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Background Aldehyde dehydrogenase 2 (ALDH2) plays an important role in the endogenous aldehyde detoxification of various types of cells. ALDH2*2, a variant allele of the ALDH2 polymorphism rs671, leads to decreased enzymatic activity. ALDH2*2 may enhance tumor antigen presentation due to aldehyde-induced DNA damage while suppressing peripheral blood T cell counts and T cell activation. Methods On the basis of our hypothesis that rs671 affects the sensitivity of immune checkpoint inhibitors (ICIs), we evaluated the effects of rs671 on patients with thoracic malignancies who started ICI therapy in 2016–2019. The cohort consisted of 105 cases, including 64 cases with adenocarcinoma and 30 cases with squamous cell carcinoma, 49 of whom were ALDH2*2 carriers. The first ICI was PD-1/PD-L1 inhibitor (Nivolumab, Pembrolizumab, or Atezolizumab) in all cases. Results The best response to anti-PD-1/PD-L1 therapy (partial response/stable disease/progressive disease) was 36%/50%/14% in the rs671(−) cases; however, the response was relatively poor in the rs671(+) cases (27%/29%/45%, respectively) (p = 0.002). The hazard ratio (95% confidence interval) of disease progression within the observation period of 6 months for the rs671(+) cases was estimated to be 5.0 (2.5–10) after the adjustment for covariates, including sex, Brinkman index, treatment line, tumor tissue programmed death-ligand 1 positivity rate, tumor tissue EGFR mutation. This association was also maintained in a stratified analysis, suggesting that ALDH2*2 is an independent negative predictive factor for the short-term prognosis of anti-PD-1/PD-L1 therapy. Thus, the progression-free survival (PFS) ratio of the rs671(+) cases decreased rapidly after ICI initiation but was eventually higher than that of the rs671(−) cases (restricted mean survival time in 12 months from 2 to 3 years afterward was 1.3 times that of the rs671(−) cases). Moreover, the highest PFS ratio after 2 years among sub-groups was found in the first-line treatment sub-group of rs671(+) group (40%). Conclusions Our study suggests that rs671 may be an accurate and cost-effective predictor of PD-1/PD-L1 inhibitor treatment, in which optimal case selection is an important issue.

Purpose To establish a new medical information database network (designated MID-NET® ) to provide real-world data for drug safety assessments in Japan. Methods This network was designed and developed by the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency in collaboration with 23 hospitals from 10 healthcare organizations across Japan. MID-NET® is a distributed and closed network system that connects all collaborative organizations through a central data center. A wide variety of data are available for analyses, including clinical and administrative information. Several coding standards are used to standardize the data stored in MID-NET® to allow the integration of information originating from different hospitals. A rigorous and consistent quality management system was implemented to ensure that MID-NET® data are of high quality and meet Japanese regulatory standards (good post-marketing study practice and related guidelines). Results MID-NET® was successfully established as a reliable and valuable medical information database and was officially launched in April 2018. High data quality with almost 100% consistency was confirmed between original data in hospitals and the data stored in MID-NET® . A major advantage is that approximately 260 clinical laboratory test results are available for analysis. Conclusions MID-NET® is expected to be a major data source for drug safety assessments in Japan. Experiences and best practices established in MID-NET® may provide a model for the future development of similar database networks.

PURPOSE To examine the potential role of Medical Information Database Network (MID-NET® ), a newly established Japanese medical information database network, in postmarketing drug safety assessments through the characterization of its advantages and limitations in five pilot studies. METHODS The pilot studies were designed to address three major objectives in postmarketing drug safety assessments, ie, the examination of actual drug utilization, the impact of safety-related regulatory actions, and drug-associated risks. The five studies were conducted on the following topics: (a) utilization of codeine-containing products and its relationship with respiratory depression, (b) impact of a Dear Healthcare Professional letter on hypocalcemia incidence associated with denosumab (Ranmark® ) use, (c) risk of acute myocardial infarction associated with antidiabetic drug use, (d) risk of glucose metabolism disorders associated with atypical antipsychotic drug use, and (e) prospective monitoring of abnormal laboratory test results during new drug prescriptions. RESULTS The pilot studies were successfully conducted and demonstrated the value of MID-NET® in postmarketing drug safety assessments. In particular, the ability to utilize laboratory test results as objective clinical indicators is a major advantage of this database. Potential limitations include a relatively small sample size and a lack of patient-level data linkages among hospitals. CONCLUSIONS MID-NET® was confirmed to be a valuable database for postmarketing drug safety assessments. The use of laboratory test results to define clinical outcomes may allow more objective and accurate analyses to be conducted. These studies furthered our understanding of the characteristics of MID-NET® , including its advantages and limitations.

Background Aldehyde dehydrogenase 2 (ALDH2) plays an important role in the endogenous aldehyde detoxification of various types of cells. ALDH2*2, a variant allele of the ALDH2 polymorphism rs671, leads to decreased enzymatic activity. ALDH2*2 may enhance tumor antigen presentation due to aldehyde-induced DNA damage while suppressing peripheral blood T cell counts and T cell activation. Methods On the basis of our hypothesis that rs671 affects the sensitivity of immune checkpoint inhibitors (ICIs), we evaluated the effects of rs671 on patients with chest malignancies who started ICI therapy in 2016–2019. The cohort consisted of 105 cases, including 64 adenocarcinoma and 30 squamous cell carcinoma patients, 49 of whom were ALDH2*2 carriers. Nivolumab, Pembrolizumab, or Atezolizumab was used for the first ICI treatment. Results The best response to ICI therapy (partial response/stable disease/progressive disease) was 36%/50%/14% in the rs671(−) cases; however, the response was relatively poor in the rs671(+) cases (27%/29%/45%, respectively) (p = 0.002). The hazard ratio (95% confidence interval) of disease progression within the observation period of 6 months for the rs671(+) cases was estimated to be 5.0 (2.5–10) after the adjustment for covariates, including sex, Brinkman index, treatment line, tumor tissue programmed death-ligand 1 positivity rate, and tumor tissue EGFR mutation. This association was also maintained in a stratified analysis, suggesting that ALDH2*2 is an independent negative predictive factor for the short-term prognosis of ICI therapy. Thus, the progression-free survival (PFS) ratio of the rs671(+) cases decreased rapidly after ICI initiation but was eventually higher than that of the rs671(−) cases (restricted mean survival time in 12 months from 2 to 3 years afterward was 1.3 times that of the rs671(−) cases). Moreover, the highest PFS ratio after 2 years among sub-groups was found in the first-line treatment group of rs671(+) patients (40%). Conclusions Our study suggests that rs671 may be an accurate and cost-effective predictor of ICI treatment, in which optimal case selection is an important issue.

Additional file 1: Figure S1. Plot of log (−log (progression-free survival ratio)) versus log (days of progression-free survival). Hazard proportionality was tested by the parallelism between the curve of rs671(−) (cases with ALDH2*1/*1) and rs671(+) (cases with ALDH22*1/*2 and ALDH2*2/*2) to examine the suitability for the Cox proportional hazard model. Table S1. Immune-related adverse events (IrAEs) and second or subsequent ICI doses. Sas code. SAS code for the Cox proportional hazards model using time-dependent explanatory variables. Table S2. Overall best response per RECIST Ver1.1. by ALDH2 genotype limited to patients with non-small cell lung cancer. Table S3. Progression-free survival rate after the initiation of immune checkpoint inhibitors limited to patients with non-small cell lung cancer. Table S4. Hazaed ratio of cancer progression estimated from a 6-month observation in the model 4 in Table 4. Figure S2. Overall survival after the initiation of immune checkpoint inhibitor therapy. Kaplan–Meier plots were shown for patients with chest malignancies. ICI, immune checkpoint inhibitor; Rs671(−), ALDH2*1/*1 (n = 56), rs671(+); ALDH2*1/*2 or ALDH2*2/*2 (n = 49). p, p value for Gahan–Breslow–Wilcoxon test. Table S5. Hazard ratio of overall death for ALDH2*2 carriers estimated from a 6-month observation. Table S6. Stratified hazard ratio of overall death for ALDH2*2 carriers estimated from a 6-month observation.

There is a report that an infection by medicine resistant bacteria will be the number one cause of death in 2050 according to the recommendation of WHO, and the CPE (carbapenem-producing

To examine the potential role of Medical Information Database Network (MID-NETThe pilot studies were designed to address three major objectives in postmarketing drug safety assessments, ie, the examination of actual drug utilization, the impact of safety-related regulatory actions, and drug-associated risks. The five studies were conducted on the following topics: (a) utilization of codeine-containing products and its relationship with respiratory depression, (b) impact of a Dear Healthcare Professional letter on hypocalcemia incidence associated with denosumab (RanmarkThe pilot studies were successfully conducted and demonstrated the value of MID-NETMID-NET

Background: Adult T-cell leukemia-lymphoma (ATL), which is a hematological malignancy related to human T-lymphotropic virus type I (HTLV-1), is known as a malignant lymphoid disease with poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered a treatment modality to contribute prolonging the survival in some population of patients (Katsuya H et al. 2015 Blood). A small study indicated that ATL cells frequently have chromosomal abnormalities including various numerical aberrations and complex structural abnormalities (Kamada N et al. Cancer Res. 1992). However, there has been no large study to examine the relationship between chromosomal abnormalities and survival. Here we report the impact of chromosomal abnormalities on survival in ATL patients with conventional chemotherapy. Patients and Methods: In this study, we extracted a population of patients from the database of ATL-PI project, which is a nation-wide survey of ATL patients newly diagnosed between January 2000 and May 2009, and the overall results were reported elsewhere (Katsuya H et al. JCO 2012, Blood 2015). Fifteen hundred and twelve patients were registered in this project, and we excluded the patients who received allo-HSCT, and who were diagnosed with smoldering and chronic type ATL. Moreover, patients whose chromosomal analysis with G-banding stain showed normal, multiploid or no mitosis, or no information on chromosomal analysis and on the factors to determine the ATL-PI were also excluded. As a consequence, 210 patients with acute (n=157) and lymphoma (n=53) types were selected for this analysis. Abnormal karyotypes were analyzed from the aspect of numerical and structural break points. To identify the specific abnormalities and to avoid the secondary changes, the stem-line karyotype, which meant the simplest abnormal clone, was used as the representative karyotype for this study. A statistical analysis was performed with 'EZR' (Kanda T. BMT 2013). We examined an overall survival (OS) in relation to chromosomal abnormalities using cox proportional hazard regression model, and p-value of less than 0.05 was considered as statistically significant. Results: Among the 210 patients, 119 and 91 patients were male and female, respectively. The median age of patients was 66 years (40-89). With respect to other factors of ATL-PI, the median level of soluble interleukin-2 receptor (sIL-2R), serum albumin, were 30800 U/mL (620-1,219,000), 3.6 g/dL (1.6-5.3), respectively. Almost all patients were diagnosed with stage II-IV of clinical stage (n=200), and almost half of patients certified 2-4 of ECOG-PS (n=113). Sixty-nine, 106, and 35 patients were classified as high, intermediate and low risk by ATL-PI, respectively. Specimens used for chromosomal analysis were taken from lymph nodes (n=77), bone marrow (n=72), peripheral blood (n=50), pleural fluids (n=4), ascites (n=4) and 1 each of stomach, sinusoidal tumor, and tonsillar lesions. The median number of numerical abnormalities and marker chromosomes were 2 (0-20) and 1 (0-20), and the median number of structural break points was 6 (0-21). The numerical abnormalities were loss of sex chromosomes (31%) followed in decreasing order by -14 (24%), -13 (19%), -9 (12%) and -17 (12%) while the structural break points were located at 1p (30%), 3q (30%), 14q (30%), 6q (26%) and 1q (22%). The median OS was 286 days (1-2565). ECOG-PS, serum albumin level, sIL-2R, and structural break points at 9q or 19p, and the number of structural break points over 4 or 5 points were shown to be the significant factors affecting the survival by univariate analysis. Then, the multivariate analysis indicated that 2-4 of ECOG-PS (HR: 2.021, 95%CI: 1.436-2.791, p Discussions and Conclusion: This is the first large study showing the impact of chromosomal abnormality in acute and lymphoma types ATL on OS. It demonstrated that structural break points at 9q and 19p were the independent risk factors for OS in addition to those of ATL-PI. Disclosures Katsuya: The Uehara Memorial Foundation: Research Funding. Utsunomiya:Daiichi Sankyo Co., Ltd.: Speakers Bureau. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding. Suzumiya:Takeda: Honoraria; Astellas: Research Funding; Kyowa Hakko kirin: Research Funding; Chugai: Honoraria, Research Funding; Toyama Chemical: Research Funding; Eisai: Honoraria, Research Funding.

We investigated the relevance of direct identification method for bacteria from blood culture bottles using MALDI Biotyper(Bruker Co.). One hundred fourteen bacterial strains obtained from blood culture bottles were analyzed using the pretreatment method recommended by Bruker Corporation. The identification rate with recommended pretreatment was 76.3% (87/114). Twenty seven samples that were not identified with the pretreatment method were further analyzed using our modified method. Of these, twelve were identified, improving the identification rate to 86.8% (99/114). These results suggest that our modified pretreatment combined with pretreatment method recommended by Bruker Corporation yields improved identification of bacteria from blood culture bottles using MALDI Biotyper system.

We attempted to analyze any influences to %TMIC achievement probability due to the difference of the MIC measurement concentration range of MEPM for 613 strains of Pseudomonas aeruginosa by the Monte Carlo simulation method. As for the analysis, we calculated the achievement probability of 30% and 50% for MEPM %TMIC by the administration volume of MEPM: 250 mg, 500 mg, and 1,000 mg, the administration time: 0.5 h, and 3 h, the administration frequency: 2 times, and 3 times, and the renal excretion capability: Normal, Slight, Moderate, and High abnormal with the 3 types of MIC concentration measurement level 1)=0.06~=256 µg/ml: 13 levels, 2)=0.5~=32 µg/ml: 7 levels, and 3)=1~=16 µg/ml: 5 levels. As the result, we found the following findings; 1. In terms of the administration of normal renal excretion capability, 250 mg, in comparison with 500 mg and 1,000 mg, indicated the differential due to the difference of MIC measurement concentration range. 2. The administration volume of MEPM 500 mg which has been recommended shown the less differential of the achievement probability due to the difference of MIC measurement concentration range. As the renal excretion was shifted through Normal to Slight to Moderate to High abnormal, the differential of the achievement probability due to the difference of MIC measurement concentration range was gradually decreased. With these results, PK/PD analysis is possible for the 5 levels measurement concentration. It is significant that the facility using the automated microbiology analyzer can provide not only the MIC report, but also the information on the appropriate administration method for antibacterial drug by PK/PD analysis.

The need for examinations of single nucleotide polymorphisms (SNPs) on drug metabolizing enzymes is accelerating. Especially, SNPs of UTG1A1 and CYP2C19 are important for patients who are treated with irinotecan and proton pump inhibitors, respectively. Thus, a method for the rapid, fully automated, and accurate measurement of these SNPs is desired. We genotyped 109 Japanese volunteers for UGT1A1 * 6, UGT1A1 * 28, CYP2C19 * 2, and CYP2C19 * 3 with the quenching probe (QP) method. Only 90 min after whole blood was applied, QP method enabled to detect these SNPs automatically. The results obtained by QP method were absolutely identical to those examined by the conventional direct sequencing. These findings indicate that the QP method will enable point-of-care testing in clinical laboratories and patient-oriented therapy with its convenience and speed for patients who are treated with irinotecan or proton pump inhibitors.

Sixty-four Japanese patients with diffuse non-Hodgkin's lymphoma (NHL) were classified into human T-cell leukemia virus type I (HTLV-I) non-related diffuse NHL (41 cases) and HTLV-I related diffuse NHL, i.e. lymphoma type of adult T-cell leukemia (ATL-lymphoma, 23 cases) on the bases of serological detection of HTLV-I antibody and the detection of HTLV-I proviral DNA in malignant cells. The survival curves between diffuse NHL and ATL-lymphoma were quite different. Therefore, it is important to know the differences in prognostic factors, if any, affecting the survival in two groups: diffuse NHL and ATL-lymphoma cases. In diffuse NHL patients, factors found to be important were age, performance status, stage, organ involvement, hemoglobin concentrations and platelet count in the peripheral blood, serum lactic dehydrogenase (LDH) and calcium levels. However, none of these factors were useful for ATL-lymphoma patients, except for the serum calcium level. Thus, prognostic factors should be considered separately for diffuse NHL and ATL-lymphoma.

Background In surface antigen of hepatitis B virus (HBsAg)-positive carrier for anticancer treatment of malignant lymphoma, it is well recognized that reactivation of hepatitis B virus (HBV) occasionally occurs. However, there have been only a few studies of HBV reactivation in serum HBsAg-negative and hepatitis B core antigen (HBcAb)-positive occult HBV carriers. We looked at both retrospective and prospective studies to determine the prevalence, clinical course and risk factor of HBV reactivation during chemotherapy in lymphoma patients. Patients and methods Forty-eight of 127 (37.8%) lymphoma patients were HBsAg negative and HBcAb positive, and 24 of these patients were then given liver function tests and HBsAg tests monthly and serum HBV DNA every 3 months. Results HBV reactivation was observed in two patients (4.1%) who had received intensive chemotherapy including steroid and rituximab. Immediate administration of entecavir therapy after elevation of HBV DNA level was conducted, and this resulted in reduction of it and improvement of liver function test. Conclusions Rituximab plus steroid-containing regimens may increase the risk of HBV reactivation in HBsAg-negative and HBcAb-positive lymphoma patients. More ambitious prospective studies are required to establish clinically useful or cost-effective follow-up methods for control of HBV reactivation in lymphoma patients with occult HBV infection.

We examined mortality from adult T-cell leukemia/lymphoma (ATL/ATLL) and other diseases alleged to be associated with human T-lymphotropic virus type I (HTLV-I) among anti-HTLV-I antibody-positive blood donors in Kyushu, Japan. During 1984-87, a total of 3,991 blood donors aged 40 years or over were followed from the date of donation to the date of death or the end of the study. Crude mortality rates from ATL (with 95 percent confidence intervals) were 68 per 100,000 (13-202) for males and 36 per 100,000 (3-132) for females. The rates were underestimated by approximately 50 percent because of self-selection and short observation periods. Neither death rates from other cancers nor death rates from all cancers were elevated.

Mina53 (mina) was identified as a gene, which is directly induced by the oncogene c-myc. Elevated expression of Mina53 protein was found in >80% of colon cancer and esophageal squamous cell carcinoma (ESCC). Patients with high expression of Mina53 had shorter survival, suggesting the prognostic usefulness of Mina53. We studied Mina53 expression in lymphoma subtypes to examine its diagnostic significance and its possible role in lymphoma-genesis. Surgical cases of 28 lymphoma and 4 non-neoplastic tissues were stained immunochemically using anti-Mina53 monoclonal antibody. Mina53 expression correlated well with c-Myc expression in lymphoma, suggesting that c-Myc is a controlling factor for mina53 expression also in lymphomas. Although the expression of Mina53 as well as c-Myc was less frequent in lymphoma compared with those of colon and ESCC, increased expression of Mina53 was found in Burkitt-like lymphoma (1/1), Hodgkin's lymphoma (3/5), diffuse large B cell lymphoma (DLBCL) (5/13), lymphomas with a transition from follicular to DLBCL (1/2), with none in follicular (0/4) and T cell lymphoma (0/3). Analyses of the data suggested that Mina53 was frequently expressed in aggressive types of B cell lymphoma. To get more information about the expression of Mina53 in DLBCL, which most frequently occurs among lymphomas, we analyzed the expression of Mina53 in another 21 DLBCL specimens, which were in more advanced stages than those described above. The expression level of Mina53 correlated to the international prognostic index (IPI) values with statistical significance (r=0.477, P=0.0275). Notably, in this group, Mina53 expression did not correlate with c-Myc expression, suggesting that other factor(s) besides c-Myc largely affect the expression of Mina53 in advanced DLBCL. These results suggest that although Mina53 expression is not prominent in lymphoma in general, it may be related to tumor progression of B cell lymphoma.

Purpose The prognosis of acute and lymphoma type adult T-cell leukemia/lymphoma (ATL) has remained very poor, but there is a marked diversity in survival outcomes. The aim of this study was to develop a prognostic index (PI) for acute and lymphoma type ATL (ATL-PI). Patients and methods In a retrospective review, data from 807 patients newly diagnosed with acute and lymphoma type ATL between January 2000 and May 2009 were evaluated. We randomly divided subjects into training (n = 404) and validation (n = 403) samples, and developed an original PI employing the multivariable fractional polynomial model. Results The overall median survival time (MST) for 807 patients was 7.7 months. The Ann Arbor stage (I–II versus III–IV), performance status (0–1 versus 2–4), and the three continuous variables of age, serum albumin and soluble interleukin-2 receptor (sIL-2R) were identified as independent prognostic factors in the training sample. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. In the validation sample, MSTs were 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively (log-rank test, P 1) + 1 (if age > 70) + 1 (if Albumin 20,000). The scores from 0 to 2 were categorized into low-risk group, 3 and 4 into intermediate risk, and from 5 to 6 into high-risk group. This classification also yielded a good separation of OS curves (log-rank test, P Conclusion We developed the PI based on five prognostic factors in patients with acute and lymphoma type ATL, and further proposed its simplified version which is clinically accessible and useful. (J Clin Oncol 2012, in press.)

Adult T-cell leukemia/lymphoma (ATL) cells are generally CD4+, CD8- and CCR4+. A 76-year-old man was diagnosed with a rare case of CD4-/CD8+ ATL in 2013. He was initially treated with the THP-COP regimen. The number of ATL cells in lymph nodes and peripheral blood (PB) and the level of soluble interleukin-2 receptor (sIL2R) were decreased initially after chemotherapy but increased within 3 months and hypercalcemia appeared. Thus, the patient was diagnosed with ATL progression. Since CCR4 expression in CD4-/CD8+ ATL cells was confirmed by flow cytometry, the patient was treated with the newly developed CCR4 antibody mogamulizumab. Treatment significantly eradicated ATL cells in PB. To our knowledge, this is the first case of CD4- ATL treated with mogamulizumab.

Detection of EGFR mutations is indispensable to determine appropriate lung cancer treatment. Although 70% of lung cancer patients with EGFR activating/sensitive mutations benefit from EGFR tyrosine kinase inhibitor (EGFR-TKI), they eventually acquire resistance. Re-treatment with EGFR-TKI often produces long survival for advanced lung cancer patients. However, it has yet to be elucidated what subpopulation of patients is amenable to re-challenge with EGFR-TKI. We have sought a non-invasive monitoring system for EGFR mutation status using circulating plasma DNA and have established novel methods to identify EGFR mutations: wild inhibiting PCR and quenched probe system (WIP-QP) for exon 19 deletions and mutation-biased PCR and quenched probe system (MBP-QP) for L858R. These detection systems include fully automated genotyping based on the analysis of the probe DNA melting curve, which binds the target mutated site using a fluorescent guanine quenched probe (QP-system) combined with MBP or WIP to achieve higher sensitivity. Detection limit was 0.005-0.04 ng in genomic DNA and 0.1–0.3% with mutant plasmids. DNA isolated from lung cancer specimens and circulating plasma DNA samples of 39 adenocarcinoma patients whose primary tumors harbored EGFR exon 19 deletions or L858R were examined. Results in cancer tissue specimens were identical to those based on existing systems [nucleic acid-locked nucleic acid PCR clamp (PCR clamp) or cycleave PCR], except that two samples evidenced both exon 19 deletions and L858R. Using plasma DNA, exon 19 deletions and L858R were detected in 44.7 and 8.7% of patients, respectively. Serial monitoring of exon19 deletion and L858R demonstrated correlations with the disease state. These monitoring systems are simple, sensitive and, intriguingly, reflective of the clinical course, which can be applicable for deciding lung cancer treatment.

SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly post-translational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand–glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family.

Overexpression of MET has been reported in various malignancies and is associated with cell proliferation, inhibition of apoptosis and metastasis. MET amplification has been reported to contribute to acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in non-small-cell lung cancer (NSCLC), being observed among 5–10% of those patients. Therefore, MET gene alterations could be both prognostic and predictive, and evaluation of that is indispensable in practice. However, the frequency of positive cases varies due to a lack of standardized criteria of fluorescence in situ hybridization (FISH). The purpose of this study is to find which criteria could be useful in terms of the association with clinical characteristics. We evaluated the MET gene copy number of FISH using two different criteria in lung adenocarcinoma: the Cappuzzo scoring system and PathVysion and its association with clinicopathological characteristics. MET positive cases according to the Cappuzzo scoring system evidenced both aneuploidy and true amplification, whereas PathVysion revealed only amplification. One hundred and thirty-eight lung adenocarcinoma tissue samples were evaluated, and the proportion of MET FISH positive cases was 15 and 4% determined by the Cappuzzo system and PathVysion, respectively. PathVysion demonstrated higher frequencies of MET FISH positives among men and smokers and evidenced no MET FISH positives in patients with bronchioloalveolar carcinoma. Prognosis was significantly associated with MET FISH positive only as defined by the PathVysion system (gene amplification), not by the Cappuzzo system. However, the progression-free survival time of patients with both EGFR mutations and MET FISH positive defined by the Cappuzzo scoring system was significantly shorter than with EGFR mutations alone. These results suggest that MET FISH is a potential prognostic factor and co-existence of MET FISH with EGFR mutations signifies worse prognosis.

A W127X mutation in platelet glycoprotein (GP)IX is the most common genetic defect in Japanese Bernard-Soulier Syndrome (BSS). Patients having this mutation are often misdiagnosed as having immune thrombocytopenia (ITP) because of residual expression of GPIbα on the platelet surface. The purpose of the present investigation was to determine whether the residual amount of GPIbα present on the surface of GPIXW127X BSS platelets might be sufficient to support adhesive functions of the GPIb complex. Flow cytometric analysis of platelets from our GPIXW127X BSS patient revealed 7–11% of the normal level of GPIbα (3,700 receptors/platelet), although the expression of GPIbα estimated by western blot analysis was only 1% of normal. Expression levels of other receptors such as GPIIb, GPVI, and α2 integrin were 3–4 times higher per platelet than that of normal controls–probably due to the increased size of the BSS platelets. To characterize the ability of GPIXW127X BSS platelets to bind VWF, we evaluated their agglutination in the presence of various concentrations of ristocetin, and found that ristocetin-induced agglutination was absent at 1.2 and 1.5 mg of ristocetin/ml, but present at 2.0 mg/ml. We then evaluated the ability of GPIXW127X BSS platelets to adhere under conditions of flow to immobilized VWF, type 1 collagen, and type III collagen. Whereas platelets derived from a Type I BSS patient having a TGTG deletion within the GPIbα gene in which GPIbα is completely absent (Thrombosis and Haemost 77:1055,1997) were unable to adhere to immobilized VWF under conditions of high shear, GPIXW127X BSS platelets bound well, demonstrating that the residual amount of GPIbα present GPIXW127X BSS platelets is sufficient to mediate adhesion to VWF. Finally, recent studies (J Thromb Haemost 5:797,2007) have shown that platelet adhesion to Type III collagen can be mediated by either interaction of GPIbα with VWF, or by interaction of the integrin α2β1 with collagen under high shear flow. In support of this notion, adhesion of GPIbαTGTG del BSS platelets to immobilized Type III collagen could be completely inhibited by addition of the anti-α2β1 blocking mAb, Gi9, while adhesion of GPIXW127X BSS platelets to Type III collagen was only marginally affected. Taken together, we conclude that platelets having a W127X mutation in GPIX express residual amounts of functional GPIbα, and both GPIb-VWF and integrin α2β1-collagen interactions are physiologically important under conditions of high shear stress. Residual expression of GPIbα in GPIXW127X platelets, therefore, likely accounts for the relatively mild bleeding phenotype in this variant form of BSS.

症例1は47才,男牲,歩行障害の進行と精神発達遅延があり当院に入院した.低身長,知能低下,構音障害,〓性麻痺を認めた.検査所見上,血清コレステロール低値,β-リポ蛋白,アポ蛋白Bの低下を認め,症例2(症例1の二男)にも同様の所見を認めた.血縁者について神経学的および血液学的検索を行ない, 10名中2名に神経学的異常を, 10名中8名に低コレステロール血症を, 2名に明らかなβ-リポ蛋白の低下を認めた.アポ蛋白の明かな低下は9名中6名に認めた.以上より,本家系はFHBLの1家系と考えられた. FHBLのヘテロ接合体例における神経障害の合併は少なく,本例のように親子に精神発達遅延,〓性脊髄麻痺を認めた症例の報告は少ない. FHBLと神経障害について,文献的考察をふまえ報告する.

Forty-three patients with adult T-cell leukemia (ATL), admitted to the hospital from 1982 to 1987, were studied. Five of those were found to have additional cancer; two of the five had two additional kinds of cancers besides ATL. During the same period, in contrast, the authors encountered only three patients with some superimposed cancer among 155 cases of hematologic malignancies which had no association with human T-cell lymphotropic virus type I (HTLV-I). These facts strongly suggest that HTLV-I infection is not only associated with ATL, but it is likely to increase the incidence of other types of malignancy as well.

症例は76才,女性.全身倦怠感,両下肢脱力および貧血が急速に進行した. Hb 5.4g/d1,白血球数900/μ1,骨髄は赤芽球系過形成では環状鉄芽球を15%認め顆粒球系異常芽球を散見した.血中ビタミンB6濃度は低値で,筋電図検査はポリニューロパチーを示唆した.ピリドキサルリン酸60mg/日の内服で貧血,脱力共に改善した.原発性後天性鉄芽球性貧血とポリニューロパチーの合併はまれで,さらにビタミンB6で軽快したことが本例の特徴である.