Abstract
Background
It has been shown previously that a relevant proportion of childhood cancer survivors suffers from late effects, which are often directly related to the cancer itself or its ...therapy, resulting in particular follow-up needs, additionally burdening healthcare systems. Being diagnosed with cancer at a vulnerable stage of development, this group of cancer survivors is at comparatively higher risk of relapse or subsequent cancer. Although national and international follow-up guidelines based on treatment modalities have been developed, their implementation seems to leave room for improvement. Additionally, they lack a sufficient consideration of the survivors’ psychosocial needs, affecting their adherence to them. The aim of the VersKiK study is to provide representative information on late effects in childhood and adolescence cancer survivors in Germany. The main research objectives are: (1) to describe the state of follow-up care among survivors after a cancer diagnosis in childhood or adolescence; (2) to quantify the occurrence of late effects among this group of survivors; (3) to examine the adherence to selected audiological and cardiological follow-up guidelines and to identify factors affecting it; (4) to explore actual follow-up needs of paediatric cancer survivors; (5) to review selected follow-up guidelines with the aim to improve and expand them.
Methods
VersKiK is designed as a mixed-methods non-interventional study. We will use claims data from statutory health insurance companies in combination with individually linked population-based registry data from the German Childhood Cancer Registry (GCCR). This data base will permit us to quantify diagnoses and procedures in comparison to the general population as well as the adherence to existing follow-up guidelines. Additional information will be obtained through interviews with childhood and adolescence cancer survivors and their informal caregivers, as well as in focus groups with healthcare professionals.
Discussion
The present study aims to research the actual needs of individuals after cancer diagnosis and treatment in childhood or adolescence – physical, psychological and organisational – in order to improve existing follow-up guidelines. These improvements might further positively affect not only actual care provided to paediatric cancer survivors, but also benefit healthcare systems in general while decreasing consequent medical visits in this group of patients.
Trial registration
Registered at German Clinical Trial Register (ID: DRKS00025960 and DRKS00026092).
Pulmonary hypertension (PH) is a leading cause of death in sickle cell disease (SCD) patients. Hemolysis and oxidative stress contribute to SCD-associated PH. We have reported that the protein ...thrombospondin-1 (TSP1) is elevated in the plasma of patients with SCD and, by interacting with its receptor CD47, limits vasodilation of distal pulmonary arteries ex vivo. We hypothesized that the TSP1-CD47 interaction may promote PH in SCD. We found that TSP1 and CD47 are upregulated in the lungs of Berkeley (BERK) sickling (Sickle) mice and patients with SCD-associated PH. We then generated chimeric animals by transplanting BERK bone marrow into C57BL/6J (
= 24) and CD47 knockout (CD47KO,
= 27) mice. Right ventricular (RV) pressure was lower in fully engrafted Sickle-to-CD47KO than Sickle-to-C57BL/6J chimeras, as shown by the reduced maximum RV pressure (
= 0.013) and mean pulmonary artery pressure (
= 0.020). The afterload of the sickle-to-CD47KO chimeras was also lower, as shown by the diminished pulmonary vascular resistance (
= 0.024) and RV effective arterial elastance (
= 0.052). On myography, aortic segments from Sickle-to-CD47KO chimeras showed improved relaxation to acetylcholine. We hypothesized that, in SCD, TSP1-CD47 signaling promotes PH, in part, by increasing reactive oxygen species (ROS) generation. In human pulmonary artery endothelial cells, treatment with TSP1 stimulated ROS generation, which was abrogated by CD47 blockade. Explanted lungs of CD47KO chimeras had less vascular congestion and a smaller oxidative footprint. Our results show that genetic absence of CD47 ameliorates SCD-associated PH, which may be due to decreased ROS levels. Modulation of TSP1-CD47 may provide a new molecular approach to the treatment of SCD-associated PH.
Cryotherapy has emerged as a primary treatment option for prostate cancer (CaP); however, incomplete ablation in the periphery of the cryogenic lesion can lead to recurrence. Accordingly, we ...investigated the use of a non-toxic adjunctive agent, vitamin D3 (VD3), with cryotherapy to sensitize CaP to low temperature-induced, non-ice rupture-related cell death. VD3 (calcitriol) has been identified as a possible adjunct in the treatment of cancer because of its antiproliferative and antitumorigenic properties. This study aimed to identify the cellular responses and molecular pathways activated when VD3 (calcitriol) is combined with cryotherapy in a murine CaP model. Single freeze-thaw events above -15 degreesC had little effect on cancer cell viability; however, pretreatment with calcitriol in conjunction with cryo significantly increased cell death. The -15 degreesC calcitriol combination increased cell death to 55% following a single freeze compared with negligible cell loss by freezing or calcitriol alone. Repeated cryo combination yielded 90% cell death compared with 65% in dual freeze-only cycles. Western blot analysis following calcitriol cryosensitization regimes confirmed the activation of apoptosis. Specifically, proapoptotic Bid and procaspase-3 were found to decrease at 1 h following combination treatment, indicating cleavage to the active forms. A parallel in vivo study confirmed the increased cell death when combining cryotherapy with calcitriol pretreatment. The development of an adjunctive therapy combining calcitriol and cryotherapy represents a potentially highly effective, less toxic, minimally invasive treatment option. These results suggest a role for calcitriol and cryo as a combinatorial treatment for CaP, with the potential for clinical translation. Prostate Cancer and Prostatic Diseases (2011) 14, 97-104; doi: 10.1038/pcan.2010.52; published online 11 January 2011 Keywords: vitamin D; cryosurgery; apoptosis
Background:
Diverse thermal ablative therapies are currently in use for the treatment of cancer. Commonly applied with the intent to cure, these ablative therapies are providing promising success ...rates similar to and often exceeding “gold standard” approaches. Cancer-curing prospects may be enhanced by deeper understanding of thermal effects on cancer cells and the hosting tissue, including the molecular mechanisms of cancer cell mutations, which enable resistance to therapy. Furthermore, thermal ablative therapies may benefit from recent developments in computer hardware and computation tools for planning, monitoring, visualization, and education.
Methods:
Recent discoveries in cancer cell resistance to destruction by apoptosis, autophagy, and necrosis are now providing an understanding of the strategies used by cancer cells to avoid destruction by immunologic surveillance. Further, these discoveries are now providing insight into the success of the diverse types of ablative therapies utilized in the clinical arena today and into how they directly and indirectly overcome many of the cancers’ defensive strategies. Additionally, the manner in which minimally invasive thermal therapy is enabled by imaging, which facilitates anatomical features reconstruction, insertion guidance of thermal probes, and strategic placement of thermal sensors, plays a critical role in the delivery of effective ablative treatment.
Results:
The thermal techniques discussed include radiofrequency, microwave, high-intensity focused ultrasound, laser, and cryosurgery. Also discussed is the development of thermal adjunctive therapies—the combination of drug and thermal treatments—which provide new and more effective combinatorial physical and molecular-based approaches for treating various cancers. Finally, advanced computational and planning tools are also discussed.
Conclusion:
This review lays out the various molecular adaptive mechanisms—the hallmarks of cancer—responsible for therapeutic resistance, on one hand, and how various ablative therapies, including both heating- and freezing-based strategies, overcome many of cancer’s defenses, on the other hand, thereby enhancing the potential for curative approaches for various cancers.
Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF; World Health Organization Group II) secondary to left ventricular (LV) diastolic dysfunction is ...the most frequent cause of PH. It is an increasingly recognized clinical complication of the metabolic syndrome. To date, no effective treatment has been identified, and no genetically modifiable mouse model is available for advancing our understanding for PH-HFpEF. To develop a mouse model of PH-HFpEF, we exposed 36 mouse strains to 20 weeks of high-fat diet (HFD), followed by systematic evaluation of right ventricular (RV) and LV pressure-volume analysis. The HFD induces obesity, glucose intolerance, insulin resistance, hyperlipidemia, as well as PH, in susceptible strains. We observed that certain mouse strains, such as AKR/J, NON/shiLtJ, and WSB/EiJ, developed hemodynamic signs of PH-HFpEF. Of the strains that develop PH-HFpEF, we selected AKR/J for further model validation, as it is known to be prone to HFD-induced metabolic syndrome and had low variability in hemodynamics. HFD-treated AKR/J mice demonstrate reproducibly higher RV systolic pressure compared with mice fed with regular diet, along with increased LV end-diastolic pressure, both RV and LV hypertrophy, glucose intolerance, and elevated HbA1c levels. Time course assessments showed that HFD significantly increased body weight, RV systolic pressure, LV end-diastolic pressure, biventricular hypertrophy, and HbA1c throughout the treatment period. Moreover, we also identified and validated 129S1/SvlmJ as a resistant mouse strain to HFD-induced PH-HFpEF. These studies validate an HFD/AKR/J mouse model of PH-HFpEF, which may offer a new avenue for testing potential mechanisms and treatments for this disease.
The relationship between cardiovascular disease and abnormalities in sleep architecture is complex and bi-directional. Sleep disordered breathing (SDB) often confounds human studies examining sleep ...in the setting of heart failure, and the independent impact of isolated right or left heart failure on sleep is difficult to assess. We utilized an animal model of right heart failure using pulmonary artery banding (PAB) in mice to examine the causal effect of right heart failure on sleep architecture. Four weeks after PAB or sham (control) surgery, sleep was measured by polysomnography for 48 hours and right ventricular (RV) hypertrophy confirmed prior to sacrifice. PAB resulted in right ventricular hypertrophy based on a 30% increase in the Fulton Index (p < 0.01). After PAB, mice spent significantly more time in NREM sleep compared to the control group over a 24 hour period (53.5 ± 1.5% vs. 46.6 ± 1.4%; p < 0.01) and exhibited an inability to both cycle into REM sleep and decrease delta density across the light/sleep period. Our results support a phenotype of impaired sleep cycling and increased 'sleepiness' in a mouse model of RV dysfunction.
Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for ...therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population.
The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15-39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018.
CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors.
Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018).
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