Pulmonary Hypertension in Extremely premature born infants:prevalence, risk factors and survival

In the Netherlands, approximately 12,000 children are born prematurely every year. These preterm infants did not had the chance to fully develop. Therefore, premature birth is often associated with poorer survival. This is often due to the disorders bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). BPD involves immature lungs with lung damage due to mechanical ventilation and oxygen administration. PH is characterized by increased pressure in the pulmonary vascular bed. If PH persists, it can lead to overload of the heart, leading to heart failure and eventual death. However, there is currently little knowledge about the condition PH in these preterm infants. With this dissertation we aim to gain more knowledge about PH. We show that PH is a common and indeed a dangerous condition in preterm infants. That PH in the first week of life can have several causes, each with their own risks and survival rate. That children with PH have a greatly increased risk of also getting BPD. And that in the early stages of life before the disease is even clinically visible, there are already indications in the blood that children have a higher risk of getting both BPD and PH. With this knowledge, a contribution can be made to improved care for the premature infants with PH, which hopefully contributes to an improved quality of life and survival

Preclinical targeting of the tumor microenvironment:Possibilities and consequences

Gemetastaseerde ziekte is momenteel de hoofdoorzaak van alle aan kanker gerelateerde sterfte. Dit onderstreept het belang van het vinden van nieuwe behandelstrategieën. Onlangs bleek dat het normale weefsel dat de tumor omgeeft, de tumormicro-omgeving, een belangrijke rol speelt bij tumorgroei en metastasering. Door nieuwe behandelopties te richten tegen zowel de kankercellen als de tumormicro-omgeving, kan de effectiviteit van huidige therapieën mogelijk worden verbeterd. Voor de ontwikkeling van een dergelijke nieuwe behandeloptie, is het noodzakelijk om moleculaire factoren in de tumormicro-omgeving te identificeren. Twee potentiële factoren zijn transforming growth factor (TGF)-β en vascular endothelial growth factor (VEGF). In preklinische modellen bestaande uit stromale- en borstkankercellen wordt de tumor met zijn micro-omgeving nagebootst. Deze in vitro en in vivo modellen laten zien dat stromale cellen nodig zijn voor het TGF-β gemedieerde anti-borstkankereffect van het bisfosfonaat zoledronaat. Daarnaast wordt de preklinische ontwikkeling van een TGF-β tracer beschreven. Bij deze techniek wordt een radioactief gelabeld antilichaam afgebeeld met positron emissie tomografie (PET). Middels deze TGF-β tracer kon de aanwezigheid van TGF-β in tumoren worden afgebeeld. Voor VEGF werd het effect van anti-VEGF therapie op geneesmiddelopname geëvalueerd met behulp van PET beeldvorming. Anti-VEGF therapie vermindert de opname van andere geneesmiddelen in twee verschillende preklinische modellen. Concluderend beschrijft dit proefschrift preklinisch onderzoek naar de mogelijkheden en consequenties van therapieën gericht op factoren in de tumormicro-omgeving

Human stromal cells are required for an anti-breast cancer effect of zoledronic acid

Previous studies suggested that bisphosphonate zoledronic acid exerts an antitumor effect by interacting with the microenvironment. In this study, we aimed to elucidate the mechanism behind the anti-breast cancer effect of zoledronic acid.Here we showed that zoledronic acid did not influence in vitro human breast cancer cell survival, but did affect human stromal cell survival. Breast cancer cell death in co-culture with stromal cells was analyzed in vitro by fluorescent microscopy and flowcytometry analysis. In co-culture, the addition of stromal cells to breast cancer cells induced tumor cell death by zoledronic acid, which was abolished by transforming growth factor (TGF)-beta. In the in vivo chicken chorioallantoic membrane model, zoledronic acid reduced the breast cancer cells fraction per tumor only in the presence of human stromal cells. Zoledronic acid decreased TGF-beta excretion by stromal cells and co-cultures. Moreover, supernatant of zoledronic acid treated stromal cells reduced phospho-Smad2 protein levels in breast cancer cells. Thus, zoledronic acid exerts an anti-breast cancer effect via stromal cells, accompanied by decreased stromal TGF-beta excretion and reduced TGF-beta signaling in cancer cells.</p

Pulmonary hypertension in extremely preterm infants:a call to standardize echocardiographic screening and follow-up policy

Pulmonary hypertension (PH) is a frequent complication in extremely preterm born infants that seriously affects outcome. We aimed to describe the prevalence of PH in extremely preterm infants and the policy on screening and follow-up in the ten Dutch intensive care units (NICUs). We performed a retrospective cohort study at the University Medical Centre Groningen on infants with gestational age <30 weeks and/or birthweight <1000 g, born between 2012 and 2013. Additionally, we carried out a survey among the Dutch NICUs covering questions on the awareness of PH, the perceived prevalence, and policy regarding screening and following PH in extremely preterm infants. Prevalence of early-onset PH in our study was 26% and 5% for late-onset PH. PH was associated with poor survival and early-onset PH was associated with subsequent development of bronchopulmonary dysplasia (BPD). All the NICUs completed the questionnaire and we found that no standardized policy existed regarding screening and following PH in extremely preterm infants. Conclusion: Despite the frequent occurrence of PH and its clinically important consequences, (inter-)national standardized guidelines regarding screening and following of PH in extremely preterm infants are lacking. Standardizing screening and follow-up will enable early identification of infants with late-onset PH and allow for earlier treatment. Additionally, greater clarity is required regarding the prevalence of early PH as are new preventive treatment strategies to combat BPD. What is known? center dot Pulmonary hypertension (PH) substantially impairs the survival of extremely preterm infants. center dot PH is associated with bronchopulmonary dysplasia (BPD): Early-onset PH predicts the development of BPD. Late-onset PH is prevalent in infants with severe BPD. What is new? center dot Pulmonary hypertension (PH) is prevalent in preterm infants. Its consequences for morbidity and mortality justify a standardized policy aimed at early detection to improve prevention and treatment. center dot No structured policy exists in the Netherlands regarding screening/follow-up for PH in extremely preterm infants

Fate of pulmonary hypertension associated with bronchopulmonary dysplasia beyond 36 weeks postmenstrual age

Objective To determine the survival and evolution of pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD) in extremely premature born infants beyond 36 weeks postmenstrual age (PMA). Design A single-centre retrospective cohort study from a university hospital. Patients Extremely preterm (gestational age Main outcome measures Survival, mortality rate and PH resolution. Patient characteristics, treatment, presence and evolution of PH were collected from patient charts. Results Twenty-eight infants were included. All had BPD, while 23 (82%) had severe BPD and 11 infants (39%) died. Survival rates at 1, 3 and 7 months from 36 weeks PMA were 89%, 70% and 58%, respectively. In 16 of the 17 surviving infants, PH resolved over time, with a resolution rate at 1 and 2 years corrected age of 47% and 79%, respectively. At 2.5 years corrected age, the resolution rate was 94%. Conclusions These extremely preterm born infants with PH-BPD had a survival rate of 58% at 6 months corrected age. Suprasystemic pulmonary artery pressure was associated with poor outcome. In the current study, infants surviving beyond the corrected age of 6 months showed excellent survival and resolution of PH in almost all cases. Prospective follow-up studies should investigate whether resolution of PH in these infants can be improved by multi-modal therapies, including respiratory, nutritional and cardiovascular treatments

VEGF pathway targeting agents, vessel normalization and tumor drug uptake:from bench to bedside

Vascular endothelial growth factor (VEGF) pathway targeting agents have been combined with other anticancer drugs, leading to improved efficacy in carcinoma of the cervix, stomach, lung, colon and rectum, ovary, and breast. Vessel normalization induced by VEGF pathway targeting agents influences tumor drug uptake. Following bevacizumab treatment, preclinical and clinical studies have shown a decrease in tumor delivery of radiolabeled antibodies and two chemotherapeutic drugs. The decrease in vessel pore size during vessel normalization might explain the decrease in tumor drug uptake. Moreover, the addition of bevacizumab to cetuximab, or panitumumab in colorectal cancer patients or to trastuzumab in breast cancer patients, did not improve efficacy. However, combining bevacizumab with chemotherapy did increase efficacy in some cancer types. Novel biomarkers to select patients who may benefit from combination therapies, such as the effect of an angiogenesis inhibitor on tumor perfusion, requires innovative trial designs and large clinical trials. Small imaging studies with radiolabeled drugs could be used in the interphase to gain further insight into the interplay between VEGF targeted therapy, vessel normalization and tumor drug delivery

What is known about melatonin, chemotherapy and altered gene expression in breast cancer

Melatonin, synthesized in and released from the pineal gland, has been demonstrated by multiple in vivo and in vitro studies to have an oncostatic role in hormone?dependent tumors. Furthermore, several clinical trials point to melatonin as a promising adjuvant molecule to be considered for cancer treatment. In the past few years, evidence of a broader spectrum of action of melatonin as an antitumor agent has arisen; thus, melatonin appears to also have therapeutic effects in several types of hormone?independent cancer, including ovarian, leukemic, pancreatic, gastric and non?small cell lung carcinoma. In the present study, the latest findings regarding melatonin molecular actions when concomitantly administered with either radiotherapy or chemotherapy in cancer were reviewed, with a particular focus on hormone?dependent breast cancer. Finally, the present study discusses which direction should be followed in the next years to definitely clarify whether or not melatonin administration could protect against non?desirable effects (such as altered gene expression and post?translational protein modifications) caused by chemotherapy or radiotherapy treatments. As treatments move towards personalized medicine, comparative gene expression profiling with and without melatonin may be a powerful tool to better understand the antitumor effects of melatonin, the pineal gland hormone