Search

Carotenoids are naturally occurring pigments and essential for light-harvesting and photoprotection in photosynthesis of plants, algae, and bacteria. Carbonyl-containing carotenoids exhibit unique excited state properties due to the occurrence of intramolecular charge transfer (ICT) in the excited state. In the present study, we performed femtosecond pump-probe spectroscopy on the short-chain polyene compound 2-(all-trans-β-ionylideneetinylidene)-indan-1,3-dione with three conjugated double bonds and two carbonyl groups, denoted as C15Ind in acetone and in n-hexane. The spectroscopic properties of C15Ind both in polar and nonpolar solvents suggests an ICT character based on the observations of the stimulated emission due to the coupled 1Ag-/ICT state. In acetone, an additional excited state was found to be located below the 1Ag-/ICT state. The ultrafast triplet generation via the 1nπ* state was also observed both in acetone and in n-hexane, while the amplitude of the triplet transient absorption of C15Ind was rather small compared with those in retinal and Retinyl-1 reported previously. Thus, an ICT character of carbonyl-containing carotenoids may prevent a triplet generation upon excitation into the optically allowed 1Bu+ (S2) state.

Background The ACTS-CC 02 trial demonstrated that S-1 plus oxaliplatin (SOX) was not superior to tegafur-uracil and leucovorin (UFT/LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) and subgroup analysis according to the pathological stage (TNM 7th edition) for treatment efficacy. Patients and methods Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, five cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2/day of S-1 on days 1-14, every 21 days, eight cycles). The primary endpoint was DFS and the patients’ data were updated in February 2020. Results A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the final analysis. With a median follow-up time of 74.3 months, the 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group [stratified hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.76-1.11; P = 0.3973], and the 5-year OS rates were 78.3% and 79.1%, respectively (stratified HR 0.97; 95% CI 0.76-1.24; P = 0.8175). In the subgroup analysis, the 5-year OS rates in patients with T4N2b disease were 51.0% and 64.1% in the UFT/LV and SOX groups, respectively (HR 0.72; 95% CI 0.40-1.31). Conclusion Our final analysis reconfirmed that SOX as adjuvant chemotherapy is not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer. The 5-year OS rate was similar in the UFT/LV and SOX groups., Highlights • This final analysis reconfirmed that SOX is not superior to UFT/LV in high-risk stage III colon cancer in terms of DFS. • With a median follow-up time of 74.3 months, the 5-year OS rate was similar in both groups. • The 5-year OS rates in patients with T4N2b disease were 51.0% and 64.1% in the UFT/LV and SOX groups, respectively.

Recent advances in adjuvant chemotherapy for early colon cancer have widened physicians' recommendations on the regimen and duration (3 or 6 months) of the treatment. We conducted this prospective study to evaluate whether the 12-gene recurrence score (12-RS) assay affected physicians' recommendations on adjuvant treatment selection., Patients with stage IIIA/IIIB or stage II colon cancer were enrolled. After the patients discussed adjuvant treatment with their treating physicians, the physicians filled in the questionnaire before assay indicating the treatment recommendation. When the 12-RS assay results were available, the physicians again filled in the questionnaire after assay. The primary endpoint was the rate of change in treatment recommendations from before to after the assay, with a threshold rate of change being 20%. Patients with stage IIIA/B to II were enrolled in a ratio of 2 :1., Overall, the treatment recommendations changed in 40% of cases after obtaining 12-RS assay results. Recommendations were changed in 45% (80/178; 95% confidence interval, 37% to 53%; P < 0.001) and 30% (29/97; 95% confidence interval, 21% to 40%; P < 0.001) of patients with stage IIIA/B and II colon cancer, respectively. Patients with stage IIIA/B cancer had significantly more change than those with stage II cancer (P= 0.0148). From before to after the 12-RS assay, the percentage of patients whose physicians reported being confident in their treatment recommendations significantly increased from 54% to 81% in stage IIIA/B (P < 0.001) and from 65% to 83% in stage II (P < 0.001)., Our study confirmed the usefulness of the 12-RS assay in aiding the physician-patient decision-making process for tailoring adjuvant chemotherapy for stage IIIA/B colon cancer.

The aim of this study was to investigate the relationship between heparanase expression and prognostic factors in endometrial cancer, as well as the relationship between heparanase expression during phases of the normal endometrial cycle. Immunohistochemical analysis of 166 endometrial cancers and 34 normal endometria in various phases of growth was performed. The heparanase expression in the late-proliferative phase of normal endometria was found to be significantly higher than in either the early-proliferative or the secretory phases (P = .012 and P = .044, respectively). Heparanase expression was also significantly higher in endometrial cancer patients with tumors of an advanced FIGO stage (P = .0003) and high FIGO grade (P = .004) and with cancers showing either deep myometrial invasion (P = .023), lymph node metastasis (P = .006), lymphvascular space involvement (P = .048), or positive peritoneal cytology (P = .010). The disease-free and overall survival rates of patients with intense heparanase expression were significantly lower than those of patients with absent or moderate heparanase expression (P = .004 and P = .002, respectively). Heparanase may participate in normal endometrial remodeling and can serve as an indicator of the aggressive potential and poor prognosis of endometrial cancers.

Environmental changes in lake-catchment systems due to climatic, tectonic, and anthropogenic activities (processes) have been imprinted on lacustrine sediments. Long continuous observation in a small pond-catchment system at Kobe, Japan following the 1995 Kobe earthquake provides good data on environmental changes. These records are available for establishing a mathematical model in which the rate of sedimentation varies in two stages before arriving at the pre-earthquake stage. The model’s calculations are fairly consistent with observational results, indicating that the model is acceptable. The 1995 earthquake is faintly recorded in the physical properties of sediments obtained in the system (increase in density and slight change in grain size). A combination of grain density (or mineral content) and grain size may be useful as an indicator for the occurrence of comparatively large earthquakes in tectonically active and climatically humid areas. The Tong-hai earthquake of 1970 in Yunnan, China was detected in the combination (density increase and grain size decrease) for the core sediments obtained from Qilu-he. The Kanbun earthquake of 1662 in Lake Biwa catchment was also detected in the corresponding data from some cores obtained from Lake Biwa, Japan.

We present an RGB multi-color electroluminescence (EL) display, in which a blue organic EL display was combined with color changing media (CCM). The CCM were basically made up of organic fluorescent media which changed the emission color from blue to green or red. For the blue organic device, we improved a multi-layer structure in which a distyrylarylene (DSA) emitting layer included a slight amount of an amino-substituted DSA dopant. We achieved a high efficiency of 6 Im/W and a half life time of 20 000 h at an initial luminance of 100 cd/m 2 . Furthermore, the device showed a very fast response time of less than 600 ns. It is possible to operate a simple-matrix panel with 500 lines under a video-rate driving. In order to realize the simple-matrix panel with a large number of micro-pixels, we found new fabrication methods for micro-patterning of the CCM and a cathode. We succeeded in patterning the CCM by a photolithographic method. In addition, the cathode patterning method was developed, by which the cathode was found to be automatically separated to form the pixels by the use of inter-insulator ribs formed on anodes. By using the latter method for the fabrication of a blue mono-color display, we realized a 5 inch QVGA (quarter VGA) display, which imaged video-rate pictures with 256 gray scale. To our knowledge, this is the first report of an organic EL display with high resolution, video-rate pictures (60 frames/s), a large number of pixels (240 × 960) and full gray scale (256).

To examine the correlation between histopathology and magnetic resonance imaging (MRI) measured tumor size and define whether patients with Stage IB1 cervical cancer with an MRI-measured tumor sizeor = 2 cm can be candidates for less-radical surgery.The authors retrospectively reviewed 200 patients with Stage IB1 cervical cancer who underwent radical hysterectomy (class III) and pelvic lymphadenectomy. The largest diameter of the tumor was determined by MRI in 52 consecutive cases.Regarding risk factors for parametrial involvement, only tumor size and age are known before definitive surgery without conization. Multivariate analysis of these risk factors revealed that both tumor size and old age were independently associated with parametrial involvement. Eighty-eight patients had a tumor sizeor = 2 cm and an ageor = 50 years, two of which (2.3%) had parametrial involvement. In 52 consecutive patients, a significant correlation between histopathology- and MRI-measured tumor size was found (r = 0.787). Twenty-three patients had an MRI-measured tumor sizeor = 2 cm, none of which had parametrial involvement.Patients with Stage IB1 cervical cancer lesions with a tumor sizeor = 2 cm measured by MRI and ageor = 50 years can be treated with less-radical surgery.

To investigate the greatest therapeutic efficacy, we investigated the effect of scheduling on the cytotoxic interaction between hyperthermia and seven different platinum complexes in vitro and in vivo using the FSaII murine fibrosarcoma cells. Hyperthermia treatment (43 degrees C, 1 h) was administered at various times relative to exposure of the cells to the IC90 (at 37 degrees C, 1 h) of each platinum complex. Greater-than-additive killing of FSaII cells was obtained with cis-diamminedichloroplatinum (II) (CDDP) and hyperthermia when the drug and heat exposure were overlapping simultaneous. The same cell killing effect with carboplatin and hyperthermia resulted from heat exposure up to 5 h prior to, simultaneous with, or immediately after the drug exposure D-Tetraplatin and K2PtCl4 were synergistic with hyperthermia only if the drug and heat exposure were simultaneous. PtCl4(Nile Blue)2 and hyperthermia produced greater-than-additive cell killing if the heat and drug exposure occurred in immediate sequence, simultaneously, or with drug exposure up to 5 h prior to heat exposure. PtCl4(Rh-123)2 and hyperthermia produced greater-than-additive cell killing if the drug and heat occurred in immediate sequence, overlapping, or simultaneously. PtCl4(Fast Black)2 and hyperthermia were additive over a wide range of scheduling from heat exposure 2 h prior to 5 h after drug exposure. When animals bearing FSaIIC tumours were treated with single doses of CDDP (10 mg/kg). carboplatin/PtCl4(Nile Blue)2 (50 mg/kg), PtCl4(Rh-123)2/PtCl4(Fast Black)2 (100 mg/kg) under various combined schedules with hyperthermia treatment (43 degrees C, 30 min), similar cytotoxicity patterns were observed. To administer hyperthermia at a time when the drug concentration in the tumour tissue is at peak level, careful scheduling of systemically administered anticancer drugs with hyperthermia is needed. Modelling studies can identify the stringency/flexibility of drug/heat scheduling to achieve synergistic tumour cell killing.

The majority of extreme ultraviolet (EUV) lithography mask blank defects originate from chemical mechanical polishing (CMP) of the substrate. The fact that CMP has not yet been able to yield EUV substrates with low defect counts highlights the challenges of polishing doped fused silica surfaces. Here we investigate alternative techniques based on processing either the substrate or coatings of amorphous silicon thin films and inorganic metal oxides. In particular, we evaluate a novel polymer-based non-abrasive a-Si CMP process, a photo-induced dry etching of substrate protrusions, a smoothing coat of spin-on or capillary coated Inpria metal oxide solution, CO2 laser polishing of the substrate surface, and annealing an a-Si thin film surface in reducing atmospheres. Although CMP still remains the best process with respect to overall process integration, these techniques have the potential to support CMP in solving the substrate defectivity issue and help pave the way to commercializing EUV mask blanks.

The cytotoxic and mutagenic properties of the anticancer drug cis -diammine-dichloroplatinum (II) (cisplatin) are mediated by bifunctional adducts between purines. Experiments performed in this study employed a new repetitive thermal-cycling technique to detect cisplatin adduct formation following exposure of cells in culture ( in vivo ) or following treatment of purified DNA ( in vitro exposure). The initial goal of this study was to determine if cisplatin-DNA adduct formation could be measured accurately using phosphorimaging over a broad concentration range. If this proved possible, it would then be feasible to determine if adduct formation differed within chromatin compared with purified DNA. There were no significant differences in the cisplatin-DNA adduct pattern induced in closed circular or linear double-stranded plasmids in vitro , suggesting that this type of tertiary structural change does not affect the formation of adduct sites. Sequence-specific DNA adduct formation within a human repetitive DNA target sequence, alphoid DNA, following cisplatin treatment of prostate cancer cells in culture ( in vivo ) and treatment of purified DNA in vitro revealed consistent increases in adduct formation over a broad concentration range, validating the experimental technique. Comparing preferences for cisplatin adduct site formation under these different conditions of exposure demonstrated statistically significant differences. Similar differences were detected for cisplatin repair-deficient Xeroderma pigmentosum cells treated in cell culture, indicating that in vivo / in vitro preferences for adduct site formation are not the result of DNA repair in vivo .

Oxygen profiles of the rat mammary 13672 carcinoma were determined using a pO2 histograph prior to treatment and 24 h and 48 h after i.p. administration of a single dose of cyclophosphamide (300 mg/kg). The tumors were severely hypoxic at 24 h post the administration of cyclophosphamide. There was little increase in oxygenation of the tumors at 48 h post therapy compared with 24 h post therapy indicating that reoxygenation after cyclophosphamide was occurring very slowly in this tumor. Carbogen breathing improved the oxygenation of the tumors under each of the conditions studied. Administration of the perflubron emulsion (8 ml/kg) produced little or no change in the oxygenation of the tumors under normal air breathing conditions. However, the addition of carbogen breathing to administration of the perflubron emulsion increased the oxygenation of the tumors to levels equal to or greater than carbogen breathing at the mean/median pO2's. Perhaps most significantly, administration of the perflubron emulsion with carbogen breathing increased the oxygenation of the most hypoxic regions of the tumors but carbogen breathing alone did not. The growth delay of the Lewis lung carcinoma increased with increasing dose.of the perflubron emulsion along with cyclophosphamide (3 x 150 mg/kg) and carbogen breathing (6 h). This combination treatment was most effective when the cyclophosphamide was prepared in the perflubron emulsion. The number of lung metastases decreased in a manner parallel with increased efficacy of the treatment toward the primary tumor.

Drug resistance is a major problem in cancer therapy. The MCF-7/CDDP cell line, a subline of the MCF-7 human breast carcinoma cell line which is resistant to cis-diamminedichloroplatinum(II), is also resistant to carboplatin, D-tetraplatin and to a lesser degree to melphalan, thiotepa and BCNU compared with the MCF-7 parental cell line. This resistance persists both under normally oxygenated conditions and after 2 h of exposure to hypoxic conditions prior to exposure to the antitumor alkylating agents under normally oxygenated conditions. When the MCF-7 parental cells and MCF-7/CDDP cells were treated with SR-4233 (20 muM) or etanidazole (5 mM) for 2 h prior to and during exposure to the antitumor alkylating agents there was no change in the sensitivity and resistance patterns of the cell lines. However, if the MCF-7 parental cells and the MCF-7/CDDP cells were exposed to SR-4233 (20 muM) or etanidazole (5 mM) for 2 h under hypoxic conditions followed by release of the hypoxia and exposure to the antitumor alkylating agents for 1 h under normally oxygenated conditions the resistance of the MCF-7/CDDP was reversed so that both the MCF-7 parental and MCF-7/CDDP cell lines were essentially equally sensitive to the six antitumor alkylating agents. These results indicate that non-cytotoxic concentrations of modulators such as SR-4233 or etanidazole may be useful in reversing resistance to the.

The purpose of the present study was to evaluate the efficacy of diagnostic laser conization and the obstetric outcomes of patients undergoing diagnostic laser conization during pregnancy.The study population consisted of a consecutive series of 47 patients who presented with histologically proven carcinoma in situ microinvasive carcinoma and were treated with laser conization during pregnancy.Diagnostic laser conization was performed at 3-28 weeks (median, 13 weeks) of gestation. Intraoperative blood loss of500 ml was observed in two cases (4.3%); however, hemotransfusion was not required in either case. In the early postoperative period, two miscarriages due to preterm premature rupture of the membrane were observed. In the late postoperative period, one spontaneous abortion, three preterm deliveries, and one neonatal death were observed. All the poor obstetric outcomes were observed in the case of patients who underwent conization in the first trimester. The pathology report for the laser conization revealed that two patients (4.3%) had invasive carcinoma. Of the 47 patients, 29 (61.7%) had positive cervical margin, and 13 required postpartum surgical intervention. All patients treated were disease-free at the time of the subsequent follow-up.The results of the present study suggest that laser conization in pregnant patients is feasible and is comparable to cold-knife conization and loop electrosurgical excision procedures with regard to the rates of complication and obstetric outcomes. Furthermore, they indicate that the optimal time for conization is probably the second trimester.

Although laparoscopic total extraperitoneal repair (TEP) has been reported to have a low recurrence rate and relatively little postoperative pain, there have been few studies reported regarding contralateral occurrence after TEP. Although a high incidence of occult contralateral hernias has been reported in the literature, it is unknown whether occult hernias have any significance in clinical settings. The aim of this study was to evaluate the incidence of contralateral occurrence after TEP for unilateral inguinal hernia. We retrospectively reviewed the medical charts of 157 TEPs between April 2003 and May 2009. No patients had undergone contralateral exploration during TEP for unilateral inguinal hernias. Five (3.2%) of 157 unilateral TEPs developed a hernia on the contralateral side. In three patients, the initial hernia was on the right side, and in two it was on the left side. In four patients the initial hernia was indirect, and in one it was direct. The mean duration to contralateral occurrence was 12.2 months. Three patients had contralateral occurrence within 6 months after the primary TEP, while in two over a year passed before contralateral occurrence. All five patients had undergone TEP for contralateral occurrence. The mean operation time was 87.2 min, and there was little intraoperative blood loss. There were no complications during and after the second TEP. The incidence of contralateral occurrence after TEP was found to be low. TEP is a valuable procedure with a low contralateral occurrence rate, and repeated TEP for contralateral occurrence can be performed easily.

Cyclic J-R curves for compact specimens of a 2 1 2 CrMo steel were obtained by varying the stress ratio and the crack-growth rate under displacement as a control parameter. The results were compared with the monotonic J-R curve and the upper-limit characteristic of elastic-plastic fatigue-crack growth. The significance of the cyclic J-R curve was clarified. In the case of ductile tearing, the cyclic J-R curve is gradually changed to the monotonic J-R curve, and unstable fracture can occur on the monotonic J-R curve. The stress ratio is of particular importance to the transitional behaviour.

The chemokine receptors CXCR4 and CCR7 have been suggested to play an important role in cancer progression but their expression in human endometrial cancer has not been fully characterized. The aim of this study was to investigate CXCR4 and CCR7 expression in endometrial cancers.We immunohistochemically investigated the expression of CXCR4 and CCR7 protein in 166 endometrial cancers and analyzed the correlation with various observed clinicopathological features, including patient outcome. Fresh tumor specimens were obtained from 55 of the 166 endometrial cancer patients, and the expression levels of the CXCR4 and CCR7 genes were also examined in this subgroup.Our results indicate that CXCR4 and CCR7 transcripts levels are significantly higher in tumors that express the corresponding protein products. CXCR4 and CCR7 protein expression levels were found to be significantly lower in patients with endometrial tumors of a high grade. Consistent with this, the overall survival rates were significantly better in patients exhibiting higher levels of CXCR4 and CCR7 expression.We thus hypothesize that CXCR4 and CCR7 protein levels are suppressed in high-grade endometrial tumors, but that the expression of these receptors per se may not be a crucial role in tumor progression or metastasis in these cancers.

Perlecan is a major heparan sulfate proteoglycan (HPSG) of the basement membrane (BM) and binds to various cytokines and growth factors via its heparan sulfate glycosaminoglycan (HS-GAG) chains. The aim of this study was to investigate BM HS-GAG expression in endometrial cancers. We investigated the expression of BM HS-GAG by immunohistochemistry in 109 endometrial cancers and analyzed correlations with various clinicopathological features. The HS-GAG expression index was significantly lower in cases of advanced stage, high-grade, deep myometrial invasion, positive peritoneal cytology, lymph vascular space invasion and lymph node metastasis. There was no association between HS-GAG expression status and patient outcome. Decreased HS-GAG expression of BM is associated with tumor progression, but is not be a useful prognostic factor in patients presenting with endometrial cancer.

The magnetic phase diagram of the solid solutions of Ce(Ru 1− x Pd x ) 2 Si 2 has been established as a function of the composition from magnetic susceptibility, specific heat and 29 Si NMR measurements. An onset of weak antiferromagnetic (AF) order with T N ≈ 3 K has been found for 0.05 ⩽ x ⩽ 0.20.

Pharmacokinetic and clinical evaluation of an injectable cephem antibiotics, cefozopran (SCE-2787, CZOP), was conducted in newborn patients and the following results were obtained: 1. Clinical results The clinical efficacy of CZOP was evaluated in one each patient with intrauterine infection and suspected septicemia. The efficacy was "excellent" in both patients. No clinically serious adverse drug reactions of signs and symptoms and abnormal alterations of the laboratory test values were recognized. 2. Pharmacokinetics CZOP was intravenously given to newborn patients at doses of 25.0, 20.0, and 18.75 mg/kg. The blood CZOP concentrations were 44.7 +/- 7.0 micrograms/ml (n = 3), 48.3 micrograms/ml and 48.2 micrograms/ml at one hour after administration, respectively. The elimination half life (T 1/2) was 4.22 +/- 1.17 hours (n = 3) in the patients given 25.0 mg/kg and 2.74 hours in the patient given 20.0 mg/kg. The urinary drug excretion rate was 44.5 +/- 8.7% and 31.3 +/- 9.7% of dose within 8 hours after administration of 25.0 mg/kg and 20.0 mg/kg, respectively.

In this paper, we present a novel design for a signal processor based on rapid-single-flux-quantum (RSFQ) circuits for a compact neutron diffraction system with an array of 10B-enriched MgB2 nanowire neutron detectors. By introducing an RSFQ signal processor, the system is able to accommodate a large number of detectors and determine the kinetic energy of each incident neutron. The processor consists of quasi-one-junction SQUIDs (QOSs), time-to-digital converters, and a multiplexer. A QOS is connected to each detector that operates at 27 K. The QOS picks up a voltage impulse with a width smaller than 2 ns generated across a detector and creates an SFQ pulse for RSFQ signal processing. The diffraction patterns are determined by the position and the kinetic energy of the incident neutrons. The time-to-digital converter is used to measure these energies by the time-of-flight method. Time resolution down to tens of picoseconds is possible, even with an array of detectors, and it is easy to multiplex signals in the time domain. We successfully demonstrated the RSFQ signal processor in liquid helium, and also tested a prototype, consisting of the processor connected with four MgB2 nanowire detectors in a Gifford-McMahon cryocooler, by irradiating a focused pulsed laser instead of neutrons, and obtained preliminary experimental results.

Apoptosis is induced by various anticancer agents or radiation through the tumor suppressor gene p53-dependent pathway and is also induced by other factors, including transforming growth factor-beta 1 (TGF-beta 1). In this study, the authors investigated whether TGF-beta 1 would induce apoptosis in gastrointestinal cancer cells, and its relation to the status of the p53 gene.The induction of apoptosis by TGF-beta 1 was determined in 12 gastrointestinal cancer cell lines using DNA ladder formation. Status of the p53 gene was examined by sequencing of cDNA from p53 mRNA and expressions of TGF-beta 1 mRNA and TGF receptors I and II mRNAs were determined by Northern blot analysis and the reverse transcriptase-polymerase chain reaction analysis, respectively.Of 12 cell lines, wild-type p53 was present in 3 lines, point mutation was detected in 7 lines, and p53 mRNA was absent in 2 lines. TGF-beta 1 was expressed in all 12 lines, but both TGF receptors I and II were expressed in only 6 lines. Addition of TGF-beta 1 induced DNA ladder formation only in KATOIII cells, with deleted p53 mRNA, but expressed TGF receptors I and II.These findings show that TGF-beta 1 induces apoptosis in gastric cancer cells through TGF-beta receptors I and II and a p53-independent pathway.

The interaction of cis-1,1-cyclobutanedicarboxylato(2R)-2-methyl-1,4- butanediammineplatinum(II) (NK121) and cis-diammine(glycolato)platinum(II) (254-S), analogues of cis-diamminedichloroplatinum(II) (CDDP), with hyperthermia was examined in vivo. Antitumor activity of the platinum complexes at the maximum tolerated dose (MTD) with or without hyperthermia was evaluated by the tumor growth delay assay using B16F10 melanoma growing in the legs of C57BL/6J mice. MTD of CDDP, NK121 or 254-S at the single intraperitoneal injection with hyperthermia was 8, 50 or 30 mg/kg, respectively. Treatment of the tumor-bearing limb at 43 degrees C for 30 min resulted in a tumor growth delay of 1.1 days. A single dose of CDDP produced a 3.3-day tumor growth delay. When CDDP was injected just before hyperthermia (43 degrees C, 30 min), the growth delay increased to 5.5 days (1.7-fold increase). With NK121, there was a 1.5-day growth delay. In combination with hyperthermia, the tumor growth delay by NK121 was 3.2 days (2.1-fold increase). Injection of 254-S led to a growth delay of 3.5 days, and this delay was extended to 5.7 days (1.6-fold increase) when combined with hyperthermia. Changes in serum blood urea nitrogen (BUN) were determined 5 days after intraperitoneal drug administration with or without hyperthermia. A single administration of CDDP 8 mg/kg resulted in an elevated BUN level, and this was enhanced in combination with hyperthermia (66.3 mg/dl, 2.7-fold over control). NK121 50 mg/kg at 37 degrees C did not result in elevation of BUN, but mild nephrotoxicity was noted in combination with hyperthermia (40.3 mg/dl, 1.6-fold increase over control). The administration of 254-S 30 mg/kg resulted in an elevated BUN level, and this elevation was enhanced in combination with hyperthermia (48.6 mg/dl, 2.0-fold increase over control). Our data showed that NK121 and 254-S as well as CDDP produced greater tumor growth delay together with hyperthermia than did the drug alone. Though these new compounds were designed with reduced nephrotoxicity, attention should be paid to increased nephrotoxicity when combined with hyperthermia.

The effect of PSK, a protein-bound polysaccharide and an immunomodulator, on lymphocytes was examined in vitro for 36 patients with gastric cancer and 26 with colorectal cancer. Cultured lymphocytes with PSK at 100 micrograms/ml increased the level of DNA synthesis, as determined by the 3H-thymidine uptake, from 0.9 to 3.0 fold, compared to the PSK non-treated cells. The increase was 1.36 +/- 0.46 fold for the gastric cancer cases and 1.37 + 0.45 fold for the colorectal cancer cases, and these levels were significantly the finding of 1.93 + 0.55 fold for a control group consisting of 15 healthy volunteers (P0.01). When the 1.3 fold increase of 3H-thymidine uptake was defined as the PSK-reactive group, 52.8% (19/36) of the patients with gastric cancer and 50.0% (13/26) for colorectal cancer were found in the PSK-reactive group. The PSK-reactive group demonstrated no relation to the age and sex of the patients, tissue differentiation type or tumor advancement. Our findings thus show that the in vitro activation of lymphocytes by PSK can help identify the candidates with either gastric or colorectal cancer who are the best suited to undergo immunochemotherapy including treatment with PSK.

DNA ploidy pattern was determined by flow cytometry and p53 overexpression was investigated immunohistochemically in 145 primary gastric cancers. Aneuploid patterns were found in 78 (65%) and diploid patterns in 67 (46%). Metastasising to lymph nodes was observed more frequently in cases with aneuploid tumors, as compared to those with diploid tumors (p0.01). DNA ploidy patterns were related to overexpression of p53. The incidences of overexpression of p53 in aneuploid tumors and diploid ones were 65% and 33%, respectively (p0.05). Thus, we suggest that gastric carcinomas with the aneuploid pattern have mutation of tumor suppressor gene p53 and high potential to metastasize to lymph nodes.

The appearance of a second cancer in patients who had undergone curative operation for the first gastric cancer is one of the crucial problems for the clinician. We analysed data on 910 patients with gastric cancer treated with curative resection, with respect to the risk factors for second primary cancer and the prognosis. Of 910 patients, 69 (7.6%) died with a second primary cancer. In patients with a second primary cancer, there were more men and age was more advanced, compared to the survivors. The gastric tumor was larger, the serosal invasion was more prominent and lymphatic involvement was more frequent. The postoperative 5-year survival for patients with a second primary cancer was 60.9%, the 10-year rate was 31.9% and the 15-year was 19.6%. Multivariate analysis revealed that risk factors for a second primary cancer was advanced age, male sex and a larger tumor. Our findings suggest that during the follow-up of patients with gastric cancer treated by curative resection and risk factors, a second primary cancer may occur in other organs, in addition to a recurrence of the first cancer.

The rat 13762 mammary carcinoma and the rat 9L gliosarcoma were grown subcutaneously in a hind limb of female, Fisher 344 rats. The oxygen content of the tumors was determined using an Eppendorf pO2 histograph. Fifty-to-sixty oxygen measurements were made per tumor and there were 8-to-10 animals per group. The percent of pO2 readingsor = 5 mmHg in the mammary carcinoma was 49%, this was decreased to 34% by administration of the hemoglobin preparation (8 ml/kg) and further decreased to 29% when carbogen (95% O2/5% CO2) breathing was added to administration of the hemoglobin preparation. The percent of pO2 readingsor = 5 mmHg in the gliosarcoma was 49%, this was decreased to 24% by administration of the hemoglobin preparation and further decreased to 0% when carbogen breathing was added to administration of the hemoglobin preparation. Therapeutic response was assessed over a single-dose range of radiation therapy (10, 20 and 30 Gray). The dose modifying factor produced by the hemoglobin preparation/air was 1.6 and by the hemoglobin preparation/carbogen was 2.7 in the rat 13762 mammary carcinoma. The dose modifying factor produced by the hemoglobin preparation/air was 1.9 and by the hemoglobin preparation/carbogen was 2.9 in the rat 9L gliosarcoma. Administration of a hemoglobin-based oxygen carrier reduced tumor hypoxia and increased tumor response to radiation therapy.

Purpose: A Phase I study was undertaken to determine the maximum tolerated dose of the hypoxic cell sensitizer etanidazole which could be administered with carboplatin and cyclophosphamide, to determine whether adequate serum levels of etanidazole were achieved to allow for alkylating agent sensitization, and whether pretreatment with etanidazole altered carboplatin pharmacokinetics. Methods and Materials Patients received 2 g/m 2 of intravenous etanidazole followed by a second dose of 4 g/m 2 90 min later, followed by intravenous carboplatin (300 mg/m 2 ) and cyclophosphamide (600 mg/m 2 ) for four treatment cycles. Patients received an additional two cycles of carboplatin and cyclophosphamide without etanidazole. Results: Two patients who received a total of 24 g/m 2 of etanidazole developed Grade 1 neurotoxicity, and therefore etanidazole doses were not escalated further. The grade of granulocytopenia was worse after cycles with etanidazole than after those without ( p = 0.03), but clinical outcome was not different. Etanidazole levels were adequate for alkylating agent sensitization (> 70 ug/ml) in all patients for the majority of the 7 h of testing. Pharmacokinetic data suggested t12α and t12β for carboplatin were prolonged after pretreatment with etanidazole. Conclusion: Etanidazole, 2 g/m 2 followed by 4 g/m 2 90 min later, is safe and results in adequate serum levels for alkylating agent sensitization. Neurotoxicity appears to prevent dose escalation of etanidazole, and an interaction between etanidazole and carboplatin may have enhanced neurotoxicity in these patients.

Serum carcinoembryonic antigen (CEA) levels were determined preoperatively in 221 patients with well-differentiated gastric cancer. The mean preoperative serum CEA level was 15.9 +/- 88.5 ng/ml (1.0-1,133.0 ng/ml) for all patients, and the incidence of an elevated CEA (5 ng/ml) was 11.8% (26/221). The CEA-positive patients had larger tumors, a more prominent serosal invasion, more frequent lymphatic and vascular involvement, less expansive tumor growth and higher rates of lymph node and hepatic metastases than did the CEA-negative patients. Thus, the CEA-positive patients had a more advanced stage of disease, and 61.5% underwent noncurative resection (vs. 11.3% in CEA-negative patients). The survival rate of the CEA-positive patients was lower than that of the CEA-negative ones (p0.01). As the multivariate analysis revealed the preoperative CEA level to be an independent prognostic factor for survival, an assay for this antigen prior to surgery is to be recommended.

Three human tumor cell lines made resistant to cis-diamminedichloroplatinum(II) (CDDP), SCC-25/CP, MCF-7/CP, and C13, are more sensitive to rhodamine-123 [tetrachloroplatinum(II)] [(PtCl4(Rh-123)2] than are the corresponding parental cell lines. The CDDP-resistant cells have higher intracellular concentrations of PtCl4(Rh-123)2 for the same exposure than do the parent cells. Each of the CDDP-resistant cell lines has an increased level of cytochrome c oxidase activity compared with the parent cell lines, indicating that the resistant cells have greater mitochondrial mass or activity than the parent cells. In fact, there was a linear correlation between the increase in cytochrome c oxidase activity and the increased sensitivity to PtCl4(Rh-123)2 in the CDDP-resistant lines. Exposure of the cells to each of the mitochondrial effectors, chloramphenicol, FCCP, oligomycin, or antimycin prior to and during exposure to CDDP or PtCl4(Rh-123)2 had variable effects on the cytotoxicity of the platinum complexes in the parental lines. However, there was a consistent decrease in the cytotoxicity of PtCl4(Rh-123)2 in the CDDP-resistant cells in the presence of the mitochondrial effectors such that, in some cases, the CDDP-resistant lines were now less responsive to PtCl4(Rh-123)2 than were the parent cell lines. These studies indicate that mitochondrial alterations may be an important component of CDDP resistance in these cell lines and that PtCl4(Rh-123)2 may represent a prototype platinum complex useful in the treatment of CDDP resistant tumors.

Rat 13672 mammary carcinoma tumors were grown subcutaneously in the hind legs of female Fischer 344 rats to a volume of about 1 cm3. Tumor oxygenation was measured using an Eppendorf PO2 histograph. Tumor oxygen measurements were made under four conditions: (a) normal air breathing, (b) carbogen breathing, (c) after intravenous administration of a perflubron emulsion (8 ml/kg) with air breathing and (d) after intravenous administration of a perflubron emulsion (8 ml/kg) with carbogen breathing. Tumor oxygenation was examined without treatment or 24 h and 48 h after treatment with cyclophosphamide (300 mg/kg, i.p.) or cisplatin (8 mg/kg, i.p.] or after the fifth dose of a daily regimen of 3-Gy irradiation (5 x 3 Gy). Under normal air-breathing conditions 49% of the tumor had a PO2 < or = 670 Pa (5 mm Hg). The degree of hypoxia in the tumors increased after each treatment such that 24 h after treatment 65%-85% of the oxygen readings were < or = 670 Pa and 48 h after treatment 60%-74% of the oxygen readings were < or = 670 Pa. Administration of the perflubron emulsion/carbogen atmosphere increased the oxygen content of the tumors both without treatment and after each of the treatments. A knowledge of tumor oxygen content over the course of treatment and the ability to increase tumor oxygen should allow for the development of more rational treatment combinations and better treatment outcomes.

Oxygen profiles of the rat mammary 13672 carcinoma were determined using a pO2 histograph prior to treatment and 24 hrs. and 48 hrs. after 2 or 5 fractions of 3 gray given once daily. The tumors were much more hypoxic at 24 hrs. post radiation therapy than prior to therapy. There was little increase in the oxygenation of the tumors at 48 hrs. post therapy compared with 24 hrs. post therapy indicating that reoxygenation was occurring very slowly in this tumor. Carbogen breathing improved the oxygenation of the tumors under each of the conditions studied. Administration of a perflubron emulsion (8 ml/kg) produced little or no change in the oxygenation of the tumors under normal air breathing conditions. However, with the addition of carbogen breathing to administration of the perflubron emulsion there was an increase in the mean/median pO2's of the tumors to levels equal to or greater than carbogen breathing alone. Perhaps most significantly administration of the perflubron emulsion with carbogen breathing increased the oxygenation of the most hypoxic regions of the tumors but carbogen breathing alone did not.

Drug resistance is a major problem in cancer therapy. The MCF-7/CDDP cell line, a subline of the MCF-7 human breast carcinoma cell line which is resistant to cis-diamminedichloroplatinum(II), is also resistant to carboplatin, D-tetraplatin and to a lesser degree to melphalan, thiotepa and BCNU compared with the MCF-7 parental cell line. This resistance persists both under normally oxygenated conditions and after 2 h of exposure to hypoxic conditions prior to exposure to the antitumor alkylating agents under normally oxygenated conditions. When the MCF-7 parental cells and MCF-7/CDDP cells were treated with SR-4233 (20 muM) or etanidazole (5 mM) for 2 h prior to and during exposure to the antitumor alkylating agents there was no change in the sensitivity and resistance patterns of the cell lines. However, if the MCF-7 parental cells and the MCF-7/CDDP cells were exposed to SR-4233 (20 muM) or etanidazole (5 mM) for 2 h under hypoxic conditions followed by release of the hypoxia and exposure to the antitumor alkylating agents for 1 h under normally oxygenated conditions the resistance of the MCF-7/CDDP was reversed so that both the MCF-7 parental and MCF-7/CDDP cell lines were essentially equally sensitive to the six antitumor alkylating agents. These results indicate that non-cytotoxic concentrations of modulators such as SR-4233 or etanidazole may be useful in reversing resistance to the.

We used B 16 melanoma cells both in vitro and in vivo to determine whether Flavone acetic acid (FAA) can increase the cytotoxicity of mitomycin C (MMC) under normothermic and hyperthermic (HT) conditions. The significantly increased cytotoxicity of MMC combined with FAA and HT seems to be mainly related to activation of alkylating species under FAA mediated hypoxic condition.

Using atomic absorption spectrophotometry, we determined the concentration of platinum in tissues obtained at autopsy of 4 patients with recurrent gastric cancer. Patients had been given intraperitoneal cis-diamminedichloroplatinum(II) (cisplatin, CDDP). There was no correlation between the concentration of platinum and the dose of CDDP. Platinum was distributed in all organs examined, the highest amount being in the liver. Thus, when CDDP is administered intraperitoneally for treatment of patients with malignant disease, the toxicity to various organs, including the liver and the kidney, needs to be considered.

The combined effects of flavone acetic acid (FAA), a synthetic flavonoid, and hyperthermia on B16 melanoma cells were investigated. In vitro, FAA alone at concentrations below 100 micrograms/ml was not cytotoxic with a 60-min exposure at 37 degrees C. Hyperthermia at 43 degrees C for 60 min enhanced the cytotoxicity of FAA only at concentrations over 100 micrograms/ml. Inhibition of the growth of B16 melanoma solid tumor by FAA and/or hyperthermia was examined in vivo. FAA (100-200 mg/kg) inhibited tumor growth in a dose-dependent manner. The combined treatment of FAA (200 mg/kg) and hyperthermia (43 degrees C, 15 min) significantly inhibited tumor growth compared to a treatment of FAA or hyperthermia alone. The maximum antitumor effect of FAA combined with hperthermia was obtained when FAA was administered 2 or 4 h before heat. The significantly increased cytotoxicity of FAA combined with hyperthermia seems to relate to specific decreases in tumor blood flow, a reduction in tumor pH, and an increased tumor temperature, without altering pH in the normal tissues. This combined treatment of FAA and hyperthermia warrants further study for treating subjects with solid tumors.

We designed a simple and reliable method of intrahepatic biliary drainage for patients with obstructive jaundice owing to a recurrent gastric cancer. This approach can be used for selected patients treated by partial gastrectomy and reconstructive surgery, using the Billroth II procedure and antecolic anastomosis. Anastomosis between the intrahepatic bile duct and the afferent jejunal loop is performed at the anterior edge of the liver, thus facilitating the prevention of recurrence of jaundice caused by tumor infiltration. Application of this technique led to a long-term palliation, control of the jaundice and a fairly normal life.

A comparison of the chemosensitivity of well-differentiated human gastric cancer tissues was made between histological venous invasion positive (v(+)) and negative (v(-)) tissues, using the succinate dehydrogenase inhibition (SDI) test. These tissues obtained at the time of surgery were exposed to six anticancer drugs: carboquone (CQ), adriamycin (ADM), mitomycin C (MMC), aclacinomycin A (ACR), cisplatin (DDP) and 5-fluorouracil (5-FU). Chemosensitivity was judged to be positive when the succinate dehydrogenase (SD) activity of the drug exposed cells decreased to below 50% of that of control cells. Decrease in the SD activity was more apparent in the v(-) tissues than in the v(+) tissues, exposed to the anticancer drugs and in particular to ADM (P less than 0.01), MMC (P less than 0.02) and DDP (P less than 0.05). The sensitivity rates to all six anticancer drugs were lower in the v(+) tissues. The resistance rates to all drugs tested were 0% in the v(-) tissues, but 21% in the v(+) tissues. In light of these observations, patients with gastric cancer of the well differentiated type and the histological venous invasion, will probably show a less positive response to cancer chemotherapy.

The antitumor effects of 5-fluorouracil (5-FU) and its analogues when combined with dipyridamole (DP) were investigated using B16 melanoma cells, in vitro and in vivo. First, the enhancement of 5-FU cytotoxicity by DP was examined in vitro. Cell growth was suppressed significantly by combining 5-FU and a nontoxic dose of DP (2.5 micrograms/ml) as compared to 5-FU alone. Next, the effect of DP was examined in vivo in combination with 5-FU, tegafur (FT) and UFT. UFT had the most remarkable antitumor effect when given in a single equimolar dose. Although DP alone did not affect tumor growth, the growth inhibition by antitumor drugs was augmented by DP. DP enhanced the antitumor effect of UFT significantly (P less than 0.05), and combination treatment with UFT and DP proved to be the most effective regimen for inhibiting growth of B16 melanoma. Combination treatment with UFT and DP shows promise for clinical cancer.