[Refractory multiple myeloma with impaired consciousness accompanied by hyperammonemia and leukoencephalopathy-like findings].

A 81-year-old female was diagnosed with symptomatic multiple myeloma (MM; IgG κ type, D&S: IIB, ISS: 2) in August 2017. Although treatment with lenalidomide and dexamethasone was started, she developed deep venous thrombosis in the lower extremities as a complication; therefore, the treatment was changed to DBd. In February 2018, she required hospitalization due to general weakness and altered consciousness. Her IgG level and κ/λ ratio were elevated at 4,156 mg/dl and 605.56, respectively, revealing that MM was treatment-resistant. A protein-cell dissociation (cell blood count, 0/µl; protein, 100.6 mg/dl) was detected in the cerebrospinal fluid, whereas the ammonia level in serum was high (172 µg/dl). T2-weighted magnetic resonance imaging showed a broad range of high-density area in deep cerebral white matter suggesting leukoencephalopathy, whereas the cerebrospinal fluid was negative for JC virus. No pathological conditions causing secondary hyperammonemia were found. Although the involvement of drug-induced leukoencephalopathy in altered consciousness could not be ruled out since the chromosome with the normal karyotype at the first visit had a complex chromosomal abnormality, an originally minor clone of MM cells with a chromosomal abnormality might have contributed to the ammonia production resulting in altered consciousness.

[Delivery of a Healthy Newborn by the Partner of a Patient with CML Undergoing Treatment with Nilotinib].

A man in his 40s was diagnosed with CML. He and his partner expressed their desire to have a child. We recommended planning the pregnancy after the achievement of major molecular response and completion of TKI therapy because we could not promise complete safety of the fetus, However, he and his partner insisted on starting the TKI therapy immediately and planned the pregnancy during the therapy. The patient was started on nilotinib 600mg/body. CCyR, MMR, and CMR were achieved in 3, 8, and 12 months, respectively. The patient's partner got pregnant when he had been on TKI therapy for 15 months, and she gave birth to a healthy boy. Since many patients with CMLcan live for a long time after receiving TKI therapy, the quality of life of these patients is more important. Even if the percentage of patients with CML who are under 50 years of age is approximately 30%, the safety information of TKI with respect to pregnancy is unsatisfactory. Doctors struggle to address the problems of the patient's wish of childbearing, priority of TKI therapy, and fetal risks of the treatment. Although only a few cases of pregnancy and delivery of the partners of male patients with CML treated with TKI have been reported, all cases showed healthy childbirth and normal child growth. Our experience also showed that the partner of a male patient with CML treated with TKI became pregnant and delivered a healthy baby.

Performance evaluation of an Indoxyl Sulfate Assay Kit "NIPRO".

Background The relationship between renal disease and cardiovascular disease (CVD) is currently known as cardiorenal syndrome. Indoxyl sulfate (IS) is one of the uremic toxins that accelerates the progression of cardiorenal syndrome. This report presents a new method for measuring IS in a simpler way. Methods We evaluated the analytical performance of an IS Assay Kit "NIPRO" loaded on LABOSPECT 008. The evaluated analytical performances included accuracy, precision, dilution linearity, limit of detection (LOD), limit of quantitation (LOQ), recovery test, interference test and comparison against assays performed by high-performance liquid chromatography (HPLC). Results Total precision showed a <5.3% coefficient of variation at IS concentrations of 3.57-277.73 µmol/L, and satisfactory results were observed in the dilution linearity, LOD, LOQ, recovery and interference tests. The IS Assay Kit "NIPRO" showed a high correlation with the HPLC conventional method (r = 0.993). Conclusions The IS Assay Kit "NIPRO" demonstrated satisfactory analytical performance, and this suggests it could shortly become another common method to measure circulating IS.

[Recurrent amylase-producing multiple myeloma responding to pomalidomide and carfilzomib-containing therapies].

A 73-year-old woman diagnosed with symptomatic multiple myeloma (MM; IgG-κ type, D&S: IIIA, ISS: 2) was administered bortezomib plus dexamethasone (BD) therapy. Post BD therapy, although autologous hematopoietic stem cell transplantation and thalidomide, lenalidomide, and melphalan/prednisolone/thalidomide (MPT) therapies were also performed, the patient remained unresponsive. However, the disease relapsed, and she eventually developed pantalgia. Therefore, the patient was admitted to our hospital and was administered pomalidomide and dexamethasone (Pd) therapy. The serum amylase (AMY) and urine AMY levels were 6,329 and 6,098 IU/l, respectively, which were salivary gland-type amylase (S-AMY). Notably, the markedly high levels immediately decreased after the first course of the Pd therapy; additionally, the pantalgia also disappeared. The S-AMY level in the supernatant from cultured bone marrow mononuclear cells was higher than that observed in a normal control. In addition, AMY was high when MM previously relapsed, suggesting the presence of AMY-producing MM. Although AMY-producing MM was first reported by Hata et al. in 1988, few cases have been reported in the new-drug era. In conclusion, AMY-producing MM frequently, including in our case (as the patient was refractory to treatment), is difficult to treat. However, our patient positively responded to the novel next-generation drugs such as pomalidomide and carfilzomib.

Low-dose immunoglobulin G is not associated with mortality in patients with sepsis and septic shock.

BACKGROUND: The administration of low-dose intravenous immunoglobulin G (IVIgG) (5 g/day for 3 days; approximate total 0.3 g/kg) is widely used as an adjunctive treatment for patients with sepsis in Japan, but its efficacy in the reduction of mortality has not been evaluated. We investigated whether the administration of low-dose IVIgG is associated with clinically important outcomes including intensive care unit (ICU) and in-hospital mortality. METHODS: This is a post-hoc subgroup analysis of data from a retrospective cohort study, the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study. The JSEPTIC DIC study was conducted in 42 ICUs in 40 institutions throughout Japan, and it investigated associations between sepsis-related coagulopathy, anticoagulation therapies, and clinical outcomes of 3195 adult patients with sepsis and septic shock admitted to ICUs from January 2011 through December 2013. To investigate associations between low-dose IVIgG administration and mortalities, propensity score-based matching analysis was used. RESULTS: IVIgG was administered to 960 patients (30.8%). Patients who received IVIgG were more severely ill than those who did not (Acute Physiology and Chronic Health Evaluation (APACHE) II score 24.2 ± 8.8 vs 22.6 ± 8.7, p < 0.001). They had higher ICU mortality (22.8% vs 17.4%, p < 0.001), but similar in-hospital mortality (34.4% vs 31.0%, p = 0.066). In propensity score-matched analysis, 653 pairs were created. Both ICU mortality and in-hospital mortality were similar between the two groups (21.0% vs 18.1%, p = 0.185, and 32.9% vs 28.6%, p = 0.093, respectively) using generalized estimating equations fitted with logistic regression models adjusted for other therapeutic interventions. The administration of IVIgG was not associated with ICU or in-hospital mortality (odds ratio (OR) 0.883; 95% confidence interval (CI) 0.655-1.192, p = 0.417, and OR 0.957, 95% CI, 0.724-1.265, p = 0.758, respectively). CONCLUSIONS: In this analysis of a large cohort of patients with sepsis and septic shock, the administration of low-dose IVIgG as an adjunctive therapy was not associated with a decrease in ICU or in-hospital mortality. TRIAL REGISTRATION: University Hospital Medical Information Network Individual Clinical Trials Registry, UMIN-CTR000012543 . Registered on 10 December 2013.

[Successful Prophylactic Minocycline Treatment for Recurrent Helicobacter Cinaedi Sepsis during Chemotherapy in a Patient with Follicular Lymphoma].

A 63-year-old man with follicular lymphoma was administered standard R-CHOP chemotherapy. Six days after the second course of chemotherapy, the patient developed fever and chills. Blood cultures yielded rod-shaped gram-negative bacteria, but no further identification was obtained. High fever and chills returned on the fifth and sixth days after the third and fourth courses of R-CHOP, respectively. These blood cultures were also positive. Since we detected spiral-shaped gram-negative rods, we performed a prolonged culture during the febrile period after the fourth course of R-CHOP. This revealed the formation of characteristic film-like colonies, and Helicobacter cinaedi(H. cinaedi)bacteria was identified. After final identification, the patient was administered prophylactic minocycline treatment. Subsequent blood cultures were negative, fever did not recur, and we were able to complete 6 courses of R-CHOP. Although H. cinaedi has been reported to be a cause of sepsis in immunocompromised patients, standard correlation has not been established. Our case suggests that H. cinaedi should be considered when recurrent fever is observed after chemotherapy. Prophylactic antibiotic treatment with minocycline may prevent sepsis, as observed in our case.

Totally implantable central venous device-associated blood stream infection in elderly malignant disease patients.

AIM: We investigated the rate of bloodstream infections in elderly malignant disease patients whose totally implantable central venous device (CV ports) had been removed for any reason at our hospital. METHODS: We evaluated 22 elderly malignant disease patients who had had their CV ports removed for any reason between May 2014 to April 2015. RESULTS: The patients were 12 males and 10 females between 62 and 86 years of age with a median age of 75.5 years. The catheter tip cultures were positive in 6 out of 22 cases (27.3%). Gram-positive cocci were detected in 5 cases, and gram-positive bacilli were detected in 1 case. Five of these 6 cases (83%) found to have positive catheter tip cultures were cultured at the time of death. In addition, 5 of the 13 catheters removed at the time of death resulted in positive culture results (38%). The positive culture ratio correlated well with the ratio of death and the age in cases of hematopoietic tumors. CONCLUSION: In cancer patients, the CV port is frequently used for the delivery of anti-cancer medicines. However, CV port infections are underestimated and typically not recognized in a timely manner. Patients suspected of having a CV port infection should be closely observed and the catheter removed immediately. However, it is very difficult to decide to discontinue a CV port, since its removal may render patients more susceptible to blood stream infections due to their poor general health and old age. CV port use should be considered in such cases to prevent future blood stream infections.

[A methotrexate-associated lympholiferative disorder patient with gastrointestinal perforation].

A 70-year-old woman was diagnosed with chronic rheumatoid arthritis and treated with methotrexate and prednisolone. She visited our hospital to determine the cause of her continuous fatigue and fever for the past three weeks. She consumed no food orally and was provided antibiotics because free air was found on computed tomography (CT). Intraperitoneal small lymphadenopathy and swelling of both adrenal glands was also found on CT, and MTX-associated lymphoproliferative disorder (MTX-LPD) was suspected. Am adrenal gland biopsy showed diffuse large B-cell lymphoma (DLBCL) associated with MTX-LPD. The causes of gastrointestinal perforation with collagen diseases have been reported to be functional gastrointestinal disorders with collagen diseases like amyloidosis, gastrointestinal infections in immunocompromised patients, and side effects of medication, such as steroids or NSAIDs and MTX. MTX-LPD is an uncommon side effect of methotrexate. To ensure its appropriate diagnosis and treatment, it is important to improve the degree of recognition of MTX-LPD, and a prompt response is needed.

[Successful treatment of venous thromboembolism with a Factor Xa inhibitor, edoxaban, in patients with lenalidomide-treated multiple myeloma].

Two multiple myeloma (MM) patients developed venous thromboembolism (VTE) while being treated with lenalidomide and low-dose dexamethasone. Aspirin is recommended for VTE prophylaxis when using lenalidomide/dexamethasone for MM patients with a standard risk of VTE. Despite aspirin administration, however, these two patients experienced VTE. Following VTE development, warfarin and then a Factor Xa inhibitor, edoxaban, were administered. The edoxaban treatment, especially, resulted in favorable and effective control of VTE. Considering these observations, Factor Xa inhibitors may in future become a preferred option for prevention and treatment of VTE when managing MM patients.

Impact of physician-staffed ground emergency medical services-administered pre-hospital trauma care on in-hospital survival outcomes in Japan.

PURPOSE: In Japan, the vehicle used in pre-hospital trauma care systems with physician-staffed ground emergency medical services (GEMS) is referred to as a "doctor car". Doctor cars are highly mobile physician-staffed GEMS that can provide complex pre-hospital trauma management using various treatment strategies. The number of doctor car operations for patients with severe trauma has increased. Considering facility factors, the association between doctor cars and patient outcomes remains unclear. Therefore, this study aimed to examine the relationship between doctor cars for patients with severe trauma and survival outcomes in Japan. METHODS: A nationwide retrospective cohort study was conducted to compare the impact of the doctor car group with the non-physician-staffed GEMS group on in-hospital survival in adult patients with severe trauma. The data were analyzed using multivariable logistic regression models with generalized estimating equations. RESULTS: This study included 372,365 patients registered in the Japan Trauma Data Bank between April 2009 and March 2019. Of the 49,144 eligible patients, 2361 and 46,783 were classified into the doctor car and non-physician staffed GEMS groups, respectively. The adjusted odds ratio (OR) for survival was significantly higher in the doctor car group than in the non-physician staffed GEMS group (adjusted OR = 1.228 [95% confidence interval 1.065-1.415]). CONCLUSION: Using nationwide data, this novel study suggests that doctor cars improve the in-hospital survival rate of patients with severe trauma in Japan. Therefore, doctor cars could be an option for trauma strategies.

[Activities for laboratory medicine support after the Great East Japan Earthquake by the Japanese Society of Laboratory Medicine].

The Great East Japan Earthquake caused a tragic tsunami and resulted in serious damage to north region of Japan on March 11, 2011. The Japanese Society of Laboratory Medicine, JSLM launched an ad hoc Committee to support Laboratory Medicine affairs in the affected area. We expected that laboratory testing demands would increase during the weeks following the disaster. We decided to support the use of Point-of-Care Testing. Many POCT devices use battery-powered analyzers. This is definite advantage for their use in areas with limited access to power and water supplies. We contacted many companies about the possibility of providing POCT devices, IVD reagents and/or any laboratory supplies including disposable materials. Finally, forty companies agreed to support this project and we received list of reagents materials for more than one hundred IVD tests. We entered this information on our web site and continued to update it as additional support was received. Once a request of support was received, communication were made to confirm the amount of material, the method of shipping/receipt and if any specific training that would be required for its use at the testing site. Also, we dispatched volunteer Medical Technologists for eight weeks to assist in the laboratory work. Some of the crucial points in recruiting volunteer laboratory professions are expenses and accommodations. We prepared not only accommodations but also transportation methods and covered all expenses including insurance and meals. Our relief activities have shown that Laboratory Medicine and Medical Technologists are useful in disaster-affected area.

[Serum indoxyl sulfate is a useful predictor for progression of chronic kidney disease].

BACKGROUND: Indoxyl sulfate, an endogenous metabolite of tryptophan is normally excreted into urine. In patients with chronic kidney disease (CKD), however, the reduced indoxyl sulfate renal clearance leads to elevated indoxyl sulfate serum level. In this study we determined whether the serum levels of indoxyl sulfate are related to the progression rate of CKD stage in CKD patient. METHODS: The association between indoxyl sulfate and progression of CKD stage was studied in 47 CKD patients (19 male, 28 female). Serum levels of IS were measured by using high performance liquid chromatography and the measured values of the study cohort were divided into quintiles. RESULTS: The mean serum amount indoxyl sulfate in the healthy subject was 0.06 +/- 0.04 mg/dL (mean +/- SD). Those with indoxyl sulfate serum levels of > or = 0.3 mg/dL had a significantly progression of CKD than with <0.3 mg/dL. Especially, those patients with indoxyl sulfate serum levels of 0.47 mg/dL had the highest CKD progression. CONCLUSION: High serum levels of indoxyl sulfate are related with a progression of CKD stage in CKD patients. Thus, serum indoxyl sulfate is one of the clinical factors that affect CKD progression.

[Comparison of intravenous fentanyl analgesia and epidural analgesia for postoperative pain relief].

BACKGROUND: Epidural analgesia is available for postoperative pain relief except for the patients with bleeding tendency or under anticoagulation. Intravenous fentanyl analgesia can be applied for such patients but its effect has not been evaluated enough. We compared these two methods after abdominal surgery. METHODS: In the intravenous fentanyl analgesia group (group iv, n = 15), 0.7 microg x kg(-1) x hr(-1) fentanyl infusion was started during operation and decreased to 0.5 microg x kg(-1) x hr(-1) on the next morning. In the epidural analgesia group (group e, n = 15), 0.4 microg x kg(-1) x hr(-1) fentanyl and 5 ml x hr(-1) 1% mepivacaine infusion was started during operation. The VAS pain score (at rest and at coughing), the level of consciousness, respiratory and cardiovascular depression, nausea and vomiting were evaluated for 3 days. RESULTS: The VAS scores at rest were similar in two groups but the VAS scores at coughing were similar or lower in the group iv. In the group iv, five patients suffered from nausea and one patient had somnolence. In the group e, only one patient had nausea but two patients had hypotension. CONCLUSIONS: Intravenous fentanyl analgesia is safe and possibly more effective than epidural analgesia.

[Plasma creatinine and cystatin C ratio is useful for discriminate diagnosis of postrenal renal failure].

Acute renal failure (ARF) is an acute loss of kidney function that occurs over days to weeks and results in an inability to appropriately excrete nitrogenous wastes and creatinine (Cre). ARF is diagnosed by elevations of blood urea nitrogen and serum Cre level, which is classified as prerenal, intrinsic and postrenal according to their mechanisms. However, discriminate diagnosis of these types by blood biochemistry findings is difficult. Recently, cystatin C (Cys-C), a basic protein having isoelectric point 9.3 with a molecular weight of 13.3 kDa, is freely filtered at the level of the glomerulus and virtually all is reabsorbed and metabolized by the proximal tubular cells. Therefore, assuming constant cellular production, serum Cys-C level has the potential to be an excellent surrogate marker of glomerular filtration rate. Because Cre is electrically charged neutrally, there is a possibility that the permeation of Cys-C, which is positively charged, is diffluent from that of Cre through glomerular basement membrane due to the type of the renal failure. We determined blood concentrations of Cys-C and Cre in a patients with prerenal renal failure (17 patients), intrinsic renal failure (232 patients) and postrenal renal failure (13 patients) as compared with healthy subjects (n = 771). We found that patients with postrenal renal failure displayed significantly elevated Cre/Cys-C ratio (mean +/- standard deviation) (8.3 +/- 8.0, p < 0.001) as compared with healthy subjects (1.1 +/- 0.2), prerenal (0.6 +/- 0.2) and intrinsic (1.6 +/- 0.5). These findings suggest that measurement of Cys-C concentration and Cre/Cys-C ratio may be useful for the discriminate diagnosis of postrenal renal failure.

Antithrombin Supplementation and Mortality in Sepsis-Induced Disseminated Intravascular Coagulation: A Multicenter Retrospective Observational Study.

Supplemental doses of antithrombin (AT) are widely used to treat sepsis-induced disseminated intravascular coagulation (DIC) in Japan. However, evidence on the benefits of AT supplementation for DIC is insufficient. This multicenter retrospective observational study aimed to clarify the effect of AT supplementation on sepsis-induced DIC using propensity score analyses. Data from 3,195 consecutive adult patients admitted to 42 intensive care units for severe sepsis treatment were retrospectively analyzed; 1,784 patients were diagnosed with DIC (n = 715, AT group; n = 1,069, control group). Inverse probability of treatment-weighted propensity score analysis indicated a statistically significant association between AT supplementation and lower in-hospital all-cause mortality (n = 1,784, odds ratio [95% confidence intervals]: 0.748 [0.572-0.978], P = 0.034). However, quintile-stratified propensity score analysis (n = 1,784, odds ratio: 0.823 [0.646-1.050], P = 0.117) and propensity score matching analysis (461 matching pairs, odds ratio: 0.855 [0.649-1.125], P = 0.263) did not show this association. In the early days after intensive care unit admission, the survival rate was statistically higher in the propensity score-matched AT group than in the propensity score-matched control group (P = 0.007). In DIC patients without concomitant heparin administration, similar results were observed. In conclusion, AT supplementation may be associated with reduced in-hospital all-cause mortality in patients with sepsis-induced DIC. However, the statistical robustness of this connection was not strong. In addition, although the number of transfusions needed in patients with AT supplementation increased, severe bleeding complications did not.

Characteristics, treatments, and outcomes of severe sepsis of 3195 ICU-treated adult patients throughout Japan during 2011-2013.

Severe sepsis is a major concern in the intensive care unit (ICU), although there is very little epidemiological information regarding severe sepsis in Japan. This study evaluated 3195 patients with severe sepsis in 42 ICUs throughout Japan. The patients with severe sepsis had a mean age of 70 ± 15 years and a mean Acute Physiology and Chronic Health Evaluation II score of 23 ± 9. The estimated survival rates at 28 and 90 days after ICU admission were 73.6 and 56.3 %, respectively.

The action of D-dopachrome tautomerase as an adipokine in adipocyte lipid metabolism.

Adipose tissue is a critical exchange center for complex energy transactions involving triacylglycerol storage and release. It also has an active endocrine role, releasing various adipose-derived cytokines (adipokines) that participate in complex pathways to maintain metabolic and vascular health. Here, we found D-dopachrome tautomerase (DDT) as an adipokine secreted from human adipocytes by a proteomic approach. DDT mRNA levels in human adipocytes were negatively correlated with obesity-related clinical parameters such as BMI, and visceral and subcutaneous fat areas. Experiments using SGBS cells, a human preadipocyte cell line, revealed that DDT mRNA levels were increased in an adipocyte differentiation-dependent manner and DDT was secreted from adipocytes. In DDT knockdown adipocytes differentiated from SGBS cells that were infected with the adenovirus expressing shRNA against the DDT gene, mRNA levels of genes involved in both lipolysis and lipogenesis were slightly but significantly increased. Furthermore, we investigated AMP-activated protein kinase (AMPK) signaling, which phosphorylates and inactivates enzymes involved in lipid metabolism, including hormone-sensitive lipase (HSL) and acetyl-CoA carboxylase (ACC), in DDT knockdown adipocytes. The AMPK phosphorylation of HSL Ser-565 and ACC Ser-79 was inhibited in DDT knockdown cells and recovered in the cells treated with recombinant DDT (rDDT), suggesting that down-regulated DDT in adipocytes brings about a state of active lipid metabolism. Furthermore, administration of rDDT in db/db mice improved glucose intolerance and decreased serum free fatty acids levels. In the adipose tissue from rDDT-treated db/db mice, not only increased levels of HSL phosphorylated by AMPK, but also decreased levels of HSL phosphorylated by protein kinase A (PKA), which phosphorylates HSL to promote its activity, were observed. These results suggested that DDT acts on adipocytes to regulate lipid metabolism through AMPK and/or PKA pathway(s) and improves glucose intolerance caused by obesity.

Isolation and characterization of a novel antistress gene from Chlamydomonas sp. W80.

Here we report the isolation and characterization of the Chlamydomonas sp. W80-derived CFo ATP synthase subunit II WCFII homologue gene. Intracellular ATP concentration and stress-tolerance of Escherichia coli were increased by transformation with WCFII. We propose that WCFII-mediated stress tolerance is due to enhanced accumulation of intracellular ATP.

Comparative analysis of a CFo ATP synthase subunit II homologue derived from marine and fresh-water algae.

Comparative analysis was performed with a CFo ATP synthase subunit II homologue (CFo-II) derived from marine or fresh-water algae. The marine algae-derived CFo-II-transformed Escherichia coli grew and accumulated ATP more vigorously in NaCl or Cadmium containing medium, suggesting that this gene was useful for the development of stress-tolerant plant.