Tracked ultrasound registration for intraoperative navigation during pediatric bone tumor resections with soft tissue components: a porcine cadaver study.

PURPOSE: Resection of pediatric osteosarcoma in the extremities with soft tissue involvement presents surgical challenges due to difficult visualization and palpation of the tumor. Therefore, an adequate image-guided surgery (IGS) system is required for more accurate tumor resection. The use of a 3D model in combination with intraoperative tracked ultrasound (iUS) may enhance surgical decision making. This study evaluates the clinical feasibility of iUS as a surgical tool using a porcine cadaver model. METHODS: First, a 3D model of the porcine lower limb was created based on preoperative scans. Second, the bone surface of the tibia was automatically detected with an iUS by a sweep on the skin. The bone surface of the preoperative 3D model was then matched with the bone surface detected by the iUS. Ten artificial targets were used to calculate the target registration error (TRE). Intraoperative performance of iUS IGS was evaluated by six pediatric surgeons and two pediatric oncologic orthopedists. Finally, user experience was assessed with a post-procedural questionnaire. RESULTS: Eight registration procedures were performed with a mean TRE of 6.78 ± 1.33 mm. The surgeons agreed about the willingness for clinical implementation in their current clinical practice. They mentioned the additional clinical value of iUS in combination with the 3D model for the localization of the soft tissue components of the tumor. The concept of the proposed IGS system is considered feasible by the clinical panel, but the large TRE and degree of automation need to be addressed in further work. CONCLUSION: The participating pediatric surgeons and orthopedists were convinced of the clinical value of the interaction between the iUS and the 3D model. Further research is required to improve the surgical accuracy and degree of automation of iUS-based registration systems for the surgical management of pediatric osteosarcoma.

The use of microtracers in food-effect trials: An alternative study design for toxic drugs with long half-lives exemplified by the case for alectinib.

The traditional design of food-effect studies has a high patient burden for toxic drugs with long half-lives (e.g., anticancer agents). Microtracers could be used to assess food-effect in patients without influencing their ongoing treatment. The feasibility of a microtracer food-effect study during steady-state of the therapeutic drug was investigated in an in silico simulation study with alectinib as an example for a relative toxic drug with a long half-life. Microtracer pharmacokinetics were simulated based on a previously published population pharmacokinetic model and used for estimation of a model with and a model without food as a covariate on oral bioavailability of alectinib (assuming a 40% food-effect). Power was defined as the fraction of clinical trials where a significant (p < 0.01) food-effect was identified. The proposed study design of 10 patients on steady-state treatment, 10 blood samples collected within 24 h after administration and an assumed food-effect of 40% had a power of 99.9%. The mean estimated food-effect was 39.8% (80% confidence interval: 31.0%-48.6%). The feasibility of microtracer food-effect studies was demonstrated. The design of the microtracer food-effect study allowed estimation of the food-effect with minimal influence on therapeutic treatment and reducing patient burden compared to the traditional study design for toxic drugs with long half-lives.

Characterization of denosumab treatment response in giant cell tumors of bone with dynamic contrast-enhanced MRI.

RATIONALE AND OBJECTIVES: Denosumab is a monoclonal antibody used neo-adjuvantly in giant cell tumor of bone (GCTB) to facilitate surgery, or long term for axial tumors where surgery comes with high morbidity. Time intervals for treatment effects to occur are unclear and monitoring tools are limited, complicating optimal drug dose titration. We assessed changes in time intensity curve (TIC) - derived perfusion features on DCE-MRI in GCTB during denosumab treatment and evaluated the duration of treatment effects on tumor perfusion. MATERIALS AND METHODS: Patients with GCTB who underwent dynamic contrast enhanced (DCE) MRI before (t = 0) and after 3 (t = 3), 6 (t = 6) or 12 (t = 12) months of denosumab treatment were retrospectively included in a single center. Regions of interest were placed on tumor compartments with visually most intense enhancement and TICs were created. Time-to-enhancement (TTE), wash-in rate (WIR), maximal relative enhancement (MRE), and area-under-the-curve (AUC) were calculated. Differences in perfusion features were calculated with the Wilcoxon signed-rank test. RESULTS: In all 24 patients decreased perfusion on DCE-MRI after start of denosumab treatment was seen. TTE increased between t = 0 and t = 3 (p < 0.001). WIR, MRE and AUC decreased between t = 0 and t = 3 (p < 0.001, p = 0.01 and p = 0.02, respectively). No significant differences in features were found between t = 3 and t = 6 or t = 6 and t = 12. No significant perfusion differences in primary versus recurrent, or axial versus appendicular tumors, were found. CONCLUSION: MRI perfusion significantly changed in GCTB within 3 months of denosumab treatment compared to baseline. No further significant change occurred between 3 and 6, and 6 and 12 months of treatment. These findings suggest that evaluation of treatment response and subsequent consideration of maintenance with lower doses of denosumab, may already be indicated after 3 months. In cases where long term denosumab is the preferred therapy, monitoring change in tumor characteristics on DCE-MRI may aid optimal drug dose titration, minimizing side effects.

Malignant Transformation of Giant Cell Tumor of Bone and the Association with Denosumab Treatment: A Radiology and Pathology Perspective.

Objective: Malignancy in giant cell tumor of bone (mGCTB) is categorized as primary (concomitantly with conventional GCTB) or secondary (after radiotherapy or other treatment). Denosumab therapy has been suggested to play a role in the etiology of secondary mGCTB. In this case series from a tertiary referral sarcoma center, we aimed to find distinctive features for malignant transformation in GCTB on different imaging modalities. Furthermore, we assessed the duration of denosumab treatment and lag time to the development of malignancy. Methods: From a histopathology database search, 6 patients were pathologically confirmed as having initial conventional GCTB and subsequently with secondary mGCTB. Results: At the time of mGCTB diagnosis, 2 cases were treated with denosumab only, 2 with denosumab and surgery, 1 with multiple curettages and radiotherapy, and 1 with surgery only. In the 4 denosumab treated patients, the mean lag time to malignant transformation was 7 months (range 2-11 months). Imaging findings suspicious of malignant transformation related to denosumab therapy are the absence of fibro-osseous matrix formation and absent neocortex formation on CT, and stable or even increased size of the soft tissue component. Conclusion: In 4 patients treated with denosumab, secondary mGCTB occurred within the first year after initiation of treatment. Radiotherapy-associated mGCTB has a longer lag time than denosumab-associated mGCTB. Close clinical and imaging follow-up during the first months of denosumab therapy is key, as mGCTB tends to have rapid aggressive behavior, similar to other high-grade sarcomas. Nonresponders should be (re) evaluated for their primary diagnosis of conventional GCTB.

A highly sensitive bioanalytical method for the quantification of vinblastine, vincristine, vinorelbine and 4-O-deacetylvinorelbine in human plasma using LC-MS/MS.

A highly sensitive method was developed for the quantification of vinblastine, vincristine, vinorelbine, and its active metabolite 4-O-deacetylvinorelbine in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Deuterated isotopes were used as internal standard and liquid-liquid extraction with tert-butyl methyl ether (TBME) was used for sample pre-treatment. The final extract was injected on a C18 column (50 × 2.1 mm ID, 5 µm). Gradient elution was used in combination with Reversed Phase chromatography to elute the analytes and internal standards from the column in 5 min and the API4000 triple quadrupole MS detector was operating in the positive ion mode. The calibration model, accuracy and precision, selectivity and specificity, dilution integrity, carryover, matrix factor and recovery, and stability were evaluated over a concentration range from 0.025 to 10 ng/mL for vinblastine, vinorelbine, and 4-O-deacetylvinorelbine and from 0.1 to 40 ng/mL for vincristine. The intra- and inter-assay bias and precisions were within ± 12.4% and ≤ 10.6%, respectively. This method was successfully applied to study the pharmacokinetics of vincristine in paediatrics and vinorelbine and 4-O-deacetylvinorelbine using in vivo mouse models.

Highly Variable Paracetamol Pharmacokinetics After Multiple Oral Dosing in Frail Older People: A Population Pharmacokinetic Analysis.

INTRODUCTION: Paracetamol pharmacokinetics (PK) is highly variable in older fit adults after intravenous administration. Frailty and oral administration likely result in additional variability. The aim was to determine oral paracetamol PK and variability in geriatric inpatients. METHODS: A population PK analysis, using NONMEM 7.2, was performed on 245 paracetamol samples in 40 geriatric inpatients (median age 87 [range 80-95] years, bodyweight 66.4 [49.3-110] kg, 92.5% frail [Edmonton Frail Scale]). All subjects received paracetamol 1000 mg as tablet (72.5%) or granulate (27.5%) three times daily. Simulations of dosing regimens (1000 mg every 6 hours [q6h] or q8h) were performed to determine target attainment, using mean steady-state concentration (Css-mean) of 10 mg/L as target. RESULTS: A one-compartment model with first order absorption and lag time best described the data. The inter-individual variability was high, with absorption rate constant containing the highest variability. The inter-individual variability could not be explained by covariates. Simulations of 1000 mg q6h and q8h resulted in a Css-mean of 10.8 [25-75th percentiles 8.2-12.7] and 8.13 [6.3-9.6] mg/L, respectively, for the average geriatric inpatient. The majority of the population remained off-target (22.2% [q6h] and 52.2% [q8h] <8 mg/L; 31.3 [q6h] and 7.6% [q8h] >12 mg/L). CONCLUSION: A population of average geriatric inpatients achieved target Css-mean with paracetamol 1000 mg q6h, while q8h resulted in underexposure for the majority of them. Due to high unexplained variability, a relevant proportion remained either above or below the target concentration of 10 mg/L. Research focusing on PK, efficacy and safety is needed to recommend dosing regimens.

Quantitative food web modeling unravels the importance of the microphytobenthos-meiofauna pathway for a high trophic transfer by meiofauna in soft-bottom intertidal food webs.

Meiofauna are known to have an important role on many ecological processes, although, their role in food web dynamics is often poorly understood, partially as they have been an overlooked and under sampled organism group. Here, we used quantitative food web modeling to evaluate the trophic relationship between meiofauna and their food sources and how meiofauna can mediate the carbon flow to higher trophic levels in five contrasting soft-bottom intertidal habitats (including seagrass beds, mudflats and sandflats). Carbon flow networks were constructed using the linear inverse model-Markov chain Monte Carlo technique, with increased resolution of the meiofauna compartments (i.e. biomass and feeding ecology of the different trophic groups of meiofauna) compared to most previous modeling studies. These models highlighted that the flows between the highly productive microphytobenthos and the meiofauna compartments play an important role in transferring carbon to the higher trophic levels, typically more efficiently so than macrofauna. The pathway from microphytobenthos to meiofauna represented the largest flow in all habitats and resulted in high production of meiofauna independent of habitat. All trophic groups of meiofauna, except for selective deposit feeders, had a very high dependency on microphytobenthos. Selective deposit feeders relied instead on a wider range of food sources, with varying contributions of bacteria, microphytobenthos and sediment organic matter. Ecological network analyses (e.g. cycling, throughput and ascendency) of the modeled systems highlighted the close positive relationship between the food web efficiency and the assimilation of high-quality food sources by primary consumers, e.g. meiofauna and macrofauna. Large proportions of these flows can be attributed to trophic groups of meiofauna. The sensitivity of the network properties to the representation of meiofauna in the models leads to recommending a greater attention in ecological data monitoring and integrating meiofauna into food web models.

Trophic importance of microphytobenthos and bacteria to meiofauna in soft-bottom intertidal habitats: A combined trophic marker approach.

Meiofauna can play an important role in the carbon fluxes of soft-bottom coastal habitats. Investigation of their feeding behavior and trophic position remains challenging due to their small size. In this study, we determine and compare the food sources used by nematodes and benthic copepods by using stable isotope compositions, fatty acid profiles and compound specific isotope analyses of fatty acids in the mudflats, seagrass beds and a sandflat of the Marennes-Oléron Bay, France, and the Sylt-Rømø Bight, Germany. Suspended particulate organic matter was much more 13C-depleted than other food sources and meiofauna, highlighting its poor role in the different studied habitats. The very low proportions of vascular plant fatty acid markers in meiofauna demonstrated that these consumers did not rely on this food source, either fresh or detrital, even in seagrass beds. The combined use of stable isotopes and fatty acids emphasized microphytobenthos and benthic bacteria as the major food sources of nematodes and benthic copepods. Compound specific analyses of a bacteria marker confirmed that bacteria mostly used microphytobenthos as a substrate.

Maintenance interventions for overweight or obesity in children: a systematic review and meta-analysis.

Childhood obesity is associated with significant health consequences. Although several intervention programmes for children result in weight loss or stabilization in the short-term, preventing relapse after treatment remains an important challenge. This systematic review summarizes the evidence about maintenance interventions after treatment in childhood obesity. Studies were identified by searching PubMed, Embase, Cochrane Library, Scopus, Web of Science, PsycINFO, CINAHL and SocINDEX. The primary outcome measure for this review was body mass index standard deviation score (BMI-Z-score). Data were pooled using quality effect models. Eleven studies (1,532 participants, age 2-18 years) were included, covering a wide range of maintenance approaches. Included studies varied widely in methodological quality. Pooled analysis showed that the BMI-Z-score of maintenance intervention participants remained stable, whereas control participants experienced a slight increase. No differences were observed regarding intensity and duration of therapy. A slight preference for 'face-to-face' versus 'on distance' interventions was shown. In summary, this review shows that, although there is limited quality data to recommend one maintenance intervention over another, continued treatment does have a stabilizing effect on BMI-Z-score. Considering the magnitude of the problem of childhood obesity, this is an important finding that highlights the need for further research on weight loss maintenance.

Functional outcome and quality of life after the surgical treatment for diffuse-type giant-cell tumour around the knee: a retrospective analysis of 30 patients.

We retrospectively reviewed 30 patients with a diffuse-type giant-cell tumour (Dt-GCT) (previously known as pigmented villonodular synovitis) around the knee in order to assess the influence of the type of surgery on the functional outcome and quality of life (QOL). Between 1980 and 2001, 15 of these tumours had been treated primarily at our tertiary referral centre and 15 had been referred from elsewhere with recurrent lesions. The mean follow-up was 64 months (24 to 393). Functional outcome and QOL were assessed with range of movement and the Knee injury and Osteoarthritis Outcome Score (KOOS), the Musculoskeletal Tumour Society (MSTS) score, the Toronto Extremity Salvage Score (TESS) and the SF-36 questionnaire. There was recurrence in four of 14 patients treated initially by open synovectomy. Local control was achieved after a second operation in 13 of 14 (93%). Recurrence occurred in 15 of 16 patients treated initially by arthroscopic synovectomy. These patients underwent a mean of 1.8 arthroscopies (one to eight) before open synovectomy. This achieved local control in 8 of 15 (53%) after the first synovectomy and in 12 of 15 (80%) after two. The functional outcome and QOL of patients who had undergone primary arthroscopic synovectomy and its attendant subsequent surgical procedures were compared with those who had had a primary open synovectomy using the following measures: range of movement (114º versus 127º; p = 0.03); KOOS (48 versus 71; p = 0.003); MSTS (19 versus 24; p = 0.02); TESS (75 versus 86; p = 0.03); and SF-36 (62 versus 80; p = 0.01). Those who had undergone open synovectomy needed fewer subsequent operations. Most patients who had been referred with a recurrence had undergone an initial arthroscopic synovectomy followed by multiple further synovectomies. At the final follow-up of eight years (2 to 32), these patients had impaired function and QOL compared with those who had undergone open synovectomy initially. We conclude that the natural history of Dt-GCT in patients who are treated by arthroscopic synovectomy has an unfavourable outcome, and that primary open synovectomy should be undertaken to prevent recurrence or residual disease.

Giant cell tumors of the sacrum--a nationwide study on midterm results in 26 patients after intralesional excision.

PURPOSE: Evaluation of recurrences, complications and function at mid-term follow-up after curettage for sacral giant cell tumor (GCT). METHODS: We retrospectively studied all 26 patients treated for sacral GCT in the Netherlands (from 1990 to 2010). Median follow-up was 98 (6-229) months. All patients underwent intralesional excision, 21 with local adjuvants, 5 radiotherapy, 3 IFN-α, 1 bisphosphonates. Functional outcome was assessed using Musculoskeletal Tumor Society (MSTS) score. Statistics were performed with Kaplan-Meier, Cox regression, log rank and Mann-Whitney U. RESULTS: Recurrence rate was 14/26 after median 13 (3-139) months and was highest after isolated curettage (4/5). Soft tissue masses >10 cm increased recurrence risk (HR = 3.3, 95 % CI = 0.81-13, p = 0.09). Complications were reported in 12/26 patients. MSTS was superior in patients without complications (27 vs. 21; p = 0.024). CONCLUSION: Recurrence rate for sacral GCT was highest after isolated curettage, indicating that (local) adjuvant treatment is desired to obtain immediate local control. Complications were common and impaired function.

Giant cell tumours of the small bones of the hands and feet: long-term results of 30 patients and a systematic literature review.

Giant cell tumours (GCTs) of the small bones of the hands and feet are rare. Small case series have been published but there is no consensus about ideal treatment. We performed a systematic review, initially screening 775 titles, and included 12 papers comprising 91 patients with GCT of the small bones of the hands and feet. The rate of recurrence across these publications was found to be 72% (18 of 25) in those treated with isolated curettage, 13% (2 of 15) in those treated with curettage plus adjuvants, 15% (6 of 41) in those treated by resection and 10% (1 of 10) in those treated by amputation. We then retrospectively analysed 30 patients treated for GCT of the small bones of the hands and feet between 1987 and 2010 in five specialised centres. The primary treatment was curettage in six, curettage with adjuvants (phenol or liquid nitrogen with or without polymethylmethacrylate (PMMA)) in 18 and resection in six. We evaluated the rate of complications and recurrence as well as the factors that influenced their functional outcome. At a mean follow-up of 7.9 years (2 to 26) the rate of recurrence was 50% (n = 3) in those patients treated with isolated curettage, 22% (n = 4) in those treated with curettage plus adjuvants and 17% (n = 1) in those treated with resection (p = 0.404). The only complication was pain in one patient, which resolved after surgical removal of remnants of PMMA. We could not identify any individual factors associated with a higher rate of complications or recurrence. The mean post-operative Musculoskeletal Tumor Society scores were slightly higher after intra-lesional treatment including isolated curettage and curettage plus adjuvants (29 (20 to 30)) compared with resection (25 (15 to 30)) (p = 0.091). Repeated curettage with adjuvants eventually resulted in the cure for all patients and is therefore a reasonable treatment for both primary and recurrent GCT of the small bones of the hands and feet.

Sotalol as first-line treatment for fetal tachycardia and neonatal follow-up.

OBJECTIVES: In fetal tachycardia, pharmacological therapy with digoxin, flecainide and sotalol has been reported to be effective. In a recent retrospective multicenter study, sotalol was considered to be less effective than the other drugs in treatment of fetal supraventricular tachycardia (SVT). The aim of this study was to re-evaluate the efficacy and safety of maternally administered sotalol in the treatment of fetal tachycardia. METHODS: This was a retrospective review of the records of 30 consecutive fetuses with tachycardia documented on M-mode echocardiography between January 2004 and December 2010 at Wilhelmina Children's Hospital, a tertiary referral university hospital. Patients were subdivided into those diagnosed with supraventricular tachycardia and those with atrial flutter (AF) and presence of hydrops was noted. Other variables investigated included QTc interval measured on maternal electrocardiogram before and after initiation of antiarrhythmic therapy, fetal heart rhythm and heart rate pre- and postnatally, oral maternal drug therapy used, time to conversion to sinus rhythm (SR), percentage of fetuses converted following transplacental treatment, maternal adverse effects, presence or absence of tachycardia as noted on postnatal ECG, postnatal therapy or prophylaxis and neonatal outcome. Findings are discussed with reference to the literature. RESULTS: A total of 28 patients (18 with SVT, 10 with AF) were treated with sotalol as first-line therapy. Fetal hydrops was present in six patients (five with SVT, one with AF). All hydropic patients converted antenatally to SR (67% with sotalol as a single-drug therapy, 33% after addition of flecainide). Of the non-hydropic patients, 91% converted to SR (90% with sotalol only, 10% after addition of flecainide or digoxin). In 9% (with AF) rate control was achieved. There was no mortality. No serious drug-related adverse events were observed. Postnatally, rhythm disturbances were detected in 10 patients, two of whom still had AF. In eight, SVT was observed within 3 weeks postnatally, and in five of these within 72 hours. CONCLUSIONS: Sotalol can be recommended as the drug of first choice for treatment of fetal AF and has been shown to be an effective and safe first-line treatment option for SVT, at least in the absence of hydrops. Postnatal maintenance therapy after successful prenatal therapy is not necessarily indicated, as the risk of recurrence is low beyond 72 hours of age.

Soft tissue extension increases the risk of local recurrence after curettage with adjuvants for giant-cell tumor of the long bones.

BACKGROUND AND PURPOSE: Risk factors for local recurrence of giant-cell tumor of bone (GCTB) have mostly been studied in heterogeneous treatment groups, including resection and intralesional treatment. The aim of the study was the identification of individual risk factors after curettage with adjuvants in GCTB. METHODS: Of 147 patients treated for primary GCTB between 1981 and 2009, 93 patients were included in this retrospective single-center study. All patients were treated with curettage and polymethylmethacrylate (PMMA) with (n = 75) or without (n = 18) phenol. Mean follow-up was 8 (2-24) years. Recurrence-free survival was assessed for treatment modalities. Age, sex, tumor location, soft tissue extension, and pathological fractures were scored for every patient and included in a Cox regression analysis. RESULTS: The recurrence rate after the first procedure was 25/93. Recurrence-free survival for PMMA and phenol and for PMMA alone was similar. Eventually, local control was achieved using 1 or multiple intralesional procedures in 85 patients. Resection was required in 8 patients. A higher risk of local recurrence was found for soft tissue extension (HR = 5, 95% CI: 2-12), but not for age below 30, sex, location (distal radius vs. other), or pathological fracture. INTERPRETATION: Curettage with adjuvants is a feasible first-choice treatment option for GCTB, with good oncological outcome and joint preservation. Soft tissue extension strongly increased the risk of local recurrence, whereas age, sex, location, and pathological fractures did not.

The management of diffuse-type giant cell tumour (pigmented villonodular synovitis) and giant cell tumour of tendon sheath (nodular tenosynovitis).

Giant cell tumours (GCT) of the synovium and tendon sheath can be classified into two forms: localised (giant cell tumour of the tendon sheath, or nodular tenosynovitis) and diffuse (diffuse-type giant cell tumour or pigmented villonodular synovitis). The former principally affects the small joints. It presents as a solitary slow-growing tumour with a characteristic appearance on MRI and is treated by surgical excision. There is a significant risk of multiple recurrences with aggressive diffuse disease. A multidisciplinary approach with dedicated MRI, histological assessment and planned surgery with either adjuvant radiotherapy or systemic targeted therapy is required to improve outcomes in recurrent and refractory diffuse-type GCT. Although arthroscopic synovectomy through several portals has been advocated as an alternative to arthrotomy, there is a significant risk of inadequate excision and recurrence, particularly in the posterior compartment of the knee. For local disease partial arthroscopic synovectomy may be sufficient, at the risk of recurrence. For both local and diffuse intra-articular disease open surgery is advised for recurrent disease. Marginal excision with focal disease will suffice, not dissimilar to the treatment of GCT of tendon sheath. For recurrent and extra-articular soft-tissue disease adjuvant therapy, including intra-articular radioactive colloid or moderate-dose external beam radiotherapy, should be considered.

Hormonal regulation of phospholipase D activity in Ca(2+) transporting cells of rabbit connecting tubule and cortical collecting duct.

Phospholipase D (PLD) is distributed widely in mammalian tissues where it is believed to play an important role in the regulation of cell functions and cell fate by a variety of extracellular signals. In this study, we used primary cultures of rabbit connecting tubule (CNT) and cortical collecting duct (CCD) cells, grown to confluence on a permeable support, to investigate the possible involvement of PLD in the mechanism of action of hormones that regulate Ca(2+) reabsorption. RT-PCR revealed the presence of transcripts of PLD1b and PLD2, but not PLD1a, in these cultures. Moreover, the expression of substantial amounts of PLD1 protein was demonstrated by Western blotting. To measure PLD activity, cells were labelled with [(3)H]myristic acid after which the PLD-catalysed formation of radiolabelled phosphatidylethanol ([(3)H]PtdEth) was measured in the presence of 1% (v/v) ethanol. Deamino-Cys,D-Arg(8)-vasopressin (dDAVP) and N(6)-cyclopentyladenosine (CPA), two potent stimulators of Ca(2+) transport across these monolayers, stimulated PLD activity as was indicated by a marked increase in [(3)H]PtdEth. Similarly, ATP, a potent inhibitor of dDAVP- and CPA-stimulated Ca(2+) transport, increased the formation of [(3)H]PtdEth. PLD activity was furthermore increased by 8Br-cAMP and following acute (30 min) stimulation of protein kinase C (PKC) with a phorbol ester (PMA). Chronic PMA treatment (120 h) to downregulate phorbol ester-sensitive PKC isoforms did not affect PLD activation by dDAVP, CPA and 8Br-cAMP, while markedly decreasing the effect of ATP and abolishing the effect of PMA. The PKC inhibitor chelerythrine significantly reduced PLD activation by dDAVP, CPA and 8Br-cAMP, without changing the effect of ATP. The inhibitor only partially reduced the effect of PMA. This study shows that Ca(2+) transporting cells of CNT and CCD contain a regulated PLD activity. The physiological relevance of this activity, which is not involved in Ca(2+) reabsorption, remains to be established.

[Trends in incidence and treatment of ductal carcinoma in situ of the breast in southeast Netherlands]. / Trends in incidentie en behandelbeleid van ductaal carcinoma in situ van de mamma in Zuidoost-Nederland.

OBJECTIVE: To analyse the incidence and treatment of ductal carcinoma in situ (DCIS) of the breast in the population. DESIGN: Retrospective, descriptive. METHOD: The incidence of DCIS in the period 1975-1997 in 8 hospitals in southeastern North Brabant and northern Limburg, the Netherlands, was analysed, using data from the Eindhoven Cancer Registry. Changes in the treatment of DCIS in the period 1984-1997 were studied, using information from the Breast Cancer Documentation Project. RESULTS: Between 1975 and 1997, 448 cases of DCIS were detected in 442 women. After adjustment for age according to the European Standard Population, the incidence rate of DCIS increased from 0.3 per 100,000 in 1975 to 13.4 in 1997. Of the 87 patients with DCIS between 50 and 69 years of age in 1996 and 1997, 68% was detected by the screening programme. The proportion of patients with DCIS undergoing ablation of the breast was 53% during the period 1984-1989, and varied around 45% thereafter. The other patients underwent local excision. The proportion of patients receiving radiotherapy after local excision decreased from 78% in the period 1984-1989 to 24% in the period 1994-1995 and rose to 41% during the last few years. Substantial differences in the treatment of DCIS were observed between the 8 hospitals.

Comorbidity and colorectal cancer according to subsite and stage: a population-based study.

In developed countries the growing proportion of elderly colorectal cancer patients with comorbidity will probably complicate clinical management. The aim of this study was to investigate the prevalence of prognostically relevant comorbidity in unselected colorectal cancer patients diagnosed in the Eindhoven Cancer Registry, according to age, gender and subsite and the association with stage of disease, treatment and short-term survival. Comorbid conditions were recorded, according to Charlson's index. The most common concomitant illnesses were cardiovascular diseases, previous cancers and hypertension. The prevalence of comorbidity, especially of cardiovascular disease, previous cancer and diabetes, was highest in the ascending colon. It was slightly higher in patients with Dukes' stage A, probably due to early detection because of regular monitoring for the comorbid condition. Comorbidity was not associated with the resection rate, but was negatively associated with short-term survival. Elder male colorectal cancer patients particularly suffer from substantial comorbidity, influencing the prognosis.

Long-term survival of prostate cancer in southeastern Netherlands.

With the increase in detection at an early stage, only a few and conflicting results have been reported on the long-term outcome for prostate cancer beyond 10 years. The vast majority of prostate cancer patients diagnosed between 1955 and 1984 in southeastern Netherlands, with a population of almost one million inhabitants, did not receive any curative treatment. We calculated the prognosis for 10-year survivors of prostate cancer diagnosed in the era preceding prostate-specific antigen (PSA) testing to determine how long these patients exhibited excess mortality. All patients under age 70 diagnosed with prostate cancer and registered in the population-based Eindhoven Cancer Registry between 1955 and 1984 were included in the study. Relative survival was calculated for those who survived for at least 10 years (n = 174). Initially, these patients still exhibited an almost 25% excess mortality risk, but this decreased with time and no excess mortality was found after 15 years.

The relationship between findings on pre-treatment mammograms and local recurrence after breast-conserving therapy for invasive breast cancer.

AIMS: This study was planned (a) to determine the correlation between findings on the pre-treatment mammogram and local recurrence after breast-conserving therapy (BCT), and (b) to analyse the relationship between mammographical features, specific pathological characteristics and the need for re-excision. METHOD: The size and outline of the lesion, the presence of suspect microcalcifications and signs of multifocality on pre-treatment mammograms of 39 patients with local recurrence after BCT and 126 randomly selected control patients without local recurrence were compared. Tissue slides of the primary tumour were reviewed to confirm the histological type and grade, the aspect of the margins, microscopic margin involvement, presence of vascular invasion and the presence and extent of an intraductal component. RESULTS: Among patients /=50 years, 67% of the patients with local recurrence had a non-circumscribed lesion compared to 9% of the control group (P<0.001). Suspect microcalcifications on the mammogram were associated with the finding of an extensive intraductal component, vascular invasion and a higher histological grade by the pathologist. Patients with a non-circumscribed density or a scirrhous lesion needed re-excision more often (30 and 33%, respectively) than those with a well-circumscribed density (9%). CONCLUSIONS: Although the number of patients was small, this study indicates that some mammographical features are associated with a higher risk of local recurrence after BCT and the need for re-excision. This was supported by the findings of the pathological review.