"Transmural air leak": a computed tomographic finding following endoscopic submucosal dissection of gastric tumors.

BACKGROUND AND STUDY AIMS: A small amount of free air, visible on CT but not on plain chest radiography, which appeared following endoscopic submucosal dissection (ESD) of a gastric neoplasm without endoscopically visible perforation, was defined as a "transmural air leak", and a prospective, consecutive entry study was performed to determine its incidence and clinical significance. PATIENTS AND METHODS: Between January 2006 and September 2008, ESD was performed for 246 gastric lesions in 246 consecutive patients. Abdominal CT scan was performed 1 day after ESD. In addition, chest radiography and blood biochemistry tests were performed at different time points before and after ESD. RESULTS: Two hundred and nineteen lesions (89 %) were curatively removed by ESD. Among the total of 246 patients, we encountered endoscopically visible perforation during ESD in 2 patients (0.8 %), and clinically suspected perforation diagnosed by the presence of free air on chest radiography but invisible during ESD in 3 patients (1 %), while transmural air leak was observed in another 33 (13 %). Air leak occurred in cases where resection size was larger, procedure time longer, and the muscularis propria on the ulcer base was exposed at the end of ESD. Patients with air leaks developed pyrexia at a higher rate than those without (36 % vs. 16 %, P = 0.018). These patients recovered with antibiotics and required no endoscopic or surgical intervention. The presence of an air leak did not affect the duration of hospital stay. CONCLUSIONS: A transmural air leak was observed in 13 % of the patients undergoing ESD. Larger resection size, prolonged procedure time, and exposure of the muscularis propria on the ulcer base were risk factors for transmural air leak, but the outcome of patients with this complication was good.

Analysis of the interaction of an anti-HIV peptide, T22 ([Tyr5, 12, Lys7]-polyphemusin II), with gp120 and CD4 by surface plasmon resonance.

We have previously found that T22 ([Tyr5, 12, Lys7]-polyphemusin II) exhibits strong anti-human immunodeficiency virus (HIV) activity comparable to that of 3'-azido-2', 3'-dideoxythymidine (AZT). The inhibition mechanism of T22 on HIV-replication has not been elucidated precisely yet, and hence the target molecules of T22 have not been identified. However, our recent research suggested that T22 exerts its effect by blocking virus-cell fusion at an early stage of HIV infection and that T22 might interact with an HIV envelope protein and/or a T-cell surface protein, both of which are critical for HIV infection. In this paper we demonstrated that T22 binds specifically to both gp120 (an envelope protein of HIV) and CD4 (a T-cell surface protein) and that both bindings can be inhibited by an anti-T22 antibody, using biosensor technology (BIAcoreTM) based on the principles of surface plasmon resonance. Linearization by the BIAcoreTM system (BIAlogue software) and nonlinear least squares analysis by curve fitting with exponential equations showed that both interactions have close dissociation constants (approximately 10(-7) M). The present study suggests that T22 inhibits the virus-cell fusion process through binding to both gp120 and CD4.

Synthesis and cytotoxicity of 1,2-disubstituted naphth[2,3-d]imidazole-4,9-diones and related compounds.

As part of our continuing search for potential anticancer drug candidates that are selective against slowly growing solid tumors, we have synthesized several series of 1- and 2-substituted derivatives of the lead structure, 1-ethyl-2-methylnaphth[2,3-d]imidazole-4,9-dione (5). Their cytotoxic activity in the National Cancer Institute's in vitro cancer cell line panel is reported. In general, substitution of various alkyl, phenyl, or benzyl moieties did not improve activity, and compound 5 remains the most active naphth[2,3-d]imidazole-4,9-dione derivative. However, high levels of activity and selectivity were found with several related 2-(acylamino)-3-chloro-1,4-naphthoquinones (2f-j). Compound 2i, 2-[(2-fluorophenyl)acetamido]-3-chloro-1,4-naphthoquinone, has been selected for further in vivo testing and as an additional lead compound for further structural modification.

Antitumor agents. 16. Steroidal alpha-methylene-gamma-lactones.

Several novel steroidal alpha-methylene-gamma-lactones and related derivatives have been synthesized as potential steroid alkylating antitumor agents. The synthesis of these compounds involved the convenient Reformatsky-type reaction between ethyl-alpha-(bromomethyl)acrylate and the proper steroidal ketones. In vitro assay for the cytotoxicity of these compounds against the growth of tissue culture cells originating from human epidermoid carcinoma of the larynx (H.Ep.-2) has shown significant activity. Cytotoxicity was improved at least sixfold with the introduction of lipophilic steroidal character. Preliminary in vivo tumor assay also indicated that these compounds were active against Walker 256 carcinosarcoma in rats and were inactive against both L1210 lymphoid leukemia and Ehrlich ascites carcinoma in mice. However, the simple alpha-methylene-beta,beta-dicarbethoxy-gamma-butyrolactone significantly inhibited Ehrlich ascites tumor growth.

Antitumor agents. 44. Bis(helenalinyl) esters and related derivatives as novel potent antileukemic agents.

Bis(helenalinyl), bis(plenolinyl), bis(2,3-dihydrohelenalinyl), and bis(2,3,11,13-tetrahydrohelenalinyl) esters have been synthesized in an effort to elucidate the role of the two enone alkylating centers, beta-unsubstituted cyclopentenone and alpha-methylene gamma-lactone, as well as the significance of the diester linkage with respect to the enhanced in vivo P-388 lymphocytic leukemia antileukemic activity of bis(helenalinyl) malonate (2) against P-388 lymphocytic leukemia in the mouse. The bisesters (2-5; 7, 8; 10, 11) are, in general, more potent and less toxic than their corresponding parent alcohols (1, 6; 9; 14). The beta-unsubstituted cyclopentenone ring and the alpha-methylene gamma-lactone moiety in the bisesters play important roles for the enhancement of the P-388 antileukemic activity. Removal of the enone double bonds in both alkylating centers of 2 gave rise to inactive compounds. Except for 2, the potent antileukemic activity of the bis(helenalinyl) esters (3-5) appears to be independent of the ester chain length.

Gene amplification of Japanese non-Hodgkin lymphoma with involvement of the BCL2 gene.

Twenty cases of Japanese non-Hodgkin's lymphoma with B cell markers were studied with respect to their immunoglobulin heavy (IgH) chain gene loci on chromosome 14 and BCL2 loci on chromosome 18. All of the 20 cases showed IgH gene rearrangement on at least one of the alleles. Molecular analysis using two chromosome 18-specific DNA probes (pFL1 and pFL2) showed rearrangement of the BCL2 region in three of 20 cases. As these three samples showed the rearranged allele of the IgH gene comigrating with that of the BCL2 gene, polymerase chain reaction (PCR) was carried out to amplify the juncture between IgJH on chromosome 14 and BCL2 on chromosome 18. In all of these three cases, gene amplification between the two loci was found to occur, indicating that molecular mechanisms involved in this type of chromosomal translocation in Japan might be similar to cases in the United States (U.S.) in a limited number of cases. Furthermore, this amplification technique revealed minimal tumor cells circulating in peripheral blood, even though lymphoma cells could not be identified morphologically. Thus, the PCR technique is useful for both the detection of minimal tumor cells as well as for the determination of the molecular nature of chromosomal translocation in some of Japanese cases.

Effect of a new bombesin receptor antagonist, (E)-alkene bombesin isostere, on amylase release from rat pancreatic acini.

The short-chain pseudopeptide, [D-Phe6, Leu13 psi (CH2NH)Leu14]bombesin(6-14) (RDI), is reported to be a potent antagonist of bombesin, and development of this type of compound has greatly contributed to the investigation of biological actions of bombesin and its related peptides. We recently synthesized (E)-alkene bombesin isostere by replacing the peptide bond with an (E)-double bond: [D-Phe6, Leu13 psi [(E)CH = CH]Leu14] bombesin(6-14) (EABI). The present study examined the effect of EABI on amylase release from rat pancreatic acini. EABI showed no agonistic activity at concentrations up to 1 microM, and RBI showed slight agonistic activity at concentrations > 10 nM. EABI caused a dose-dependent inhibition of amylase release stimulated by 0.1 nM bombesin, with an IC50 of 6.7 +/- 1.7 nM, and induced almost-complete inhibition at 0.3 microM. RDI caused a dose-dependent inhibition of amylase release, with an IC50 of 68.7 +/- 16 nM. EABI caused a parallel and rightward shift of the entire dose-response curve of bombesin-stimulated amylase release, and the degree of the shift was dependent on the concentrations of EABI. EABI (100 nM) and RDI (100 nM) inhibited amylase releases stimulated by gastrin-releasing peptide (1 nM) and neuromedin-C (1 nM). In contrast, amylase release stimulated by cholecystokinin octapeptide (0.1 nM), carbachol (10 microM), vasoactive intestinal peptide (1 nM), and gastrin-17 (10 nM) was not inhibited by EABI and RDI. The results indicate that EABI is a potent and specific bombesin receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of structural modulation on biological activity of bombesin analogues with (E)-alkene bond.

The specific bombesin receptor antagonist, (E)-alkene bombesin isostere (EABI-1), [D-Phe6,Leu13psi[(E)CH=CH]Leu14]bombesin(6-14) is a potent antagonist in terms of inhibition of bombesin-stimulated amylase release from rat pancreatic acini. This study examined the effects of EABI-1 (L-L diastereomer) and three novel bombesin analogues on amylase release in rat pancreatic acini. EABI-2 is a L-D diastereomer of EABI-1. EABI-3 is an analogue, of which leucine at position 13 of EABI-1 was replaced with valine. EABI-4 is a L-D diastereomer of EABI-3 (L-L). The order of agonist potency was EABI-2>EABI-3>EABI-4. EABI-1 showed no agonist activity at concentrations up to 100nM. On the other hand, all of four analogues had antagonist activity. The order of antagonist potency was EABI-1>EABI-3>EABI-4>EABI-2. EABI-1 was a complete antagonist, EABI-2 and EABI-3 were partial agonists, and EABI-4 had a weak agonist effect. The present study provides a useful information on the future development of peptide analogues for anticancer agents and biological tools for investigating actions of bombesin family peptides.

Antitumor agents XLII: Comparison of antileukemic activity of helenalin, brusatol, and bruceantin and their esters on different strains of P-388 lymphocytic leukemic cells.

Based on the fact that some known antineoplastic agents possess an ester moiety within their structure, the esters of helenalin, a sesquiterpene lactone, and of brusatol and bruceantin, quassinoids, were synthesized and tested for antileukemic activity in the P-388 screen. These agents gave different T/C% values dependent on the P-388 lymphocytic leukemia strain and the host strain of mice used. Later studies demonstrated that the agents caused different degrees of inhibition of nucleic acid and protein synthesis in the various P-388 strains. The higher the degree of inhibition of precursor incorporation into the nucleic acid or protein, the higher was the T/C% value obtained in a given P-388 strain. The study demonstrates the lack of consistency of P-388 lymphocytic leukemia cell lines used in various laboratories and indicates that the inbred strain of mice is a critical factor in the tolerance of drug toxicity and, thus, T/C% obtained.

Antitumor agents XXXVIII: Isolation and structural elucidation of novel germacranolides and triterpenes from Elephantopus mollis.

The ethanolic extract of Elephantopus mollis yielded three novel cytotoxic antitumor germacranolides, molephantin, molephantinin, and phantomolin. The extract also yielded three inactive known triterpenes, beta-amyrin acetate, lupeol acetate, and epifriedelanol, as well as stigmasterol. The structure and stereochemistry of the cytotoxic antitumor agents molephantin, molephantinin, and phantomolin were determined on the basis of chemical transformations and spectral evidence. Preliminary in vivo tumor assays indicated that molephantinin and phantomolin were potent inhibitors of Ehrlich ascites carcinoma and Walker 256 carcinosarcoma. Molephantinin also showed significant antileukemic activity in the P-388 lymphocytic leukemia screen.

Antitumor agents XXX: Evaluation of alpha-methylene-gamma-lactone-containing agents for inhibition of tumor growth, respiration, and nucleic acid synthesis.

Evidence is presented that a number of sesquiterpene lactones isolated from plants and synthesized pyrimidines containing the alpha-methylene-gamma-lactone moiety are potent inhibitors of Walker 256 carcinosarcoma and Ehrlich ascites tumor growth and marginal inhibitors of P-388 lymphocytic leukemia and Lewis lung tumor growth. In vitro aerobic basal respiration and oxidative phosphorylation processes of Ehrlich ascites cells were inhibited by these agents as well as deoxyribonucleic acid polymerase and thymidylate synthetase enzymatic activities. These studies indicate that the alpha-methylene-gamma-lactone moiety, the beta-unsubstituted cyclopentenone ring, and the alpha-epoxycyclopentanone system are the essential moieties for inhibition of these biochemical parameters.

Disseminated necrotizing leukoencephalopathy following irradiation and methotrexate therapy for central nervous system infiltration of leukemia and lymphoma.

The authors report four adult patients with disseminated necrotizing leukoencephalopathy (DNL) following therapy for central nervous system (CNS) involvements of leukemia and lymphoma. Five to fourteen months after starting therapy with 30.6-62.5 Gy of whole brain irradiation and 120-500 mg of intrathecal methotrexate (MTX), DNL developed. Brain CT scans demonstrated a characteristic symmetrical white matter low density area. Furthermore, the brain CT scans disclosed tumorous lesions with contrast enhancement in three cases. In two of the three cases autopsy proved the tumorous lesions to be necrotic foci but not leukemic tumors. Post-mortem neuropathological studies of three patients disclosed characteristic features of DNL: multiple coagulative necrosis in the white matter with myelin degeneration, swollen axons, prominent calcification, and enlarged reactive astrocytes. Three of the four patients obviously received greater doses of whole brain irradiation and intrathecal MTX than patients who remained free from DNL after treatment with whole brain irradiation and/or MTX. Analysis of the etiological factors in this series underscores the prevailing danger of treatment for neoplastic CNS involvement with excessive doses of whole brain irradiation combined with intrathecal MTX.

[A phase II study of mitoxantrone in malignant lymphoma].

A phase II study of mitoxantrone (MIT) was performed in 13 cases of refractory malignant lymphoma, 1 of Hodgkin's disease and 12 of non-Hodgkin lymphoma. The twelve non-Hodgkin lymphomas were previously treated with adriamycin. MIT was diluted in 50 approximately 100 ml saline solution and intravenously administered by drip infusion in 15 approximately 30 minutes. The dose of MIT was 3 mg/m2/day for 5 days (A) or 10 approximately 14 mg/m2/day, for 1 day (B). There were 2 CR, 1 MR, 1 NC and 2 PD among 8 cases treated by schedule A, and two cases were not evaluable. With schedule B, there was 1 MR among 5 cases, and four cases were not evaluable. In the 7 evaluable cases, remission rate was 2/7 (29%) with remission durations of 6+ weeks and 55 weeks. The dose limiting toxicity was granulocytopenia but no serious infection was observed. With schedule A, it was difficult to repeat the treatment every 3 weeks because of the delay in granulocyte recovery. Gastrointestinal toxicities were observed in about half of the treatment courses but they were mild in degree. A prolongation of QTc (greater than 0.44) was observed in 3 cases (4 treatment courses) among 9 cases (10 treatment courses) whose baseline QTc values were within normal limits. Baseline QTc values were above the normal limit in 4 cases and in two of them, QTc showed further prolongation after MIT treatment. No arrhythmia or congestive heart failure was observed.

[The subrenal capsule assay modified with three-dimensional measurement (volume method) and its higher predictivity].

Subrenal Capsule Assay (SRCA) developed by Bogden et al. is a new in vivo sensitivity test for anticancer agents. However, the presence of host reaction on about day 6 is largest problem for this method, and now many researchers are scrutinizing or introducing several modifications for this assay chiefly by immunosuppressing procedures. As one of the means to measure the actual change of the tumor volume and minimize the misreading of host reactions, we introduced three dimensional measurements of the grafts (volume method) instead of original mean diameter measurement. Using this method, prospective quantitative study was made. The results of 16 assays with 15 cases of miscellaneous malignancies showed 94% evaluability and in 22 treatments predictive accuracy was 77%. Assay/clinical correlation coefficient was 0.38 and coincidence of ranking order of the effectiveness was 6/6, with good contrast to those of 78%, 56%, 0.00 and 1/3, by original method respectively. Clinical responses more than PR were obtained in 9 of 15 cases. Two cases are still in CR for two years by assay directed single agent treatments. Many other minor modifications were also adopted and evaluated by quantitative observation of assay/clinical correlations. SRCA with our modifications seemed to have utilities than original.

[Low-dose methotrexate and sequential 5-FU treatment in advanced gastric cancer].

Combination chemotherapy of low-dose methotrexate and sequential 5-FU was given to 16 patients with advanced gastric cancer. Treatment regimen : methotrexate 30 mg/m2 followed 3 hours later with 5-FU, 750 mg and 24 hours later with leucovorin 30 mg/m2. Each drug was administered as a bolus. Treatment was repeated weekly. The median ECOG PS was 3 (range 2-4) and median age was 55.1 years (range 28-87). Of these 16 patients who were evaluated, four had PR, and 5 had MR, giving a response rate of 25%. Of the 7 patients who had been previously treated with a combination of chemotherapy including 5-FU, the figures were 2 PR and 3 MR. This regimen has been well tolerated by the patients. No patient had a WBC nadir of less than 2000 cells/mm3, and no patient had a platelet count nadir of less than one hundred thousand platelets/mm3. No other toxicity was detected.

[Sequential MTX and 5-FU therapy of gastric cancer with systemic bone metastasis and disseminated intravascular coagulation].

UNLABELLED: Sequential therapy consisting of methotrexate (MTX) and 5-FU was performed together with the administration of heparin and FOY in 10 cases of gastric cancer with disseminated intravascular coagulation (DIC) causing systemic bone metastasis. The ages of the subjects ranged from 29 to 65 years (median: 49 years) with systemic bone metastasis and bone marrow carcinosis observed in all cases. Histological types consisted of 6 cases of poorly differentiated adenocarcinoma, 2 cases of signet-ring cell carcinoma, and one case each of mucocellular and tubular adenocarcinoma. Therapy consisted of intravenous injection of 30 mg-100 mg/m2 (one case, 20 mg) of MTX followed three hours later by intravenous injection of 600 mg/m2 of 5-FU weekly. Determination of DIC was made in accordance with the DIC diagnostic standards of the Ministry of Health and Welfare, and determination of tumor effectiveness was based on gastric cancer handling codes. RESULTS: PR was observed in 3 cases. Diffuse metastasis observed in the entire lung field disappeared in one case, while remarkable improvement was observed in systemic bone metastasis in scintigram findings for the other 2 cases. All 3 cases were able to be discharged. Reduction of DIC score and absence of pain were observed in 8 cases. Based on the above, aggressive implementation of this treatment method is suggested.

[Combination chemotherapy with cis-diammine-di-chloro-platinum (II) and bleomycin in advanced head and neck cancer].

Combination chemotherapy of cis-diammine dichloro platinum (II) (CDDP) and bleomycin was given to 10 patients with advanced squamous cell carcinoma of the head and neck. Nine patients had received prior radical radiotherapy, 2 had major ablative surgical procedures, and one had been previously treated with chemotherapy. Responses were as follows (duration in months): 2 CRs (4,6+), 2 PRs (1.5,1.5), and 2 minors. Vomiting related to CDDP was observed in 5 patients, nephrotoxicity and hypocalcemia in one patient were also observed.

[Combination chemotherapy with cisplatin and bleomycin in esophageal cancer].

Combination chemotherapy of cis-diammine dichloro platinum (II) (CDDP) and bleomycin was given to 10 patients with advanced squamous cell carcinoma of the esophagus. Nine patients had had major ablative surgical procedures, 8 had received prior radiotherapy, and 4 had been previously treated with chemotherapy. Responses were as follows (duration in months): 3 complete (1, 1.5, 7), 1 partial (1.5), and 3 minor. Vomiting related to CDDP was observed in 6 patients, and nephrotoxicity in 2 patients.