Adrenocortical carcinomas are rare, highly malignant tumors that account for only 0.2% of deaths due to cancer. Given the limited number of patients seen in most medical centers with this diagnosis, ...series usually reported are small and clinical trials not randomized or blinded. In an attempt to answer important questions concerning the management of patients with adrenal cancer, a consensus conference was organized and held at the University of Michigan in Ann Arbor, MI, 11–13 September 2003, with the participation of an international group of physicians who had reported on the largest series of patients with this disease and who had recognized basic and clinical research expertise in adrenal cortical cancer. Totally 43 questions were addressed by the presenters and recommendations discussed in plenary and breakout sessions. Evidence for the recommendations of this conference was at the 2–4+ level and based on available literature and participants’ experience. In addition to setting up guidelines in specific areas of the diagnosis and treatment of adrenal cancer, the conference recommended and initiated the planning of an international prospective trial for treatment of patients with adrenal cancer in stages III and IV. In terms of new therapies, first trials of dendritic cell therapy in human subjects with adrenal cancer have been started, but it is too early to comment on efficacy. Different strategies of immunotherapy, including DNA vaccination are currently being tried in animal models. There are no clinical gene therapy trials for human adrenal cortical cancer. The adrenals are a preferred target for adenovirus and the results of gene therapy in preclinical studies are promising. In addition, there is evidence that histone deacetylase inhibitors can further enhance the rate of adenoviral infectivity in human adrenal cancer cells. Testing of retroviral vectors, non-viral vectors, small interfering RNA technology, and combined approaches could be performed in various laboratories. Anti-angiogenic substances have only been applied in preclinical studies. The use of these and other agents in the treatment of adrenal cancer should be hypothesis-driven and based on a thorough analysis of tumor biology.
The National Institute for Occupational Safety and Health and the Environmental Protection Agency sponsored the completion of an interlaboratory study to compare two fitting protocols specified by ...ANSI S12.6-1997 (R2002) (2002). American National Standard Methods for the Measuring Real-Ear Attenuation of Hearing Protectors, American National Standards Institute, New York. Six hearing protection devices (two earmuffs, foam, premolded, custom-molded earplugs, and canal-caps) were tested in six laboratories using the experimenter-supervised, Method A, and (naive) subject-fit, Method B, protocols with 24 subjects per laboratory. Within-subject, between-subject, and between-laboratory standard deviations were determined for individual frequencies and A-weighted attenuations. The differences for the within-subject standard deviations were not statistically significant between Methods A and B. Using between-subject standard deviations from Method A, 3-12 subjects would be required to identify 6-dB differences between attenuation distributions. Whereas using between-subject standard deviations from Method B, 5-19 subjects would be required to identify 6-dB differences in attenuation distributions of a product tested within the same laboratory. However, the between-laboratory standard deviations for Method B were -0.1 to 3.0 dB less than the Method A results. These differences resulted in considerably more subjects being required to identify statistically significant differences between laboratories for Method A (12-132 subjects) than for Method B (9-28 subjects).
Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the ...efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism.
In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed.
From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio HR 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths.
In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants.
Bayer AG and Janssen Research & Development.
Maternal-derived immunity is a critical component for the survival and success of offspring in pigs to protect from circulating pathogens such as Type 2 Porcine Reproductive and Respiratory Syndrome ...Virus (PRRSV-2). The purpose of this study is to investigate the transfer of anti-PRRSV immunity to piglets from gilts that received modified-live virus (MLV) alone (treatment (TRT) 0), or in combination with one of two autogenous inactivated vaccines (AIVs, TRT 1+2). Piglets from these gilts were challenged with the autogenous PRRSV-2 strain at two weeks of age and their adaptive immune response (IR) was evaluated until 4 weeks post inoculation (wpi). The systemic humoral and cellular IR was analyzed in the pre-farrow gilts, and in piglets, pre-inoculation, and at 2 and 4 wpi. Both AIVs partially protected the piglets with reduced lung pathology and increased weight gain; TRT 1 also lowered piglet viremia, best explained by the AIV-induced production of neutralizing antibodies in gilts and their transfer to the piglets. In piglets, pre-inoculation, the main systemic IFN-γ producers were CD21α
B cells. From 0 to 4 wpi, the role of these B cells declined and CD4 T cells became the primary systemic IFN-γ producers. In the lungs, CD8 T cells were the primary and CD4 T cells were the secondary IFN-γ producers, including a novel subset of porcine CD8α
CCR7
CD4 T cells, potentially terminally differentiated CD4 T
cells. In summary, this study demonstrates that maternal AIV vaccination can improve protection of pre-weaning piglets against PRRSV-2; it shows the importance of transferring neutralizing antibodies to piglets, and it introduces two novel immune cell subsets in pigs-IFN-γ producing CD21α
B cells and CD8α
CCR7
CD4 T cells.
IMPORTANCE Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). OBJECTIVE To ...determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. DESIGN, SETTING, AND PARTICIPANTS The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. INTERVENTIONS Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. MAIN OUTCOMES AND MEASURES The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability. CONCLUSIONS AND RELEVANCE Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00833690
Receptor tyrosine kinases play an important role in malignant transformation of epithelial cells by activating signal transduction pathways important for proliferation, invasion and metastasis. In a ...pilot study (n = 40), we evaluated expression of the c‐Met and Her2/neu receptor tyrosine kinases and the c‐Met ligand hepatocyte growth factor/scatter factor (HGF/SF) in primary breast cancers and their lymph node metastases using both conventional immunohistochemistry and confocal immunofluorescence. Neither c‐Met and HGF/SF nor Her2/neu expression correlated with established prognostic factors such as age, lymph node involvement, estrogen receptor (ER), progesterone receptor (PR), tumor size, or grade. Both staining methods confirmed a significant correlation between c‐Met overexpression and a high risk of disease progression. Furthermore, among tumors with c‐Met overexpression, only 50% also overexpress Her2/neu, thus identifying a subset of patients with aggressive disease in addition to Her2/neu. Median disease‐free survival in patients with c‐Met overexpressing tumors was 8 months compared to 53 months when c‐Met expression was low (p = 0.037; RR = 3.0). This significant impact of c‐Met on tumor aggressiveness independent of Her2/neu was also confirmed by multivariate analysis. In conclusion, the role of c‐Met expression as a prognostic variable and consequently as an interesting target for novel therapeutic approaches deserves further analysis in a larger cohort of patients.
Purpose
Commercial parabolic flights accessible to customers with a wide range of health states will become more prevalent in the near future because of a growing private space flight sector. ...However, parabolic flights present the passengers’ cardiovascular system with a combination of stressors, including a moderately hypobaric hypoxic ambient environment (HH) and repeated gravity transitions (GT). Thus, the aim of this study was to identify unique and combined effects of HH and GT on the human cardiovascular, pulmonary and fluid regulation systems.
Methods
Cardiac index was determined by inert gas rebreathing (CI
rb
), and continuous non-invasive finger blood pressure (FBP) was repeatedly measured in 18 healthy subjects in the standing position while they were in parabolic flight at 0 and 1.8 G
z
. Plasma volume (PV) and fluid regulating blood hormones were determined five times over the flight day. Eleven out of the 18 subjects were subjected to an identical test protocol in a hypobaric chamber in ambient conditions comparable to parabolic flight.
Results
CI
rb
in 0 G
z
decreased significantly during flight (early, 5.139 ± 1.326 L/min; late, 4.150 ± 1.082 L/min) because of a significant decrease in heart rate (HR) (early, 92 ± 15 min
−1
; late, 78 ± 12 min
−1
), even though the stroke volume (SV) remained the same. HH produced a small decrease in the PV, both in the hypobaric chamber and in parabolic flight, indicating a dominating HH effect without a significant effect of GT on PV (−52 ± 34 and −115 ± 32 ml, respectively). Pulmonary tissue volume decreased in the HH conditions because of hypoxic pulmonary vasoconstriction (0.694 ± 0.185 and 0.560 ± 0.207 ml) but increased at 0 and 1.8 G
z
in parabolic flight (0.593 ± 0.181 and 0.885 ± 0.458 ml, respectively), indicating that cardiac output and arterial blood pressure rather than HH are the main factors affecting pulmonary vascular regulation in parabolic flight.
Conclusion
HH and GT each lead to specific responses of the cardiovascular system in parabolic flight. Whereas HH seems to be mainly responsible for the PV decrease in flight, GT overrides the hypoxic pulmonary vasoconstriction induced by HH. This finding indicates the need for careful and individual medical examination and, if necessary, health status improvement for each individual considering a parabolic flight, given the effects of the combination of HH and GT in flight.
This study analyzed independent factors associated with post-thyroidectomy Emergency Room (ER) visits and Hospital Readmissions (HR).
This is a retrospective review from the CESQIP registry of 8381 ...thyroidectomy patients by 173 surgeons at 46 institutions. A total of 7142 ER visits and 7265 HR were analyzed. Multivariable logistic regression analysis was performed to determine the risk factors for an ER visit or HR.
Within 30-days of surgery, rates of all ER visits were 3.4% (n = 250) and all HR were 2.3% (n = 170). Hypocalcemia was the reason for 21.9% of ER encounters and 36.4% of HR. BMI >40 kg/m2 was a risk factor for both ER visit (OR1.86) and HR (OR1.94). Surgical duration >3 h (OR2.63), and transection of recurrent laryngeal nerve (OR4.58) were risk factors for HR.
Strategies to decrease hypocalcemia and improve perioperative care of patients with BMI >40 kg/m2 may improve post-thyroidectomy outcome.
•Hypocalcemia was the most common reason for post-thyroidectomy related complication.•Minor complaints or complaints unrelated to thyroidectomy made up half of the reasons for ER visits.•Complications of swelling/seroma, infection, respiratory distress and neck hematoma are rare.•Patient BMI >40 kg/m2 is a risk factor for ER visit and hospital readmission after thyroidectomy.
Context: Primary hyperparathyroidism (HPT) is a systemic disease causing bone loss. Periodontal disease is a local inflammatory disease characterized by alveolar bone loss. The older literature ...records that HPT is associated with loss of radicular lamina dura and brown tumors of the bone, but contemporary studies are lacking.
Objective: The objective of the study was to determine the effects of HPT on oral bony structures and periodontal disease in a contemporary population.
Design: This was a cross-sectional, case-controlled study.
Setting: The study was conducted at the clinics of endocrine surgery and hospital dentistry.
Patients and Other Participants: Fifty-nine patients, 39 with HPT and 20 thyroid controls, were included in the study.
Main Outcome Measures: Periodontal clinical measures and dental radiographic analyses were used in this study.
Results: HPT patients were more likely to have tori and reductions in radicular lamina dura on dental radiographs. Widening of the periodontal ligament space surrounding teeth correlated with serum PTH levels. Panoramic radiographs demonstrated reduced cortical bone thickness at the angle of the mandible in HPT patients but no evidence of brown tumors or other overt pathologies.
Conclusions: Changes in the oral cavity observed in patients with HPT suggested both decreased cortical density and increased likelihood of oral tori. The contemporary oral manifestations of primary HPT are different from those previously reported, and health care providers should be aware of newer, more subtle findings that may be present when treating patients with HPT.
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