Comparison of intracorporeal versus extracorporeal urinary diversion after robot-assisted radical cystectomy at a medium-sized facility

International Journal of Clinical Oncology - The aim of this study is to compare the perioperative outcomes and learning curves between intracorporeal and extracorporeal urinary diversion at our...     

Effects of nasal obstruction on maturation of the jaw-opening reflex in growing rats

Objective

Nasal obstruction during growth changes craniofacial morphology and function. However, the etiological mechanisms of these changes are unknown. The aim of the present study was to investigate the effects of nasal obstruction during growth on the maturation of the jaw-opening reflex (JOR) using an electrophysiological technique. We focused on the oral sensory receptors that regulate the activities and reflexes of the orofacial muscles.

Design

Sixty 6-day-old male Wistar rats were randomly divided into control and experimental groups (n = 30 each). The experimental group underwent unilateral nasal obstruction at 8 days of age. The JOR was evoked by bilateral, low-intensity electrical stimulation of the inferior alveolar nerve. The electromyographic responses were recorded bilaterally from the digastric muscles at 5, 7, and 9 weeks of age.

Results

The latency of the JOR was significantly longer and the peak-to-peak amplitude was significantly smaller in the experimental group than in the control group at each age, while the duration was not significantly different. Intragroup comparison of the latency, peak-to-peak amplitude, and duration at 5, 7, and 9 weeks of age revealed no significant differences in either the control or experimental groups.

Conclusions

Unilateral nasal obstruction during growth may have significant effects on maturation of craniofacial function.     

Cytapheresis for the treatment of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis: report of five cases.

To minimize the adverse effects of high-dose administration of steroids and cyclophosphamide in patients with myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA), granulocytapheresis (GCAP) or leukocytapheresis (LCAP) was performed to reduce inflammation. Four patients with rapidly progressive glomerulonephritis (RPGN) and one patient with pulmonary hemorrhage due to MPO-ANCA-associated vasculitis were treated by cytapheresis. The prednisolone (PSL) dose was 0.28 +/- 0.15 mg/kg/day (mean +/- SD) (range 0.18-0.50 g/kg/day). In the 4 RPGN patients, the peak serum creatinine level was 3.7 +/- 1.9 mg/dl (range 1.7 to 5.6 mg/dl). GCAP was performed in 3 RPGN patients and in 1 pulmonary hemorrhage patient. LCAP was performed in 1 RPGN patient. In the 4 RPGN patients, renal function improved after combined therapy with cytapheresis and corticosteroids. In the pulmonary hemorrhage patient, evidence of pulmonary hemorrhage on chest computed tomography scanning diminished after combined therapy with cytapheresis and corticosteroids. Cytapheresis, when combined with a low-dose or intermediate-dose PSL regimen, is effective in the treatment of ANCA-associated vasculitis.     

Phase I/II Study of Erlotinib to Determine the Optimal Dose in Patients With Non‐Small Cell Lung Cancer Harboring Only EGFR Mutations

The recommended daily dose of erlotinib was determined for patients with all types of non‐small cell lung cancer (NSCLC). We determined the optimal dose (OD) in patients with NSCLC harboring only epidermal growth factor receptor (EGFR) sensitizing mutations. EGFR‐tyrosine kinase inhibitor‐naïve patients with sensitizing mutations were eligible. Clinical OD was determined in a phase I/II study based on the continual re‐assessment method (CRM) of both disease control and dose‐limiting toxicity, defined as any toxicity of grade 2 (G2) or higher within 8 weeks. We also determined the pharmacologic OD via a pharmacokinetic (PK) study. Thirty‐eight patients were enrolled. Clinical OD was 25 mg/day by the CRM. Median progression‐free survival (mPFS) was 9.3 months. In receiver operating characteristic (ROC) analysis of mPFS, the trough concentration ( Cminss) was ≥ 0.30 μg/mL. The area under the curve (AUC) and Cminss were predicted via population PK (PopPK) or a bootstrap of 100 iterations (PopPK₁₀₀). TOX20 was defined as < 20% duration of any toxicity ≥ G2 during the PFS period. In ROC analysis of mPFS and TOX20 in the PopPK₁₀₀ study, Cminss was ≥ 0.17 and < 0.32 μg/mL, respectively. In ROC analysis of mPFS and TOX20 in the PopPK₁₀₀ study, Cminss was ≥ 0.15 and < 0.31 μg/mL, AUC was ≥ 14.4 and < 14.5 μg/mL•hour, and the dosage was ≥ 58.4 and < 58.8 mg/day, respectively. Clinical and pharmacologic ODs were 25 by CRM and 50–60 mg/day by PK, respectively. The proposed starting OD is 50–60 mg/day, with personalized adjustment of 0.15–0.31 μg/mL based on Cminss as determined by PopPK monitoring.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ The recommended daily dose of erlotinib was determined for patients with all types of non‐small cell lung cancer (NSCLC). Many patients suffer severe and long‐term adverse events related to treatment despite tumors harboring sensitizing mutations.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What is the optimal dose of erlotinib for patients with NSCLC harboring sensitizing mutations?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ In terms of therapy with a reduced dose of erlotinib, modest benefit was achieved when all patients received the same reduced dose, but greater benefit is obtained if each patient receives a personalized optimal dose via population pharmacokinetic monitoring based on interpatient variations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The method can be adapted to determine the optimal dose of molecular targeting agents other than erlotinib. The most benefit for patients is realized if their tumors are treated with a personalized optimal dose of molecular targeting agent, balancing toxicity and efficacy to adjust to interpatient differences.

Five epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) are currently available for use in clinical practice. ¹ All of these EGFR‐TKIs improve progression‐free survival (PFS) compared with standard chemotherapy as first‐line treatment for patients with non‐small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. ² , ³ Erlotinib is a first‐generation EGFR‐TKI with a recommended once‐daily oral dose of 150 mg. This dose was intended to target all types of EGFR (i.e., wild type and any EGFR mutations) based on dose‐escalation experiments in a phase I study of cytotoxic agents ⁴ and is the maximum tolerated dose. EGFR‐tyrosine kinase sensitizing mutations include exon 19 deletions (E19DEL) and a point mutation in exon 21 (L858R); thus, erlotinib exhibits excellent efficacy in patients with NSCLC harboring these sensitizing mutations. ⁵ At a 150 mg/day dose, the mean trough steady‐state concentration ( Cminss) of erlotinib is > 2.5 µM. ⁴ However, several basic research studies reported a 50% growth inhibitory concentration in NSCLC cell lines harboring sensitizing mutations of < 0.1 µM. ⁶ , ⁷ , ⁸ It is, therefore, likely that erlotinib can be given at doses < 150 mg/day while maintaining clinical efficacy.A postmarketing surveillance study of erlotinib in Japan involving 3,488 patients ⁹ reported the following rates of adverse events (AEs) of grade 2 (G2) or higher; eruptions = 38.8%, paronychia = 3.4%, diarrhea = 7.1%, hepatic disorders = 5.4%, and interstitial lung disease = 3.7%. About 90% of the patients were given 150 mg/day of erlotinib during treatment in this surveillance study. Because 55.1% of the patients had a history of gefitinib treatment and patients with all types of EGFR were eligible for this study, median PFS was only 64 days (95% confidence interval (CI) 60–68 days). Several AEs induced by erlotinib persisted during treatment. Long‐term, persistent AEs, even of low grade, can restrict patients’ normal activities and adversely affect their quality of life (QOL). ¹⁰ In interpatient dose escalation, the degree of AEs became more and more severe depending on increasing the daily dose of erlotinib from 25 to 200 mg/day. ⁴ During long‐term treatment, reduced toxicity can lead to improved QOL. It is, therefore, likely that reducing the required dose of erlotinib would have beneficial toxicity and QOL effects.The purpose of the present two‐phase study was to determine the optimal dose (OD) of erlotinib in patients with NSCLC harboring only sensitizing mutations. The first phase determined the minimum effective dose (MED) and OD of erlotinib in the target patient population, and the second phase determined the clinical and pharmacologic ODs. The study’s overall goal was to facilitate personalized dosing of erlotinib with the objective of balancing toxicity and efficacy.     

Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain

Proinflammatory agents trypsin and mast cell tryptase cleave and activate PAR2, which is expressed on sensory nerves to cause neurogenic inflammation. Transient receptor potential A1 (TRPA1) is an excitatory ion channel on primary sensory nerves of pain pathway. Here, we show that a functional interaction of PAR2 and TRPA1 in dorsal root ganglion (DRG) neurons could contribute to the sensation of inflammatory pain. Frequent colocalization of TRPA1 with PAR2 was found in rat DRG neurons. PAR2 activation increased the TRPA1 currents evoked by its agonists in HEK293 cells transfected with TRPA1, as well as DRG neurons. Application of phospholipase C (PLC) inhibitors or phosphatidylinositol-4,5-bisphosphate (PIP(2)) suppressed this potentiation. Decrease of plasma membrane PIP(2) levels through antibody sequestration or PLC-mediated hydrolysis mimicked the potentiating effects of PAR2 activation at the cellular level. Thus, the increased TRPA1 sensitivity may have been due to activation of PLC, which releases the inhibition of TRPA1 from plasma membrane PIP(2). These results identify for the first time to our knowledge a sensitization mechanism of TRPA1 and a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by TRPA1 activation.     

Gd‐EOB‐DTPA‐enhanced MR imaging: Prediction of hepatic fibrosis stages using liver contrast enhancement index and liver‐to‐spleen volumetric ratio

Purpose:

To develop and evaluate a quantitative parameter for staging hepatic fibrosis by contrast enhancement signal intensity and morphological measurements from gadoxetic acid (Gd‐EOB‐DTPA)‐enhanced MR imaging.

Materials and Methods:

MR images were obtained in 93 patients; 75 patients had histopathologically proven hepatic fibrosis and 18 patients who had healthy livers were evaluated. The liver‐to‐muscle signal intensity ratio (SI_post = SIliver/SImuscle), contrast enhancement index (CEI = SIpost/SIpre), and liver‐to‐spleen volumetric ratio (VR = Vliver/Vspleen) were evaluated for staging hepatic fibrosis.

Results:

VR was most strongly correlated with fibrosis stage (7.21; r = ?0.83; P < 0.001). Sensitivity, specificity, and area under the ROC curve demonstrated by linear regression formula generated by VR and CEI in predicting fibrous scores were 100%, 73%, and 0.91, respectively, for the detection of hepatic fibrosis F1 or greater (≥ F1),100%, 87%, and 0.96 for ≥ F2, 74%, 98%, and 0.93 for ≥ F3 and 91%, 100%, and 0.97 for F4.

Conclusion:

The liver‐to‐spleen volumetric ratio and contrast enhancement index were reliable biomarkers for the staging of hepatic fibrosis on Gd‐EOB‐DTPA‐enhanced MR imaging. J. Magn. Reson. Imaging 2012;36:1148–1153. © 2012 Wiley Periodicals, Inc.