Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer.

BACKGROUND: Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data. PATIENTS AND METHODS: Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan-Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model. RESULTS: OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883-1.775, P = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312-0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively. CONCLUSION: G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.

Evaluation of the compliance with antiemetic guidelines for prevention of chemotherapy-induced nausea and vomiting in patients with hematologic malignancy.

To assess compliance with the Japanese antiemetic guidelines for chemotherapy-induced nausea and vomiting (CINV), the frequencies of CINV occurrence and use of antiemetic rescue medications were examined in patients with hematological malignancy. A total of 40 patients with hematologic malignancy were eligible in this study. This study was performed in the Department of Hematology, Kyushu University Hospital, as a subgroup analysis from a nationwide, multicenter prospective cohort study conducted by the CINV Study Group of Japan. In the patients with hematological malignancy, the guideline compliance rate was 45 %. Five patients (22.7 %) experienced vomiting during the observation period after receiving non-guideline-consistent antiemetic prophylaxis, whereas no patient experienced vomiting after receiving guideline-consistent antiemetic prophylaxis. The study was not sufficiently powered to reach a statistical significance in its frequency of occurrence between the compliance and non-compliance groups. In the entire study period, 8 out of 40 patients required rescue medication, but there was no association between the status of compliance and the antiemetic guidelines. A total of 22 (55.0 %) patients achieved complete response, which was defined as no vomiting and no use of antiemetic rescue medication, during the study period. The rate of compliance with the prophylactic antiemetic treatment guidelines seemed to be low in patients with hematological malignancy, although the status of the guideline compliance did not always influence the antiemetic effects.

Elevation of serum KL-6 in patients with psoriasis treated with anti-tumour necrosis factor-α therapy.

We report three patients with psoriasis whose serum level of Krebs Von Den Lungen (KL)-6 increased during therapy with anti-tumour necrosis factor (TNF)-α. A diagnosis of early-phase or subclinical interstitial pneumonia was made in two patients, and their KL-6 level decreased after anti-TNF-α discontinuation. The rise in KL-6 in the other patient was attributed to methotrexate. We propose that serum KL-6 should be monitored routinely in patients treated with anti-TNF agents.

Correlation of progression-free and post-progression survival with overall survival in phase III trials of first-line chemotherapy for advanced epithelial ovarian cancer.

PURPOSE OF INVESTIGATION: The authors examined the relation between post-progression survival (PPS) and overall survival (OS) in phase III trials of first-line chemotherapy for advanced epithelial ovarian cancer. MATERIALS AND METHODS: The authors partitioned OS into progression-free survival (PFS) and PPS and evaluated the relation between OS and either PFS or PPS. They also examined whether any association might be affected by the year of completion of trial enrollment. RESULTS: The average PPS was longer in recent trials than in older trials (26.9 vs. 20.2 months,p = 0.0002). For all trials, PPS was strongly associated with OS (r = 0.94), whereas PFS was more moderately but still strongly correlated with OS (r = 0.83). The average proportion of median OS accounted for by median PPS significantly increased from 54.1% in older trials to 60.3% in recent trials (p = 0.0001). CONCLUSION: The present findings indicate that, especially for recent trials, PPS is more highly associated than PFS with OS in first-line chemotherapy for advanced epithelial ovarian cancer.

A phase I/II trial of irinotecan plus amrubicin supported with G-CSF for extended small-cell lung cancer.

OBJECTIVE: This study reports the findings of a Phase I/II, cohort, dose-escalation trial of amrubicin and irinotecan with the support of granulocyte colony-stimulation factor. This study aimed to determine the dose-limiting toxicity of the combination and to define the maximum-tolerated dose, as a recommended dose for Phase II trials. We also sought to obtain preliminary data on the efficacy of this combination as a frontline therapy for extensive-disease small-cell lung cancer. METHODS: We included 23 chemo-naïve patients with extensive-disease small-cell lung cancer in the trial. The amrubicin dose was escalated from 35 to 40 mg/m(2) (Levels 1 and 2, respectively) to determine the dose-limiting toxicity, with an unchanged dose of irinotecan at 50 mg/m(2). RESULTS: Of nine patients, three experienced dose-limiting toxicities at Level 1 of prolonged Grade 4 neutropenia, Grade 3 febrile neutropenia and Grade 3 febrile neutropenia with Grade 3 diarrhea. At Level 2, two patients experienced dose-limiting toxicities of Grade 4 neutropenia and Grade 3 neutropenia with Grade 4 diarrhea. The maximum-tolerated doses and recommended doses for amrubicin and irinotecan were therefore determined to be 35 and 50 mg/m(2), respectively. The Level 1 trial was then expanded to 21 patients, 14 (70%) of whom showed partial responses to the recommended dose. The median progression-free and overall survival times were 6.37 and 15.21 months, respectively. CONCLUSIONS: The combination of amrubicin and irinotecan with the support of granulocyte colony-stimulation factor produced a potent effect in chemo-naïve extensive-disease small-cell lung cancer patients. The use of biomarkers for this regimen may identify patients who are likely to suffer from treatment-ending severe adverse effects.

Assessment of the albumin-bilirubin grade as a prognostic factor in patients with non-small-cell lung cancer receiving anti-PD-1-based therapy.

INTRODUCTION: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood. METHODS: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan-Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis. RESULTS: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan-Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival. CONCLUSION: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size.

PCR Analysis Methods for Detection and Identification of Beer-Spoilage Lactic Acid Bacteria.

Polymerase chain reaction (PCR) analysis enables rapid and accurate detection of beer-spoilage lactic acid bacteria (LAB). Hop resistance genes, horA and horC, are utilized as genetic markers to determine the spoilage ability of LAB strains. PCR analysis of horA and horC, combined with multiplex PCR methods of 12 beer-spoilage species, enables simultaneous and comprehensive detection easily and inexpensively.

Prognostic significance of inflammatory biomarkers in hepatocellular carcinoma following hepatic resection.

Background: Cancer-related inflammation has been correlated with cancer prognosis. This study evaluated inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR), programmed death ligand (PD-L) 1 expression, and tumour microenvironment in relation to prognosis and clinicopathological features of patients with hepatocellular carcinoma (HCC) undergoing curative hepatic resection. Methods: Patients who had liver resection for HCC in 2000-2011 were analysed. Univariable and multivariable analyses were conducted for overall (OS) and recurrence-free (RFS) survival. Immunohistochemical analyses of PD-L1, CD8 and CD68 expression were performed. HCC cell lines were evaluated for PD-L1 expression. A subgroup analysis was conducted to determine patient features, survival and the tumour microenvironment. Results were validated in a cohort of patients with HCC treated surgically in 2012-2016. Results: Some 281 patients who underwent hepatic resection for HCC were included. Multivariable analysis showed that low LMR was an independent prognostic factor of OS (hazard ratio (HR) 1·59, 95 per cent c.i. 1·00 to 2·41; P = 0·045) and RFS (HR 1·47, 1·05 to 2·04; P = 0·022) after resection. Low preoperative LMR values were correlated with higher α-fetoprotein values (P < 0·001), larger tumour size (P < 0·001), and high rates of poor differentiation (P = 0·035) and liver cirrhosis (P = 0·008). LMR was significantly lower in PD-L1-positive patients than in those with PD-L1 negativity (P < 0·001). Results were confirmed in the validation cohort. PD-L1 expression was upregulated in HCC cell lines treated with interferon-γ and co-cultured with THP-1 monocyte cells. Conclusion: LMR is an independent predictor of survival after hepatic resection in patients with HCC. Modulation of the immune checkpoint pathway in the tumour microenvironment is associated with a low LMR.

trans-5-prostaglandin E2 stimulates plasminogen activation by tissue-type plasminogen activator.

The effect of trans-5-prostaglandin E2 (trans-PGE2) on fibrinolysis was examined in vitro using synthetic chromogenic substrate S-2251. trans-PGE2 was found to enhance plasminogen (PLG) activation mediated by tissue-type plasminogen activator (tPA). The enhancing effect was dependent on the concentration of trans-PGE2. cis-PGE2 and the other PGs (PGE1 and PGI2) did not show such an effect as trans-PGE2, despite to the fact that their structures are similar to that of trans-PGE2. trans-Configuration around the double bond at the 5-position seems to be important in the enhancement of the fibrinolytic activity.

Different effect of 5,6-trans-prostaglandin E2 on plasminogen activation by urokinase and streptokinase.

We examined the effects of 5,6-trans-prostaglandin E2 (trans-PG E2) on fibrinolysis and plasminogen activation by either urokinase or streptokinase. trans-PG E2 was found to enhance fibrinolysis induced by urokinase and inhibit the one by streptokinase. These effects were also appeared in the method using synthetic chromogenic substrate S-2251, which suggested that the effects of trans-PG E2 were induced in the circumstances without coagulation factors such as fibrinogen, thrombin or fibrin. Moreover, the enhancement effect of trans-PG E2 on fibrinolysis by urokinase was investigated. The result of SDS-PAGE indicated that plasmin formation rate from plasminogen by urokinase was accelerated in the presence of trans-PG E2. As trans-PG E2 increased the hydrolyzing rate of S-2288 by urokinase, trans-PG E2 directly interacted with urokinase. Therefore, the enhancement effect of trans-PG E2 on plasminogen activation by urokinase could be explained, at least in part, as follows: at first trans-PG E2 directly exerts its effect on urokinase, then it causes the increase of generation rate of plasmin from plasminogen.

Effect of artificial (CTG) repeat expansion on the expression of myotonin protein kinase (MtPK) in COS-1 cells.

A major challenge in the study of a new genetic entity called triplet-repeat disease is to identify the role of triplet repeats in the pathogenesis of the disease. We have developed a strategy to demonstrate the effect in the 3'-untranslated end of the (CTG) repeats in myotonic dystrophy gene (MtPK) and found that repeat expansion (CTG46) causes a slight decrease in the translation rate of MtPK cDNA which correlates with the finding in patients with myotonic dystrophy of a low amount of MtPK protein in muscle. These results provide an important clue for characterizing the genetic abnormality in other triplet-repeat diseases.

Early skin toxicity predicts better outcomes, and early tumor shrinkage predicts better response after cetuximab treatment in advanced colorectal cancer.

Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4-8 weeks after the start of treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P = 0.0001). Patients with early skin toxicity showed significantly longer overall survival (P = 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P = 0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab.

Inhibitory spectra of purified protease nexin-II and related proteins towards cellular proteinases.

Amyloid beta protein (beta/A4) is deposited in senile plaques of patients with Alzheimer's disease. This protein is derived from a larger membrane-associated protein, termed amyloid precursor protein (APP). The constitutive processing of APP occurs at the central portion of beta/A4, resulting in the release of large N-terminal peptides. We have purified these peptides from the culture medium of cDNA-transfected COS-1 cells. Some of the isoforms contain the Kunitz-type protease inhibitor (KPI) domain and strongly inhibit trypsin, chymotrypsin and plasmin, but do not inhibit kallikrein, prolyl endopeptidase or granzyme A. The peptides also do not inhibit cysteine proteases such as cathepsin B or calpain. Soluble APPs lacking the KPI domain fail to inhibit any of these proteases. The results indicate that the KPI domain in soluble APPs has protease inhibitory activity against certain serine proteases.

Developmental regulation of myotonic dystrophy protein kinase in human muscle cells in vitro.

From our previous studies, myotonic dystrophy protein kinase: gene product of myotonic dystrophy is localized at the terminal cisternae of sarcoplasmic reticulum of human adult muscle. Now we have studied the developmental expression of myotonic dystrophy protein kinase in aneurally cultured human muscles and contracting cross-striated muscles innervated with fetal rat spinal cord using a semi-quantitative reverse transcription-polymerase chain reaction method for myotonic dystrophy protein kinase messenger RNA expression, Western blot analysis, immunohistochemical examinations by laser scanning confocal microscopy and immunoelectron microscopy. About 65,000 mol. wt myotonic dystrophy protein kinase was detected in aneurally cultured muscles. Myotonic dystrophy protein kinase messenger RNA was expressed in both aneurally and innervated cultured muscles, but in early innervated cultured muscles the message was transiently lower than in aneurally cultured muscles and innervated cultured muscles in long-term co-culture. In aneurally cultured muscles, immature aneurally cultured muscles show a diffuse and irregular distribution of myotonic dystrophy protein kinase in the deeper cytoplasm near the nuclei. Ultrastructurally the immuno-products against myotonic dystrophy protein kinase were observed as dense deposits in parts of the membranes near the mitochondria. In innervated cultured muscles, immunofluorescent microscopy showed myotonic dystrophy protein kinase to be localized regularly in the I bands and A-I junctions. Ultrastructurally myotonic dystrophy protein kinase was localized in branched duct-like membranes in the early stage of innervated cultured muscles and then in small sacs at the I bands and A-I junctions of the sarcolemma in the mature stage. Our present studies strongly suggest that innervation plays an important role in the localization of myotonic dystrophy protein kinase in human skeletal muscle during development. We conclude that the expression of myotonic dystrophy protein kinase during development is under neuronal influence.

Immunocytochemical localization of a full-length myotonin protein kinase in rat L6 myoblasts.

Expansion mutation of CTG-repeat motifs within myotonin protein kinase (MtPK) gene is responsible for pathological changes in myotonic dystrophy (DM). To explore its pathological role in skeletal muscle, a full-length human MtPK cDNA was transfected into rat L6 myogenic cell line. Recombinantly expressed human MtPK protein in L6 cell line has a predicted molecular mass of 70 kDa. We have raised a polyclonal antibody against a synthetic peptide in the deduced sequence of the C-terminal portion of MtPK. MtPK in L6 cell is localized to perinuclear region, that resembles with sarcoplasmic reticulum. The MtPK-transfected myoblast cells established in this study will allow us to elucidate the molecular pathomechanism of muscle manifestations in DM.

Decreased expression of myotonic dystrophy protein kinase and disorganization of sarcoplasmic reticulum in skeletal muscle of myotonic dystrophy.

Pathological expression of myotonic'dystrophy protein kinase (DMPK) in skeletal muscle of myotonic dystrophy (DM) was studied by Western blot analysis, immunohistochemistry, and immunoelectron microscopy of DMPK. Western blot analysis showed that DMPK protein in DM skeletal muscles dramatically decreased. DMPK-positive muscle fibers showed typical DM pathological changes such as type I atrophy, central nuclei, nuclear chains, and sarcoplasmic masses. In degenerated DMPK-positive muscle fibers, cross-striated bands disappeared, and irregular granular DMPK-positive materials appeared in sarcoplasm. By immunoelectron microscopy, DMPK was localized in the terminal cisternae of the sarcoplasmic reticulum (SR) in DM muscle. Swollen DMPK-positive SRs were detected between well preserved myofibrils in the early stage of DM muscle degeneration, and degenerated intramembranous structures with DMPK and an accumulation of mitochondria were observed between disorganized myofibrils in degenerated DM muscle. We concluded that SR is the primary site of the degeneration of DM skeletal muscle and that the decreased DMPK might cause dysregulation of intracellular calcium metabolism, which is followed by DM muscle degeneration.

Hypertensive encephalopathy: reversible CT and MR appearance.

The authors present a case of hypertensive encephalopathy in which CT and MR were performed. The brain stem and cerebellum were revealed as low density areas on CT and high intensity areas on T2-weighted MR images with mass effect. Slight abnormality was also noticed in the deep cerebral white matter. This distribution pattern is contrary to that described in previous reports in which cerebral white matter was mainly involved. The lesions showed definite improvement when the blood pressure was normalized. MR is more sensitive than CT, and is useful for early detection of the abnormality and follow-up study.

[A case of angiotropic lymphoma diagnosed by adrenal biopsy].

We reported the first case of angiotropic lymphoma diagnosed by adrenal biopsy in Japan. Immunohistochemical study and southern blot hybridization analysis proved it to be B-lymphocyte origin. A 61-year-old man with history of mild hypertension and diabetes mellitus was admitted to our department because of recurrent minor stroke. On admission, general physical findings were normal. Laboratory investigations showed an elevated erythrocyte sedimentation rate and increased serum lactic dehydrogenase (LDH) level. The serial computed tomographic (CT) scan of the brain showed multifocal abnormal density lesions in bilateral hemispheres. Magnetic resonance imaging (MRI) of the brain demonstrated multiple lesions of increased signal intensity in the brainstem and bilateral hemispheres. A subsequent CT scan of the abdomen revealed swelling of bilateral adrenal glands. Adrenal biopsy was performed. Biopsy samples showed the intravascular proliferation of malignant lymphoma cells, non-Hodgkin, diffuse large cell type. These cells had the immunophenotype of a B cell lymphoma (reactive with the antileukocyte common antigen, anti-MB-1, anti-MB-2 and anti-MX-pan B, and unreactive with the anti-MT-1, anti-UCHL, anti-Ki, anti-kappa, anti-lambda and antifactor-VIII). Southern blot hybridization analysis showed monoclonal rearrangements of the immunoglobulin heavy-chain gene, which strongly suggested a B-lymphocyte origin. Thus, a diagnosis of angiotropic lymphoma was made. As soon as chemotherapy was begun, the patient fell into deep coma. A repeat CT scan of the brain was normal. His clinical status gradually deteriorated, and he died 18 months after his initial symptom. Autopsy, which was limited to the body, revealed characteristic systemic intravascular stagnation of lymphoma cells.(ABSTRACT TRUNCATED AT 250 WORDS)

[Myotonin protein kinase].

The mutation underlying myotonic dystrophy is the expansion of polymorphic CTG repeat in the 3'-noncoding region of the myotonin protein kinase (MtPK) gene mapping to chromosome 19q13.3. A full-length cDNA of human MtPK was cloned and expressed in COS-1 cells. MtPK is recovered from the COS cell extract as a 70 kDa protein, which coincides with the size deduced from the predicted amino acid sequence. Biochemical characteristics of MtPK expressed in COS cells and its expression are investigated.

[Comparison of methylprednisolone and droperidol in the prevention of nausea and vomiting following major gynaecological surgery].

The efficacy of methylprednisolone (MP) (500 or 250 mg) or droperidol 2.5 mg administered i.v., was studied in 200 women undergoing major gynaecological surgery. Following a standardised general anaesthesia technique with intrathecal morphine, the incidence of nausea and vomiting was assessed. The frequency of postoperative nausea and vomiting in the non-treated group was 59% and 35%; the group of MP 500 mg has a significant reduction of nausea and vomiting to 21% and 13%. Droperidol 2.5 mg decreased the incidence of postoperative nausea alone (nausea: 36%, vomiting: 19%). MP 250 mg was not effective in reducing either nausea or vomiting (nausea: 44%, vomiting: 38%). It was concluded that, of the drugs studied, MP 500 mg was most effective in preventing nausea and vomiting after major gynaecological surgery.