A comparison of intranasal fentanyl spray with oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain: an open-label, randomised, crossover trial.

OBJECTIVE: The efficacy of intranasal fentanyl spray (INFS) was compared with that of oral transmucosal fentanyl citrate (OTFC) for the relief of cancer-related breakthrough pain (BTP) in an open-label, crossover trial. METHODS: Adult cancer patients receiving stable background opioid treatment and experiencing BTP episodes were recruited from 44 study centres in seven European countries (Austria, France, Germany, Italy, Poland, Spain and the United Kingdom); of the 196 patients enrolled, 139 were randomised to receive INFS followed by OTFC, or vice versa. Patients were titrated to an effective dose of one agent (50, 100 or 200 microg INFS; 200, 400, 600, 800, 1200 or 1600 microg OTFC) to treat six BTP episodes, then titration and treatment were repeated with the other agent. The primary outcome was patient-recorded time to onset of 'meaningful' pain relief. Secondary outcomes included pain intensity difference (PID) at 10 and 30 minutes (PID(10), PID(30)), sum of PID at 15 and 60 minutes (SPID(0-15), SPID(0-60)), ease of administration, treatment preference and relationship between background opioid dose and effective INFS dose. Additional outcome measures included proportions of episodes with > or =33% and > or =50% pain intensity (PI) reduction, and PID at additional time points. CLINICAL TRIAL REGISTRATION NUMBER: NCT00496392. RESULTS: Among the intention-to-treat population (n = 139), median time to onset of 'meaningful' pain relief was 11 minutes with INFS versus 16 minutes with OTFC; 65.7% of patients attained faster time to 'meaningful' pain-relief onset with INFS (p < 0.001). PID was statistically significantly greater for INFS than OTFC from 5 minutes post-dosing. Significantly more INFS-treated breakthrough pain episodes achieved clinically important pain relief (> or =33% and > or =50% PI reduction) up to 30 minutes post-dosing. The proportions of episodes treated with INFS and OTFC achieving a PI reduction of > or =33% at 5 minutes were 25.3% versus 6.8% (p < 0.001), and at 10 minutes were 51.0% versus 23.6% (p < 0.001), respectively; the proportions of episodes treated with INFS and OTFC achieving a > or =50% PI reduction at 5 minutes were 12.8% versus 2.1% (p < 0.001), and at 10 minutes were 36.9% versus 9.7% (p < 0.001), respectively. Higher SPID(0-15) and SPID(0-60) scores were achieved with INFS (p < 0.001). More patients preferred INFS than OTFC (p < 0.001) and more patients found it very easy/easy to use. Both treatments were well tolerated. In the safety population (n = 139), 56.8% (n = 79) of patients experienced > or =1 AE during the trial. The only AE that occurred in > or =5% of patients in either treatment group was nausea. Among those patients who experienced serious AEs (13.7%, n = 19), none were considered to be related to either study medication. There was a weak correlation between effective INFS doses and background opioid doses. CONCLUSION: In this open-label, randomised, crossover trial, significantly more patients attained faster 'meaningful' pain relief with INFS than OTFC, and more patients preferred INFS to OTFC.

What are patients' priorities for palliative care research? Focus group study.

To elucidate the research priorities of palliative care patients we conducted focus groups with day therapy and hospice in-patients with cancer with an estimated prognosis of 6 months or less. Patients were positive about taking part in this research project identifying five main priorities for future research--talking with patients; help for patients and families; oncology; symptoms; medication/treatments. Patients gave great emphasis to communication issues and little to symptom control. A patient questionnaire was created with these themes which is currently being used in five hospices across East Anglia. This paper describes the qualitative component of the study.

Chemiluminescent measurements of nitric oxide pulmonary diffusing capacity and alveolar production in humans.

Measurements of nitric oxide (NO) pulmonary diffusing capacity (DL(NO)) multiplied by alveolar NO partial pressure (PA(NO)) provide values for alveolar NO production (VA(NO)). We evaluated applying a rapidly responding chemiluminescent NO analyzer to measure DL(NO) during a single, constant exhalation (Dex(NO)) or by rebreathing (Drb(NO)). With the use of an initial inspiration of 5-10 parts/million of NO with a correction for the measured NO back pressure, Dex(NO) in nine healthy subjects equaled 125 +/- 29 (SD) ml x min(-1) x mmHg(-1) and Drb(NO) equaled 122 +/- 26 ml x min(-1) x mmHg(-1). These values were 4.7 +/- 0.6 and 4.6 +/- 0.6 times greater, respectively, than the subject's single-breath carbon monoxide diffusing capacity (Dsb(CO)). Coefficients of variation were similar to previously reported breath-holding, single-breath measurements of Dsb(CO). PA(NO) measured in seven of the subjects equaled 1.8 +/- 0.7 mmHg x 10(-6) and resulted in VA(NO) of 0.21 +/- 0.06 microl/min using Dex(NO) and 0.20 +/- 0.6 microl/min with Drb(NO). Dex(NO) remained constant at end-expiratory oxygen tensions varied from 42 to 682 Torr. Decreases in lung volume resulted in falls of Dex(NO) and Drb(NO) similar to the reported effect of volume changes on Dsb(CO). These data show that rapidly responding chemiluminescent NO analyzers provide reproducible measurements of DL(NO) using single exhalations or rebreathing suitable for measuring VA(NO).

Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma.

PURPOSE: Flavopiridol is the first cyclin-dependent kinase inhibitor to enter clinical trials. Activity in gastric cancer xenografts and in a patient with gastric cancer on the phase I trial led to this phase II study of flavopiridol in patients with metastatic gastric cancer. PATIENTS AND METHODS: Sixteen patients were entered onto the study, and 14 were assessable for response. Flavopiridol was administered initially at a dose of 50 mg/m(2)/d by continuous infusion for 72 hours every 2 weeks. Assessment of plasma pharmacokinetics was performed in all patients. Peripheral mononuclear cells were collected throughout the 72-hour infusion for determinants of apoptosis. RESULTS: There were no major objective responses (exact confidence interval 0% to 23%). One patient achieved a minor response in his liver metastases, though the primary progressed. Other patients exhibited histologic and radiographic evidence of tumor necrosis. Common toxicities included fatigue in 93% of patients (grade 3 or 4 in 27%) and diarrhea in 73% of patients (grade 3 or 4 in 20%). Five patients (33%) developed venous thromboses at the central catheter tip. The studies performed on peripheral mononuclear cells indicated no induction of apoptosis. CONCLUSION: Flavopiridol administered as a single agent for 72 hours every 14 days is inactive in the treatment of gastric cancer. The drug also induced an unexpected higher incidence of vascular thrombosis and fatigue than was anticipated from the phase I trials. Future development of flavopiridol will depend on other doses and schedules in combination with chemotherapy.

The outcome of knee synovitis in early arthritis provides guidelines for management.

The aim of the study was to examine the clinical outcome of patients presenting to an early arthritis clinic with synovitis of the knee. The patients were assessed at presentation for evidence and pattern of joint inflammation. These patients were then reassessed at 3, 6 and 12 months and thereafter annually to determine clinical outcome. One thousand six hundred and thirty-three consecutive referrals were examined, 903 of whom had early synovitis. One hundred and thirty had knee synovitis at presentation, of whom 73 fulfilled ACR criteria for rheumatoid arthritis (RA) during the study. All 73 presented with a symmetrical polyarthritis that included the small joints and had persistent disease at 1 year. Of the remaining 57 patients, 61% of those presenting with an oligoarthritis and 33% with a polyarthritis (including knee synovitis) were in remission at 1 year. None of those presenting as a monoarthritis of the knee had inflammation at 1 year or fulfilled ACR criteria for RA at any time. It was concluded that patients presenting with knee synovitis in the absence of a small joint polyarthritis usually have a benign course following standard therapy. No patient who presented with monoarthritis developed RA. Knee synovitis as part of a polyarthritis (even when not fulfilling ACR criteria) probably justifies disease-modifying antirheumatic drug at presentation.

Simultaneous measurement of nitric oxide production by conducting and alveolar airways of humans.

Human airways produce nitric oxide (NO), and exhaled NO increases as expiratory flow rates fall. We show that mixing during exhalation between the NO produced by the lower, alveolar airways (VL(NO)) and the upper conducting airways (VU(NO)) explains this phenomenon and permits measurement of VL(NO), VU(NO), and the NO diffusing capacity of the conducting airways (DU(NO)). After breath holding for 10-15 s the partial pressure of alveolar NO (PA) becomes constant, and during a subsequent exhalation at a constant expiratory flow rate the alveoli will deliver a stable amount of NO to the conducting airways. The conducting airways secrete NO into the lumen (VU(NO)), which mixes with PA during exhalation, resulting in the observed expiratory concentration of NO (PE). At fast exhalations, PA makes a large contribution to PE, and, at slow exhalations, NO from the conducting airways predominates. Simple equations describing this mixing, combined with measurements of PE at several different expiratory flow rates, permit calculation of PA, VU(NO), and DU(NO). VL(NO) is the product of PA and the alveolar airway diffusion capacity for NO. In seven normal subjects, PA = 1.6 +/- 0.7 x 10(-6) (SD) Torr, VL(NO) = 0.19 +/- 0.07 microl/min, VU(NO) = 0.08 +/- 0.05 microl/min, and DU(NO) = 0.4 +/- 0.4 ml. min(-1). Torr(-1). These quantitative measurements of VL(NO) and VU(NO) are suitable for exploring alterations in NO production at these sites by diseases and physiological stresses.

Platelets from thrombocytopenic ponies acutely infected with equine infectious anemia virus are activated in vivo and hypofunctional.

Thrombocytopenia is a consistent finding and one of the earliest hematological abnormalities in horses acutely infected with equine infectious anemia virus (EIAV), a lentivirus closely related to human immunodeficiency virus. Multifactorial mechanisms, including immune-mediated platelet destruction and impaired platelet production, are implicated in the pathogenesis of EIAV-associated thrombocytopenia. This study was undertaken to investigate whether regenerative thrombopoiesis and platelet destruction occurred in ponies acutely infected with EIAV. Circulating large, immature platelets were increased in ponies acutely infected with EIAV late in the infection when platelet count was at a nadir. Morphometric analysis of bone marrow from acutely infected ponies revealed significant increased in megakaryocyte area and megakaryocyte nuclear area. A trend toward increased numbers of megakaryocytes was also observed. Platelets from acutely infected ponies had increased surface-bound fibrinogen and ultrastructural changes consistent with in vivo platelet activation. Platelets also had hypofunctional aggregation responses to three agonists in vitro. We conclude that thrombocytopenia in ponies acutely infected with EIAV is regenerative and suggest that bone marrow platelet production is not severely compromised in these ponies. Our findings reveal that in vivo platelet activation occurs in ponies acutely infected with EIAV, and as a result platelets are hypofunctional in vitro. Activation of platelets in vivo may cause platelet degranulation or formation of platelet aggregates, which would result in removal of these damages platelets from circulation. This may represent a form of nonimmune-mediated platelet destruction in ponies acutely infected with EIAV.

Platelet-associated immunoglobulin (antiplatelet antibody) in canine Rocky Mountain spotted fever and ehrlichiosis.

Antiplatelet antibodies were detected in the sera of dogs with naturally occurring and experimentally induced Rickettsia rickettsii and Ehrlichia canis infections. This is the first known report documenting elevated platelet-associated immunoglobulin (PAIg) titers in Rocky Mountain spotted fever (RMSF) infections. In the naturally occurring RMSF infections and ehrlichiosis, the antibodies persisted for weeks or months, even when the platelet counts had normalized. Results of this study indicate an immunological component for rickettsial thrombocytopenia. Therefore, current therapeutic recommendations, especially regarding avoiding the use of immunosuppressive drugs in patients with rickettsial diseases, need to be critically reviewed.

Rate of nitric oxide production by lower alveolar airways of human lungs.

This report describes methods for measuring nitric oxide production by the lungs' lower alveolar airways (VNO), defined as those alveoli and bronchioles well perfused by the pulmonary circulation. Breath holding or vigorous rebreathing for 15-20 s minimizes removal of NO from the lower airways and results in a constant partial pressure of NO in the lower airways (PL). Then the amount of NO diffusing into the perfusing blood will be the pulmonary diffusing capacity for NO (DNO) multiplied by PL and by mass balance equals VNO, or VNO = DNO(PL). To measure PL, 10 normal subjects breath held for 20 s followed by exhalation at a constant flow rate of 0.83 +/- 0.14 (SD) l/s or rebreathed at 59 +/- 15 l/min for 20 s while NO was continuously measured at the mouth. DNO was estimated to equal five times the single-breath carbon monoxide diffusing capacity. By using breath holding, PL equaled 2.9 +/- 0.8 mmHg x 10(-6) and VNO equaled 0.39 +/- 0.12 microl/min. During rebreathing PL equaled 2.3 +/- 0.6 mmHg x 10(-6) and VNO equaled 0.29 +/- 0.11 microl/min. Measurements of NO at the mouth during rapid, constant exhalation after breath holding for 20 s or during rebreathing provide reproducible methods for measuring VNO in humans.

Nonpharmacologic therapy of osteoarthritis.

Studies of the nonpharmacologic treatment of osteoarthritis (OA) have fallen behind that of pharmacologic therapy for a variety of reasons. The design of studies that involve a therapist-delivered physical intervention presents several problems with respect to patient and observer blinding, the beneficial effect of therapist contact alone, and separation of the effects of individual components of the "package" of delivered care. Important developments in the design and reporting of OA trials are discussed. Recent studies have demonstrated the modest but definite benefits of exercise therapy for OA of the knee, delivered either in hospital, primary care, or community settings. The reduction in pain and disability through an arthritis self-management group education program may extend to at least 1 year. Recent data that low intake of micronutrients (vitamins C, E, and D, and beta-carotene) may adversely influence the progression of knee OA and the incidence of hip OA suggest potential avenues for primary and secondary prevention of large joint OA.

Random amplified polymorphic DNA (RAPD) analysis of Lutzomyia longipalpis laboratory populations.

The phlebotomine sand fly Lutzomyia longipalpis has been incriminated as a vector of American visceral leishmaniasis, caused by Leishmania chagasi. However, some evidence has been accumulated suggesting that it may exist in nature not as a single but as a species complex. Our goal was to compare four laboratory reference populations of L. longipalpis from distinct geographic regions at the molecular level by RAPD-PCR. We screened genomic DNA for polymorphic sites by PCR amplification with decamer single primers of arbitrary nucleotide sequences. One primer distinguished one population (Marajó Island, Pará State, Brazil) from the other three (Lapinha Cave, Minas Gerais State, Brazil; Melgar, Tolima Department, Colombia and Liberia, Guanacaste Province, Costa Rica). The population-specific and the conserved RAPD-PCR amplified fragments were cloned and shown to differ only in number of internal repeats.

Cutaneous ulcers of refractory adult dermatomyositis responsive to intravenous immunoglobulin.

We report the case of a woman from the Bahamas who presented with many of the classic manifestations of dermatomyositis. She responded well to initial therapy, which included oral corticosteroids, low-dosage methotrexate, and hydroxychloroquine. The cutaneous component of her disease flared dramatically months later, and progressed despite aggressive therapy with the higher dosages of the same medications. Therapy with intravenous immunoglobulin (IVIG) was initiated and the patient stopped forming new cutaneous ulcers within 1 to 2 weeks. Theories about the mechanism of action of IVIG, and practical guidelines for its use in treating patients with dermatomyositis, are briefly reviewed.

Prognostic biomarker study in pathologically staged N1 non-small cell lung cancer.

PURPOSE: The prognostic influence of 6 biomarkers correlated to histologic subtypes of non-small cell lung cancer (NSCLC) on loco-regional control, overall survival, disease-free survival (DFS), and distant disease control (DDC) rates, all measured at 5 years, were examined. MATERIALS & METHODS: Cell blocks from the primary tumors of 137 patients with pathologically staged N1 NSCLC at MDACC were analyzed by 6-biomarker status correlated to histological subtypes and their outcomes. RESULTS: The ranges of biomarker values were as follows: apoptotic index, 0.2-2.8%; mitotic index, 0-1.8%; the proportion of cells in S+G2M, 3-36%; p53 status, 0-100%; Ki-67, 0-9.3%; DNA index, 1.0-2.74. Subtypes of 137 cases from the postoperative pathology specimen showed that 74 patients had squamous carcinoma and 63 patients had adenocarcinoma. Mean and median lengths of follow-up were 4.21 years and 2.43 years, respectively. Patients with squamous cell carcinoma (SCC) had a better 5-year survival (p = 0.006), DFS (p = 0.002), and distant metastasis control (p = 0.002) than patients with adenocarcinoma (AC). Among patients with AC, the DNA index was a significant predictor of 5-year DFS (p = 0.02), DDC rate (p = 0.04), and local-regional control (p < 0.05). Higher apoptosis (p = 0.03) and mitosis indices (p = 0.03) were also univariate predictors of increased distant disease among patients with AC. Multivariate analysis of patients with AC revealed that the DNA index and Ki-67 were the only significant independent predictors of distant metastasis (p < 0.04 and p < 0.02, respectively) and DFS (p < 0.04 for both). Among patients with SCC, univariate analysis showed that S+G2M proportion (p < 0.05) and Ki-67 levels (p < 0.02) were significant predictors for local-regional control; for SC, multivariate analysis showed that only mitosis was a significant predictor in this case for overall survival (p < 0.04). CONCLUSION: Spontaneous apoptotic index and Ki-67 were significantly higher in SC than in AC. Patients with SC had less distant metastasis better DFS and overall survival than those with AC. Multivariate analysis revealed that DNA index and Ki-67 status were significant predictors for DDC and DFS in patients with AC, but only mitotic index was a significant predictor of overall survival for patients with SCC.

Flow cytometric method for detecting thiazole orange-positive (reticulated) platelets in thrombocytopenic horses.

OBJECTIVE: To evaluate a method for detecting thiazole orange-positive (TO+, reticulated) platelets in equine blood, using flow cytometry. ANIMALS: 16 healthy, equine infectious anemia virus (EIAV)-negative horses and ponies; 9 thrombocytopenic, EIAV-positive horses and ponies; and 2 thrombocytopenic, EIAV-negative horses. PROCEDURE: Blood from healthy and thrombocytopenic horses was collected by jugular venipuncture. Appropriate sample requirement and incubation time for the assay were evaluated, using blood anticoagulated with EDTA or sodium citrate, or platelet-rich plasma in sodium citrate. The sample of blood or platelet-rich plasma was incubated with thiazole orange, and flow cytometric analysis was performed. Percentage of circulating TO+ platelets was determined from fluorescence (FL-1) logarithmic histograms. RESULTS: Healthy ponies (n = 9) had 1.28 to 2.83% (mean +/- SD, 2.03 +/- 0.50%) and horses (n = 7) had 0.9 to 3.44% (2.12 +/- 1.14%) TO+ platelets in circulation. Thrombocytopenic ponies (n = 7) had 11.14 to 48.41% (26.51 +/- 11.99%) and thrombocytopenic horses (n = 4) had 2.33 to 8.52% (6.19 +/- 2.68%) TO+ platelets in circulation. Mean platelet counts for the thrombocytopenic ponies and horses were 24,400 +/- 20,500 and 39,300 +/- 13,500 platelets/microliters, respectively (reference range, 94,000 to 232,000 platelets/ microliters). CONCLUSION: Thiazole orange-positive platelets can be detected in equine blood and percentages of TO+ platelets are increased in thrombocytopenic horses. CLINICAL RELEVANCE: Enumeration of TO+ platelets may prove to be a helpful noninvasive clinical measurement of bone marrow platelet production and aid in the assessment of platelet kinetics in thrombocytopenic horses.

Myosin I is associated with zymogen granule membranes in the rat pancreatic acinar cell.

BACKGROUND & AIMS: The mechanisms whereby intracellular messengers mediate zymogen granule transport and exocytosis in the pancreatic acinar cell are not well defined. Electron microscopy has shown a periluminal network of actin in the acinar cell, suggesting a role for actin and myosin in the transport process. The possible involvement of two types of myosin in the secretory process was investigated, and their distribution in acinar cells was determined. METHODS: Antibodies specific to myosin I or to myosin II were used for immunocytochemistry and Western blot analysis. Ultrastructural studies were also performed. RESULTS: Western blot analysis showed that myosin I and myosin II were present in total pancreatic homogenate but that only myosin I was present on isolated zymogen granules and their membranes. By immunocytochemistry, myosin I was shown in the apical aspect of acinar cells colocalized with glycoprotein 2, a marker for zymogen granules, and actin. By immunocytochemistry, myosin I was also localized on isolated zymogen granules. CONCLUSIONS: The immunolocalization of myosin I to zymogen granule membranes and its close association with periluminal actin suggest that myosin I plays a direct role in the process of transport and exocytosis of zymogen granules in the pancreatic acinar cell.