Treatment selection of early stage non-small cell lung cancer: the role of the patient in clinical decision making.

BACKGROUND: The objective of this study is to investigate the role and experience of early stage non-small cell lung cancer (NSCLC) patient in decision making process concerning treatment selection in the current clinical practice. METHODS: Stage I-II NSCLC patients (surgery 55 patients, SBRT 29 patients, median age 68) were included in this prospective study and completed a questionnaire that explored: (1) perceived patient knowledge of the advantages and disadvantages of the treatment options, (2) experience with current clinical decision making, and (3) the information that the patient reported to have received from their treating physician. This was assessed by multiple-choice, 1-5 Likert Scale, and open questions. The Decisional Conflict Scale was used to assess the decisional conflict. Health related quality of life (HRQoL) was measured with SF-36 questionnaire. RESULTS: In 19% of patients, there was self-reported perceived lack of knowledge about the advantages and disadvantages of the treatment options. Seventy-four percent of patients felt that they were sufficiently involved in decision-making by their physician, and 81% found it important to be involved in decision making. Forty percent experienced decisional conflict, and one-in-five patients to such an extent that it made them feel unsure about the decision. Subscores with regard to feeling uninformed and on uncertainty, contributed the most to decisional conflict, as 36% felt uninformed and 17% of patients were not satisfied with their decision. HRQoL was not influenced by patient experience with decision-making or patient preferences for shared decision making. CONCLUSIONS: Dutch early-stage NSCLC patients find it important to be involved in treatment decision making. Yet a substantial proportion experiences decisional conflict and feels uninformed. Better patient information and/or involvement in treatment-decision-making is needed in order to improve patient knowledge and hopefully reduce decisional conflict.

Development and evaluation of a blended educational programme for general practitioners' trainers to stimulate proactive HIV testing.

BACKGROUND: In the Netherlands, a substantial proportion of newly diagnosed HIV patients present late for care, therefore, we investigated the effectiveness of a blended educational programme for trainers of GPs designed to stimulate proactive HIV testing. METHODS: GP trainers at the Academic Medical Center in Amsterdam were invited to participate in a two days training programme incorporating evidence-based practice guidelines and multiple teaching strategies, including interactive lectures, discussion groups, e-learning and quality improvement targets. The GP trainers completed questionnaires before and after the programme to evaluate the effect of the programme. We also used six-monthly cumulative laboratory data from 2010 to 2015 to compare the participating GPs' HIV tests to the general trend in testing among non-participating GPs. RESULTS: 150 GP trainers attended the first session, and 74 completed the questionnaires for both sessions. GPs median score on achieving their quality improvement targets was high and the quality of the programme highly appreciated. Between 2010 and 2013, the mean annual number of laboratory-documented HIV tests decreased by 9.1% in the 624 GPs in the control group, and by 13.0% for 11 GPs in the intervention group. After the programme, the annual decreases were 2.3% and 1.8%, respectively. Before the programme, the GPs in the intervention group had 50% more laboratory-documented HIV tests than GPs in the control group. After the programme, GPs in the intervention group had twice as many laboratory-documented HIV tests as the controls. CONCLUSIONS: We provided a detailed description of a programme based on educational and clinical evidence. We could not retrieve laboratory-documented HIV testing data for the majority of GPs in both the intervention and control groups. Therefore, the limited results should be interpreted with caution as our findings may not be representative of all participants. The blended educational programme appears to have stabilized - at a higher level - the initially stronger downward trend in testing for 11 GPs undergoing the intervention, indicating that the programme may have had an impact on their HIV testing behaviour.

The value of prognostic and predictive parameters in early-stage lung adenocarcinomas: A comparison between biopsies and resections.

INTRODUCTION: Since lung adenocarcinoma (LUAD) biopsies are usually small, it is questionable if their prognostic and predictive information is comparable to what is offered by large resection specimens. This study compares LUAD biopsies and resection specimens for their ability to provide prognostic and predictive parameters. METHODS: We selected 187 biopsy specimens with stage I and II LUAD. In 123 cases, subsequent resection specimens were also available. All specimens were evaluated for growth pattern, nuclear grade, fibrosis, inflammation, and genomic alterations. Findings were compared using non-parametric testing for categorical variables. Model performance was assessed using the area under the curve for both biopsies and resection specimens, and overall (OS) and disease-free survival (DFS) was calculated. RESULTS: The overall growth pattern concordance between biopsies and resections was 73.9%. The dominant growth pattern correlated with OS and DFS in resected adenocarcinomas and for high-grade growth pattern in biopsies. Multivariate analysis of biopsy specimens revealed that T2-tumors, N1-status, KRAS mutations and a lack of other driver mutations were associated with poorer survival. Model performance using clinical, histological and genetic data from biopsy specimens for predicting OS and DSF demonstrated an AUC of 0.72 and 0.69, respectively. CONCLUSIONS: Our data demonstrated the prognostic relevance of a high-grade growth pattern in biopsy specimens of LUAD. Combining clinical, histological and genetic information in one model demonstrated a suboptimal performance for DFS prediction and good performance for OS prediction. However, for daily practice, more robust (bio)markers are required to predict prognosis and stratify patients for therapy and follow-up.

New roads open up for implementing immunotherapy in mesothelioma.

Treatment options for malignant mesothelioma are limited, and the results with conventional therapies have been rather disappointing to this date. Chemotherapy is the only evidence-based treatment for mesothelioma patients in good clinical condition, with an increase in median survival of only 2 months. Therefore, there is urgent need for a different approach to battle this malignancy. As chronic inflammation precedes mesothelioma, the immune system plays a key role in the initiation of this type of tumour. Also, many immunological cell types can be found within the tumour at different stages of the disease. However, mesothelioma cells can evade the surveillance capacity of the immune system. They build a protective tumour microenvironment to harness themselves against the immune system's attacks, in which they even abuse immune cells to act against the antitumour immune response. In our opinion, modulating the immune system simultaneously with the targeting of mesothelioma tumour cells might prove to be a superior treatment. However, this strategy is challenging since the tumour microenvironment possesses numerous forms of defence strategies. In this paper, we will discuss the interplay between immunological cells that can either inhibit or stimulate tumour growth and the challenges associated with immunotherapy. We will provide possible strategies and discuss opportunities to overcome these problems.

ETV6-NTRK3 translocation-associated low-grade mucinous bronchial adenocarcinoma: A novel bronchial salivary gland-type non-small cell lung cancer subtype.

INTRODUCTION: NTRK fusion genes have been found in several solid tumors, among which NSCLC and sarcoma. Novel NTRK translocation-related tumors are still being discovered. METHODS: We report a 49-year-old patient with a mass in the left lower lung lobe that was resected. This specimen was analyzed and sequenced using targeted DNA next generation sequencing (NGS) and anchored-multiplex-PCR (AMP) targeted RNA NGS. RESULTS: On pathological evaluation, a peribronchial mucinous neoplasm with a unique morphology was found. RNA NGS analysis showed anETV6-NTRK3 translocation in a low-grade mucinous bronchial adenocarcinoma. CONCLUSIONS: This entity represents a novel subtype of non-small cell lung cancer, which we would like to term 'ETV6-NTRK3 translocation-associated low-grade mucinous bronchial adenocarcinoma'.

A nationwide population-based cohort study of surgical care for patients with superior sulcus tumors: Results from the Dutch Lung Cancer Audit for Surgery (DLCA-S).

OBJECTIVES: Data on national patterns of care for patients with superior sulcus tumors (SST) is currently lacking. We investigated the distribution of surgical care and outcome for patients with SST in the Netherlands. MATERIAL AND METHODS: Data was retrieved from the Dutch Lung Cancer Audit for Surgery (DLCA-S) for all patients undergoing resection for clinical stage IIB-IV SST from 2012 to 2019. Because DLCA-S is not linked to survival data, survival for a separate cohort (2015-2017) was obtained from the Netherlands Cancer Registry (NCR). RESULTS: In the study period, 181 patients had SST surgery, representing 1.03% (181/17488) of all lung cancer pulmonary resections. For 2015-2017, the SST resection rate was 14.4% (79/549), and patients with stage IIB/III SST treated with trimodality had a 3-year overall survival of 67.4%. 63.5% of patients were male, and median age was 60 years. Almost 3/4 of tumors were right sided. Surgery was performed in 20 hospitals, with average number of annual resections ranging from ≤ 1 (n = 17) to 9 (n = 1). 39.8% of resections were performed in 1 center and 63.5% in the 3 most active centers. 12.7% of resections were extended (e.g. vertebral resection). 85.1% of resections were complete (R0). Morbidity and 30-day mortality were 51.4% and 3.3% respectively. Despite treating patients with a higher ECOG performance score and more extended resections, the highest volume center had rates of morbidity/mortality, and length of hospital stay that were comparable to those of the medium volume (n = 2) and low-volume centers (n = 1). CONCLUSION: In the Netherlands, surgery for SST accounts for about 1% of all lung cancer pulmonary resections, the number of SST resections/hospital/year varies widely, with most centers performing an average of ≤ 1/year. Morbidity and mortality are acceptable and survival compares favourably with the literature. Although further centralisation is possible, it is unknown whether this will improve outcomes.

Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial.

The European Organisation for Research and Treatment of Cancer (EORTC; protocol 08031) phase II trial investigated the feasibility of trimodality therapy consisting of induction chemotherapy followed by extrapleural pneumonectomy and post-operative radiotherapy in patients with malignant pleural mesothelioma (with a severity of cT3N1M0 or less). Induction chemotherapy consisted of three courses of cisplatin 75 mg·m⁻² and pemetrexed 500 mg·m⁻². Nonprogressing patients underwent extrapleural pneumonectomy followed by post-operative radiotherapy (54 Gy, 30 fractions). Our primary end-point was "success of treatment" and our secondary end-points were toxicity, and overall and progression-free survival. 59 patients were registered, one of whom was ineligible. Subjects' median age was 57 yrs. The subjects' TNM scores were as follows: cT1, T2 and T3, 36, 16 and six patients, respectively; cN0 and N1, 57 and one patient, respectively. 55 (93%) patients received three cycles of chemotherapy with only mild toxicity. 46 (79%) patients received surgery and 42 (74%) had extrapleural pneumonectomy with a 90-day mortality of 6.5%. Post-operative radiotherapy was completed in 37 (65%) patients. Grade 3-4 toxicity persisted after 90 days in three (5.3%) patients. Median overall survival time was 18.4 months (95% CI 15.6-32.9) and median progression-free survival was 13.9 months (95% CI 10.9-17.2). Only 24 (42%) patients met the definition of success (one-sided 90% CI 0.36-1.00). Although feasible, trimodality therapy in patients with mesothelioma was not completed within the strictly defined timelines of this protocol and adjustments are necessary.

The distinction between retractor and protractor muscles of the freshwater snail's male organ has no physiological basis.

Many animals are equipped with organs that can be everted, a notable example being male copulatory organs. The ability to protrude or evert an organ generally requires protractor and retractor muscles. Male copulatory behaviour of the pond snail Lymnaea stagnalis (L.) involves eversion (protraction) and retraction of the relatively large penis-carrying organ. For this preputium, protractor and retractor muscle bands have been defined, which implies eversion and retraction through the activity of these muscle bands. However, no physiological data are available that confirm that the terms protractor and retractor are appropriate. To test whether eversion and retraction are possible without protractor and/or retractor muscle bands, lesion experiments were performed. The results show that with either one or several muscle bands lesioned, snails were still capable of everting their preputium and using it for copulation. However, the majority of animals that had six or more muscle bands lesioned were unable to retract its preputium. Hence, retractor muscle bands serve their designated function whereas protractor muscle bands do not. We therefore suggest that a different terminology is used in which all muscle bands are retractors and, based on their location, are either called distal or proximal retractors. The findings furthermore indicate that the preputium muscle bands are normally contracted, possibly in a catch state, retaining the organ inside without high-energy expenditure.

[A dyspnoeic woman with an abnormal chest image]. / Een benauwde vrouw met een afwijkende thoraxfoto.

A 19-year-old woman presented with a productive cough, fever and chest pain. Clinical and chest X-ray findings prompted us to do a CT-scan, which revealed a mediastinal mass extending in the left thoracic cavity, suggestive of a teratoma with an obstructive pneumonia. The patient was successfully treated with intravenous antibiotics and surgical removal of the tumour.

Donor-specific immune regulation by CD8 lymphocytes expanded from rejecting human cardiac allografts.

To assess whether regulatory T cells are present in rejecting human cardiac allografts, we performed functional analyses of graft lymphocytes (GLs) expanded from endomyocardial biopsies (EMB; n = 5) with histological signs of acute cellular rejection. The GL cultures were tested for their proliferative capacity and regulatory activity on allogeneic-stimulated peripheral blood mononuclear cells (PBMC) of the patient (ratio PBMC:GLs = 5:1). Three of these GL cultures were hyporesponsive to donor antigens and suppressed the antidonor proliferative T-cell response of PBMC, but not the anti-third-party response. Interestingly, it was the CD8(+) GL subset of these cultures that inhibited the antidonor response (65-91% inhibition of the proportion of proliferating cells); the CD4(+) GLs of the expanded GL cultures were not suppressive. In conclusion, CD8(+) GLs expanded from rejecting human cardiac allografts can exhibit donor-specific immune regulatory activities in vitro. We suggest that during acute cellular rejection, GLs may not only consist of graft-destructing effector T cells, but also of cells of the CD8(+) type with the potential to specifically inhibit antidonor immune reactivity.

Donor-derived mesenchymal stem cells remain present and functional in the transplanted human heart.

Mesenchymal stem cells (MSC) are characterized by their multilineage differentiation capacity and immunosuppressive properties. They are resident in virtually all tissues and we have recently characterized MSC from the human heart. Clinical heart transplantation offers a model to study the fate of transplanted human MSC. In this study, we isolated and expanded MSC from heart tissue taken before, and 1 week up to 6 years after heart transplantation. MSC from posttransplantation tissue were all of donor origin, demonstrating the longevity of endogenous MSC and suggesting an absence of immigration of recipient MSC into the heart. MSC isolated from transplanted tissue showed an immunophenotype that was characteristic for MSC and maintained cardiomyogenic and osteogenic differentiation capacity. They furthermore preserved their ability to inhibit the proliferative response of donor-stimulated recipient peripheral blood mononuclear cells. In conclusion, functional MSC of donor origin remain present in the heart for several years after transplantation.

Selective recording and stimulation of individual identified neurons in freely behaving Aplysia.

A neuroethological technique is described for selective recording and stimulation of an individual neuron in freely behaving Aplysia by means of a fine wire glued into the connective tissue sheath above the identified cell body. A whole-nerve cuff electrode simultaneously monitored functionally related multiunit axon activity. For biophysical analysis the soma was impaled with a microelectrode when the ganglion was subsequently exposed. The technique is illustrated for several identified neurons involved in different behaviors.

Towards the Optical Detection of Field Cancerization in the Buccal Mucosa of Patients with Lung Cancer.

INTRODUCTION: An increase in detection of early-stage asymptomatic lung tumors could increase the overall survival rate of lung cancer patients. A new approach to cancer (pre-)screening focusses on detecting field cancerization instead of the tumor itself. The objective of this study was to investigate the use of optical spectroscopy to detect field cancerization in the buccal mucosa of lung cancer patients. METHODS: Optical buccal mucosa measurements were performed in lung cancer patients and controls using multidiameter single-fiber reflectance spectroscopy. We analyzed whether the measured optical parameters could distinguish lung cancer patients from controls. RESULTS: Twenty-three lung cancer patients, 24 chronic obstructive pulmonary disease (COPD) control patients, and 36 non-COPD controls were included. The majority of tumors were non-small-cell lung carcinomas (96%) and classified as stage I (48%). The tissue scattering properties µs' and γ at 800 nm and the tissue bilirubin concentration were all near-significantly different (P=.072, 0.058, and 0.060, respectively) between the lung cancer and COPD group. µs' at 800 nm had a sensitivity of 74% and a specificity of 63%. The microvascular blood oxygen saturation of the lung cancer patients was also higher than the COPD patients (78% vs. 62%, P=.002), this is probably a consequence of the systemic effect of COPD. CONCLUSIONS: We have demonstrated that µs' at 800 nm is increased in the buccal mucosa of patients with lung cancer compared to controls with COPD. This might be an indication of field cancerization in the oral cavity of patients with lung cancer.

Guidelines for heart transplantation.

Based on the changes in the field of heart transplantation and the treatment and prognosis of patients with heart failure, these updated guidelines were composed by a committee under the supervision of both the Netherlands Society of Cardiology and the Netherlands Association for Cardiothoracic surgery (NVVC and NVT).THE INDICATION FOR HEART TRANSPLANTATION IS DEFINED AS: 'End-stage heart disease not remediable by more conservative measures'.CONTRAINDICATIONS ARE: irreversible pulmonary hypertension/elevated pulmonary vascular resistance; active systemic infection; active malignancy or history of malignancy with probability of recurrence; inability to comply with complex medical regimen; severe peripheral or cerebrovascular disease and irreversible dysfunction of another organ, including diseases that may limit prognosis after heart transplantation.Considering the difficulties in defining end-stage heart failure, estimating prognosis in the individual patient and the continuing evolution of available therapies, the present criteria are broadly defined. The final acceptance is done by the transplant team which has extensive knowledge of the treatment of patients with advanced heart failure on the one hand and thorough experience with heart transplantation and mechanical circulatory support on the other hand. (Neth Heart J 2008;16:79-87.).

WWW mesothelioma information: Surfing on unreliable waters. A cross-sectional study into the content and quality of online informational resources for mesothelioma patients.

OBJECTIVE: Malignant Mesothelioma (MM) is a rare asbestos related disease mostly diagnosed in low-skilled patients. The decision-making process for MM treatment is complicated, making an adequate provision of information necessary. The objective of this study is to assess the content and quality of online informational resources available for Dutch MM patients. METHODS: The first 100 hits of a Google search were studied using the JAMA benchmarks, the Modified Information Score (MIS) and the International Patient Decision Aid Standard Scoring (IPDAS). RESULTS: A total of 37 sources were included. Six of the 37 resources were published by hospitals. On average, the informational resources scored 37 points on the MIS (scale 0-100). The resources from a (bio)medical sources scored the best on this scale. However, on the domain of use of language, these resources scored the worst. CONCLUSIONS: The current level of medical content and quality of online informational resources for patient with MM is below average and cannot be used as decision-aids for patients. PRACTICE IMPLICATIONS: The criteria used in this article could be used for future improvements of online informational resources for patients, both online, offline and through health education in the care path.

[Long-term results of the multidisciplinary surgical treatment of non-small-cell bronchial carcinoma in the superior sulcus (Pancoast tumour): a retrospective study]. / Langetermijnresultaten van de multidisciplinaire chirurgische behandeling van niet-kleincellig bronchuscarcinoom in de thoraxkoepel (pancoasttumor); retrospectief onderzoek.

OBJECTIVE: To establish the long-term results of a combination of radiotherapy or chemoradiotherapy and surgery for the treatment of patients with a Pancoast tumour in the Erasmus MC-Daniel den Hoed, Rotterdam, the Netherlands, with special attention for the prognostic factors. DESIGN: Retrospective. METHODS: During the period from 1 January 1991 to 31 December 2004, 36 patients underwent surgical treatment combined with radiotherapy or chemoradiotherapy for a non-small-cell bronchial carcinoma with invasion of the superior sulcus. The study was terminated on 31 January 2006. The data were analysed according to the intention-to-treat principle, with overall survival and disease-free survival as the outcome variables. Cox regression analysis revealed differences between the subgroups on the basis of which prognostic factors could be studied. RESULTS: 36 patients with a non-small-cell bronchial carcinoma invading the superior sulcus (Pancoast tumour) underwent multidisciplinary treatment consisting of pre-operative radiotherapy (since 2002 concomitant chemoradiotherapy), superior-sulcus resection and (partial) lung resection with intra-operative brachytherapy. 2 patients died postoperatively. In 80% of the patients there was a positive histological effect of the preoperative treatment. The median follow-up was 26 months. The 2-year overall and disease-free survival was 45 and 31%, respectively, and at 5 years this was 28 and 19%. These results were comparable with those for stage IIB lung cancer without invasion. Favourable prognostic factors were: at least 75% necrosis of the tumour after pre-treatment, lack of positive mediastinal lymph nodes, and younger age.

[Legally capable care refuser has rights as well as responsibilities]. / Wilsbekwame zorgmijder heeft rechten én plichten.

It is hard to determine how a doctor should act when a patient with a somatic condition refuses medical care. The Dutch law obliges a doctor to inform a patient about his condition and the possible treatment options. This includes an effort to reach out and make contact with the patient. But how far should a doctor's responsibility reach when a patient refuses contact? We point out that refusal of medical care can also be seen in the light of a patient's autonomy. We thereby propose that falling ill gives responsibilities to a patient too, which include making the effort to seek medical care and cooperate with treatment.

Intracochlear misdirected implantation of a cochlear implant.

This paper discusses a rare complication of an intracochlear misdirection of the electrode of a cochlear implant in a 55-year-old male. The patient received a cochlear implant using the mastoid-saving surgical approach. Intraoperative measurements showed impedance and NRT reactions suggesting a reasonable function of the inner ear and the implant. Postoperatively our patient suffered from passing vertigo. Postoperative CT scans revealed a misdirection implantation of the cochlear implant into the vestibular part of the inner ear. A deformed implant was removed and a reimplantation was successfully performed after enlarging and reshaping the cochleostomy. Our patient now enjoys all the benefits of an optimal functioning cochlear implant. Intracochlear misdirection of the electrode can occur even when intraoperative measurements seem to be normal. When a patient suffers from unexplained vertigo after cochlear implantation with a poor function of the implant a misdirection of the active electrode must be considered. New high resolution peroperative three-dimensional imaging techniques can probably help to avoid such insertion failures.

[Anxiety disorders and epilepsy: not unknown, but sometimes unexpected. A case study]. / Angstklachten en epilepsie: niet onbekend, maar soms onverwacht.

Epileptic disorders can manifest themselves with symptoms of anxiety and panic. In clinical practice it is not always easy to achieve a correct diagnosis. The subject of this case study is an adult with symptoms of anxiety and panic who was referred to the mental health care service but who was diagnosed as having epilepsy when subjected to a supplementary examination. Psychological and in particular anxiety symptoms in epilepsy are discussed. The psychiatrist needs to consider the possibility of epilepsy in a patient presenting with anxiety symptoms.