On the isoperimetric problem for the Laplacian with Robin and Wentzell boundary conditions

Doctor of PhilosophyWe consider the problem of minimising the eigenvalues of the Laplacian with Robin boundary conditions $\frac{\partial u}{\partial \nu} + \alpha u = 0$ and generalised Wentzell boundary conditions $\Delta u + \beta \frac{\partial u}{\partial \nu} + \gamma u = 0$ with respect to the domain $\Omega \subset \mathbb R^N$ on which the problem is defined. For the Robin problem, when $\alpha > 0$ we extend the Faber-Krahn inequality of Daners [Math. Ann. 335 (2006), 767--785], which states that the ball minimises the first eigenvalue, to prove that the minimiser is unique amongst domains of class $C^2$. The method of proof uses a functional of the level sets to estimate the first eigenvalue from below, together with a rearrangement of the ball's eigenfunction onto the domain $\Omega$ and the usual isoperimetric inequality. We then prove that the second eigenvalue attains its minimum only on the disjoint union of two equal balls, and set the proof up so it works for the Robin $p$-Laplacian. For the higher eigenvalues, we show that it is in general impossible for a minimiser to exist independently of $\alpha > 0$. When $\alpha < 0$, we prove that every eigenvalue behaves like $-\alpha^2$ as $\alpha \to -\infty$, provided only that $\Omega$ is bounded with $C^1$ boundary. This generalises a result of Lou and Zhu [Pacific J. Math. 214 (2004), 323--334] for the first eigenvalue. For the Wentzell problem, we (re-)prove general operator properties, including for the less-studied case $\beta 0$ establish a type of equivalence property between the Wentzell and Robin minimisers for all eigenvalues. This yields a minimiser of the second Wentzell eigenvalue. We also prove a Cheeger-type inequality for the first eigenvalue in this case

Health-related quality of life of long-term advanced melanoma survivors treated with anti-CTLA-4 immune checkpoint inhibition compared to matched controls

Background: Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer.Material and methods: Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines.Results: A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17-121) months, survivors scored significantly lower on physical (83.7vs. 89.8, difference (diff) = -5.80,p=.005), role (83.5vs.90, diff = -5.97,p=.02), cognitive (83.7vs.91.9, diff = -8.05,p=.001), and social functioning (86.5vs.95.1, diff = -8.49,p= <.001) and had a higher symptom burden of fatigue (23.0vs.15.5, diff = 7.48,p=.004), dyspnea (13.3vs.6.7, diff = 6.47p=.02), diarrhea (7.9vs.4.0, diff = 3.78,p=.04), and financial impact (10.5vs.2.5, diff = 8.07,p=.001) than matched controls. Group differences were indicated as clinically relevant.Discussion: Compared to matched controls, long-term advanced melanoma survivors had overall worse functioning scores, more physical symptoms, and financial difficulties. These data may contribute to the development of appropriate survivorship care.Experimentele farmacotherapi

Evaluation and management of side effects of breast cancer treatment

Breast cancer is one of the most common malignant diseases. Adjuvant systemic therapies such as chemotherapy, immunotherapy and endocrine therapy play an important role in the treatment of breast cancer. These therapies reduce the risk of relapse of breast cancer and increase cure rates. However, these therapies are associated with short- and long-term side-effects. Sometimes these side-effects are irreversible and disabling, which may affect the quality of life, treatment continuation and treatment adherence. The research described in this thesis is focused on treatment of anti-cancer therapy induced menopausal symptoms and on trastuzumab-related cardiac dysfunction in women with early and advanced breast cancer. The aim was to investigate new treatment options for the management of hot flashes, and new modalities for the detection and prevention of trastuzumab-related cardiotoxicity. Results of a prospective randomized double blind three-armed trial comparing clonidine, venlafaxine and placebo in the management of hot flashes in women with a history of breast cancer are described. Venlafaxine treatment resulted in a more immediate reduction of hot-flash scores when compared with clonidine, however hot-flash scores at week 12 were lower in the clonidine group than in the venlafaxine group. The main conclusion of this study was that both drugs reduced the hot-flash scores in women after a diagnosis of breast cancer. However, since venlafaxine showed a better reduction of hot flashes score over the whole treatment period of 12 weeks, venlafaxine might be the preferred treatment. Several studies into the cardiac safety of trastuzumab treatment are described in this thesis. Trastuzumab is a humanized monoclonal antibody against the extracellular domain of HER2 and treatment with trastuzumab has resulted in clinical benefit in HER2 positive advanced breast cancer and improved disease-free and overall survival in combination with adjuvant chemotherapy in HER2 positive primary breast cancer. Overall trastuzumab treatment is well tolerated, however cardiac dysfunction is one of the clinically relevant side-effects of trastuzumab treatment manifested by left ventricular systolic dysfunction and in a small proportion of patients even in advanced congestive heart failure. Only prior or concomitant treatment with anthracyclines was identified as a significant predictive factor of cardiac dysfunction. However, no statistically significantly association was seen between potential risk factors for the development of cardiotoxicity, such as age, high body mass index and use of antihypertensive drug or co-morbidity and the incidence of cardiac events. Serum biomarkers such as NT-proBNP and the troponines were not statistically significantly related to trastuzumab-associated cardiotoxicity or recovery. Trastuzumab induced cardiac toxicity was partly reversible also in patients with a decreased left ventricular function prior to treatment with trastuzumab. The development of a pharmacokinetic-pharmacodynamic (PK-PD) model is described. This PK-PD model can be used to address clinical questions regarding optimal management of trastuzumab-associated cardiotoxicity and to develop monitoring strategies. The tentative blinded results of a prospective, placebo-controlled, pharmacological intervention study (CANDY) are described. In this study, patients were treated concurrently with adjuvant trastuzumab and an angiotensin II-receptor blocker (candesartan) for HER2 positive breast cancer. Currently, the effect of candesartan in the prevention of trastuzumab-associated cardiotoxicity can not be disclosed. In conclusion, longer follow-up studies in large patient populations are needed to evaluate long-term tolerability and cardiac safety of trastuzumab treatment. Unblinding and final results of the CANDY study are needed to evaluate the effect of candesartan in the prevention of trastuzumab-associated cardiotoxicity in early breast cancer patients

The risk of developing cardiovascular disease is increased for patients with prostate cancer who are pharmaceutically treated for depression

Objective To examine the associations between pharmaceutically treated anxiety and depression and incident cardiovascular disease (CVD) among 1‐year prostate cancer survivors. Patients and methods A registry‐based cohort study design was used to describe the risk of incident CVD in adult 1‐year prostate cancer survivors without a history of CVD. Patients with prostate cancer diagnosed between 1999 and 2011 were selected from the Netherlands Cancer Registry. Drug dispenses were retrieved from the PHARMO Database Network and were used as proxy for CVD, anxiety, and depression. Data were analysed using Cox regression analysis to examine the risk associations between pharmaceutically treated anxiety and depression entered as a time‐varying predictor with incident CVD in 1‐year prostate cancer survivors, while controlling for age, traditional CVD risk factors, and clinical characteristics. Results Of the 5262 prostate cancer survivors, 327 (6%) developed CVD during the 13‐year follow‐up period. Prostate cancer survivors who were pharmaceutically treated for depression had an increased risk of incident CVD after full adjustment compared to prostate cancer survivors who were not pharmaceutically treated for depression (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.06–2.15). The increased risk of incident CVD amongst those pharmaceutically treated for depression compared to those who were not pharmaceutically treated for depression, was only valid among: prostate cancer survivors who were aged ≤65 years (HR 2.91; 95% CI 1.52–5.55); those who were not treated with radiotherapy (HR 1.63; 95% CI 1.01–2.65); those who were treated with hormones (HR 1.76; 95% CI 1.09–2.85); those who were not operated upon (HR 1.55; 95% CI 1.07–2.25); and those with tumour stage III (HR 2.21; 95% CI 1.03–4.74) and stage IV (HR 2.47; 95% CI 1.03–5.89). Conclusion Patients with prostate cancer who were pharmaceutically treated for depression had a 51% increased risk of incident CVD after adjustment for anxiety, age, traditional CVD risk factors, and clinical characteristics. The results emphasise the need to pay attention to (pharmaceutically treated) depressed patients with prostate cancer prior to deciding on prostate cancer treatment and for a timely detection and treatment of CVD

The risk of developing cardiovascular disease is increased for patients with prostate cancer who are pharmaceutically treated for depression

Objective To examine the associations between pharmaceutically treated anxiety and depression and incident cardiovascular disease (CVD) among 1‐year prostate cancer survivors. Patients and methods A registry‐based cohort study design was used to describe the risk of incident CVD in adult 1‐year prostate cancer survivors without a history of CVD. Patients with prostate cancer diagnosed between 1999 and 2011 were selected from the Netherlands Cancer Registry. Drug dispenses were retrieved from the PHARMO Database Network and were used as proxy for CVD, anxiety, and depression. Data were analysed using Cox regression analysis to examine the risk associations between pharmaceutically treated anxiety and depression entered as a time‐varying predictor with incident CVD in 1‐year prostate cancer survivors, while controlling for age, traditional CVD risk factors, and clinical characteristics. Results Of the 5262 prostate cancer survivors, 327 (6%) developed CVD during the 13‐year follow‐up period. Prostate cancer survivors who were pharmaceutically treated for depression had an increased risk of incident CVD after full adjustment compared to prostate cancer survivors who were not pharmaceutically treated for depression (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.06–2.15). The increased risk of incident CVD amongst those pharmaceutically treated for depression compared to those who were not pharmaceutically treated for depression, was only valid among: prostate cancer survivors who were aged ≤65 years (HR 2.91; 95% CI 1.52–5.55); those who were not treated with radiotherapy (HR 1.63; 95% CI 1.01–2.65); those who were treated with hormones (HR 1.76; 95% CI 1.09–2.85); those who were not operated upon (HR 1.55; 95% CI 1.07–2.25); and those with tumour stage III (HR 2.21; 95% CI 1.03–4.74) and stage IV (HR 2.47; 95% CI 1.03–5.89). Conclusion Patients with prostate cancer who were pharmaceutically treated for depression had a 51% increased risk of incident CVD after adjustment for anxiety, age, traditional CVD risk factors, and clinical characteristics. The results emphasise the need to pay attention to (pharmaceutically treated) depressed patients with prostate cancer prior to deciding on prostate cancer treatment and for a timely detection and treatment of CVD

Validation of a modified algorithm for the identification of yeast isolates using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS)

Optimising antifungal treatment requires the fast and species-specific identification of yeast isolates. We evaluated a modified protocol for the rapid identification of clinical yeast isolates using matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) technology. First, we evaluated a simplified extraction procedure using 54 clinical yeast isolates. Second, we validated a new protocol with this simplified extraction procedure and lower identification threshold by analysing 167 isolates with either MALDI-TOF or conventional identification techniques. MALDI-TOF analysis with both the standard and short extraction procedure yielded identical identification results, although the log-scores were lower with the latter. With the modified protocol, 163/167 (97.6%) isolates showed a correct identification as compared to conventional identification techniques. A total of 135 out of the 163 (82.8%) correct identifications showed log-scores above 1.7, which we considered as the minimum log-score for secure species identification. The rapid identification of clinical yeast isolates is crucial in patient management. The MALDI-TOF technique using a short extraction procedure can be an alternative for the labourious standard procedure, although the log-scores will be lower. The identification of clinical yeast isolates with the modified protocol is a practical and accurate alternative for conventional identification techniques. If the isolate shows a log-score below 1.7, the standard extraction procedure should be used

Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens

Pharmacolog

Madurella real-time PCR, a novel approach for eumycetoma diagnosis

The genus Madurella comprising four species, M. fahalii, M. mycetomatis, M. pseudomycetomatis, and M. tropicana, represents the prevalent cause of eumycetoma worldwide. The four species are phenotypically similar and cause an invariable clinical picture, but differ markedly in their susceptibility to antifungal drugs, and epidemiological pattern. Therefore, specific identification is required for optimal management of Madurella infection and to reveal proper epidemiology of the species. In this study, a novel multiplex real-time PCR targeting the four Madurella species was developed and standardized. Evaluation of the assay using reference strains of the target and non-target species resulted in 100% specificity, high analytical reproducibility (R2 values >0.99) and a lowest detection limit of 3 pg target DNA. The accuracy of the real-time PCR was further assessed using biopsies from eumycetoma suspected patients. Unlike culture and DNA sequencing as gold standard diagnostic methods, the real-time PCR yielded accurate diagnosis with specific identification of the causative species in three hours compared to one or two weeks required for culture. The novel method reduces turnaround time as well as labor intensity and high costs associated with current refere

Common toxicities associated with immune checkpoint inhibitors and targeted therapy in the treatment of melanoma:A systematic scoping review

IntroductionThis systematic scoping review compares the toxicities experienced by patients receiving immune checkpoint inhibitors (ICIs) or targeted therapy (TT) for stage III (resected and unresectable) and stage IV melanoma.MethodsOVID Medline, Embase, and PsycInfo were searched to identify Phase III trials reporting toxicities of FDA-approved ICIs and TT for advanced melanoma. AEs that were reported by ≥ 10% of patients in the evaluated trials were included.ResultsToxicity profiles of 11208 patients from 24 studies were reviewed. The rate of AEs was lower with ICIs compared to TT. However, ICIs were associated with higher rates of long-term or permanent AEs compared to TT, where toxicities generally were shortterm and reversible with treatment discontinuation.ConclusionThe toxicity profiles of ICIs and TT vary substantially. Whilst the rate of AEs was lower with ICIs than during TT, it was also associated with higher rates of potentially chronic AEs

The Amsterdam Declaration on Fungal Nomenclature

The Amsterdam Declaration on Fungal Nomenclature was agreed at an international symposium convened in Amsterdam on 19–20 April 2011 under the auspices of the International Commission on the Taxonomy of Fungi (ICTF). The purpose of the symposium was to address the issue of whether or how the current system of naming pleomorphic fungi should be maintained or changed now that molecular data are routinely available. The issue is urgent as mycologists currently follow different practices, and no consensus was achieved by a Special Committee appointed in 2005 by the International Botanical Congress to advise on the problem. The Declaration recognizes the need for an orderly transitition to a single-name nomenclatural system for all fungi, and to provide mechanisms to protect names that otherwise then become endangered. That is, meaning that priority should be given to the first described name, except where that is a younger name in general use when the first author to select a name of a pleomorphic monophyletic genus is to be followed, and suggests controversial cases are referred to a body, such as the ICTF, which will report to the Committee for Fungi. If appropriate, the ICTF could be mandated to promote the implementation of the Declaration. In addition, but not forming part of the Declaration, are reports of discussions held during the symposium on the governance of the nomenclature of fungi, and the naming of fungi known only from an environmental nucleic acid sequence in particular. Possible amendments to the Draft BioCode (2011) to allow for the needs of mycologists are suggested for further consideration, and a possible example of how a fungus only known from the environment might be described is presented