Prognostic factors in patients with advanced and recurrent colorectal cancer receiving last-line chemotherapy.

For patients with advanced/recurrent colorectal cancer, the trifluridine/tipiracil combination tablet (TAS 102) and regorafenib are last-line treatments. This study aimed to clarify prognostic factors in patients receiving last-line chemotherapy. Between April 2014 and December 2016, 47 patients received last-line chemotherapy at Ogaki Municipal Hospital, Japan. The primary outcome was overall survival. To determine factors associated with survival, those considered significant in the univariate analysis (p <0.10), were entered into a multivariate Cox proportional hazards model. KRAS type and the use of opioid formulations were independently and significantly associated with survival in the multivariate analysis. For patients with KRAS-wild relative to KRAS-mutation cancers, the hazard ratio for death was 0.478 (95% CI, 0.249-0.919; p = 0.03). For patients taking opioid formulations, relative to those not, the hazard ratio for death was 3.557 (95% CI, 1.032-12.257; p = 0.04). The median overall survival duration for patients with KRAS-wild (n = 24) and KRAS-mutation (n = 23) cancers were 223.5 days (range: 115-703) and 154 days (range: 51-503), respectively (p = 0.05). This finding provides a useful index to make an early decision on discontinuation of treatment and to guide decisions around agents to use in last-line chemotherapy.

Evaluation of the safety of ramucirumab in Japanese patients with advanced gastric cancer.

As a result of the RAINBOW trial, ramucirumab plus paclitaxel was established as a second-line treatment of advanced gastric cancer. Regarding the safety of ramucirumab plus paclitaxel in the Japanese, a subgroup analysis of the RAINBOW trial was conducted. The incidence of neutropenia was higher in Japanese patients. However, information is lacking concerning the safety of ramucirumab after marketing in Japanese patients. Therefore, the aim of this study was to evaluate the safety of ramucirumab in Japanese patients with advanced gastric cancer. The inclusion criteria were patients diagnosed with advanced gastric cancer who had commenced treatment with ramucirumab plus paclitaxel or paclitaxel only at Ogaki Municipal Hospital (Gifu, Japan) between January 2015 and December 2016. There were 26 patients in the ramucirumab plus paclitaxel group and 22 patients in the paclitaxel only group. Treatment-related adverse events were documented in 100.0% of the patients in the ramucirumab plus paclitaxel group (Grade 3-4, 73.1%) and 90.9 % of the patients in the paclitaxel only group (Grade 3-4, 45.5 %). The most frequently observed adverse event in both treatment groups was anemia. The second common adverse event was neutropenia. The incidence of neutropenia of Grade ≥3 was significantly higher in the ramucirumab plus paclitaxel group than in the paclitaxel only group. In conclusion, the incidence of neutropenia is high. However, we believe that ramucirumab plus paclitaxel can be safely administered.

Risk factors contributing to the development of neutropenia in patients receiving oral trifluridine-tipiracil (TAS-102) chemotherapy for advanced/recurrent colorectal cancer.

Elucidating the factors influencing severe neutropenia could aid in earlier management of neutropenia during oral trifluridine-tipiracil (TAS-102) chemotherapy in advanced and recurrent colorectal cancer (CRC). This study was conducted to assess the risk of TAS-102-induced grade 3 or more neutropenia. Between August 2014 and July 2017, 60 patients underwent oral TAS-102 monotherapy at Ogaki Municipal Hospital, Japan. The patients were divided into two groups based on the development of grade 3 or more neutropenia (9 patients) or not (51 patients). Risk factors for grade 3 or more neutropenia were examined by univariate and multivariate analyses. Creatinine clearance rate (CrCl) before TAS-102 administration significantly correlated with the incidence of Grade 3 or more neutropenia after TAS-102 administration (odds ratio 6.5, 95% confidence interval 1.14-30.00; p = 0.02). Multivariate analysis revealed that a CrCl of lower than 57.1 mL/min before TAS-102 administration (odds ratio 54.06, 95% confidence interval 2.14-1364.2; p = 0.02) was an independent risk factor significantly contributing to the development of grade 3 or more neutropenia, induced by TAS-102. CrCl < 57.1 mL/min in patients with advanced and recurrent CRC who underwent TAS-102 chemotherapy was associated with grade 3 or more neutropenia.

Mutual relationships between structural and functional changes in a PsbM-deletion mutant of photosystem II.

Photosystem II (PSII) is a membrane protein complex that performs light-induced electron transfer and oxygen evolution from water. PSII consists of 19 or 20 subunits in its crystal form and binds various cofactors such as chlorophyll a, plastoquinone, carotenoid, and lipids. After initial light excitation, the charge separation produces an electron, which is transferred to a plastoquinone molecule (QA) and then to another plastoquinone (QB). PsbM is a low-molecular-weight subunit with one transmembrane helix, and is located in the monomer-monomer interface of the PSII dimer. The function of PsbM has been reported to be stabilization of the PSII dimer and maintenance of electron transfer efficiency of PSII based on previous X-ray crystal structure analysis at a resolution of 4.2 Å. In order to elucidate the structure-function relationships of PsbM in detail, we improved the quality of PSII crystals from a PsbM-deleted mutant (ΔPsbM-PSII) of Thermosynechococcus elongatus, and succeeded in improving the diffraction quality to a resolution of 2.2 Å. X-ray crystal structure analysis of ΔPsbM-PSII showed that electron densities for the PsbM subunit and neighboring carotenoid and detergent molecules were absent in the monomer-monomer interface. The overall structure of ΔPsbM-PSII was similar to wild-type PSII, but the arrangement of the hydrophobic transmembrane subunits was significantly changed by the deletion of PsbM, resulting in a slight widening of the lipid hole involving QB. The lipid hole-widening further induced structural changes of the bicarbonate ion coordinated to the non-heme Fe(ii) atom and destabilized the polypeptide chains around the QB binding site located far from the position of PsbM. The fluorescence decay measurement indicated that the electron transfer rate from QA to QB was decreased in ΔPsbM-PSII compared with wild-type PSII. The functional change in electron transfer efficiency was fully interpreted based on structural changes caused by the deletion of the PsbM subunit.

Severe neutropenia: a prognosticator in patients with advanced/recurrent colorectal cancer under oral trifluridine-tipiracil (TAS-102) chemotherapy.

BACKGROUND/AIM: The effect of oral trifluridine-tipiracil (TAS-102)-induced neutropenia on survival of patients with advanced/recurrent colorectal cancer was investigated. PATIENTS AND METHODS: Between August 2014 and May 2016, 41 patients underwent TAS-102 monotherapy at Ogaki Municipal Hospital. Risk factors for survival were examined by univariate and multivariate analyses. RESULTS: In 41 patients, mild neutropenia (grade 1-2) occurred in 10 patients (24.4%), severe neutropenia (grade 3-4) occurred in 13 (31.7%), and 18 (43.9%) did not experience neutropenia. The median overall survival times in the absent, mild, and severe groups were 120 days (95% confidence interval [CI], 67-179), 184 days (95% CI, 94-274), and 299 days (95% CI, 192-404), respectively (p = 0.045). In patients with severe neutropenia, the death hazard ratio was 0.442 (95% CI, 0.201-0.974; p = 0.042). CONCLUSION: In patients with advanced/recurrent colorectal cancer, TAS-102-induced severe neutropenia was associated with superior survival.

Safety of an oral anticancer agent (trifluridine/tipiracil combination tablet) in patients with advanced and recurrent colorectal cancer.

We retrospectively studied the safety of trifluridine/tipiracil combination tablet (TAS-102) monotherapy in patients with advanced and recurrent colorectal cancer. Adverse events to TAS-102 monotherapy were observed in 22 out of 23 cases (95.7%). The most frequent adverse events were neutropenia (69.6%), nausea (53.2%), and malaise (30.4%). Treatment was postponed in 54 (59.3%) out of 91 courses, and in 34 (66.7%) of these 54 courses, the delay in treatment was due to bone marrow suppression. Seven patients with peritoneal metastases suffered from nausea, whilst none of the patients without peritoneal metastases had nausea (p = 0.0139). Nausea and vomiting during a previous chemotherapy cycle was significantly associated with nausea after TAS-102 treatment (p = 0.0007), and the treatment cycles were significantly longer in patients with grade 3 or 4 neutropenia (p = 0.0061). Our results suggest that the incidence of nausea was higher in patients treated with TAS-102. Therefore, it is important to inform patients of the risk of these toxicities and to provide enhanced supportive care. Moreover, we recommend that, for patients with repeated treatment postponement due to neutropenia, the dosage should be fixed based on therapeutic efficacy and prognosis.

Lower-Extremity Torque Capacity and Physical Function in Mobility-Limited Older Adults.

OBJECTIVES: Skeletal muscle weakness and an increase in fatigability independently contribute to age-related functional decline. The objective of this study was to examine the combined contribution of these deficiencies (i.e., torque capacity) to physical function, and then to assess the functional implications of progressive resistance training (PRT) mediated-torque capacity improvements in mobility-limited older adults. DESIGN: Randomized controlled trial. SETTING: Exercise laboratory on the Health Sciences campus of an urban university. PARTICIPANTS: Seventy mobility-limited (Short Physical Performance Battery (SPPB) ≤9) older adults (~79 yrs). INTERVENTION: Progressive resistance training or home-based flexibility 3 days/week for 12 weeks. MEASUREMENTS: Torque capacity was defined as the sum of peak torques from an isokinetic knee extension fatigue test. Relationships between torque capacity and performance-based and patient-reported functional measures before and after PRT were examined using partial correlations adjusted for age, sex, and body mass index. RESULTS: Torque capacity explained (P<0.05) 10 and 28% of the variance in six-minute walk distance and stair climb time, respectively. PRT-mediated torque capacity improvements were paralleled by increases (P<0.05) in self-reported activity participation (+20%) and advanced lower extremity function (+7%), and associated (P<0.05) with a reduction in activity limitations (r=0.44) and an improved SPPB score (r=0.32). CONCLUSION: Skeletal muscle torque capacity, a composite of strength and fatigue, may be a proximal determinant of physical function in mobility-limited older individuals. To more closely replicate the musculoskeletal demands of real-life tasks, future studies are encouraged to consider the combined interaction of distinct skeletal muscle faculties to overall functional ability in older adults.

Cost-effectiveness and safety of the molecular targeted drugs afatinib, gefitinib and erlotinib as first-line treatments for patients with advanced EGFR mutation-positive non-small-cell lung cancer.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, erlotinib and afatinib are standard first-line treatments for EGFR gene mutation-positive non-small cell lung cancer. The present study aimed to compare the cost-effectiveness of using erlotinib, afatinib or gefitinib. The safety of EGFR-TKIs was also investigated. Expected costs were calculated based on data from patients with advanced EGFR mutation-positive non-small-cell lung cancer who were treated with gefitinib, erlotinib or afatinib. Literature was collected to obtain the necessary clinical information for calculating the probability and the validity of each chemotherapy. Median survival time (MST) was used to evaluate the therapeutic effect of the regimens. The cost-effectiveness ratio was calculated using expected costs and MSTs for the three regimens. The cost-effectiveness ratio per month was JPY 386,859.4/MST for afatinib, JPY 264,788.7/MST for gefitinib and JPY 397,039.9/MST for erlotinib. Significant differences were observed between the three groups (p<0.001). The incremental cost-effectiveness ratio (ICER) of gefitinib compared with afatinib per month was JPY 122,070.7/MST. The ICER of gefitinib compared with erlotinib was JPY -69,605.9/MST. Adverse effects of Grade 3 and higher, including diarrhoea (28.6%) and paronychia (14.3%) were observed in the afatinib treatment group. Paronychia (23.1%) was observed in the erlotinib treatment group, while none were observed in the gefitinib treatment group. These findings demonstrate that gefitinib is more cost effective in comparison with the afatinib and erlotinib regimens, although the afatinib and erlotinib regimens were well-tolerated and produce sufficient effects.

High incidence of secondary failure of platelet recovery after autologous and syngeneic peripheral blood stem cell transplantation in acute promyelocytic leukemia.

Secondary failure of platelet recovery (SFPR), which is a delayed decline in platelet count after primary recovery following myeloablative hematopoietic SCT, is a significant problem in allogeneic SCT. However, its clinical characteristics have not been well described in autologous SCT for acute myeloid leukemia. We reviewed 11 consecutive patients who had received autologous or syngeneic SCT for acute promyelocytic leukemia. Seven of 11 patients (64%) had SFPR, which is defined as a decline in the platelet count to less than 30,000/microl for more than 7 days. The median onset of SFPR was day 36 (range, 25-51 days) and the median duration of thrombocytopenia was 13 days (range, 4-25 days). Of nine patients who received busulfan-containing preparative regimens, seven (78%) had SFPR and one had delayed primary platelet count recovery. Neither patient who received cyclophosphamide and total body irradiation as preparative regimens had SFPR. The clinical courses of SFPR were transient and self-limited. SFPR was not associated with relapse of underlying diseases, graft failure or other fatal morbidities. The unexpectedly high prevalence and the characteristics of SFPR may provide additional information on management following autologous SCT for acute myeloid leukemia.

Dimensional contraction by principal component analysis as preprocessing for independent component analysis at MCG.

We propose a noise reduction method for magnetocardiograms (MCGs) based on independent component analysis (ICA). ICA is useful to separate the noise and signal components, but ICA-based automatic noise reduction faces two main difficulties: the dimensional contraction process applied after the principal component analysis (PCA) used for preprocessing, and the component selection applied after ICA. The results of noise reduction vary among people, because these two processes typically depend on personal qualitative evaluations of the obtained components. Therefore, automatic quantitative ICA-based noise reduction is highly desirable. We will focus on the first difficulty, by improving the index used in the dimensional contraction process. The index used for component ordering after PCA affects the accuracy of separation obtained with ICA. The contribution ratio is often used as an index. However, its efficacy is highly dependent on the signal-to-noise ratio (SNR) it unsuitable for automation. We propose a kurtosis-based index, whose efficacy does not depend on SNR. We compare the two decision indexes through simulation. First, we evaluate their preservation rate of the MCG information after dimensional contraction. In addition, we evaluate their effect on the accuracy of the ICA-based noise reduction method. The obtained results show that the kurtosis-based index does preserve the MCG signal information through dimensional contraction, and has a more consistent behavior when the number of components increases. The proposed index performs better than the traditional index, especially in low SNRs. As such, it paves the way for the desired noise reduction process automation.

TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas.

TTF-1, also known as NKX2-1, is a transcription factor that has indispensable roles in both lung development and physiology. We and others have reported that TTF-1 frequently exhibits high expression with increased copy number in lung adenocarcinomas, and also has a role as a lineage-survival oncogene through transcriptional activation of crucial target genes including ROR1 and LMO3. In the present study, we employed a global proteomic search for proteins that interact with TTF-1 in order to provide a more comprehensive picture of this still enigmatic lineage-survival oncogene. Our results unexpectedly revealed a function independent of its transcriptional activity, as TTF-1 was found to interact with DDB1 and block its binding to CHK1, which in turn attenuated ubiquitylation and subsequent degradation of CHK1. Furthermore, TTF-1 overexpression conferred resistance to cellular conditions under DNA replication stress (RS) and prevented an increase in consequential DNA double-strand breaks, as reflected by attenuated induction of pCHK2 and γH2AX. Our findings suggest that the novel non-transcriptional function of TTF-1 identified in this study may contribute to lung adenocarcinoma development by conferring tolerance to DNA RS, which is known to be inherently elicited by activation of various oncogenes.

Interferon-gamma induces AT(2) receptor expression in fibroblasts by Jak/STAT pathway and interferon regulatory factor-1.

The expression of angiotensin II type 2 (AT(2)) receptor is closely associated with cell growth, differentiation, and/or injury. We examined the effect of interferon (IFN)-gamma on AT(2) receptor expression in mouse fibroblast R3T3 cells and demonstrated that IFN-gamma treatment increased the expression of AT(2) receptor mRNA as well as its binding. Interferon regulatory factor (IRF)-1 was induced in mouse fibroblast R3T3 cells after IFN-gamma stimulation, and electrophoretic mobility shift assay showed an increase in IRF-1 binding with the IRF-specific binding sequence in the AT(2) receptor gene promoter region after IFN-gamma stimulation. The IRF-1 gene promoter contains an IFN-gamma-activated sequence (GAS) motif for possible binding of signal transducer(s) and activator(s) of transcription (STAT). Indeed, in R3T3 cells, IFN-gamma treatment resulted in rapid activation of Janus kinase (Jak) 1, Jak2, and STAT1 via tyrosine phosphorylation. Electrophoretic mobility shift assay with the GAS probe revealed increased STAT1 binding to the IRF-1 gene promoter in response to IFN-gamma stimulation. Transfection of GAS-binding oligonucleotides inhibited the effect of IFN-gamma on IRF-1 production, resulting in the AT(2) receptor trans-activation. Taken together, our data show that IFN-gamma upregulates AT(2) receptor expression in R3T3 cells via the activation of the intracellular Jak/STAT pathway and production of IRF-1.

Expression and methylation status of the FHIT gene in acute myeloid leukemia and myelodysplastic syndrome.

To clarify the role of fragile histidine triad (FHIT) in hematological malignancies, we examined the methylation status and the expression level of the FHIT gene in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells in comparison with the methylation of the p15(INK4B) gene. The FHIT methylation was found in 13 of 94 (13.8%) AML and 22 of 40 (55.0%) MDS cases, but not in normal mononuclear cells (MNCs). Both the frequency and density of methylation increased in the advanced-stages MDS and the relapsed AML cases. Although FHIT and p15(INK4B) methylations were not correlated in MDS and AML, increased FHIT methylation at the relapse in AML was associated with p15(INK4B) methylation. The median expression level in AML was significantly higher than in normal MNCs, although the median expression level in those with methylation was significantly lower than in those without methylation. Furthermore, the methylation level at relapse was significantly higher than at diagnosis in AML. These results suggested that FHIT methylation was accumulated through the disease progression of MDS and AML, and the role of the FHIT gene as a tumor suppressor seemed different in AML and MDS.

Assessment of efficacy of a live oral poliovirus vaccine for virulent Sabin-like poliovirus 1 strains in Japan.

Virulent Sabin-like poliovirus (VSLP) was isolated from river and sewage waters between October 1993 and September 1995 in Toyama Prefecture, Japan (Yoshida et al., Lancet 356, 1461-1463, 2000). In this study, to assess the possibility of an epidemic of poliomyelitis caused by a VSLP in Japan under the current vaccination policy of administration of live attenuated oral poliovirus vaccine (OPV), we determined titers of serum neutralizing antibodies to poliovirus 1 (PV-1) strains Sabin (vaccine strain), Mahoney (wild-type strain) and G4-12 (VSLP) in various groups of residents of Toyama Prefecture, Japan. The seropositivity and geometric mean neutralizing antibody titers against these strains in the individuals who obtained two doses of OPV were 99.1%, 94.5% and 95.5%, respectively, and 564, 186 and 194, respectively. Although the antibody titers to G4-12 were lower compared with those to Sabin, these results indicate that the OPV vaccination policy in Japan has been effective in preventing poliomyelitis caused by VSLPs. These results also suggest that (i) an epidemic of poliomyelitis caused by a VSLP has not occurred in Japan due to herd immunity, and (ii) the possibility of reemergence of VSLPs will be prevented if sufficient herd immunity is acquired immediately after completion of the OPV vaccination in accordance with the poliomyelitis eradication program.

[Rapidly enlarging giant left ventricular pseudo-false aneurysm after myocardial infarction; report of a case].

A 71-year-old man was admitted to our hospital with acute myocardial infarction and cardiac tamponade. After pericardial drainage, his hemodynamics was improved. Because more than 3 days had been passed after the onset of myocardial infarction and he had severe renal dysfunction, emergent coronary angiography (CAG) was not performed. After improvement of his general status, coronary angiography and percutaneous catheter intervention was carried out, and his course was uneventful. But transthoracic echocardiography before discharge revealed a giant posterior psudoaneurysm. Patch closure and coronary artery bypass grafting was carried out under cardiopulmonary bypass, and postoperative course was uneventful. Postoperative left ventriculogram revealed disappearance of pseudoaneurysm, but relatively large akinetic area of posterior-inferior wall was left around a patch. Pseudo-false aneurysm was diagnosed by histological examination.

Glyceride synthesis by four kinds of microbial lipase.

Apart from their usual mechanism of action, lipases from Aspergillus niger and Rhizopus delemar also catalyzed the synthesis of glycerides from oleic acid and glycerol. Lipases from Geotrichum candidum and Penicillium cyclopium were inactivated by oleic acid, but were stable in the presence of casein, albumin or buffer of appropriate pH. Lipases from Aspergillus niger and Rhizopus delemar synthesized glycerides from, not only fatty acid, but dibasic acids and aromatic acids, making ester bonds only at position 1 and 3 of glycerol. In contrast, lipases from Geotricum candidum and Penicillium cyclopium synthesized glycerides only from long chain fatty acids, and made ester bonds at all three available positions of the glycerol molecule.

Synthesis of various kinds of esters by four microbial lipases.

Ester synthesis by microbial lipases, using homogeneous enzyme preparations, were investigated. The amount of synthesized ester was estimated by alkalimetry, and products were identified by thin-layer chromatography and infrared spectroscopy. Lipases from Aspergillus niger, Rhizopus delemar, Geotrichum candidum and Penicillium cyclopium synthesized esters from oleic acid and various primary alcohols. Only Geotrichum candidum lipase synthesized esters of secondary alcohols. Esters of tertiary alcohols, phenols or sugar alcohols were not synthesized by any lipase. Rather high concentrations of alcohol were required to synthesize the esters of ethylene glycol, propylene glycol or trimethylene glycol. Lipases from Aspergillus niger and Rhizopus delemar synthesized oleyl esters of various fatty acids and some dibasic acids. In contrast, lipases from Geotrichum candidum and Penicillium cyclopium synthesized oleyl esters only from medium or long chain fatty acids.

Reduced hepatic release of apoprotein B after enteral nutrition in rats.

To investigate the effects of enteral and parenteral alimentation on VLDL release from the liver, a lipid-free liquid nutriment was continuously administered to free-moving rats via the oral cavity (oral group), stomach (enteral group) or superior caval vein (parenteral group). After 1-week of nutrition, the plasma VLDL concentrations were significantly lowered in the enterally-fed group. By immunoblotting assay using a specific antiserum, plasma contents of both apoprotein B-100 and B-48, the major components of rat apoprotein B, were found to be decreased in the enteral group, whereas only that of apoprotein B-48 was reduced in the parenteral group as compared with the oral group. Sucrose gradient centrifugation of the lipid droplets in the liver from the enteral group showed an increase of the free-triacylglycerol fraction with a concomitant increase of the apoprotein B-48-rich triacylglycerol fraction. These results suggest that enteral nutrition causes triacylglycerol accumulation in the liver, at least in part by impairment of lipoprotein release from the liver.

Isolation and cDNA-derived amino acid sequences of hemoglobin and myoglobin from the deep-sea clam Calyptogena kaikoi.

The heterodont clam Calyptogena kaikoi, living in the cold-seep area at a depth of 3761 m of the Nankai Trough, Japan, has abundant hemoglobins and myoglobins in erythrocytes and adductor muscle, respectively. Two types of hemoglobins (Hb I and Hb II) were isolated, and the complete amino acid sequences of Hb I (145 residues) and Hb II (137 residues) were obtained with combination of cDNA and protein sequencing. The amino acid sequences of C. kaikoi Hbs I and II differed from homologous chains of the congeneric clam Calyptogena soyoae in eight and five positions, respectively. The distal (E7) His, one of the functionally important residues in hemoglobin and myoglobin, was replaced by Gln in hemoglobins of C. kaikoi. A phylogenetic analysis of clam hemoglobins indicates that the evolutionary rate of Calyptogena hemoglobins is rather faster than those of other clams, suggesting that the mutation rate might be accelerated in the deep-sea animals around the areas of cold seeps or hydrothermal vents. On the other hand, it was found unexpectedly that two myoglobins Mbs I and II, isolated from the red adductor muscle, are identical in amino acid sequence Hbs I and II, respectively. Thus it was assumed that genes for Hbs I and II are also expressed in the muscle of C. kaikoi in substitution for myoglobin gene. This suggests that the major physiological role of globins in C. kaikoi is storage of oxygen under the low oxygen conditions, rather than circulating of oxygen.