Single-arm trials supporting the approval of anticancer medicinal products in the European Union: contextualization of trial results and observed clinical benefit.

BACKGROUND: Single-arm trials (SATs) can sometimes be used to support marketing authorization of anticancer medicinal products in the European Union. The level and durability of antitumor activity of the product as well as context are important aspects to determine the relevance of trial results. The aim of this study is to provide details on the contextualization of trial results and to evaluate the magnitude of benefit of medicinal products approved based on SATs. MATERIALS AND METHODS: We focused on anticancer medicinal products for solid tumors approved on the basis of SAT results (2012-2021). Data were retrieved from European public assessment reports and/or published literature. The benefit of these medicinal products was evaluated via the European Society for Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS). RESULTS: Eighteen medicinal products were approved based on 21 SATs-few medicinal products were supported by >1 SAT. For the majority of clinical trials, a clinically relevant treatment effect was (pre)specified (71.4%) and most often an accompanying sample size calculation was provided. For 10 studies, each testing a different medicinal product, a justification for the threshold for a clinically relevant treatment effect could be identified. At least 12 out of 18 applications included information to facilitate the contextualization of trial results, including six supportive studies. Of the pivotal SATs analyzed (n = 21), three were assigned an ESMO-MCBS score of 4, which corresponds to 'substantial' benefit. CONCLUSIONS: The clinical relevance of the treatment effects shown by medicinal products for solid tumors tested in SATs is dependent on the effect size and context. To better facilitate regulatory decision making, prespecifying and motivating a clinically relevant effect and aligning the sample size to that effect is important. External controls may facilitate in the contextualization process, but the associated limitations must be addressed.

Calcium signalling links MYC to NUAK1.

NUAK1 is a member of the AMPK-related family of kinases. Recent evidence suggests that NUAK1 is an important regulator of cell adhesion and migration, cellular and organismal metabolism, and regulation of TAU stability. As such, NUAK1 may play key roles in multiple diseases ranging from neurodegeneration to diabetes and metastatic cancer. Previous work revealed a crucial role for NUAK1 in supporting viability of tumour cells specifically when MYC is overexpressed. This role is surprising, given that NUAK1 is activated by the tumour suppressor LKB1. Here we show that, in tumour cells lacking LKB1, NUAK1 activity is maintained by an alternative pathway involving calcium-dependent activation of PKCα. Calcium/PKCα-dependent activation of NUAK1 supports engagement of the AMPK-TORC1 metabolic checkpoint, thereby protecting tumour cells from MYC-driven cell death, and indeed, MYC selects for this pathway in part via transcriptional regulation of PKCα and ITPR. Our data point to a novel role for calcium in supporting tumour cell viability and clarify the synthetic lethal interaction between NUAK1 and MYC.

Impact of a multifaceted strategy to improve perioperative diabetes care.

AIMS: To assess the impact of a multifaceted strategy to improve perioperative diabetes care throughout the hospital care pathway. METHODS: We conducted a controlled before-and-after study in six hospitals. The purpose of the strategy was to target four predominant barriers that obstruct optimal care delivery. We provided feedback on baseline indicator performance, developed a multidisciplinary protocol and patient information, and provided professional education. After a 6-month intervention, we determined the performance changes against three outcome indicators and nine process indicators using data on 811 patients with diabetes who underwent major surgery. The progress of the interventions was monitored closely. RESULTS: Two process indicators improved significantly in the intervention hospitals: the proportion of patients for whom glycaemic control had been evaluated preoperatively increased by 9% (P < 0.002) and the proportion of patients with blood glucose measurements within 1 h after surgery increased by 29% (P < 0.0001). Four other process indicators and all three outcome indicators improved more in the intervention hospitals than in the control hospitals, but the differences were not statistically significant. These included the proportion of patients with all glucose values at 6-10 mmol/l (+3%) and the proportion of patients with hyperglycaemia (-8%). The implementation of the multidisciplinary protocol was still ongoing after the 6-month intervention period. CONCLUSIONS: The multifaceted improvement strategy had a limited impact on the quality of perioperative diabetes care. This study demonstrates the complexity of improving perioperative diabetes care throughout the multiprofessional hospital care pathway.

Perioperative diabetes care: room for improving the person centredness.

AIMS: Person centredness is an important principle for delivering high-quality diabetes care. In this study, we assess the level of person centredness of current perioperative diabetes care. METHODS: We conducted a survey in six Dutch hospitals, among 690 participants with diabetes who underwent major abdominal, cardiac or large-joint orthopaedic surgery. The survey included questions regarding seven dimensions of person-centred perioperative diabetes care. RESULTS: Complete data were obtained from 298 participants. The survey scores were low for many of the dimensions of person centredness. The dimensions 'information', 'patient involvement' and 'coordination and integration of care' had the lowest scores. Only half the participants had received information about perioperative diabetes treatment, and approximately one-third had received information about the effect of surgery on blood glucose values, target glucose values and glucose measurement times. Similarly, half the participants had an opportunity to ask questions preoperatively, and only one-third of the participants felt involved in the decision-making regarding diabetes treatment. Most participants knew neither the caregiver in charge of perioperative diabetes treatment nor whom to contact in case of diabetes-related problems during their hospital stay. CONCLUSIONS: Current perioperative diabetes care is characterized by a lack of patient information and limited patient involvement. These results indicate that there is ample room for improving the person centredness of perioperative diabetes care.

A database system for the registration of complications and failures in cochlear implant surgery applied to over 1000 implantations performed in Nijmegen, The Netherlands.

OBJECTIVE: To create a system for the uniform registration and classification of complications and failures in cochlear implant surgery, and apply it to all the patients who underwent implantation in our clinic. METHOD: The definition of a medical complication was established, and data for all cochlear implantations performed between 1987 and 2012 were entered into a custom-made database system. RESULTS: One or more medical complications were registered in 19.0 per cent of 1003 cochlear implantations. The incidence of 'hard failure' was 2.3 per cent. Findings revealed a decrease in device failures over the years; the rate of medical complications remained constant. CONCLUSION: Our database system, which is available free of charge, enables fast and accurate data entry. There were a relatively high number of (minor) complications in our series, but comparison with the relevant literature is difficult. This emphasises the need for a uniform definition of 'complication' as it relates to cochlear implant surgery, and an appropriate classification system for such complications.

The use of cone beam CT for the removal of wisdom teeth changes the surgical approach compared with panoramic radiography: a pilot study.

This prospective study evaluated the role of cone beam computed tomography (CBCT) in the treatment of patients with impacted mandibular third molars at increased risk of inferior alveolar nerve (IAN) injury. Subjects with an increased risk of IAN injury, as diagnosed on panoramic radiographs, were enrolled in this study and underwent additional CBCT imaging. Two oral maxillofacial surgeons independently planned the surgical technique and estimated the risk of IAN injury on panoramic radiographs and on CBCT images. A test of symmetry and the McNemar test were executed to calculate the differences between the two imaging modalities. The study sample comprised 40 patients (mean age 27.6 years) presenting 53 mandibular third molars. Risk assessment for IAN injury based on panoramic radiography compared with CBCT imaging differed significantly (P<0.005). After reviewing the CBCT images, significantly more subjects were reclassified to a lower risk for IAN injury compared with the panoramic radiograph assessments. This change in risk assessment also resulted in a significantly different surgical approach (P<0.03). The results of this study show that CBCT contributes to optimal risk assessment and, as a consequence, to more adequate surgical planning, compared with panoramic radiography.

[Secular trends of caries prevalence among 6 and 12 year-old youths in the Netherlands]. / Trends in de prevalentie van cariës bij de 6- en 12-jarige jeugd in Nederland.

In order to gain insight into the development of caries prevalence and caries experience among Dutch youth, a meta-analysis was carried out on epidemiological caries data collected in 5 and 6 and 11 and 12 year-olds between 1980 and 2009. From the present analysis it appears that after the mid-1980's a halt occurred in the decline of caries experience in the primary dentition among 5 and 6 year-olds. At the same time, the percentage of children with a caries-free primary dentition who were covered by public health insurance or participated in institutions for youth dental care decreased. Among 11 to 12 year-olds there is no indication that the prevalence of caries in the permanent dentition has changed. Considering the high percentage of 12 year-olds with a caries-free permanent dentition, an additional improvement in oral health for this age-group will be difficult to achieve. The average restorative index of the primary dentition in 5-6 year-old children covered by public health insurance and children in The Hague appears not to have changed dramatically in the last 15 years.

Treatment of age-related hearing loss in dogs with the vibrant soundbridge middle ear implant: short-term results in 3 dogs.

BACKGROUND: Age-related hearing loss (ARHL), or presbycusis, is the most common form of acquired hearing loss in dogs. Middle ear implants have been used successfully in people with ARHL who cannot benefit from conventional hearing aids. HYPOTHESIS: Audibility improves in dogs with ARHL after implantation of the Vibrant Soundbridge (VSB) middle ear implant. ANIMALS: Three Beagle dogs with ARHL, mean age 11.1 years. METHODS: The dogs were assessed pre- and postoperatively by brainstem-evoked response audiometry (BERA), otoscopy, and computed tomography scans of the ears. A VSB middle ear implant was implanted unilaterally. Three months later the functionality of the implants was assessed by auditory steady-state responses (ASSRs), after which the dogs were euthanized for histopathological examination. RESULTS: The VSB was implanted successfully in all dogs. Recovery from surgery was uneventful, except for transient facial nerve paralysis in 2 dogs. ASSRs showed that hearing improved after activation of the implants with a mean of 20.7, 13, and 16.3 dB at 1, 2, and 4 kHz, respectively. The implantation procedure did not affect residual hearing (with inactive implants) as measured by BERA. CONCLUSIONS AND CLINICAL IMPORTANCE: Implantation of the VSB resulted in lower ASSR thresholds, but only at the higher gain settings of the audioprocessor. As in humans, a more powerful audioprocessor is required to treat sensorineural hearing loss exceeding 20 dB in dogs. A substantial improvement in patient-owner communication will have to be demonstrated in future studies before the procedure can be recommended in clinical practice.

Position of the impacted third molar in relation to the mandibular canal. Diagnostic accuracy of cone beam computed tomography compared with panoramic radiography.

This study investigated the diagnostic accuracy of cone beam computed tomography (CBCT) compared to panoramic radiography in determining the anatomical position of the impacted third molar in relation with the mandibular canal. The study sample comprised 53 third molars from 40 patients with an increased risk of inferior alveolar nerve (IAN) injury. The panoramic and CBCT features (predictive variables) were correlated with IAN exposure and injury (outcome variables). Sensitivity and specificity of modalities in predicting IAN exposure were compared. The IAN was exposed in 23 cases during third molar removal and injury occurred in 5 patients. No significant difference in sensitivity and specificity was found between both modalities in predicting IAN exposure. To date, lingual position of the mandibular canal was significantly associated with IAN injury. CBCT was not more accurate at predicting IAN exposure during third molar removal, however, did elucidate the 3D relationship of the third molar root to the mandibular canal; the coronal sections allowed a bucco-lingual appreciation of the mandibular canal to identify cases in which a lingually placed IAN is at risk during surgery. This observation dictates the surgical approach how to remove the third molar, so the IAN will not be subjected to pressure.

Effect of HIV viral load, CD4 cell count and antiretroviral therapy on human papillomavirus prevalence in urine samples of HIV-infected men.

HIV-infected patients are at increased risk for persistent human papillomavirus (HPV) infection, the major cause of anogenital cancer. The present study describes the HPV prevalence in urine samples of 243 HIV-infected men and a control group of 231 men. HPV DNA was amplified by the SPF10 polymerase chain reaction primer set. The overall HPV prevalence in HIV-infected men was 27.5% compared with 12.6% in controls (P < 0.01). Infections with high-risk and multiple HPV genotypes were present in both groups. Differences were not statistically significant. A multivariate logistic regression model showed a decreased HPV prevalence associated with use of a nucleoside and a non-nucleoside reverse transcriptase inhibitor combination (P = 0.03). A trend was observed towards a higher HPV prevalence and a lower CD4 cell count. Further prospective studies are needed to determine the role of HPV DNA testing in urine in future screening programmes for anal cancer in men.

Tissue expansion for correction of baldness in aplasia cutis congenita.

UNLABELLED: Aplasia cutis is a congenital absence of the skin, usually presenting on the scalp. In 20% of all cases, part of the skull is also absent. A residual area of baldness may still be present some years after surgical or conservative treatment. It is possible to excise the scarred hairless region and cover that area with expanded hair-bearing skin from the rest of the skull. We present three patients who underwent tissue expansion and discuss the indications and pitfalls of this procedure. CONCLUSION: Tissue expansion can be used to cover a residual alopecia defect in young children with aplasia cutis congenita and associated bone abnormalities. The quality of the bone appears to be normal in our three patients. We demonstrate that even in young children with aplasia cutis and an underlying bony defect, tissue expansion is a safe and effective modality as a second stage reconstruction procedure.

[A tooth located in a mandibular fracture line. Treatment by oral- and maxillofacial surgeons in The Netherlands]. / Mandibulafracturen met een gebitselement in de fractuurlijn. Behandelbeleid van kaakchirurgen in Nederland.

Mandibular fractures are among the most common facial bone injuries. Approximately 50% of the fractures occur in teeth bearing areas. Consequently, the likelihood that a tooth will be in the fracture line is substantial. A review of the literature reveals that there is not a clear guideline for preserving or removing a tooth in a mandibular fracture line. By means of a questionnaire, information was collected about how dental surgeons in The Netherlands deal with this problem. The research sample consisted of 194 active oral and maxillofacial surgeons in The Netherlands in 2005. One hundred and two surgeons responded (52.6%). The response rate was sufficient to allow for reliable deductions and statistical analysis. The results of the questionnaire showed that the respondents were in agreement. Generally, the respondents strove to preserve a tooth in the mandibular fracture line. The respondent's treatment of a mandibular fracture was in agreement with the state of the art as presented in the current literature. The respondent's choice of treatment did not depend on age, gender, university clinic at which the respondent was trained to be a dental surgeon, year of registration as a specialist, place of work and position. According to the respondents, the dentist's role in the aftercare of a mandibular fracture is treatment of the teeth injuries, follow-up of the posttraumatic oral self care, and regularly testing the vitality of the teeth in and around the mandibular fracture line.

Split rib cranioplasty for aplasia cutis congenita and traumatic skull defects: more than 30 years of follow-up.

Aplasia cutis is a rare skin defect usually presenting over the vertex of the skull. An underlying bone defect is found in approximately 20% of patients. Most skull defects close spontaneously. However, when there are no signs of ossification, closure is mandatory. We present our experience in three patients. Our first patient had an aplasia cutis with a skull defect. The split rib graft procedure was used without complications, and a good cosmetic and functional result was achieved. The second patient was operated on for cerebral bleeding after an arteriovenous aneurysm, and a bony defect could not be closed after that procedure. At a later stage, the defect was filled with split rib grafts, and sufficient protection was achieved and documented after more than 30 years. The third patient was born with an aplasia cutis congenita with a skull defect. The bony defect was filled with split rib grafts without complications at an age of 5 years. Follow-up shows a functional result with a firm skull. Patients with aplasia cutis may have skull defects that will not close by themselves. We present three patients with a bony defect who were reconstructed with split rib grafts. After a long period of follow-up, there remains good cosmetic and functional results. Defects of the skull in children can be reconstructed with split rib grafts that will accommodate the growing skeleton and give good protection of the brain from an early age on.

Systematically generated antibodies against human gene products: high throughput screening on sections from the rat nervous system.

Completion of the Human Genome Project and recent developments in proteomics make it possible to systematically generate affinity reagents to a large portion of the proteome. Recently an antibody-based human protein atlas covering many organs including four areas of the brain has been released (www.proteinatlas.org). Due to the heterogeneity, size, and availability of tissue a more thorough analysis of the human brain is associated with considerable difficulties. Here we applied 120 antibodies raised against 112 human gene products to the smaller rat brain, a rodent animal model, where a single section represents a 'superarray' including many brain areas, and consequently allowing analysis of a huge number of cell types and their neurochemicals. Immunoreactive structures were seen in the investigated brain tissue after incubation with 56 antibodies (46.6%), of which 25 (20.8%) showed a clearly discrete staining pattern that was limited to certain areas, or subsets of brain cells. Bioinformatics, pre-adsorption tests and Western blot analysis were applied to identify non-specific antibodies. Eleven antibodies, including such raised against four 'ambiguous' proteins, passed all validation criteria, and the expression pattern and subcellular distribution of these proteins were studied in detail. To further explore the potential of the systematically generated antibodies, all 11 antibodies that passed validation were used to analyze the spinal cord and lumbar dorsal root ganglia after unilateral transection of the sciatic nerve. Discrete staining patterns were observed for four of the proteins, and injury-induced regulation was found for one of them. In conclusion, the study presented here suggests that a significant portion (10%) of the antibodies generated to a human protein can be used to analyze orthologues present in the rodent brain and to produce a protein-based atlas of the rodent brain. It is hoped that this type of antibody-based, high throughput screening of brain tissue from various rodent disease models will provide new information on the brain chemical neuroanatomy and insights in processes underlying neurological pathologies.

Loss to follow-up of cervical smears without endocervical columnar cells is not disturbing.

OBJECTIVE: To investigate the six-month recommended follow-up after mass screening of Pap smears because of the absence of endocervical columnar cells (ECC-) or ECC+ smears with atypical squamous or glandular cells of undetermined origin (ASCUS/AGUS) or low-grade squamous or glandular intraepithelial lesions (LSIL/LGIL) in a Dutch mass screening cervical cancer programme. METHODS: Data were extracted from computerised medical records of national representative Dutch general practices. We have studied the attendance at and the outcome of the subsequent Pap smears after a 6-month recommendation. RESULTS: The six-month follow-up was linked to 8.7% of the Pap smears (n = 1,002); 77.6% were without endocervical columnar cells (ECC-). Clear differences were found between the follow-up of ECC+ and ECC- smears; after 36 weeks of follow-up of 43.5% the women had an ECC- smear and 66.9% had other conditions. For initial ECC- Pap smears, 84.1% had no abnormalities in the subsequent Pap smear; for initial ECC+ Pap smears, in about 64% of the cases no abnormalities were found (p < 0.0001). CONCLUSIONS: Repeating ECC- smears has a low follow-up rate but also lacks evidence-based necessity. However, for the other 6-month recommended Pap smears, one in five women had still not responded within one year, so improvement is necessary.

Loss of pesticides from agricultural fields in SE Norway--runoff through surface and drainage water.

Loss of two pesticides with different mobility characteristics, bentazone (Koc approximately 34) and propiconazole (Koc approximately 1800), were studied at three agricultural fields (Askim, Bjørnebekk and Syverud) in SE Norway. A conservative tracer (Br) was used to follow the flow of water. The loss of pesticides varied among the fields, depending on hydrological characteristics and soil properties. The loss of pesticides was higher from two artificially levelled silty clay loam soils with poor aggregate stability (Askim and Bjørnebekk) compared to a loam/silt loam soil with increased content of organic carbon and better aggregate stability (Syverud). The total accumulated loss was <0.5% from all fields. The highest pesticide concentrations were measured at the first runoff episode after application for both the mobile (bentazone) and less mobile pesticide (propiconazole) in the surface runoff. In the drainage water, the peak for the less mobile pesticide coincided with the Br tracer, while the peak for mobile pesticide appeared earlier than the Br tracer. Rapid movement of water, particles and pesticides through soils indicate flow through macropores. Larger proportions (in percent of total applied) of both the mobile and the strongly sorbed pesticides were lost through the drainage as compared to the loss through surface runoff at Askim. Here, it is suggested that macropore flow contribute to the increased loss of pesticides through the drainage. At Syverud, high infiltration capacity reduces the amount of water available for surface runoff, and somewhat higher loss of the mobile pesticide was registered in the drainage compared to the surface runoff. For the strongly sorbed pesticide, however, propiconazole was neither detected in surface nor in drainage water at Syverud. Generally, there was a higher percentage loss of the mobile compared to the strongly sorbed pesticide in both surface and drainage water, which is in agreement with the pesticides mobility characteristics in soil. An exception was, however, the erodible soil Bjørnebekk, where a higher fraction of propiconazole was lost in the surface runoff compared to bentazone. Large amounts of sediment transport from the Bjørnebekk field probably contributed to enhanced transport of the strongly sorbed pesticide.

Influences of suspended particles on the runoff of pesticides from an agricultural field at Askim, SE-Norway.

Field and laboratory experiments were conducted to study the loss of particles from agricultural fields, and the role of suspended particles in carrying pesticides in surface runoff and drainage water. Propiconazole, a widely used fungicide was applied to experimental fields located at Askim, SE-Norway. Samples from surface runoff and drainage water were collected and analyzed for sediment mass, pesticides, particulate and dissolved organic carbon through a whole year. The surface soil and the runoff material were characterized by its particle size distribution, organic carbon content in size fractions and its ability to bind propiconazole. The results show that (1) particle runoff mostly occurred during the rainfall event shortly after harrowing in autumn. The highest particle concentration observed in the surface runoff water was 4600 mg l(-1), and in the drainage water 1130 mg l(-1); (2) the erosion of surface soil is size selective. The runoff sediment contained finer particle/aggregates rich in organic matter compared to its original surface soil; (3) the distribution coefficient (Kd) of propiconazole was significantly higher in the runoff sediment than in the parent soil. According to our calculation, particle-bound propiconazole can represent up to 23% of the total amount of propiconazole in a water sample with a sediment concentration of 7600 mg l(-1), which will significantly influence the transport behavior of the pesticide.

Predictors of patients' choices for breast-conserving therapy or mastectomy: a prospective study.

A study was undertaken to describe the treatment preferences and choices of patients with breast cancer, and to identify predictors of undergoing breast-conserving therapy (BCT) or mastectomy (MT). Consecutive patients with stage I/II breast cancer were eligible. Information about predictor variables, including socio-demographics, quality of life, patients' concerns, decision style, decisional conflict and perceived preference of the surgeon was collected at baseline, before decision making and surgery. Patients received standard information (n=88) or a decision aid (n=92) as a supplement to support decision making. A total of 180 patients participated in the study. In all, 72% decided to have BCT (n=123); 28% chose MT (n=49). Multivariate analysis showed that what patients perceived to be their surgeons' preference and the patients' concerns regarding breast loss and local tumour recurrence were the strongest predictors of treatment preference. Treatment preferences in itself were highly predictive of the treatment decision. The decision aid did not influence treatment choice. The results of this study demonstrate that patients' concerns and their perceptions of the treatment preferences of the physicians are important factors in patients' decision making. Adequate information and communication are essential to base treatment decisions on realistic concerns, and the treatment preferences of patients.

[Methicillin resistant Staphylococcus aureus (MRSA) infection in a dog in the Netherlands]. / Een meticilline-resistente Staphylococcus aureus (MRSA)-infectie bij een hond in Nederland.

In the Netherlands, methicillin resistant Staphylococcus aureus (MRSA) are regularly isolated from humans. We present the first isolation of MRSA from animal origin in the Netherlands. A coagulase positive staphylococcus was cultured from an infected wound in a Dutch dog that recently underwent surgery abroad. The staphylococcus was resistant to methicillin, ampicillin, amoxycillin + clavulanic acid, cephalexin, erythromycin, lincomycin, tetracycline, gentamicin and enrofloxacin. It was identified as S. aureus by fermentation of mannitol and Martineau-PCR. The presence of mecA was confirmed by PCR.