Positive Circumferential Resection Margin in Rectal Cancer Is a Robust Predictor of Poor Long-term Prognosis With Clinicopathological Bias Between Groups Compensated by Propensity-score Matching Analysis.

BACKGROUND/AIM: Circumferential resection margin (CRM) is the most reliable predictor of local and distant recurrence in locally-advanced rectal cancer (LARC). The present study was conducted to compare the long-term outcomes between CRM (+) and (-) groups using propensity-score (PS) matching analysis to compensate for bias between groups. PATIENTS AND METHODS: Of 563 consecutive patients with Stage II/III rectal cancer who were treated surgically with curative-intent at Juntendo University Hospital between Jan 1989 and Mar 2018, 412 patients were enrolled retrospectively in the study. The patients were divided into a CRM (+) group (n=21; 5.1%) and a CRM (-) group (n=391; 94.9%). RESULTS: In the entire cohort, recurrence-free survival (RFS), local recurrence-free survival (LRFS), non-local recurrence-free survival (NLRFS), and cancer-specific survival (CSS) were significantly worse among patients in the CRM (+) group compared with those in the CRM (-) group. Univariate analysis demonstrated patients in the CRM (+) group had significantly larger primary tumors (p=0.02), more frequently had open surgery (p=0.009), had an abdominoperineal resection (APR) procedure (p=0.01) and a T4 primary tumor (p<0.0001). After PS matching analysis, in the propensity-matched cohort, RFS, LRFS, NLRFS and CSS were significantly worse among patients in the CRM (+) group compared with those in the CRM (-) group. CONCLUSION: PS matching analysis demonstrated that RFS, LRFS, NLRFS, and CSS were significantly worse among patients in the CRM (+) group compared with those in the CRM (-) group. The present results indicate that CRM (+) is a robust predictor of long-term outcome of LARC, independent of tumor size.

Paliperidone-Induced Acute Hyperglycemia Is Caused by Adrenaline Secretion via the Activation of Hypothalamic AMP-Activated Protein Kinase.

Although paliperidone-related hyperglycemia has been extensively examined, the underlying mechanisms have not yet been elucidated. We investigated the effects of a single intravenous injection of paliperidone (0.2, 0.4, or 0.6 mg/kg) on serum concentrations of glucose and other endogenous metabolites in rats. We also examined the effects of a single intravenous injection of paliperidone (0.4 mg/kg) on AMP-activated protein kinase (AMPK) activity in the hypothalamus and liver. To clarify the relationship between AMPK activity and adrenaline secretion, the effects of berberine, which inhibits hypothalamic AMPK, on paliperidone-induced hyperglycemia were assessed. Significant increases were observed in serum glucose, adrenaline, and insulin concentrations following intravenous injections of paliperidone at doses of 0.4 and 0.6 mg/kg. A propranolol pretreatment attenuated paliperidone-induced increases in serum concentrations of glucose, but not adrenaline. Significant increases were also noted in phosphorylated AMPK concentrations in the hypothalamus following the administration of paliperidone at a dose of 0.4 mg/kg. A berberine pretreatment attenuated paliperidone-induced increases in blood concentrations of glucose, adrenaline, and insulin and phosphorylated AMPK concentrations in the hypothalamus. Collectively, the present results demonstrated that an acute treatment with paliperidone induced hyperglycemia, which was associated with the effects of hypothalamic AMPK activation on the secretion of adrenaline.

Case of laparoscopic parastomal hernia repair using modified Sugarbaker mesh method.

A 75-year-old woman underwent sigmoid colon resection and transverse colostomy for perforation of the diverticulum of the sigmoid colon at 70 years of age at another hospital. She was referred to our hospital with complaints of abdominal discomfort 3 months prior to presentation. Abdominal computed tomography revealed a parastomal hernia (PSH). We performed laparoscopic repair using the Sugarbaker approach with a Symbotex Composite Mesh™ and laparoscopic adhesive intestinal repair. The patient's post-operative course was unremarkable, and she was transferred to the Department of Internal Medicine after 10 days. There was no recurrence 6 months after surgery. Tension-free surgery using a mesh has been reported to be effective in preventing the recurrence of PSH. We performed a laparoscopic modified Sugarbaker mesh method using the Symbotex Composite Mesh™ with collagen film to repair an abdominal hernia.

[A Case Report of a Giant GIST Markedly Responsive to Neoadjuvant Chemotherapy with Imatinib Mesylate].

Male in his 50s complaining of abdominal pain was referred to our hospital. Abdominal CT scan showed a giant tumor which had diameter of approximately 50 mm in lower rectum. A biopsy specimen was positive for CD34 and c-kit. Based on these findings, it was diagnosed as gastrointestinal stromal tumor(GIST). We treated the patient with neoadjuvant therapy using imatinib mesylate(IM)to reduce the tumor size and to avoid the extensive surgery. The patient started to take IM at a daily dose of 400 mg. After 3 months, CT and MRI revealed that the tumor size decreased(40% reduction). We performed the robot assisted intersphincteric resection(ISR). Although it has been 28 months since the surgery, there are no obvious signs of recurrence. A patient diagnosed with giant GIST could avoid an extensive surgery due to neoadjuvant therapy with IM.

Comparison of the Safety and Effectiveness of Four Direct Oral Anticoagulants in Japanese Patients with Nonvalvular Atrial Fibrillation Using Real-World Data.

Direct oral anticoagulants (DOACs) are widely used for the prevention of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). However, the differences in safety and effectiveness among four DOACs, dabigatran, rivaroxaban, apixaban, and edoxaban, in Japanese patients have not been clarified. Therefore, we conducted a retrospective cohort study to directly compare the safety and effectiveness among the four DOACs using the Japan Medical Data Center (JMDC) claims database. We identified 3823 patients with NVAF who started receiving a DOAC between March 2011 and June 2017. The safety outcome was major bleeding (a composite outcome of intracranial, gastrointestinal, respiratory, or renal/urinary tract bleeding) and the effectiveness outcome was the composite of ischemic stroke including transient ischemic attack (TIA) or systemic embolism. We constructed a Cox proportional hazard model to calculate the hazard ratio (HR) for all four DOAC combinations. The risk of major bleeding was significantly lower in the dabigatran group than in the apixaban group (HR, 0.55; 95% confidence interval (CI), 0.31-0.93; p = 0.03). In contrast, there was no significant difference in the risk of major bleeding among the other DOACs. In the composite risk of ischemic stroke including TIA or systemic embolism, there was no significant difference among the four DOACs. This study suggested that in the current use of DOACs in Japanese patients with NVAF, dabigatran had a significantly lower risk of major bleeding than apixaban, but there was no significant difference in effectiveness among the four DOACs.

One-Year Adherence to Continuous Positive Airway Pressure With Telemonitoring in Sleep Apnea Hypopnea Syndrome: A Randomized Controlled Trial.

Study Objective: Telemedicine (TM) for continuous positive airway pressure (CPAP) treated patients may save health-care resources without compromising treatment effectiveness. We assessed the effect of TM (AirView Online System, ResMed) during the CPAP habituation phase on 3-month and 1-year treatment adherence and efficacy in patients with moderate-to-severe obstructive sleep apnea (OSA). Methods: At CPAP initiation, 120 patients diagnosed with OSA were randomized to either usual care (UC) or TM during the habituation phase (clinical registration: ISRCTN12865936). Both groups received a first face-to-face appointment with a sleep care giver at CPAP initiation. Within the following month, 2 other physical visits were scheduled in the UC group whereas two phone consultations were planned in the TM group, in which CPAP parameters were remotely adapted. Additional physical visits were programmed at the patient's request. Face-to-face consultations were scheduled at 3 and 12 months after CPAP initiation. The primary outcome was the mean CPAP daily use over the course of 12 months. Results: Twenty of 60 patients stopped CPAP therapy in the UC group vs. 14 of 60 in the TM group (p = 0.24). In per protocol analysis, mean [95% CI] daily CPAP use among 86 patients still using CPAP at 12 months was 279 [237; 321] min in the 38 patients on UC and 279 [247; 311] min in the 43 patients on TM, mean difference [95% CI]: 0 [-52; 52] min, P = 0.99. Total consultation time per patient was not different between groups, TM: 163 [147; 178] min, UC: 178 [159; 197] min, difference: -15 [-39; 9] min, p = 0.22. Conclusions: Telemedicine during the CPAP habituation phase did not alter daily CPAP use or treatment adherence and did not require more healthcare time. Telemedicine may support clinic attendance for CPAP titration. Clinical Trial Registration: [ISRCTN], identifier [ISRCTN12865936].

Intravenous Infusion of Fentanyl Has No Effect on Blood Concentration of Tacrolimus in Patients Receiving Hematopoietic Stem-Cell Transplantation.

BACKGROUND: Both tacrolimus (TAC) and fentanyl are frequently used in patients receiving allogeneic hematopoietic stem-cell transplantation. A recently published report demonstrated that fentanyl can reduce the total body clearance of TAC; however, most patients in this study were administered concomitantly with azole antifungal agents, which are known to be strong inhibitors of CYP3A. Hence, the exact effect of fentanyl on TAC pharmacokinetics was unclear. In the current study, the authors retrospectively investigated the pharmacokinetic interaction between TAC and fentanyl in patients who were not concomitantly administered drugs that affect TAC metabolism. METHODS: Patients with continuous infusion of TAC and fentanyl after hematopoietic stem-cell transplantation at the Tokyo Medical and Dental University between January 2014 and December 2018 were enrolled. The total body clearance of TAC was compared before and after the initiation or discontinuation of fentanyl. RESULTS: Thirty patients (24 men and 6 women; median age, 11 years) were screened for their eligibility. Twenty-eight patients were enrolled for evaluating the effects of the fentanyl initiation on TAC pharmacokinetics; 2 patients were excluded because of the absence of data related to the TAC blood concentrations or the concomitant use of azole antifungals. Twenty patients were enrolled for investigating the effects of fentanyl discontinuation on TAC pharmacokinetics, whereas 10 patients were excluded because of the absence of data related to the blood concentration of TAC or the additional administration of azole antifungals. Furthermore, the total body clearance of TAC was not significantly affected by the initiation or discontinuation of fentanyl, although there were large interindividual variations. In addition, the results remained the same even when the analysis was performed independently for adults and children. CONCLUSIONS: Intravenous infusion of fentanyl does not affect the pharmacokinetics of TAC.

Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass in adult patients undergoing cardiac surgery.

PURPOSE: The aims of the present study were to establish a population pharmacokinetic (PPK) model of cefazolin for adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to assess the probability of target attainment (PTA) for the prophylaxis of surgical site infection (SSI) using cefazolin. METHODS: Adult patients who underwent cardiac surgery with CPB were enrolled in the prospective study. Blood samples for plasma cefazolin assay were collected, and total and unbound drug concentrations were measured and analysed using the nonlinear mixed-effects modelling (NONMEM) software considering saturable plasma protein binding. Using the PPK model, plasma unbound cefazolin concentration-time courses with current prophylaxis protocols were simulated, and the PTA for common SSI pathogens was estimated. RESULTS: A total of 199 blood samples were obtained from 27 patients. A one-compartment model with first-order elimination plus an on/off CPB compartment best described the data. The population mean for systemic drug clearance (CL) was reduced and that for the volume of distribution (V) was increased during CPB compared with the pre-CPB values. CPB-induced hypoalbuminemia was associated with reduced maximum protein binding (Bmax). The simulation studies suggested that the current dosing protocols are insufficient for attaining PTA > 0.9 throughout surgery against pathogens with minimum inhibitory concentrations (MICs) >8 mg/L. A new dosing protocol that achieves a PTA > 0.9 for pathogens with a MIC of 16 mg/L was proposed. CONCLUSION: PPK modelling with simulation may be valuable for devising a cefazolin prophylaxis protocol for patients undergoing cardiac surgery with CPB.

Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu,Zn-superoxide dismutase.

Cu, Zn superoxide dismutase (SOD1) is one of the genes implicated in the devastating neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Although the precise mechanisms of SOD1 mutant (SOD1mut)-induced motoneuron toxicity are still unclear, defects in SOD1 proteostasis are known to have a critical role in ALS pathogenesis. We previously reported that the SOD1mut adopts a conformation that exposes a Derlin-1-binding region (DBR) and that DBR-exposed SOD1 interacts with Derlin-1, leading to motoneuron death. We also found that an environmental change, i.e. zinc depletion, induces a conformational change in WT SOD1 (SOD1WT) to the DBR-exposed conformation, suggesting the presence of an equilibrium state between the DBR-masked and DBR-exposed states even with SOD1WT Here, we conducted a high-throughput screening based on time-resolved FRET to further investigate the SOD1WT conformational change, and we used a genome-wide siRNA screen to search for regulators of SOD1 proteostasis. This screen yielded 30 candidate genes that maintained an absence of the DBR-exposed SOD1WT conformation. Among these genes was one encoding DDB1- and CUL4-associated factor 4 (DCAF4), a substrate receptor of the E3 ubiquitin-protein ligase complex. Of note, we found that DCAF4 mediates the ubiquitination of an ALS-associated protein and autophagy receptor, optineurin (OPTN), and facilitates autophagic degradation of DBR-exposed SOD1. In summary, our screen identifies DCAF4 as being required for proper proteostasis of DBR-exposed SOD1, which may have potential relevance for the development of therapies for managing ALS.

A Case of Refractory Hypothyroidism due to Poor Compliance Treated with the Weekly Intravenous and Oral Levothyroxine Administration.

Refractory hypothyroidism is caused by decreased gut absorption, increased metabolism, and poor compliance. Previous studies suggested that the weekly oral, suppository, or intramuscular administration of levothyroxine (LT4) is an effective treatment for refractory hypothyroidism. However, limited information is currently available on treatment involving the weekly intravenous administration of LT4. We managed a case of refractory hypothyroidism due to poor compliance, for which, by weekly intravenous LT4 administration, LT4 was intravenously administered weekly at a dose of 300 µg without any adverse effects such as acute ischemic heart diseases or liver dysfunction and effectively maintained the euthyroid status for 14 months. The weekly oral administration of LT4 (700 µg) was also safely performed and was as effective as its intravenous administration. We herein present precise clinical course of the present case including pharmacokinetic data during the weekly intravenous and oral administration of LT4 and discuss the safety and efficacy of the treatments.

Effects of cardiopulmonary bypass on the disposition of cefazolin in patients undergoing cardiothoracic surgery.

The aim of the study was to evaluate the disposition of plasma unbound cefazolin in patients undergoing cardiothoracic surgery with cardiopulmonary bypass (CPB). Adult patients undergoing cardiothoracic surgery with CPB were enrolled in the study. Cefazolin sodium was given intravenously before skin incision (1 g) and at the beginning of CPB (2 g). Thereafter, an additional dose (1 g) was given every 4 hours. Seven to ten blood samples were collected before and during surgery. Plasma total and unbound (ultrafiltrated) cefazolin concentrations were analyzed using an HPLC-UV method. Plasma protein binding was analyzed with the Langmuir model. Twenty-seven patients (aged 70 ± 12 years, body weight 62 ± 12 kg, mean ± SD) with GFR >30 mL min-1 completed the study. There was a significant (P < 0.001) increase in median plasma unbound fraction of cefazolin from 21% before skin incision to 45% during CPB (P < 0.001), which was accompanied by a significant (P < 0.001) reduction in median plasma albumin concentration from 36 to 27 g L-1. Plasma concentrations of unbound cefazolin exceeded the assumed target thresholds of 2 µg mL-1 in all samples and of 8 µg mL-1 in all but one of 199 samples. The increased plasma unbound fraction of cefazolin would be attributable to dilutional reduction of serum albumin at the beginning of CPB and to saturable plasma protein binding of cefazolin. These data reveal CPB may alter the plasma protein binding and possibly distribution of cefazolin. Further studies are warranted to reappraise the protocol of antimicrobial prophylaxis with cefazolin in patients undergoing surgery with CPB.

Clozapine-Induced Acute Hyperglycemia Is Accompanied with Elevated Serum Concentrations of Adrenaline and Glucagon in Rats.

Clozapine, an atypical antipsychotic agent, has been reported to cause acute hyperglycemia. However, the mechanism of clozapine-induced rapidly developing hyperglycemia is not well elucidated. To clarify the mechanism underlying clozapine-induced acute hyperglycemia, we investigated the effects of single intravenous administration of clozapine on the serum concentrations of glucose and several endogenous substances in rats. Male Wistar rats received an intravenous injection of saline (control) or clozapine 2.5, 5, 10 mg/kg. Blood samples were obtained periodically after clozapine administration to determine the serum concentrations of glucose, adrenaline, glucagon, insulin, corticosterone, and clozapine. The serum concentrations of glucose, adrenaline, and glucagon increased dose-dependently after the administration of clozapine at 2.5-10 mg/kg, and reached maxima at 5 mg/kg of clozapine. The serum concentration of corticosterone increased after the administration of clozapine, but no significant variation was observed with the dosage of clozapine. The concentration of serum insulin increased in a dose-dependent manner after clozapine administration. In conclusion, a single administration of clozapine increased the serum concentration of glucose in rats, and adrenaline and/or glucagon would be associated with clozapine-induced acute hyperglycemia.

Effects of Miconazole Oral Gel on Blood Concentrations of Tacrolimus and Cyclosporine: A Retrospective Observational Study.

BACKGROUND: Although azole antifungal agents have been shown to affect the pharmacokinetics of calcineurin inhibitors such as tacrolimus (TAC) and cyclosporine (CyA) by inhibiting drug metabolism, there are few clinical reports on drug interactions between miconazole (MCZ) oral gel and calcineurin inhibitors. In this study, the effects of MCZ oral gel on the blood concentrations of TAC and CyA were investigated. METHODS: In this retrospective study, 18 patients concomitantly administered MCZ oral gel and TAC (9 for dermatomyositis, 3 for myasthenia gravis, 2 for systemic lupus erythematosus, 2 for rheumatoid arthritis, 1 for polymyositis, 1 for prevention of graft-versus-host disease after bone marrow transplantation), and 15 patients concomitantly administered MCZ oral gel and CyA (11 for interstitial pneumonia, 2 for pemphigus, 1 for eosinophilic granulomatosis with polyangiitis, 1 for systemic lupus erythematosus) were evaluated. The dose-adjusted blood concentrations of TAC or CyA were compared before and after the initiation of MCZ oral gel. RESULTS: The trough blood concentration/dose (C/D) ratios of TAC and CyA increased significantly with the administration of MCZ oral gel. The median C/D ratios of TAC and CyA increased by 108% (range: -44% to 216%) and 44% (range: -34% to 195%), respectively. CONCLUSIONS: These results suggest that MCZ oral gel affects the pharmacokinetics of TAC and CyA. Detailed monitoring of the blood concentrations of these drugs, followed by dose adjustments, is needed for each patient because of the difficulties associated with accurately predicting the degree of the effects of MCZ oral gel.

Mechanism Underlying Induction of Hyperglycemia in Rats by Single Administration of Olanzapine.

Acute administration of olanzapine rapidly elevates blood glucose levels. However, the mechanism underlying the rapid development of hyperglycemia with the administration of olanzapine remains unclear. The aim of the present study was to clarify the mechanism underlying olanzapine-induced acute hyperglycemia. Male Wistar rats received an intravenous infusion of saline (control) or olanzapine 2.5, 5, or 10 mg/kg. Blood samples were obtained periodically after olanzapine infusion to determine serum concentrations of glucose, olanzapine, and several endogenous substances. In a separate experiment, rats received an intravenous injection of propranolol (2 mg/kg) 30 min before infusion of olanzapine (10 mg/kg). The intravenous infusion of olanzapine induced dose-dependent increases in the serum concentrations of glucose, epinephrine, and insulin. Pretreatment with propranolol suppressed olanzapine-induced elevations in the serum concentration of glucose, but did not affect the serum concentration of olanzapine or olanzapine-induced increase in the serum concentration of epinephrine. Although the serum concentration of corticosterone increased after administration of olanzapine, no significant differences were observed among the olanzapine dose groups. Furthermore, administration of olanzapine did not affect the serum concentration of glucagon or histamine. We developed a pharmacokinetic-pharmacodynamic model assuming that the olanzapine-induced secretion of epinephrine leads to elevated serum glucose concentrations. This model appeared to satisfactorily characterize olanzapine-induced hyperglycemia. In conclusion, a single intravenous dose of olanzapine dose-dependently increased the serum concentration of glucose in rats, and epinephrine plays a role in olanzapine-induced acute hyperglycemia.

Eta Carinae's Thermal X-ray Tail Measured with XMM-Newton and NuSTAR.

The evolved, massive highly eccentric binary system, η Car, underwent a periastron passage in the summer of 2014. We obtained two coordinated X-ray observations with XMM-Newton and NuSTAR during the elevated X-ray flux state and just before the X-ray minimum flux state around this passage. These NuSTAR observations clearly detected X-ray emission associated with η Car extending up to ~50 keV for the first time. The NuSTAR spectrum above 10 keV can be fit with the bremsstrahlung tail from a kT ~6 keV plasma. This temperature is ΔkT ~2 keV higher than those measured from the iron K emission line complex, if the shocked gas is in collisional ionization equilibrium. This result may suggest that the companion star's pre-shock wind velocity is underestimated. The NuSTAR observation near the X-ray minimum state showed a gradual decline in the X-ray emission by 40% at energies above 5 keV in a day, the largest rate of change of the X-ray flux yet observed in individual η Car observations. The column density to the hardest emission component, N H ~1024 H cm-2, marked one of the highest values ever observed for η Car, strongly suggesting the increased obscuration of the wind-wind colliding X-ray emission by the thick primary stellar wind prior to superior conjunction. Neither observation detected the power-law component in the extremely hard band that INTEGRAL and Suzaku observed prior to 2011. The power-law source might have faded before these observations.

A systematic immunoprecipitation approach reinforces the concept of common conformational alterations in amyotrophic lateral sclerosis-linked SOD1 mutants.

Mutations in the Cu, Zn superoxide dismutase (SOD1) gene are one of the causative agents of amyotrophic lateral sclerosis (ALS). Although more than 100 different mutations in SOD1 have been identified, it is unclear whether all the mutations are pathogenic or just single nucleotide polymorphisms (SNPs) unrelated to the disease. Our previous systematic analysis found that all pathogenic SOD1 mutants (SOD1(mut)) have a common property, namely, an association with Derlin-1, a component of the endoplasmic reticulum-associated degradation machinery. For the proposed mechanism, we found that most pathogenic SOD1(mut) have a constitutively exposed Derlin-1-binding region (DBR), which is concealed in wild-type SOD1 (SOD1(WT)). Moreover, we generated MS785, a monoclonal antibody against DBR. MS785 distinguished most ALS-causative SOD1(mut) from both SOD1(WT) and non-toxic SOD1(mut). However, MS785 could not recognize SOD1(mut) that has mutations in the MS785 epitope region. Here, we developed a new diagnostic antibody, which could compensate for this shortcoming of MS785. We hypothesized that in ALS-causative SOD1(mut), the DBR-neighboring region [SOD1(30-40)] may also be exposed. We then generated MS27, a monoclonal antibody against SOD1(30-40). We found that MS27 could distinguish SOD1(WT) from the pathogenic SOD1(mut), which has mutations in the MS785 epitope region. Moreover, all pathogenic SOD1(mut), without exception, were immunoprecipitated with a combination of MS785 and MS27. The MS785-MS27 combination could be developed as a novel mechanism-based biomarker for the diagnosis of ALS.

Pharmacokinetic-pharmacodynamic analysis of sunitinib-induced thrombocytopenia in Japanese patients with renal cell carcinoma.

The aim of the present study was to clarify the therapeutic range and adequate dose of sunitinib in Japanese renal cell carcinoma patients by means of a pharmacokinetic-pharmacodynamic analysis of sunitinib-induced thrombocytopenia. Six patients with renal cell carcinoma were enrolled in this study. After starting the sunitinib treatment, between three and seven blood samples were obtained from each patient just before the administration of sunitinib. Serum concentrations of sunitinib and its active metabolite N-desethyl-sunitinib were fit to the 1-compartment model with first-order absorption. Changes in platelet counts were fit to the pharmacokinetic-pharmacodynamic model, in which the proliferation of platelet progenitor cells was assumed to be linearly inhibited by sunitinib and its metabolite. All patients using 50 mg as an initial dose of sunitinib developed grade 2 or 3 thrombocytopenia. The pharmacokinetic-pharmacodynamic model created successfully described the time course of sunitinib-induced thrombocytopenia and could predict changes in platelet counts after alterations to the dosage of sunitinib administered. The simulation results indicated that the total trough level of sunitinib to avoid severe thrombocytopenia should be <100 ng/mL, and also that the initial daily dose of sunitinib could be reduced to 37.5 mg or 25 mg in most Japanese patients. In addition to the pharmacokinetic-guided dosage adjustment, the careful monitoring of platelet counts is required for the safe use of sunitinib.

Polysomnography in stable COPD under non-invasive ventilation to reduce patient-ventilator asynchrony and morning breathlessness.

BACKGROUND: Stable severe chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnic respiratory failure treated by nocturnal bi-level positive pressure non-invasive ventilation (NIV) may experience severe morning deventilation dyspnea. We hypothesised that in these patients, progressive hyperinflation, resulting from inappropriate ventilator settings, leads to patient-ventilator asynchrony (PVA) with a high rate of unrewarded inspiratory efforts and morning discomfort. METHODS: Polysomnography (PSG), diaphragm electromyogram and transcutaneous capnography (PtcCO(2)) under NIV during two consecutive nights using baseline ventilator settings on the first night, then, during the second night, adjustment of ventilator parameters under PSG with assessment of impact of settings changes on sleep, patient-ventilator synchronisation, morning arterial blood gases and morning dyspnea. RESULTS: Eight patients (61 ± 8 years, FEV(1) 30 ± 8% predicted, residual volume 210 ± 30% predicted) were included. In all patients, pressure support was decreased during setting adjustments, as well as tidal volume, while respiratory rate increased without any deleterious effect on nocturnal PtcCO(2) or morning PaCO(2). PVA index, initially high (40 ± 30%) during the baseline night, decreased significantly after adjusting ventilator settings (p = 0.0009), as well as subjective perception of PVA leaks, and morning dyspnea while quality of sleep improved. CONCLUSION: The subgroup of COPD patients treated by home NIV, who present marked deventilation dyspnea and unrewarded efforts may benefit from adjustment of ventilator settings under PSG or polygraphy.

[Early exercise training after exacerbation in patients with chronic respiratory failure]. / Réentraînement a l'effort précoce chez l'insuffisant respiratoire après décompensation aiguë.

Patients who suffered from an exacerbation of a chronic respiratory disorder are often very limited in terms of their exercise capacity because of severe dyspnea and amyotrophy of peripheral muscles. Early implementation of pulmonary rehabilitation may help these patients to avoid the complications of a prolonged bedridden period, and increase more rapidly their mobility. Early rehabilitation has become more frequent, but requires special skills from the care givers (chest therapists). Techniques which enhance muscular performance and motility of patients who are recovering from an exacerbation such as electromoystimulation or mobilisation under non-invasive ventilation, give encouraging results; their impact on length of hospital stay requires further studies.