metabolic disturbances. In contrast, formalin injection led to an elevation of dialysate glucose concentrations which may be interpreted as an indication of enhanced metabolic activity. The sequential release of glutamate and NO in the dorsal horns of the spinal cord in response to peripheral nociceptive stimulation supports the theory that NO may act as a retrograde transmitter. The metabolic changes observed after formalin and zymosan injection suggest that an intense peripheral nociceptive stimulation may not only activate but also disturb metabolic activity and possibly membrane integrity in the spinal cord.
In light of a recent demonstration that probenecid enhanced the central nervous system (CNS) upta... more In light of a recent demonstration that probenecid enhanced the central nervous system (CNS) uptake of morphine-3glucuronide (M3G), we investigated the consequences of probenecid co-administration for the spinal cord concentrations and antinociceptive effects of morphine-6-glucuronide (M6G) in rats. Spinal cord tissue concentrations of M6G were assessed by in-vivo microdialysis. Ten rats were administered M6G by intravenous infusion for 8 h, five of them additionally received an infusion of probenecid. Antinociceptive effects of M6G were assessed by means of formalin tests during the 8th h of the M6G infusion in another five rats that received M6G together with probenecid. Five additional rats per groups received probenecid only, M6G only and placebo. The inhibition of probenecid-sensitive transporters caused a raise in both plasma (statistically significant) and spinal cord tissue (not statistically significant) concentrations of M6G by a factor of 1.3, without affecting the tissue to plasma concentration ratio of M6G (0.0812^0.034 for M6G alone, 0.0824^0.021 for M6G plus probenecid). Co-administration of probenecid with M6G resulted in a significant reduction of the number of flinches by a factor of 2.5 as compared to M6G alone. The study showed that probenecid sensitive transporters play a role for the CNS concentrations of M6G via an increase of its plasma concentrations, but the effect of probenecid co-administration is small as compared to the reported effects on the CNS concentrations of M3G in rats.
Background: Excellent results after resection of colorectal liver metastases are associated with ... more Background: Excellent results after resection of colorectal liver metastases are associated with a high rate of recurrence. Influenced by positive results of palliative and adjuvant treatment in advanced cancer, various chemotherapy regimens were evaluated to improve long-term results. Methods: The databases Medline and Cancerlit (1982-1998) gave information about 675 patients who were treated either by means of systemic, intra-arterial, intraportal or intraperitoneal administration before or after liver resection. Results: In general, the feasibility of an adjuvant treatment was tested. Proof has been furnished for the practicability of systemic and arterial therapy and for immunotherapy after liver resection whereas, for peritoneal and portal treatment, further studies are necessary. In a few non-randomised trials, it has been possible to discern a trend towards an improvement due to adjuvant postoperative therapy using historical or matched-pair control groups. Until now, only one of five randomised studies has been published. Six months of postoperative adjuvant intra-arterial treatment using 5-fluorouracil (1000 mg/m 2 for 5 days every 28 days) and folinic acid (200 mg/m 2 for 5 days every 28 days) was compared with observation only. Neither in the intention-totreat nor in the as-treated analysis was median survival time (34.5 months versus 40.8 months and 39.7 months versus 44.8 months, respectively) significantly increased. As neoadjuvant treatment was successful in primary non-resectable patients, this approach is now being tested in resectable patients. Conclusion: Despite several theoretical reasons for post-or preoperative treatment in resectable patients, every approach should be tested using of controlled studies.
Morphine-6-glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms an outward tran... more Morphine-6-glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms an outward transporter at the bloodbrain barrier. Inhibition of P-gp may therefore be expected to cause increased CNS uptake of M6G. We directly assessed the spinal concentrations of M6G and its antinociceptive effects in rats following pharmacological inhibition of P-gp. Spinal cord tissue concentrations of M6G were assessed by microdialysis with probes transversally implanted through the dorsal horns of the spinal cord at level L4. Ten rats received M6G intravenously (0.018 mg/kg loading dose plus 0.00115 mg/kg/min for an 8-h infusion), five of them together with PSC833 to inhibit P-gp (32-h infusion, starting 24 h before the addition of M6G). Antinociceptive effects were explored by means of formalin tests. After having obtained evidence for enhanced CNS uptake and antinociception of M6G in the presence of PSC833, additional behavioural experiments were performed in another 32 rats to assess the dose dependency of the antinociceptive effects of M6G either with or without PSC833 in comparison with both PSC833 alone and placebo. Inhibition of P-gp increased the M6G concentrations in the spinal cord approximately threefold whereas the plasma concentrations were increased only by a factor of 1.4, which resulted in a more than doubled spinal cord/plasma concentration ratio (from 0.08 ± 0.03 for M6G alone to 0.17 ± 0.08 for M6G plus PSC833). Antinociceptive effects of M6G were significantly enhanced by inhibition of P-gp. Inhibition of P-gp alters the transport of M6G across the blood-brain barrier, resulting in enhanced spinal cord uptake and enhanced antinociception.
Effects of selective COX-1 and -2 inhibition on formalin-evoked nociceptive behaviour and prostaglandin E2 release in the spinal cord
Journal of Neurochemistry, 2008
Nociception evoked prostaglandin (PG) release in the spinal cord considerably contributes to the ... more Nociception evoked prostaglandin (PG) release in the spinal cord considerably contributes to the induction of hyperalgesia and allodynia. To evaluate the relative contribution of cyclooxygenase-1 (COX-1) and COX-2 in this process we assessed the effects of the selective COX-1 inhibitor SC560 and the selective COX-2 inhibitor celecoxib on formalin-evoked nociceptive behaviour and spinal PGE(2) release. SC560 (10 and 20 mg/kg) significantly reduced the nociceptive response and completely abolished the formalin-evoked PGE(2) raise. In contrast, celecoxib (10 and 20 mg/kg) was ineffective in both regards, i.e. the flinching behaviour was largely unaltered and the formalin-induced PGE(2) raise as assessed using microdialysis was only slightly, not significantly reduced. This suggests that the formalin-evoked rapid PG release was primarily caused by COX-1 and was independent of COX-2. Mean free spinal cord concentrations of celecoxib during the formalin assay were 32.0 +/- 4.5 nM, thus considerably higher than the reported IC50 for COX-2 (3-7 nM). Therefore, the lack of efficacy of celecoxib is most likely not to be a result of poor tissue distribution. COX-2 mRNA and protein expression in the spinal cord were not affected by microdialysis alone but the mRNA rapidly increased following formalin injection and reached a maximum at 2 h. COX-2 protein was unaltered up to 4 h after formalin injection. The time course of COX-2 up-regulation suggests that the formalin-induced nociceptive response precedes COX-2 protein de novo synthesis and may therefore be unresponsive to COX-2 inhibition. Considering the results obtained with the formalin model it may be hypothesized that the efficacy of celecoxib in early injury evoked pain may be less than that of unselective NSAIDs.
Inhibition of Noxious Stimulus-Induced Spinal Prostaglandin E2 Release by Flurbiprofen Enantiomers
Journal of Neurochemistry, 2008
Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E2 release at the site of... more Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E2 release at the site of inflammation and in the spinal cord. The antiinflammatory and antinociceptive effects of cyclooxygenase-inhibiting drugs are thought to depend on the inhibition of PG synthesis. R-Flurbiprofen, however, does not inhibit cyclooxygenase activity in vitro but still produces antinociceptive effects. To find out whether R-flurbiprofen acts via inhibition of spinal PG release, concentrations of PGE2 and flurbiprofen in spinal cord tissue were assessed by microdialysis. The catheter was transversally implanted through the dorsal horns of the spinal cord at level L4. R- and S-flurbiprofen (9 and 27 mg kg(-1), respectively) were administered intravenously 10-15 min before subcutaneous injection of formalin into the dorsal surface of one hindpaw. Flurbiprofen was rapidly distributed into the spinal cord with maximal concentrations after 30-45 min. Baseline PGE2 dialysate concentrations were 100.6 +/- 6.4 pg ml(-1) (mean +/- SEM). After formalin injection they rose about threefold with a maximum of 299.4 +/- 68.4 pg ml(-1) at 7.5 min. After approximately 1 h PGE2 levels returned to baseline. Both flurbiprofen enantiomers completely prevented the formalin-induced increase of spinal PGE2 release and reduced PGE2 concentrations below basal levels. S- and R-flurbiprofen at 9 mg kg(-1) produced a minimum of 15.8 +/- 5.2 and 27.7 +/- 14.9 pg ml(-1), respectively, and 27 mg kg(-1) S- and R-flurbiprofen resulted in 11.7 +/- 1.7 and 9.3 +/- 4.7 pg ml(-1), respectively. PGE2 levels remained at the minimum up to the end of the observation period at 5 h. When 27 mg kg(-1) R-flurbiprofen was injected intravenously without subsequent formalin challenge, baseline immunoreactive PGE2 concentrations were not affected. S-Flurbiprofen (27 mg kg(-1)), however, led to a moderate reduction (approximately 40%). The data suggest that antinociception produced by R-flurbiprofen is mediated at least in part by inhibition of stimulated spinal PGE2 release and support the current view that increased spinal PGE2 release significantly contributes to nociceptive processing.
Purpose This study was designed to evaluate whether the mechanical axis deviation (MAD) of the le... more Purpose This study was designed to evaluate whether the mechanical axis deviation (MAD) of the leg correlates with an increased hip alpha angle as described by Nötzli, which is associated with femoroacetabular impingement (FAI). Methods In a retrospective analysis, standing full-length anteroposterior radiographs were analysed in patients who suffered from symptomatic leg alignment. The study included 85 radiographs of 80 patients with an average age of 43.11 years (range 18-60 years). Five patients underwent a bilateral longleg X-ray examination. All radiographs were transferred as Digital Imaging and Communications in Medicine data files from the Picture Archiving and Communications System into the OrthoPlanner software version 2.3.2. The radiographs were measured by one orthopaedic surgeon and one independent radiologist. Results The mean value of the alpha angle of Nötzli was 61.43°(49.07-74.04°). A total of 57 (67 %) radiographs showed a varus deviation, 25 (29.5 %) had a valgus malalignment and three (3.5 %) a straight leg axis. Of 82 radiographs, 40 (48.8 %) had a moderate axis deviation with a MAD <15 or >−15 mm and a mean alpha angle of 57.81°, and 42 (51.2 %) with extended axis deviation of a MAD>15 or <−15 mm had a mean alpha angle of 62.93°; 40 (95.2 %) of these 42 showed an alpha angle >55°. The alpha angle was significantly increased in extended axis deviation compared to moderate axis deviation (P =0.001). Conclusions This study confirmed that increased alpha angles were found significantly at higher degrees of axis deviation on the full-length radiograph. In cases of a MAD >15 or <−15 mm and symptomatic coxalgia, diagnostic tests must be pursued for FAI.
Background: Preoperative bowel preparation is still routinely used prior to colorectal surgery. T... more Background: Preoperative bowel preparation is still routinely used prior to colorectal surgery. This concept is based on traditional and personal empiricism and usually not evidence based. The objective of the present review was to reassess this dogma against the background of the highest level of evidence published thus far. Methods: The Medline database was searched using the search terms ‘preoperative’, ‘bowel’ and ‘preparation’ limited to ‘randomized controlled trials’ and ‘meta-analyses’. Ten randomised controlled trials and seven meta-analyses comparing orthograde bowel cleansing to no preoperative bowel preparation were considered for rates of anastomotic leakages, surgical infections and other types of complications, reoperations and mortality. Results: All the most recent meta-analyses showed a significant increase of anastomotic dehiscences in patients with preoperative orthograde bowel cleansing. Additionally, a trend towards higher rates of surgical infectious complicati...
Die Stellung der regionalen Langzeitchemotherapie bei Lebermetastasen
Der Chirurg, 1999
Summary. In numerous tumors, metastasis can be limited to the liver. In non-resectable patients... more Summary. In numerous tumors, metastasis can be limited to the liver. In non-resectable patients, regional treatment modalities, especially arterial cytostatic infusion, are favored in contrast to systemic chemotherapy, whereas intraportal or intraperitoneal application is not successful. Improved results with high response rates have been reported after development of intra-arterial (i.a.) long-term regimens with FUdR in patients with colorectal liver metastases
Is the Kinect system suitable for evaluation of the hip joint range of motion and as a screening tool for femoroacetabular impingement (FAI)?
Technology and health care : official journal of the European Society for Engineering and Medicine, 2015
In the clinical evaluation of femoroacetabular impingement (FAI), there is a lack of quantitative... more In the clinical evaluation of femoroacetabular impingement (FAI), there is a lack of quantitative, reliable and informative assessment methods for the overall functional capability of an individual. We compared clinical and radiological measurements of the hip joint with a new methodology based on the concept of 3-dimensional reachable workspace using Microsoft Kinect. We assessed the correlation between the alpha angle of Nötzli on full-length radiographs and the clinical internal rotation. We evaluated the accuracy of joint positions and angles of the hip between the Kinect system and clinical examination including range of motion (ROM). The results of our clinical trial with 24 study participants showed a significant difference between normal internal rotation (> 21°) and reduced internal rotation (⩽ 21°) in comparison to the radiological alpha angle of Nötzli (P=0.026). The acquired reachable Kinect data demonstrated a moderate agreement between the Kinect and clinical examin...
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Papers by Gregor Vetter