Phase II study of combined chemotherapy with docetaxel, CDDP and 5-FU for highly advanced esophageal cancer

Advanced esophageal cancer with widespread metastasis to lymph nodes or other organs is difficult to treat and has an extremely poor prognosis. A new combined chemotherapy of docetaxel with cisplatin (CDDP) and 5-fluorouracil (5-FU) (DPF therapy) was performed and its efficacy and safety were examined. Among those hospitalized between May 2003 and October 2009, 30 patients with stage III or stage IV unresectable, untreated advanced esophageal squamous cell carcinoma which had invaded other organs were enrolled in this study. The regimen of DPF therapy was as follows: a set of intravenous drips of 60 mg/m(2) of docetaxel (day 1), 60 mg/m(2) of CDDP (day 1) and 800 mg/m(2) of 5-FU (days 1-5) was administered twice at an interval of 3 to 4 weeks. Antitumor effects, adverse reactions and treatment outcomes were then examined. The patients included 26 men and 4 women aged 40 to 73 years (average age, 58.1 years), and the performance status (PS) was 1 in 18 cases and 2 in 12 cases. The main location of the esophageal cancer was the upper/middle/lower thoracic esophagus in 7/14/9 cases, respectively. Clinical stage was III in 5 cases and IV in 25. The effective rate of DPF therapy was 83.3% for the primary lesion (complete response, CR: 4 cases, partial response, PR: 21 cases), 72.4% for lymph node metastasis (CR: 3 cases, PR: 18 cases) and 72.0% for distant organ metastasis (CR: 3 cases, PR: 15 cases). The observed adverse reactions of grade 2 or higher of National Cancer Institute-Common Toxicity Criteria (NCI-CTC) included anemia (16.7%), leukopenia (73.3%), liver dysfunction (20.0%), anorexia (16.7%), stomatitis (33.3%), esophagitis (16.7%), alopecia (16.7%) and diarrhea (26.7%). The therapy completion rate was 96.7% and the therapy-related death rate was 3.3%. Treatments given after the completion of the DPF therapy were surgery in 6 cases, chemotherapy such as additional DPF in 12, chemoradiation in 4, esophageal stent placement in 1, and no treatment in 7. The patients' median survival time was 271 days, the 1-year survival rate was 41.9% and the 5-year survival rate was 13.3%. DPF therapy can be used as a standard chemotherapy for advanced esophageal cancer in view of its strong antitumor effect and relatively safe outcome.     

Characteristics of acrylic acid-modified temperature-responsive polymers and application as cement liquid

To reduce the adverse effects of water on the mechanical properties and bonding durability of glass ionomer cements, experimental cements which used a temperature-responsive polymer as the cement liquid were prepared and evaluated in this study. Temperature-responsive copolymers were synthesized using radical polymerization with varying molar ratios of N-isopropylacrylamide (NIPAM) and acrylic acid (AA). It was found that copolymer synthesis with varying ratios of NIPAM and AA was able to modify the lower critical solution temperature to range between 27 and 42°C. Bond strength of the cement prepared from AA/NIPAM copolymer containing 53 mol% AA was better than that prepared from polyacrylic acid (PAA) - the conventional cement liquid. However, compressive strength of the experimental cement was slightly lower than that of PAA cement.     

Structure-activity relationship study of a CXC chemokine receptor type 4 antagonist, FC131, using a series of alkene dipeptide isosteres

A structure-activity relationship study on a highly potent CXC chemokine receptor type 4 (CXCR4) antagonist, FC131 [cyclo(-d-Tyr(1)-Arg(2)-Arg(3)-Nal(4)-Gly(5)-)], was carried out using a series of alkene isosteres of the d-Tyr(1)-l/d-Arg(2) dipeptide to investigate the binding mode of FC131 and its derivatives with CXCR4. The structure-activity relationships of isostere-containing FC131 analogues were similar to those of the parent FC131 and its derivatives, suggesting that a trans-conformer of the d-Tyr(1)-Arg(2) peptide bond is the dominant contributor to the bioactive conformations of FC131. Although NMR analysis demonstrated that the two conformations of the peptidomimetic containing the d-Tyr(1)-d-Arg(2) isostere are possible, binding-mode prediction indicated that the orientations of the alkene motif within d-Tyr(1)-MeArg(2) peptidomimetics depend on the chirality of Arg(2) and the β-methyl group of the isostere unit, which makes the dominant contribution for binding to the receptor. The most potent FC122 [cyclo(-d-Tyr(1)-d-MeArg(2)-Arg(3)-Nal(4)-Gly(5)-)] bound with CXCR4 by a binding mode different from that of FC131.     

Reliability evaluation of nonlinear design space in pharmaceutical product development

Formulation design space of indomethacin tablets was investigated using a nonlinear response surface method incorporating multivariate spline interpolation (RSM-S). In this study, a resampling method with replacement was applied to evaluate the reliability of border on the design space estimated by RSM-S. The quantities of lactose, cornstarch, and microcrystalline cellulose were chosen as the formulation factors. Response surfaces were estimated using RSM-S, and the nonlinear design space was defined under the restriction of more than 3 kgf hardness and more than 70% dissolution 30 min before and after an accelerated test. The accuracy of the resampling method was elucidated and high correlation coefficients were produced. However, the distribution of the border on the design space generated by the resampling method was far from normal, and the confidence interval of the border was estimated using a nonparametric percentile technique. Consequently, the reliability of the design space was decreased by approaching the edge of the experimental design. RSM-S and this resampling method might be useful for estimating the reliability of nonlinear design space.     

Novel anti-HIV-1 activity produced by conjugating unsulfated dextran with polyL-lysine

A conjugate of polyL-lysine (PLL) with unsulfated dextran produced by reductive amination was found to have remarkable anti-HIV-1 activity against both the macrophage-tropic R5 virus Ba-L and T-cell line tropic X4 virus IIIB strains, although neither PLL nor dextran has such activity. The conjugate is a pseudoproteoglycan (pseudoPG) that simulates the structure of a proteoglycan. Conjugation with dextran was found to produce an antiviral effect in three kinds of assay systems including a human CD4(+) T-cell line, and the pseudoPG synthesized using 10 kDa PLL and 10 kDa dextran showed EC(50) 4-40 times lower than that of sulfated dextran or heparin against Ba-L and EC(50) equal to that against IIIB, indicating that PLL-dextran (PLL-Dex) was more effective against R5 virus than sulfated polysaccharides. PLL-Dex significantly suppressed a clinically isolated R5 virus from primary peripheral blood mononuclear cells. PLL-Dex interacted with the virus during adsorption to the cell and also decreased virus entry into the cell, suggesting PLL-Dex has multiple preventive mechanisms against HIV-1.     

Papillary adenoma of the lung with a peculiar raw macroscopic feature

We report a case of papillary adenoma of the lung with a peculiar raw macroscopic feature at intraoperative consultation. A 52-year-old man was admitted to our hospital for the evaluation of a solitary peripheral nodule in the left lower lobe which was detected with chest CT. When we took staples off from the stump of the partially resected lung in order to make a frozen section diagnosis, granular fragments leaked out from the stump. On the cut surface, the dark reddish and granular tumor grew expansively; however, hemorrhage and necrosis were absent. Histologically, granular fragments were mainly composed of papillary structures, which consisted of a single layer of cuboidal to low columnar cells with round to oval nuclei lining the surface of the fibrovascular cores. Characteristically, papillary structures lacked elastic fibers in the stroma and were packed within an elastic fiber framework derived from pre-existing alveolar structures. We considered that high intratumoral pressure might have made the granular fragments leak out of the stump as soon as we removed staples and that peculiar macroscopic findings before fixation may be a diagnostic clue for papillary adenoma.     

Effect of renal impairment on the pharmacokinetics of memantine

The effect of renal impairment on the pharmacokinetics of a single oral dose of memantine (10 mg) was determined in Japanese subjects. Subjects were assigned to four groups based on baseline creatinine clearance (CL(CR)): normal renal function (> 80 mL/min, n = 6), and mild (50 to ≤ 80 mL/min, n = 6), moderate (30 to < 50 mL/min, n = 6), and severe renal impairment (5 to < 30 mL/min, n = 7). Mean memantine maximum plasma concentration (C(max)) was similar in the groups (12.66, 17.25, 15.75, and 15.83 ng/mL, respectively), as was mean time to C(max) (6.2, 5.2, 4.3, and 5.4 h, respectively). However, exposure to memantine determined from mean area under the plasma concentration-time curve was 1.62-, 1.97-, and 2.33-times higher in subjects with mild, moderate, and severe renal impairment, respectively, as compared to controls with normal renal function. Mean memantine plasma elimination half-life increased according to increasing renal impairment (61.15, 83.00, 100.13, and 124.31 h, respectively), while mean cumulative urinary recovery of unchanged memantine in 72 h after dosing decreased according to increasing renal impairment (33.68%, 33.47%, 23.60%, and 16.17%, respectively). These results are the same as those in the previous study on caucasian individuals, when compared per body weight. It is suggested that the dose of memantine should be halved in patients with renal impairment.     

Diagnosis of undifferentiated type early gastric cancers by magnification endoscopy with narrow-band imaging

Background and Aims: The diagnostic use of magnification endoscopy with narrow‐band imaging (ME‐NBI) to assess histopathologically undifferentiated‐type early gastric cancers (UD‐type EGCs) is not well elucidated. The purpose of this study was to examine the comparative relationship between ME‐NBI images and histopathological findings in UD‐type EGCs. Methods: We analyzed 78 consecutive cases of UD‐type EGCs ≤ 20 mm in diameter that underwent ME‐NBI ≤ 2 weeks prior to resection. The ME‐NBI images were compared with histopathological findings following either endoscopic submucosal dissection (ESD) or surgery. Applying the comparative results, we prospectively evaluated the success of identifying the lateral extent of UD‐type EGCs resected by ESD in additional consecutive cases. Results: Lesions with preserved but irregular surface microstructures (S‐type based on ME‐NBI) showed mucosal atrophy and corresponded histologically to the non‐whole‐layer type of intramucosal cancer (24/24, 100%). Lesions with an irregular microvasculature type (V‐type, for example, corkscrew pattern) or mixed type upon ME‐NBI corresponded histopathologically to the non‐whole‐layer type of intramucosal cancer (15/54, 27.8%), the whole‐layer type of intramucosal cancer (27/54, 50.0%) or submucosal (sm) invasion cancer (12/54, 22.2%). Applying these comparative results, we used ME‐NBI to successfully predict the lateral extent of cancer, which corresponded to the histopathological lateral extent in all 18 additional consecutive UD‐type EGCs resected by ESD. Conclusions: ME‐NBI images of UD‐type EGCs were very closely related to the histopathological findings. Thus, ME‐NBI can be useful in the pretreatment assessment of the histopathological patterns of cancer development and the lateral extent of such lesions.     

A case of idiopathic basal ganglia calcification associated with membranoproliferative glomerulonephritis

Idiopathic basal ganglia calcification (IBGC) is a syndrome in which bilateral cerebral calcification occurs despite the absence of abnormal calcium metabolism. A 17-year-old Japanese female was admitted for investigation of intermittent proteinuria from the age of 12 years. On admission, her blood pressure was 126/60 mmHg and her serum creatinine was 0.8 mg/dL. Although computed tomography revealed bilateral striopallidodentate calcinosis, her level of intelligence and neurological findings were normal, as were the results of endocrine tests including parathyroid hormone. Asymptomatic IBGC was diagnosed. Renal biopsy showed membranoproliferative glomerulonephritis. Peritoneal dialysis was started for end-stage renal failure when she was 24 years old. Pyramidal and extrapyramidal signs started to develop at the age of 27 years and progressed, resulting in death from aspiration pneumonia at the age of 32 years. Post-mortem revealed bilateral calcification of the basal ganglia, dentate nucleus, thalamus, and centrum semiovale. On light microscopy, there was circumferential calcification of the media and intima of affected vessels in the brain, including small arteries, small veins, and capillaries, and luminal narrowing was seen. On electron microscopy, layers of differing electron density were arranged in concentric laminae. This is the first report of IBGC with bilateral and symmetrical cerebral calcification accompanied by membranoproliferative glomerulonephritis resulting in end-stage renal failure.