Citations

OBJECTIVESTo report the oncology and functional outcomes of transoral laser microsurgery (TLM) for untreated glottic carcinoma.STUDY DESIGNA 2 center prospective case series analysis.SETTINGAcademic, tertiary referral centers.RESULTSSeventy‐six patients underwent TLM. Pathologic T stages were: T1, 45 (59%); T2, 21 (28%); T3, 5 (7%); and T4, 5 (7%). Five (7%) patients had neck dissections. Five (7%) patients received adjuvant radiotherapy. Mean follow‐up was 42 months. Respective T1 and T2 5‐year Kaplan‐Meier estimates were: local control, 90% and 93%; loco‐regional control, 90% and 93%; disease specific survival, 90% and 93%; and overall survival, 94% and 93%. The average hospital stay was 2 days. Two (3%) patients experienced major complications. The overall laryngeal preservation rate was 95% (72 of 76).CONCLUSIONSTLM is a safe and effective treatment in select carcinoma of the glottic larynx. Low morbidity and mortality and short periods of hospitalization make TLM an attractive therapeutic option.SIGNIFICANCETLM is an emerging strategy in the treatment of laryngeal cancer.

Abstract Purpose: Incidence and mortality rates for renal cell carcinoma (RCC) have been rising for decades. Unfortunately, the molecular events that support RCC carcinogenesis remain poorly understood. In an effort to gain a better understanding of signaling events in clear cell RCC (cRCC), we investigated the antitumor activity of secreted frizzled-related protein 1 (sFRP1), a negative regulator of Wnt signaling. Experimental Design: Genomic profiling of cRCC tumors and patient-matched normal tissues was done and confirmed using quantitative PCR and immunohistochemistry. Methylation-specific PCR was done on patient samples to evaluate the mechanism responsible for sFRP1 loss. sFRP1 expression was restored in cRCC cells and the effects on tumor phenotype were characterized. Results: Genomic profiling, quantitative PCR, and immunohistochemistry indicated that loss of sFRP1 occurred in cRCC and papillary RCC patient tissues. Twelve Wnt-regulated genes were up-regulated in cRCC tissues, including c-myc and cyclin D1, potentiators of cell proliferation and survival. Methylation of the sFRP1 gene was one mechanism identified for attenuation of sFRP1 mRNA. Stable reexpression of sFRP1 in cRCC cells resulted in decreased expression of Wnt target genes, decreased growth in cell culture, inhibition of anchorage-independent growth, and decreased tumor growth in athymic nude mice. Conclusions: To our knowledge, this is the first report to show that stable restoration of sFRP1 expression in cRCC cells attenuates the cRCC tumor phenotype. Our data support a role for sFRP1 as a tumor suppressor in cRCC and that perhaps loss of sFRP1 is an early, aberrant molecular event in renal cell carcinogenesis.

Abstract Context: We reported recently the induction of iodide accumulation in prostate cancer cells (LNCaP) by prostate-specific antigen promoter-directed sodium iodide symporter (NIS) expression that allowed a significant therapeutic effect of 131iodine (131I). These data demonstrated the potential of the NIS gene as a novel therapeutic gene, although in some extrathyroidal tumors, therapeutic efficacy may be limited by rapid iodide efflux due to a lack of iodide organification. Objective: In the current study, we therefore studied the potential of 188rhenium (188Re), as an alternative radionuclide, also transported by NIS, with a shorter half-life and higher energy β-particles than 131I. Results: NIS-transfected LNCaP cells (NP-1) concentrated 8% of the total applied activity of 188Re as compared with 16% of 125I, which was sufficient for a therapeutic effect in an in vitro clonogenic assay. γ-Camera imaging of NP-1 cell xenografts in nude mice revealed accumulation of 8–16% injected dose (ID)/g 188Re (biological half-life 12.9 h), which resulted in a 4.7-fold increased tumor absorbed dose (450 mGy/MBq) for 188Re as compared with 131I. After application of 55.5 MBq 131I or 188Re, smaller tumors showed a similar average volume reduction of 86%, whereas in larger tumors volume reduction was significantly increased from 73% after 131I treatment to 85% after application of 188Re. Conclusion: Although in smaller prostate cancer xenografts both radionuclides seemed to be equally effective after prostate-specific antigen promoter-mediated NIS gene delivery, a superior therapeutic effect has been demonstrated for 188Re in larger tumors.

Introduction The earliest lesion in the kidneys of idiopathic calcium oxalate stone formers is deposition of calcium phosphate in the interstitium, termed a Randall's plaque. Yet the cellular and molecular factors leading to their formation are unknown. Methods The influence of urinary proteins on adhesion of preformed calcium oxalate crystals to rat continuous inner medullary collecting duct (cIMCD) cells was studied in vitro, and cIMCD cells were also exposed to calcifying media containing β-glycerophosphate for up to 28 days. Renal tissue was obtained from a stone-forming and non-stone-forming individual at the time of nephrectomy. These nanoparticles, isolated from renal stones obtained at the time of surgical resection, were analyzed and propagated in standard cell culture medium. Results Urinary proteins influence crystal adhesion to renal epithelial cells, and this activity is abnormal in the urine of stone-forming patients. cIMCD cells assumed an osteoblastic phenotype when exposed to the calcifying medium, expressing two bone matrix proteins (osteopontin and bone sialoprotein) that were also identified in the kidney of the stone-forming patient and associated with crystal deposition. Nanoparticles were propagated from the majority of renal stones. Isolates were susceptible to selected metabolic inhibitors and antibiotics and contained conserved bacterial proteins and deoxyribonucleic acid (DNA). Conclusions These results suggest new paradigms for Randall's plaque formation and idiopathic calcium oxalate stone disease. It seems unlikely that these events are driven solely by physical chemistry; rather, they are critically influenced by specific proteins and cellular responses, and understanding these events will provide clues toward novel therapeutic targets.

Background The origin of advanced arterial and renal calcification remains poorly understood. Self-replicating, calcifying entities have been detected and isolated from calcified human tissues, including blood vessels and kidney stones, and are referred to as nanobacteria. However, the microbiologic nature of putative nanobacteria continues to be debated, in part because of the difficulty in discriminating biomineralized microbes from minerals nucleated on anything else (eg, macromolecules, cell membranes). To address this controversy, the use of techniques capable of characterizing the organic and mineral content of these self-replicated structures at the submicrometer scale would be beneficial. Methods Calcifying gram-negative bacteria ( Caulobacter crescentus, Ramlibacter tataouinensis) used as references and self-replicating calcified nanoparticles cultured from human samples of calcified aneurysms were examined using a scanning transmission x-ray microscope (STXM) at the Advanced Light Source at Lawrence Berkeley National Laboratory. This microscope uses a monochromated and focused synchrotron x-ray beam (80-2,200 eV) to yield microscopic and spectroscopic information on both organic compounds and minerals at the 25 nm scale. Results High-spatial and energy resolution near-edge x-ray absorption fine structure (NEXAFS) spectra indicative of elemental speciation acquired at the C K-edge, N K-edge, and Ca L 2,3 -edge on a single-cell scale from calcified C. crescentus and R. tataouinensis displayed unique spectral signatures different from that of nonbiologic hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ). Further, preliminary NEXAFS measurements of calcium, carbon, and nitrogen functional groups of cultured calcified nanoparticles from humans revealed evidence of organics, likely peptides or proteins, specifically associated with hydroxyapatite minerals. Conclusion Using NEXAFS at the 25 nm spatial scale, it is possible to define a biochemical signature for cultured calcified bacteria, including proteins, polysaccharides, nucleic acids, and hydroxyapatite. These preliminary studies suggest that nanoparticles isolated from human samples share spectroscopic characteristics with calcified proteins.

Since the discovery of the cardiac hormone atrial natriuretic peptide by de Bold and colleagues in 1981, the field of natriuretic peptides has significantly advanced with translation of new knowledge to the clinical practice of heart failure. This new knowledge builds on the importance of cardiorenal mechanisms that contribute to optimal cardiovascular regulation. Recent investigations by our group and others have also established the direct myocardial actions of the natriuretic peptides, broadening their therapeutic potential beyond renal mechanisms. Indeed, a potential therapeutic target is cardiac remodeling and fibrosis based on the unique cardiorenal and humoral protective properties that natriuretic peptides possess. We review new insights into the natriuretic peptide system and specifically focus on the possible role of natriuretic peptides as a new therapeutic strategy to limit cardiac remodeling and fibrosis to delay worsening of cardiac function and the progression of heart failure.

Abstract B7 coregulatory ligands can be aberrantly expressed in human disease. In the context of cancer, these ligands may act as antigen-specific inhibitors of T-cell–mediated antitumoral immunity. We recently reported that B7-H1 expression by carcinomas of the kidney and bladder portends aggressive disease and diminished survival. The expression of these proteins in prostate cancer, however, has not been investigated. We evaluated B7-H3 and B7-H1 protein expression in the pathologic specimens of 338 men treated for clinically localized prostate cancer between 1995 and 1998 with radical retropubic prostatectomy. Expression levels of B7-H3 in prostate cancer were correlated with pathologic indicators of aggressive cancer as well as clinical outcome. We report that B7-H3 is uniformly and aberrantly expressed by adenocarcinomas of the prostate, high-grade prostatic intraepithelial neoplasia, and four prostate cancer cell lines, whereas B7-H1 is rarely expressed. B7-H3 is expressed by benign prostatic epithelia, although at a more reduced level relative to neoplastic tissue. Increasing levels of B7-H3 intensity correlate with worsening clinicopathologic features of prostate cancer. Marked B7-H3 intensity, present in 67 (19.8%) specimens, confers a >4-fold increased risk of cancer progression after surgery (risk ratio, 4.42; P < 0.001). A survey of normal tissues revealed that B7-H3 is expressed within the liver, urothelium, and fetal kidney. In summary, B7-H3 is aberrantly expressed in all prostate cancers and represents an independent predictor of cancer progression following surgery. Moreover, B7-H3 encompasses a novel diagnostic and potential therapeutic target for the clinical management of prostate cancer and, perhaps, other malignancies as well. [Cancer Res 2007;67(16):7893–900]

Background— Quality improvement efforts have focused on strategies to improve the timeliness of reperfusion therapy in ST-elevation myocardial infarction patients who present to hospitals with and without percutaneous coronary intervention (PCI) capability. We implemented and evaluated a protocol to optimize the timeliness of reperfusion therapy and to coordinate systems of care for a PCI center and 28 regional hospitals located up to 150 miles away across 3 states. Methods and Results— The present study focused on a prospective, observational cohort of 597 patients who presented with ST-segment elevation and within 12 hours of symptom onset to Saint Marys Hospital and 28 regional hospitals up to 150 miles away between May 2004 and December 2006. The Mayo Clinic ST-elevation myocardial infarction protocol implemented strategies to improve timeliness of reperfusion therapy and to coordinate systems of care for transfer between hospitals. The study sample consisted of 258 patients who presented to Saint Marys Hospital and were treated with primary PCI (group A), 105 patients who presented to a regional hospital with symptom onset >3 hours and then were transferred for primary PCI (group B), and 131 patients who presented to a regional hospital with symptom onset <3 hours and were treated with full-dose fibrinolytic therapy (group C). For groups A and B, median door-to-balloon times were 71 and 116 minutes, respectively. Door-to-balloon time <90 minutes was achieved in 75% of group A and 12% of group B. Median door-to-needle time was 25 minutes for group C, and 70% had door-to-needle time <30 minutes. Conclusions— The Mayo Clinic ST-elevation myocardial infarction protocol demonstrates the feasibility of implementing strategies to optimize the timeliness of reperfusion therapy and the times that can be achieved through coordinated systems of care for ST-elevation myocardial infarction patients presenting to a PCI center (Saint Marys Hospital) and 28 regional hospitals without PCI capability located up to 150 miles away across 3 states.