Real-world evidence of trifluridine/tipiracil plus bevacizumab in metastatic colorectal cancer using an administrative claims database in Japan.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) are standard therapies for refractory metastatic colorectal cancer (mCRC). No results of large real-world data directly comparing FTD/TPI + bevacizumab (BEV) with FTD/TPI or REG monotherapy have been reported. We evaluated the efficacy and safety of FTD/TPI + BEV in a real-world setting. MATERIALS AND METHODS: This retrospective study used a Japanese claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). Eligible patients were aged 20 years and over with a diagnosis of mCRC, and received their first dose of FTD/TPI or REG from 2014 to 2021. The primary endpoint was overall survival (OS) in a propensity score matching (PSM) population in which PSM was carried out by matching using a 1 : 1 ratio for the FTD/TPI + BEV group and the control group (FTD/TPI or REG) by propensity score. To enhance robustness, sensitivity analyses of OS were carried out using the inverse probability treatment weighted (IPTW) approach and the analysis in the all eligible population. Secondary endpoints included time to treatment discontinuation (TTD), incidence of adverse events, and post-treatment. RESULTS: Eligible population was 2369 for the FTD/TPI + BEV group and 9318 for the control group. The PSM population was 1787 for each group. Median OS (mOS) was longer in the FTD/TPI + BEV group compared to the control group [17.0 versus 11.6 months, hazard ratio (HR) = 0.70, P < 0.001] in the PSM population. Similarly, mOS was longer for the FTD/TPI + BEV group compared to that for the control group in IPTW analyses and in the all eligible population (both HRs = 0.68). Median TTD was 3.3 months for the FTD/TPI + BEV group and 1.8 months for the control group in the PSM population (P < 0.001). CONCLUSIONS: Real-world data showed that FTD/TPI + BEV was significantly associated with OS and TTD compared to FTD/TPI or REG. In clinical practice, FTD/TPI + BEV can be a favorable regimen for refractory mCRC.

New method of on-line quantification of regional wall motion with automated segmental motion analysis.

We have recently developed an automated segmental motion analysis (A-SMA) system, based on an automatic "blood-tissue interface" detection technique, to provide real-time and on-line objective echocardiographic segmental wall motion analysis. To assess the feasibility of A-SMA in detecting regional left ventricular (LV) wall motion abnormalities, we performed 2-dimensional echocardiography with A-SMA in 13 healthy subjects, 22 patients with prior myocardial infarction (MI), and 9 with dilated cardiomyopathy (DCM). Midpapillary parasternal short-axis and apical 2- and 4-chamber views were obtained to clearly trace the blood-tissue interface. The LV cavity was then divided into 6 wedge-shaped segments by A-SMA. The area of each segment was calculated automatically throughout a cardiac cycle, and the area changes of each segment were displayed as bar graphs or time-area curves. The systolic fractional area change (FAC), peak ejection rate (PER), and filling rate (PFR) were also calculated with the use of A-SMA. In the control group, a uniform FAC was observed in real time among 6 segments in the short-axis view (60% +/- 10% to 78% +/- 9%), or among 5 segments in either the 2-chamber (59% +/- 12% to 75% +/- 16%) or 4-chamber view (58% +/- 13% to 72% +/- 12%). The variations of FAC, PER, and PFR were obviously decreased in infarct-related regions in the MI group and were globally decreased in the DCM group. We conclude that A-SMA is an objective and time-saving method for assessing regional wall motion abnormalities in real time. This method is a reliable new tool that provides on-line quantification of regional wall motion.

Predominant inner-half wall thickening of left ventricle is attenuated in dilated cardiomyopathy: an application of tissue Doppler tracking technique.

The importance of the inner half (IH) of the left ventricular (LV) wall has been reported in hearts that contract normally. However, it is difficult to verify this fact in an in vivo human heart with clinical echocardiography. By using a recently developed tissue Doppler tracking technique, we could assess the systolic wall thickening of the IH and outer half (OH) of the LV wall in 11 normal and 7 dilated cardiomyopathic hearts. Percent wall thickening and the fractional contribution of the IH and OH to the transmural wall thickening were calculated. In healthy subjects, percent wall thickening of the IH, OH, and transmural wall of the left ventricle were 75.8% +/- 24.1%, 39.4% +/- 14.4% (P <.001 versus IH), and 57.6% +/- 17.6%, respectively. In patients with dilated cardiomyopathy, those values were 31.3% +/- 17.1%, 31.2% +/- 20.1% (not significant versus IH), and 31.2% +/- 16.5%, respectively. On the other hand, the fractional contributions of the IH and OH were 66.2% +/- 7.7% and 33.8% +/- 7.7% (P <.01 versus IH) in healthy subjects and 50.5% +/- 11.8% and 49.5% +/- 11.8% (not significant versus IH) in patients with dilated cardiomyopathy. Specifically, the IH contributed to the transmural wall thickening nearly twice as much as the OH did in healthy subjects, however, the predominance of IH contribution was attenuated in dilated cardiomyopathy. The tissue Doppler tracking technique is useful in assessing the IH and OH LV wall thickening separately in the clinical situation.

Usefulness of transesophageal echocardiographic monitoring in transluminal endovascular stent-graft repair for thoracic aortic aneurysm.

The endovascular stent-graft has been devised for the treatment of thoracic aortic aneurysm (TAA) to reduce complications associated with conventional surgical repair. The present study assessed the usefulness of transesophageal echocardiography (TEE) for intra- and post-operative examinations in patients treated with transluminal endovascular stent-graft repair for TAA. Nine patients with TAA and 2 with chronic type B aortic dissection were studied. Immediately after stent-graft deployment, perigraft leakage was evaluated with both intraoperative TEE and aortography. In 9 of 11 patients, TEE and aortography immediately after stent-graft deployment revealed the same perigraft leakage results. TEE might therefore be useful for evaluating perigraft leakage and thrombus formation after stent-graft repair for TAA and could be an alternative to aortography, especially for patients with renal dysfunction who have the possibility of contrast agent-induced complications.

Assessment by transesophageal echography of atherosclerosis of the descending thoracic aorta in patients with hypercholesterolemia.

This study assesses atheromatous lesions and aortic stiffness of the descending thoracic aorta (DTA) in patients with hyperlipidemia by transesophageal echography (TEE) and investigates the relations between atherosclerotic lesions and aging or serum cholesterol levels in these patients. Subjects included 16 patients with familial hypercholesterolemia (FH), 15 non-FH hyperlipidemic patients (non-FH), and 17 age-matched normal subjects. With use of TEE, the DTA was divided into 4 longitudinal portions of equal length, and the atheromatous lesions of each portion of DTA were scored according to their character and extension by biplane 2-dimensional TEE. The scores of atheromatous lesions from all 4 portions were added together to give the total atheromatous score. Then, after measuring the instantaneous dimensional changes of DTA in a cardiac cycle by M-mode TEE and blood pressure (BP) by a cuff method, we calculated the aortic stiffness parameter beta = ln(systolic BP/diastolic BP)/([Dmaximum - Dminimum]/Dminimum). The beta was significantly higher in FH and non-FH subjects than in normal subjects. In both FH and non-FH subjects, the total atheromatous score correlated with total serum cholesterol levels (r = 0.64 [p <0.01]; r = 0.58 [p <0.05], respectively). There were significant correlations between age and beta in all 3 groups (FH, r = 0.67 [p <0.005]; non-FH, r = 0.53 [p <0.05]; normal subjects, r = 0.49 [p <0.05]), and the slopes of the regression lines of FH and non-FH subjects were much steeper than those of normal subjects. The incidence of atherosis in the DTA was significantly higher in hyperlipidemic patients than in normal subjects, even among the younger members of the hyperlipidemic population with progressive aortic stiffness.

Effects of nifedipine on mechanical properties of the normal and atherosclerotic descending aorta assessed by transesophageal echocardiography.

We assessed the effects of calcium ion (Ca++) entry blockade (nifedipine) on the static elastic properties of the thoracic descending aorta in 60 subjects classified into 4 groups according to age and complications. The stiffness index (beta), which expresses the mechanical properties of the arterial wall, was calculated from the dimensional changes of the thoracic aorta by transesophageal echocardiography and blood pressure was determined by conventional cuff method. After administration of nifedipine, beta was significantly decreased in all groups. There was a significant correlation between beta at rest and the value of a decrease in beta after nifedipine in the relatively younger and the older groups with complications, but no significant correlation was observed in the older group without complications. Nifedipine directly reduces the stiffness of the descending aorta. The effect is stronger in relatively younger subjects, especially in subjects with risk factors of atherosclerosis and stiff descending aorta at rest. These results suggest that there may be a reversible sclerotic property of the descending aorta, probably caused by high smooth muscle tone before an irreversible atherosclerosis occurs in patients with risk factors promoting atherosclerosis.

Suppression of H-ras-mediated transformation in NIH3T3 cells by a ras ribozyme.

Murine NIH3T3 cells were used to study the effect of ribozymes on H-ras-mediated transformation. Parental 3T3 cells were transfected with the activated H-ras gene. H-ras-transformed cells had altered morphology and increased colony formation in soft agar in contrast to untransfected 3T3 cells. A hammerhead ribozyme (site-specific ribonuclease) designed to cleave codon 12 (GUC) of the activated H-ras RNA was expressed in transformed cells. 3T3 clones expressing the ras ribozyme displayed decreased expression of activated H-ras RNA. The ras ribozyme reversed the transformed phenotype to resemble that of untransfected 3T3 cells. Furthermore, 3T3 cells containing the ras ribozyme were shown to suppress transformation when they were subsequently transfected with activated H-ras. Insertion of a mutant ribozyme largely devoid of cleaving capacity into H-ras-transformed cells resulted in smaller reductions in H-ras gene expression and colony formation in soft agar when compared with the ras ribozyme. Finally, the ras ribozyme alone did not perturb normal 3T3 cell growth. This study suggests the possible utility of anti-oncogene ribozymes as suppressors of tumor cell growth as well as inhibitors of cellular transformation.

Figural characteristics associated with random appearance of dot patterns.

43 subjects judged the amount of visual randomness of dot patterns in two experiments. The properties of stimuli were changed from Exp. 1 to Exp. 2, but the common characteristics associated with visual randomness were found.

Assessment of flow profile of left anterior descending coronary artery in hypertrophic cardiomyopathy by transesophageal pulsed Doppler echocardiography.

This study assessed the flow velocity profiles of the left anterior descending coronary artery (LAD) in 7 patients with nonobstructive hypertrophic cardiomyopathy (HC) and in 6 normal subjects by transesophageal pulsed Doppler echocardiography, and evaluated their characteristics and the hemodynamic determinants. Systolic peak flow velocity of the LAD (7 +/- 30 cm/sec) was significantly lower in patients with HC than in normal subjects (34 +/- 11 cm/s, p < 0.05), and there was a significant inverse correlation between systolic peak flow velocity and the thickness of the ventricular septum (r = 0.81, p < 0.01). In 2 cases of HC with ventricular septal thickness of > 20 mm, a remarkable systolic reverse flow was observed in the LAD. However, there was no significant difference in diastolic peak flow velocity between HC and normal subjects. During early diastole, the acceleration time of LAD flow velocity was significantly prolonged (210 +/- 67 vs 95 +/- 15 ms, p < 0.01) and the acceleration rate was significantly decreased (3.6 +/- 2.0 vs 6.6 +/- 1.8 m/s2, p < 0.02) in patients with HC. The time constant of the left ventricular pressure decay was significantly prolonged in patients with HC (55 +/- 6 ms) compared with normal subjects (39 +/- 2 ms, p < 0.001). In HC, increased intramural perivascular pressure of the thickened ventricular septum during systole may be attributed to systolic LAD flow pattern. However, the early and mid-diastolic LAD flow pattern may be affected by impaired left ventricular relaxation.

Suppression of EJ cells tumorigenicity.

Ribozymes, site-specific ribonucleases, are a new vehicle for the manipulation of gene expression. A hammerhead ribozyme designed to cleave the GUC sequence in codon 12 of activated H-ras RNA was cloned into a plasmid (pH beta Apr-1) and transfected into EJ human bladder carcinoma cells. Expression of the ribozyme dramatically reduced H-ras gene expression and inhibited growth of EJ transformants in vitro. In vivo, the H-ras ribozyme suppressed EJ cell tumorigenicity in nude mice. In contrast, the insertion of a mutant ribozyme with no demonstrable cleavage capacity into EJ cells resulted in smaller reductions in H-ras gene expression and growth inhibition while also suppressing tumorigenicity in nude mice. The ribozyme's effect on tumorigenicity was stable, as the cells were cultured for up to five months in vitro prior to injection into nude mice. These studies define a role for anti-oncogenic ribozymes as a unique class of tumor suppressing agents.

1 alpha,25-dihydroxy vitamin D3 modulation of HLA-DR mRNA induced by gamma-interferon in cultured epithelial tumor cell lines.

Using three cultured epithelial tumor cell lines, we investigated and analyzed the effects of gamma-interferon (gamma-IFN) and 1 alpha,25-dihydroxy vitamin D3 (1,25-(OH)2D3) on the levels of HLA-DR (alpha) mRNA and HLA-DR (beta) mRNA by Northern blot analysis. After treatment with gamma-IFN alone, the levels of the mRNA increased. Treatment with both gamma-IFN and 1,25-(OH)2D3 at the same time resulted in a significant decrease in the levels of mRNA in K-TL-1, IK-TL-2, and M-TL cells as compared to those induced by gamma-IFN alone.

[Detection of drug resistant-genes in cisplatin-resistant colon carcinoma cells by RT-PCR assay. II].

The c-fos, c-Ha-ras and c-myc oncogenes have been proposed to play an important role in DNA synthesis. Expression of c-fos, c-Ha-ras and c-myc genes were compared with the human colon carcinoma cell line HCT8S cells and a subline that was 4.5 resistant to cis-diamminedichloro-platinum (cisplatin). Resistant cells (HCT8DDP) exhibited a 4.0, 2.8 and 1.1 fold in mRNA for these genes when compared with the parent cells by Northern blotting analysis, respectively. The reverse transcription (RT)-PCR method has been demonstrated to quantify a sequence of these oncogenes. This method allowed the detection of gene expression from minimal cells. Thus RT-PCR assay could be an effective device in th early detection of oncogenes to cisplatin-resistance.

[Detection of drug resistant-gene in cisplatin-resistant colon carcinoma cells by RT-PCR assay. I].

Expression of the TS and DNA polymerase beta genes as a drug resistant-gene were compared with the human colon carcinoma cell line HCT8S and a subline that was 4.5 fold resistant to cisplatin. Resistant cells (HCT8DDP) exhibited 3.4 fold and 2.5 fold increase in mRNA for both TS and DNA polymerase beta gene when compared with the parent cells by Northern blotting analysis, respectively. The RT (reverse transcription)-PCR (polymerase chain reaction) method has been modified to quantify a sequence of a drug resistance gene. This method exhibited greater sensitivity than conventional methods (Northern blotting analysis), requiring less than 1 fetogram of mRNA from cell lines. The RT-PCR assay could be an effective device in the early detection of resistance to chemotherapy.

Enhancing effects of fluorescein on beta-lactam rash. I: High incidence of cefclidin rashes in an ophthalmological volunteer trial.

Disseminated maculopapular eruptions were frequently observed in a volunteer trial of cefclidin's use in ophthalmological and neurological examinations (8/12; 67%) It appeared at 8-12 days (mean +/- SD, 9.6 +/- 1.1 days) from the initiation of the trial and subsided within 1-2 days (mean +/- SD, 1.8 +/- 0.4 days). Patch testing with cefclidin produced a +/- reaction in 1 of 8 cases, and the drug-induced lymphocyte stimulation test (DLST) elicited a positive response (SI: 2.8) in 1 of 8 and a weakly positive response (1.8 < or = SI < 2) in 2 of 8. From these findings, it seems likely that the eruptions may be partially mediated by delayed type hypersensitivity (DTH) reactions to cefclidin. No such eruption was observed in the phase II trial of cefclidin where only 2.8% of 1.122 volunteers developed the eruption. The volunteers were given both fluorescein and oxybuprocain in their eyes to measure ocular tension on days -1, 0, 1, 3, 5, 7, 9, 11, 13 and weeks 3, 5, 7 after the initiation of cefclidin. Fluorescein and/or oxybuprocain may affect cefclidin to induce these abnormal reactions in the volunteers.

Characterization of a cisplatin-resistant human ovarian carcinoma cell line expressing cross-resistance to 5-fluorouracil but collateral sensitivity to methotrexate.

In vitro exposure of the TR170 ovarian carcinoma cell line to six intermittent 24-h treatments with a 90% inhibitory concentration of cisplatin (CDDP) (0.15 micrograms/ml; 0.5 microM) resulted in a 2-fold stably resistant subline designated TR170/CP+ (B.T. Hill et al., Int. J. Cancer, 39: 219-225, 1987). Resistance to CDDP in these CP+ cells has now been associated with reduced uptake of 195mCDDP (2-fold; P less than 0.01) and decreased removal of specific Pt-DNA adducts, quantitated immunochemically, indicative of an apparent increased tolerance of CDDP-induced DNA damage. Specifically these resistant cells appeared deficient in removal of the major cis-Pt-(NH3)2d(pGpG) adduct and the difunctional cis-Pt(NH3)2d(GMP)2 lesion, showed less efficiency in removing cis-Pt(NH3)2d(pApG) adducts, but proved as proficient as the parental cell line in removing DNA-DNA interstrand cross-links. Activities of DNA polymerase-alpha and -beta were comparable in both lines, and no significant alterations in glutathione metabolism were identified. Response to acute X-irradiation was not modified in these TR170/CP+ cells, but they showed marked (10-fold) cross-resistance to 5-fluorouracil and, unusually, proved collaterally sensitive (12-fold) to methotrexate. Resistance to 5-fluorouracil was associated with significantly increased thymidylate synthase activity (P less than 0.01), but this was not reflected in altered gene expression, while increased sensitivity to methotrexate was accompanied by increased drug uptake but by unaltered activity and expression of dihydrofolate reductase. These results indicate that exposure to CDDP can result in numerous alterations, both intracellularly and at the cellular membrane, reflected in significant changes in the tumor cells' responses to the cytotoxic effects of a range of antitumor drugs. The clinical relevance of these observations remains to be established.

Common histopathological processes of phenytoin drug eruption.

Fifteen patients (6 males and 9 females) with phenytoin drug eruptions which ultimately resulted in various skin manifestations were analyzed histopathologically. The following types of skin manifestations were noted; 2 cases of toxic epidermal necrolysis, 2 cases of mucocutaneous ocular syndrome, 6 cases of erythema exudative multiform, 3 cases of lichenoid, and 2 cases of the maculopapular type. All of the biopsied specimens from these different skin manifestations exhibited some of the more common histopathological findings: 1) adhesion of the infiltrated cells to the basal layer of the epidermis, 2) cell infiltration into the epidermis, 3) vacuolation of the basal cells, 4) dyskeratotic cells in the epidermis, and epidermal necrosis. Immunohistopathological examinations in 5 typical cases with different skin manifestations revealed that epidermal cells and infiltrating cells were HLA-DR antigen positive. The infiltrating cells in the dermis consisted of almost equal numbers of CD4+ and CD8+ cells; CD8+ cells were predominant in the cells infiltrating into the epidermis. These findings suggest a possibility that the various clinical features in phenytoin drug eruptions may share some common mechanisms.

The utility of an anti-fos ribozyme in reversing cisplatin resistance in human carcinomas.

The results presented here demonstrate that expression of a fos ribozyme limits Fos protein synthesis and enhances sensitivity of A2780DDP cells to antineoplastic agents, including cisplatin. Moreover, the reversal of this resistance is associated with down-regulation of dTMP synthase, DNA polymerase beta, topoisomerase I and hMTII-A, genes previously linked to DNA synthesis and repair. Thus these studies further implicate the role of the c-fos gene in DNA synthesis through modulation of expression of dTMP syntase, DNA polymerase beta and topoisomerase I. Finally, the use of ribozymes to circumvent drug resistance suggests their potential utility as agents to inhibit tumor cell growth.

Reversal of the malignant phenotype by an anti-ras ribozyme.

In this study a ribozyme (catalytic RNA) was designed to site specifically cleave the mRNA of the activated H-ras gene expressed in human bladder carcinoma EJ cells. The optimal conditions for catalytic cleavage by the ribozyme were demonstrated in vitro. A synthetic DNA encoding the ribozyme was cloned into a mammalian expression vector (pH beta APr-1) and transfected into EJ cells. The expressed ribozyme significantly altered the morphology and suppressed the growth of EJ cells in vitro. These cell lines were examined for their malignant potential in athymic (nude) mice by an orthotopic (transurethral) implantation model, which recapitulates the invasive potential of various bladder carcinomas. EJ tumors expressing the H-ras ribozyme were characterized by a marked reduction in tumor take and invasion compared to those formed by control EJ cells. These differences resulted in almost a twofold increase in survival of mice implanted with ribozyme-containing EJ cells. These results further elucidate the role of ras genes in tumorigenicity and invasion, as well as introduce ribozymes as a new class of anticancer agents.

Ribozyme-mediated cleavage of c-fos mRNA reduces gene expression of DNA synthesis enzymes and metallothionein.

The c-fos gene product Fos has been implicated in many cellular processes, including signal transduction, DNA synthesis, and resistance to antineoplastic agents. A fos ribozyme (catalytic RNA) was designed to evaluate the effects of suppressing Fos protein synthesis on expression of enzymes involved in DNA synthesis, DNA repair, and drug resistance. DNA encoding the fos ribozyme (fosRb) was cloned into the pMAMneo expression plasmid, and the resultant vector was transfected into A2780DDP cells resistant to the chemotherapeutic agent cisplatin. The parental drug-sensitive A2780S cells were transfected with the pMMV vector containing the c-fos gene. Morphological alterations were accompanied by significant changes in pharmacological sensitivity in both c-fos- and fosRb-transfected cells. pMAMneo fosRb transfectants revealed decreased c-fos gene expression, concomitant with reduced thymidylate (dTMP) synthase, DNA polymerase beta, topoisomerase I, and metallothionein IIA mRNAs. In contrast, c-myc expression was elevated after fos ribozyme action. Insertion of a mutant ribozyme, mainly capable of antisense activity, into A2780DDP cells resulted in smaller reductions in c-fos gene expression and in cisplatin resistance than the active ribozyme. These studies establish a role for c-fos in drug resistance and in mediating DNA synthesis and repair processes by modulating expression of genes such as dTMP synthase, DNA polymerase beta, and topoisomerase I. These studies also suggest the utility of ribozymes in the analysis of cellular gene expression.