Small RNA sequencing reveals snoRNAs and piRNA-019825 as novel players in diabetic kidney disease.

INTRODUCTION: Micro- and macrovascular complications are common among persons with type 2 diabetes. Recently there has been growing interest to investigate the potential of circulating small non-coding RNAs (sncRNAs) as contributors to the development of diabetic complications. In this study we investigate to what extent circulating sncRNAs levels associate with prevalent diabetic kidney disease (DKD) in persons with type 2 diabetes. METHODS: Plasma sncRNAs levels were determined using small RNA-seq, allowing detection of miRNAs, snoRNAs, piRNAs, tRNA fragments, and various other sncRNA classes. We tested for differentially expressed sncRNAs in persons with type 2 diabetes, with DKD (n = 69) or without DKD (n = 405). In secondary analyses, we also tested the association with eGFR, albuminuria (UACR), and the plasma proteome. RESULTS: In total seven sncRNAs were negatively associated with prevalent DKD (all PFDR ≤ 0.05). Including one microRNA (miR-143-5p), five snoRNAs (U8, SNORD118, SNORD24, SNORD107, SNORD87) and a piRNA (piR-019825 | DQ597218). Proteomic analyses showed that the seven sncRNAs, and especially the piRNA piR-019825, were associated with plasma levels of 24 proteins of which several have known associations with kidney function including TNF sR-I (TNFRFS1A), DAN (NBL1) and cystatin C (CST3). CONCLUSION: We have identified novel small non-coding RNAs, primarily from classes other than microRNAs, that are associated with diabetic kidney disease. Our results show that the involvement of small non-coding RNAs in DKD goes beyond the already known microRNAs and also involves other classes of sncRNA, in particular snoRNAs and the piRNA piR-019825, that have never been studied before in relation to kidney function.

Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.

Partial maxillectomy for ameloblastoma of the maxilla with infratemporal fossa involvement: A combined endoscopic endonasal and transoral approach.

Ameloblastoma represents the most common epithelial odontogenic tumor. Because of the proximity of the maxillary tumors to the orbit and skull base, it should be managed as radically as possible. Maxillectomy, mainly via the transfacial or transoral approach, represents the most common type of surgical procedure. Drawback of these approaches is limited control of the superiomedial extent of the tumour in the paranasal area. We report the use of a combined endoscopic endonasal and transoral approach to manage maxillary plexiform ameloblastoma in a 48-year-old male patient. A combined endoscopic endonasal and transoral approach enabled the radical removal of tumour with a 1.5cm margin of radiographically intact bone with good control from both intrasinusal and intraoral aspects. Adequate visualization of the extent of the lesion (e.g. orbit, infratemporal fossa, anterior cranial base) had been achieved. Non-complicated healing was achieved. This technique of partial maxillectomy led to very good aesthetic and functional results. No recurrence had been noted during review appointments. The combination of endoscopic endonasal and transoral approach for a partial maxillectomy allows sufficient reduction of the defect, thus eliminating the necessity for reconstruction and reducing the morbidity associated with it.

TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

PURPOSE: This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. METHODS: Sixty-seven patients received TAK-228 6-40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m2 (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1. RESULTS: TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months. CONCLUSION: TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors. CLINICALTRIALS. GOV IDENTIFIER: NCT01351350.

Persistence of external signs in Pacific herring Clupea pallasii Valenciennes with ichthyophoniasis.

The progression of external signs of Ichthyophonus infection in Pacific herring Clupea pallasii Valenciennes was highly variable and asynchronous after intraperitoneal injection with pure parasite preparations; however, external signs generally persisted through the end of the study (429 days post-exposure). Observed signs included papules, erosions and ulcers. The prevalence of external signs plateaued 35 days post-exposure and persisted in 73-79% of exposed individuals through the end of the first experiment (147 days post-exposure). Among a second group of infected herring, external signs completely resolved in only 10% of the fish after 429 days. The onset of mortality preceded the appearance of external signs. Histological examination of infected skin and skeletal muscle tissues indicated an apparent affinity of the parasite for host red muscle. Host responses consisted primarily of granulomatous inflammation, fibrosis and necrosis in the skeletal muscle and other tissues. The persistence and asynchrony of external signs and host response indicated that they were neither a precursor to host mortality nor did they provide reliable metrics for hindcasting on the date of exposure. However, the long-term persistence of clinical signs in Pacific herring may be useful in ascertaining the population-level impacts of ichthyophoniasis in regularly observed populations.

A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer.

BACKGROUND: Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC. PATIENTS AND METHODS: The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0-1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization. RESULTS: Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145). CONCLUSIONS: Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.

Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT.

BACKGROUND: Oxaliplatin is an integral component of colorectal cancer treatment, but its use is limited by neurotoxicity. The Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT) tested intermittent oxaliplatin (IO) administration and the use of concurrent calcium and magnesium salts (Ca/Mg), two modifications intended to reduce neurotoxicity and extend the duration of treatment. PATIENTS AND METHODS: In this trial involving double randomization, 140 patients were randomized to receive modified FOLFOX7 plus bevacizumab with IO (eight-cycle blocks of oxaliplatin treatment) versus continuous oxaliplatin (CO); and Ca/Mg versus placebo (pre- and postoxaliplatin infusion). The primary end point was time-to-treatment failure (TTF). RESULTS: One hundred thirty-nine patients were entered and treated up to the point of early study termination due to concerns by the data-monitoring committee (DMC) that Ca/Mg adversely affected tumor response. Tumor response was not a study end point. Given DMC concerns, an additional independent, blinded radiology review of all images showed no adverse effect of treatment schedule or Ca/Mg on response by Response Evaluation Criteria In Solid Tumors. The IO schedule was superior to CO [hazard ratio (HR) = 0.581, P = 0.0026] for both TTF and time-to-tumor progression (TTP) (HR = 0.533, P = 0.047). CONCLUSIONS: An IO dosing schedule had a significant benefit on both TTF and TTP versus CO dosing in this trial despite the very attenuated sample. There was no effect of Ca/Mg on response.

Phase III trial of gemcitabine plus docetaxel versus capecitabine plus docetaxel with planned crossover to the alternate single agent in metastatic breast cancer.

BACKGROUND: Safety and efficacy of gemcitabine plus docetaxel (GD) and capecitabine plus docetaxel (CD) were compared in patients with metastatic breast cancer, where the alternate crossover monotherapy (GD→C or CD→G) was predetermined. PATIENTS AND METHODS: Patients were randomly assigned to 3-week cycles of either gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 75 mg/m(2) on day 1 or capecitabine 1000 mg/m(2) twice daily on days 1-14 plus docetaxel 75 mg/m(2) day 1. Upon progression, patients received crossover monotherapy. Primary end point was time to progression (TtP). Secondary end points evaluated overall response rate (ORR), overall survival (OS), and adverse events (AEs). RESULTS: Despite over-accrual of 475 patients, the trial matured with only 324 of 385 planned TtP events due to patient discontinuations. Human epidermal growth factor receptor 2 status was not captured in this study. More CD patients (28%) discontinued due to AEs than GD patients (18.0%, P = 0.009). TtP [hazard ratio (HR) = 1.101, 95% confidence interval (CI) 0.885-1.370, P = 0.387] and OS (HR = 1.031, 95% CI 0.830-1.280, P = 0.785) were not significantly different comparing GD and CD. ORR was not statistically different (P = 0.239) comparing GD (72 of 207, 34.8%) and CD (78 of 191, 40.8%). TtP, OS, and ORR were not significantly different comparing crossover groups. GD caused greater fatigue, hepatotoxicity, neutropenia, and thrombocytopenia but not febrile neutropenia; CD caused more hand-foot syndrome, gastrointestinal toxicity, and mucositis. CONCLUSIONS: GD and CD produced similar efficacy and toxicity profiles consistent with prior clinical experience.

Experience with academic detailing services for quality improvement in primary care practice.

BACKGROUND: Despite longstanding experimental evidence about effectiveness of academic detailing, transitioning this research-based concept into acceptable primary care quality improvement services has been slow in the USA. The purpose of this study was to describe primary care uptake, retention and response to an academic-detailing-led service in the USA. Exploration of accessible performance indicators of service acceptance, and feasibility of use of an Australian academic detailing service model were secondary objectives. METHODS: Over a 29-month period, an academic-detailing-led drug and therapeutics information service was offered to all primary care physicians providing ongoing patient care in Fayette County, Kentucky. Two programmes (on type 2 diabetes management and chronic pain management) incorporating up to four office visits were offered. RESULTS: 102 of 130 (78%) eligible primary care physicians participated in the service, 72% receiving visits for the type 2 diabetes management programme, and 58% the chronic non-malignant pain programme. At all successive encounters, participants expressed a willingness to continue to receive visits. Difficulties were experienced in obtaining appointments for subsequent visits, although on direct enquiry, only one participant explicitly declined further visits. No notable differences existed between physicians accepting visits and those who did not. Across successive visits, passive indicators of satisfaction with the service included: duration of visits, office waiting times, retention of printed materials from one visit to the next, whether physicians wished their extender colleagues to also receive visits, and observed levels of interest and participation within encounters. CONCLUSIONS: Ongoing primary care quality improvement services spearheaded by academic detailing can be acceptable to US primary care physicians in practice.

Access to cancer services for rural colorectal cancer patients.

CONTEXT: Cancer care requires specialty surgical and medical resources that are less likely to be found in rural areas. PURPOSE: To examine the travel patterns and distances of rural and urban colorectal cancer (CRC) patients to 3 types of specialty cancer care services--surgery, medical oncology consultation, and radiation oncology consultation. METHODS: Descriptive cross-sectional study using linked Surveillance, Epidemiology, and End Results (SEER) cancer registry and Medicare claims data for 27,143 individuals ages 66 and older diagnosed with stages I through III CRC between 1992 and 1996. FINDINGS: Over 90% of rural CRC patients lived within 30 miles of a surgical hospital offering CRC surgery, but less than 50% of CRC patients living in small and isolated small rural areas had a medical or radiation oncologist within 30 miles. Rural CRC patients who traveled outside their geographic areas for their cancer care often went great distances. The median distance traveled by rural cancer patients who traveled to urban cancer care providers was 47.8 miles or more. A substantial proportion (between 19.4% and 26.0%) of all rural patients bypassed their closest medical and radiation oncology services by at least 30 miles. CONCLUSIONS: Rural CRC patients often travel long distances for their CRC care, with potential associated burdens of time, cost, and discomfort. Better understanding of whether this travel investment is paid off in improved quality of care would help rural cancer patients, most of whom are elderly, make informed decisions about how to use their resources during their cancer treatment.

A longitudinal analysis of the general surgery workforce in the United States, 1981-2005.

HYPOTHESIS: The overall supply of general surgeons per 100 000 population has declined in the past 2 decades, and small and isolated rural areas of the United States continue to have relatively fewer general surgeons per 100 000 population than urban areas. DESIGN: Retrospective longitudinal analysis. SETTING: Clinically active general surgeons in the United States. PARTICIPANTS: The American Medical Association's Physician Masterfiles from 1981, 1991, 2001, and 2005 were used to identify all clinically active general surgeons in the United States. MAIN OUTCOME MEASURES: Number of general surgeons per 100 000 population and the age, sex, and locale of these surgeons. RESULTS: General surgeon to population ratios declined steadily across the study period, from 7.68 per 100 000 in 1981 to 5.69 per 100 000 in 2005. The overall urban ratio dropped from 8.04 to 5.85 (-27.24%) across the study period, and the overall rural ratio dropped from 6.36 to 5.02 (-21.07%). The average age of rural surgeons increased compared with their urban counterparts, and women were disproportionately concentrated in urban areas. CONCLUSIONS: The overall number of general surgeons per 100 000 population has declined by 25.91% during the past 25 years. The decline has been most marked in urban areas. However, more remote rural areas continue to have significantly fewer general surgeons per 100 000 population. These findings have implications for training, recruiting, and retaining general surgeons.

Measuring participant rurality in Web-based interventions.

BACKGROUND: Web-based health behavior change programs can reach large groups of disparate participants and thus they provide promise of becoming important public health tools. Data on participant rurality can complement other demographic measures to deepen our understanding of the success of these programs. Specifically, analysis of participant rurality can inform recruitment and social marketing efforts, and facilitate the targeting and tailoring of program content. Rurality analysis can also help evaluate the effectiveness of interventions across population groupings. METHODS: We describe how the RUCAs (Rural-Urban Commuting Area Codes) methodology can be used to examine results from two Randomized Controlled Trials of Web-based tobacco cessation programs: the ChewFree.com project for smokeless tobacco cessation and the Smokers' Health Improvement Program (SHIP) project for smoking cessation. RESULTS: Using RUCAs methodology helped to highlight the extent to which both Web-based interventions reached a substantial percentage of rural participants. The ChewFree program was found to have more rural participation which is consistent with the greater prevalence of smokeless tobacco use in rural settings as well as ChewFree's multifaceted recruitment program that specifically targeted rural settings. CONCLUSION: Researchers of Web-based health behavior change programs targeted to the US should routinely include RUCAs as a part of analyzing participant demographics. Researchers in other countries should examine rurality indices germane to their country.

Prevalence and trends in smoking: a national rural study.

CONTEXT: Cigarette smoking is the leading preventable cause of death in the United States. PURPOSE: To estimate the prevalence of and recent trends in smoking among adults by type of rural location and by state. METHODS: Random-digit telephone survey of adults aged 18 years or older who participated in the Behavioral Risk Factor Surveillance System in 1994-1996 (n = 342,055) and 2000-2001 (n = 385,384). The main outcome measure was current cigarette smoking, defined as persons who smoke every day or some days, while nonsmokers were those who smoke not at all or reported never having smoked as many as 100 cigarettes. FINDINGS: The prevalence of smoking changed little from the mid-1990s; in 2000-2001, it was 22.0% in urban areas, 24.9% in rural adjacent areas, 24.0% in large rural nonadjacent areas, and 24.9% in small rural nonadjacent areas. For rural locations combined, smoking prevalence was not below the 12% goal of Healthy People 2010 for any state, although the 12.5% prevalence in rural Utah approached this target. Prevalence was > or = 28% for rural residents of Kentucky, Ohio, and Indiana. Since the mid-1990s, the prevalence of smoking for rural respondents decreased by more than 2 percentage points in 6 states: California, Connecticut, Maryland, North Carolina, Tennessee, and Utah. However, it increased by 2 percentage points or more in 10 states: Alabama, Delaware, Georgia, Massachusetts, Michigan, Mississippi, New Hampshire, Oklahoma, South Carolina, and Texas. CONCLUSIONS: Smoking remains a refractory public health problem. Better ways to curb smoking in rural America are needed.

Geographic access to health care for rural Medicare beneficiaries.

CONTEXT: Patients in rural areas may use less medical care than those living in urban areas. This could be due to differences in travel distance and time and a utilization of a different mix of generalists and specialists for their care. PURPOSE: To compare the travel times, distances, and physician specialty mix of all Medicare patients living in Alaska, Idaho, North Carolina, South Carolina, and Washington. METHODS: Retrospective design, using 1998 Medicare billing data. Travel time was determined by computing the road distance between 2 population centroids: the patient's and the provider's zone improvement plan codes. FINDINGS: There were 2,220,841 patients and 39,780 providers in the cohort, including 6,405 (16.1%) generalists, 24,772 (62.3%) specialists, and 8,603 (21.6%) nonphysician providers. There were 20,693,828 patient visits during the study. The median overall 1-way travel distance and time was 7.7 miles (interquartile range 1.9-18.7 miles) and 11.7 minutes (interquartile range 3.0-25.7 minutes). The patients in rural areas needed to travel 2 to 3 times farther to see medical and surgical specialists than those living in urban areas. Rural residents with heart disease, cancer, depression, or needing complex cardiac procedures or cancer treatment traveled the farthest. Increasing rurality was also related to decreased visits to specialists and an increasing reliance on generalists. CONCLUSIONS: Residents of rural areas have increased travel distance and time compared to their urban counterparts. This is particularly true for rural residents with specific diagnoses or those undergoing specific procedures. Our results suggest that most rural residents do not rely on urban areas for much of their care.

Characterizing the general surgery workforce in rural America.

BACKGROUND: General surgeons form a crucial component of the medical workforce in rural areas of the United States. Any decline in their numbers could have profound effects on access to adequate health care in such areas. HYPOTHESIS: We hypothesize that the rural areas of the United States are relatively undersupplied with general surgeons. DESIGN AND SETTING: The American Medical Association's Physician Masterfile was used to identify all clinically active general surgeons as well as their locations and characteristics. Their geographic distribution was examined using the ZIP code version of the Rural-Urban Commuting Areas. Surgeons were classified as practicing in urban areas, large rural areas, or small/isolated rural areas. RESULTS: There are currently 17 243 general surgeons practicing in the United States. Nationally, the number of general surgeons per population of 100 000 varies from 6.53 in urban areas to 7.71 in large rural areas and 4.67 in small/isolated rural areas. Only 10.6% of the nation's general surgeons are female. Wide variations in numbers of general surgeons were found between and within individual states. General surgeons in the smallest rural areas are more likely than those in urban areas to be male (92.7% vs 88.3%, P<.001), 50 years of age or older (51.6% vs 42.1%, P<.001), or international medical graduates (25.2% vs 20.1%, P<.001). CONCLUSIONS: The overall size of the rural general surgical workforce has remained static over the last decade, but its demographic characteristics suggest that numbers will decline. Many rural residents have limited access to surgical services. Steps to reverse this trend are needed to preserve the viability of health care in many parts of rural America.

Characteristics of visits to licensed acupuncturists, chiropractors, massage therapists, and naturopathic physicians.

BACKGROUND: Despite growing popularity of complementary and alternative medical (CAM) therapies, little is known about the patients seen by CAM practitioners. Our objective was to describe the patients and problems seen by CAM practitioners. METHODS: We collected data on 20 consecutive visits to randomly sampled licensed acupuncturists, chiropractors, massage therapists, and naturopathic physicians practicing in Arizona, Connecticut, Massachusetts, and Washington. Data were collected on patient demographics, smoking status, referral source, reasons for visit, concurrent medical care, payment source, and visit duration. Comparative data for conventional physicians were drawn from the National Ambulatory Medical Care Survey. RESULTS: In each profession, at least 99 practitioners collected data on more than 1,800 visits. More than 80% of visits to CAM providers were by young and middle-aged adults, and roughly two thirds were by women. Children comprised 10% of visits to naturopathic physicians but only 1% to 4% of all visits to other CAM providers. At least two thirds of visits resulted from self-referrals, and only 4% to 12% of visits were from conventional physician referrals. Chiropractors and massage therapists primarily saw musculoskeletal problems, while acupuncturists and naturopathic physicians saw a broader range of conditions. Visits to acupuncturists and massage therapists lasted about 60 minutes compared with 40 minutes for naturopathic physicians and less than 20 minutes for chiropractors. Most visits to chiropractors and naturopathic physicians, but less than one third of visits to acupuncturists and massage therapists, were covered by insurance. CONCLUSIONS: This information will help inform discussions of the roles CAM practitioners will play in the health care system of the future.

GM-CSF expression in pulmonary epithelial cells is regulated negatively by posttranscriptional mechanisms.

Incubation of pulmonary A549 cells with D609, a phosphatidyl-choline specific phospholipase C (PC-PLC)-inhibitor, or the anti-oxidant, pyrrolidine dithiocarbamate (PTDC), markedly increased IL-1beta-induced GM-CSF elaboration. This effect was observed at the mRNA level and could be partially reproduced by the protein synthesis inhibitor, cycloheximide. Following the peak in GM-CSF mRNA, the mRNA half-life (t(1/2)) was 0.5-1 h. This was increased to around 3 h by cycloheximide, whilst following D609 or PDTC treatment there was essentially no degradation. These data suggest the existence of inhibitory pathways that posttranscriptionally regulate GM-CSF expression via new protein synthesis and D609- and PDTC-sensitive steps. These observations may have important clinical implications. First, drugs that target gene induction may also knock out these inhibitory pathways to lessen their effect. Second, defects in such pathways could lead to overexpression of cytokines or growth factors and contribute to the pathogenesis of inflammatory or proliferative diseases.

Long-term safety of oral transmucosal fentanyl citrate for breakthrough cancer pain.

This open-label study evaluated the long-term safety and tolerability of oral transmucosal fentanyl citrate (OTFC) in ambulatory cancer patients with breakthrough pain undergoing cancer care at 32 university- or community-based practices. Patients had participated in a previous short-term titration trial of OTFC, were experiencing at least one episode per day of breakthrough pain, and had achieved relief of their breakthrough pain with an opioid. Patients received OTFC units at a starting dosage strength determined in the short-term trial (200-1600 microg). Outcome measures included number of successfully treated breakthrough pains, global satisfaction rating (0 = poor through 4 = excellent), and side effects. In total, 41,766 units of OTFC were used to treat 38,595 episodes of breakthrough pain in 155 patients. Number of treatment days ranged from 1 to 423 (mean, 91 days). Patients averaged 2.9 breakthrough pain episodes per day. About 92% of episodes were successfully treated with OTFC and there was no trend toward decreased effectiveness over time. Most patients (61%) did not require dose escalation during treatment. Global satisfaction ratings were consistently above 3, indicating very good to excellent relief. Common adverse events associated with OTFC were somnolence (9%), constipation (8%), nausea (8%), dizziness (8%), and vomiting (5%). Six patients (4%) discontinued therapy due to an OTFC-related adverse event. There were no reports of abuse and no concerns about the safety of the drug raised by patients or families. OTFC was used safely and effectively during long-term treatment of breakthrough pain in cancer patients at home.

Color Doppler imaging of untreated and irradiated choroidal melanomas.

PURPOSE: We examined untreated and irradiated choroidal melanomas with color Doppler imaging (CDI), a noninvasive method providing quantitative measures of blood flow, to determine if the tumor vessel damage associated with irradiation can be detected using this technology. METHODS: CDI was performed on 122 untreated and 76 previously irradiated tumors using a Q2000 color Doppler ultrasound unit. Spectral analysis was performed on all detectable vascular regions within the tumor to obtain estimates of the peak systolic and end diastolic flow velocities and resistive index ((syst-diast)/syst). RESULTS: Vessels were detected in 93% of the untreated tumors and in 63% of the treated tumors (p<0.001, X2), and the median number of vascular regions found was higher among untreated tumors (3 vs 1, p=0.001, Wilcoxon Rank Sum). The effect of treatment status on the detection of tumor vessels was significant (p=0.039), controlling for age, sex, largest tumor pretreatment diameter, and tumor height at CDI in a logistic regression model. Mean resistive index was lower in the untreated tumors (0.53 vs 0.58, p=0.0050), controlling for tumor height and other covariates in an analysis of variance. CONCLUSIONS: On examination with CDI, irradiated tumors had fewer detectable vascular regions and greater resistance to flow than untreated tumors, a pattern consistent with known radiation effects.

Characteristics of adolescent cancer survivors who pursue postsecondary education.

This study aimed to identify differences between adolescent cancer survivors who participate in postsecondary education and those who do not, as well as factors that helped these survivors to cope. American College Testing records for 129,824 adolescents were meshed with Iowa's Cancer Registry to identify Iowans who had received a diagnosis of cancer between the ages of 12 and 17 years. The potential subject pool contained 85 persons. A questionnaire was sent to the 28 persons who agreed to participate in the study, and 75% responded. Most of the respondents were girls with normal levels of physical function. Measures of adjustment and mood state indicated low distress levels. Fatigue was their area of highest distress. All the respondents were enrolled in education programs or had graduated. Help from family, friends, and teachers was seen as supportive, but lack of knowledge about their disease was cited most frequently by this same group as interfering with their coping. The respondents demonstrated more discipline, stamina, and commitment than was expected. However, the accrual protocol and respondents' comments revealed a stigmatization of patients with cancer by professional health workers, indicating a need to confront the value that health professionals place on this stigmatized population and health professionals' contribution to this societal posture.