Economic evaluation of a preemptive treatment strategy for invasive fungal infection in neutropenic patients with hematological diseases.

We compared the expected medical costs of empirical and preemptive treatment strategies for invasive fungal infection in neutropenic patients with hematological diseases. Based on the results of two clinical trials with different backgrounds reported by Oshima et al. [J Antimicrob Chemother 60(2):350-355; Oshima study] and Cordonnier et al. [Clin Infect Dis 48(8):1042-1051; PREVERT study], we developed a decision tree model that represented the outcomes of empirical and preemptive treatment strategies, and estimated the expected medical costs of medications and examinations in the two strategies. We assumed that micafungin was started in the empirical group at 5 days after fever had developed, while voriconazole was started in the preemptive group only when certain criteria, such as positive test results of imaging studies and/or serum markers, were fulfilled. When we used an incidence of positive test results of 6.7 % based on the Oshima study, the expected medical costs of the empirical and preemptive groups were 288,198 and 150,280 yen, respectively. Even in the case of the PREVERT study, in which the incidence of positive test results was 32.9 %, the expected medical costs in the empirical and preemptive groups were 291,871 and 284,944 yen, respectively. A sensitivity analysis indicated that the expected medical costs in the preemptive group would exceed those in the empirical group when the incidence of positive test results in the former was over 34.4 %. These results suggest that a preemptive treatment strategy can be expected to reduce medical costs compared with empirical therapy in most clinical settings.

Risk factors for pre- and post-engraftment bloodstream infections after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Bloodstream infections (BSI) are frequently observed after allogeneic hematopoietic stem cell transplant (HSCT), and could cause morbidity and mortality. METHODS: We retrospectively evaluated the incidence, characteristics of, and risk factors for BSI at both pre- and post-engraftment in 209 adult HSCT patients at our institute between June 2006 and December 2013. The median age at transplantation was 45 years (range, 15-65). A total of 122 patients received bone marrow, 68 received peripheral blood stem cells, and 19 received umbilical cord blood. RESULTS: The cumulative incidences of pre- and post-engraftment BSI were 38.9% and 17.2%, respectively. Nine patients had both pre- and post-engraftment BSI. In the pre- and post-engraftment periods, respectively, 67.4% and 84.1% of isolates were gram-positive bacteria (GPB), 28.3% and 11.4% were gram-negative bacteria (GNB), and 4.3% and 4.5% were fungi. Coagulase-negative staphylococci were the most commonly isolated GPB, while Stenotrophomonas maltophilia and Pseudomonas aeruginosa were the most commonly isolated GNB. Pre-engraftment BSI was associated with an increased risk of death. Overall survival at day 180 for patients with or without pre-engraftment BSI was 70.0% and 82.7%, respectively (P = 0.02). CONCLUSIONS: Risk factors for BSI in the pre-engraftment period were the interval between diagnosis and transplantation (261 days or more), engraftment failure, and high-risk disease status at HSCT in a multivariate analysis. No significant risk factor for BSI in the post-engraftment period was identified by a univariate analysis. These findings may be useful for deciding upon empiric antibacterial treatment for HSCT recipients.

Allotype analysis to determine the origin of cytomegalovirus immunoglobulin-G after allogeneic stem cell transplantation.

BACKGROUND: Cytomegalovirus (CMV) reactivation still remains a major problem following allogeneic hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: In this study, we analyzed an immunoglobulin allotype, IgG1m(f), in CMV-seropositive HSCT recipients and their donors to distinguish donor-derived antibody from recipient-derived antibody. Eight donor-recipient pairs were informative regarding the appearance of donor-derived immunoglobulin-G (IgG), as the recipients were homozygous null for the IgG1m(f) allotype and the donors were IgG1m(f) positive. In these patients, total IgG, IgM, and allotype-specific IgG against CMV were measured by enzyme-linked immunosorbent assay. All subjects were monitored for at least 9 months after HSCT with (n = 5) or without (n = 3) CMV reactivation. RESULTS: Donor-derived CMV IgG tended to be elevated earlier in patients with CMV-seropositive donors than in those with CMV-seronegative donors. In 1 patient with a CMV-negative donor, donor-derived CMV IgG was not detected until late CMV reactivation. In 3 patients without CMV reactivation, donor-derived CMV IgG was also elevated within 1-6 months after HSCT. CONCLUSION: In conclusion, the CMV serostatus of the donor may be related to the timing of the appearance of donor-derived CMV IgG and the reconstitution of humoral immunity against CMV, regardless of the CMV antigenemia level after HSCT.

Persistence of recipient-derived as well as donor-derived clones of cytomegalovirus pp65-specific cytotoxic T cells long after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Cytomegalovirus (CMV)-specific CD8(+) cytotoxic T lymphocytes (CMV-CTLs) play a crucial role in preventing CMV disease. However, the actual in vivo dynamics of CMV-CTL clones after allogeneic hematopoietic stem cell transplantation (alloHCT) are still unclear. METHODS: Using a single-cell T-cell receptor repertoire analysis, we monitored clones and chimerism of CMV-CTLs in 3 CMV-seropositive alloHCT recipients from CMV-seronegative donors, with or without CMV reactivation. RESULTS: Nearly all of the CMV-CTLs during follow-up were CD45RA(-) CCR7(-) effector memory/CD45RA(+) CCR7(-) effector T cells, and were highly matured. In each case, the use of BV gene families was restricted, especially in BV5, 7, 28, and 29. Although no common predominant CMV-CTL clones were found, several shared motifs of complementarity-determining region-3 were identified among the 3 cases; QGA in all, TGE and TDT in Case 1 and Case 2, and RDRG in Case 2 and Case 3. In all cases, CMV-CTL clones that were detected for the first time after alloHCT persisted as the dominant clones. In Case 1, without CMV reactivation, recipient-derived CMV-CTLs exclusively persisted as a dominant clone, while all CMV-CTLs in the other 2 cases, with CMV reactivation, were donor derived. CONCLUSION: Clone monitoring and chimerism analyses should help to further clarify novel aspects of immuno-reconstitution after alloHCT.

Low-dose acyclovir prophylaxis for the prevention of herpes simplex virus disease after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Currently, acyclovir (ACV) at 1000 mg/day is widely used as prophylaxis in the early phase of hematopoietic stem cell transplant (HSCT) in Japan. However, low-dose ACV (200 mg/day) has been shown to prevent varicella zoster virus reactivation in the middle and late phases of HSCT. METHODS: Therefore, in this study, we decreased the dose of ACV to 200 mg/day in the early phase after HSCT. We analyzed 93 consecutive herpes simplex virus (HSV)-seropositive patients who underwent allogeneic HSCT for the first time in our center between June 2007 and December 2011. RESULTS: Before August 2009, 38 patients received oral ACV at 1000 mg/day (ACV1000) until day 35 after HSCT, whereas 55 patients received oral ACV at 200 mg/day (ACV200) after September 2009. We compared the cumulative incidence of HSV infection in the 2 groups. Oral ACV was changed to intravenous administration because of intolerance in 66% and 45% of the patients in the ACV1000 and ACV200 groups, respectively (P = 0.060). The probability of severe stomatitis (Bearman grade II-III) was 76% and 60% in the ACV1000 and ACV200 groups, respectively (P = 0.12). The number of patients who developed HSV disease before day 100 after HSCT was 0 in the ACV1000 group and 2 in the ACV200 group, with a cumulative incidence of 3.6% (P = 0.43). HSV disease in the latter 2 patients was limited to the lips and tongue and was successfully treated with ACV or valacyclovir at a treatment dose. CONCLUSION: ACV at 200 mg/day appeared to be effective for preventing HSV disease in the early phase after HSCT.

Inverse association between soy intake and non-Hodgkin lymphoma risk among women: a case-control study in Japan.

BACKGROUND: Non-Hodgkin lymphoma (NHL) is one of the common malignant tumors worldwide. Environmental factors, such as diet have an important association with the risk of cancer. Although soy intake has been associated with a reduced risk of several cancers, its association with NHL is not known. PATIENTS AND METHODS: We evaluated the association between soy consumption and risk of NHL by conducting a hospital-based case-control study in 302 patients with NHL and 1510 age- and sex-matched control subjects. Odds ratio (OR) and 95% confidence intervals (CIs) for groups with moderate (27-51 g/day) to high (>51 g/day) relative to low (<27 g/day) intake were calculated using multivariate conditional logistic regression model. RESULTS: Soy intake was significantly associated with a reduced risk of NHL in women but not in men (OR [95% CI] for moderate and high intake: women, 0.64 [0.42-1.00] and 0.66 [0.42-1.02], respectively; men, 1.40 [0.87-2.24] and 1.33 [0.82-2.15], respectively; P-interaction = 0.02). This finding appeared consistent across NHL subtypes. CONCLUSION: These results indicate the potential importance of certain ingredients in soy for lymphomagenesis. Further studies to evaluate the mechanism behind the association between soy intake and lymphomagenesis are warranted.

Impact of the presence of HLA 1-locus mismatch and the use of low-dose antithymocyte globulin in unrelated bone marrow transplantation.

HLA 1-locus-mismatched unrelated donors (1MMUD) have been used in allogeneic hematopoietic stem cell transplantation (allo-HCT) for patients who lack an HLA-matched donor. We retrospectively analyzed 3313 patients with acute leukemia or myelodysplastic syndrome who underwent bone marrow transplantation from an HLA allele-matched unrelated donor (MUD) or 1MMUD between 2009 and 2014. We compared the outcomes of MUD (n=2089) and 1MMUD with antithymocyte globulin (ATG) (1MM-ATG(+); n=109) with those of 1MMUD without ATG (1MM-ATG(-); n=1115). The median total dose of ATG (thymoglobulin) was 2.5 mg/kg (range 1.0-11.0 mg/kg) in the 1MM-ATG(+) group. The rates of grade III-IV acute GvHD, non-relapse mortality (NRM) and overall mortality were significantly lower in the MUD group than in the 1MM-ATG(-) group (hazard ratio (HR) 0.77, P=0.016; HR 0.74; P<0.001; and HR 0.87, P=0.020, respectively). Likewise, the rates of grade III-IV acute GVHD, NRM and overall mortality were significantly lower in the 1MM-ATG(+) group than in the 1MM-ATG(-) group (HR 0.42, P=0.035; HR 0.35, P<0.001; and HR 0.71, P=0.042, respectively). The outcome of allo-HCT from 1MM-ATG(-) was inferior to that of allo-HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared with the use of low-dose ATG without increasing the risk of relapse.

GvHD prophylaxis after single-unit reduced intensity conditioning cord blood transplantation in adults with acute leukemia.

To investigate better GVHD prophylaxis in reduced intensity conditioning umbilical cord blood transplantation (RIC-UCBT), we compared transplant outcomes after UCBT among GvHD prophylaxes using the registry data. We selected patients transplanted for AML or ALL with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 748 first RIC-UCBT between 2000 and 2012 (MTX+ group, 446, MMF+ group, 302) were included. The cumulative incidence of neutrophil and platelet counts higher than 50 000/µL was significantly better in the MMF+ group (relative risk (RR), 1.55; P<0.001: RR, 1.34; P=0.003, respectively). In multivariate analyses, the risk of grade II-IV and III-IV acute GvHD was significantly higher in the MMF+ group than in the MTX+ group (RR, 1.75; P<0.001: RR, 1.97; P=0.004, respectively). In disease-specific analyses of AML, the risk of relapse of high-risk disease was significantly lower in the MMF+ group (RR, 0.69; P=0.009), whereas no significant difference was observed in the risk of relapse-free and overall survival in high-risk disease. In patients with standard-risk disease, no significant differences were noted in the risk of relapse or survival between the MTX+ and MMF+ groups. Collectively, these results suggest that MMF-containing prophylaxis may be preferable in RIC-UCBT, particularly for high-risk disease.

Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation.

The effect of graft-versus-host disease (GVHD) on transplant outcomes after unrelated cord blood transplantation (UCBT) has not been fully elucidated. We analyzed the impact of acute and chronic GVHD on outcomes in adult patients with acute leukemia or myelodysplastic syndrome who underwent their first UCBT (n=2558). The effect of GVHD on outcomes was analyzed after adjusting for other significant variables. The occurrence of GVHD was treated as a time-dependent covariate. The occurrence of grade 1-2 or 3-4 acute GVHD was significantly associated with a lower relapse rate. Grade 3-4 acute GVHD was associated with a higher risk of non-relapse and overall mortality than no acute GVHD, whereas grade 1-2 acute GVHD was associated with a lower risk of non-relapse and overall mortality than no acute GVHD. Limited or extensive chronic GVHD was significantly associated with a lower relapse rate. Limited chronic GVHD was associated with a lower overall and non-relapse mortality than no chronic GVHD. In conclusion, mild acute or chronic GVHD was associated not only with a low risk of relapse but also with a low risk of non-relapse mortality, and provides a survival benefit in UCBT.

Risk factors and prognosis of hepatic acute GvHD after allogeneic hematopoietic cell transplantation.

Hepatic acute GvHD (aGvHD) is associated with high mortality owing to poor response to immunosuppressive therapy. The pathogenesis of hepatic aGvHD differs from that of other lesions, and specific risk factors related to pre-transplant liver conditions should be determined. We conducted a cohort study by using a Japanese transplant registry database (N=8378). Of these subjects, 1.5% had hepatitis C virus Ab (HCV-Ab) and 9.4% had liver dysfunction (elevated transaminase or bilirubin levels) before hematopoietic cell transplantation (HCT). After HCT, the cumulative incidence of hepatic aGvHD was 6.7%. On multivariate analyses, HCV-Ab positivity (hazard ratio (HR), 1.93; P=0.02) and pre-transplant liver dysfunction (HR, 1.85; P<0.01), as well as advanced HCT risk, unrelated donors, HLA mismatch and cyclosporine as GvHD prophylaxis, were significant risk factors for hepatic aGvHD, whereas hepatitis B virus surface Ag was not. Hepatic aGvHD was a significant risk factor for low overall survival and high transplant-related mortality in all aGvHD grades (P<0.01). This study is the first to show the relationship between pre-transplant liver conditions and hepatic aGvHD. A prospective study is awaited to validate the results of this study and establish a new strategy especially for high-risk patients.

Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation.

The impact of the conditioning intensity and TBI on acute GVHD (aGVHD) is still a matter of debate. We analyzed 6848 adult recipients who received allogeneic hematopoietic cell transplants (HCT) between 2006 and 2011 in Japan. The subjects were divided into groups who had received myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), either with or without TBI. There was a significant difference in the incidence of aGVHD 2-4 among the different conditioning types: 39% in TBI-MAC, 35% in TBI-RIC and 32% in both no-TBI MAC and no-TBI-RIC (P<0.001). In a multivariate analysis, TBI-MAC, but not no-TBI MAC, was significantly associated with an increased risk of aGVHD 2-4 (hazard ratio (HR) 1.33, P<0.01), whereas TBI-RIC was associated with an increased risk of GVHD 3-4 (HR 1.36, P=0.048). TBI-MAC and TBI-RIC were significantly associated with skin and gastrointestinal aGVHD. Subgroup analyses demonstrated that not only TBI-MAC, but also TBI-RIC, was significantly associated with aGVHD 2-4 in older patients. Furthermore, high-dose TBI only had an adverse impact on aGVHD 2-4 in HLA-matched HCT. Impacts of intensity and TBI on aGVHD differ by patient backgrounds, and this difference should be considered to establish a risk-adapted strategy for the prevention of aGVHD.

Risk factors for second cancers of the upper respiratory and digestive systems: a case-control study.

A case-control study of determinants of multiple cancers of the upper respiratory and digestive system (URDS) was conducted using a patient cohort-nested design. We analyzed demographic and risk factor information and clinical variables related to the index cancer for 85 cases of multiple cancers and 170 controls matched on sub-site of the index cancer of the case and date of hospital admission. Follow-up information for the control group was used to infer the person-years-at-risk for the cohort of 1977 patients. URDS cancer patients experienced a 10.7 times (95% confidence interval: 8.5-13.2) higher risk of additional related cancers than the general population. Although controls had cancers of the same sites as those of cases and thus, strongly tobacco and alcohol-related, there were marked residual effects for these two risks factors. In addition, characteristics related to the extension and clinical course of the index cancer were strongly associated with the patient's risk of developing additional cancers.

Effects of N-methyl-D-aspartate, kainate or veratridine on extracellular concentrations of free D-serine and L-glutamate in rat striatum: an in vivo microdialysis study.

Using an in vivo microdialysis technique, we have investigated the effect of N-methyl-D-aspartate (NMDA) or kainate on the extracellular concentrations of free D-serine and L-glutamate in the striatum. A intrastriatal perfusion of NMDA or kainate caused a significant increase in the extracellular release of L-glutamate, but a significant decrease in that of D-serine. Co-perfusion of an NMDA receptor antagonist, MK-801, or an alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), with NMDA or kainate significantly reversed the NMDA- or kainate-induced decrease in the extracellular level of D-serine, respectively. The NMDA- or kainate-evoked increase in the extracellular L-glutamate level was also reversed by co-perfusion of MK-801 or CNQX, respectively. Because D-serine acts as a potent and selective agonist for the glycine site of the NMDA receptor and because intracerebroventricularly injected D-serine is accumulated in the astrocytes, D-serine could be taken up by the astrocytes following synaptic activation. Furthermore, because cortical ablation to remove corticostriatal glutamatergic inputs attenuates the excitotoxic effects of kainate in the striatum, L-glutamate may enhance its own release through a presynaptic NMDA and/or non-NMDA receptor-mediated mechanism.

Coronary artery bypass grafting in a patient with cryoglobulinemia.

Coronary artery bypass grafting (CABG) was performed in a patient with cryoglobulinemia. In order to decrease the concentration of cryoglobulin, the patient underwent double filtration plasmapheresis (DFPP) pre- and postoperatively as well as during cardiopulmonary bypass. Bypass surgery was performed under total cardiopulmonary bypass, moderate systemic hypothermia, and ventricular fibrillation without aortic crossclamping. No adverse effects of cryoglobulin appeared during the peri- and postoperative course. Technical considerations for open heart surgery in patients with cryoglobulinemia are described.

Responsiveness of equine basilar artery to transmural nerve stimulation differs from that of porcine and bovine basilar arteries in vitro.

Transmural nerve stimulation (TNS) induced relaxations in porcine and bovine basilar arteries which were abolished by tetrodotoxin (TTX) and by L-nitro-arginine (LNAG). However, TNS induced contractions in equine basilar artery which were abolished by TTX and by guanethidine, but not by LNAG. These results suggest that the TNS-induced contractions of equine basilar arteries may be mediated by norepinephrine release.

An outbreak of goose parvovirus infection in Japan.

In a Muscovy duck breeding-growing farm in Aomori prefecture, most of ducklings hatched during spring in 1994 died within two-week-old. The mortality was nearly 100%. In most cases, birds died without clinical signs and some with leg weakness. By serological and virological tests, the outbreak was identified as a goose parvovirus infection. In pathological test, however, no typical manifestations of goose parvovirus infections (hepatitis and intranuclear inclusion bodies in hepatic cells) were detected.

Stability of free Mg2+ concentration and increased concentration of free Ca2+ in vascular smooth muscle cells during dietary magnesium deficiency in rat.

Intracellular free calcium and magnesium ion concentrations ([Ca2+]i and [Mg2+]i respectively) were estimated in thoracic aorta smooth muscle strips isolated from magnesium-deficient and control rats using fura-2/AM and mag-fura-2/AM, respectively. Adult male Wistar rats were fed a magnesium-deficient diet (10 mg Mg/kg diet) or a control diet (700 mg Mg/kg diet) for 30 days. Plasma magnesium level in magnesium-deficient rats was half of that in control rats at 30th day. Therefore, thoracic aorta strips, denuded of endothelium, were loaded with fura-2/AM or mag-fura-2/AM in the presence of 0.5 or 1.0 mM Mg2+, and [Ca2+]i or [Mg2+]i was measured under the same Mg2+ conditions. The [Ca2+]i in the aorta strips isolated from magnesium-deficient rats in the presence of 0.5 mM Mg2+ (254.9 +/- 13.1 nM) was approximately three times greater than in those from control rats in the presence of 1.0 mM Mg2+ (86.5 +/- 9.2 nM). The [Mg2+]i was not significantly different between the two groups at either Mg2+ level. The muscle tension and [Ca2+]i increased after [Mg2+]o was exchanged from 1.0 to 0.5 mM; however, [Mg2+]i showed no change. The total calcium content increased and total magnesium content decreased in thoracic aorta strips isolated from magnesium-deficient rats. These results suggest that [Mg2+]i is stable, but that [Ca2+]i increases in vascular smooth muscle cells of thoracic aortas isolated from dietary magnesium-deficient rats.

The value of therapeutic planning and the degree of experience of the surgical team on the results of cancer treatment of the larynx and hypopharynx.

This is a prospective study supported by 170 cases of epidermoid carcinoma of the larynx or hypopharynx, treated during the period from January of 1981 to January of 1988, at the Head and Neck Surgery Service of the Heliópolis Hospital Complex, São Paulo. The objective of this project was to evaluate the importance of surgeon experience with regard to the rates of post-operative complications and the rates of relapse and survival. The results of the 8 surgical specialists who integrate the permanent staff at the institute and who different varying degrees of experience with regard to time spent exercising their specialties were compared. The results obtained did not show a significant difference among the various surgeons, and this uniformity is explained by the fact that all the therapeutic planning was elaborated through consensus of the whole group, and this could have minimized the effect of experience of a surgeon responsible for the operation. The authors emphasize the importance of pre-operative evaluation for good results and propose that it is in the direction of complete mastery of preliminary work in the area that programs for the formation of new specialists should be directed.

Perioperative frozen section examination in parotid gland tumors.

CONTEXT: The minimal recommended surgical approach to parotid tumors is partial parotidectomy with resection of the superficial lobe of the gland. Histologic diagnosis prior to surgery is not possible, as incisional biopsies are contraindicated due to the possibility of facial nerve injury or incomplete tumor resection. Thus, the biopsies tend to be perioperative. OBJECTIVE: To compare the results of frozen section examination with the definitive pathological diagnosis. DESIGN: Accuracy study by retrospective analysis. SETTING: Head and Neck Surgery Service of Heliópolis Hospital, São Paulo, Brazil. SAMPLE: 153 cases of parotid gland tumors treated between 1977 and 1994. DIAGNOSTIC TEST: Frozen section and pathological diagnosis. MAIN MEASUREMENTS: Sensibility and specificity of the frozen section examination. RESULTS: Frozen section study diagnosed 19 (12.4%) malignant and 127 (83.7%) benign tumors. Sensitivity of the frozen sections for malignancy was 61.5% (95% CI 54 to 69%) and specificity was 98% (95% CI 94 to 100%), and this result is comparable to the literature. CONCLUSIONS: We consider that frozen section examination for salivary gland tumors is not sufficient on its own for deciding on the best management. Their interpretation must be correlated with clinical and intraoperative findings, in association with the surgeon's experience.