Citations

Abstract Recent population-based studies demonstrate an increased fracture risk with monoclonal gammopathy of undetermined significance (MGUS). The etiology of this increased risk remains unclear, however, because areal bone mineral density (aBMD) measurements by dual-energy x-ray absorptiometry cannot assess bone microstructural properties critical to determining bone quality and strength. To better define the skeletal effects of MGUS, we performed aBMD and high-resolution peripheral quantitative computed tomography volumetric bone mineral density (vBMD) measurements in 50 MGUS patients (20 females, 30 males; mean ± SEM age, 70.5 ± 1.4 years) and 100 matched control subjects. Relative to controls, MGUS patients had decreased aBMD at the femoral neck (P = .05) and total femur (P < .05) but no differences at other sites. In contrast, high-resolution peripheral quantitative computed tomography showed markedly diminished cortical thickness (P < .05) and increased endocortical area (P < .01). Average vBMD (P < .01), cortical vBMD (P < .001), and trabecular thickness (P < .01) were all significantly decreased in MGUS patients, suggestive of impaired bone formation. Serum levels of the Wnt pathway inhibitor Dickkopf-related protein 1 (P < .001) and osteoclast-activating factor MIP-1α (P < .05) also were significantly elevated in MGUS patients. Our data provide the first evidence of altered bone microstructure in MGUS and suggest that cytokines elevated in osteolytic myeloma also may be associated with bone loss in MGUS.

Purpose NCCTG (North Central Cancer Treatment Group) N9831 is the only randomized phase III trial evaluating trastuzumab added sequentially or used concurrently with chemotherapy in resected stages I to III invasive human epidermal growth factor receptor 2–positive breast cancer. Patients and Methods Patients received doxorubicin and cyclophosphamide every 3 weeks for four cycles, followed by paclitaxel weekly for 12 weeks (arm A), paclitaxel plus sequential trastuzumab weekly for 52 weeks (arm B), or paclitaxel plus concurrent trastuzumab for 12 weeks followed by trastuzumab for 40 weeks (arm C). The primary end point was disease-free survival (DFS). Results Comparison of arm A (n = 1,087) and arm B (n = 1,097), with 6-year median follow-up and 390 events, revealed 5-year DFS rates of 71.8% and 80.1%, respectively. DFS was significantly increased with trastuzumab added sequentially to paclitaxel (log-rank P < .001; arm B/arm A hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.85). Comparison of arm B (n = 954) and arm C (n = 949), with 6-year median follow-up and 313 events, revealed 5-year DFS rates of 80.1% and 84.4%, respectively. There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration (arm C/arm B HR, 0.77; 99.9% CI, 0.53 to 1.11), but the P value (.02) did not cross the prespecified O'Brien-Fleming boundary (.00116) for the interim analysis. Conclusion DFS was significantly improved with 52 weeks of trastuzumab added to adjuvant chemotherapy. On the basis of a positive risk-benefit ratio, we recommend that trastuzumab be incorporated into a concurrent regimen with taxane chemotherapy as an important standard-of-care treatment alternative to a sequential regimen.

Atherosclerotic renal artery stenosis has a range of manifestations depending on the severity of vascular occlusion. The aim of this study was to examine whether exceeding the limits of adaptation to reduced blood flow ultimately leads to tissue hypoxia, as determined by blood oxygen level dependent MRI. We compared 3 groups of hypertensive patients, 24 with essential hypertension, 13 with “moderate” (Doppler velocities 200–384 cm/s), and 17 with “severe” atherosclerotic renal artery stenosis (ARAS; velocities >384 cm/s and loss of functional renal tissue). Cortical and medullary blood flows and volumes were determined by multidetector computed tomography. Poststenotic kidney size and blood flow were reduced with ARAS, and tissue perfusion fell in the most severe lesions. Tissue medullary deoxyhemoglobin, as reflected by R2* values, was higher as compared with the cortex for all of the groups and did not differ between subjects with renal artery lesions and essential hypertension. By contrast, cortical R2* levels were elevated for severe ARAS (21.6±9.4 per second) as compared with either essential hypertension (17.8±2.3 per second; P <0.01) or moderate ARAS (15.7±2.1 per second; P <0.01). Changes in medullary R2* after furosemide administration tended to be blunted in severe ARAS as compared with unaffected (contralateral) kidneys. These results demonstrate that severe vascular occlusion overwhelms the capacity of the kidney to adapt to reduced blood flow, manifest as overt cortical hypoxia as measured by blood oxygen level–dependent MRI. The level of cortical hypoxia is out of proportion to the medulla and may provide a marker to identify irreversible parenchymal injury.

Abstract Insulin-like growth factor (IGF) signaling has been implicated in the resistance to hormonal therapy in breast cancer. Using a model of postmenopausal, estrogen-dependent breast cancer, we investigated the antitumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor BMS-754807 alone and in combination with letrozole or tamoxifen. BMS-754807 exhibited antiproliferative effects in vitro that synergized strongly in combination with letrozole or 4-hydroxytamoxifen and fulvestrant. Similarly, combined treatment of BMS-754807 with either tamoxifen or letrozole in vivo elicited tumor regressions not achieved by single-agent therapy. Notably, hormonal therapy enhanced the inhibition of IGF-1R/InsR without major side effects in animals. Microarray expression analysis revealed downregulation of cell-cycle control and survival pathways and upregulation of erbB in response to BMS-754807 plus hormonal therapy, particularly tamoxifen. Overall, these results offer a preclinical proof-of-concept for BMS-754807 as an antitumor agent in combination with hormonal therapies in hormone-sensitive breast cancer. Cooperative cell-cycle arrest, decreased proliferation, and enhanced promotion of apoptosis may contribute to antitumor effects to be gauged in future clinical investigations justified by our findings. Cancer Res; 71(24); 7597–607. ©2011 AACR.

BACKGROUND: An increasing number of patients require prolonged mechanical ventilation (PMV), which is associated with high morbidity and poor long-term survival, but there are few data regarding the incidence and outcome of PMV patients from a community perspective. METHODS: We retrospectively reviewed the electronic medical records of adult Olmsted county, Minnesota, residents admitted to the intensive care units at the 2 Mayo Clinic Rochester hospitals from January 1, 2003, to December 31, 2007, who underwent tracheostomy for PMV. RESULTS: Sixty-five patients, median age 68 years (interquartile range [IQR] 49–80 y), 39 male, underwent tracheostomy for PMV, resulting in an age-adjusted incidence of 13 (95% CI 10–17) per 100,000 patient-years at risk. The median number of days on mechanical ventilation was 24 days (IQR 18–37 d). Forty-six patients (71%) survived to hospital discharge, and 36 (55%) were alive at 1-year follow-up. After adjusting for age and baseline severity of illness, the presence of COPD was independently associated with 1-year mortality (hazard ratio 3.4, 95% CI 1.4–8.2%). CONCLUSIONS: There was a considerable incidence of tracheostomy for PMV. The presence of COPD was an independent predictor of 1-year mortality.

Snoring is the sound of soft tissues vibrating within the upper throat during sleep. The vibration is a result of turbulent air flow through the throat as it narrows during sleep. Snoring is very common in adults and may occur alone or be a feature of other conditions characterized by greater throat narrowing during sleep, namely upper airway resistance syndrome (UARS) and obstructive sleep apnea syndrome (OSA). UARS is marked by daytime sleepiness and/or fatigue in the context of frequent respiratory-effort related arousals (RERAs). RERAs are episodic arousals that follow periods of more intense breathing effort as resistance to airflow in the throat increases. Once the throat is very narrow, hypopneas (partial reduction in airflow) and apneas (complete cessation of airflow) occur, and these events comprise OSA. Whether UARS is an entity distinct from OSA remains still debated. Risk factors for snoring and UARS are similar and include obesity, nasal congestion, alcohol and drug consumption before bed, and abnormalities of the bony and soft tissue structures of the head and neck. Snoring can be a nuisance, but generally does not produce daytime sequelae, while UARS may lead to daytime fatigue and sleepiness. Treatment options for snoring and UARS include risk factor modifications, nasal-directed therapies, oral appliances, upper airway surgery, while continuous positive airway pressure (CPAP) is an additional option for UARS.

A preponderance of patients with neuroendocrine tumors (NETs) will experience hepatic metastases during the course of their disease. Many diagnoses of NETs are made only after the neoplasms have spread from their primary gastroenteropancreatic sites to the liver. This paper reviews current evidence-based treatments for neuroendocrine hepatic metastases, encompassing surgery, hepatic artery embolization (HAE) and chemoembolization (HACE), radioembolization, hepatic artery infusion (HAI), thermal ablation (radiofrequency, microwave, and cryoablation), alcohol ablation, and liver transplantation as therapeutic modalities. Consideration of a multidisciplinary approach to liver-directed therapy is strongly encouraged to limit morbidity and mortality in this patient population.