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1.
Pediatr Int ; 64(1): e15326, 2022 Jan.
Article in English | MEDLINE | ID: mdl-36331232

ABSTRACT

BACKGROUND: A decrease in pediatric hospitalizations during the COVID-19 pandemic has been reported worldwide; however, few studies have examined areas with a limited number of COVID-19 cases, where influenced by viral interference by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is minimum. METHODS: We conducted an epidemiological study of pediatric hospitalizations on Sado, an isolated island in Niigata, Japan, that was unique environment with few COVID-19 cases and reliable pediatric admissions monitoring. We compared numbers of monthly hospitalizations and associated diagnoses for the periods April 2016 to March 2020 (pre-pandemic period) and April 2020 to March 2021 (pandemic period). RESULTS: Data were analyzed for 1,144 and 128 patients in the pre-pandemic and pandemic periods, respectively. We observed only three adults and no pediatric COVID-19 cases during the pandemic period. The number of monthly admissions was significantly lower in the pandemic period (median [interquartile ranges (IQR)]: 11.0 [7.0-14.0]) than in the pre-pandemic period (23.0 [20.8-28.3]; P < 0.001). Similar decreases were observed for hospitalizations due to respiratory tract infection (P < 0.01), but not for asthma exacerbation (P = 0.15), and gastrointestinal tract infection (P = 0.33). CONCLUSIONS: Pediatric hospitalizations during the pandemic significantly decreased on an isolated Japanese island where COVID-19 was not endemic and all pediatric admissions were ascertainable. This observation highlights the impact of decreased travel and increased awareness of infection control measures on pediatric hospitalizations due to infectious diseases, not by the SARS-CoV-2 viral interference.


Subject(s)
COVID-19 , Respiratory Tract Infections , Adult , Humans , COVID-19/epidemiology , Pandemics , SARS-CoV-2 , Hospitalization , Respiratory Tract Infections/epidemiology
2.
Pediatr Int ; 58(5): 400-402, 2016 May.
Article in English | MEDLINE | ID: mdl-27173420

ABSTRACT

Four infants born prematurely presented with multiple apnea episodes caused by human parechovirus type 3 (HPeV3) infection. All patients required oxygen supplementation, and one patient required mechanical ventilation. HPeV3 infection might be included in the differential diagnosis of apnea in neonates and young infants, especially those born prematurely.

3.
Pediatr Int ; 58(9): 855-61, 2016 Sep.
Article in English | MEDLINE | ID: mdl-26769572

ABSTRACT

BACKGROUND: Many pregnant women take vitamin supplements during pregnancy. The aim of this paper was to clarify the effects of dietary supplementation prior to and/or during pregnancy on child behavior. METHODS: A prospective birth cohort study from pregnancy to 3 years of age involving 1271 pairs of Japanese pregnant women and their newborns, was carried out. The women completed a self-administered questionnaire during the third trimester of pregnancy. To evaluate deviations in child behavior as an endpoint, each mother completed the Japanese Child Behavior Checklist for ages 2-3 years after 3 years of birth. Participant characteristics were compared between supplement takers and non-takers. RESULTS: Among many kinds of supplements, intake of supplemental vitamin A/ß-carotene prior to and/or during pregnancy was associated with hazardous effects on child behavior at 3 years of age (total t-score, P = 0.003; internal t-score, P = 0.027; external t-score, P = 0.013). This association held true even after adjusting for age, number of deliveries, infertility treatment, consumption of fast food, smoking status, maternal and paternal education, maternal and paternal income, gestational age at birth, anthropometry at birth (weight, height, head circumference and body circumference), and the State-Trait Anxiety Inventory at 3 years of age by means of multiple imputation. CONCLUSIONS: Intake of supplemental vitamin A prior to and/or during pregnancy may worsen child behavior at 3 years of age.


Subject(s)
Child Behavior/drug effects , Dietary Supplements , Infant, Premature, Diseases/psychology , Prenatal Care/methods , Vitamin A/adverse effects , Birth Weight , Child, Preschool , Female , Follow-Up Studies , Gestational Age , Humans , Incidence , Infant , Infant, Newborn , Infant, Premature, Diseases/epidemiology , Infant, Premature, Diseases/etiology , Japan/epidemiology , Male , Pregnancy , Prospective Studies , Surveys and Questionnaires , Time Factors , Vitamins/adverse effects , Young Adult
4.
Tohoku J Exp Med ; 238(2): 113-21, 2016 02.
Article in English | MEDLINE | ID: mdl-26806610

ABSTRACT

The current School Health and Safety Act in Japan states that children with influenza infection should stay home until day 6(th) after symptoms onset. This was an amendment of a previous version recommending school return on day 3 after defervescence. Here, we investigated the duration of fever and virus shedding after laninamivir treatment in 7 children infected with influenza A(H3N2) virus and 21 children with influenza B virus in relation to the school return timing recommended by the School Health and Safety Act during the 2011-2012 influenza season. Nasal discharge was collected on the first, second, and third hospital visits and virus titers were assessed by virus culture and real-time PCR. Duration of fever after laninamivir treatment was 1 day longer for influenza B than for influenza A(H3N2). Virus detection rates with 50% tissue culture infectious dose and viral RNA were highest at the first visit and gradually decreased at subsequent visits. Virus positivity rates were detectable at the time of defervescence in less than half of the enrolled patients (14.3-42.9%). Virus shedding rates were similarly low (0.0-19.0%) on day 3 or later from defervescence and on day 6 or later from fever onset (school return dates per the old and current School Health and Safety Act) regardless of the influenza type. In conclusion, despite the higher efficacy of laninamivir against A(H3N2) viruses than B viruses, viral shedding is low after return to school for both types, regardless of the version of the School Health and Safety Act.


Subject(s)
Health , Influenza A Virus, H3N2 Subtype/drug effects , Influenza, Human/drug therapy , Influenza, Human/virology , Schools , Virus Shedding/drug effects , Zanamivir/analogs & derivatives , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Child , Demography , Female , Guanidines , Humans , Influenza A Virus, H3N2 Subtype/isolation & purification , Male , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Pyrans , RNA, Viral/genetics , Sialic Acids , Zanamivir/pharmacology , Zanamivir/therapeutic use
5.
Int J Clin Oncol ; 20(3): 474-9, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25073954

ABSTRACT

BACKGROUND: The objective of the present clinical study is to determine the maximum tolerated dose (MTD)/recommended dose (RD) of combination therapy with nanoparticle albumin-bound paclitaxel (nab-PTX) and cyclophosphamide (CPA) in patients with metastatic or recurrent breast cancer. METHODS: nab-PTX and CPA were administered on the first day of each 21-day treatment cycle. The dose of CPA was fixed at 600 mg/m(2), while the dose of nab-PTX was increased from 180 mg/m(2) (Level 1) to 220 mg/m(2) (Level 2) and then to 260 mg/m(2) (Level 3). RESULTS: A total of 11 patients from two institutions were enrolled in the present study. At Level 3, a dose-limiting toxicity (DLT) was observed in 1 patient. Considering treatment continuity and the risk of adverse events in Cycle 2 and thereafter at this level, further subject enrollment at Level 3 was discontinued after two patients had been enrolled. Since the doses used at Level 3 were considered the MTD of nab-PTX and CPA and the doses used at Level 2 were considered the RD of nab-PTX and CPA, three additional subjects were enrolled at Level 2. No DLTs were observed at Level 2. CONCLUSION: The RD of combination therapy with nab-PTX and CPA was 220 mg/m(2) and 600 mg/m(2), respectively, in patients with metastatic or recurrent breast cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Aged , Albumin-Bound Paclitaxel/administration & dosage , Breast Neoplasms/pathology , Breast Neoplasms/secondary , Cyclophosphamide/administration & dosage , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Humans , Maximum Tolerated Dose , Middle Aged , Nanoparticles
6.
Hum Mol Genet ; 21(7): 1665-72, 2012 Apr 01.
Article in English | MEDLINE | ID: mdl-22180457

ABSTRACT

Although many association studies of polymorphisms in candidate genes with the clinical outcomes of breast cancer patients receiving adjuvant tamoxifen therapy have been reported, genetic factors determining individual response to tamoxifen are not fully understood. To identify genetic polymorphisms associated with clinical outcomes of patients with tamoxifen treatment, we conducted a genome-wide association study (GWAS). We studied 462 Japanese patients with hormone receptor-positive, invasive breast cancer receiving adjuvant tamoxifen therapy. Of them, 240 patients were analyzed by genome-wide genotyping using the Illumina Human610-Quad BeadChips, and two independent sets of 105 and 117 cases were used for replication studies. In the GWAS, we detected significant associations with recurrence-free survival at 15 single-nucleotide polymorphisms (SNPs) on nine chromosomal loci (1p31, 1q41, 5q33, 7p11, 10q22, 12q13, 13q22, 18q12 and 19p13) that satisfied a genome-wide significant threshold (log-rank P= 2.87 × 10(-9)-9.41 × 10(-8)). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrence-free survival in the replication study (log-rank P= 2.02 × 10(-4)) and a combined analysis indicated a strong association of this SNP with recurrence-free survival in breast cancer patients treated with tamoxifen (log-rank P= 1.26 × 10(-10)). Hazard ratio per C allele of rs10509373 was 4.51 [95% confidence interval (CI), 2.72-7.51; P= 6.29 × 10(-9)]. In a combined analysis of rs10509373 genotype with previously identified genetic makers, CYP2D6 and ABCC2, the number of risk alleles of these three genes had cumulative effects on recurrence-free survival among 345 patients receiving tamoxifen monotherapy (log-rank P= 2.28 × 10(-12)). In conclusion, we identified a novel locus associated with recurrence-free survival in Japanese breast cancer patients receiving adjuvant tamoxifen therapy.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Chromosomes, Human, Pair 10 , Genetic Loci , Polymorphism, Single Nucleotide , Tamoxifen/therapeutic use , Adult , Aged , Aged, 80 and over , Breast Neoplasms/diagnosis , Disease-Free Survival , Female , Genome-Wide Association Study , Humans , Japan , Middle Aged , Multidrug Resistance-Associated Protein 2 , Treatment Outcome
7.
Gan To Kagaku Ryoho ; 40(6): 769-71, 2013 Jun.
Article in Japanese | MEDLINE | ID: mdl-23863655

ABSTRACT

We report our experience with two cases of postoperative multiple liver metastases that were reduced remarkably by S-1, VNR, and MPA combination therapy for breast cancer. A case diagnosed as Stage II B(T2, N1, M0)breast cancer was treated postoperatively with LH-RH agonist and TAM. Another case, diagnosed as Stage III B(T4b, N2, M0), was treated with postoperative CE therapy. Tumor markers were normalized and liver metastases were shrunk significantly in both cases which received combination chemotherapy of S-1, VNR, and MPA as first-line therapy after recurrence. We conclude that this combination chemotherapy is a useful regimen for metastatic breast cancer patients, because it can be continuously implemented over a long period of time while maintaining high QOL without serious adverse events.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Adult , Breast Neoplasms/pathology , Drug Combinations , Female , Gonadotropin-Releasing Hormone/agonists , Humans , Liver Neoplasms/secondary , Medroxyprogesterone/administration & dosage , Middle Aged , Oxonic Acid/administration & dosage , Tamoxifen/administration & dosage , Tegafur/administration & dosage , Vinblastine/analogs & derivatives , Vinorelbine
8.
Mol Clin Oncol ; 18(5): 44, 2023 May.
Article in English | MEDLINE | ID: mdl-37090744

ABSTRACT

The present study aimed to evaluate the rate of positive surgical margins for magnetic resonance imaging (MRI) performed in the supine position prior to breast-conserving surgery (BCS). The rate of positive surgical margins and the clinicopathological factors were examined in consecutive patients with BCS who underwent preoperative MRI performed in the supine position at Sapporo Medical University Hospital (Sapporo, Japan) and related hospitals and clinics between January 2012 and December 2013. Of 1,175 eligible patients, 1,150 were included after excluding 25 patients with either bilateral breast cancer or stage IV disease. Positive margin was defined as no cancer seen on the resected margin. The primary endpoint was the rate of positive surgical margins when preoperative MRI was performed in the supine position and the secondary endpoint was identification of the factors that predict positive margins. Of the 1,150 female patients (median age, 55 years; range, 29-97 years) who underwent BCS for breast cancer following MRI performed in the supine position, 215 (18.8%) had positive margins, which is similar to the rate with MRI in the prone position, and 930 (81.2%) had negative margins. The rate of positive surgical margins in patients of the human epidermal growth factor receptor 2 (HER2) type was significantly higher than that in the non-HER2 type group (6.5 and 2.9%; χ2 P=0.0103). There was no increase in the rate of positive margins in breast cancers with a diameter of >T2. The rate of positive surgical margins following MRI performed in the supine position was 18.8%. Supine MRI appears to be suitable for informing on the extent of resection of breast cancer.

9.
J Hum Genet ; 57(12): 766-71, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22951594

ABSTRACT

In Japan, breast cancer is the most common cancer among women and the second leading cause of cancer death among women worldwide. To identify genetic variants associated with the disease susceptibility, we performed a genome-wide association study (GWAS) using a total of 1086 Japanese female patients with hormonal receptor-positive (HRP) breast cancer and 1816 female controls. We selected 33 single-nucleotide polymorphisms (SNPs) with suggestive associations in GWAS (P-value of <1 × 10(-4)) as well as 4 SNPs that were previously implicated their association with breast cancer for further replication by an independent set of 1653 cases and 2797 controls. We identified significant association of the disease with a SNP rs6788895 (P(combined) of 9.43 × 10(-8) with odds ratio (OR) of 1.22) in the SIAH2 (intron of seven in absentia homolog 2) gene on chromosome 3q25.1 where the involvement in estrogen-dependent diseases was suggested. In addition, rs3750817 in intron 2 of the fibroblast growth factor receptor 2 gene, which was reported to be associated with breast cancer susceptibility, was significantly replicated with P(combined) of 8.47 × 10(-8) with OR=1.22. Our results suggest a novel susceptibility locus on chromosome 3q25.1 for a HRP breast cancer.


Subject(s)
Asian People/genetics , Breast Neoplasms/genetics , Carcinoma, Intraductal, Noninfiltrating/genetics , Neoplasms, Hormone-Dependent/genetics , Nuclear Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Receptors, Estrogen/metabolism , Ubiquitin-Protein Ligases/genetics , Aged , Breast Neoplasms/metabolism , Carcinoma, Intraductal, Noninfiltrating/metabolism , Case-Control Studies , Chromosomes, Human, Pair 3/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Humans , Middle Aged , Neoplasms, Hormone-Dependent/metabolism , Nuclear Proteins/metabolism , Receptor, Fibroblast Growth Factor, Type 2/genetics , Risk Factors , Ubiquitin-Protein Ligases/metabolism
10.
J Infect Chemother ; 18(2): 213-8, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22038124

ABSTRACT

Identification of Haemophilus influenzae type b (Hib) in asymptomatic carriers is critical to control the spread of disease. This study was conducted between January 2008 and August 2011 as part of a birth cohort study in Sado Island, Japan, to elucidate the prevalence of Hib and its clones in a specific region. Nasopharyngeal cultures were obtained from 349 subjects at 4-, 7-, 10-, 18-, and 36-month health checkups and analyzed for H. influenzae. The Hib and nontypeable H. influenzae detection rates ranged from 0 to 1.5% (12 isolates) and from 7.9 to 32.9%, respectively. Twelve pediatric patients diagnosed with invasive or non-invasive Hib infections during the study period were also enrolled. The Hib isolates were analyzed for carriage of the beta-lactamase gene and ftsI mutations, and multilocus sequence type (MLST, ST type). Of the 24 Hib isolates, 18 (75%) were ST54, 5 (21%) were ST190, and 1 isolate (4%) was ST95. All of the ST190 isolates were genetically beta-lactamase-negative ampicillin-susceptible isolates, while all but one of the ST54 isolates were genetically beta-lactamase-positive amoxicillin/clavulanic acid-resistant isolates. The geographic distribution of Hib isolates in the study period was scattered. There were 2 day-care cases and 1 family case of Hib infection. The ST54 and ST190 strains circulated in Sado Island and were detected in both asymptomatic carriers and patients. We note that surveillance of healthy subjects to identify Hib carriers is important to understand the transmission of Hib.


Subject(s)
Carrier State/epidemiology , Haemophilus Infections/epidemiology , Haemophilus influenzae type b/genetics , Anti-Bacterial Agents/pharmacology , Carrier State/microbiology , Child , Child, Preschool , Cohort Studies , DNA, Bacterial/genetics , Female , Genotype , Haemophilus Infections/microbiology , Haemophilus Vaccines , Haemophilus influenzae type b/classification , Haemophilus influenzae type b/drug effects , Haemophilus influenzae type b/isolation & purification , Humans , Infant , Japan/epidemiology , Male , Microbial Sensitivity Tests , Multilocus Sequence Typing , Nasopharynx/microbiology , Prevalence , Vaccination
11.
Kansenshogaku Zasshi ; 86(2): 103-8, 2012 Mar.
Article in Japanese | MEDLINE | ID: mdl-22606876

ABSTRACT

Haemophilus influenzae type b (Hib) remains the leading cause of invasive bacterial infection in Japanese children. More than 110 countries that have included Hib conjugate vaccines in their routine vaccination programs have seen dramatical decrease in the incidence of Hib infections. In Japan, the vaccine has been introduced for voluntary immunization since December 2008 and has been provided free of charge only since January 2011. This review reports the prevalence of Hib and its clones among healthy children and pediatric patients diagnosed with invasive or non-invasive Hib infections in Sado Island, Japan. Of 25 Hib isolates collected in this surveillance, 4 genotypic patterns (ST54-gBLPACR-III, ST54-gBLNAR-I/II, ST190-gBLNAS, and ST95-gBLPACR-I/II) were detected. These STs were double or triple-locus variants of each other. Under the same antimicrobial selective pressure, high prevalence of gBLPACR strain (76.0%) was confirmed in Hib isolates, while gBLPACR prevalence in nontypeable H. influenzae was very low (5.2%). These data suggested that each ST strain may be brought into Sado Island by different routes. We note that surveillance of healthy subjects to identify Hib carriers is important to understand their role in transmission of Hib.


Subject(s)
Haemophilus Infections/transmission , Haemophilus influenzae type b/growth & development , Child , Haemophilus influenzae type b/isolation & purification , Humans
12.
Breast Cancer ; 28(3): 684-697, 2021 May.
Article in English | MEDLINE | ID: mdl-33638810

ABSTRACT

BACKGROUND: Previously, we conducted the 5-year open-label, randomized controlled trial (RCT) of leuprorelin adjuvant therapy in post-operative premenopausal patients with endocrine-responsive breast cancer, which was a pilot study to investigate the optimal duration of leuprorelin treatment. Since, however, long-term outcomes became required for the adjuvant endocrine therapy, we performed this follow-up observation study. METHODS: Follow-up observation study was performed up to 10th year after randomization, continuing RCT to evaluate the efficacy and safety of leuprorelin every 3 months for ≥ 3 versus 2 years, with daily tamoxifen for 5 years. Primary endpoints were disease-free survival (DFS) and 2-year landmark DFS. RESULTS: Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or ≥ 3 years (N = 110) with tamoxifen. Leuprorelin treatment for ≥ 3 years versus 2 years provided no significant difference in DFS (HR 0.944, 95% CI 0.486-1.8392) or 2-year landmark DFS (N = 99 and 102 in 2-year and ≥ 3-year groups, HR 0.834, 0.397-1.753). In small, higher-risk subgroup (n = 17); however, 2-year landmark DFS in ≥ 3-year group was significantly longer (HR 0.095, 0.011-0.850) than that in 2-year group. The incidence of bone-related adverse events was around 5% in both groups. CONCLUSIONS: Adjuvant leuprorelin treatment for ≥ 3 years with tamoxifen only showed similar efficacy and safety profiles to those for 2 years in analyses among all patients but suggested greater benefit in higher-risk patients. No new safety signal was identified for long-term leuprorelin treatment. TRIAL REGISTRATION NUMBER: Not applicable. This was an observational study.


Subject(s)
Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant/methods , Leuprolide/administration & dosage , Tamoxifen/administration & dosage , Antineoplastic Agents, Hormonal , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Follow-Up Studies , Humans , Leuprolide/adverse effects , Premenopause , Tamoxifen/adverse effects , Time Factors
13.
Pharmacogenet Genomics ; 20(9): 565-8, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20574415

ABSTRACT

We earlier reported a significant association between the cytochrome P450 2D6 (CYP2D6) genotype and the clinical outcome in 282 Japanese breast cancer patients receiving tamoxifen monotherapy. Although many research groups have provided evidence indicating the CYP2D6 genotype as one of the strongest predictors of tamoxifen response, the results still remain controversial. We hypothesized that concomitant treatment was one of the causes of these controversial results. We then studied 167 breast cancer patients who received tamoxifen-combined therapy to evaluate the effects of concomitant treatment on the association analysis and observed no significant association between CYP2D6 genotype and recurrence-free survival (P=0.44, hazard ratio: 0.64, 95% confidential interval: 0.20-1.99 in patients with two variant alleles vs. patients without a variant allele). When we carried out two subgroup analyses for nodal status and tumor size, we observed a positive association between the CYP2D6 genotype and the clinical outcome only in patients who received tamoxifen monotherapy. This study explained a part of the discrepancies among the reported results.


Subject(s)
Cytochrome P-450 CYP2D6/genetics , Genetic Association Studies , Pharmacogenetics , Tamoxifen/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Female , Gene Frequency/genetics , Genotype , Humans , Kaplan-Meier Estimate , Proportional Hazards Models
14.
Int J Oncol ; 34(2): 361-70, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19148470

ABSTRACT

Neoadjuvant chemotherapy with docetaxel for advanced breast cancer can improve the radicality for a subset of patients, but some patients suffer from severe adverse drug reactions without any benefit. To establish a method for predicting responses to docetaxel, we analyzed gene expression profiles of biopsy materials from 29 advanced breast cancers using a cDNA microarray consisting of 36,864 genes or ESTs, after enrichment of cancer cell population by laser microbeam microdissection. Analyzing eight PR (partial response) patients and twelve patients with SD (stable disease) or PD (progressive disease) response, we identified dozens of genes that were expressed differently between the 'responder (PR)' and 'non-responder (SD or PD)' groups. We further selected the nine 'predictive' genes showing the most significant differences and established a numerical prediction scoring system that clearly separated the responder group from the non-responder group. This system accurately predicted the drug responses of all of nine additional test cases that were reserved from the original 29 cases. Moreover, we developed a quantitative PCR-based prediction system that could be feasible for routine clinical use. Our results suggest that the sensitivity of an advanced breast cancer to the neoadjuvant chemotherapy with docetaxel could be predicted by expression patterns in this set of genes.


Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Gene Expression Profiling , Genome, Human , Taxoids/therapeutic use , Biopsy , Breast Neoplasms/pathology , DNA, Complementary/genetics , Docetaxel , Female , Humans , Neoplasm Proteins/genetics , Neoplasm Staging , Oligonucleotide Array Sequence Analysis , Postmenopause , Predictive Value of Tests , Premenopause , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Reverse Transcriptase Polymerase Chain Reaction , Treatment Outcome
15.
Pediatr Infect Dis J ; 28(2): 128-30, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19106776

ABSTRACT

BACKGROUND: To reduce the spread of drug-resistant pathogens, appropriate use of antimicrobials is an indispensable measure. From January 2002, we undertook campaigns about antimicrobial treatment in Sado Island, Japan. METHODS: The subjects were born in 1996 (group-1996) or during 2002-2004 (group-2002-2004) and received outpatient treatment at our hospital. We evaluated the subjects' medical information from patient records during their first 3 years of life. Demographic data, duration of breast-feeding, and attending a day-care center (DCC) were evaluated using a questionnaire. RESULTS: Average visit-based antimicrobial prescription rates significantly decreased from 535 for group-1996, to 70 for group-2002-2004 per 1000 hospital visits (P < 0.001). The rate of cephalosporin prescriptions significantly decreased (77.1%-16.7%; P < 0.001), while amoxicillin (0.8%-29.5%) and macrolides (21.0%-52.4%) significantly increased (P < 0.001). Regarding 417 nasopharyngeal cultures from group-2002-2004, 77.8% (179/230) of Streptococcus pneumoniae strains were nonsusceptible to penicillin. For Haemophilus influenzae strains, 30.6% (59/193) were nonsusceptible to ampicillin. Living with older sibling(s) and early DCC attendance were associated with carriage of resistant pathogens. CONCLUSIONS: In a closed area under controlled antimicrobial use, our data indicated that decreasing antimicrobial prescriptions alone could not achieve elimination of resistant pathogens. Strategies to control transmission at DCCs or from older sibling(s) are also essential.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Carrier State/microbiology , Nasopharynx/microbiology , Practice Patterns, Physicians'/statistics & numerical data , Anti-Bacterial Agents/administration & dosage , Child, Preschool , Drug Resistance, Bacterial , Drug Utilization , Female , Humans , Infant , Infant, Newborn , Japan , Male , Retrospective Studies , Surveys and Questionnaires
16.
J Transl Med ; 6: 24, 2008 May 10.
Article in English | MEDLINE | ID: mdl-18471305

ABSTRACT

BACKGROUND: We previously reported that survivin-2B, a splicing variant of survivin, was expressed in various types of tumors and that survivin-2B peptide might serve as a potent immunogenic cancer vaccine. The objective of this study was to examine the toxicity of and to clinically and immunologically evaluate survivin-2B peptide in a phase I clinical study for patients with advanced or recurrent breast cancer. METHODS: We set up two protocols. In the first protocol, 10 patients were vaccinated with escalating doses (0.1-1.0 mg) of survivin-2B peptide alone 4 times every 2 weeks. In the second protocol, 4 patients were vaccinated with the peptide at a dose of 1.0 mg mixed with IFA 4 times every 2 weeks. RESULTS: In the first protocol, no adverse events were observed during or after vaccination. In the second protocol, two patients had induration at the injection site. One patient had general malaise (grade 1), and another had general malaise (grade 1) and fever (grade 1). Peptide vaccination was well tolerated in all patients. In the first protocol, tumor marker levels increased in 8 patients, slightly decreased in 1 patient and were within the normal range during this clinical trial in 1 patient. With regard to tumor size, two patients were considered to have stable disease (SD). Immunologically, in 3 of the 10 patients (30%), an increase of the peptide-specific CTL frequency was detected. In the second protocol, an increase of the peptide-specific CTL frequency was detected in all 4 patients (100%), although there were no significant beneficial clinical responses. ELISPOT assay showed peptide-specific IFN-gamma responses in 2 patients in whom the peptide-specific CTL frequency in tetramer staining also was increased in both protocols. CONCLUSION: This phase I clinical study revealed that survivin-2B peptide vaccination was well tolerated. The vaccination with survivin-2B peptide mixed with IFA increased the frequency of peptide-specific CTL more effectively than vaccination with the peptide alone, although neither vaccination could induce efficient clinical responses. Considering the above, the addition of another effectual adjuvant such as a cytokine, heat shock protein, etc. to the vaccination with survivin-2B peptide mixed with IFA might induce improved immunological and clinical responses.


Subject(s)
Breast Neoplasms/immunology , Breast Neoplasms/therapy , Cancer Vaccines/therapeutic use , Carcinoma/immunology , Carcinoma/therapy , Microtubule-Associated Proteins/immunology , Neoplasm Proteins/immunology , Adult , Aged , Antibody Formation/physiology , Breast Neoplasms/pathology , Cancer Vaccines/immunology , Carcinoma/pathology , Female , Humans , Immunotherapy , Inhibitor of Apoptosis Proteins/immunology , Microtubule-Associated Proteins/chemistry , Middle Aged , Neoplasm Proteins/chemistry , Peptide Fragments/immunology , Recurrence , Serologic Tests , Survivin
17.
PLoS One ; 13(8): e0201606, 2018.
Article in English | MEDLINE | ID: mdl-30161160

ABSTRACT

PURPOSE: Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen. EXPERIMENTAL DESIGN: We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study. RESULTS: The combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10-6, 1.64 x 10-5, and 9.77 x 10-6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10-12), suggesting the cumulative effect of the three SNPs. CONCLUSION: We identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer.


Subject(s)
Breast Neoplasms/drug therapy , Genetic Markers , Genome-Wide Association Study/methods , Polymorphism, Single Nucleotide , Tamoxifen/therapeutic use , Adult , Aged , Aged, 80 and over , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/surgery , Chromosomes, Human/genetics , Female , Genetic Markers/drug effects , Humans , Ki-67 Antigen/metabolism , Middle Aged , Preoperative Care , Prospective Studies , Receptor, ErbB-2/metabolism , Sequence Analysis, DNA , Tamoxifen/pharmacology , Treatment Outcome
19.
Clin Cancer Res ; 23(8): 2019-2026, 2017 04 15.
Article in English | MEDLINE | ID: mdl-27797974

ABSTRACT

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, "endoxifen." There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.Experimental Design: We enrolled 279 patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor-positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019-26. ©2016 AACR.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cytochrome P-450 CYP2D6/genetics , Tamoxifen/therapeutic use , Adult , Aged , Aged, 80 and over , Female , Genotype , Humans , Ki-67 Antigen/analysis , Middle Aged , Polymorphism, Single Nucleotide , Prospective Studies , Treatment Outcome
20.
Clin Cancer Res ; 11(4): 1474-82, 2005 Feb 15.
Article in English | MEDLINE | ID: mdl-15746049

ABSTRACT

We reported previously a HLA-A24-restricted antigenic peptide, survivin-2B80-88 (AYACNTSTL), recognized by CD8(+) CTL. This peptide was derived from survivin protein, an inhibitor of apoptosis proteins, expressed in a variety of tumors, such as adenocarcinoma, squamous cell carcinoma, and malignant melanoma. In this report, we provide further evidence that survivin-2B80-88 peptide might serve as a potent immunogenic cancer vaccine for various cancer patients. Overexpression of survivin was detected in surgically resected primary tumor specimens of most breast and colorectal cancers and some gastric cancers as assessed by immunohistochemical study. HLA-A24/survivin-2B80-88 tetramer analysis revealed that there existed an increased number of CTL precursors in peripheral blood mononuclear cells (PBMC) of HLA-A24(+) cancer patients, and in vitro stimulation of PBMCs from six breast cancer patients with survivin-2B80-88 peptide could lead to increases of the CTL precursor frequency. Furthermore, CTLs specific for this peptide were successfully induced from PBMCs in all 7 (100%) patients with breast cancers, 6 of 7 (83%) patients with colorectal cancers, and 4 of 7 (57%) patients with gastric cancers. These data indicate that survivin expressed in tumor tissues is antigenic in cancer patients, and survivin-2B80-88-specific CTLs are present in PBMCs of various cancer patients. Our study raises the possibility that this peptide may be applicable as a general cancer vaccine to a large proportion of HLA-A24(+) cancer patients.


Subject(s)
Apoptosis/immunology , Cancer Vaccines/immunology , Microtubule-Associated Proteins/immunology , Adenocarcinoma/immunology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adult , Aged , Amino Acid Sequence , Breast Neoplasms/immunology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Transformed , Colonic Neoplasms/immunology , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Cytotoxicity, Immunologic/immunology , Female , HLA-A Antigens/immunology , HLA-A24 Antigen , Humans , Immunohistochemistry , Inhibitor of Apoptosis Proteins , K562 Cells , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunology , Male , Microtubule-Associated Proteins/analysis , Middle Aged , Neoplasm Proteins , Oligopeptides/immunology , Stomach Neoplasms/immunology , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Survivin , T-Lymphocytes, Cytotoxic/cytology , T-Lymphocytes, Cytotoxic/immunology
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