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Objective: The aim of this phase I study was to determine the maximum tolerated dose (MTD) and to evaluate the toxicity of the biweekly paclitaxel and carboplatin combination chemotherapy in frail patients with advanced non-small cell lung cancer (NSCLC). Method: Seventeen unresectable and previously untreated NSCLC patients participated in this study. Frail patients (>80 years old with PS 0-1 and adequate organ functions, or

Purpose: To determine the maximum tolerated dose (MTD) of irinotecan combined with carboplatin, to evaluate its efficacy and toxicity for patients with lung cancer, and to examine its pharmacokinetics and pharmacodynamics. Methods: The dose of irinotecan was escalated from 40 mg/m2 per week in increments of 10 mg/m2. Carboplatin was fixed at 300 mg/m2. Multivariate regression models with an interaction term were used to evaluate synergistic pharmacodynamic interactions. Results: The MTD and recommended dose of irinotecan were 60 and 50 mg/m2, respectively. Dose-limiting toxicities were grade 4 neutropenia and grade 3 or 4 diarrhea. In phase II studies, response rates were 81.3% (95% confidence interval 61.8–100%) in 16 patients with small-cell lung cancer and 22.2% (2.7–41.8%) in 18 patients with non-small-cell lung cancer. Two patients (6%) experienced grade 4 neutropenia, thrombocytopenia, and grade 3 diarrhea. The area under the plasma concentration versus time curve (AUC) of carboplatin ranged from 2.87 to 9.31 mg·min/ml, with a median of 4.66 mg·min/ml. In pharmacodynamic analyses, the log-transformed surviving fraction in platelet count (SFp) showed a significant association with the AUC of carboplatin (P=0.010), while that in neutrophil count (SFn) was not significantly correlated with any pharmacokinetic parameter. The interaction term was not significant in either case. Conclusions: These results indicate that AUC-based dosing of carboplatin is still rational in combination chemotherapy. A more sensitive method for predicting life-threatening toxicities is needed, however, because traditional pharmacokinetic parameters were not adequate tools for identifying patients at high risk of severe neutropenia and diarrhea. This combination regimen has only modest activity, and further studies are necessary to evaluate a different dose schedule.

Accuracy in the assessment of performance status by oncologists has not been well evaluated. We investigated possible discrepancies in the assessment of performance status among patients, nurses, and oncologists, and evaluated the prognostic importance of each assessment. Two hundred and six inpatients with inoperable, advanced non-small cell lung cancer were investigated prospectively. Weighted Kappa statistics for inter-observer agreement were 0.53 between oncologists and patients and 0.63 between oncologists and nurses. There was a significant difference among the assessments by the three groups (P < 0.001). Oncologists gave the healthiest performance status assessment, nurses an intermediate assessment, and patients the poorest. When included separately in the Cox model, the assessment by each group was significantly correlated with survival. However, the assessment by the patients themselves failed to distinguish survival of patients with performance status 1 and 2. Among the three models including patient-, nurse-, and oncologist-assessed PS, that including oncologist-assessed PS best fitted to the observed survival data. These results showed that the assessment by the patients themselves is different from those by the nurses and the oncologists and provided additional support for the use of the assessment by oncologists in clinical oncology. © 2001 Cancer Research Campaign http://www.bjcancer.com

Prognostic factors which can forecast short-term survival in patients with stage IV non-small cell lung cancer have not been well evaluated. Characteristics of such factors may be different from those for overall survival, and would be an important eligibility criterion for clinical trials of chemotherapy. We retrospectively analyzed the data of 158 patients with stage IV non-small cell lung cancer whose performance status was 0, 1 or 2. Univariate and multivariate logistic regression models revealed demographic variables which significantly correlated with the survival at 8 or 12 weeks. The univariate model showed the following significant variables: T factor, N factor, number of organs with metastases, grade of performance status, weight loss within 6 months, evidence of metastasis either at bone or lymph node, and lactate dehydrogenase level. The subsequent multivariate model demonstrated that both grade of performance status under 2 and number of metastasized organs less than 3 are important factors for 8- or 12-week survival. The survival rate in patients meeting the two criteria (grade of performance status under 2 and number of metastasized organs less than 3) and in those meeting only one of them was 93% versus 80% at 8 weeks (P = 0.030) and 88% versus 62% at 12 weeks (P < 0.001), respectively. Grade of performance status and number of organs with metastases appear to be important prognostic factors for short-term survival in patients with stage IV non-small cell lung cancer.

The three-dimensional structure of an exo-type alpha-amylase from Pseudomonas stutzeri which degrades starch from its non-reducing end to produce maltotetraose has been determined by X-ray structure analysis. The catalytic domain of this enzyme (G4-2), whose structure was determined, is a product of spontaneous limited proteolysis in culture broth. It has 429 amino acid residues and a molecular mass of 47,200, and crystallizes in ammonium sulfate solution at pH 7.5. The structure was elucidated by the multiple isomorphous replacement method and refined at 2.0 A resolution, resulting in a final R-factor of 0.178 for significant reflections with a root-mean-square deviation from ideality in bond distances of 0.013 A. The polypeptide chain of this molecule folds into three domains; the first with a (beta/alpha)8 barrel structure, the second with an excursed part from the first one, and the third with five-stranded antiparallel beta-sheets. The active cleft is formed on the C-terminal side of the beta-sheets in the (beta/alpha)8 barrel as in the known endo-type alpha-amylases. A histidine side-chain nitrogen ND1 is coordinated to one of the bound calcium ion. The recognition site of the non-reducing end of the amylose that determines exo-wise degradation is presumed to be at one end of this cleft where there is a disordered loop consisting of the 66th to 72nd residues, and a loop carrying an aspartic acid (Asp160). These structural features may be responsible for the binding of the non-reducing end of the substrate amylose.

Carboplatin clearance depends on the glomerular filtration rate (GFR), and Calvert's formula is frequently used to achieve a target area under the time vs concentration curve (mg ml(-1) min). Creatinine clearance is a substitute for GFR when creatinine values are determined by the Jaffé method, which is being replaced by the enzymatic method. When the enzymatic method is used, the corresponding creatinine clearance theoretically exceeds GFR, and the use of creatinine clearance as GFR in Calvert's formula results, accordingly, in overdosing of carboplatin. In this study, we have established a model for adjusting the creatinine clearance to offset this bias based on a relationship between creatinine values measured by the Jaffé method and by the enzymatic method: adjusted creatinine clearance (ml min(-1)) = creatinine clearance (ml min(-1)) x [serum creatinine (mg dl(-1))]/[serum creatinine (mg dl(-1)) + 0.2]. Subsequently, we validated this model using the data from 35 lung cancer patients. Estimated clearances of carboplatin with the original equation [creatinine clearance + 25] were systematically higher than observed clearances [mean prediction error (MPE) +/- standard error (s.e.) = 26 +/- 5%]. This positive bias was corrected by the adjustment (MPE +/- s.e. = 5 +/- 4%). When the enzymatic method is used, the adjusted creatinine clearance should be used in Calvert's formula.

We aimed to determine whether or not therapeutic drug monitoring is applicable to 21-day oral etoposide treatment for lung cancer. As the starting dose, a 25-mg capsule of etoposide was taken orally three times daily (75 mg/body). To achieve the target concentration range of 1.0 to 1.5 micrograms/ml, the dose was changed to two (50 mg/body) or four (100 mg/body) times a day from day 5, depending on the mean concentration obtained on days 3 and 4 (Cbefore). The mean concentration was calculated by use of a limited sampling model we constructed previously. Among 26 courses in 15 patients, two patients experienced grade 4 leukopenia plus neutropenia, and one of them died on day 20. Because nausea/emesis prevented the planned dose escalation in one patient, we excluded two courses of this patient from the pharmacokinetic analysis of dose modification. Among 5 courses with dose reduction, the Cbefore of 1.7 +/- 0.1 (microgram/ml, mean +/- SE) was decreased to 1.3 +/- 0.2 after day 5 (Cafter). Among 7 courses with dose escalation, the Cbefore of 0.9 +/- 0.0 was increased to the Cafter of 1.2 +/- 0.1. Among the remaining 12 courses without dose modification, the Cbefore and the Cafter were 1.2 +/- 0.0 and 1.3 +/- 0.1, respectively. Hematologic toxicities tended to correlate with the drug concentration. TDM is thus applicable to oral etoposide given according to this schedule, and a larger study is now needed to confirm that the therapeutic efficacy is improved by introducing TDM.

We investigated whether a constant plasma concentration could be obtained by the individualized administration of low-dose, prolonged-infusional etoposide. Etoposide was infused for 14 days at 40 mg/m2/day initially in patients with inoperable non-small-cell lung cancer. The infusion rate was modified based upon the etoposide concentration at 24 h following the initiation of the infusion (C24) to achieve a target concentration of 1.5 microgram/ml. We postulated that severe toxicities could be avoided by maintaining the steady-state concentration at less than 2 microgram/ml, while antitumor activity could be expected if the steady-state concentration was maintained at more than 1 microgram/ml. In a total of 21 courses in 12 patients, the mean etoposide dose was 35+/-6 mg/m2 daily. The C24 was 1.8+/-0.4 microgram/ml and ranged from 1.1 to 2.9 microgram/ml. Following dose modification, the mean concentration from 96 to 336 h (C mean) was 1.6+/-0.2 microgram/ml and ranged from 1.2 to 2.0 microgram/ml. The toxicities were well-tolerated except for one patient with WHO grade 4 leukopenia and neutropenia who developed infectious complications. There were no treatment-related deaths. Following dose modification, the inter-patient variability was decreased successfully. Although this pharmacologically-guided method needs to be validated using more patients, it could be used for therapeutic drug monitoring.

The change in fluorescence spectra of crystalline pullulanase from Klebsiella pneumoniae caused by the addition of alpha-, beta-, and gamma-cyclodextrins and 6-O-alpha-glucosyl-alpha-cyclodextrin and 6-O-alpha-glucosyl-beta-cyclodextrin was investigated at 25 degrees C and pH 5.6. The fluorescence intensity at around 325 nm (excitation at 280 nm) was increased by the addition of all the cyclodextrins studied. The dissociation constant, Kd, of the enzyme-cyclodextrin complex was evaluated by fluorometric titration for each cyclodextrin, and was consistent with the inhibitor constant, Ki, obtained previously [Iwamoto et al. (1993) J. Biochem. 113, 93-96]. The Kd values of beta-cyclodextrin and 6-O-alpha-glucosyl-beta-cyclodextrin were approximately two orders of magnitude smaller than those of alpha- and gamma-cyclodextrins. Fluorescence titration of a cyclodextrin in the presence of another cyclodextrin revealed competition among alpha-, beta-, and gamma-cyclodextrins for binding with the enzyme, which indicates that the binding region of beta-cyclodextrin overlaps those of alpha- and gamma-cyclodextrins. On the other hand, with excitation at 295 nm, a fluorescence spectral change similar to that excited at 280 nm was observed for alpha- and gamma-cyclodextrins and 6-O-alpha-glucosyl-alpha-cyclodextrin, whereas beta-cyclodextrin and 6-O-alpha-glucosyl-beta-cyclodextrin did not show any such change. These results suggest that the binding site or the binding mode of beta-cyclodextrin is slightly different from those of alpha- and gamma-cyclodextrins.(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated the interbronchoscopist variability in the diagnosis of lung cancer by flexible bronchoscopy.A retrospective review of the bronchoscopic records and clinical charts of patients at a university-affiliated hospital.All records of flexible bronchoscopic procedures performed for the diagnosis of lung cancer were retrospectively reviewed, and procedures that obtained histologic or cytologic evidence of malignancy were considered positive. Rates of positivity were compared according to the following factors: operator, operator experience, bronchoscopic findings, tumor location, and tumor laterality. Factors that affected the positivity rate were evaluated using logistic regression analysis.Of 384 bronchoscopic procedures performed in 353 patients, 275 (72 percent) were positive. The positivity rate differed significantly depending on the operator (p = 0.003) and the bronchoscopic findings (p0.001). A difference between operators was noted in technically difficult cases without epithelial or subepithelial findings and when tumors were located in the upper lobe or the superior segment of the lower lobe. The bronchoscopic findings and the operator also emerged as factors significantly affecting the positivity rate in the logistic analysis.The diagnostic yield of bronchoscopy for lung cancer is dependent on both the type of bronchial lesion present and the bronchoscopist.

Lactosucrose is a non-digestible carbohydrate available for fermentation as a substrate for the intestinal microflora. It has been reported that lactosucrose is selectively used by the Biffidobacterium, and that its number significantly increase after the oral administration. In this study, we have examined the changes of the postoperative serum endotoxin level in ten patients with colorectal cancer. Five patients were served as controls, and the remaining five patients were given 30g of lactosucrose daily, during 1 week up to 3 days before operation. Serum endotoxin levels were measured prior and after lactosucrose ingestion, and also on day 1, 3, 5, and 7 postoperatively. Fecal pH, organic acid contents and intestinal microflora were also analyzed before and after lactosucrose administration. The control group had blood and fecal samples taken in a similar manner to the lactosucrose group. Fecal pH had the tendency to decrease, and the concentration of fecal organic acids had the tendency to increase in the lactosucrose group when compared with the control group. The count of Gram-negative rods, which were reported to produce endotoxin, decreased in a ratio statistically significant (p

The interaction between pullulanase from Klebsiella pneumoniae and alpha-, beta-, and gamma-cyclodextrins and 6-O-alpha-glucosyl-alpha-cyclodextrin and 6-O-alpha-glucosyl-beta-cyclodextrin was examined by means of inhibition studies of the enzyme activity, UV difference spectroscopy, and flow calorimetry. All the above cyclodextrins were found to be competitive inhibitors, but beta-cyclodextrin and 6-O-alpha-glucosyl-beta-cyclodextrin showed strong inhibition, the inhibitor constants being two orders of magnitude less than those of alpha- and gamma-cyclodextrins. The difference spectra of beta-cyclodextrin were slightly but significantly different from those of the other cyclodextrins, showing blue shift of a few nanometers. Moreover, only beta-cyclodextrin has a positive entropy change upon binding with the enzyme; all the other cyclodextrins have negative values. These results show that the binding mode of beta-cyclodextrin is subtly different from those of alpha- and gamma-cyclodextrins.

Cyclomaltodextrin glucanotransferase from Bacillus stearothermophilus produced a series of oligosaccharides by the transglycosylation reaction with cyclomaltohexaose as a glycosyl donor and D-lactose as its acceptor. The content of oligosaccharide A as the main transfer product was 22.1% of the total sugar. The content was increased to 34.1% by hydrolysis with glucoamylase. Oligosaccharide A was isolated by column chromatography and crystallized. By chemical and enzymatic analyses, oligosaccharide A was found to be a novel non-reducing trisaccharide; O-beta-D-galactopyranosyl-(1--4)-O- beta-D-glucopyranosyl alpha-D-glucopyranoside.

B. stearothermophzlus由来のCGTaseを高濃度のα-CDに作用させることによりアミロース粒子が生成することを見出し,その生成条件ならびにその諸性質を調べ,以下の結果を得た.1) アミロース粒子の生成は,主に反応温度,基質濃度に影響され,α-CD濃度35%,反応温度30℃で最高の生成率96%を示した.2) 他の細菌起源のCGTaseにおいてもアミロース粒子の生成が認められた.3) 得られるアミロース粒子は3～20gumの球状で,そのλmaxは560～580nmを示し,数平均分子量は5500～7000で,グルコース・ユニットとして34～43個からなるアミロースであった.4) 本物質はX線回折により澱粉のB形X線回折図を示し,偏光十字が観察されることから規則性のある結晶構造を有するアミロースであることがわかった.

The changes in the intestinal microflora were examined in patients with advanced carcinoma of the large intestine, and healthy subjects were surved as control. Comparing to control, patients group revealed high fecal moisture and fecal pH, but showed low levels in various organic acids except succinic acid. Only succinic acid was detected in high level and frequency. No significant difference in the number and occupation rate of Gram-positive bacteria participating in the endogenous endotoxin production was noted between both groups. The pattern of fecal microflora in patients group was similar to that in control. However, the aerobic microorganisms including Staphylococcus were highly found in patients group. These results suggested that the colonic enviornment of the patients with large bowel carcinoma was in aerobic state in comparison with healthy subjects.

高純度ラクトスクロース (LS-98) を1%ならびに10%含有する飼料をラットに投与し, 盲腸内における発酵代謝の状況, ならびに盲腸内細菌叢に与える影響を調査した。ラクトスクロース含有飼料投与により,1) 盲腸内容物重量は増加傾向を示した。2) 盲腸内に到達したラクトスクロースの大部分は腸内細菌によって発酵代謝され, 盲腸内容物のpHが低下するとともに内容物中のSCFA濃度は上昇した。3) 乳酸産生菌 (Lactobacillus, Bifidobacterium) の菌数ならびに占有率の増加が観察された。4) 盲腸ならびに結腸粘膜上皮細胞の増殖が電顕像から推定された。以上の観点から, ラクトスクロースは腸内細菌の主要生息部位において速やかに発酵代謝されるとともに, 発酵代謝産物によって腸内環境を整える機能を有することが示唆された。

Cyclomaltodextrin glucanotransferase (CGTase) [EC 2.4.1.19] was found to catalyze the transglycosylation from α-cyclodextrin (α-CD) to l-ascorbic acid (AA). A main product formed by this reaction was identified as 2-O-α-d-glucopyranosyl l-ascorbic acid (AA-2G) with the enzymatic hydrolysis and ultraviolet absorption spectra using standard AA-2G. A series of maltooligosaccharide substituted 2-O-derivatives of AA were also detected by HPLC. These were thoroughly hydrolized to AA-2G and glucose by treatment with glucoamylase [EC 3.2.1.3].A large amount of AA-2G was prepared with 500 g of AA and 1000 g of α-CD. Two hundred and fifty grams of purified AA-2G, the content of which was 97%, was obtained through enzyme reactions and purification with HPLC using an ion-exchange resin.

During the studies on application of amylases, some a-amylases showed a remarkable transglycosylation action in a high concentration of starch. Using the action, the production of novel and useful saccharides was undertaken, and CGTase was selected. The enzyme catalyzes “cyclization” forming cyclodextrins, “disproportionation” and “coupling reaction, ” in which glycosyl residues are transferred from α-1, 4-glucan or cyclodextrins to an acceptor such as glucose or sucrose. Through the coupling reaction of CGTase we succeeded in the conjugation with glycosyl residue and various substances, and established their usages in food industry and related fields.

ラクトスクロースは人工消化酵素系での消化試験では胃酸で1.5%,小腸粘膜の酵素系で5%の分解率であった.また経口投与では血糖値およびインスリン量の増加量はごくわずかであり難消化性であった.さらに呼気中への水素ガスの排出においても典型的な腸内易発酵性の糖質としての性質を示した. In vitroではBifidobacterium bifidum以外の Bifidobacteriumによく資化され,他の腸内細菌によってはほとんど資化されず,ビフィズス菌の選択的糖源であることが確認された.またin vivoでは1日あたり20gのLS-55を摂取した場合,Bifidobacteriumの増加と,Bacteroidaceaeの大幅な減少が観察され,腸内細菌叢に占めるBifidobacteriumの割合は70～90%まで大幅に増加し,腸内菌叢の改善効果が見られた.

The 3-dimensional X-ray crystallographic structure of cyclodextrin glucanotransferase (CGT-ase) from B. stearothermophilus showed that the CGTase molecule fold into four globular domains, A, B, C and D. The N-terminal domains, A and B, are similar to those of Taka-amylase. The C and D domains, which are unique to this enzyme, both consist of antiparallel β-barrel structure. With a substrate binding analysis in the crystal, two binding sites have been found on the enzyme molecule, one in a cleft of the A-domain and the other in the D-domain. The first one is considered to be related to the enzyme activity in a same manner with a-amylase and the second to the raw starch binding activity of the CGTase.

健康成人男性を対象としたプルラン(10g/日)摂取に伴う影響を調査し,以下の結果を得た.1)プルラン摂取に伴う糞便中への水溶性糖質の排せつ量増加は観察されなかったことから,摂取したプルランの全量はヒト体内で代謝され消失した.2)プルラン摂取前の糞便pH6.53は,摂取によりpH5.97へと低下する傾向を示した.3)糞便中の短鎖脂肪酸濃度はプルラン摂取に伴い増加する傾向を示し,糞便pH低下との関連性が示唆された.4)被験者1日当りの糞便重量は,摂取前の1329から摂取後1769へと増加する傾向を示した.この間の糞便重量増加率は33%であった.5)腸内細菌叢を測定した結果,6名中5名にBifidobacterium菌数の増加が認められ,腸内細菌叢におけるBifidobacterium占有率の平均値は,摂取前の11.9%から摂取後21.9%に増加した.6)プルラン摂取に伴う血液生化学的性状に変化は認められなかった. 以上のことより,プルラン摂取は,便性改善効果と,ヒトの健康維持・増進に大切な機能として望まれるビフィズス因子としての効果をあわせ持つことが示唆された.

An isoamylase-hyperproducing mutant, strain MI-414, was isolated by treating Pseudomonas amyloderamosa SB-15 with N-methyl-N'-nitro-N-nitrosoguanidine. Strain MI-414 produced 10-fold more isoamylase than strain SB-15. SI nuclease mapping of isoamylase mRNAs from the strains showed that the level of isoamylase mRNA was higher in MI-414 than in SB-15. The copy number of the isoamylase gene (iam) was not changed by the mutation. Moreover, the nucleotide sequence of the promoter region of iam, the transcription initiation site, and the expression patterns of iam in the presence of glucose and of maltose were the same in these strains. However, the half-lives of iam-mRNAs in SB-15 and MI-414 were approximately 3 and 22min, respectively. Therefore, hyperproduction of isoamylase in the mutant results, at least partly, from the greater stability of its mRNA.

A case of primary chondrosarcoma of the lung is presented. The tumor, located in the medial segment of the right lower lobe, was successfully resected surgically. Clinical survey did not reveal any primary lesion elsewhere. The tumor consisted of myxomatous, chondromatous, and fibrous lesions. Immunohistochemical study revealed that tumor cells were positive for S-100 protein and vimentin, and negative for other antisera which characterize epithelial tumors. With these clinical, histological, and immunohistochemical studies we diagnosed the tumor as a primary chondrosarcoma of the lung.

ヒト生体内における糖質の消化条件に適応する, in vitro消化試験系を確立した。この試験系により, プルランの消化性を調べたところ, 胃酸ではまったく消化されず, 唾液アミラーゼと膵液アミラーゼにより低分子化され, さらに小腸粘膜酵素では低分子化されるとともに, 少量のグルコースを生成することが明らかとなった。小腸以前の上部消化管でグルコースまで消化されて吸収されるプルランは摂取量の5%以下であると推定された。この結果はプルランが「ヒトの消化酵素で消化されない食物中の難消化性成分の総体」と定義される食物繊維にあてはまることを示唆している。また大腸内での発酵を, 糞便培養法によるin vitro試験系で再現した。その結果, プルランは大腸内ですべて発酵されることが明らかとなった。発酵により生成する短鎖脂肪酸は, 酢酸プロピオン酸, n-酪酸が多く, コハク酸, がわずかに生成した。酢酸, プロピオン酸, n-酪酸の生成量はプルラン中のグルコース1残基当りそれぞれ0.58, 0.21, 0.24であった。また炭素回収率は47.8%となった。生体におけるプルランのエネルギー評価は, 消化試験および発酵試験の結果を用いて行った。エネルギーは2.10kcal/g-プルラン (8.79kJ/g-プルラン) と計算された。しかし実際には, 糞便への短鎖脂肪酸の排泄量の増加が考えられ, プルランのエネルギーはさらに低いと推定した。

Three patients who exhibited endobronchial mucosal bridges that formed at the site of tumor regression following chemotherapy for small cell lung carcinoma are presented. Histopathologic examination showed residual malignant cells in 2 of the 3 patients within the submucosal fibrous tissue and an overlying benign epithelium. Although these mucosal bridges were previously thought to represent a complete remission following chemotherapy or radiotherapy for small cell lung carcinoma, they may, in fact, harbor a residual malignancy under the benign mucosa.

We present a rare case of simultaneous bilateral pneumothorax complicating bronchioloalveolar cell carcinoma. Autopsy revealed that numerous subpleural alveolar spaces were distended and most of the small airways were narrowed by cancer cells. We conclude that a check-valve mechanism may be responsible for pneumothorax in patients with bronchioloalveolar cell carcinoma. (Chest 1991; 100:853-55)

Cytomegalovirus (CMV)-induced interstitial pneumonitis is a well-known lethal complication in bone marrow recipients. CMV is also known to cause gastroenteritis. We report the first case of a bone marrow recipient who developed CMV-induced gastritis which is verified both histologically and virologically. The gastritis preceded the interstitial pneumonitis which was detected in an early stage and was successfully treated. We propose that bone marrow recipients who show signs and symptoms of gastritis undergo an endoscopic examination, and that biopsied specimens should be scrutinized for CMV by both histological examination and culture investigation.

We investigated whether carboplatin pharmacokinetics is altered when the drug is delivered daily over 5 days, compared to a single-day infusion. Carboplatin was infused in 11 patients with lung cancer, who were randomly assigned to 2 groups. In the first group, the agent was administered on a conventional single-day schedule in the first course and then on a 5-day schedule in the second course. In the second group, the order was reversed (crossover design). The dose was calculated using Calvert's formula with 24 h creatinine clearance (Ccr, ml/min) as a substitute for glomerular filtration rate (GFR): carboplatin (mg) = AUCx(Ccr+25), where AUC denotes the area under the concentration versus time curve (mg ml-1 min). No difference of carboplatin clearance between the single-day and 5-day schedule was observed (94.8 +/- 19.9 versus 96.1 +/- 29.9 ml/min, P = 0.818, paired t test). The formula systematically overestimated the carboplatin clearance: the ratio of estimated clearance/ observed clearance ranged from 1.01 to 1.58 (median 1.28; 95% confidence interval, 1.18 to 1.39). We concluded that the individual dosing strategy based on renal function can be applied with a 5-day schedule as well as a single-day schedule. Carboplatin is overdosed when Ccr is substituted for GFR in Calvert's formula.

Prolonged oral administration of etoposide may have a theoretical advantage over intravenous infusion, and carboplatin has a more favorable toxicity profile than cisplatin. A combination of carboplatin 300 mg/m2 and oral etoposide 40 mg/m2/day for 21 days was assessed in 74 (42 limited, 32 extensive disease) previously untreated patients with small-cell lung cancer. Response rate was 69% (CR 19%, PR 50%,) for limited disease and 72% (CR 9%, PR 63%) for extensive disease. Median response duration and overall survival was 6.6 and 10.1 months for limited disease, and 5.3 and 9.1 months for extensive disease, respectively. One-year and two-year survival was 36 and 10% for limited disease and 31 and 2% for extensive disease, respectively. The major toxicity was hematological with grade 4 or greater neutropenia in 36% and grade 4 thrombocytopenia in 16%, and one patient died of neutropenic fever. Non-hematologic toxicities were mild and grade 3 emesis was observed in 5% of patients. Carboplatin combined with 21-day oral etoposide showed only modest activity against small-cell lung cancer with high toxicity and did not merit further evaluation.

This study was conducted to determine whether patients with brain metastases from non-small-cell lung cancer (NSCLC) should be included in clinical trials of chemotherapy. Patients with metastatic NSCLC and good performance status were studied. The survival of patients with brain metastases was compared with that of patients without brain metastases. Of 100 eligible patients, 22 had brain metastases at diagnosis. The median survival time was poorer in patients with brain metastases than in other patients with metastatic NSCLC (96.5 vs. 181.5 days). However, the difference in survival was not significant on univariate analysis (p = 0.106). Multivariate analysis confirmed that the prognostic value of brain metastases was limited in this sample (p = 0.129). There was little difference in survival curves during the first 8 weeks. Patients with brain metastases who have good performance status and minimal neurologic symptoms can be observed for approximately 8 weeks in clinical trials to determine their response to chemotherapy. However, it is doubtful that patients with brain metastases would be eligible for phase III trials, in which survival is an endpoint.

The prolonged continuous infusion of low-dose etoposide is a new approach to treating cancer. Whether or not a circadian variation in the plasma levels of etoposide existed was investigated in nine patients with non-small-cell lung cancer. Etoposide was infused for 14 days and blood samples were obtained every 4 h for 1 day. There was no significant circadian variation, and the observed small within-day variations seemed to lack clinical significance.

A 66-year-old woman who presented with malignant cardiac tamponade of unknown origin was eventually found to have a tiny squamous cell carcinoma of the thymus. Thus, even a small thymic carcinoma can exhibit highly aggressive behavior. It should be included in the differential diagnosis of malignant cardiac tamponade of unknown origin.

PURPOSE The antitumor effect of etoposide is increased by maintaining a low blood level, whereas high peak levels may cause myelotoxicity. We investigated whether a constant low blood level could be obtained by the administration of oral etoposide three times daily. PATIENTS AND METHODS Nineteen patients with non-small-cell lung cancer were treated with oral etoposide (25 mg three times daily for 21 days) as monotherapy or in combination with cisplatin 80 mg/m2. A pharmacokinetic model that predicted the mean blood concentration (Cmean) was developed in the 10 patients on etoposide monotherapy and validated in the nine patients on combination chemotherapy. Pharmacodynamic relationships were evaluated in each group. RESULTS Etoposide dose per body-surface area ranged from 45 to 63 mg/m2/d (median, 53), but did not correlate with plasma level. Cmean was 1.1 +/- 0.3 micrograms/mL. Peak concentrations ranged from 0.6 to 2.5 micrograms/mL. The intrapatient coefficient of variation for plasma etoposide concentrations was 22% +/- 10%. Cmean was accurately estimated as follows: Cmean = 0.098 + 0.413 x C0 + 0.458 x C2 (r = .97, P = .0001), where C0 and C2 represent concentrations before and 2 hours after administration. This model was unbiased (mean predictive error [MPE], 0.0 microgram/mL) and precise (root mean square error [RMSE], 0.1 microgram/mL). Leukopenia was the major toxicity. The surviving fraction of leukocytes (SF; nadir count/pretreatment count) was correlated to Cmean as follows: SF = 0.87 - 0.34 x Cmean (r = .67, P = .03) in the monotherapy group and SF = 0.64 - 0.33 x Cmean (R = .77, P = .03) in the combination chemotherapy group. Two and four patients treated with monotherapy and combination chemotherapy showed responses, respectively. All responders had a Cmean > or = 1.0 microgram/mL. CONCLUSION Hyperfractionated oral etoposide achieveda stable plasma level that could be predicted by measurement at only two times.

PURPOSE A phase I study was conducted to determine the maximum-tolerated dose (MTD) of a 14-day continuous infusion of etoposide, and to evaluate the pharmacokinetics in patients with lung cancer. PATIENTS AND METHODS Etoposide was administered continuously through a central venous catheter using a pump. The starting dose level was 300 mg/m2 over 14 days, with dose escalations of 100 mg/m2 over 14 days until unacceptable toxicities occurred. Pharmacokinetic studies were performed in all patients. RESULTS Twenty-one patients, 20 with non-small-cell lung cancer and one with refractory small-cell lung cancer, received 37 courses. No World Health Organization (WHO) grade III or greater toxicity occurred at doses up to 400 mg/m2 over 14 days. At 700 mg/m2 over 14 days, all four patients experienced grade III or IV leukocytopenia, and two developed grade III stomatitis. No cumulative toxicity was observed. A steady concentration of etoposide was achieved 24 hours after the start of chemotherapy, and it was significantly correlated with surviving fractions of leukocytes (r = -.64, P = .001) and platelets (r = -.68, P < .001). The leukocyte count at the termination of chemotherapy predicted the nadir count (r = .93, P < .001). CONCLUSION Steady blood levels of etoposide were maintained for prolonged periods, during 14-day continuous infusions. Leukocytopenia and stomatitis were dose-limiting. Nadir counts and surviving fractions of leukocytes were predicted by the leukocyte count at the end of chemotherapy and the concentration of etoposide, respectively. The recommended dose for phase II trials is 600 mg/m2 over 14 days.

We conducted a phase II study to evaluate the antitumor activity and safety of concurrent continuous infusion of cisplatin and etoposide in advanced non-small-cell lung cancer (NSCLC). Cisplatin (30 mg/m2 daily) and etoposide (80 mg/m2 daily) were given as a 24-h continuous infusion for 72 h to 48 patients with previously untreated advanced NSCLC. Of the 46 evaluable patients, 9 achieved a partial response, for an overall response rate of 20% (95% confidence interval, 9.4%-33.9%). The median duration of response was 23 weeks. The median duration of survival for all patients was 34.4 weeks. The major toxicity was hematologic. Leukopenia (WHO gradeor = 3) was observed in 22 patients (48%) and thrombocytopenia (WHO gradeor = 3), in 13 patients (28%). In all, 20 patients (43%) experienced severe anemia (WHO gradeor = 3). Nonhematologic toxicity mainly consisted of moderate to severe alopecia in 33 patients (72%) and moderate to severe nausea and vomiting in 25 patients (54%). No significant nephrotoxicity was seen. We conclude that a 72-h concurrent continuous infusion of cisplatin and etoposide does not appear to be active against advanced NSCLC.

The stable L-ascorbic acid glucoside produced by the action of the cyclomaltodextrin glucanotransferase (CGTase, EC 2.4.1.19) from Bacillus stearothermophilus was crystallized from an aqueous solution. Determination of the molecular structure by single crystal X-ray analysis showed the compound to be 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G). The crystals are orthorhombic, space group P2(1)2(1)2(1), with unit-cell dimensions a = 11.929 A, b = 24.351 A, and c = 4.864 A. The D-glucopyranose residue has the 4C1 conformation. These conclusions are in good agreement with those based on the 13C-NMR spectrum. The general physicochemical properties of crystalline AA-2G are reported.

The relationship between the clinical parameters and chest film appearance was studied in patients with activ pulmonary tuberculosis. Patients with extended disease were often malnourished and had weak tuberculin reaction accompanied by lymphopenia. They excreted a large amount of mycobacterial bacilli and a longer period was required for negative conversion of sputum culture. We confirmed that the criteria for chest roentgenogram classification established by the Japanese Society for Tuberculosis ("Gakkai Classification") is useful in the estimation of the risk of infection and the prognosis of tuberculosis patients.(Internal Medicine 31 : 185-188, 1992)

The pharmacokinetics of a 72-hour infusion of 240 mg/m2 etoposide administered concurrently with 90 mg/m2 cisplatin was studied in 12 lung cancer patients. The area under the curve (AUC), elimination half-life, steady state concentration, systemic clearance, renal clearance of etoposide and distribution volume at steady state were 225.4 +/- 39.2 micrograms x h/ml, 8.1 +/- 3.4 h, 3.1 +/- 0.6 micrograms/ml, 18.8 +/- 3.1 ml/min/m2, 3.1 +/- 1.4 ml/min/m2, 9.6 +/- 3.8 l/m2, respectively, which were in accordance with those reported previously in patients treated with etoposide alone. Although concentration at 24 hours, total bilirubin level and total protein level were correlated with the AUC which in turn correlated with hematologic toxicity, the variables were not predictive of hematologic toxicity. We conclude that the concomitant administration of cisplatin at a dose level of 30 mg/m2/day might not affect the pharmacokinetics of prolonged etoposide infusion.

To determine the presence of chest wall and mediastinal invasion by lung cancer and to establish the origin of chest tumors, we studied 12 patients with intrathoracic tumors by using chest CT combined with artificial pneumothorax. Six patients had primary lung cancer, two had metastases, and one each had neurofibroma, pericardial cyst, chondroma of the rib, and malignant mesothelioma. All 12 tumors abutted the chest wall or mediastinum and could not be separated by conventional CT. Between 400 and 800 ml of air was injected into the pleural space before a second CT scan was obtained. No invasion was found at surgery in cancers that were separated from chest wall or mediastinum on CT scans. Surgery revealed chest wall invasion in three patients in whom the CT scans showed that the tumor was not separated from the chest wall. Only one patient with a tumor that was not separated from the mediastinum on CT did not have mediastinal invasion: in this case, only adhesions were found at surgery. Thus, in the eight patients with primary lung cancer and metastasis, sensitivity, specificity, and accuracy were 100%, 80%, and 88%, respectively. In four patients with mediastinal or pleural tumor, CT combined with pneumothorax was useful for establishing the origin of tumors. In all, 11 of the 12 patients were correctly evaluated by using this method. No complications occurred, except for mild chest discomfort in one patient. This study suggests that chest CT combined with artificial pneumothorax is useful for the evaluation of the extension of lung cancer into the chest wall and mediastinum and for the diagnosis of the site of origin of intrathoracic tumors.

We have followed 106 recipients of allogeneic bone marrow transplantation (BMT), and observed 47 episodes of interstitial pneumonitis (IP) in 37 patients. Cytomegalovirus (CMV) pneumonitis was seen in 18 episodes in 18 patients, of whom 10 patients were diagnosed by bronchoalveolar lavage (BAL), 7 patients by autopsy, and 1 patient by sputum culture. There was one varicella-zoster virus pneumonitis diagnosed by autopsy. However, we could find no apparent etiology of pneumonitis in the other 18 patients. The median interval between BMT and episodes of IP was 74 days (range, 23-578 days) for CMV pneumonitis, and 180 days (range, 41-428 days) for idiopathic pneumonitis (p less than 0.05). BAL was more sensitive than transbronchial lung biopsy in the diagnosis of CMV pneumonitis, and CD4/CD8 ratio in BAL fluid was inverted in all episodes of CMV pneumonitis. Computed tomography (CT) scans were performed in 31 episodes in 26 patients, and all scans revealed abnormalities. CT scans were more sensitive than routine chest X-rays against micro- or small-nodular patterns, air bronchogram, and air alveologram (p less than 0.05). CT scan and arterial blood gas analysis were most useful and necessary in approaching the problem of pneumonitis in allogeneic marrow transplant patients. Based on these findings, when CMV pneumonitis is suspected, it is recommended to perform BAL for the final diagnosis of CMV pneumonitis.

A total of 42 evaluable patients with previously untreated advanced non-small-cell lung cancer were treated with a combination of cisplatin (80 mg/m2, day 1), vinblastine (5 mg/m2, days 1 and 15), and ifosfamide (1.2 g/m2, days 1-3). In all, 1 complete response and 15 partial responses were obtained, for an overall response rate of 38% (95% confidence limits, 23.6%-54.4%). The median duration of response was 15 weeks, and the median overall survival was 56 weeks. Toxicity mainly consisted of moderate to severe alopecia in 28 patients (67%), moderate to severe nausea and vomiting in 27 subjects (64%), and leukopenia comprising less than 1,000 leukocytes/mm3 in 6 cases (14%). In all, 16 patients (38%) had microscopic hematuria (WHO grade 1), but no hemorrhagic cystitis was documented. Although this three-drug combination appears to have moderate antitumor activity against non-small-cell lung cancer, the addition of ifosfamide to the combination of cisplatin and vinblastine did not seem to improve the response rate.

肺癌患者136例についてッ反, DNCB皮膚反応, PHA反応, T細胞の検索をか色行した.DNCB皮膚反応, PHA反応は肺癌例が対照例に比べ低下を示した.ツ反, PHA反応, T細細数は病期により差を生じた.放射線照射によりツ反陽性率は低下し, PHA反応も低下したが, 数ヶ月で回復を示した.生存率は病期の進行に従い低下を示した.III期症例においてはM0群とM1群に生存率の差を認めた.またIII期症例のうちPHA反応の高い群は予後がよかった.

The action of Pseudomonas isoamylase on branched cyclomaltohexaoses (α-cyclodextrins, cG 6 s) with side chains of various lengths and the reverse condensation reaction between malto-oligosaccharides (G 2 -G 7 ) and cG 6 have been studied. The rates of reaction for the liberation and the attachment of maltotriose were maximal in both the hydrolysis and the condensation reactions, and the activity decreased with increasing length of the side chain. The values of V max (U/mg) for the hydrolytic reactions for G 2 -, G 3 -, G 4 -, and G 5 -cG 6 were 2.6, 690, 320, and 290, respectively, and the values of K m (m m ) were 72, 204, 92, and 47, respectively. The structures of the new branched cG 6 s (G 4 -cG 6 and G 5 -cG 6 ), obtained through the condensation reaction, were identified by means of enzymic analyses, and 13 C-n.m.r. and f.a.b.-mass spectra. The haemolytic activities of these branched cG 6 s are reported.