Collagen type X is essential for successful mesenchymal stem cell-mediated cartilage formation and subsequent endochondral ossification.

in tissue engineering, endochondral ossification (EO) is often replicated by chondrogenically differentiating mesenchymal stromal cells (MSCs) in vitro and achieving bone formation through in vivo implantation. The resulting marrow-containing bone constructs are promising as a treatment for bone defects. However, limited bone formation capacity has prevented them from reaching their full potential. This is further complicated since it is not fully understood how this bone formation is achieved. Acellular grafts derived from chondrogenically differentiated MSCs can initiate bone formation; however, which component within these decellularised matrices contribute to bone formation has yet to be determined. Collagen type X (COLX), a hypertrophy-associated collagen found within these constructs, is involved in matrix organisation, calcium binding and matrix vesicle compartmentalisation. However, the importance of COLX during tissue-engineered chondrogenesis and subsequent bone formation is unknown. The present study investigated the importance of COLX by shRNA-mediated gene silencing in primary MSCs. A significant knock-down of COLX disrupted the production of extracellular matrix key components and the secretion profile of chondrogenically differentiated MSCs. Following in vivo implantation, disrupted bone formation in knock-down constructs was observed. The importance of COLX was confirmed during both chondrogenic differentiation and subsequent EO in this tissue engineered setting.

Mesenchymal stem cell-mediated endochondral ossification utilising micropellets and brief chondrogenic priming.

With limited autologous and donor bone graft availability, there is an increasing need for alternative graft substitutes. We have previously shown that chondrogenically priming mesenchymal stem cell (MSC) pellets for 28 d in vitro will reproducibly result in endochondral bone formation after in vivo implantation. However, pellet priming time for clinical applications is quite extensive. A micropellet (µpellet)-fibrin construct was developed and coupled, with a shorter priming period, determined by an in vitro time course experiment. In vitro data showed expression of chondrogenic genes and matrix production after 7 d of chondrogenic priming, indicating that briefer priming could possibly be used to induce bone formation in vivo. 7 and 28 d primed pellet, pellet-fibrin and µpellet-fibrin constructs were cultured for in vitro analysis and implanted subcutaneously for 8 weeks into nude mice. µpellet-fibrin constructs, cultured in vitro for 7 or 28 d, produced comparable bone to standard pellets in vivo. MSC-mediated bone formation was achieved following only 7 d of in vitro priming. Bone formation in vivo appeared to be influenced by overall matrix production pre-implantation. Given this short priming time and the injectable nature of the µpellet-fibrin constructs, this approach might be further developed as an injectable bone substitute, leading to a minimally-invasive treatment option, which would allow for tailored filling of bone defects.

Quantitative simulation tools to analyze up- and downstream interactions of soil and water conservation measures: supporting policy making in the Green Water Credits program of Kenya.

Upstream soil and water conservation measures in catchments can have positive impact both upstream in terms of less erosion and higher crop yields, but also downstream by less sediment flow into reservoirs and increased groundwater recharge. Green Water Credits (GWC) schemes are being developed to encourage upstream farmers to invest in soil and water conservation practices which will positively effect upstream and downstream water availability. Quantitative information on water and sediment fluxes is crucial as a basis for such financial schemes. A pilot design project in the large and strategically important Upper-Tana Basin in Kenya has the objective to develop a methodological framework for this purpose. The essence of the methodology is the integration and use of a collection of public domain tools and datasets: the so-called Green water and Blue water Assessment Toolkit (GBAT). This toolkit was applied in order to study different options to implement GWC in agricultural rainfed land for the pilot study. Impact of vegetative contour strips, mulching, and tied ridges were determined for: (i) three upstream key indicators: soil loss, crop transpiration and soil evaporation, and (ii) two downstream indicators: sediment inflow in reservoirs and groundwater recharge. All effects were compared with a baseline scenario of average conditions. Thus, not only actual land management was considered but also potential benefits of changed land use practices. Results of the simulations indicate that especially applying contour strips or tied ridges significantly reduces soil losses and increases groundwater recharge in the catchment. The model was used to build spatial expressions of the proposed management practices in order to assess their effectiveness. The developed procedure allows exploring the effects of soil conservation measures in a catchment to support the implementation of GWC.

Spatiotemporal distribution of thrombospondin-4 and -5 in cartilage during endochondral bone formation and repair.

During skeletal development most bones are first formed as cartilage templates, which are gradually replaced by bone. If later in life those bones break, temporary cartilage structures emerge to bridge the fractured ends, guiding the regenerative process. This bone formation process, known as endochondral ossification (EO), has been widely studied for its potential to reveal factors that might be used to treat patients with large bone defects. The extracellular matrix of cartilage consists of different types of collagens, proteoglycans and a variety of non-collagenous proteins that organise the collagen fibers in complex networks. Thrombospondin-5, also known as cartilage oligomeric matrix protein (TSP-5/COMP) is abundant in cartilage, where it has been described to enhance collagen fibrillogenesis and to interact with a variety of growth factors, matrix proteins and cellular receptors. However, very little is known about the skeletal distribution of its homologue thrombospondin-4 (TSP-4). In our study, we compared the spatiotemporal expression of TSP-5 and TSP-4 during postnatal bone formation and fracture healing. Our results indicate that in both these settings, TSP-5 distributes across all layers of the transient cartilage, while the localisation of TSP-4 is restricted to the population of hypertrophic chondrocytes. Furthermore, in fractured bones we observed TSP-4 sparsely distributed in the periosteum, while TSP-5 was absent. Last, we analysed the chemoattractant effects of the two proteins on endothelial cells and bone marrow stem cells and hypothesised that, of the two thrombospondins, only TSP-4 might promote blood vessel invasion during ossification. We conclude that TSP-4 is a novel factor involved in bone formation. These findings reveal TSP-4 as an attractive candidate to be evaluated for bone tissue engineering purposes.

A new semi-orthotopic bone defect model for cell and biomaterial testing in regenerative medicine.

In recent decades, an increasing number of tissue engineered bone grafts have been developed. However, expensive and laborious screenings in vivo are necessary to assess the safety and efficacy of their formulations. Rodents are the first choice for initial in vivo screens but their size limits the dimensions and number of the bone grafts that can be tested in orthotopic locations. Here, we report the development of a refined murine subcutaneous model for semi-orthotopic bone formation that allows the testing of up to four grafts per mouse one order of magnitude greater in volume than currently possible in mice. Crucially, these defects are also "critical size" and unable to heal within the timeframe of the study without intervention. The model is based on four bovine bone implants, ring-shaped, where the bone healing potential of distinct grafts can be evaluated in vivo. In this study we demonstrate that promotion and prevention of ossification can be assessed in our model. For this, we used a semi-automatic algorithm for longitudinal micro-CT image registration followed by histological analyses. Taken together, our data supports that this model is suitable as a platform for the real-time screening of bone formation, and provides the possibility to study bone resorption, osseointegration and vascularisation.

The (R)-enantiomer of the 6-chromanol derivate SUL-121 improves renal graft perfusion via antagonism of the α1-adrenoceptor.

SUL-compounds are protectants from cold-induced ischemia and mitochondrial dysfunction. We discovered that adding SUL-121 to renal grafts during warm machine reperfusion elicits a rapid improvement in perfusion parameters. Therefore, we investigate the molecular mechanisms of action in porcine intrarenal arteries (PIRA). Porcine kidneys were stored on ice overnight and perfusion parameters were recorded during treatment with SUL-compounds. Agonist-induced vasoconstriction was measured in isolated PIRA after pre-incubation with SUL-compounds. Receptor binding and calcium transients were assessed in α1-adrenoceptor (α1-AR) transgenic CHO cells. Molecular docking simulation was performed using Schrödinger software. Renal pressure during warm reperfusion was reduced by SUL-121 (-11.9 ± 2.50 mmHg) and its (R)-enantiomer SUL-150 (-13.2 ± 2.77 mmHg), but not by the (S)-enantiomer SUL-151 (-1.33 ± 1.26 mmHg). Additionally, SUL-150 improved renal flow (16.21 ± 1.71 mL/min to 21.94 ± 1.38 mL/min). SUL-121 and SUL-150 competitively inhibited PIRA contraction responses to phenylephrine, while other 6-chromanols were without effect. SUL-150 similarly inhibited phenylephrine-induced calcium influx and effectively displaced [7-Methoxy-3H]-prazosin in CHO cells. Docking simulation to the α1-AR revealed shared binding characteristics between prazosin and SUL-150. SUL-150 is a novel α1-AR antagonist with the potential to improve renal graft perfusion after hypothermic storage. In combination with previously reported protective effects, SUL-150 emerges as a novel protectant in organ transplantation.

Prosthodontic rehabilitation of oral function in head-neck cancer patients with dental implants placed simultaneously during ablative tumour surgery: an assessment of treatment outcomes and quality of life.

The aim of this prospective study was to assess treatment outcome and impact on quality of life of prosthodontic rehabilitation with implant-retained prostheses in head-neck cancer patients. Fifty patients were evaluated by standardized questionnaires and clinical assessment. All received the implants during ablative tumour surgery in native bone in the interforaminal area. About two-thirds of the patients (n=31) needed radiotherapy post-surgery. Both in irradiated and non-irradiated bone two implants were lost 18-24 months after installation. Peri-implant tissues had a healthy appearance. No cases of osteoradionecrosis occurred. In 15 patients no functional implant-retained lower dentures could be made for various reasons. The other 35 patients all functioned well, with an improvement in quality of life. Major improvement was observed in the non-irradiated patients. In the irradiated patients, less improvement in many functional items was observed, while items related to the oral sequelae of radiotherapy did not improve. Similar to the quality-of-life assessments, denture satisfaction was improved and tended to be higher in non-irradiated than irradiated patients. Implant-retained lower dentures can substantially improve the quality of life related to oral functioning and denture satisfaction in head-neck cancer patients. This effect is greater in non-irradiated than irradiated cancer patients.

A whole-farm strategy to reduce environmental impacts of nitrogen.

Dutch regulations for ammonia emission require farmers to inject slurry into the soil (shallow) or to apply it in narrow bands at the surface. For one commercial dairy farm in the Netherlands it was hypothesized that its alternative farming strategy, including low-protein feeding and surface spreading, could be an equally effective tool for ammonia emission abatement. The overall objective of the research was to investigate how management at this farm is related to nitrogen (N) losses to the environment, including groundwater and surface water. Gaseous emission of ammonia and greenhouse gasses from the naturally ventilated stables were 8.1 and 3.1 kg yr(-1) AU(-1) on average using the internal tracer (SF(6))-ratio method. Measurements on volatilization of ammonia from slurry application to the field using an integrated horizontal flux method and the micrometeorological mass balance method yielded relatively low values of ammonia emissions per ha (3.5-10.9 kg NH(3)-N ha(-1)). The mean nitrate concentration in the upper ground water was 6.7 mg L(-1) for 2004 and 3.0 mg L(-1) for 2005, and the half-year summer means of N in surface water were 2.3 mg N L(-1) and 3.4 mg N L(-1) for 2004 and 2005, respectively. Using a nutrient budget model for this farm, partly based on these findings, it was found that the calculated ammonia loss per ton milk (range 5.3-7.5 kg N Mg(-1)) is comparable with the estimated ammonia loss of a conventional farm that applies animal slurry using prescribed technologies.

[The influence of the pharmaceutical industry in patient organisations]. / Invloed van de farmaceutische industrie in patiëntenverenigingen.

Most patient organisations have no objection to sponsoring by the pharmaceutical industry. Only 5% of all organisations are against sponsoring. When patient organisations were asked whether or not their activities could continue without sponsoring, 42% answered no, 6% yes, and 52% felt that they might continue, but restricted. In a report of the public health inspector on the subject, transparency is considered to be a remedy for the entanglement between patient organisations and the pharmaceutical industry. However, the authors doubt that this is effective. The government should provide sufficient support for patient organisations so that they can become independent from the industry.

Recall bias did not affect perceived magnitude of change in health-related functional status.

BACKGROUND AND OBJECTIVE: It was hypothesized that within an invasively treated group and within a group that improved in angina pectoris no difference in effect size would occur between prospective and retrospective measures. Furthermore, it was hypothesized that assessment of perceived change at post-test may be invalid because of recall bias and present-state bias. STUDY DESIGN AND SETTING: Effect sizes (as standardized response means) were used as indicators of magnitude of change. Linear structural equation analysis (with LISREL) was used to investigate the relationship between the estimates of recall accuracy and retrospectively assessed change. RESULTS: No significant differences were found between prospective and retrospective measures of change over time in health-related functional status. Recall bias was not associated with retrospective measurement of change within a 12-week interval. An expected present-state effect was found in a structural equation model. CONCLUSION: Prospective and retrospective indices of magnitude of change were similar between groups receiving treatment of known efficacy. Recall bias seems to be an acceptable risk in short-term follow-up studies.

Endocytosis and breakdown of ribonuclease oligomers by sinusoidal rat liver cells in vivo. I. Effect of size.

Aspects of protein structure determining endocytosis of proteins by sinusoidal rat liver cells in vivo have been studied, using cross-linked or aggregated derivatives of bovine pancreatic ribonuclease A (labelled with 125I) as probes. Ribonuclease was cross-linked by reaction with dimethylsuberimidate, a way of modification that does not change the charge of the protein. Monomer, dimer and polymer fractions were isolated by gel filtration and characterized in respect of size and number of amino groups modified. Maintenance of enzyme activity, stability of disulfide bonds, and lack of susceptibility to endoproteases showed that the cross-linking procedure did not result in gross conformational changes of the ribonuclease molecules. Monomer, dimer and polymer fractions were injected into nephrectomized rats and plasma clearance and uptake in liver and spleen were determined. About 30% of the injected polymer fraction was found in liver 15 min after injection; for dimer and monomer fractions values of 6% and 2% of the dose were found. Similar differences were found in spleen. Autoradiography, cell isolation, and subcellular fractionation showed that in liver the radioactive proteins were taken up in lysosomes of sinusoidal cells. Similar results were obtained with fractions of aggregated ribonuclease prepared by freeze-drying the protein from 50% acetic acid. Our results demonstrate that the rate of uptake of the ribonuclease derivatives is positively correlated with the size of the molecules. Similarity of the results obtained with cross-linked and aggregated fractions suggests that the number of ribonuclease 'subunits'/molecule, rather than the procedures used to prepare the polymers, determine the rate of uptake by liver and spleen.

Localization and some properties of lysosomal dipeptidases in rat liver.

1. The rates of hydrolysis of 26 synthetic dipeptides by extracts from highly purified lysosomal fractions from rat liver at pH 5.0 and by whole liver homogenates at pH 7.4 have been determined. Extracts from the lysosomal fractions hydrolysed most peptides at a lower rate per mg protein than the homogenates, and some peptides not at all. 2. Properties of two dipeptidases present in the extracts from the lysosomal fractions, splitting Ile-Glu and Leu-Gly, respectively, were studied in greater detail. The enzyme that hydrolysed Ile-Glu was strongly activated by dithiothreitol, showed optimal activity at pH 4.5 and had a molecular weight of about 120 000. Leu-Gly dipeptidase did apparently not contain an essential thiol group and had a molecular weight of approx. 90 000. It showed maximal activity at pH 6.5. 3. After differential centrifugation of liver homogenates, Ile-Glu and Leu-Gly-splitting activities were determined in the fractions, under the optimal conditions mentioned above. The Ile-Glu-hydrolysing enzyme activity showed about the same distribution as the lysosomal marker enzyme acid phosphatase. Leu-Gly-splitting activity, however, was largely present in the cytosol fraction, with only a small peak in the lysosomal fraction. We obtained evidence that the activities present in the lysosomal fraction and in the cytosol fraction were due to different enzymes, and that one of these enzymes was localized exclusively in lysosomes. 4. It is concluded that some dipeptides originating from intralysosomal proteolysis might be split by lysosomal dipeptidases, whereas others are probably hydrolysed only in the extra-lysosomal compartment of the cell.

Rapid uptake by liver sinusoidal cells of serum albumin modified with retention of its compact conformation.

The clearance from the blood and the conformation of serum albumin modified by nitroguanidination and labeled with 125-I have been studied. Like formaldehyde-denatured albumin, but in contrast to native albumin, the nitroguanidinated derivative is rapidly cleared from the blood and taken up in lysosomes of liver sinusoidal cells. Although 94% of the free amino groups were blocked by nitroguanidination, we could not detect significant conformational changes using gel filtration, determination of reducible disulfide groups, and titration of tyrosine residues. It is concluded that extensive denaturation is no prerequisite for the uptake of albumin derivatives in liver sinusoidal cells. It is suggested that the nitroguanidinated protein, in contrast to native albumin, is bound on membrane receptors of sinusoidal cells. The nitroguanidino groups themselves might be bound on these receptors, but it seems equally possible that the blocking of positive charges of the albumin molecule or minor, local conformational changes of the protein are sufficient for the binding on the receptors.

Effect of size and charge on endocytosis of lysozyme derivatives by sinusoidal rat liver cells in vivo.

Hen egg-white lysozyme has been modified by intermolecular cross-linking with dimethyl suberimidate or by acylation with acetic or succinic anhydride. Retention of the native conformation of the modified enzyme was checked by measuring enzyme activity, resistance of disulfide bridges to reduction by thiols, and susceptibility to proteases. Unmodified lysozyme and its derivatives (labelled with 125I) were intravenously injected into nephrectomized rats, and plasma clearance and uptake by liver cells were determined. Under these conditions, about 6% of the unmodified lysozyme was taken up by liver 15 min after injection. Cross-linking led to a greatly increased uptake (up to 89% of the dose in 15 min), whereas acylation reduced the uptake to 3-4%. Cell isolations showed that the unmodified enzyme and the cross-linked derivatives were taken up by sinusoidal cells. Differential fractionation of liver homogenates indicated tht the unmodified enzyme was taken up in lysosomes. The cross-linked derivatives were concentrated in the nuclear and microsomal fractions as well as in the lysosomal fraction, suggesting adsorption on plasma membranes besides uptake in lysosomes. The experiments described in this paper, together with previous results on ribonuclease and lactate dehydrogenase, indicate that endocytosis of some proteins by sinusoidal liver cells is positively correlated with size and positive charge of the molecules.

Endocytosis and breakdown of ribonuclease oligomers by sinusoidal rat liver cells in vivo. II. Effect of charge.

Experiments presented in this paper suggest that sinusoidal rat liver cells recognize basic groups on proteins and that this recognition results in endocytosis of the proteins. Evidence for involvement of basic groups was obtained in two ways. Firstly, we changed the positively charged amino groups of the cross-linked ribonuclease molecules to neutral or negative by acetylation or succinylation, respectively. The modified proteins did not contain easily reducible disulfide bonds and they were not very sensitive to endoproteases, suggesting that they were not denatured by the acetylation procedures. Acetylation and succinylation reduced uptake of the injected cross-linked ribonuclease derivatives by liver and spleen and abolished their rapid clearance from plasma. In nephrectomized rats about 75% of the polymer, 36% of the acetylated polymer and 32% of the succinylated polymer were endocytosed by liver after 6 h. For the dimer fractions these values were 59%, 23% and 27%, respectively. Autoradiography and subcellular fractionation of liver 30 min post-injection localized the acetylated polymer in the lysosomal/microsomal fraction of sinusoidal liver cells, probably endothelial cells. Secondly, a positive correlation was found between binding of a number of ribonuclease derivatives to the cation exchanger SP-Sephadex G-25 and the rate of endocytosis by sinusoidal liver cells.

Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma.

One hundred ninety-one patients with advanced epithelial ovarian carcinoma were treated with either a combination of doxorubicin and a five-day course of cisplatin alternating with cyclophosphamide and hexamethylmelamine orally for 14 days (CHAP-5) or cyclophosphamide and cisplatin both administered intravenously (IV) on a single day at 3-week intervals (CP). At a median follow-up time of 45 months, treatment with each of these combinations resulted in the same remission rates (80% and 74%, respectively) and exactly the same progression-free survival and overall survival (median, 26 months). Despite adequate hydration, more renal toxicity was encountered in the CP-treated patients than in those who received CHAP-5. Disabling neurotoxicity and severe myelosuppression were encountered more frequently in the patients treated with CHAP-5. Because the toxicity was lower and CP treatment required shorter hospitalization, the single-day regimen was considered preferable for future use. The Karnofsky index was the only independent predictor for response, whereas both this index and the size of residual tumor before chemotherapy were predictive of survival. After correcting for other prognostic factors, it was determined that tumor size associated with improved survival was less than 1 cm. The site of metastases in International Federation of Gynecology and Obstetrics (FIGO) stage IV patients did not influence survival within this category. The results of this study confirm our previous findings that patients with microscopic remnants at second-look have a survival similar to that of patients who are histopathologically free of disease. This makes the significance of so-called pathologically confirmed complete remission questionable. The survival benefit of debulking surgery performed during chemotherapy seems only minimal for patients in whom debulking has already been attempted before treatment. Like others, we have found the CP regimen to have a good therapeutic index.

Cost and benefits of a multidisciplinary intensive diabetes education programme.

OBJECTIVES: To determine the cost and benefits of an intensive diabetes education programme for patients with prolonged self-management problems and to determine the inclusion criteria for optimal outcomes. METHODS: Sixty-one participants of a multidisciplinary intensive diabetes education programme (MIDEP) were measured before they started the intervention (T0), and at 1-year follow-up (T1). Data on glycaemic control (HbA1c), diabetes-related distress (PAID) and costs were obtained. Changes over time were analysed and means at T0 and T1 were compared to a reference group of 230 non-referred consecutive outpatients. The number needed to treat (NNT), that is, the number of patients to be treated to achieve one successful case, was calculated for different baseline values of HbA1c and PAID to determine optimal inclusion criteria. RESULTS: Diabetes-related costs decreased significantly and participants improved significantly in HbA1c and diabetes-related distress following MIDEP. HbA1c and distress reached the levels of the reference group. The T1 costs remained higher than in the reference group, but the reduction in costs outweighed the intervention costs. Including patients with baseline HbA1c>or=8.0% and/or PAID scores>or=40 would improve the NNT to achieve clinically relevant outcomes, while 76% of the patients matched these inclusion criteria. CONCLUSIONS: MIDEP is effective in improving glycaemic control and diabetes-related distress for patients with prolonged self-management difficulties. Besides the immediate reduction in costs found in the present study, improved glycaemic control may reduce future costs of diabetic complications. Stricter inclusion criteria with respect to HbA1c and PAID scores may further improve the programme's efficiency.

Environmental impacts of innovative dairy farming systems aiming at improved internal nutrient cycling: A multi-scale assessment.

Several dairy farms in the Netherlands aim at reducing environmental impacts by improving the internal nutrient cycle (INC) on their farm by optimizing the use of available on-farm resources. This study evaluates the environmental performance of selected INC farms in the Northern Friesian Woodlands in comparison to regular benchmark farms using a Life Cycle Assessment. Regular farms were selected on the basis of comparability in terms of milk production per farm and per hectare, soil type and drainage conditions. In addition, the environmental impacts of INC farming at landscape level were evaluated with the integrated modelling system INITIATOR, using spatially explicit input data on animal numbers, land use, agricultural management, meteorology and soil, assuming that all farms practised the principle of INC farming. Impact categories used at both farm and landscape levels were global warming potential, acidification potential and eutrophication potential. Additional farm level indicators were land occupation and non-renewable energy use, and furthermore all farm level indicators were also expressed per kg fat and protein corrected milk. Results showed that both on-farm and off-farm non-renewable energy use was significantly lower at INC farms as compared with regular farms. Although nearly all other environmental impacts were numerically lower, both on-farm and off-farm, differences were not statistically significant. Nitrogen losses to air and water decreased by on average 5 to 10% when INC farming would be implemented for the whole region. The impact of INC farming on the global warming potential and eutrophication potential was, however, almost negligible (<2%) at regional level. This was due to a negligible impact on the methane emissions and on the surplus and thereby on the soil accumulation and losses of phosphorus to water at INC farms, illustrating the focus of these farms on closing the nitrogen cycle.

Zeniplatin in patients with advanced ovarian cancer, a phase II study with a third generation platinum complex.

25 patients with residual or recurrent ovarian cancer were treated with the new platinum complex zeniplatin (CL 286,558) and 23 patients were evaluable for response. Responses were achieved in 4 patients, 1 complete and 3 partial remissions (16%). 7 patients had stable disease and 12 patients had tumour progression. At a median follow-up of 12 months, the median progression-free survival in responding patients was 11 months and overall survival 81%. The median overall survival of progressive patients amounted to 9 months, indicating the advanced stage of disease in most patients. Renal function was monitored by isotope clearance studies. There was no significant change in effective renal plasma flow (ERPF) or glomerular filtration rate (GFR) in 10 patients who completed six cycles of treatment. 1 patient with a marginal creatinine clearance at baseline suffered from sudden and severe renal failure during the first cycle. Zeniplatin may be active in relapsing, platinum-pretreated patients, and has no direct effects on renal function as measured by isotope clearance. Despite these findings, occasional nephrotoxicity may occur in patients with compromised kidney function, even with prophylactic hydration, and thus limit the application of this new analogue.

Risks and benefits of cisplatin in ovarian cancer. A quality-adjusted survival analysis.

Both the efficacy and toxicity of short intensive cisplatin-based chemotherapy was established in an unselected group of patients with stage III-IV ovarian cancer. The impact of this treatment on quality of life (QOL) was assessed by the TWIST index, expressed as Time Without Symptoms of Treatment and Disease, in relation to the individual length of progression free survival (PFS). Sixty-eight patients were treated with six cycles of a combination of cyclophosphamide, Adriamycin and cisplatin (CAP-5), every 4 weeks. Patients with a clinical response to treatment were evaluated by second look laparotomy (SLL), which could be performed in 52 patients. There were 20 pathological CR, seven microscopic disease, 17 PR and eight SD in these 52 patients. Median follow up at evaluation was 22 months. The median progression free survival (PFS) was 18 months and the median overall survival 22 months. The median duration of TWIST was 10 months, indicating that about 8 months were lost to symptoms due to treatment or hospital admissions for chemotherapy or laparotomy. Of 45 patients receiving six cycles, only eight patients had no symptoms of peripheral neuropathy, and four patients were free of nephropathy at the end of treatment. The overall survival for this limited duration of treatment is similar to that after more protracted treatment. Despite its limited duration, however, about 28% of the cumulative period of progression free survival is consumed by the treatment and its side-effects. Correction of PFS by TWIST may be a suitable instrument to compare the impact of different cytotoxic schedules on quality of life.