Preston W. Campbell

Association of poor clinical status and heavy exposure to tobacco smoke in patients with cystic fibrosis who are homozygous for the F508 deletion

We examined the association between clinical status and exposure to tobacco smoke in 44 patients homozygous for the F508 cystic fibrosis mutation. Heavy exposure to tobacco smoke was significantly associated with lower Shwachman scores, poorer results of pulmonary function tests, and a fivefold increase in the number of pulmonary-related hospitalizations during the previous year.

Cystic fibrosis: Relationship between clinical status and F508 deletion

The gene responsible for cystic fibrosis has recently been identified and cloned. 1,2 The most commonly identified mutation, F508, accounts for approximately 70% of all CF genes in North America, and preliminary evidence indicates that in patients homozygous for this 3 base pair deletion, pancreatic insufficiency is present or eventually develops) The remaining 30% of abnormal CF alleles include a number of different defects, including some that appear to confer pancreatic sufficiency and milder disease. 4-6 Identification of other CF alleles and their relationship to the clinical expression of disease is currently under study by many investigators. 7 It is hoped that precise genetic analysis will facilitate prediction of CF severity, which would be valuable both for genetic counseling and for the proper design and interpretation of future clinical trials. Rapid and reliable methods of detecting CF genotypes will be needed to accomplish these aims. In addition, the relationship between clinical status and the most commonly occurring alleles must be evaluated. The purpose of this preliminary study was (1) to examine the feasibility of using a new polymerase chain reactionbased method of DNA analysis to determine the deletion status of 60 nonrelated CF patients and (2) to examine the relationship between the deletion status and Clinical status as determined by Shwachman score, weight percentile, and pulmonary function variables.

Cystic fibrosis, intravenous antibiotics, and home therapy

The survival rate of patients with cystic fibrosis has improved considerably in the last 20 years. Although not all of the factors accounting for this change are understood, aggressive nutritional management and treatment of pulmonary exacerbations certainly play a role. Home intravenous (IV) antibiotic delivery for pulmonary exacerbation has proved to be as effective as hospital treatment and offers significant advantages to the patient and family. This article examines the microbiology of pulmonary infections in patients with cystic fibrosis, as well as antimicrobial therapy, methods of IV administration, home IV therapy, and the nurse practitioners role in this home program in the future.

Dual targeting c-met and VEGFR2 in osteoblasts suppresses growth and osteolysis of prostate cancer bone metastasis

Prostate cancer characteristically induces osteoblastic bone metastasis, for which no therapies are available. A dual kinase inhibitor of c-Met and VEGFR-2 (cabozantinib) was shown to reduce prostate cancer growth in bone, with evidence for suppressing osteoblastic activity. However, c-Met and VEGFR2 signaling in osteoblasts in the context of bone metastasis remain unclear. Here we show using cultured osteoblasts that hepatocyte growth factor (HGF) and VEGF-A increased receptor activator of NFκB ligand (RANKL) and M-CSF, two essential factors for osteoclastogenesis. Insulin-like growth factor-1 (IGF1) also increased RANKL and M-CSF via c-Met transactivation. The conditioned media from IGF1-, HGF-, or VEGFA-treated osteoblasts promoted osteoclastogenesis that was reversed by inhibiting c-Met and/or VEGFR2 in osteoblasts. Inxa0vivo experiments used cabozantinib-resistant prostate cancer cells (PC-3 and C4-2B) to test the effects of c-Met/VEGFR2 inhibition specifically in osteoblasts. Cabozantinib (60xa0mg/kg, 3 weeks) suppressed tumor growth in bone and reduced expression of RANKL and M-CSF and subsequent tumor-induced osteolysis. Collectively, inhibition of c-Met and VEGFR2 in osteoblasts reduced RANKL and M-CSF expression, and associated with reduction of tumor-induced osteolysis, suggesting that c-Met and VEGFR2 are promising therapeutic targets in bone metastasis.

Involvement of sympathetic nerves in bone metastasis

Early determinants of metastatic formation or recurrence in bone remain poorly characterized. This chapter describes how the activation of sympathetic nerves triggered by chronic stress or depression might contribute to the early steps of metastatic establishment in the skeleton, and the effect of beta-blockers on breast cancer patient survival and relapse.

Abstract 1172: Targeting c-Met and VEGFR2 in the stromal compartment of prostate cancer bone metastasis

Advanced-stage prostate cancer patients commonly develop bone metastasis, accounting for significant morbidity and mortality. Metastatic prostate cancer cells characteristically induce osteoblastic reactions, for which no targeted therapies are currently available. Recent clinical and experimental data showed that dual inhibition of c-Met and VEGF receptor (VEGFR)-2 kinase activity reduced prostate cancer growth in bone with indications for suppressing osteoblastic activities, while the specific functions of c-Met and VEGFR2 in osteoblasts remain unclear. In our in vitro studies using three types of osteoblasts (MC3T3-E1 subclone 4, hFOB1.19 and murine calvarial osteoblasts), hepatocyte growth factor (HGF, a ligand for c-Met) and VEGFA increased expression of receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony stimulating factor (M-CSF), two essential factors for osteoclastogenesis. In addition, siRNA-mediated knockdown of c-Met or VEGFR2 in osteoblasts suppressed HGF- or VEGFA-dependent gene expression, respectively. We demonstrate that insulin growth factor (IGF) increased RANKL and M-CSF expression in osteoblasts via c-Met transactivation. Furthermore, the conditioned media from IGF-, HGF-, or VEGFA-treated osteoblasts promoted in vitro osteoclastogenesis that was suppressed by inhibition of c-Met and VEGFR2 in osteoblasts. Subsequently, we examined whether cabozantinib, a dual kinase inhibitor of c-Met and VEGFR2 currently in clinical trials for metastatic prostate cancer, could suppress prostate cancer bone metastasis via inhibition of osteoblasts. To examine the effects of cabozantinib specifically in osteoblasts, cabozantinib-resistant PC-3 prostate cancer cells were generated and implanted in the tibiae of male nude mice. Cabozantinib (60mg/kg) or control diluent was administered via daily oral gavage for 3 weeks. In agreement with our in vitro data, cabozantinib suppressed tumor growth in bone (determined by in vivo bioluminescence) and tumor-induced osteolysis (determined by X-ray). Tumor cells were isolated and in vitro cultured to demonstrate that cabozantinib resistance was maintained during 3-week in vivo growth. Osteoblasts and osteoclasts numbers were reduced in the bones of cabozantinib-treated mice, and these histological changes were accompanied by significantly lower levels of RANKL and M-CSF levels in bone. Collectively, inhibition of c-Met and VEGFR2 in osteoblasts reduces RANKL and M-CSF expression, associated with decreased osteoclastogenesis and tumor-induced osteolysis. Therefore, we conclude that c-Met and VEGFR2 are promising therapeutic targets in the stromal compartment of prostate cancer bone metastasis, suggesting hat the effects of cabozantinib on skeletal-related events of prostate cancer are, at least in part, mediated by suppression of osteoblast function. Citation Format: Changki Lee, Preston Campbell, Young Mi Whang, Jamey D. Young, Florent Elefteriou, Serk In Park. Targeting c-Met and VEGFR2 in the stromal compartment of prostate cancer bone metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1172. doi:10.1158/1538-7445.AM2014-1172

SupplementImproving the Care of Infants Identified through Cystic Fibrosis Newborn Screening

O n behalf of the Cystic Fibrosis Foundation, we are pleased to share the enclosed clinical practice guidelines for the care of infants identified through cystic fibrosis (CF) newborn screening (NBS). The widespread implementation of NBS for CF throughout the USA presents an incredible opportunity to improve health outcomes for this patient population. The evidence documenting the magnitude of the opportunity is growing.We are entering a new era in which the devastating symptomatic presentations of CF such as failure to thrive will become a thing of the past. The CF Foundation Patient Registry data shows that a growing proportion of newly diagnosed infants are identified byNBS (Figure). If we are to fully capitalize on this opportunity, we must develop a rigorous approach to these newly diagnosed infants including frequent follow-up, institution of appropriate preventive measures to maintain health and early intervention when problems arise. The clinical practice guidelines published herein are aimed at promoting a standardized approach to the care provided for these infants. The development of evidence-based clinical practice guidelines is a core component of the CF Foundation’s quality improvement (QI) initiative. Although we believe the CF Foundation’s system of care is a model for the care of individuals with a complex, chronic disease, variability in practice patterns and outcomes among CF care centers uncovered in the CF Foundation Patient Registry data indicated that we could do even better. We developed and implemented a strategic plan to identify and enable ‘‘best practices’’ across our care center network. Many of the more than 100 accredited care centers and more than 50 affiliates across the United States have incorporated QI into their daily work. Registry analyses since the launch of the QI initiative in 2002 suggest that the CF Foundation’s investment in this area is having a substantive impact on key pulmonary and nutritional outcomes (manuscript in preparation). The current focus on the care of infants identified by NBS is a natural extension of this work. The first article in this supplement contains the recommendations for management of infants identified by NBS who have a clear diagnosis of CF. A care grid with recommended frequency of follow-up and what should be done and when is included in the article. The important partnerships between the family and the health care team and between the primary pediatrician and the CF care team are also highlighted in this document. The second article describes the method used to develop the guidelines recommendations including the search and selection criteria, the data collection process, and production of a narrative report of the evidence and evidence tables to facilitate the deliberations of the guidelines committee. The CF Foundation has moved from a consensus-driven approach to an evidence-based approach for most of our practice guidelines work. The clinical expertise of the guidelines committee is important in putting the evidence into the proper context and in developing recommendations on important clinical questions for which there is little or no evidence. The third article addresses infants who are identified by NBS as possibly having CF but do not fulfill the standard diagnostic criteria. The uncertainty surrounding the diagnosis, prognosis, and optimal medical care of this important but relatively small number of infants has created a great deal of angst among families and clinicians. As opposed to older individuals with cystic fibrosis transmembrane conductance regulator–related disorders who present for evaluation with symptoms but do not meet diagnostic criteria for CF, these infants identified by NBS are typically symptom-free. This article defines this ‘‘CFTR-related metabolic syndrome’’ group and provides recommendations on their follow-up and care. Given the paucity of evidence in this area, we used a Delphi approach to arrive at consensus recommendations from a panel of experts. A standardized approach to the care of these infants, coupled with collection of genotypephenotype data in our patient registry will hopefully advance knowledge on this important patient population, ultimately allowing a more rapid diagnosis in some patients and reassurance for others. We hope that these articles are helpful to CF care teams, general pediatricians, and families. As with all practice guidelines, they provide a framework that must be customized to the care setting. Individual decisions on specific interventions must be made on the basis of the specific circumstances of the individual patient and family. We are thankful to those who provided input on earlier draft versions and eager to hear from you about your experience in implementing the guidelines, which will be incorporated into updates as new data and treatments become available. n