Determinants of clinic doctors' attitudes concerning antimicrobial prescription for patients with common colds or bronchitis: Additional analysis of a nationwide survey conducted by the Japanese Society of Chemotherapy and the Japanese Association for Infectious Diseases.

BACKGROUND: In 2019, the Japanese Society of Chemotherapy and the Japanese Association for Infectious Diseases reported nationwide, cross-sectional questionnaire survey data investigating the clinical status of clinic doctors' attitudes to antimicrobial stewardship. This study aimed to identify factors determining clinic doctors' attitudes concerning antimicrobial prescription for patients with a common cold or bronchitis. METHODS: In February 2018, 1500 randomly selected community-based medical clinics in Japan were sent a questionnaire. Primary and secondary endpoints were clinic doctors' attitudes concerning antimicrobial prescription, and antimicrobial medication types prescribed for patients with a common cold or bronchitis, respectively. We used multivariable linear regression analysis to identify factors associated with primary and secondary outcomes. RESULTS: We analyzed 269 of 274 responses (response rate, 18.3%). Linear regression analysis was used to identify determinants of proactive attitudes to antimicrobial prescription, including whether clinic doctors encountering patients with upper respiratory symptoms and no underlying illnesses, and diagnosed with a common cold would prescribe antimicrobial medication (ß = 0.283, t = 4.279, p = 0.000); whether clinic doctors frequently experienced requests from patients (or their families) with a common cold to prescribe antimicrobial medication (ß = 0.389, t = 6.133, p = 0.000), and; clinic doctors' awareness of antimicrobial stewardship in the past year (ß = -0.157, t = -2.456, p = 0.015). Determinants of proactive attitudes to prescribing broader-spectrum antimicrobials for patients with a common cold included clinic doctors' attitudes concerning antimicrobial prescription (ß = 0.165, t = 2.622, p = 0.009), whether the respondent was a pediatrician (ß = -0.288, t = -4.583, p = 0.000), and clinic doctors' attitudes to antimicrobial prescription (ß = 0.262, t = 4.075, p = 0.000) for patients with bronchitis. CONCLUSION: This study identified factors among clinic doctors that determined their attitudes to antimicrobial prescription concerning patients with a common cold or bronchitis. Identification and targeting of clinic doctors who unnecessarily prescribe antimicrobial medication is urgently required to promote antimicrobial stewardship in an outpatient setting.

A nationwide questionnaire survey of clinic doctors on antimicrobial stewardship in Japan.

BACKGROUND: Clinics are high prescribers of antimicrobials in Japan, but the present situation and the attitude of clinic doctors toward prescribing them remain unclear. OBJECTIVE: To investigate the present situation at clinics and clinic doctors' attitude toward antimicrobial stewardship. STUDY DESIGN: A questionnaire survey of clinic doctors. METHODS: A questionnaire targeting doctors was sent to 1500 clinics that were randomly selected from across the country. RESULTS: Among 274 respondents (response rate, 18.3%), 269 provided consent and their responses were analyzed. Awareness of the National Action Plan on Antimicrobial Resistance and the Manual of Antimicrobial Stewardship was low, but awareness of antimicrobial stewardship was high. A certain proportion of doctors prescribed antimicrobials for the common cold and acute bronchitis, and macrolides were the most commonly prescribed group of antimicrobials. Such prescription was not based solely on the doctors' knowledge but was also influenced by complex factors such as the doctor-patient relationship. CONCLUSION: Various measures such as improving doctor-patient communication and improving clinic doctors' knowledge are necessary to promote antimicrobial stewardship in the outpatient setting.

Ability of suvorexant to prevent delirium in patients in the intensive care unit: a randomized controlled trial.

AIM: There are no effective, tolerable, and established medications for preventing delirium in critically ill patients admitted to the intensive care unit (ICU). We investigated whether suvorexant was effective in preventing ICU delirium. METHODS: This randomized controlled study evaluated 70 adult patients (age ≥20 years) admitted to the mixed medical ICU of the Tokyo Medical University Hospital (Tokyo, Japan) between May 2015 and February 2017. Patients were randomized using a sealed envelope method to receive either suvorexant (n = 34; 15 mg for elderly patients and 20 mg for younger adults) or conventional treatment (n = 36) for a 7-day period. The primary outcome was delirium incidence based on the definition in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders. RESULTS: No significant between-group differences were observed in the demographic or clinical characteristics. Kaplan-Meier estimates revealed that time to delirium onset was significantly longer in the suvorexant group than in the conventional group (P < 0.05). CONCLUSION: Suvorexant might be effective in preventing delirium in ICU patients.

A survey on infection control in emergency departments in Japan.

AIM: Infection control in the emergency department is important for hospital risk management; however, few clinical guidelines have been established. This study aimed to determine whether hospitals in Japan have infection control manuals, and investigate the contents of manuals, consulting systems, and isolation facilities for emergency departments. METHODS: A total of 517 hospitals certified as educational institutions for board-certified acute care physicians in Japan were requested between March and May 2015 to provide a written evaluation of the infection control in the emergency department. RESULTS: A total of 51 of 303 (16.8%) hospitals had no manuals regarding infection control in the emergency department. Among 250 hospitals having emergency department manuals, 115 (46.0%) did not include contents regarding disinfection and sterilization for imaging examination rooms, and only 44 (17.6%) had criteria for contacting the emergency medical service when patients are suspected of, or diagnosed with, communicable diseases. Of the 303 hospitals, 277 (91.4%) prepared specific manuals for the 2009 pandemic influenza. Of the 303 hospitals, 80 (26.4%) did not prepare manuals for the Ebola virus disease outbreak in West Africa in 2014. Furthermore, 92 (30.4%) of the 303 hospitals did not have any negative-pressure isolation rooms. CONCLUSIONS: Practices and guidelines necessary for infection control in the emergency department were not sufficiently covered in the hospitals studied. Education, information sharing, and a checklist for preparing manuals are needed to establish better infection control systems in emergency departments.

CpG island methylator phenotype is associated with the efficacy of sequential oxaliplatin- and irinotecan-based chemotherapy and EGFR-related gene mutation in Japanese patients with metastatic colorectal cancer.

BACKGROUND: The CpG island methylator phenotype (CIMP) with multiple promoter methylated loci has been observed in a subset of human colorectal cancer (CRC) cases. CIMP status, which is closely associated with specific clinicopathological and molecular characteristics, is considered a potential predictive biomarker for efficacy of cancer treatment. However, the relationship between the effect of standard chemotherapy, including cytotoxic drugs and anti-epidermal growth factor receptor (EGFR) antibodies, and CIMP status has not been elucidated. METHODS: In 125 metastatic colorectal cancer (mCRC) patients, we investigated how clinical outcome of chemotherapy was related to CIMP status as detected by methylation-specific PCR (MSP) and to genetic status in five EGFR-related genes (KRAS, BRAF, PIK3CA, NRAS, and AKT1) as detected by direct sequencing. RESULTS: CIMP-positive status was significantly associated with proximal tumor location and peritoneum metastasis (all P values <0.05). The progression-free survival of patients with CIMP-positive tumors receiving sequential therapy with FOLFOX as the first-line treatment followed by irinotecan-based therapy as the second-line treatment (median = 6.6 months) was inferior to that of such patients receiving the reverse sequence (median = 15.2 months; P = 0.043). Furthermore, CIMP-positive tumors showed higher mutation frequencies for the five EGFR-related genes (74.1 %) than the CIMP-negative tumors did (50.0 %). Among the KRAS wild-type tumors, CIMP-positive tumors were associated with a worse clinical outcome than CIMP-negative tumors following anti-EGFR antibody therapy. CONCLUSION: Sequential FOLFOX followed by an irinotecan-based regimen is unfavorable in patients with CIMP-positive tumors. High frequencies of mutation in EGFR-related genes in CIMP-positive tumors may cause the lower response to anti-EGFR antibody therapy seen in patients with wild-type KRAS and CIMP-positive tumors.

Gene-expression profiles correlate with the efficacy of anti-EGFR therapy and chemotherapy for colorectal cancer.

BACKGROUND: Comprehensive gene-expression analysis is very useful for classifying specific cancers into subgroups on the basis of their biological characteristics; it is used both prognostically and predictively. The purpose of this study was to classify unresectable advanced or recurrent colorectal cancer (CRC) by gene-expression profiling of formalin-fixed paraffin-embedded tissues and to correlate CRC subgroups with clinicopathological and molecular features and clinical outcomes. METHODS: One hundred patients with advanced or recurrent CRC were enrolled. RNA extracted from FFPE tissues was subjected to gene-expression microarray analysis. RESULTS: The patients were stratified into four subgroups (subtypes A1, A2, B1, and B2) by unsupervised hierarchical clustering. By use of principle-components analysis (PCA), the patients were divided into subtypes A and B on the basis of component 1 and into subtypes 1 and 2 on the basis of component 2. Subtype A was significantly enriched among patients without the KRAS mutation and with an earlier clinical stage at diagnosis. With regard to anti-EGFR therapy, progression-free survival (PFS) was better for patients in subtype A without the KRAS mutation than for those with the KRAS mutation (P = 0.047). PFS for patients without the KRAS mutation in subtype B was comparable with that for patients with the KRAS mutation (P = 0.55). Similar results were observed in a validation set. CONCLUSION: We found that gene-expression profiles enabled stratification of CRC patients into four subgroups. The efficacy of anti-EGFR therapy was correlated with component 1 from PCA. This comprehensive study may explain the heterogeneity of unresectable advanced or recurrent CRC and could be useful for identifying novel biomarkers for CRC treatment.

Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain.

MUTYH-associated polyposis (MAP) is an adenomatous polyposis transmitted in an autosomal-recessive pattern, involving biallelic inactivation of the MUTYH gene. Loss of a functional MUTYH protein will result in the accumulation of G:T mismatched DNA caused by oxidative damage. Although p.Y179C and p.G396D are the two most prevalent MUTYH variants, more than 200 missense variants have been detected. It is difficult to determine whether these variants are disease-causing mutations or single-nucleotide polymorphisms. To understand the functional consequences of these variants, we generated 47 MUTYH gene variants via site-directed mutagenesis, expressed the encoded proteins in MutY-disrupted Escherichia coli, and assessed their abilities to complement the functional deficiency in the E. coli by monitoring spontaneous mutation rates. Although the majority of variants exhibited intermediate complementation relative to the wild type, some variants severely interfered with this complementation. However, some variants retained functioning similar to the wild type. In silico predictions of functional effects demonstrated a good correlation. Structural prediction of MUTYH based on the MutY protein structure allowed us to interpret effects on the protein stability or catalytic activity. These data will be useful for evaluating the functional consequences of missense MUTYH variants detected in patients with suspected MAP.

Treatment of lethal acetylsalicylic acid poisoning without hemodialysis.

Case: A woman aged in her 20s ingested approximately 99 g acetylsalicylic acid, and was transported to our hospital 2 h later. She was lucid, but complained of hearing loss and tinnitus. We performed gastric lavage and gave her activated charcoal several times. We attempted to maintain the urinary pH at 7.5 and output above 100 mL/h while preparing for urgent hemodialysis. Outcome: It was revealed after discharge that the blood concentration of acetylsalicylic acid was 103.8 mg/dL on admission (lethal dose level) and had decreased to 35.4 mg/dL by the next morning. The half-life was 8.5 h. Conclusion: Hemodialysis is strongly recommended for patients who take a lethal dose of acetylsalicylic acid. However, by carefully evaluating the vital signs and urinary output and pH, while preparing for emergency hemodialysis, we consider that it is possible to treat acetylsalicylic acid poisoning by alkaline diuresis and critical supportive care.

Phase II trial of cetuximab plus irinotecan for oxaliplatin- and irinotecan-based chemotherapy-refractory patients with advanced and/or metastatic colorectal cancer: evaluation of efficacy and safety based on KRAS mutation status (T-CORE0801).

BACKGROUND: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy by patients with metastatic colorectal cancer (mCRC). However, it has been based on the study of mainly Caucasian mCRC patients. This prospective study investigated the relationship between the mutation status of EGFR-related genes including KRAS and the response rate (RR) to cetuximab plus irinotecan therapy in Japanese mCRC patients. METHODS: Samples taken from 43 chemotherapy-refractory mCRC patients who had undergone cetuximab plus irinotecan therapy at 11 medical centers in Japan were subjected to direct DNA sequencing to determine the KRAS, BRAF, PIK3CA, NRAS, and AKT1 mutation status. The clinical outcome after the treatment was evaluated for each mutation status. RESULTS: KRAS mutations were detected in 31.7% of 41 eligible patients. The RR to cetuximab plus irinotecan therapy was found to be 17.9 and 0% in the KRAS wild-type and mutant subgroups, respectively. CONCLUSION: Despite the identification of a lower-than-expected RR to treatment by the KRAS wild-type subgroup, KRAS mutation status appears to be a useful predictive marker of response to cetuximab plus irinotecan therapy in Japanese mCRC patients.

KRAS mutation in patients with metastatic colorectal cancer does not preclude benefit from oxaliplatin-or irinotecan-based treatment.

Fluoropyrimidine-based chemotherapy plus antibody therapy is currently the standard first-line treatment for metastatic colorectal cancer (mCRC). In this study, we investigated the hypothesis that mutations in several of the targeted oncogenes are correlated with treatment outcomes in mCRC patients receiving different first-line regimens. Our study included a total of 194 patients who had undergone various forms of first-line chemotherapy. The KRAS, BRAF, PIK3CA, NRAS and AKT1 mutational status of the tumors was assessed and the association between mutational status and treatment outcome was evaluated. The median progression-free survival (mPFS) of the wild-type and mutated KRAS subgroups that had received oxaliplatin-based treatment was 8.6 and 6.8 months, respectively (P=0.41), whereas the mPFS of the wild-type KRAS, BRAF, PIK3CA, NRAS and AKT1 subgroups and that of their respective mutant subgroups was 9.7 and 7.2 months, respectively (P=0.10). The mPFS of the wild-type and mutated KRAS subgroups that had received irinotecan-based treatments was 7.7 and 9.7 months, respectively (P= 0.43). The mPFS of the wild-type KRAS, BRAF, PIK3CA, NRAS and AKT1 subgroups and that of their respective mutant subgroups was 7.1 and 10.0 months, respectively (P=0.76). Our data indicated that mCRC patients with activation of KRAS, BRAF, PIK3CA, NRAS and AKT1 mutations, even those being treated with oxaliplatin- and irinotecan-based regimens as first-line treatment, may benefit from cytotoxic drug therapy.

Preliminary estimation of the prevalence of chemotherapy-induced dysgeusia in Japanese patients with cancer.

BACKGROUND: Although dysgeusia is a common adverse event in chemotherapy patients; it has not been evaluated using objective methods, and its prevalence and frequency have not been quantified. METHODS: Salt-impregnated taste strips were used to objectively assess dysgeusia in patients receiving chemotherapy at Akita University (n = 38) and those off chemotherapy (n = 9). Participant characteristics, and ongoing and previous chemotherapies were evaluated, and their associations with dysgeusia analyzed. RESULTS: Dysgeusia developed in 38.8% (14/38) of chemotherapy patients, and was most prevalent in patients receiving 5-fluorouracil (5-FU) or its oral analogs (48.1%, 13/27). Particularly, dysgeusia developed in 55.6% (10/18) of patients receiving oral 5-FU analogs; however, prevalence in patients receiving and off chemotherapy was not significantly different. Patients aged ≥70 years also tended to experience dysgeusia (75.0%, 6/8). CONCLUSIONS: Association with dysgeusia may be higher for some chemotherapeutic drugs. Dysgeusia should be routinely assessed in chemotherapy patients with objective methods such as paper strips; interventions for its prevention may be required.

Development and validation of the Japanese version of the Decisional Conflict Scale to investigate the value of pharmacists' information: a before and after study.

BACKGROUND: The information provided in patient-centered care and shared decision-making influences patients' concerns and adherence to treatment. In the decision-making process, patients experience decisional conflict. The Decisional Conflict Scale (DCS) is a 16-item, self-administered questionnaire consisting of 5 subscales developed to assess patients' decisional conflict. This study aimed to develop the Japanese version of the DCS and to clarify the influence of the information provided by pharmacists' on decisional conflict among patients with cancer. METHODS: We developed the Japanese version of the DCS by using the forward-backward translation method. One hundred patients who were recommended a new chemotherapy regimen were recruited. The psychometric properties of the Japanese DCS, including internal consistency, convergent validity, discriminant validity, and construct validity, were examined. We assessed the decisional conflict of patients before and after the pharmacists' provision of information. RESULTS: Ninety-four patients, predominately female, with an average age of 58.1 years were sampled. The scores on the 5 subscales of the DCS showed high internal consistency (Cronbach's alpha = 0.84-0.96). Multi-trait scaling analysis and cluster analysis showed strong validity. The mean total DCS score decreased significantly from 40.2 to 31.7 after patients received information from the pharmacists (p < 0.001, paired t-test). Scores on all 5 subscales, namely, uncertainty, informed, values clarity, support, and effective decision, also significantly improved (p < 0.001 for all categories, paired t-test). CONCLUSIONS: The psychometric properties of the Japanese version of the DCS are considered appropriate for it to be administered to patients with cancer. Pharmacists' provision of information was able to decrease decisional conflict among patients with cancer who were recommended a new chemotherapy regimen.

Practical utility of circulating tumour cells as biomarkers in cancer chemotherapy for advanced colorectal cancer.

Molecular-targeted therapies require the assessment of targets and their related molecules. Circulating tumour cells (CTCs) are considered a very good source of samples for these purposes. In this study, we applied a practical method for examining CTCs to evaluate the effects of chemotherapy on advanced colorectal cancer (CRC). Even in stage IV CRC, CTCs were detected in only 38.5% (n=5/13) of the cases. However, in cases where CTCs were detected, the change in the number of CTCs compared before and after chemotherapy appeared to be associated with the therapeutic outcome. Changes in the number of CTCs may be a good predictive biomarker. Problems with this method are yet to be resolved, including the detection rate and the stability of the sample source for subsequent molecular analysis.

Clinical usefulness of KRAS, BRAF, and PIK3CA mutations as predictive markers of cetuximab efficacy in irinotecan- and oxaliplatin-refractory Japanese patients with metastatic colorectal cancer.

BACKGROUND: Anti-epidermal growth factor receptor (EGFR) antibodies, cetuximab, and panitumumab are established as a new treatment option for metastatic colorectal cancer (mCRC). Among activating mutations downstream of EGFR, the KRAS mutation, which is present in 30-45 % of CRC patients, has shown to be a predictive biomarker of resistance to anti-EGFR antibody therapy based on Caucasian studies. METHODS: Forty-three chemotherapy-refractory Japanese patients with mCRC were treated with cetuximab monotherapy or cetuximab plus irinotecan. KRAS, BRAF, and PIK3CA mutational status of tumors was assessed. The association between mutational status and treatment outcome was evaluated. RESULTS: Of 43 tumors, KRAS, BRAF, and PIK3CA mutations were identified in 12 (27.9 %), 2 (4.7 %), and 2 (4.7 %) tumors, respectively. The wild-type KRAS subgroup showed better clinical outcomes than the mutant KRAS subgroup in terms of response rate (RR) (31.3 % vs. 0 %, P = 0.034) and progression-free survival (PFS) (5.1 vs. 3.0 months, P = 0.017). No responder to treatment was shown in 16 (37.2 %) patients with tumors harboring mutations in any one of the three genes (KRAS, BRAF, and PIK3CA). The wild-type subgroup without any mutations in KRAS, BRAF, and PIK3CA had a better RR (37.0 %) and PFS (6.4 months) than did the wild-type KRAS subgroup. CONCLUSION: Our data indicated that KRAS status is predictive of cetuximab response in the Japanese population. The additional analysis of BRAF and PIK3CA genes in wild-type KRAS patients could improve selection of patients who are most likely to benefit from anti-EGFR antibody therapy.

[Predictive biomarkers of anti-EGFR monoclonal anti-body in colorectal cancer].

The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, triggers a downstream signaling cascade through areas such as the RAS-RAF-MAPK and PI3K-AKT pathways, which are involved in cell proliferation, survival and motility.Inhibiting EGFR activation has demonstrated significant promise as a molecular targeting therapy for various solid tumors. Two monoclonal antibodies (mAbs) targeting EGFR, cetuximab and panitumumab, are established to be new treatment options for metastatic colorectal cancer (mCRC). Among activating mutations in downstream of EGFR, the KRAS mutation, which is present in 40% of mCRC patients, has shown to be a predictive biomarker for resistance to anti-EGFR antibody therapy based on Caucasian studies. However, only a small proportion of patients achieved an objective response and benefit from anti-EGFR antibody, even among those with wild-type KRAS tumors. Other downstream factors in EGFR signaling are now being explored, such as the BRAF, PIK3CA, PTENgenes. Cetuximab, a chimeric immunoglobulin 1 (IgG1) monoclonal antibody, may also exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC is influenced by FCrR1 a-H131R and FC7RIKa-V158F polymorphisms. Additional analysis of BRAF, PIK3CA, PTEN and FcqR genes in KRAS wild-type patients could narrow down the selection of patients who are most likely to benefit from anti-EGFR antibody therapy.

[Antibody-dependent cellular cytotoxicity in the immunotherapeutic mechanisms of anti-EGFR monoclonal antibody].

EGFR constitute an attractive target for tumor therapy, because it is a transmembrane receptor tyrosine kinase which is critically involved in tumorigenesis by stimulating cell proliferation and inhibiting apoptosis or other biological functions. The anti-tumor effects of targeted therapy by anti-EGFR monoclonal antibodies are mainly based on direct inhibition of the EGFR signal transduction pathway. In addition, monoclonal antibody has the potential advantage of recruiting immune effect or mechanisms to kill tumor cells. The pre-clinical and clinical data indicated that antibody-dependent cellular cytotoxicity (ADCC) contributes to tumor cell lysis by anti-EGFR monoclonal antibodies. Some polymorphisms in Fc gamma receptor genes have been shown to be a predictive marker for the efficacy of anti-EGFR antibodies. Continued research on the immunotherapeutic mechanisms of monoclonal antibodies will improve the efficacy of antibody-based targeted therapy for cancer.

[Status of components in EGFR-related signal transduction as predictive markers for anti-EGFR antibody therapy in colorectal cancer treatment].

Anti-EGFR antibodies were designed to inhibit the receptor tyrosine kinase activity of EGFR by directly binding to the extracellular domain. Anti-EGFR antibodies have been approved or will be approved for use in Japan, the USA or Europe. Recently, many studies have investigated molecular markers can predict the response to anti-EGFR antibodies so as to discriminate responders and non-responders. Activating KRAS mutation has been shown to be a potent predictive marker of resistance to anti-EGFR antibodies. Moreover, BRAF mutations, PIK3CA mutations or loss of PTEN have also been shown to be other molecular markers to predict resistance to anti-EGFR antibodies. Further studies must integrate these markers into clinical decisions to use or not use anti-EGFR antibodies.