The objective of this study was to evaluate trends in survival and health care costs in metastatic melanoma in the era of targeted and immunotherapeutic drugs.
Data on survival and health care ...resource use were retrieved from the Dutch Melanoma Treatment Registry. The Kaplan–Meier method was used to estimate overall survival. Health care costs and budget impact were computed by applying unit costs to individual patient resource use. All outcomes were stratified by year of diagnosis.
Baseline characteristics were balanced across cohort years. The percentage of patients receiving systemic treatment increased from 73% in 2013 to 90% in 2018. Patients received on average 1.85 standard deviation (SD): 1.14 lines of treatment and 41% of patients received at least two lines of treatment. Median survival increased from 11.8 months in 2013 95% confidence interval (CI): 10.7-13.7 months to 21.1 months in 2018 (95% CI: 18.2 months-not reached). Total mean costs were €100 330 (SD: €103 699); systemic treatments accounted for 84% of the total costs. Costs for patients who received systemic treatment €118 905 (SD: €104 166) remained reasonably stable over the years even after the introduction of additional (combination of) novel drugs. From mid-2013 to 2018, the total budget impact for all patients was €452.79 million.
Our study shows a gain in survival in the era of novel targeted and immunotherapeutic drugs. These novel drugs came, however, along with substantial health care costs. Further insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in the treatment of patients with metastatic melanoma.
•The median survival of patients with metastatic melanoma increased from 11.8 months in 2013 to 21.1 months in 2018.•The gain in survival came along with substantial health care costs; health care costs were on average €100 300 per patient.•Costs were much higher for patients with systemic treatment (€118 905) than for patients without systemic treatment (€8316).•Costs for patients who received systemic treatment remained stable even after the introduction of additional novel drugs.•Insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in metastatic melanoma.
Context: Medullary thyroid carcinoma (MTC) metastasizes early in its clinical course. No effective systemic therapy is available. Generally (somatic or germline), mutations in the rearranged during ...transfection gene are considered essential in the pathogenesis of MTC.
Objective: We investigated imatinib, a tyrosine kinase inhibitor, as a potential treatment in patients with disseminated MTC.
Design: A phase II study was initiated using 600 mg imatinib daily with a possible dose increase to 800 mg in case of progression. Standard Response Evaluation Criteria in Solid Tumors were used using computed tomography or magnetic resonance imaging every 2 months.
Results: There were 15 patients with disseminated MTC treated for up to 12 months. No objective responses were observed. Four patients had stable disease over 24 months. Three patients stopped treatment due to toxic effects fatigue (n = 2) and nausea (n = 1). In four cases the dose of imatinib was decreased because of toxicity rash and malaise (n = 2) and laryngeal swelling (n = 2). Emergency tracheotomy was performed in two cases due to mucosal swelling of the larynx in patients with recurrent nerve palsy and a narrow vocal cleft. In nine patients with a history of a thyroidectomy, the dose of supplemental thyroid hormone was increased because of serious hypothyroidism.
Conclusions: Imatinib therapy yielded no objective responses and induced considerable toxicity in patients with MTC. A minority of patients had stable disease. Patients with supplemented hypothyroidism or with recurrent nerve palsy are specifically at risk for serious adverse events and need special attention when treated with imatinib.
To study the impact of fetal gender on the risk of spontaneous preterm birth in various ethnicities.
National cohort study in which all singleton live births from 25
weeks onwards without congenital ...anomalies were included of African, Asian, and Mediterranean women (1999-2010). Our primary outcome measure was preterm birth before 37 weeks. Per ethnic group, male and female neonates were compared.
In each ethnic group, male fetuses were at increased risk of preterm birth (adjusted odds ratio (aOR) 1.63 for African, aOR 1.71 for Asian, and aOR 1.84 for Mediterranean males). The population-attributable risk of male gender on spontaneous preterm birth is lower in African women (3.9%) than in Asian (10.3%) and Mediterranean women (9.0%).
Male fetal gender is associated with spontaneous preterm birth in African, Asian, and Mediterranean women, but the total impact of ethnicity on spontaneous preterm birth rate is different.
Abstract
STUDY QUESTION
Does a previous Caesarean section affect reproductive outcomes, including live birth, in women after IVF or ICSI?
SUMMARY ANSWER
A previous Caesarean section impairs live ...birth rates after IVF or ICSI compared to a previous vaginal delivery.
WHAT IS KNOWN ALREADY
Rates of Caesarean sections are rising worldwide. Late sequelae of a Caesarean section related to a niche (Caesarean scar defect) include gynaecological symptoms and obstetric complications. A systematic review reported a lower pregnancy rate after a previous Caesarean section (RR 0.91 CI 0.87–0.95) compared to a previous vaginal delivery. So far, studies have been unable to causally differentiate between problems with fertilisation, and the transportation or implantation of an embryo. Studying an IVF population allows us to identify the effect of a previous Caesarean section on the implantation of embryos in relation to a previous vaginal delivery.
STUDY DESIGN, SIZE, DURATION
We retrospectively studied the live birth rate in women who had an IVF or ICSI treatment at the IVF Centre, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands, between 2006 and 2016 with one previous delivery. In total, 1317 women were included, of whom 334 had a previous caesarean section and 983 had previously delivered vaginally.
PARTICIPANTS/MATERIALS, SETTING, METHODS
All secondary infertile women, with only one previous delivery either by caesarean section or vaginal delivery, were included. If applicable, only the first fresh embryo transfer was included in the analyses. Patients who did not intend to undergo embryo transfer were excluded. The primary outcome was live birth. Multivariate logistic regression analyses were used with adjustment for possible confounders ((i) age; (ii) pre-pregnancy BMI; (iii) pre-pregnancy smoking; (iv) previous fertility treatment; (v) indication for current fertility treatment: (a) tubal, (b) male factor and (c) endometriosis; (vi) embryo quality; and (vii) endometrial thickness), if applicable. Analysis was by intention to treat (ITT).
MAIN RESULTS AND THE ROLE OF CHANCE
Baseline characteristics of both groups were comparable. Live birth rates were significantly lower in women with a previous caesarean section than in women with a previous vaginal delivery, 15.9% (51/320) versus 23.3% (219/941) (OR 0.63 95% CI 0.45–0.87) in the ITT analyses. The rates were also lower for ongoing pregnancy (20.1 versus 28.1% (OR 0.64 95% CI 0.48–0.87)), clinical pregnancy (25.7 versus 33.8% (OR 0.68 95% CI 0.52–0.90)) and biochemical test (36.2 versus 45.5% (OR 0.68 95% CI 0.53–0.88)). The per protocol analyses showed the same differences (live birth rate OR 0.66 95% CI 0.47–0.93 and clinical pregnancy rate OR 0.72 95% CI 0.54–0.96).
LIMITATIONS, REASONS FOR CAUTION
This study is limited by its retrospective design. Furthermore, 56 (16.3%) cases lacked data regarding delivery outcomes, but these were equally distributed between the two groups.
WIDER IMPLICATIONS OF THE FINDINGS
The lower clinical pregnancy rates per embryo transfer indicate that implantation is hampered after a caesarean section. Its relation with a possible niche (caesarean scar defect) in the uterine caesarean scar needs further study. Our results should be discussed with clinicians and patients who consider an elective caesarean section.
STUDY FUNDING/COMPETING INTEREST(S)
Not applicable.
TRIAL REGISTRATION NUMBER
This study has been registered in the Dutch Trial Register (Ref. No. NL7631 http://www.trialregister.nl).
Introduction
Caring for a significant other during cancer treatment can be demanding. Little is known about the well-being of informal caregivers of patients with colon cancer. This study aims to ...examine informal caregiver well-being during adjuvant chemotherapy for colon cancer.
Material and methods
This exploratory longitudinal, prospective study measured the course of informal caregiver burden (Self-Perceived Pressure of Informal Care), distress (Hospital Anxiety and Depression Scale), health-related quality of life (RAND-36), marital satisfaction (Maudsley Marital Questionnaire), social support (Social Support List – Discrepancies), fatigue (Abbreviated Fatigue Questionnaire), and self-esteem (Caregiver Reaction Assessment) before (T0), during (T1), and after (T2) patients’ treatment.
Results
Baseline data of 60 out of 76 eligible dyads (79%) were analyzed. Mean levels of informal caregiver burden and distress improved significantly over time, as did their health-related quality of life and perceived social support. At baseline, 30% and 26.7% of informal caregivers reported moderate-to-high levels of burden and clinically relevant levels of distress, respectively, which changed to 20% and 18.8% at T2. Informal caregiver burden and distress at baseline were the strongest predictors of informal caregiver burden and distress during and following patients’ treatment, respectively.
Conclusion
When informal caregivers and patients experience problems before start of adjuvant chemotherapy, problems seem to improve over time. Approximately 20% of informal caregivers remain burdened and distressed after patients’ end of treatment. Paying attention to baseline distress and burden seems indicated, as these were strong predictors of informal caregivers’ well-being during and after treatment.
In many forest types, over half of the total stand biomass is located in the forest floor. Carbon emissions during wildland fire are directly related to biomass (fuel) consumption. Consumption of ...forest floor fuel varies widely and is the greatest source of uncertainty in estimating total carbon emissions during fire. We used experimental burn data (59 burns, four fuel types) and wildfire data (69 plots, four fuel types) to develop a model of forest floor fuel consumption and carbon emissions in nonpeatland standing-timber fuel types. The experimental burn and wildfire data sets were analyzed separately and combined by regression to provide fuel consumption models. Model variables differed among fuel types, but preburn fuel load, duff depth, bulk density, and Canadian Forest Fire Weather Index System components at the time of burning were common significant variables. The regression R2 values ranged from 0.206 to 0.980 (P < 0.001). The log-log model for all data combined explained 79.5% of the regression variation and is now being used to estimate annual carbon emissions from wildland fire. Forest floor carbon content at the wildfires ranged from 40.9% to 53.9%, and the carbon emission rate ranged from 0.29 to 2.43 kg·m-2.
The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision‐making. Analysis were performed on advanced ...melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune‐ or targeted therapy, who met ≥1 trial exclusion criteria. These criteria were derived from the KEYNOTE‐006 and CHECKMATE‐067/‐066 phase III trials. Prognostic importance of factors associated with overall survival (OS) was assessed with the Kaplan‐Meier method, Cox models, predicted OS probabilities of prognostic subgroups and a conditional inference survival tree (CIST). A nationwide population‐based registry was used as data source. Of 2536 systemically treated patients with advanced melanoma, 1004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria strongly associated with OS in systemically treated ineligible patients were Eastern Cooperative Oncology Group Performance Score (ECOG PS) ≥2, brain metastases (BM) and lactate dehydrogenase (LDH) of >500 U/L. Patients with ECOG PS of ≥2 with or without symptomatic BM had a predicted mOS of 6.5 and 11.3 months and a 3‐year survival probability of 9.3% and 23.6%, respectively. The CIST showed the strongest prognostic covariate for survival was LDH, followed by ECOG PS. The prognosis of patients with LDH of >500 U/L is poor, but long‐term survival is possible. The prognosis of ineligible patients with advanced melanoma in real‐world was very heterogeneous and highly dependent on LDH value, ECOG PS and symptomatic BM.
What's new?
By necessity, randomized controlled trials (RCTs) exclude many patients. However, these ineligible patients are often still treated with new systemic therapies on an individual basis. In this study, the authors examined how various subgroups of ineligible patients fared following treatment for advanced melanoma. They found that several criteria were strongly associated with prognosis in these patients, including lactate dehydrogenase (LDH) levels. These results should provide clinicians with a decision tree of prognostic factors to help guide treatment decisions.
Mycoplasma pneumoniae and Streptococcus pneumoniae are the most common bacterial causes of pneumonia in children. The clinical characteristics of pneumonia differ significantly between the two ...bacteria. We aimed to elucidate the differences in pathogenesis between M. pneumoniae and S. pneumoniae by characterizing the respiratory epithelial cell immune response to both pathogens. Using primary human bronchial epithelial cells in air-liquid interface cultures, we observed lower production of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in response to M. pneumoniae than to S. pneumoniae. In contrast to the differences in proinflammatory cytokine production, Toll-like receptor 2 (TLR2)-mediated signaling in response to M. pneumoniae was stronger than to S. pneumoniae. This difference largely depended on TLR1 and not TLR6. We found that M. pneumoniae, but not S. pneumoniae, also induced signaling of TLR10, a coreceptor of TLR2 that has inhibitory properties. M. pneumoniae-induced TLR10 signaling on airway epithelial cells was partially responsible for low IL-8 production, as blocking TLR10 by specific antibodies increased cytokine production. M. pneumoniae maintained Th2-associated cytokine production by epithelial cells, which concurs with the known association of M. pneumoniae infection with asthma. M. pneumoniae left IL-33 levels unchanged, whereas S. pneumoniae downregulated IL-33 production both under homeostatic and Th2-promoting conditions. By directly comparing M. pneumoniae and S. pneumoniae, we demonstrate that M. pneumoniae avoids induction of proinflammatory cytokine response despite its ability to induce robust TLR2 signaling. Our new findings suggest that this apparent paradox may be partially explained by M. pneumoniae-induced signaling of TLR2/TLR10.
Abstract Early detection and subsequent treatment of developmental dysplasia of the hip (DDH) is thought to improve its prognosis. Frequently reported risk factors for DDH are a positive family ...history of DDH, female sex and breech presentation, but there is not a lot of systematic knowledge about DDH risk factors. We performed a systematic review and meta-analysis of the available evidence on DDH risk factors. We searched Medline, EMBASE and The Cochrane Library from conception up until October 2011 for primary articles on the subject. All studies reporting on potential risk factors for DDH that allowed construction of a two-by-two table were selected. Language restrictions were not applied. Two reviewers independently selected studies, extracted data and assessed study quality. The association between risk factors and DDH was expressed as a common odds ratio (OR) with a 95% confidence interval (CI). We identified 30 relevant studies reporting on 1,494,387 children; 26 studies were cohort studies and four studies used a case–control design. The risk of DDH was strongly increased in case of breech delivery (OR 5.7, 95% CI 4.4–7.4), female sex (OR 3.8, 95% CI 3.0–4.6) a positive family history of DDH (OR 4.8, 95% CI 2.8–8.2) and clicking hips at clinical examination (OR 8.6, 95% CI 4.5–16.6). This meta-analysis shows that infants born in breech presentation, female infants, infants with a positive family history and clicking hips at clinical examination have an increased risk for DDH. This knowledge can be helpful in the development of screening programs for DDH.
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