A Belgian registry of interleukin-2 administration for treatment of metastatic renal cell cancer and confrontation with literature data.

In an effort to map the use of interleukin-2 (IL-2) treatment in patients with clear cell renal cell cancer (RCC) in Belgian hospitals, 44 cases were registered from 9 hospitals between February 2003 and June 2006. It was demonstrated that the majority of these patients were treated with subcutaneous (SC) IL-2. Other methods such as the inhalation of the drug in case of intrathoracic disease or high dose intravenous (IV) administration were much less frequent (3 and 0 cases in this registry, respectively). The results of antitumour activity (around 16% partial response-absence of complete responses) and toxicity of this drug correlate with observations from the literature with the SC administration. In view of the poor results and tolerance with the currently used cytokines (IL-2 or interferon-alfa), much hope is directed towards the development of the novel targeted drugs like sunitinib or sorafenib used alone or in combination with cytokines in this disease.

Phase III study of pentosanpolysulfate (PPS) in treatment of gastrointestinal tract sequelae of radiotherapy.

OBJECTIVES: To evaluate the effectiveness of pentosanpolysulfate (PPS) in the treatment of gastrointestinal tract sequelae of radiotherapy. METHODS: Eligible patients were those with grade 1 to 3 radiation related proctitis, diarrhea and/or melena. At least 4 weeks had to elapse since the completion of the radiotherapy course. Patients with bleeding diathesis or ulcers, and patients receiving anticoagulants or chemotherapy were excluded. Stratification criteria included the type of sequelae (proctitis, diarrhea, melena), the severity grade and the onset (<3 months post-RT, >3 months post-RT). Patients were randomized to one of the following arms: 100 mg PPS 3 times per day (300 mg/day), 200 mg PPS 3 times per day (600 mg/day), or placebo 3 times per day. If there was no improvement in symptoms after 2 months, the protocol treatment was discontinued. If the symptoms improved or resolved, the protocol treatment was continued for additional 4 months. Patients under treatment were evaluated monthly, than every 2 to 3 months for the next 18 months. A symptom assessment questionnaire was used to measure quality of life endpoints. RESULTS: From June 1999 to March 2001 180 patients were accessioned from 34 institutions. A total of 168 were analyzable. Neither the best observed response within 3 months for the entire population, nor the response rate within sequelae category or the quality of life measures differed significantly between the 3 arms of the study. CONCLUSION: Administration of PPS has not been associated with an improvement in the clinical course of radiation related morbidity of the gastrointestinal tract.

The use of a mini bypass system (Cobe Synergy) without venous and cardiotomy reservoir in a mitral valve repair: a case report.

The use of mini cardiopulmonary bypass circuits is an emerging technology. The venous and cardiotomy reservoir have been excluded from the circuit. This results in a reduction of the blood contact surface area and of the priming volume. Entrainment of venous air, however, remains a drawback in the widespread acceptance of using these mini circuits. The technique described resolves this problem by automatic removal of venous air, and explains how this mini cardiopulmonary bypass circuit was utilized on a 64-year-old female presented for a mitral valve repair. In the absence of a cardiotomy reservoir, an autotransfusion cell separator was used to process shed blood and, after CPB, the residual pump blood. This mini bypass circuit, with the safety feature to remove automatically venous air, provided an additional degree of protection. In our experience, mini bypass circuits allow us safely to perform cardiopulmonary bypass during valve procedures.

DIAGNOdent: an optical method for caries detection.

The onset of caries is characterized by demineralization of dental hard tissues. Optimal fluoridation with respective oral hygiene habits and diet may stop the progression of a lesion and even allow for its remineralization. The aim of modern dentistry must be a preventive approach rather than invasive repair of the disease. This is possible only with early detection and respective preventive measures. Some of today's diagnostic tools are not sensitive enough to detect this early onset of destruction. Tools based on fluorescence could have the possibility to overcome this problem. This overview will focus on today's knowledge of one possible tool, the DIAGNOdent.

Phase II radiation therapy oncology group trial of weekly paclitaxel and conventional external beam radiation therapy for supratentorial glioblastoma multiforme.

PURPOSE: Fractionated external beam radiotherapy (EBRT) +/- carmustine (BCNU) is the standard of care for patients with glioblastoma multiforme (GBM), but survival results remain poor. Preclinical studies indicate synergy between RT and paclitaxel (TAX) in astrocytoma cell lines. Phase I studies in GBM have demonstrated a maximum tolerated dose for TAX of 225 mg/m(2)/3 h/week x 6, during EBRT, with no exacerbation of typical RT-induced toxicities. The Radiation Therapy Oncology Group (RTOG) therefore mounted a Phase II study to determine the feasibility and efficacy of conventional EBRT and concurrent weekly TAX at its MTD. PATIENTS AND METHODS: Sixty-two patients with histologic diagnosis of GBM were enrolled from 8/16/96 through 3/21/97 in a multi-institutional Phase II trial of EBRT and TAX 225 mg/m(2)/3 h (1-3 h before EBRT), administered the first treatment day of each RT week. Total EBRT dose was 60 Gy (200 cGy/fraction), 5 days per week. A smaller treatment field, to include gross disease plus a margin only, was used after 46 Gy. RESULTS: Sixty-one patients (98%) were evaluable. Median age was 55 years (range, 28-78). Seventy-four percent were > or = 50 years. Recursive partitioning analysis (RPA) Classes III, IV, V, VI included 10 (17%), 21 (34%), 25 (41%), and 5 (8%) patients, respectively. Gross total resection was performed in only 16%. There was no Grade 3 or 4 neutropenia or thrombocytopenia. Hypersensitivity reactions precluding further use of TAX occurred in 4 patients. There were 2 instances of late neurotoxicity (4% Grade 3 or 4). Ninety-one percent of patients received treatment per protocol. Seventy-seven percent completed prescribed treatment (6 weeks). Of 35 patients with measurable disease, CR/PR was observed in 23%, MR in 17%, and SD in 43%. Seventeen percent demonstrated progression at first follow-up. Median potential follow-up time is 20 months. Median survival is 9.7 months, with median survivals for RPA classes III, IV, V, and VI of 16.3, 10.2, 9.5, 2.5 months, respectively. Ten patients remain alive. CONCLUSION: Concurrent full-dose EBRT and weekly high-dose TAX is feasible in the majority of GBM patients. Acute toxicity is acceptable; myelosuppression and peripheral sensory neuropathy are surprisingly modest, despite considerably higher overall dose intensity, compared to that achievable in other disease sites. Median survival by RPA class without prolonged adjuvant therapy is comparable to RTOG controls treated with standard EBRT and BCNU (1 year of BCNU).

Comparison of three commercially available hollow fiber oxygenators: gas transfer performance and biocompatibility.

The new generation of oxygenators have improved blood flow pathways that enable reduction in priming volume and, thus, hemodilution during cardiopulmonary bypass (CPB). We evaluated three oxygenators and two sizes of venous reservoirs in relation to priming volume, gas transfer, and blood activation. To compare priming volume, gas transfer, and biocompatibility of three hollow fiber oxygenators and two different size venous reservoirs, 60 patients were randomly allocated in groups to undergo cardiopulmonary bypass. In each group, an oxygenator with a different surface area and priming volume was used: 1.8 m2 and 220 ml (group 1, n = 23), 2.2 m2 and 290 ml (group 2, n = 20), and 2.5 m2 and 270 ml (group 3, n = 17). In groups 1 and 3, a large soft shell (1900 ml) venous reservoir was used, whereas in group 2, a smaller soft shell (600 ml) venous reservoir was used. Gas transfer was assessed by calculating the oxygen transfer rate for each group and per square meter for each oxygenator group. Partial arterial oxygen pressure (paO2) and partial arterial carbon dioxide pressure (paCO2) between the groups were assessed with forward stepwise regression analysis. Biocompatibility was evaluated through measurement of platelet numbers, complement activation products (C3b/c), coagulation (thrombin anti-thrombin III complex), and fibrinolysis (plasmin anti-plasmin complex). No differences were found in oxygen transfer rate per group. However, when correcting the oxygen transfer rate for surface area, group 1 demonstrated a higher oxygen transfer rate compared with group 2 (p < 0.05) at an FiO2 of 40 and 60% and compared with group 3 at an FiO2 of 60 and 70%. The regression analysis showed that the average arterial PO2 was the highest in group 3, i.e., 79.2 mm Hg higher than in group 1 (p < 0.001) and 73.5 mm Hg higher than in group 2 (p < 0.001). Group 3 also had the lowest average arterial pCO2, 0.57 mm Hg lower than in group 1 (p = 0.004) and 0.81 mm Hg lower than in group 2 (p < 0.001). During CPB, platelet numbers decreased significantly in all groups (p < 0.001), without differences between the groups. C3b/c levels increased in all groups during CPB. At cessation of CPB the C3b/c level in group 2 (398 nmol/L(-1)) was significantly higher compared to group 1(251 nmol/L(-1); p < 0.05) and group 3 (303 nmol/L(-1); p < 0.05). Thrombin anti-thrombin III complexes and plasmin anti-plasmin complex complexes increased during CPB to significantly high levels at cessation of CPB, but there were no differences between the groups. The oxygenator with the smallest surface area and lowest priming volume (group 1) had the highest oxygen transfer rate per square meter and showed the least blood damage, as depicted by complement activation. The oxygenator with the largest blood contact surface area and improved geometric configuration (group 3) showed the lowest oxygen transfer rate per square meter. However, this oxygenator elevated oxygen partial pressure the most and reduced carbon dioxide partial pressure the most. In group 2, where a smaller venous reservoir was used, the highest blood activation was observed.

The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC)--results of an international collaborative study.

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is an autosomal dominant condition accounting for 2-5% of all colorectal carcinomas as well as a small subset of endometrial, upper urinary tract and other gastrointestinal cancers. An assay to detect the underlying defect in HNPCC, inactivation of a DNA mismatch repair enzyme, would be useful in identifying HNPCC probands. Monoclonal antibodies against hMLH1 and hMSH2, two DNA mismatch repair proteins which account for most HNPCC cancers, are commercially available. This study sought to investigate the potential utility of these antibodies in determining the expression status of these proteins in paraffin-embedded formalin-fixed tissue and to identify key technical protocol components associated with successful staining. A set of 20 colorectal carcinoma cases of known hMLH1 and hMSH2 mutation and expression status underwent immunoperoxidase staining at multiple institutions, each of which used their own technical protocol. Staining for hMSH2 was successful in most laboratories while staining for hMLH1 proved problematic in multiple labs. However, a significant minority of laboratories demonstrated excellent results including high discriminatory power with both monoclonal antibodies. These laboratories appropriately identified hMLH1 or hMSH2 inactivation with high sensitivity and specificity. The key protocol point associated with successful staining was an antigen retrieval step involving heat treatment and either EDTA or citrate buffer. This study demonstrates the potential utility of immunohistochemistry in detecting HNPCC probands and identifies key technical components for successful staining.

[Spondylolysis in the developmental stage: diagnostic contribution of MRI]. / Die Spondylolyse im Stadium der Entstehung: Diagnostischer Beitrag der MRT.

PURPOSE: To assess the value of MR imaging in demonstrating ongoing spondylolysis in adolescents. METHODS: MRI was performed in 9 juvenile patients (3 female, 6 male aged 8-16 years; mean 12.5 y) with pain during hyperextension. In 6 patients a CT scan and in 5 a plain film was available. RESULTS: In all patients bone marrow edema was found in the pars interarticularis and the pedicle, which was bilateral in 4 patients. In 7/9 cases the L5 vertebra was affected, in 2/9 cases spondylolysis was found in L4. In 3 cases the edema reached the middle third of the vertebral body and a tumor was suspected. In all CT scans a bilateral incomplete or complete cleft in the pars inter-articularis was found. In 4/6 CT-scans a sclerosis was seen in the area of the bone marrow edema. Only in 1/5 plain films was there a suspicion for a spondylolysis, four examinations were completely normal. CONCLUSIONS: To eliminate underlying causal conditions of spondylolysis and to install specific therapy, early diagnosis is mandatory. MR imaging should be the first and only imaging modality in young patients with low back pain during and after exercise and pain with hyperextension. Bone scans and CT scans should be avoided due to irradiation, plain films usually do not reveal pathological findings in developing sponylolysis.

In vitro invasiveness of human epithelioid-sarcoma cell lines: association with cell motility and inverse correlation with the expression of tissue inhibitor of metalloproteinases.

Epithelioid sarcoma (ES) is a very aggressive soft-tissue tumor in vivo, but no experimental data on its invasive and metastatic behavior have been reported. In the present study, 3 different clonal sub-populations (GRU-1A, GRU-1B and GRU-1C), derived from the same human ES cell line, GRU-1, were investigated for in vitro invasiveness in relation to migration, adhesion and the expression of different invasion- and metastasis-related genes. Tumor spheroids of GRU-1A were markedly more invasive in the chick-heart invasion assay (CHIA) than spheroids of GRU-1B and GRU-1C. These results were paralleled by a significantly higher cell motility of GRU-1A than GRU-1B and GRU-1C (p < 0.05) on distinct substrates, suggesting that the observed differences in invasion result at least in part from differences in motility. When invasion was assayed with suspended tumor cells in the Matrigel assay, differences between the 3 cell lines were much more pronounced than in the CHIA, where cell-cell contacts are established. These results indicate that interclonal differences in ES invasion result mainly from differences in motility, but also partly depend on differences in cell-cell adhesion. On the molecular level, low invasive potential was associated with over-expression of distinct tissue inhibitor of metalloproteinases (TIMPs) relative to matrix metalloproteinase-2 and -9. However, no association was found between invasion and the expression of CD44 splicing variants or nm23 isoforms. Our results suggest that differences in invasion between GRU-1A, GRU-1B and GRU-1C are caused mainly by interclonal differences in migration, and might result from differences in the expression of distinct TIMPs.

Intranet-based multi-purpose medical records in orthopaedics.

Quality assurance in orthopaedics--as in any medical speciality--relies on precise medical records. Data quality is crucial for statistical evaluation; missing values cannot be avoided but must be minimized. The quality assurance system must be accessible from many locations within the clinic; given the complex and heterogeneous computing infrastructure this is a technological challenge. Intranet technology--the application of internet-tools in local networks--can help to solve the technical problems. A generic Intranet-based quality assurance system in orthopaedics was designed, implemented and evaluated. The basic concept is an intranet data entry form which is generated semi-automatically from the data definition. This form is adapted according to the individual needs of the doctors (intelligent data entry). By flexible data transformation the same data set is used for clinical reports as well as scientific evaluations. The first use was for ultrasound examinations of neonatal hips. A report form consisting of 56 items was designed. Within the first 9-month period 1303 cases have been documented.

Improving performance with clinical decision support.

BACKGROUND: CADU/CIS (Clinical and Administrative Decision-support Utility and Clinical Information System) is a clinical decision-support workstation that allows large volumes of clinical information systems data to be analyzed in a timely and user-friendly fashion. CARE PROCESS MEASUREMENT: For any given disease, subgroups of patients are identified, and automated, customized "clinical pathways" are generated. For each subgroup, the best practice norms for use of test and therapies are identified. Practice style variations are then compared to outcomes to focus inquiry on decisions that significantly affect outcomes. CASE STUDY: INTESTINAL OBSTRUCTION: Graduate Health Systems, a multisite integrated provider in the Philadelphia area, has used CADU/CIS to improve quality problems, reduce treatment-intensity variations, and improve clinical participation in care process evaluation and decision making. A task force selected intestinal obstruction without hernia as its first study because of the related high-volume and high-morbidity complications. Use of a ten-step method for clinical performance improvement showed that the intravenous administration of unnecessary fluids to 104 patients with intestinal obstruction induced congestive heart failure (CHF) in 5 patients. Task force members and other practicing physicians are now developing guidelines and other interventions aimed at fluid use. Indeed, the task force used CADU/CIS to identify an additional 250 patients in one year whose conditions were complicated by CHF. CONCLUSION: A clinical decision support tool can be instrumental in detecting problems with important clinical and economic implications, identifying their important underlying causes, tracking the associated tests and therapies, and monitoring interventions.

Reduction in prime volume attenuates the hyperdynamic response after cardiopulmonary bypass.

BACKGROUND: A hyperdynamic response to cardiopulmonary bypass is characteristically observed in the post-operative course. To determine the effect of prime volume on the hemodynamic response, a database study was performed on patients who underwent elective coronary artery bypass grafting with an extracorporeal circuit with either a large prime volume (2,350-mL prime, n = 20) or a small prime volume (1,400-mL prime, n = 20). METHODS: Measurements were carried out at fixed time points before and after cardiopulmonary bypass (until 18 hours postoperatively) and include hematocrit, colloid oncotic pressure, fluid balance, and hemodynamic profile (mean of three measurements). RESULTS: The lower colloid oncotic pressure in the large prime group (16.2 +/- 0.6 mm Hg versus 19.1 +/- 1.1 mm Hg, p = 0.0002) was associated with a highly positive fluid balance (5.5 +/- 0.9 L versus 2.8 +/- 0.7 L, p = 0.0001). With the on-bypass hematocrit aimed at 22% to 23%, autologous blood was predonated by 16 patients in the small prime group but by none in the large prime group. Reinfusion of autologous blood resulted in a reduction in blood bank requirements (p = 0.03). Mean arterial pressure was 83 +/- 4 mm Hg for small prime versus 76 +/- 4 mm Hg for large prime (p = 0.01). Cardiac index was 2.9 +/- 0.2 L.min-1.m-2 for small prime versus 3.8 +/- 0.3 L.min-1.m-2 for large prime (p = 0.0001). Pulmonary vascular resistance index was 281 +/- 40 dyne.s.cm5.m-2 for small prime versus 188 +/- 22 dyne.s.cm5.m-2 for large prime (p = 0.0009). Oxygen delivery was 42 +/- 5 mL.min-1.m-2 for small prime versus 51 +/- 3 mL.min-1.m-2 for large prime (p = 0.004). Vasoactive medication was not different among groups. CONCLUSIONS: Reduction in prime volume attenuates the hyperdynamic response after cardiopulmonary bypass. Furthermore, an important reduction in blood bank products can be obtained with small prime volumes.

Reduced complement activation and improved postoperative performance after cardiopulmonary bypass with heparin-coated circuits.

A randomized controlled trial that involved 30 patients undergoing elective coronary artery bypass grafting was done to determine the effect of heparin-coated circuits and full heparinization on complement activation, neutrophil-mediated inflammatory response, and postoperative clinical recovery. Peak concentrations of terminal complement complex were 38% lower (p = 0.004) in 15 patients treated with heparin-coated circuits (median 775 micrograms/L, interquartile range 600 to 996) compared with those in 15 patients treated with uncoated circuits (median 1249 micrograms/L, interquartile range 988 to 1443). Although no significant intergroup differences in concentrations of polymorphonuclear neutrophil elastase were found, a positive correlation (rs = 0.74, p < 0.0007) was calculated between peak concentrations of terminal complement complex and polymorphonuclear neutrophil elastase. Differences in patient recovery were analyzed with use of a score composed of fluid balance, postoperative intubation time, and the difference between rectal temperature and skin temperature. The score was significantly lower in patients treated with heparin-coated circuits (p = 0.03), whereas its components showed no intergroup significance. We conclude that the use of heparin-coated circuits with full systemic heparinization results in improved biocompatibility, as assessed by complement activation, and leads to an improved postoperative recovery of the patient.

Oncogene overexpression in non-small-cell lung cancer tissue: prevalence and clinicopathological significance.

In contrast to small-cell lung cancer, few data are available on the role of oncogene overexpression in non-small-cell lung cancers (NSCLC). To determine the prevalence and extent of the transcriptional activation of cancer genes in NSCLC we investigated the level of mRNA of the three important cellular oncogenes--erbB2, Ki-ras, and c-myc--in 39 surgically or endoscopically obtained tumor samples and 24 samples of normal bronchopulmonary tissue taken from the same patients. Tissue RNA was prepared and the specific mRNA analyzed by the highly sensitive nuclease S1 protection assay. Oncogene mRNA in the tumors was quantified by comparison with the homogeneously weak signals in normal lung tissue preparations with densitometry. The presence of two- to four-fold excess RNA was defined as moderate and a greater than fourfold RNA amount as strong gene overexpression. In contrast to normal tissue the oncogene mRNA amount varied considerably among tumors, showing increases up to 64-fold in erbB2, 13-fold in Ki-ras, and 57-fold in c-myc. Moderate and strong (in brackets) mRNA overexpression occurred with 33% (33%) in erbB2, 36% (18%) in Ki-ras, and 18% (23%) in c-myc. Simultaneous overexpression of two genes was observed with 41% and increased mRNA of all genes tested with 20% of the NSCLC samples. Augmented oncogene mRNA was observed most frequently in large-cell carcinoma. The c-myc overexpression was significantly more prevalent in large-cell cancer than in adenocarcinoma. Tumor differentiation was negatively correlated with c-myc mRNA amounts.(ABSTRACT TRUNCATED AT 250 WORDS)

Brief preoperative exposure to saline protects rats against behavioral impairments in salt appetite following central gustatory damage.

Adult rats who receive large electrolytic lesions at the level of the thalamic taste relay display impairments in taste related behavior, specifically the appetite for salt that results from changes in sodium balance. However, if the rats are given preoperative experience of ingesting a salty taste they are protected against these impairments in salt appetite that result from the lesion. In the present study we found that a brief (30 s) preoperative exposure to saline is sufficient to protect adult rats against expected deficits in salt appetite that normally result from central gustatory damage at the level of the thalamic taste relay. It is becoming increasingly clear that preoperative events can lessen the severity of the effects of brain damage. The results are discussed in the context of the appetite for salt, and preoperative immunization from behavioral deficits that result from brain damage.

Preoperative latent place learning preserves salt appetite following damage to the central gustatory system.

Rats given the experience of tasting saline before receiving lesions in the region of the thalamic taste relay are protected from the usual lesion-induced deficits in salt appetite. In this study, the location of the saline during postoperative testing was varied from the location during preoperative training for some rats, and it was kept the same for others. A clear protective effect was evident when the preoperative and postoperative location was the same but not when it was different. This protective effect may be due to place learning, because it is known that rats can remember tasting saline in a particular place and then return there when in a state of sodium need.