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Over the last years, the knowledge of MEN2 and non-MEN2 familial forms of pheochromocytoma (PHEO) has increased. In MEN2, PHEO is the second most frequent disease: the penetrance and age at diagnosis depend on the mutation of RET. Given the prevalence of bilateral PHEO (50% by age 50), adrenal sparing surgery, aimed at sparing a part of the adrenal cortex to avoid adrenal insufficiency, should be systematically considered in patients with bilateral PHEO. Non-MEN2 familial forms of PHEO now include more than 20 genes: however, only small phenotypic series have been reported, suggesting that phenotypic features of isolated hereditary PHEO must be better explored, and follow-up series are needed to better understand the outcome of patients carrying mutations of these genes. The first part of this review will mainly focus on these points. In the second part, a focus will be given on MEN2 and non-MEN2 familial forms of hyperparathyroidism (HPTH). Again, the management of MEN2 HPTH should be aimed at curing the disease while preserving an optimal quality of life by a tailored parathyroidectomy. The phenotypes and outcome of MEN1-, MEN4- and HRPT2- related HPTH are briefly described, with a focus on the most recent literature data and is compared with familial hypocalciuric hypercalcemia. [ABSTRACT FROM AUTHOR] more...

Obesity is a global epidemic that adversely affects respiratory physiology. Sleep-disordered breathing and obesity hypoventilation syndrome (OHS) are among the most common pulmonary complications related to obesity class III. Patients with OHS may present with acute hypercapnic respiratory failure (AHRF) that necessitates immediate noninvasive ventilation (NIV) or invasive ventilation and intensive care unit (ICU) monitoring. The OHS is underrecognized as a cause of AHRF. The management of mechanical ventilation in obese ICU patients is one of the most challenging problems facing respirologists, intensivists, and anesthesiologists. The treatment of AHRF in patients with OHS should aim to improve alveolar ventilation with better alveolar gas exchange, as well as maintaining a patent upper airway, which is ideally achieved through NIV. Treatment with NIV is associated with improvement in blood gases and lung mechanics and may reduce hospital admissions and morbidity. In this review, we will address 3 main issues: (1) NIV of critically ill patients with acute respiratory failure and OHS; (2) the indications for postoperative application of NIV in patients with OHS; and (3) the impact of OHS on weaning and postextubation respiratory failure. Additionally, the authors propose an algorithm for the management of obese patients with AHRF. [ABSTRACT FROM AUTHOR] more...

Approximately 98% of patients with multiple endocrine neoplasia type 2A (MEN 2A) have an identifiable RET mutation. Prophylactic or early total thyroidectomy or pheochromocytoma/parathyroid removal in patients can be preventative or curative and has become standard management. The general strategy for RET screening on family members at risk is to sequence the most commonly affected exons and, if negative, to extend sequencing to additional exons. However, different families with MEN 2A due to the same RET mutation often have significant variability in the clinical exhibition of disease and aggressiveness of the MTC, which implies additional genetic loci exsit beyond RET coding region. Whole genome sequencing (WGS) greatly expands the breadth of screening from genes associated with a particular disease to the whole genome and, potentially, all the information that the genome contains about diseases or traits. This is presumably due to additive effect of disease modifying factors. In this study, we performed WGS on a typical Chinese MEN 2A proband and identified the pathogenic RET p.C634R mutation. We also identified several neutral variants within RET and pheochromocytoma-related genes. Moreover, we found several interesting structural variants including genetic deletions ( RSPO1, OVCH2 and AP3S1, etc.) and fusion transcripts ( FSIP1- BAZ2A, etc.). [ABSTRACT FROM AUTHOR] more...

The introduction of alien species is among the main causes of biodiversity loss. There are many documented cases of introduced mammals having severe impacts on the ecosystem. The European hare ( Lepus europaeus), native to Europe and Asia, was introduced to southern Brazil in the 1950s and has since expanded its geographic distribution considerably. In this study, we present a review of the known distribution of the European hare in Brazil, add new records of occurrence that expand the species distribution into southeastern Brazil and estimate the species dispersal rate in Brazil. We compiled at total of 135 distinct localities of occurrence for the species in Brazil, including published records and the previously unknown localities presented here. These records indicate a dispersal rate of 45.35 km/year for the introduced species. Of these known localities, 15 are in protected areas. Because of its high potential for even greater geographic dispersal and potential impacts on native species through competition and disease transmission, we recommend further research to better assess the species status and the implementation of public policies and management controls, especially in protected areas. [ABSTRACT FROM AUTHOR] more...

Copyright of Fisioterapia e Pesquisa is the property of Universidade de Sao Paulo, Faculdade de Medicina and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) more...

Background: The RET S836S variant has been associated with early onset and increased risk for metastatic disease in medullary thyroid carcinoma (MTC). However, the mechanism by which this variant modulates MTC pathogenesis is still open to discuss. Of interest, strong linkage disequilibrium (LD) between RET S836S and 3'UTR variants has been reported in Hirschsprung's disease patients. Objective: To evaluate the frequency of the RET 3’UTR variants (rs76759170 and rs3026785) in MTC patients and to determine whether these variants are in LD with S836S polymorphism. Methods: Our sample comprised 152 patients with sporadic MTC. The RET S836S and 3’UTR (rs76759170 and rs3026785) variants were genotyped using Custom TaqMan Genotyping Assays. Haplotypes were inferred using the phase 2.1 program. RET mRNA structure was assessed by Vienna Package. Results: The mean age of MTC diagnosis was 48.5±15.5 years and 57.9% were women. The minor allele frequencies of RET polymorphisms were as follows: S836S, 5.6%; rs76759170, 5.6%; rs3026785, 6.2%. We observed a strong LD among S836S and 3’UTR variants (|D’| = -1, r2 = 1 and |D’| = -1, r2 = 0,967). Patients harboring the S836S/3’UTR variants presented a higher percentage of lymph node and distant metastasis (P = 0.013 and P<0.001, respectively). Accordingly, RNA folding analyses demonstrated different RNA secondary structure predictions for WT(), S836S() or 3’UTR() haplotypes. The S836S/3’UTR haplotype presented a greater number of double helices sections and lower levels of minimal free energy when compared to the wild-type haplotype, suggesting that these variants provides the most thermodynamically stable mRNA structure, which may have functional consequences on the rate of mRNA degradation. Conclusion: The RET S836S polymorphism is in LD with 3’UTR variants. In silico analysis indicate that the 3’UTR variants may affect the secondary structure of RET mRNA, suggesting that these variants might play a role in posttranscriptional control of the RET transcripts. [ABSTRACT FROM AUTHOR] more...

Miller Fisher Syndrome is an uncommon variant of Guillain-Barre syndrome of then presents with clinical triad of ataxia, areflexia, and ophthalmoplegia. In this report, a 3 year old girl with acute ataxia and areflexia without physical sign of external ophtalmoplegia with sensory axonal neuropathy on electrophysiologic study is presented. Based on clinical and electrophysiologic findings, the diagnosis of Miller Fisher syndrome was made and the patient underwent treatment with intravenous immunoglobulin for five days. With relative resolution of ataxia. [ABSTRACT FROM AUTHOR] more...

Background: Bilateral pheochromocytoma (PHEO) is more frequently found in patients with multiple endocrine neoplasia 2A carrying a RET germline mutation located in codon 634 (C634). However, it is unclear whether different amino acid substitutions within C634 cause differences in bilateral PHEOs expression. We aimed to answer this by pooling data from two Asian institutions. Methods: Sixty-seven patients had confirmed C634 germline mutation. Age-dependent penetrance of bilateral PHEO was calculated from date of birth to the date when bilateral PHEO was first diagnosed or when the contralateral gland became a PHEO (if the patient already had one adrenal gland removed). Age-dependent penetrance was estimated by the Kaplan-Meier method and compared by log-rank test. Results: The 4 different amino acid substitutions included C634R (arginine) ( n = 19, 28.4 %), C634Y (tyrosine) ( n = 36, 38.8 %), C634G (glycine) ( n = 4, 6.0 %), and C634W (tryptophan) ( n = 8, 11.9 %). The age-related penetrance of PHEO was similar between C634R, C634Y, C634G, and C634W (by age 40, 69.8, 55.2, 25.0, and 56.2 %, respectively) ( p = 0.529). However, the age-related penetrance of bilateral PHEO in C634R was significantly higher than C634Y (by age of 40, 59.3 % vs. 25.2 %, p = 0.046) or C634Y, C634G, and C634W combined (59.3 % vs. 21.5 %, p = 0.024). Nevertheless, the accumulative risk of bilateral PHEOs across all four C634 mutations almost approached 100 % over time. Conclusion: The accumulative risk of bilateral PHEOs almost reached 100 % but its onset was significantly earlier in C634R mutation. These findings implied that those with C634R mutation might benefit from earlier screening of contralateral PHEO than other C634 mutations after an unilateral adrenalectomy. [ABSTRACT FROM AUTHOR] more...

O referido artigo trata da história da Escola de Educação Infantil e Ensino Fundamental Nossa Senhora Aparecida, localizada no município de Passos Maia/SC. A escola tem em sua gênese a vinculação com o Movimento dos Trabalhadores Rurais Sem Terra – MST. A questão central deste estudo é a omnilateralidade da educação no contexto da luta por escola considerando a educação no MST. Seus objetivos fundamentais são: compreender os elementos que compõe a formação omnilateral em Marx; delinear as principais linhas políticas e os princípios filosóficos e pedagógicos básicos da educação no MST; analisar o movimento da trajetória histórica da escola atentando para os avanços obtidos, bem como os retrocessos tendo como base as linhas políticas; e os princípios da educação no MST bem como a educação omnilateral. more...

Studies have shown a close relationship between anxiety and aversive memory processing, but few animal models are suitable for investigating the effects of a given compound on anxiety and memory simultaneously. A growing body of evidence suggests anxiolytic and amnesic effects of nociceptin/orphanin FQ (N/OFQ). The mouse elevated T-maze (ETM) has been shown to detect the effects of drugs on anxiety and memory at the same time. In this study, the effects of intracerebroventricular N/OFQ injected before or immediately after training session were assessed in the ETM task. When pretraining injected, N/OFQ 0.1 nmol significantly decreased the latency to enter an open arm in the training session compared to control, which is suggestive of anxiolysis. In addition, N/OFQ (0.1 and 1 nmol) significantly reduced the latency to enter an open arm during the test session compared to control, thus suggesting memory impairments. However, when N/OFQ was administered posttraining, it did not affect memory retrieval. No alterations in locomotion were detected in N/OFQ-treated mice in the open field test. In conclusion, these findings are discussed considering the simultaneous anxiolytic and amnesic effects of N/OFQ. [ABSTRACT FROM AUTHOR] more...

Neuroendocrine (NE) lung tumors comprise 20-25 % of all invasive lung malignancies. Currently, no effective treatments are available to cure these tumors, and it is necessary to identify a molecular alteration(s) that characterizes NE lung tumor cells. We aimed to identify a kinase mutation(s) associated with NE lung tumor by screening 517 kinase-encoding genes in human lung cancer cell lines. Our next-generation sequencing analysis of six NE lung tumor cell lines (four small cell lung cancer lines and two non-small cell lung cancer lines) and three non-NE lung tumor lines revealed various kinase mutations, including a nonsynonymous mutation in the proto-oncogene RET (c.2071G > A; p.G691S). Further evaluation of the RET polymorphism in total 15 lung cancer cell lines by capillary sequencing suggested that the frequency of the minor allele (A-allele) in NE lung tumor lines was significantly higher than its frequency in a reference population ( p = 0.0001). However, no significant difference between non-NE lung tumor lines and a reference group was detected ( p = 1.0). Nevertheless, neither RET expression levels were correlated with the levels of neuron-specific enolase (NSE), a key NE marker, nor vandetanib and cabozantinib, small molecule compounds that inhibit RET, affected NSE levels in lung cancer cells. Our data suggest a potential association of G691S RET polymorphism with NE lung tumor, proposing the necessity of more thorough evaluation of this possibility. The dataset of kinase mutation profiles in this report may help choosing cell line models for study of lung cancer. [ABSTRACT FROM AUTHOR] more...

Background: Medullary thyroid carcinoma (MTC) occurs in both sporadic (75%) and hereditary (25%) forms. The missense mutations of the rearranged during transfection (RET) proto-oncogene in MTC development have been well demonstrated. Several studies have been published that indicate the molecular analysis of RET gene may offer early identification of those patients at high risk to develop MTC and may provide the opportunity for early intervention. The aim of this study was to investigate frequency of G691S/S904S haplotype in MTC patients and their relatives. Methods: From 2004 to 2014, 358 participants were studied, including 213 patients (119 female, 94 male) and 145 their relatives (79 female, 66 male) in cellular and molecular research center of Shahid Beheshti Research Institute for Endocrine Sciences, Tehran, Iran. Genomic DNA was extracted from peripheral blood leucocytes using the standard Salting Out/Proteinase K method. Nucleotide change detection was performed using PCR and direct DNA sequencing methods. The RET mutations and SNPs, sequences were analyzed. Results: According to DNA sequencing results, 189 individuals (119 patients, 70 relatives) had both G691S (rs1799939) missense mutation in exon11 and S904S (rs1800863) synonymous mutation in exon 15 of RET proto-oncogene. The allele frequency of G691S/S904S haplotype was 35.02% in patients and 29.92% in their relatives. Conclusion: The obtained data showed the frequency of G691S/S904S RET gene haplotype among Iranian MTC patients and their relatives. The G691S and S904S nucleotide changes were in complete linkage disequilibrium, so the results were grouped together and referred to as G691S/S904S haplotype. This haplotype are not considered as oncogenic mutations at this time, its functional role should be investigated. Further analysis is needed to demonstrate the association between this haplotype and MTC development. [ABSTRACT FROM AUTHOR] more...

Thyroid cancer has a multifactorial aetiology resulting from the interaction of genetic and environmental factors. Several low penetrance susceptibility genes have been identified but their effects often vary between different populations. Somatic point mutations and translocations of the REarranged during Transfection (RET) proto-oncogene are frequently found in thyroid cancer. The aim of this case-control study was to determine the effect of four well known RET single nucleotide polymorphisms (SNPs) on the risk for differentiated thyroid carcinoma. A total of 545 Portuguese patients and 543 controls were genotyped by PCR and restriction enzyme analysis, for the following SNPs: G691S (exon 11, rs1799939 G/A), L769L (exon 13, rs1800861 T/G), S836S (exon 14, rs1800862 C/T), and S904S (exon 15, rs1800863 C/G). The minor allele of S836S was overrepresented in patients with papillary thyroid carcinoma (PTC) when compared to controls (OR 1.57; 95% CI 1.05–2.35; p = 0.026). The GGTC haplotype was also overrepresented in PTC (OR 2.51; 95% CI 1.07–5.91; p = 0.029). No associations were found in follicular thyroid carcinoma (FTC). Multivariate logistic regression analysis showed no differences regarding gender, age at diagnosis, lymph node or distant metastasis. However, a near significant overrepresentation of the minor alleles of G691S and S904S was found in patients with tumours greater than 10 mm of diameter at diagnosis. These data suggest that the RET S836S polymorphism in exon 14 and the GGTC haplotype are risk factors for PTC, but not FTC, and that the G691S/S904S polymorphisms might be associated with tumour behaviour. [ABSTRACT FROM AUTHOR] more...

Background: Syphilis point-of-care tests may reduce morbidity and ongoing transmission by increasing the proportion of people rapidly treated. Syphilis stage and co-infection with HIV may influence test performance. We evaluated four commercially available syphilis point-of-care devices in a head-to-head comparison using sera from laboratories in Australia. Methods: Point-of-care tests were evaluated using sera stored at Sydney and Melbourne laboratories. Sensitivity and specificity were calculated by standard methods, comparing point-of-care results to treponemal immunoassay (IA) reference test results. Additional analyses by clinical syphilis stage, HIV status, and non-treponemal antibody titre were performed. Non-overlapping 95% confidence intervals (CI) were considered statistically significant differences in estimates. Results: In total 1203 specimens were tested (736 IA-reactive, 467 IA-nonreactive). Point-of-care test sensitivities were: Determine 97.3%(95%CI:95.8–98.3), Onsite 92.5%(90.3–94.3), DPP 89.8%(87.3–91.9) and Bioline 87.8%(85.1–90.0). Specificities were: Determine 96.4%(94.1–97.8), Onsite 92.5%(90.3–94.3), DPP 98.3%(96.5–99.2), and Bioline 98.5%(96.8–99.3). Sensitivity of the Determine test was 100% for primary and 100% for secondary syphilis. The three other tests had reduced sensitivity among primary (80.4–90.2%) compared to secondary syphilis (94.3–98.6%). No significant differences in sensitivity were observed by HIV status. Test sensitivities were significantly higher among high-RPR titre (RPR≥8) (range: 94.6–99.5%) than RPR non-reactive infections (range: 76.3–92.9%). Conclusions: The Determine test had the highest sensitivity overall. All tests were most sensitive among high-RPR titre infections. Point-of-care tests have a role in syphilis control programs however in developed countries with established laboratory infrastructures, the lower sensitivities of some tests observed in primary syphilis suggest these would need to be supplemented with additional tests among populations where syphilis incidence is high to avoid missing early syphilis cases. [ABSTRACT FROM AUTHOR] more...

Copyright of Manual Therapy, Posturology & Rehabilitation Journal is the property of Revista Terapia Manual and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) more...

Copyright of Revista Inspirar Movimento & Saude is the property of Faculdade Inspirar and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) more...

Background: For both dengue and scrub typhus, acute respiratory failure (ARF) is a serious complication. The present study was carried out in order to investigate the clinical courses and outcomes of adult dengue and scrub typhus patients with ARF, and to identify the clinical differences between adult dengue and scrub typhus patients with ARF. Methods: We conducted a retrospective study of the serologically confirmed adult dengue or scrub typhus patients admitted between 1998 and 2008 at Kaohsiung Chang Gung Memorial Hospital. A total of 980 dengue and 102 scrub typhus adult patients were included in our study. Results: Eighteen of the 980 adult dengue patients and 8 of the 102 adult scrub typhus patients had ARF. There were significant differences that existed for eschar ( P = 0.001; dengue 0%; scrub 62.5%), cough ( P = 0.016; dengue 55.6%; scrub typhus 100%), white blood cell (WBC) count [ P = 0.026; dengue 7.40 ± 5.74; scrub typhus 11.84 ± 4.95 (×10/μL)], platelet count [ P = 0.008; dengue 42.2 ± 33.9; scrub typhus 104.1 ± 93.3 (×10/L)], prothrombin time (PT) [ P = 0.007; dengue 12.82 ± 1.36; scrub typhus 10.74 ± 0.98 (s)], activated partial thromboplastin time (APTT) [ P = 0.002; dengue 50.81 ± 10.08; scrub typhus 37.44 ± 4.06 (s)], blood urea nitrogen (BUN) [ P < 0.001; dengue 64.6 ± 43.2; scrub typhus 20.9 ± 9.1 (mg/dL)], creatinine [ P < 0.001; dengue 3.77 ± 3.37; scrub typhus 1.05 ± 0.37 (mg/dL)], admission day (A-day) [ P = 0.027; dengue 2.9 ± 1.3; scrub typhus 5.4 ± 2.6 (days)], and ventilator duration [ P = 0.022; dengue 9.4 ± 14.0; scrub typhus 14.8 ± 10.4 (days)] between both groups. Conclusions: This study provides relatively rare data regarding the clinical differences between adult dengue and scrub typhus patients with ARF. [ABSTRACT FROM AUTHOR] more...

Non-invasive positive pressure ventilation or non-invasive ventilation (NIV) has emerged as a simpler and safer alternative to invasive mechanical ventilation in patients developing acute postoperative respiratory failure. The benefits of NIV as compared to intubation and mechanical ventilation include lower complications, shorter duration of hospital stay, reduced morbidity, lesser cost of treatment and even reduced mortality rates. However, its use may not be uniformly applicable in all patient groups. This article reviews the indications, contraindications and evidence supporting the use of NIV in individual patient groups in the postoperative period. The anaesthesiologist needs to recognise the subset of patients most likely to benefit from NIV therapy so as to apply it most effectively. It is equally important to promptly identify signs of failure of NIV therapy and be prepared to initiate alternate ways of respiratory support. The author searched PubMed and Ovid MEDLINE, without date restrictions. Search terms included Non-invasive ventilation, postoperative and respiratory failure. Foreign literature was included, though only articles with English translation were used. [ABSTRACT FROM AUTHOR] more...

Copyright of Tropical Medicine & International Health is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) more...

Purpose: To assess the interobserver agreement on clinical history and physical examination when using a semi-structured questionnaire to evaluate patients with an acute febrile illness (AFI). Methods: A cross-sectional study was conducted with outpatients aged 12 years and over, presenting with an AFI defined as fever up to 7 days and no evident focus of infection. Clinical data were collected independently by two physicians using a semi-structured questionnaire. Interobserver agreement was estimated using kappa coefficients with a 95% confidence interval (CI). Results: A total of 140 patients (age range 13-73 years; 56.4% females) were enrolled. All symptoms showed weighted kappa values significantly greater than 0.6, indicating an at least substantial agreement. As most physical signs were infrequent and of mild intensity, they were recoded and analyzed as absent/present. Of the signs with prevalence ≥15%, exanthema, pallor, lymph node enlargement, and eye congestion showed agreements significantly greater than 0.6, while kappa confidence limits for pharyngeal erythema and dehydration included values classified as regular. Conclusions: High agreement was observed for most of the clinical data assessed, and symptom grading was feasible. Some physical findings were rare and their inclusion in a structured form may not be justified in this setting. The questionnaire application showed good reliability for the most frequent signs and symptoms and may prove to be useful at gathering data for surveillance and research at sentinel sites. [ABSTRACT FROM AUTHOR] more...

Introduction: There are few studies regarding the clinical characteristics of Miller Fisher syndrome (MFS) in the Latin-American population. Methods: A retrospective analysis was made of the clinical characteristics, neurophysiology, treatment and prognosis of MFS patients between 1995 and 2005. Results: Nineteen MFS cases were documented, 12 of which did not receive immunosuppressive therapy. In both groups, the mean age was 36 years, 84% were male; onset in spring and fall was also predominant (73%), and antecedents of respiratory disease were found (79%). The mean duration of infectious symptoms was 7 days (1–11 days), and the mean interval between the onset of the infection and neurological symptoms was 7 days (1–30 days). The principal sign of onset was diplopia (63%). The mean delay between the onset of neurological symptoms and the beginning of recovery from ataxia, ophthalmoplegia and areflexia was 10 (1–30 days), 11 (1–30 days) and 14 (4–45 days) days, respectively, and the mean delay of the disappearance of ataxia, ophthalmoplegia and areflexia was 35 (10–121 days), 93 (18–244 days) and 64 (10–650 days) days, respectively. There was no significant difference between the group that received immunosuppression and the one that did not. Discussion: The natural course of MSF is characterized by excellent recovery; there were no differences between the two groups. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR] more...

Copyright of Salud Pública de México is the property of Instituto Nacional de Salud Publica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) more...

A letter to the editor discussing neuro-ophthalmological manifestations in three cases of Miller Fisher syndrome, which is characterized by acute onset of gait ataxia, ophthalmoplegia, and areflexia is presented. more...

Cabozantinib is an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2. In a phase II clinical trial in advanced prostate cancer (PCa), cabozantinib treatment improved bone scans in 68% of evaluable patients. Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone. Using immunohistochemistry and tissue microarrays containing normal prostate, primary PCa, and soft tissue and bone metastases, our data show that levels of MET, P-MET, and VEGFR2 are increasing during PCa progression. Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases. To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4-2B PCa tumors. In vivo, cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors. Furthermore, cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume. In summary, the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa, and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease. [ABSTRACT FROM AUTHOR] more...