Relationship between hemoglobin levels and vancomycin clearance in patients with sepsis.

PURPOSE: It is important to accurately estimate accurate vancomycin (VCM) clearance (CLvcm) for appropriate VCM dosing in the treatment of patients with sepsis. However, the pathophysiology of sepsis can make CLvcm prediction less accurate. Clearance of hydrophilic antibiotics is disturbed by organ dysfunction, and hemoglobin levels are negatively correlated with sequential organ function assessment scores. We investigated whether hemoglobin levels are associated with CLvcm in sepsis patients. METHODS: We performed a retrospective cohort study of patients treated with VCM in the Emergency and Critical Care Center of Nihon University Itabashi Hospital between 2005 and 2015. We enrolled 72 patients after exclusion of patients who received renal replacement therapy or surgery, had a change in hemoglobin levels more than 2 g/dL or received an erythrocyte infusion during the interval between initial VCM administration and measurement of initial trough levels, had a serum baseline creatinine level of ≥ 2 mg/dL, or were under 18 years old. RESULTS: Enrolled patients consisted of 13 non-sepsis patients and 59 sepsis patients. In sepsis patients, although CLvcm was correlated with CrCl in HGB ≥ 9 group as well as in non-sepsis patients, its correlation was not observed in HGB < 9 group. Hemoglobin levels were correlated with CLvcm in sepsis patients but not in non-sepsis patient. Multiple linear regression analysis also indicated that lower CLvcm was associated with lower hemoglobin and CrCl. CONCLUSION: Lower hemoglobin levels influence a relationship between CLvcm and CrCl in sepsis patients. We propose that VCM dosing should be adjusted for hemoglobin levels in sepsis patients.

Optimal timing for pegfilgrastim administration in Japanese breast cancer patients receiving intermediate-risk chemotherapies.

Background Pegfilgrastim is widely used for prophylaxis of febrile neutropenia (FN) in cancer patients receiving chemotherapies. However, the optimal timing of pegfilgrastim administration has not been established. Objective We investigated the effect of the timing of pegfilgrastim administration on the prevention of FN in patients with breast cancer undergoing intermediate-risk chemotherapies. Method We retrospectively analysed the incidence of FN in patients with breast cancer treated at our institution with intermediate-risk chemotherapies and primary or secondary prophylactic pegfilgrastim between 2015 and 2017. The impact of the timing of pegfilgrastim administration on the incidence of FN was evaluated by univariate and multivariate logistic regression analyses. Results Overall, 87 patients received a total of 318 chemotherapy cycles with pegfilgrastim, and 14 patients (16%) experienced FN. In univariate analyses, day 2 pegfilgrastim administration, age of > 65 years, baseline haemoglobin < 12 g/dL, prior history of FN, and presence of recurrent/metastatic disease trended toward an association with FN. Adjustment for these confounding risk factors revealed that day 2 pegfilgrastim administration was associated with a significantly increased risk of FN (odds ratio 11.0, p = 0.009). Conclusion Administrating pegfilgrastim on day 3 or later may prevent FN more effectively among Japanese breast cancer patients receiving intermediate-risk chemotherapies.

A clinical prediction model for infusion-related reactions to rituximab in patients with B cell lymphomas.

Background Infusion-related reactions (IRRs) are a major adverse event of rituximab. Objective To develop a prediction model for IRRs to rituximab among patients with B cell non- Hodgkin's lymphomas (B-NHL). Setting A 1000-bed university hospital in Tokyo. Methods Patients with B-NHL treated with rituximab at our institution from 2004 to 2014 were retrospectively analysed. Chills, fever, rash, nausea, asthenia, headache, cardiovascular symptoms, and respiratory symptoms of any grade, in association with rituximab infusion, were identified as IRRs. Risk factors for IRRs to rituximab found in the intergroup analysis were subsequently evaluated by using multivariate analysis. Main outcome measure Occurrence of IRRs to rituximab. Results A total of 140 patients with various types of B-NHL, including 74% with diffuse large Bcell lymphoma, were analysed. Among them, 55 and 85 patients were assigned to the IRR group and the non-IRR group, respectively. Indolent histological subtypes, bulky disease (>10 cm), B symptoms, higher serum soluble interleukin-2 receptor concentration, and bone marrow involvement were more common in the IRR group. The multivariate logistic regression analysis identified low-grade lymphomas [odds ratio (OR) 2.81, p = 0.017] and bulky disease (OR 2.52, p = 0.037) as independent risk factors for IRRs to rituximab. The incidence rates of IRRs to rituximab among patients with neither, one, or both of these risk factors were 26, 54, and 78%, respectively (χ2 = 16.4, p < 0.001). Conclusions A simple combination of histopathological subtype and bulkiness of disease could predict the risk of IRRs to rituximab among patients with B-NHL.

Involvement of Pharmacists in Medical Care in Emergency and Critical Care Centers.

Emergency and critical care centers provide multidisciplinary therapy for critically ill patients by centralizing the expertise and technology of many medical professionals. Because the patients' conditions vary, different drug treatments are administered along with surgery. Therefore, the role of pharmacists is important. Critically ill patients who receive high-level invasive treatment undergo physiological changes differing from their normal condition along with variable therapeutic effects and pharmacokinetics. Pharmacists are responsible for recommending the appropriate drug therapy using their knowledge of pharmacology and pharmacokinetics. Further, pharmacists need to determine the general condition of patients by understanding vital signs, blood gas analysis results, etc. It is therefore necessary to conduct consultations with physicians and nurses. The knowledge required for emergency medical treatment is not provided during systematic training in pharmaceutical education, meaning that pharmacists acquire it in the clinical setting through trial and error. To disseminate the knowledge of emergency medical care to pharmacy students, emergency care training has been started in a few facilities. I believe that medical facilities and universities need to conduct joint educational sessions on emergency medical care. Moreover, compared with other medical fields, there are fewer studies on emergency medical care. Research-oriented pharmacists must resolve this issue. This review introduces the work conducted by pharmacists for clinical student education and clinical research at the Emergency and Critical Care Center of Nihon University Itabashi Hospital and discusses future prospects.

Effect of cell differentiation for neuroblastoma by vitamin k analogs.

BACKGROUND: Lack of receptor tyrosine kinase (TrkA), a high-affinity nerve growth factor (NGF) receptor, is closely associated with the malignant progression of neuroblastoma (NB) and its prognosis. Vitamin K3 (VK3) analogs inhibit the activity of protein tyrosine phosphatases (PTPases), which causes hydrolysis of the phosphate groups bound to the tyrosine residues on tyrosine kinase, resulting in sustained tyrosine phosphorylation. METHODS: In order to reverse this abnormal NGF/TrkA signal transduction in NB cells, we synthesized new VK3 analogs and examined their activity against NB cells. RESULTS: VK3 analogs increased or maintained the expression level of c-fos mRNA in the NB cells, which express the downstream genes of NGF/TrkA signal transduction. Moreover, the expression level of GAP-43 mRNA, which is a marker of neurite outgrowth and neuronal differentiation, was increased and morphological differentiation was also observed. VK3 analogs (especially COOH analog) continued to express c-fos and GAP-43 mRNAs and induced differentiation of NB cells after stimulation of NGF by strong inhibition of PTPase without affecting TrkA autophosphorylation. CONCLUSIONS: Vitamin K3 analogs may have potential as clinical therapeutic agents for NB.

Useful markers for detecting minimal residual disease in cases of neuroblastoma.

Neuroblastoma (NB), which is a malignant tumor of young children derived from neural crest cells that occurs in children, exhibits a wide range of clinical behaviors, from spontaneous regression to rapid progression. Advanced NB patients have a poor prognosis, and recently, autologous bone marrow transplantation (BMT) and autologous peripheral blood stem cell transplantation (PBSCT) have been attempted to improve the prognosis of these patients. In this study, we attempted to detect the expression of tyrosine hydroxylase (TH), neuroendocrine protein gene product (PGP) 9.5, ELAVL-4 and GD2 synthetase (GALGT), all of which are highly expressed in NBs, by the reverse transcription-polymerase chain reaction (RT-PCR) technique in order to detect minimal residual disease (MRD) in the bone marrow (BM) and peripheral blood (PB). Analysis of various tumor cell lines (Ewing's sarcoma, hepatoma, leukemias, and breast cancer cell lines in addition to NBs), and human normal samples (BM and PB cells) revealed that TH was the most specific marker for the detection of NB. On the other hand, PGP9.5 was the most sensitive marker, and was detected even when there was only one positive cell per 10(7) negative cells. We concluded that TH is a better marker before the diagnosis of NB while PGP9.5 is a better marker to detect MRD after the diagnosis. Here, we describe our results on useful markers to detect MRD in patients with NB.

Multicharged iron ions produced by using induction heating vapor source.

Multiply charged Fe ions are produced from solid pure material in an electron cyclotron resonance (ECR) ion source. We develop an evaporator by using induction heating with an induction coil which is made of bare molybdenum wire partially covered by ceramic beads in vacuum and surrounding and heating directly the pure Fe rod. Heated material has no contact with insulators, so that outgas is minimized. The evaporator is installed around the mirror end plate outside of the ECR plasma with its hole grazing the ECR zone. Helium or argon gas is usually chosen for supporting gas. The multicharged Fe ions up to Fe(13+) are extracted from the opposite side of mirror and against the evaporator, and then multicharged Fe ion beam is formed. We compare production of multicharged iron ions by using this new source with our previous methods.

Analyses of novel prognostic factors in neuroblastoma patients.

Neuroblastoma (NB) is the most common malignant solid tumor in childhood. There are well-recognized prognostic factors in NB such as age at diagnosis, organ of origin, stages, MYCN gene amplification, and expression of H-ras, trkA and survivin. Moreover, we investigated the expression of vascular endothelial growth factor (VEGF), tyrosine hydroxylase (TH), p53, stem cell factor (SCF) and c-kit of its receptor with quantitative real-time polymerase chain reaction (PCR) in 22 NBs and 4 other tumors (one malignant lymphoma, one malignant teratoma, and 2 rhabdomyosarcomas) samples. The correlation between patients' prognoses and the expression of TH or c-kit was newly recognized, particularly the good prognosis in patients in whom c-kit highly expressed and the poor prognosis contrarily associated with low or no expression, although the SCF of its ligand had no relationship with patient prognosis. It is possible that tumors without c-kit expression can not react with SCF (via the autocrine or paracrine system) and remain immature. It may be that this is a new critical clinical event in NB patients.

A case of nasopharyngeal actinomycosis leading to otitis media with effusion.

Nasopharyngeal actinomycosis is extremely rare, and to our knowledge, only seven cases have previously been reported. Diagnosis of actinomycosis is made by clinical finding, observation of the bacteria and histopathological examination. Treatment for actinomycosis is surgical debridement and administration of antibioticus, especially penicillin for several weeks with good prognosis. We report a case of nasopharyngeal actinomycosis, which lead to otitis media with effusion. Endoscopic surgery and prolonged penicillin administration for 2 months were effective for treatment of actinomycosis in the nasopharynx.

A solitary fibrous tumor in the external auditory meatus.

We herein describe a rare case of a spindle-cell neoplasm arising in the external auditory canal. A 38-year-old man presented with a progressive swelling of the entrance of left external auditory meatus. The patient underwent a surgical removal of the tumor. A light microscopic study showed a spindle-cell proliferation with a collagenous stroma and a staghorn-like vascular pattern. The tumor cells were immunohistochemically positive for vimentin and CD34. The tumor was thereafter diagnosed to be a solitary fibrous tumor (SFT). SFTs most commonly occur in the pleura and are supposed to originate from submesothelial connective tissue. Although, several cases of extrapleural SFT have been reported, no SFT arising in the entrance of left external auditory canal have ever been reported in the literature. As a basically benign tumor, it occasionally relapses or metastasizes after excision, and therefore a careful follow up is necessary.

Laryngeal solitary multiple mucosal neuromas without multiple endocrine neoplasia (MEN) type 2B.

The first case of laryngeal solitary multiple mucosal neuromas (MMN) was reported. A 73-year-old man who had complained of hoarseness and abnormal prickly sensation in the throat for 3 months visited our hospital. Many small whitish-yellow nodules were observed in the laryngeal mucosa from the right arytenoid to the interarytenoid region. Using laryngomicroscopy biopsy was performed twice. The pathological study showed neurogenic nodular lesions consisting of regularly arranged nerve bundles with many axons and Schwann cell proliferation, and so MMN was finally diagnosed. As MMN is regarded as a constant component of multiple endocrine neoplasia (MEN) type 2B, screening of MEN type 2B was performed, however, they were all within normal limits. This case was, therefore, diagnosed as a laryngeal solitary MMN without MEN type 2B.

Diagnostic significance and clinical applications of chimeric genes in Ewing's sarcoma.

Ewing's sarcoma (ES) is one of the most malignant bone and soft tissue tumors in childhood. Morphologically, ES belongs to the small round cell tumors (SRCT). ES, peripheral primitive neuroectodermal tumor (PNET), and Askin's tumor are classified as ES family tumors (ESFT) because they share a common chromosomal translocation. The EWS-FLI1 chimeric gene is generated by t (11; 22). Other reciprocal translocations resulting in formation of chimeric genes between EWS and ETS family genes (ERG, ETV1, E1AF, and FEV) are t (21; 22), t (7; 22), t (17; 22), and t (2; 22), respectively. Although it is generally difficult to distinguish ES from SRCT, we could easily and quickly distinguish ES from other SRCT by using reverse transcription polymerase chain reaction (RT-PCR). We looked for specific chimeric genes in 23 tumor samples, including three ES clinical samples. We detected five chimeric genes in the three ES samples. Three chimeric genes, all EWS-FLI1, were detected in one ES sample. Different chimeric genes, EWS-ERG and EWS-ETV1, were detected in the other two ES samples. Moreover, because we could not detect specific chimeric genes in samples from non-ESFT, it may be possible to use this technique to diagnose ESFT and to detect tumor cell contamination before hematopoietic stem cell transplantation.