What Interventions Do Physical Therapists Provide for Patients With Cardiorespiratory Conditions, Neurological Conditions, and Conditions Requiring Acute Hospital Care? A Systematic Review.

OBJECTIVE: The aim of this systematic review was to determine what percentages of physical therapists provide interventions that are of high value, low value, or unknown value for cardiorespiratory conditions, neurological conditions, or conditions requiring acute hospital care. Whether an intervention was considered high or low value was determined by reference to guidelines or systematic reviews. METHODS: Searches of numerous databases were performed by combining terms synonymous with "practice patterns" and "physical therapy" until April 2018. Studies that investigated what interventions physical therapists provide for any cardiorespiratory condition, neurological condition, or condition requiring acute hospital care through surveys and audits of clinical notes were included. Through the use of medians and interquartile ranges, the percentages of physical therapists who provided interventions that were of high value, low value, or unknown value were summarized. RESULTS: Twenty-six studies were included. The median percentages of physical therapists who provided interventions of high, low, and unknown value for chronic obstructive pulmonary disease ranged from 78% to 96%, 67% to 100%, and 56% to 91%, respectively. These percentages ranged from 61% to 97%, 87% to 98%, and 83% to 98% for adults who were critically ill in intensive care units; 70% to 93%, 38% to 50%, and 8% to 95% before or after cardiac/thoracic surgery; 25% to 96%, 23% to 84%, and 96% for acute stroke; and 11% (high value) and 13% (unknown value) for Parkinson disease, respectively. CONCLUSIONS: This review found patterns of physical therapist practice for cardiorespiratory conditions, neurological conditions, and conditions requiring acute hospital care that were both evidence based and not evidence based. A concern is that a substantial percentage of physical therapists provided interventions that were of low or unknown value despite the availability of high-value interventions. IMPACT: This systematic review is the first, to our knowledge, to summarize the percentage of physical therapist treatment choices that were high versus low value for cardiorespiratory conditions, neurological conditions, and conditions requiring acute hospital care. The findings highlight areas of practice where low-value care could be replaced with high-value care-such as in the management of patients who have chronic obstructive pulmonary disease or who are in intensive care-and identify an urgent need to develop and test strategies to ensure that patients with these conditions receive the interventions most likely to improve their outcomes.

An observational study of self-reported sedentary behaviour in people with chronic obstructive pulmonary disease and bronchiectasis.

BACKGROUND: Few studies have examined sedentary behaviour in chronic respiratory disease. The limited evidence suggests that increased levels of sedentary behaviour are associated with increased mortality. OBJECTIVES: This study aimed to compare the level of self-reported sedentary behaviour in people with chronic obstructive pulmonary disease (COPD) and bronchiectasis as well as to identify associations between sedentary time with functional performance measures and health-related quality of life in the chronic respiratory disease group. METHODS: An observational study design was used. Participants completed the Sedentary Behaviour Questionnaire from which average sedentary time (hours/day) was determined. Functional performance was measured using the six-minute walk test, the four-metre gait speed test and the five sit-to-stand test. Health-related quality of life was measured using the St George's Respiratory Questionnaire. Sedentary time was compared between groups using an unpaired t-test. Univariate analysis explored relationships amongst variables. RESULTS: The convenience sample consisted of 103 people with COPD [52% male; mean±SD age: 73±9 years, FEV1% predicted: 56±23] and 33 people with bronchiectasis [52% male; 74±8 years, FEV1% predicted: 69±25]. Average self-reported sedentary time in COPD was 7.6±2.7 hours/day and in bronchiectasis was 8.0±4.1 hours/day, with no between-group difference (-0.4, 95% CI -1.7, 0.8). No associations were found between sedentary time and any functional performance outcome or with health-related quality of life. CONCLUSION: There was no difference in the high sedentary time between people with COPD and bronchiectasis. Sedentary behaviour was not associated with functional performance or disease-related health-related quality of life in people with chronic respiratory disease.

Associations of Diet and Physical Activity with Risk for Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Rising rates of gestational diabetes mellitus (GDM) and related complications have prompted calls to identify potentially modifiable risk factors that are associated with gestational diabetes mellitus (GDM). We systematically reviewed the scientific literature for observational studies examining specific dietary and/or physical activity (PA) factors and risk of GDM. Our search included PubMed, Medline, CINAHL/EBSCO, Science Direct and EMBASE, and identified 1167 articles, of which 40 met our inclusion criteria (e.g., singleton pregnancy, reported diet or PA data during pre-pregnancy/early pregnancy and GDM as an outcome measure). Studies were assessed for quality using a modified Quality Criteria Checklist from American Dietetic Association. Of the final 40 studies, 72% obtained a positive quality rating and 28% were rated neutral. The final analysis incorporated data on 30,871 pregnant women. Dietary studies were categorised into either caffeine, carbohydrate, fat, protein, calcium, fast food and recognized dietary patterns. Diets such as Mediterranean Diet (MedDiet), Dietary Approaches to Stop Hypertension (DASH) diet and Alternate Healthy Eating Index diet (AHEI) were associated with 15­38% reduced relative risk of GDM. In contrast, frequent consumption of potato, meat/processed meats, and protein (% energy) derived from animal sources was associated with an increased risk of GDM. Compared to no PA, any pre-pregnancy or early pregnancy PA was associated with 30% and 21% reduced odds of GDM, respectively. Engaging in >90 min/week of leisure time PA before pregnancy was associated with 46% decreased odds of GDM. We conclude that diets resembling MedDiet/DASH diet as well as higher PA levels before or in early pregnancy were associated with lower risks or odds of GDM respectively. The systematic review was registered at PROSPERO (www.crd.york.ac.uk/PROSPERO) as CRD42016027795.

Epigenetics of pituitary tumors: Pathogenetic and therapeutic implications.

Genetic mutations involving oncogenes or tumor suppressor genes are relatively uncommon in human sporadic pituitary tumors. Instead, increasing evidence has highlighted frequent epigenetic alterations including DNA methylation, histone modifications, and enhanced miRNA expression. This review covers some of this evidence as it illuminates mechanisms of tumorigenesis and highlights therapeutic opportunities.

Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants.

CONTEXT: Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support. OBJECTIVE: This study sought to establish the differential clinicopathological risk of major PTC variants: conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC). METHODS: This was a retrospective study of clinicopathological outcomes of 6282 PTC patients (4799 females and 1483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range, 33-56 y) and median follow-up time of 37 months (interquartile range, 15-82 mo). RESULTS: The cohort consisted of 4702 (74.8%) patients with CPTC, 1126 (17.9%) with FVPTC, and 239 (3.8%) with TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality, and the use (need) of radioiodine treatment (all P < .001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC > CPTC ≫ FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3 and 6.7%, 16.1 and 2.5%, and 9.1 and 0.6%, corresponding to events per 1000 person-years (95% confidence interval [CI]) of 92.47 (64.66-132.26) and 24.61 (12.31-49.21), 34.46 (30.71-38.66), and 5.87 (4.37-7.88), and 24.73 (18.34-33.35) and 1.68 (0.54-5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI, 1.07-11.11) and 14.96 (95% CI, 3.93-56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients at least 45 years old. CONCLUSION: This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ≫ FVPTC, providing important clinical implications for specific variant-based management of PTC.

The role of diabetes in acromegaly associated neoplasia.

BACKGROUND: The risk and mortality due to cancer in patients with acromegaly have been previously investigated. Although GH/IGF-1 excess provides a probable pathophysiological explanation, the degree of IGF-1 excess and the role in acromegaly-associated neoplasms of diabetes, a common comorbidity in acromegaly with known association with cancer, remains unclear. METHODS: Acromegalic patients treated in three Canadian referral centers (Toronto, Montreal, Edmonton) were included. All available clinical information was recorded including: age, initial and last percentage of the upper limit of normal (%ULN) IGF-1 levels, comorbidities and other neoplasms (benign and malignant). RESULTS: 408 cases were assessed. 185 were women (45.3%), 126 (30.9%) developed extra-pituitary neoplasms: 55 malignant and 71 benign. The most frequent anatomic site was the gastrointestinal tract (46 [11.3%]), followed by head and neck (36 [8.8%]) and multiple locations (14 [3.4%]). 106 (26.0%) cases had diabetes. Initial IGF-1 was significantly higher in men older than 50 (380.15 vs. 284.78, p = 0.001) when compared to men younger than 50. Diabetics showed significantly higher initial IGF-1 (389.38 vs. 285.27, p = 0.009), as did diabetics older than 50 compared with those without diabetes. 45.3% (48/106) of cases with diabetes developed extra-pituitary neoplasms vs. 24.3% (71/292) without diabetes (p = 0.001, OR: 2.576 95%CI 1.615-4.108). 22.6% (24/106) of cases with diabetes developed malignant tumors vs. 9.2% (27/292), (p < 0.001, OR 2.873, 95%CI 1.572-5.250). CONCLUSIONS: These data suggest that acromegalic patients with diabetes are more likely to develop extra-pituitary neoplasms and their initial IGF-1 levels are higher. The contribution of IGF-1 vs. diabetes alone or in combination in the development of extra-pituitary neoplasms warrants further investigation.

Cytoplasmic expression of SSTR2 and 5 by immunohistochemistry and by RT/PCR is not associated with the pharmacological response to octreotide.

OBJECTIVE: To evaluate expression of somatostatin receptor subtypes 2 and 5 (SSTR 2 and 5) by RT/PCR and immunohistochemistry (IHC) in GH-secreting adenomas, seeking correlations with response to octreotide. METHODS: SSTR2 and 5 expression was tested by IHC (n=37), RT/PCR (n=36) or both (n=13) in GH-secreting adenomas from 60 patients with acromegaly who had undergone pituitary surgery; 36 had been treated preoperatively with octreotide LAR for 3-6 months, and were categorized as responders (achievement of GH <2.5ng/mL and a normal age-adjusted IGF-1), partial responders (GH and IGF-1 reduction >50% and >30%, respectively) or non-responders. IHC was performed on a tissue microarray using specific antibodies directed to the carboxyl terminus of SSTR2 and 5. RESULTS: SSTR5 was the predominantly expressed receptor subtype by both IHC and RT/PCR in all tumors tested, regardless of whether they came from octreotide-naïve, octreotide-responsive, or octreotide-resistant patients. Immunostaining was concentrated in the cytoplasm. Neither SSTR2 nor SSTR5 expression correlated with baseline or post-octreotide GH or IGF-1 levels or tumor volume by either method. The agreement rate between RT/PCR and IHC was 77% in all 13 adenomas in which both methods were used. CONCLUSION: Expression of these receptors does not guarantee an adequate response to somatostatin analogs; other functional aspects of this interaction, such as receptor homo- and heterodimerization, and the resulting signaling cascade, probably play a role in determining whether a patient will respond or not to these agents.

Metabolic glucose status and pituitary pathology portend therapeutic outcomes in acromegaly.

INTRODUCTION: Acromegaly is frequently associated with impaired glucose tolerance and/or diabetes. To evaluate the relationship between glucose metabolism and acromegaly disease, we evaluated 269 consecutive patients from two referral centres. METHODS: Clinical presentation, pituitary tumor size and invasiveness, and pituitary pathology were captured in a dedicated database. RESULTS: 131 women and 138 men with a mean age of 53.8 years were included. Of these, 201 (74.7%) presented with a macroadenoma and 18 (6.7%) with a microadenoma. Radiographic invasion was present in 91 cases (33.8%). Mean tumor diameter was 1.86 cm (0.2-4.6). Pituitary histopathologic findings revealed pure GH-producing somatotroph adenomas (SA) in 147 patients, prolactin-production by mixed lactotroph (LA) and SA or mammosomatotroph adenoma (MSA) in 46 [22.4%], acidophil stem cell adenoma in 6 [2.9%], and other diagnoses in 6 [2.9%]. Medical treatment included octreotide in 96 [36.9%] and in combination with pegvisomant or dopamine agonists in 63 [24.2%]. Nearly 80% of patients achieved IGF-1 normalization. Importantly, patients with pure somatotroph adenomas were significantly more likely to present with abnormal glucose metabolism [48.7%] than those with mixed adenomas [9.7%] [p<0.001] independent of GH/IGF-1 levels or tumor invasiveness. Abnormal glucose metabolism and pituitary pathology also remained linked following IGF-1 normalization. Moreover patients with pure SA and abnormal glucose metabolism were significantly (p<0.001) less likely to achieve disease remission despite the same therapeutic strategies. Conversely, patients with mixed adenomas were more likely (OR: 2.766 (95% CI: 1.490-5.136) to achieve disease remission. CONCLUSIONS: Patients with pure somatotroph adenomas are more likely than those with mixed adenomas to exhibit abnormal glucose metabolism.

Evaluation of the WHO 2010 grading and AJCC/UICC staging systems in prognostic behavior of intestinal neuroendocrine tumors.

BACKGROUND: The increasing incidence and heterogeneous behavior of intestinal neuroendocrine tumors (iNETs) pose a clinicopathological challenge. Our goal was to decribe the prognostic value of the new WHO 2010 grading and the AJCC/UICC TNM staging systems for iNETs. Moreover, outcomes of patients treated with somatostatin analogs were assessed. METHODS: We collected epidemiological and clinicopathological data from 93 patients with histologically proven iNETs including progression and survival outcomes. The WHO 2010 grading and the AJCC/UICC TNM staging systems were applied for all cases. RECIST criteria were used to define progression. Kaplan-Meier analyses for progression free survival (PFS) and overall survival (OS) were performed. RESULTS: Mean follow-up was 58.6 months (4-213 months). WHO 2010 grading yielded PFS and disease-specific OS of 125.0 and 165.8 months for grade 1 (G1), 100.0 and 144.2 months for G2 and 15.0 and 15.8 months for G3 tumors (p = 0.004 and p = 0.001). Using AJCC staging, patients with stage I and II tumors had no progression and no deaths. Stage III and IV patients demonstrated PFS of 138.4 and 84.7 months (p = 0.003) and disease-specific OS of 210.0 and 112.8 months (p = 0.017). AJCC staging also provided informative PFS (91.2 vs. 50.0 months, p = 0.004) and OS (112.3 vs. 80.0 months, p = 0.005) measures with somatostatin analog use in stage IV patients. CONCLUSION: Our findings underscore the complementarity of WHO 2010 and AJCC classifications in providing better estimates of iNETS disease outcomes and extend the evidence for somatostatin analog benefit in patients with metastatic disease.

Hormone profiling, WHO 2010 grading, and AJCC/UICC staging in pancreatic neuroendocrine tumor behavior.

Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic neoplasms, exhibiting a complex spectrum of clinical behaviors. To examine the clinico-pathological characteristics associated with long-term prognosis we reviewed 119 patients with pNETs treated in a tertiary referral center using the WHO 2010 grading and the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging systems, with a median follow-up of 38 months. Tumor size, immunohistochemistry (IHC) profiling and patient characteristics-determining stage were analyzed. Primary clinical outcomes were disease progression or death. The mean age at presentation was 52 years; 55% were female patients, 11% were associated with MEN1 (multiple endocrine neoplasia 1) or VHL (Von Hippel-Lindau); mean tumor diameter was 3.3 cm (standard deviation, SD) (2.92). The clinical presentation was incidental in 39% with endocrine hypersecretion syndromes in only 24% of cases. Nevertheless, endocrine hormone tissue immunoreactivity was identified in 67 (56.3%) cases. According to WHO 2010 grading, 50 (42%), 38 (31.9%), and 3 (2.5%) of tumors were low grade (G1), intermediate grade (G2), and high grade (G3), respectively. Disease progression occurred more frequently in higher WHO grades (G1: 6%, G2: 10.5%, G3: 67%, P = 0.026) and in more advanced AJCC stages (I: 2%, IV: 63%, P = 0.033). Shorter progression free survival (PFS) was noted in higher grades (G3 vs. G2; 21 vs. 144 months; P = 0.015) and in more advanced AJCC stages (stage I: 218 months, IV: 24 months, P < 0.001). Liver involvement (20 vs. 173 months, P < 0.001) or histologically positive lymph nodes (33 vs. 208 months, P < 0.001) were independently associated with shorter PFS. Conversely, tissue endocrine hormone immunoreactivity, independent of circulating levels was significantly associated with less aggressive disease. Age, gender, number of primary tumors, and heredity were not significantly associated with prognosis. Although the AJCC staging and WHO 2010 grading systems are useful in predicting disease progression, tissue endocrine hormone profiling provides additional information of potentially important prognostic value.

Expression of Ki-67, PTTG1, FGFR4, and SSTR 2, 3, and 5 in nonfunctioning pituitary adenomas: a high throughput TMA, immunohistochemical study.

CONTEXT: Nonfunctioning pituitary adenomas (NFPA) are the most common pituitary neoplasms. There is no clinical, biochemical, or histopathological marker that would accurately predict recurrence of NFPA. OBJECTIVE: The aim of this study was to evaluate a large group of NFPA for the presence of potential markers of biological behavior. DESIGN AND SETTING: A cross-sectional study using a high throughput tissue microarray technology was conducted at tertiary care centers. MATERIALS AND METHODS: Seventy-four gonadotroph and null cell adenomas were included in the tissue microarray. Using highly specific antibodies and appropriate controls, we determined the expression of Ki-67, pituitary tumor transforming gene 1, the N-terminally truncated pituitary tumor-derived fibroblast growth factor receptor-4 (FGFR4), as well as somatostatin receptor subtypes 2, 3, and 5 (SSTR2, -3, and -5), in an attempt to establish correlations and/or associations with clinical characteristics of the patients. RESULTS: Median Ki-67 index was 1.49 (interquartile range, 0.62-2.49). Pituitary tumor transforming gene 1 nuclear immunoreactivity was found in all but one tumor (median percentage of positive nuclei, 11.44); immunopositivity for FGFR4 was found in the majority of the tumors, with variable levels of expression. The immunostaining score for SSTR2 was significantly higher than that for SSTR3 or SSTR5. FGFR4 expression correlated positively with SSTR2 and SSTR5 immunostaining scores (r = 0.59; P < 0.001; and r = 0.46; P < 0.001, respectively). Multivariate analysis revealed that the Ki-67 index was significantly associated with a tumor size greater than 3 cm (odds ratio, 2.32; 95% confidence interval, 1.17-4.58) as well as with tumor recurrence (odds ratio, 1.4; 95% confidence interval, 1.03-1.89). CONCLUSIONS: Ki-67 is the most consistent marker of biological behavior in NFPA. The finding of significant amounts of SSTR2 and SSTR5 may have therapeutic implications regarding the use of somatostatin analogs in preventing tumor recurrence.

Pregnancy in acromegaly: experience from two referral centers and systematic review of the literature.

BACKGROUND: Acromegaly results from increased growth hormone and its target insulin-like growth factor-1, most commonly due to a pituitary tumour. As it is frequently accompanied by infertility, little is known about the course of this disease in pregnancy. OBJECTIVE: We describe 13 new pregnancies in acromegalic women and compare their outcomes in a systematic review of the literature. METHODS: We collected clinical, biochemical, imaging, and outcomes data during and following pregnancy and performed a systematic review for a total of 47 pregnancies. An extended analysis of 106 pregnancies was also performed. RESULTS: In 13 newly described cases, pregnancy was un-complicated without need for additional surgical intervention. In these pregnancies, adjunctive medical therapy was required in three patients. This was in the form of somatostatin analogs (SA) (3/13) as well as pegvisomant in 1/13 to control symptomatic and biochemical progression. One 37-year-old female succeeded in having two separate pregnancies 2 years apart both without need for any form of medical therapy. Review of an additional 34 published reports allowed for an analysis of outcomes in 47 pregnancies. Adjunctive medical therapy during pregnancy was required in 15 of these cases where 12 received SA and an additional three received dopamine agonists. None of these patients developed endocrine or neurologic complications during pregnancy. In an extended analysis of 106 pregnancies, treatment during pregnancy appears to be associated with good disease control but increased risk of microsomic or macrosomic newborns depending on the medical agent used. CONCLUSIONS: In 13 newly described pregnancies along with systematic review of an additional 34 cases indicate that pregnancy in treated acromegalic women can proceed without significant complications or teratogenicity. Medical treatment during pregnancy with DA or SA appears to be associated with altered neonatal weight. Nevertheless, gestation may have a beneficial impact on acromegaly control both during and following pregnancy.

A high-throughput proteomic approach provides distinct signatures for thyroid cancer behavior.

PURPOSE: Well-differentiated thyroid cancer (WDTC) is the most frequent form of endocrine neoplasia. One of the main challenges in the management of this disease is distinguishing low-risk patients who can be treated by surgical resection of the lesion from those with a high likelihood of recurrence who need a more extensive approach, including total thyroidectomy and radioiodine ablation. EXPERIMENTAL DESIGN: A tissue microarray (TMA) comprising 410 cases of WDTC was constructed with risk estimates for the following features: extrathyroidal extension, lymph node metastases, and vascular invasion. The variables examined were morphologic classification, candidate genetic, and proteomic biomarkers. RESULTS: BRAF (Raf kinase type B) mutant carriers showed increased risk of developing invasion compared with wild-type (WT) cases. However, when classified morphologically, classic papillary thyroid carcinomas (PTC) showed much higher risk estimates for invasive features compared with follicular variant PTCs (FVPTC); within these morphologic subgroups, BRAF mutational status did not provide independent risk estimates. Staining intensities for membranous galectin-3 (Gal3), HBME-1, and CK19 and nuclear Gal3 were statistically validated as markers of aggressive behavior. Estrogen receptor beta (ERß) was overexpressed in lesions with invasive behavior. The utility of these biomarkers remained statistically significant in the FVPTC. In contrast, a different set of biomarkers proved effective in classic PTC where upregulation of cyclin D1, loss of p27, and overexpression of ERß were associated with invasive behavior. CONCLUSION: Different proteomic signatures validate the distinction of classic and FVPTC and provide a practical clinical mechanism to predict the thyroid cancer behavior and stratify patients for clinical management.

Osteopontin (OPN) expression in thyroid carcinoma.

BACKGROUND: Osteopontin (OPN) and its interacting partner CEA-cell adhesion molecule (CEACAM1) mediate similar biological functions and have been expressed in several types of cancer. Here we investigated the prognostic significance of OPN in thyroid tumours and correlated our findings with the expression of CEACAM1. MATERIALS AND METHODS: 297 human thyroid samples were collected in a tissue microarray and as fresh frozen samples to perform immunohistochemistry and western blotting for OPN and to compare these data with our previously published data on CEACAM1 expression. RESULTS: Nearly all normal samples were negative for OPN. Some thyroid adenomas were weakly OPN positive whereas many carcinomas were strongly positive. In contrast to CEACAM1, which was preferentially expressed in metastatic papillary carcinomas, no associations were found between OPN expression and patient age, gender and tumour size. CONCLUSION: These results may have future implications for the diagnosis and management of patients with thyroid cancers.

Inhibition of the sodium potassium adenosine triphosphatase pump sensitizes cancer cells to anoikis and prevents distant tumor formation.

Normal epithelial cells undergo apoptosis upon detachment from the extracellular matrix, a process termed "anoikis." However, malignant epithelial cells with metastatic potential resist anoikis and can survive in an anchorage-independent fashion. Molecules that sensitize resistant cells to anoikis will be useful chemical probes to understand this pathway. To identify novel anoikis sensitizers in anoikis-resistant PPC-1 prostate adenocarcinoma cells, a library of 2,000 off-patent drugs and natural products was screened for their ability to preferentially induce cell death in suspension over adherent culture conditions. This screen identified five members of the family of cardiac glycosides as anoikis sensitizers, including ouabain, peruvoside, digoxin, digitoxin, and strophanthidin. We conducted further studies with ouabain to discern the mechanism of cardiac glycoside-induced anoikis sensitization. Ouabain initiated anoikis through the mitochondrial pathway of caspase activation. In addition, ouabain sensitized cells to anoikis by inhibiting its known target, the Na(+)/K(+) ATPase pump, and inducing hypoosmotic stress. Resistance to anoikis permits cancer cells to survive in the circulation and facilitates their metastasis to distant organs, so we tested the effects of Na(+)/K(+) ATPase inhibition on distant tumor formation in mouse models. In these mouse models, ouabain inhibited tumor metastases but did not alter the growth of subcutaneous tumors. Thus, we have identified a novel mechanism to sensitize resistant cells to anoikis and decrease tumor metastasis. These results suggest a potential mechanism for the observed clinical reduction in metastasis and relapse in breast cancer patients who have undergone treatments with cardiac glycosides.

Expression of the melanoma-associated antigen is associated with progression of human thyroid cancer.

Thyroid cancer exhibits a spectrum from relatively indolent tumors to tumors that are invasive, metastatic, or progress to poorly differentiated carcinoma. Microarray expression analysis of thyroid cancer cell lines has implicated a member of the melanoma-associated (MAGE) family of cancer-testis antigens in thyroid cancer development and progression. We performed this study to validate the role of MAGE in human thyroid cancers. A tissue microarray (TMA) of samples from 375 patients with thyroid cancer was analyzed with immunohistochemistry (IHC) to localize MAGE. Western blotting of fractionated proteins from MAGE-transfected cells was used to confirm intracellular localization of proteins. Automated analysis of TMA samples was evaluated and subjected to statistical analysis. MAGE immunoreactivity was identified in nuclear and cytoplasmic compartments of normal and malignant tissues. Specificity of staining was proved by fractionation studies that confirmed MAGE expression in nucleus and cytoplasm. Normal thyroid tissue exhibited weak cytoplasmic and strong nuclear MAGE reactivity. Tumors exhibited an increase in cytoplasmic MAGE scores that correlated with clinical behavior: larger tumors had higher MAGE scores, and there was a positive and significant correlation between MAGE cytoplasmic score and the number of histologically proven lymph node metastases. There was a statistically significant negative correlation between cytoplasmic MAGE and the percentage of p53-positive nuclei. Our data confirm gene-profiling evidence that members of the MAGE family play a role in thyroid cancer progression. The use of TMA analyses identifies IHC techniques that are translatable to the clinical setting for prognostic assessment of patients with thyroid cancer.

The melanoma-associated antigen A3 mediates fibronectin-controlled cancer progression and metastasis.

Tumor cells frequently exhibit decreased adhesiveness due to failure to deposit stromal fibronectin (FN), permitting more rapid proliferation, migration, invasion, and metastasis. Although up-regulation of FN has been noted in gene profiles of carcinomas compared with normal tissue, reduced FN expression has been described at the peripheral margins of invading tumors. In this study, we investigate the role of FN in cancer behavior. Using human thyroid carcinoma cells with stably down-regulated FN, we performed gene profiling and created an orthotopic mouse model. We stably overexpressed the FN target, MAGE A3, which has also been identified as a target of the breast cancer risk factor fibroblast growth factor receptor 2, and examined the functional effects in vitro and in vivo in a flank model and an orthotopic model of thyroid cancer. Mouse xenografts showed significantly enhanced tumor growth as well as larger and more numerous lung metastases in response to FN silencing. Gene profiling identified the melanoma-associated antigen (MAGE A3) as significantly up-regulated in response to FN silencing. Forced expression of MAGE A3 resulted in p21 down-regulation, accelerated cell cycle progression, increased cell migration rate, and invasion in vitro and in vivo in an orthotopic mouse model where microcomputed tomography confirmed lung metastases that recapitulate the progression of human thyroid cancer. We conclude that MAGE A3 is a functional integrator of diverse signals, including FGFR2 and FN, to modulate cancer progression.

Ectopic ACTH-secreting syndrome: a single center experience report with a high prevalence of occult tumor.

BACKGROUND: Differentiation between the two forms of ACTH-dependent Cushing's syndrome is a challenging task. Although the majority of these cases will be diagnosed as Cushing's disease secondary to an ACTH-secreting pituitary adenoma, 10-15% result from the ectopic ACTH secretion syndrome (EAS), which is usually due to neuroendocrine tumors. In the present study we report our experience with EAS in eight patients evaluated and treated during the past 10 years. METHODS: Our experience in the evaluation and management of EAS was retrospectively reviewed. The latter included a standard biochemical assessment (urinary free cortisol, low- and high-dose dexamethasone suppression tests), petrosal sinus sampling when indicated and imaging techniques such as pituitary MRI, total body CT and somatostatin receptor scintigraphy. RESULTS: The ectopic nature of the ACTH hypersecretion was confirmed with inferior petrosal sinus samplings in all cases. CT scanning localized a putative tumor in 6/8 patients, whereas octreotide scintigraphy was positive in only five. In all cases, the source was traced to the lungs. However, upon performing thoracotomy, a documented ACTH-secreting bronchial carcinoid tumor was found in only four patients. Thus, 4/8 patients with EAS remained "occult." All of these patients underwent adrenalectomy for hypercortisolism control. CONCLUSIONS: EAS is a rare cause of ACTH-dependent Cushing's syndrome. Truly "occult" tumors were frequent and these patients need to be under close surveillance for the detection of neuroendocrine tumors.

Biochemical evaluation of disease activity after pituitary surgery in acromegaly: a critical analysis of patients who spontaneously change disease status.

BACKGROUND: The definition of biochemical cure in acromegaly involves both the normalization of IGF-1 and a glucose-suppressed GH level of < 1 ng/ml. These criteria were reached by several consensus meetings, although no evidence-based recommendations as to the optimal time to perform biochemical evaluations were made, nor was the fact that several patients may change biochemically upon long-term follow-up taken into consideration. OBJECTIVES: To identify and characterize biochemical changes in the follow-up of acromegaly. PATIENTS AND METHODS: One hundred and twenty-six acromegalic patients seen at a referral centre were followed prospectively (6-108 months) with regard to glucose-suppressed GH levels and IGF-1 concentrations. RESULTS: Eighty-nine patients did not change biochemical status, whereas in 37 (29.3%), one or more changes were identified, mostly during the first year. When glucose-suppressed GH values were discordant with the IGF-1 results, the likelihood of biochemical status modification was significantly greater than when such results were concordant [concordant 19.4%, discordant 57.6%, odds ratio (OR) = 5.6, 95% confidence interval (CI) = 2.3-13.3, P = 0.0001]. Among the changing patients, four out of the nine subjects initially considered as cured remained so at the last follow-up, whereas five became discordant; of the nine initially categorized as active, only three kept such a status at the last evaluation, whereas five became GH discordant and one achieved full biochemical criteria of cure; of 17 initially GH-discordant patients, seven remained so upon the last evaluation, whereas six became concordantly active and four concordantly cured. CONCLUSION: A significant proportion of acromegalic patients change biochemical status upon long-term follow-up after surgery. Most of these changes occur within the first postoperative year and are more likely to take place if the initial GH postglucose and IGF-1 levels are discordant.

GSPalpha mutations in Mexican patients with acromegaly: potential impact on long term prognosis.

OBJECTIVE: The frequency of activating mutations of the GSPalpha gene as the etiology of GH-secreting pituitary adenomas has been the subject of important ethnogenetic variability. Whereas up to 40% of Caucasian patients with acromegaly have tumors which harbor these somatic mutations, their prevalence among Asian populations is much lower. The correlation between the presence of these mutations and the clinical and biological behavior of these tumors has also been a matter of controversy. In the present study, we investigated the prevalence of GSPalpha mutations in GH-secreting tumors obtained from a genetically homogenous population of Mexican patients with acromegaly. We also sought to establish whether or not the presence of these mutations correlates in any way with the clinical or biochemical characteristics of the disease. STUDY DESIGN AND METHODS: Fifty eight GH-secreting pituitary adenomas were examined for the presence of point mutations in either codon 201 or 227 of the GSPalpha gene, using PCR and direct sequencing of DNA extracted from either fresh or paraffin-embedded tissues. Patients were prospectively followed clinically and biochemically for up to nine years after pituitary surgery. RESULTS: Heterozygous point mutations in exon 8 (codon 201) were found in 11 patients (19%), and no molecular alterations were evident in exon 9. The frequency and severity of the different clinical features of acromegaly did not differ between patients with and without GSPalpha mutations. Patients with and without mutations had pre-operative GH and IGF-I elevations of similar magnitude, and although microadenomas appeared to be more frequent among patients with GSPalpha mutations, this did not reach statistical significance. Upon short-term follow-up, biochemical cure (normal age- and gender-adjusted IGF-I and post-glucose GH below 1 ng/mL) was similarly achieved in both groups. After 3-9 years of post-operative follow up however, a significantly greater proportion of patients with the mutation achieved a "safe" basal GH value (100% vs 33%, p=0.001) as well a lower nadir post-glucose GH (0.53+/-0.5 vs 2.9+/-6.2 ng/mL, p=0.04) although the rate of IGF-1 normalization did not differ between the 2 groups. CONCLUSIONS: Our results show that the prevalence of GSPalpha mutations in Mexican patients with acromegaly is intermediate between that found in Asian and Caucasian populations. In this well-defined genetic population the presence of codon 201 mutations appeared to be associated with a greater probability of achieving a "safe" GH value upon long-term follow-up.