Phase I/II Trial of Docetaxel and Carboplatin as a First-Line Therapy in Patients with Stage IV Non-Small-Cell Lung Cancer

A phase I/II study was conducted to determine the maximum-tolerated dose, the safety and tolerability, and the clinical efficacy of carboplatin and docetaxel in combination in patients with stage IV non–small-cell lung cancer. Patients with measurable, previously untreated, good performance status, and stage IV non–small-cell lung cancer were eligible. Increasing doses of docetaxel were given in combination with a fixed dose of carboplatin except at level 5. Cycles were repeated every four weeks. Seventy-seven patients were registered. In phase I, 27 patients were entered at five different dose levels. A docetaxel dose of 60 mg/m² and carboplatin area under the concentration time curve 6 was recommended for phase II, and an additional 50 patients were entered at this level for a total of 56 patients. Grade 3/4 neutropenia was the most common adverse event and occurred in 70% of the patients. Two patients had febrile neutropenia. Fifty-six patients were assessable for response; 21 partial responses were observed for an overall response rate of 37.5%. The median time to tumor progression was 4.0 months (range, 1.0–21.0 months), and the median survival was 12.9 months (range, 0.4–51.3 months). The one-year survival rate was 46.4%. The combination of docetaxel 60 mg/m² and carboplatin area under the concentration time curve 6 is feasible and effective in patients with stage IV non–small-cell lung cancer.     

WT1 intron 9 splice acceptor site mutation in a 46,XY male with focal segmental glomerulosclerosis

The Wilms’ tumor suppressor gene (WT1) plays crucial roles in urogenital and gonadal development. Germline mutations of WT1 have been reported in patients with Denys-Drash syndrome (DDS) and Frasier syndrome (FS). Based on clinical overlaps reported to date, it has been suggested that these two syndromes should be considered as part of a spectrum of diseases caused by WT1 gene mutations, rather than as separate diseases. We report a new mutation in an intron 9 splice acceptor site (IVS −1G→) in a Japanese 46,XY male patient with focal segmental glomerulosclerosis (FSGS) and bilateral cryptorchism. The clinical phenotype of this patient resembled FS without male pseudohermaphroditism. Interestingly, although the patient’s right kidney was diagnosed with FSGS, his left kidney showed severe hypoplasia. There are no previous case reports of FSGS and renal hypoplasia in the same individual with a WT1 mutation. The findings for this case further suggest that the renal phenotype has various manifestations and is not always decided by the type of WT1 mutation. The possibility that the position of the WT1 mutation may influence the course of the nephropathy should be evaluated in a larger patient cohort.     

Renal L-type fatty acid--binding protein in acute ischemic injury

Fatty acid-binding proteins (FABPs) bind unsaturated fatty acids and lipid peroxidation products during tissue injury from hypoxia. We evaluated the potential role of L-type FABP (L-FABP) as a biomarker of renal ischemia in both human kidney transplant patients and animal models. Urinary L-FABP levels were measured in the first urine produced from 12 living-related kidney transplant patients immediately after reperfusion of their transplanted organs, and intravital video analysis of peritubular capillary blood flow was performed simultaneously. A significant direct correlation was found between urinary L-FABP level and both peritubular capillary blood flow and the ischemic time of the transplanted kidney (both P < 0.0001), as well as hospital stay (P < 0.05). In human-L-FABP transgenic mice subjected to ischemia-reperfusion injury, immunohistological analyses demonstrated the transition of L-FABP from the cytoplasm of proximal tubular cells to the tubular lumen. In addition, after injury, these transgenic mice demonstrated lower blood urea nitrogen levels and less histological injury than injured wild-type mice, likely due to a reduction of tissue hypoxia. In vitro experiments using a stable cell line of mouse proximal tubule cells transfected with h-L-FABP cDNA showed reduction of oxidative stress during hypoxia compared to untransfected cells. Taken together, these data show that increased urinary L-FABP after ischemic-reperfusion injury may find future use as a biomarker of acute ischemic injury.     

Circadian rhythms in the CNS and peripheral clock disorders: function of clock genes: influence of medication for bronchial asthma on circadian gene

Bronchial asthma is a chronic inflammatory disorder of the airways, in which inflammation causes bronchial hyper-responsiveness and flow limitation in the presence of various stimuli. Pulmonary function in asthmatic patients frequently deteriorates between midnight and early morning, which has suggested a role for chronotherapy. Although relationships between bronchial asthma and the function of clock genes remain unclear, some medications given for asthma such as glucocorticoids or beta(2)-adrenoceptor agonists may influence clock genes in vivo. In our studies of clock gene mRNA expressions in human bronchial epithelial cells in vitro and peripheral blood cells in vivo, we demonstrated that glucocorticoid or beta(2)-adrenoceptor agonist treatment strongly induced human Per1 mRNA expression both in vitro and in vivo. Human peripheral blood cells provide a useful indication of peripheral clock gene mRNA expression in vivo.     

Risk of pancreatitis after endoscopic retrograde cholangiopancreatography and endoscopic biliary drainage

Background:

Pancreatitis is the most common and serious complication to occur after endoscopic retrograde cholangiopancreatography (ERCP). It is often associated with additional diagnostic modalities and/or treatment of obstructive jaundice. The aim of this study was to determine the risk of post-ERCP pancreatitis associated with pancreaticobiliary examination and endoscopic biliary drainage (EBD).

Methods:

A total of 740 consecutive ERCP procedures performed in 477 patients were analysed for the occurrence of pancreatitis. These included 470 EBD procedures and 167 procedures to further evaluate the pancreaticobiliary tract using brush cytology and/or biopsy, intraductal ultrasound and/or peroral cholangioscopy or peroral pancreatoscopy. The occurrence of post-ERCP pancreatitis was analysed retrospectively.

Results:

The overall incidence of post-ERCP pancreatitis was 3.9% (29 of 740 procedures). The risk factors for post-ERCP pancreatitis were: being female (6.5%; odds ratio [OR] 2.5, P= 0.02); first EBD procedure without endoscopic sphincterotomy (ES) (6.9%; OR 3.0, P= 0.003), and performing additional diagnostic procedures on the pancreatobiliary duct (9.6%; OR 4.6, P < 0.0001). Pancreatitis after subsequent draining procedures was rare (0.4%; OR for first-time drainage 16.6, P= 0.0003). Furthermore, pancreatitis was not recognized in 59 patients who underwent ES. Seven patients with post-EBD pancreatitis were treated with additional ES.

Conclusions:

Invasive diagnostic examinations of the pancreaticobiliary duct and first-time perampullary biliary drainage without ES were high-risk factors for post-ERCP pancreatitis. Endoscopic sphincterotomy may be of use to prevent post-EBD pancreatitis.     

Usefulness of Positron Emission Tomography in the Evaluation of Distribution and Activity of Systemic Lesions Associated with Autoimmune Pancreatitis

Background/Aims: Autoimmune pancreatitis (AIP) is an lgG4-related systemic disease often accompanied with a variety of lesions outside of the pancreas and is treated with steroid therapy. The aim of this study is to analyze the usefulness of positron emission tomography with ¹⁸F-fluorodeoxyglucose (FDG-PET) in the evaluation of distribution and activity of systemic lesions of AIP during steroid therapy. Methods: Eleven cases of AIP had their FDG-PET images evaluated before and 3 months after steroid therapy and another 2 cases only before therapy. AIP activity was determined by the level of serum markers, IgG and lgG4, and compared with findings of PET. Results: In all 13 cases of AIP, a moderate to intense level of FDG accumulation was recognized in the pancreatic lesion before steroid therapy. Of 13 patients, 11 (84.6%) showed FDG accumulation in the multiple organs, such as mediastinal and other lymph nodes, salivary gland, biliary tract, prostate, and aortic wall. In 11 patients who underwent PET before and after steroid therapy, FDG accumulation was diminished in almost all systemic lesions, with a mean of maximum standardized uptake value (SUV_max) in the pancreatic lesion from 5.12 to 2.69. Similar to the SUV level, serum IgG and lgG4 were decreased in most of the cases after steroid therapy. Conclusions: FDG-PET is an effective modality to evaluate the response of steroid therapy and the distribution and activity of various systemic lesions of AIP.