Risk evaluation of ampicillin/sulbactam-induced liver injury based on albumin-bilirubin score.

BACKGROUND: Drug-induced liver injury (DILI) is an adverse reaction caused by ampicillin/sulbactam (ABPC/SBT). The albumin-bilirubin (ALBI) score is an index of hepatic functional reserve. However, the relationship between ABPC/SBT-induced DILI and ALBI score remains unknown; therefore, we aimed to elucidate the risk of ABPC/SBT-induced DILI based on the ALBI score. METHODS: This was a single-center, retrospective, case-control study using electronic medical records. A total of 380 patients were enrolled in the present study, and the primary outcome was ABPC/SBT-induced DILI. The ALBI score was calculated using serum albumin and total bilirubin levels. In addition, we performed COX regression analysis using age ≥75 years, dose ≥9 g/day, alanine aminotransferase (ALT) ≥21 IU/L, and ALBI score ≥-2.00 as covariates. We also performed 1:1 propensity score matching between non-DILI and DILI groups. RESULTS: The incidence of DILI was 9.5% (36/380). According to COX regression analysis, the adjusted hazard ratio for ABPC/SBT-induced DILI with an ALBI score ≥-2.00 was 2.55 (95% confidence interval: 1.256-5.191, P = 0.010), suggesting that patients with baseline ALBI score ≥-2.00 may be at high risk for ABPC/SBT-induced DILI. However, significant differences were not observed in cumulative risk for DILI between non-DILI and DILI patients regarding an ALBI score ≥-2.00 after propensity score matching (P = 0.146). CONCLUSION: These findings suggest that ALBI score may be a simple and potentially useful index for predicting ABPC/SBT-induced DILI. In patients with an ALBI score ≥-2.00, frequent liver function monitoring should be considered to prevent ABPC/SBT-induced DILI.

Risk evaluation of carbapenem-induced liver injury based on machine learning analysis.

INTRODUCTION: Information regarding carbapenem-induced liver injury is limited, and the rate of liver injury caused by meropenem (MEPM) and doripenem (DRPM) remains unknown. Decision tree (DT) analysis, a machine learning method, has a flowchart-like model where users can easily predict the risk of liver injury. Thus, we aimed to compare the rate of liver injury between MEPM and DRPM and construct a flowchart that can be used to predict carbapenem-induced liver injury. METHODS: We investigated patients treated with MEPM (n = 310) or DRPM (n = 320) and confirmed liver injury as the primary outcome. We used a chi-square automatic interaction detection algorithm to construct DT models. The dependent variable was set as liver injury from a carbapenem (MEPM or DRPM), and factors including alanine aminotransferase (ALT), albumin-bilirubin (ALBI) score, and concomitant use of acetaminophen were used as explanatory variables. RESULTS: The rates of liver injury were 22.9% (71/310) and 17.5% (56/320) in the MEPM and DRPM groups, respectively; no significant differences in the rate were observed (95% confidence interval: 0.710-1.017). Although the DT model of MEPM could not be constructed, DT analysis showed that the incidence of introducing DRPM in patients with ALT >22 IU/L and ALBI scores > -1.87 might be high-risk. CONCLUSIONS: The risk of developing liver injury did not differ significantly between the MEPM and DRPM groups. Since ALT and ALBI score are evaluated in clinical settings, this DT model is convenient and potentially useful for medical staff in assessing liver injury before DRPM administration.

Risk assessment of micafungin-induced liver injury using spontaneous reporting system data and electronic medical records.

INTRODUCTION: There is limited information regarding antifungal-induced liver injuries, which have high mortality rates. Therefore, we used the Japanese Adverse Drug Event Report (JADER) database for signal detection associated with antifungal-induced liver injuries and medical records for risk assessment. METHODS: Reports of antifungal-induced liver injuries from JADER data were analyzed to calculate the reporting odds ratio (ROR) and 95% confidence interval (CI). A medical record-based study involving 109 adult patients treated with micafungin shows liver injury as the primary outcome in patients treated with micafungin. The albumin-bilirubin (ALBI) score was calculated based on albumin and total bilirubin levels. We selected five explanatory factors for multivariable logistic regression: alanine aminotransferase ≥20 IU/L, alkaline phosphatase ≥372 IU/L, aspartate aminotransferase ≥25 IU/L, ALBI score ≥ -1.290, and age ≥65 years. RESULTS: Signal detection for micafungin was observed in both, hepatocellular and cholestatic injuries, as per data from JADER. Univariate analyses performed on medical records suggest that alanine aminotransferase (p = 0.008), aspartate aminotransferase (p = 0.036), alkaline phosphatase (p = 0.045), and ALBI score (p = 0.028) may be factors associated with micafungin-induced liver injury. Based on multivariable logistic regression, the adjusted odds ratio for micafungin-induced liver injury in patients with ALBI score ≥ -1.290 was 2.78 (95% CI: 1.014-7.605, p = 0.047), suggesting that low hepatic functional reserve could be a risk factor for micafungin-induced liver injury. CONCLUSIONS: Careful monitoring of liver function may be necessary for micafungin administration in patients with low hepatic functional reserve.

Sindbis viral structural protein cytotoxicity on human neuroblastoma cells.

PURPOSE: Oncolytic viral therapy for neuroblastoma (NB) cells with Sindbis virus (SINV) is a promising strategy for treating high-risk NB. Here, we evaluated the possibility of using SINV structural proteins as therapeutic agents for NB since UV-inactivated SINV could induce cytopathogenic effects. METHODS: The cytotoxicity of UV-inactivated SINV toward human NB cell lines NB69, NGP, GOTO, NLF, SK-N-SH, SH-SY5Y, CHP134, NB-1, IMR32, and RT-BM-1 were analyzed. Apoptosis was confirmed by TUNEL assays. To determine the components of SINV responsible for the cytotoxicity of UV-inactivated SINV, expression vectors encoding the structural proteins, namely capsid, E2, and E1, were transfected in NB cells. Cytotoxicity was evaluated by MTT assays. RESULTS: UV-inactivated SINV elicited more significant cytotoxicity in NB69, NGP, and RT-BM-1 than in normal human fibroblasts. Results of the transfection experiments showed that all NB cell lines susceptible to UV-inactivated SINV were highly susceptible to the E1 protein, whereas fibroblasts transfected with vectors harboring capsid, E1, or E2 were not. CONCLUSIONS: We demonstrated that the cytotoxicity of the UV-inactivated SINV is due to apoptosis induced by the E1 structural protein of SINV, which can be used selectively as a therapeutic agent for NB.

DELIVER (JACCRO GC-08) trial: discover novel host-related immune-biomarkers for nivolumab in advanced gastric cancer.

Aim: Nivolumab has survival benefit in patients with previously treated advanced gastric cancer; however, about 60% of the patients did not respond to nivolumab, raising the necessity of its predictive biomarkers. Gut microbiome has been shown to be associated with efficacy of anti-PD-1 antibody in various types of cancers, but little is known about gastric cancer. Design: This is an observational/translational study to evaluate clinical outcomes of nivolumab and to discover novel immune-related biomarkers (gut microbiome, genetic polymorphism, gene expression and metabolome in plasma) in gastric cancer, using fecal and blood samples at two points before and after treatment. Candidate factors will be explored in first 200 patients and then validated in last 300 patients. Trial registration: UMIN000030850.

Recent Advances in Liquid Biopsy in Precision Oncology Research.

Liquid biopsy is a minimally invasive test for cancer genetic status based on circulating tumor DNA (ctDNA), circulating tumor cells, or other tumor-derived materials in blood plasma. Although the minimal invasiveness and time resolution are attractive features of liquid biopsy, the limited amount of ctDNA in plasma poses problems. Recent developments in digital PCR and next-generation sequencing (NGS)-based technology have improved the accuracy of liquid biopsy. In particular, molecular barcoding technology in NGS-based methods, i.e., tagging of molecular barcodes to cell-free DNA before amplification, reduces technical errors by validating the consensus of sequences originating from a single molecule, leading to marked improvement of the accuracy and detection limit. However, substitutions caused by DNA damage and somatic mutations originating from normal cells are still obstacles to the sensitive detection of mutations on ctDNA. Since there have been only a few clinical applications, a deeper understanding of ctDNA biology and more advanced analytical technology are needed for the practical application of liquid biopsy.

RlmCD-mediated U747 methylation promotes efficient G748 methylation by methyltransferase RlmAII in 23S rRNA in Streptococcus pneumoniae; interplay between two rRNA methylations responsible for telithromycin susceptibility.

Adenine at position 752 in a loop of helix 35 from positions 745 to 752 in domain II of 23S rRNA is involved in binding to the ribosome of telithromycin (TEL), a member of ketolides. Methylation of guanine at position 748 by the intrinsic methyltransferase RlmA(II) enhances binding of telithromycin (TEL) to A752 in Streptococcus pneumoniae. We have found that another intrinsic methylation of the adjacent uridine at position 747 enhances G748 methylation by RlmA(II), rendering TEL susceptibility. U747 and another nucleotide, U1939, were methylated by the dual-specific methyltransferase RlmCD encoded by SP_1029 in S. pneumoniae. Inactivation of RlmCD reduced N1-methylated level of G748 by RlmA(II) in vivo, leading to TEL resistance when the nucleotide A2058, located in domain V of 23S rRNA, was dimethylated by the dimethyltransferase Erm(B). In vitro methylation of rRNA showed that RlmA(II) activity was significantly enhanced by RlmCD-mediated pre-methylation of 23S rRNA. These results suggest that RlmCD-mediated U747 methylation promotes efficient G748 methylation by RlmA(II), thereby facilitating TEL binding to the ribosome.

[A Case Report of Clinical Complete Response with Chemotherapy for Descending Colon Cancer Complicated with Severe Pulmonary Dysfunction].

A 76-year-old male patient was diagnosed with progressive descending colon cancer. Since the patient had severe respiratoryfunction impairment after right pneumonectomy, the anesthesiologydepartment of our hospital determined that general anesthesia induction was too difficult. He was thus started on capecitabine plus oxaliplatin(XELOX)therapy. Three months after starting this treatment, colonoscopyshowed that the site had become scarred, and tissue examination revealed no indication of malignancy. Accordingly, the patient achieved clinical complete response. The patient had no findings of recurrence 1 year and 11 months after the start of chemotherapy. Chemotherapy for unresectable progressive recurrent colorectal cancer is based on the 5-FU anticancer agent, which exerts its antitumor effect byinhibiting DNA synthesis. The antitumor effect is reportedly high when the expression of thymidylate synthase(TS), a target agent, is low. In this patient, TS expression was low based on tissue examination. TS expression maybe an effective useful predictive factor for the efficacyof chemotherapyadministered to patients with unresectable progressive recurrent colorectal cancer.

FliT selectively enhances proteolysis of FlhC subunit in FlhD4C2 complex by an ATP-dependent protease, ClpXP.

We previously reported that the ClpXP ATP-dependent protease specifically recognizes and degrades the flagellar master transcriptional activator complex, FlhD4C2, to negatively control flagellar biogenesis. The flagellum-related protein, FliT, is also a negative regulator of flagellar regulon by inhibiting the binding of FlhD4C2 to the promoter DNA. We have found a novel pathway of FliT inhibition of FlhD4C2 activity connected to ClpXP proteolysis. An in vitro degradation assay using purified proteins shows that FliT selectively increases ClpXP proteolysis of the FlhC subunit in the FlhD4C2 complex. FliT behaves specifically to ClpXP-dependent proteolysis of FlhC. An in vitro interaction assay detects the ternary complex of FliT-FlhD4C2-ClpX. FliT promotes the affinity of ClpX against FlhD4C2 complex, whereas FliT does not directly interact with ClpX. Thus, FliT interacts with the FlhC in FlhD4C2 complex and increases the presentation of the FlhC recognition region to ClpX. The DNA-bound form of FlhD4C2 complex is resistant to ClpXP proteolysis. We suggest that the role of FliT in negatively controlling the flagellar gene expression involves increasing free molecules of FlhD4C2 sensitive to ClpXP proteolysis by inhibiting the binding to the promoter DNA as well as enhancing the selective proteolysis of FlhC subunit by ClpXP.

Molecular characterization of linezolid-resistant CoNS isolates in Japan.

OBJECTIVES: Linezolid has been reported to remain active against 98% of staphylococci with resistance identified in 0.05% of Staphylococcus aureus and 1.4% of CoNS. The objective of this study was to characterize the linezolid-resistance mechanisms in the linezolid-resistant CoNS strains isolated in Japan. METHODS: Staphylococcus capitis strains exhibiting linezolid MICs >8 mg/L isolated from inpatients between 2012 and 2014 were screened for cfr and mutations in 23S rRNA, L3 and L4 by PCR/sequencing. Isolates were also examined for mutations in the rlmN gene. RESULTS: S. capitis had six 23S rRNA alleles. Five S. capitis isolates displayed linezolid MICs of 8, 16 and 32 mg/L. G2576U mutations were detected in three, four or five copies of 23S rRNA in all isolates. In two isolates exhibiting the highest linezolid MIC (32 mg/L) there was a large deletion in a single copy of 23S rRNA. Repeated 10 bp sequences were found in both 16S and 23S rRNAs, suggesting deletion by recombination between the repeats. One isolate had the mutation Ala-142→Thr in the ribosomal protein L3. All linezolid-resistant isolates also demonstrated mutations in the gene encoding RlmN methyltransferase, leading to Thr-62→Met and Gly-148→Ser. CONCLUSIONS: Multiple mechanisms appeared to be responsible for the elevated linezolid resistance in S. capitis isolates: a G2576U mutation in different numbers of copies of 23S rRNA, loss of a single copy of 23S rRNA and a mutation in the ribosomal protein L3, suggesting the accumulation of independent mutational events.

[A Case of Idiopathic Thrombocytopenic Purpura during Adjuvant Chemotherapy for Colon Cancer].

A 76-year-old man underwent surgery for sigmoid colon cancer. The pathological finding was stage Ⅱ with a high-risk of recurrence (SI [bladder], l y0, v2, pN0, H0, P0, M0). He was treated with TS-1 as adjuvant chemotherapy. After the 1 course of chemotherapy, his platelet count was 4,000/mL. The high index of platelet associated IgG (PA-IgG) and bone marrow examination suggested that thrombocytopenia was caused by idiopathic thrombocytopenic purpura. The platelet count improved by prednisolone administration and Helicobacter pylori eradication treatment. After 6 months with no administration of adjuvant chemotherapy, the colon cancer recurred locally, and we performed a Hartmann's operation.

[Cardioversion for paroxysmal supraventricular tachycardia during lung surgery in a patient with concealed Wolff-Parkinson-White syndrome].

We report a case of paroxysmal supraventricular tachycardia (PSVT) that occurred during video-assisted thoracoscopic (VATS) lobectomy in a patient with concealed Wolff-Parkinson-White (WPW) syndrome. A 59-year-old man with lung cancer was scheduled for VATS lobectomy under general anesthesia. After inserting a thoracic epidural catheter, general anesthesia was induced with intravenous administration of propofol. Anesthesia was maintained with inhalation of desfurane in an air/oxygen mixture and intravenous infusion of remifentanil. Recurrent PSVT occurred three times, and the last episode of PSVT continued for 50 minutes regardless of administration of antiarrhythmic drugs. Synchronized electric shock via adhesive electrode pads on the patient's chest successfully converted PSVT back to normal sinus rhythm. The remaining course and postoperative period were uneventful. An electrophysiological study performed after hospital discharge detected concealed WPW syndrome, which had contributed to the development of atrioventricular reciprocating tachycardia. Concealed WPW syndrome is a rare, but critical complication that could possibly cause lethal atrial tachyarrhythmias during the perioperative period. In the present case, cardioversion using adhesive electrode pads briefly terminated PSVT in a patient with concealed WPW syndrome.

Successful intracranial response of lorlatinib after resistance with alectinib and brigatinib in patients with ALK-positive lung adenocarcinoma: Implications of CNS penetration rate of brigatinib.

We present the case of a 34-year-old Japanese man with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer and brain metastases. After central nervous system (CNS) disease progression with alecintib and brigatinib, treatment with lorlatinib resulted in a good intracranial response. In this case, we investigated brain penetration ratio of brigatinib using cerebrospinal fluid and paired serum samples, and the ratio was 0.012. Further, we investigated resistance mechanisms via next-generation sequencing (NGS) using lung biopsy at lung cancer diagnosis and brain biopsy sample at progressive disease of brigatinib. No apparent resistance mechanism of known ALK resistance, such as ALK mutations, amplifications, epithelial-mesenchymal transition (EMT) and bypass pathway activation were detected. Taken together, we speculate that the low CNS penetration rate of brigatinib confers CNS progression. Further studies are warranted to reveal the resistance mechanism and propose a treatment strategy for CNS progression in ALK-positive patients.

Long-Term Efficacy of Immune Checkpoint Inhibitor for Squamous Cell Carcinoma Lesion Transformed From EGFR-Mutated Adenocarcinoma After Osimertinib Treatment: A Case Report.

Histologic transformation is one of the mechanisms of resistance to EGFR tyrosine kinase inhibitor in patients with NSCLC with EGFR mutation. The transformation from adenocarcinoma to squamous cell carcinoma (SCC) has been recently recognized as a mechanism of resistance to osimertinib. The prognosis after transformation to SCC is considered to be poor, and the therapeutic strategy for these patients is unclear. Herein, we report a case of long-term response to pembrolizumab monotherapy for an SCC-transformed lesion in a patient with EGFR-mutated adenocarcinoma after osimertinib treatment. A 68-year-old man underwent right upper lobectomy and was diagnosed with lung adenocarcinoma, pathologic stage IIA, with EGFR L858R. Five years after the surgery, he was diagnosed with recurrence and administered osimertinib. Ten months after, biopsy for an enlarged subpleural lesion revealed SCC with EGFR L858R, leading to a diagnosis of histologic transformation. Notably, the programmed death-ligand 1 expression level of the transformed lesion was higher than that of the adenocarcinoma (90% versus <1%). The size of the SCC lesion had reduced with pembrolizumab monotherapy, and the reduction was maintained for over 47 months since transformation. Nevertheless, the original adenocarcinoma lesion progressed after pembrolizumab therapy and was controlled by other cytotoxic drugs and readministration of osimertinib. Immune checkpoint inhibitor therapy is generally ineffective against EGFR-mutated adenocarcinoma. Nevertheless, it may be promising for achieving a good prognosis when EGFR-mutated adenocarcinoma transforms to SCC after developing EGFR tyrosine kinase inhibitor resistance-particularly if the transformed lesion has high programmed death-ligand 1 expression.

Methylation of 23S rRNA nucleotide G748 by RlmAII methyltransferase renders Streptococcus pneumoniae telithromycin susceptible.

Several posttranscriptional modifications of bacterial rRNAs are important in determining antibiotic resistance or sensitivity. In all Gram-positive bacteria, dimethylation of nucleotide A2058, located in domain V of 23S rRNA, by the dimethyltransferase Erm(B) results in low susceptibility and resistance to telithromycin (TEL). However, this is insufficient to produce high-level resistance to TEL in Streptococcus pneumoniae. Inactivation of the methyltransferase RlmA(II), which methylates the N-1 position of nucleotide G748, located in hairpin 35 of domain II of 23S rRNA, results in increased resistance to TEL in erm(B)-carrying S. pneumoniae. Sixteen TEL-resistant mutants (MICs, 16 to 32 µg/ml) were obtained from a clinically isolated S. pneumoniae strain showing low TEL susceptibility (MIC, 2 µg/ml), with mutation resulting in constitutive dimethylation of A2058 because of nucleotide differences in the regulatory region of erm(B) mRNA. Primer extension analysis showed that the degree of methylation at G748 in all TEL-resistant mutants was significantly reduced by a mutation in the gene encoding RlmA(II) to create a stop codon or change an amino acid residue. Furthermore, RNA footprinting with dimethyl sulfate and a molecular modeling study suggested that methylation of G748 may contribute to the stable interaction of TEL with domain II of 23S rRNA, even after dimethylation of A2058 by Erm(B). This novel finding shows that methylation of G748 by RlmA(II) renders S. pneumoniae TEL susceptible.

Vitamin A facilitates enteric nervous system precursor migration by reducing Pten accumulation.

Hirschsprung disease is a serious disorder of enteric nervous system (ENS) development caused by the failure of ENS precursor migration into the distal bowel. We now demonstrate that retinoic acid (RA) is crucial for GDNF-induced ENS precursor migration, cell polarization and lamellipodia formation, and that vitamin A depletion causes distal bowel aganglionosis in serum retinol-binding-protein-deficient (Rbp4(-/-)) mice. Ret heterozygosity increases the incidence and severity of distal bowel aganglionosis induced by vitamin A deficiency in Rbp4(-/-) animals. Furthermore, RA reduces phosphatase and tensin homolog (Pten) accumulation in migrating cells, whereas Pten overexpression slows ENS precursor migration. Collectively, these data support the hypothesis that vitamin A deficiency is a non-genetic risk factor that increases Hirschsprung disease penetrance and expressivity, suggesting that some cases of Hirschsprung disease might be preventable by optimizing maternal nutrition.

[The effect of strontium-89 therapy in a patient with cholangiocellular carcinoma].

A 77-year-old man was diagnosed as having cholangiocellular carcinoma. The patient underwent partial right hepatectomy in June 2008, and multiple bone metastases occurred approximately 9 months after surgery. He refused salvage chemotherapy and radiation therapy. Although he had been treated with opiate analgesics, he was unable to sit up owing to severe pain in the left ilium. He was hospitalized because of buttock pain and left leg numbness. Even a combination of fentanyl patch, gabapentin, and subarachnoid block was ineffective in controlling pain. Strontium-89 (89Sr) therapy was successful in eliminating the intractable pain, and there were no serious side effects during therapy. The patient was discharged from the hospital, and he received palliative care at home for a short period.

Exploratory Study of Pharmacists' Monitoring Methods Based on Left Ventricular Function for Hypermagnesemia by Magnesium Oxide in Heart Failure.

Serum magnesium (Mg) monitoring in patients with heart failure (HF) receiving magnesium oxide (MgO) is not adequately performed. Furthermore, the relationship between left ventricular function (LVF) and hypermagnesemia in HF is unknown. Here, we investigated the efficacy of serum Mg monitoring by protocol-based pharmaceutical management (PBPM) and the effect of LVF on hypermagnesemia. This protocol is for patients with an estimated glomerular filtration rate of <45 mL/min, receiving MgO, and admitted to the cardiology unit. The pharmacist includes the measurement of Mg when a blood test is ordered for a patient by their physician. Rates of serum Mg measurement and hypermagnesemia detection were compared at 2 years pre-PBPM (n = 88) and at 2 years post-PBPM (n = 55). LVF parameters and reported factors for hypermagnesemia were selected as explanatory factors on multivariate logistic regression. The measurement rate of serum Mg concentration significantly increased from 19.3% pre-PBPM to 80.0% post-PBPM (P < .001). The detection rate of hypermagnesemia also increased from 3.4% to 27.3%, respectively (P < .001). Our results suggest that serum Mg monitoring by PBPM may contribute to the early detection of hypermagnesemia and prevent its progression in HF. According to logistic regression, the adjusted odds ratio for hypermagnesemia with an exacerbation of HF was 9.57 (95% confidence interval: 1.594-57.477, P = .014), and the E/e' > 15, an index of reduced left ventricular diastolic capacity, was 6.46 (95% confidence interval: 1.291-32.364, P = .023). We propose that serum Mg monitoring should be performed during exacerbations of HF in patients with left ventricular diastolic dysfunction, with a pharmacist's assistance.