Pre-induction Treatment Research Articles

Bone Marrow Plasma Cell Infiltration in Light Chain Amyloidosis: Impact on Organ Involvement and Outcome

Introduction: Immunoglobulin light-chain (AL) amyloidosis is a plasma cell disorder characterized by the production of amyloidogenic immunoglobulin light chains causing organ damage. Commonly, AL amyloidosis is a low tumor burden disease, and previous reports have found that a relatively higher number of bone marrow plasma cell (BMPCs) infiltration has a dismissal prognosis.The outcome of patients with AL amyloidosis is related to multiple factors; nevertheless, the most relevant one is the presence or not of cardiac involvement. It has long been known that the presence of multiple myeloma clinical manifestations impacts on a worse prognosis when associated to AL amyloidosis. Also the level of amyloidogenic light chain synthesis, measured by the free light chain (FLC) difference, can help to explain the heterogeneity in prognosis. In this sense, the aim of this study was to determine if the quantity of BMPCs plays a role in the outcome of the disease and the degree of organ involvement.Methods: The clinical records of 85 patients diagnosed with systemic AL amyloidosis were reviewed at a single institution between January 2006 and April 2016. Three patients were lost to follow-up, and three were excluded because BMPC measurements were not available. Seventy-nine patients (42F/37M; median age at diagnosis 65 years) were the final study population. Complete data was collected retrospectively and baseline demographics, clinical and laboratory data, treatment received, and follow-up data were available in all patients. The risk categories were established according to the revised Mayo Clinic staging system. Twenty-five patients (31.6%) received fist-line treatment with autologous stem cell transplantation (ASCT) of which 15 patients had received pre-induction treatment and 10 patients up-front ASCT. Of the 79 patients, 44 (55.7%) received novel drugs (43% bortezomib and 12.7% lenalidomide). BMPCs were identified in bone marrow (BM) aspiration with the analysis based on optic microscopic revision of May-Grünwald-Giemsa stained bone marrow smears performed according to standard procedures. All 79 patients had BM aspirates with adequate cellularity at diagnosis and BMPC percentage was calculated. In 67 of the 79 patients, a new revision of 500 cells was performed by two independent reviewers.Results: The median number of organs involved was two, being heart (75.9%) and kidney (64.6%) the most commonly involved. 62 patients (78.5%) had two or more involved organs. Median BMPC infiltration was 11% (IQR 7-18) with a significantly correlation to a higher serum free light chain difference (p<0.001). 18 patients (22.8%) showed more than 20% BMPC infiltration. Early mortality was higher for patients with BMPC >10% at diagnosis (27.3% vs. 11.4%; p=0.08) and the median progression-free survival (PFS) and overall survival (OS) was significantly shorter (18 months vs. 48 months; p=0.021, and 33 months vs. not reached; p=0.046; respectively) (Figure 1). Cardiac involvement was also more prevalent in patients with higher BMPC infiltration (86.4% vs. 62.9%; p=0.015). In a multivariate analysis with a model incorporating the revised Mayo risk stratification system and the percentage of BMPC infiltration, the presence of >10% BMPCs retained its independent prognostic value for worse PFS (HR=2.26; 95% CI, 1.048-4.866; p=0.038) but not in OS (HR=1.72; 95% CI, 0.695-4.261; p=0.24).In the group of patients who did not received novel drugs, the presence of >10% of BMPC involvement resulted in a significantly shorter 3-year PFS and OS (68.7% vs. 25%; p=0.026 and 78.8% vs. 28%; p=0.013; respectively). However, those patients who received novel drugs (bortezomib and/or lenalidomide) overcome the negative prognostic impact of higher BMPC infiltration with a 3-year PFS (46.6% in ≤10% BMPC vs. 34.6% in >10% BMPC; p=0.29) and 3-year OS (62.3% in ≤10% BMPC vs. 57.3% in >10% BMPC; p=0.58). None of our patients developed CRAB criteria or any other myeloma feature during the disease evolution.Conclusion: In patients with AL amyloidosis, a higher BMPC involvement was associated with increased cardiac involvement and a worse outcome, but this fact was never related to the presence or development of myeloma features. [Display omitted] DisclosuresRosinol:Janssen: Honoraria; Celgene: Honoraria.

The Prevalance of Sensori-Neural Hearing Loss and Ototoxicity in Acute Myeloid Leukemia Patients

Objective: The aim of this study is to investigate the prevalence of sensori-neural hearing loss and ototoxicity in acute myeloid leukemia (AML) patients. Study design: This is a prospective non-randomized study. Methods: 14 patients with the diagnosis of acute myeloid leukemia were treated with Daunorubicin and Cytarabine (ARA-C). Pure Tone Audiometry (PTA) was performed prior to induction chemotherapy and immediately after completion of induction protocol. Primary outcome was the prevalence of sensori-neural hearing loss. Secondary outcome was correlation of age, sex, absolute neutrophil counts, total white counts, platelet counts and creatinine levels in the study population. Results: Fourteen patients participated in this study (n=14). Ten patients had normal hearing prior to preinduction treatment. Four patients had pre-existing hearing loss prior to treatment. Post induction treatment, ten patients had normal hearing. However, from these ten patients, one had pre-existing hearing loss which improved. Two patients, whom had normal hearing and pre-existing hearing loss pre-induction treatment respectively, expired. Two patients who had pre-existing hearing loss had the same level of hearing post induction. The prevalence of sensori-neural hearing loss in this study is 71.4%. From our observation, there is no evidence of ototoxicity from induction therapy of Daunorubicin and Cytarabine (ARA-C) in our study population (p=0.001). Induction treatment with Daunorubicin and Cytarabine (ARA-C) shows statistically significant reduction in Absolute Neutrophils Counts (p=0.013), Total White Counts (p=0.001), Haemoglobin Counts (p=0.036) and Creatinine levels (p=0.017) in our study population. Even though Platelet counts showed reduction, this was not supported statistically (p=0.258). Conclusion: Induction treatment with Daunorubicin and Cytarabine (ARA-C) are safe chemotherapy agents to be administered during the induction phase in treatment of Acute Myeloid Leukemia with no evidence of sensorineural hearing loss. Further study is required to monitor the long-term effects of these drugs during consolidation, remission or relapse phases of treatment and if possible during stem cell transplant treatment.

Effect of the Adition of Metformin on the expressión of Multidrug-Resistance Genes (ABCB1, ABCG2) in Acute Lymphoblastic Leukemia: In Vitro and In Vivo Study

INTRODUCTION. The over expresión of the multidrug resistance genes (MDR) specifficaly ABCB1 and ABCG2 correlate with a poor prognosis in patients with ALL. Different drugs specially the chomotherapeutic agents are they substrates. This genes encode a family of different membrane transports that Works with energy specifically the ATP. Metformin is a biguanide whose mechanism of action is the activiation of AMPK and depletes the levels of ATP.PRIMARY OBJECTIVE: Evaluate the efficacy of the use of Metformin on the levels of expression of the MDR genes (ABCB1 y ABCG2) by RQ-PCR in ALL cell lines and patients with ALL during a preinduction treatment with prednisone.RESULTS.In vitro study. The ALL cell lines RS4, ReH, MOLT4 and SUB15 were elavluated. After the addition of Metformin (10uM) the expression level of ABCB1, ABCG2 started to decrease after the 24hrs of culture (mean expression level of 0.3823 ABCB1 and 0.4265 of ABCB2) with a máximum effect at 48 hours (0.2415 ABCB1 and 0.3452 ABCB2) The difference of levels were statystically significant (p= 0.0045).In vivo study. About 108 patients were evaluated, 44 (40.7%) in the arm of prednisone and 64 (59.3%) in the arm of prednisone plus metformin. Fort eh subanalysis of the MDR genes by RQ-PCR we select 25 patients (14 in the prednisone arm and 11 in the metformin arm). The mean levels of the genes was 0.1906 for the ABCB1 gene and 0.3371 of the ABDG2. At the moment of diagnosis about 32% were considerer with high level of expression (n=8), 28% (n=7) of low expression and 40% (n=10) do not express any of the both genes. After the treatment with Metformin 4 patients with high expression at diagnosis change the patter for low expression. Although there is no difference in means of the expression of genes in both arms (p = 0.391 , p = 0. 828) in the group of metformin the prognosis in the high expression group was better than in the prednisone arm (p=0.043). Fort he entire cohort the complete remission rate was higher in the Metformin cohort comparing with prednisone (86.4% versus 67.2%) and the refractoriness was higher in the group of prednisone (n=16, 25%) p=0.002. About the relapse, the addition of Metformin reduce the relapse rate ( 6 vs 21 patients, p = 0.027).Conclusion. The addition of metformin in a controlled enviroment reduce the expression of the MDR genes, but in vivo the impact is primarily on the refractory leukemias and the relapse rate DisclosuresNo relevant conflicts of interest to declare.

Optimization of cold-adapted alpha-galactosidase expression in Escherichia coli

α-Galactosidase (α-PsGal) of the cold-adapted marine bacterium Pseudoalteromonas sp. KMM 701 was cloned into the pET-40b(+) vector to study its properties and to develop an effective method for modifying human B-erythrocytes into O-blood group. The use of heat-shock as a pre-induction treatment, IPTG concentration of 0.2 mM and post-induction cultivation at 18 °C for 20 h in the developed MX-medium allowed increasing the recombinant Escherichia coli Rosetta (DE3)/40Gal strain productivity up to 30 times and the total soluble α-PsGal yield up to 40 times.

Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy

Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy

Significance of cervical ripening in pre-induction treatment for premature rupture of membranes at term.

This study aimed to determine whether mechanical cervical dilatation with a laminaria tent in women with premature rupture of membranes (PROM) at term may influence the maternal/neonatal outcomes. We reviewed the medical records and histopathologic results of the placenta in 782 women with PROM at term. Of the 486 women seen prior to 2010 (group 1), 85 had Bishop scores of 5 or less and underwent insertion of laminaria tents (group A). In the 296 women admitted after 2010 (group 2), 27 had Bishop scores of 5 or less and underwent labor management without insertion of laminaria tents (group B). The patient characteristics, delivery course and neonatal outcomes were compared between the groups. There were no significant differences in the maternal age, percentage of nulliparas, body mass index, gestational age at delivery or Bishop score between the groups. The Bishop score improved from 2.5 to 6.1 after laminaria tent insertion in group A. However, there were no significant intergroup differences in the frequency of use of labor-inducing agents or the time interval from PROM to delivery. The incidence of clinical/pathological chorioamnionitis was not higher in group A than in group B. No significant differences were found in the Apgar scores, umbilical artery pH or frequency of asphyxia neonatorum between the groups. Mechanical cervical dilatation by laminaria tent insertion neither increased the incidence of infection nor contributed to improvement of the perinatal prognosis. Mechanical cervical dilatation does not provide any benefit for women with PROM at term.

Sleeve lobectomy after induction chemoradiotherapy

The effect of induction chemoradiotherapy (CRT) on bronchial anastomoses remains uncertain. This prospective study aimed to assess the impact of neoadjuvant CRT on mortality, morbidity and survival following circular sleeve lobectomy (SL). All consecutive patients undergoing SL between June 2005 and December 2010 were prospectively included. Clinico-demographic variables were sex, age, clinical and pathologic TNM staging, comorbidities, pulmonary function, SL type, complications, neoadjuvant CRT and mortality. Of 79 patients, who underwent SL during this period, 53 (67%) patients were directly assigned to surgery and 26 (33%) patients had pre-induction treatment for N2 pathologically confirmed. Induction treatment (CRT) was based on platinum-based chemotherapy and radiation (range 45-60Gy). Twenty-one (80%) patients of the CRT group achieved a complete mediastinal pathological response. Mortality occurred in only three cases in the non-CRT [bronchovascular fistula, pulmonary artery thrombosis (reoperation and pneumonectomy and exitus due to pneumonia) and ADRS]. There were no differences with respect to complication rate between the non-CRT and CRT patients (33 versus 37%, P>0.05), and overall 5-year survival was 69 and 33%, respectively (P=0.017). Overall survival in the subgroup of CRT patients with mediastinal complete response after induction resulted significantly worse than the non-CRT group (43 versus 69%, P<0.01). The rate of distant metastases was similar in both groups and only one patient experienced local recurrence. Neoadjuvant CRT does not increase surgical morbidity, anastomotic complications or mortality in SL. Complete mediastinal response after induction therapy overcomes a significant independent prognostic factor for better survival. Although SL following induction CRT carries a good prognosis, the long-term results shows significantly lower survival compared with SL without induction CTR. In addition, patients who had complete pathological responses have a better prognosis than non-responders. SL appears to be safe and reliable after neoadjuvant concurrent CRT and can be considered the primary surgical option to save the complications related to pneumonectomy in central tumours.

Updated Results of the PRIMA Study Confirms the Benefit of 2-Years Rituximab Maintenance In Follicular Lymphoma Patients Responding to Immunochemotherapy.

AbstractAbstract 1788The GELA-sponsored intergroup PRIMA Phase III study was designed to investigate the potential benefit of 2-years of rituximab maintenance in high tumour burden follicular lymphoma patients responding to one of three non-randomised first line immunochemotherapy treatments. The results of the pre-planned interim analysis with 24 months median follow-up were positive and demonstrated a significant reduction in the risk of progression for patients randomized to rituximab maintenance (Salles et al., ASCO 2010). We present here the updated efficacy and safety results after an additional year of follow-up, when all randomized patients had completed the observation/maintenance period.From December 2004 until April 2007, 1217 patients were enrolled from 223 centres. Complete data are available for 1193 patients who had the following pre-induction treatment characteristics: median age 56 years [range 22–87]; 52% male; 90% Ann Arbor stage III-IV; 33% B symptoms; 55% bone marrow involvement; 4% ECOG performance status >1; 34% elevated LDH; 32% β2-microglobulin≥3mg/L; FLIPI score 0–1 (21%), FLIPI 2 (36%), FLIPI 3–5 (43%). Most patients (74%) received R-CHOP induction (22% R-CVP, 4% R-FCM).Patients responding to induction therapy were stratified based on their immunochemotherapy regimen and response [CR/CRu versus PR], and randomized to observation or rituximab maintenance, 1 infusion (375 mg/m2) every 8 weeks for 2 years. A total of 1018 randomised patients were analyzed according to the ITT principle (513 observation/505 rituximab maintenance). All initial pre-treatment characteristics were well balanced between arms and the response status at time of randomization was CR=39%; CRu=31% and PR=29% (others 1%).After a median follow-up of 36 months, 3-year progression free survival was 60.3% (95% confidence interval [CI] 55.8 – 64.5%) in the observation arm and 78.6% (95% CI 74.7 – 82%) in the rituximab maintenance arm, respectively (stratified Log-Rank, P<.0001; hazard ratio [HR]=0.55, 95% CI 0.44 – 0.68). In pre-planned analyses of patient subgroups categorized by age, sex, FLIPI score, induction chemotherapy and response to induction, the effect of rituximab maintenance was found to be consistent with the overall study results. In a Cox regression multivariate analysis, older age (P=.0013), male sex (P=.013), higher FLIPI group (P<.0001), R-CVP induction treatment (P=.003) and rituximab maintenance (P<.0001) were all significant variables associated with inferior progression free survival. A significant reduction in the number of patients starting a new anti-lymphoma treatment (HR=0.60, 95% CI 0.47 – 0.76) or starting a new chemotherapy (HR=0.62, 95% CI 0.47 – 0.81) was also observed for rituximab maintenance. Regarding response to treatment, 52% of the patients that were in PR at the time of randomization converted to CR or CRu at the end of 2-year maintenance in the rituximab maintenance arm compared to 30% of patients in the observation arm (P=.0001). As a result, 361 out of 482 patients evaluated (75%) in the rituximab maintenance arm were in CR or CRu as compared to 268 out of 491 patients evaluated (55%) in the observation arm (P< .0001). At the time of the data cut-off, 30 patients (6%) had died in the observation arm compared to 26 patients (5%) in the rituximab maintenance arm (HR=0.87, 95% CI 0.51 – 1.47).The most common adverse events reported were infections, which occurred in 24% and 39% of the patients in the observation and rituximab maintenance arms respectively. Grade 3–4 adverse events were reported in 17% of patients in the observation arm and 24% in the rituximab maintenance arm (neutropenia 1% vs 4%; infections 1% vs 4%, respectively) but these lead to treatment discontinuation in only 8 and 19 patients, respectively.In conclusion, after an additional year of follow-up, these data demonstrate a sustained benefit of 2 years of rituximab maintenance therapy after immunochemotherapy, resulting in improved progression free survival and complete response rates. No additional or unexpected toxicities were observed. All randomized patients have an excellent survival to date and longer follow-up will explore factors affecting overall survival in these patients. The PRIMA results indicate that rituximab maintenance should be considered in all follicular lymphoma patients who have responded to first line immunochemotherapy. Disclosures:Salles:Roche: Consultancy, Honoraria. Off Label Use: The use of rituximab maintenance in follicular lymphoma patients. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants. Feugier:roche: Consultancy, Honoraria. Belada:Roche: Consultancy, Honoraria. Tilly:Amgen: Honoraria. Leppa:Roche: Honoraria. Soubeyran:Roche: Honoraria, Research Funding. Hagenbeek:roche: Consultancy. Lister:Allos: Consultancy; Bioconnections: Consultancy; Astra Zeneca: Consultancy; Tenet: Consultancy; GSK: Chairman of Safety Monitoring Committee. Lopez-Guillermo:Roche: Consultancy, Honoraria. Seymour:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel support; Bayer-Schering: Honoraria, Travel Support.

B-lymphoblastic leukaemia presenting as autoimmune haemolytic anaemia

Dear Editor, In the March 2008 issue of Annals of Hematology, Niscola and colleagues reported a case of B-lymphoblastic leukaemia 9 months after the diagnosis of autoimmune haemolytic anaemia (AIHA) [1]. The preceding AIHA was in remission and its treatment was stopped, so nor the preceding AIHA nor its treatment influenced the leukaemia treatment. However, when Blymphoblastic leukaemia presents immediately as AIHA, treatment should be directed against both leukaemia and haemolysis, and toxicity should be limited. Recently, a 61-year-old man was admitted to the emergency department because of dyspnoea. The Hb count was 6.7 g/dl, WBC count 1.2·10/l, 5.8% blasts, neutrophil count 0.3·10/l, platelet count 84·10/l. Despite a normal reticulocyte count, there was evidence of relevant haemolysis suggested by increased lactate dehydrogenase and indirect bilirubin, and decreased haptoglobin. The peripheral blood smear showed no schistocytes. The direct antiglobulin (Coombs’) test was positive (3+) with polyvalent antibodies and anti-C3d, and negative with anti-IgG. Testing for cold agglutinins was negative. Bone marrow examination showed a common acute lymphoblastic leukaemia (ALL) with 97.5% marrow blasts and a normal karyotype. Because he had a history of myocardial ischemia, packed cells were transfused. This caused a very modest Hb increase. Because of neutropenia and the expectation of several more weeks of neutropenia and mucositis, we wanted to reduce the amount of corticosteroids. We chose to start preinduction treatment for ALL with cytarabine, etoposide and methotrexate. After 1 month, the Coombs’ test was only slightly positive, and laboratory evidence of haemolysis had disappeared. Induction therapy for ALL was started, this time with corticosteroids (dexamethasone), vincristine and adriamycin. One month later, the Coombs’ test was negative. After the induction courses, the Hb started to increase. A complete remission of ALL was achieved. After consolidation with cytarabine and asparaginase, the patient was admitted for allogeneic stem cell transplantation. Cases of ALL with a positive Coombs’ test at the time of diagnosis have been reported [2]. All had a positive Coombs’ with anti-Cd3 but not with anti-IgG, and cold agglutinins could not be found. In these patients, the Coombs’ test became negative when complete remission was achieved. Even though cytostatic drug are immunosuppressive, corticosteroids are most often used as first-line therapy for haemolytic anaemia caused by warm antibodies. Our results suggest that corticosteroids may not be necessary in the initial treatment of AIHA caused by ALL, as long as effective treatment directed against ALL is started.

Induction of labor in women with oligohydramnios

Objective. To prospectively evaluate the outcome of labor induction in women with oligohydramnios at term.Methods. This was a prospective case-control study which included 120 consecutive patients with Amniotic Fluid Index (AFI) ??5 undergoing labor induction. One hundred and sixteen patients with normal amniotic fluid matched for gestational age (?± 3 days) and Bishop-score served as controls. Inclusion criteria were: requirement of labor induction, singleton pregnancy, nulliparity, Bishop score <?5, gestational age ??266. Preinduction treatment included the use of up to 3 successive doses of dinoprostone intracervical gel (0.5?mg). Vaginal dinoprostone (2?mg) and/or oxytocin were then applied to induction labor, if necessary.Results. The rate of cesarean section in AFI???5 group (38.3%) was not significantly different to that in control group (34.2%). The interval from induction to vaginal delivery was not significantly different for AFI ??5 group (1499?±?895?min.) and control group (1398?±?852?min.). The changes in Bishop score evaluated at 6th and 12th hour after dinoprostone were not significantly different in control and AFI???5 group. More women in the latter group (11.7% vs 3.3%, Chi Square:4.86, p?=?0.027) required the use of drugs in order to manage tachysystole/hyperstimulation allowing a OR?=?3.83 (95%C.I.?=?1.13–14.27). The length of stay at hospital was 4.2?±?1.8 days for AFI ??5 group and 4.3?±?1.3 for control group.Conclusions. Oligohydranmios at term did not influence the outcome of induction of labour in nulliparous women with unfavorable cervix.

Induction of labor in women with oligohydramnios

To prospectively evaluate the outcome of labor induction in women with oligohydramnios at term. This was a prospective case-control study which included 120 consecutive patients with Amniotic Fluid Index (AFI) < or =5 undergoing labor induction. One hundred and sixteen patients with normal amniotic fluid matched for gestational age (+/- 3 days) and Bishop-score served as controls. Inclusion criteria were: requirement of labor induction, singleton pregnancy, nulliparity, Bishop score <5, gestational age > or =266. Preinduction treatment included the use of up to 3 successive doses of dinoprostone intracervical gel (0.5 mg). Vaginal dinoprostone (2 mg) and/or oxytocin were then applied to induction labor, if necessary. The rate of cesarean section in AFI < or = 5 group (38.3%) was not significantly different to that in control group (34.2%). The interval from induction to vaginal delivery was not significantly different for AFI < or =5 group (1499 +/- 895 min.) and control group (1398 +/- 852 min.). The changes in Bishop score evaluated at 6th and 12th hour after dinoprostone were not significantly different in control and AFI< or =5 group. More women in the latter group (11.7% vs 3.3%, Chi Square:4.86, p = 0.027) required the use of drugs in order to manage tachysystole/hyperstimulation allowing a OR = 3.83 (95%C.I. = 1.13-14.27). The length of stay at hospital was 4.2 +/- 1.8 days for AFI < or =5 group and 4.3 +/- 1.3 for control group. Oligohydranmios at term did not influence the outcome of induction of labour in nulliparous women with unfavorable cervix.

Disease- and treatment-related elevation of the neurodegenerative marker tau in children with hematological malignancies.

Children acquire neuropsychologic dysfunctions after chemotherapy for hematologic malignancy. In this study, putative changes in levels of CSF-tau (a marker of neural dysintegrity) in leukemic children prior to and during chemotherapy were studied. Cerebrospinal fluid (CSF) samples were obtained before and during treatment from patients with B cell non-Hodgkin's lymphoma (NHL, n = 10), non-B cell acute lymphoblastic leukemia/NHL (non-B-ALL, n = 48), acute myeloid leukemia (AML, n = 9), other malignant diseases (n = 9), and six control children. A sandwich-type ELISA (INNOTEST hTAU-Ag) was used for measuring CSF-tau. Sixteen out of 50 patients with hematological malignancies, including the patients with proven leukemic CNS invasion, already showed high CSF-tau levels at baseline (>300 pg/ml). The pre-induction treatment for non-B-ALL, consisting of only corticosteroids and methotrexate (MTX), resulted in a significant increase of tau at day 8 (on average to 535 pg/ml). Larger increases as compared to baseline levels of CSF-tau were observed in patients treated for B-NHL with systemic vincristine, corticosteroids and cyclophosphamide, and intrathecal MTX (mean 776 pg/ml at day 8). In two AML patients with CNS invasion, CSF-tau increased during chemotherapy up to 1,500 and 948 pg/ml, respectively. In one non-B-ALL patient with MTX-induced clinical neurotoxicity, CSF-tau was above the detection limit of 2,000 pg/ml. Almost one-third of the patients with hematological malignancies had elevated CSF-tau levels at diagnosis. Transient high levels of CSF-tau, reaching levels observed in other neurodegenerative disorders, were observed during induction chemotherapy for non-B-ALL, B-NHL and CNS+ AML. The clinical implications of both observations will be the subject of further study.

The effects of preinduction warming on temperature and blood pressure during propofol/nitrous oxide anesthesia

BACKGROUND Core temperature decreases rapidly after induction of anesthesia, largely because heat is redistributed to peripheral tissues. The hypothesis that warming peripheral tissues before induction of general anesthesia (prewarming) minimizes hypothermia was tested. Because circulating blood volume may be greater during exposure to heat compared to cold, the hypothesis that prewarming decreases the amount of hypotension associated with induction of anesthesia was tested also. Finally, the hypothesis that the difference between direct radial arterial blood pressure and blood pressure measured oscillometrically at the brachial artery depends on thermoregulatory and anesthetic conditions was tested. METHODS Each of six volunteers underwent general anesthesia (propofol and nitrous oxide) twice on the same day. Each anesthetic lasted 1 h and was preceded by either 2 h of active warming with forced air or 2 h of passive cooling by exposure to a typical operating room environment. After induction of each anesthetic, volunteers were fully exposed to the ambient environment. Volunteers recovered for 2 h before starting the second preinduction treatment. RESULTS Initial tympanic membrane temperatures were similar before each preinduction treatment: 36.7 +/- 0.4 degrees C when volunteers were not warmed and 36.7 +/- 0.6 degrees C when volunteers were warmed. Tympanic membrane temperature did not change during the preinduction period without warming but increased slightly (delta T = 0.4 +/- 0.2 degree C) during warming. After induction of anesthesia, core temperatures decreased to 36.1 +/- 0.4 degree C over 1 h when volunteers were prewarmed but decreased to 34.9 +/- 0.4 degrees C when they were not. Radial arterial systolic, diastolic, and mean blood pressures were lower before induction of anesthesia when volunteers were warmed compared to when no warming was given. Oscillometric diastolic and mean pressures also were lower during prewarming; however, oscillometric systolic pressure did not differ significantly. Prewarming did not result in less hypotension after induction. Without warming, the difference (radial arterial minus oscillometric) in systolic blood pressure measurements was approximately 17 mmHg. Warming was associated with a reversal of the systolic pressure difference to approximately -6 mmHg. After induction of anesthesia, the differences in systolic and mean pressure measurements became more negative with respect to the preinduction values regardless of preinduction warming treatment. CONCLUSIONS These data confirm our hypothesis that redistribution hypothermia can be minimized by preinduction warming of peripheral tissues. Prewarming decreases blood pressure but does not prevent subsequent hypotension after induction. The difference between radical arterial blood pressure and oscillometric blood pressure depends on thermoregulatory vasomotor changes but also may be influenced by vasodilation associated with administration of propofol and nitrous oxide.

Net economic benefit of a manufactured dinoprostone gel for pre-induction cervical ripening.

The purpose of this study was to estimate the net economic cost or benefit of pretreating women who have a medical indication for induction of labour, and an unprepared (unripe) cervix, with a manufactured dinoprostone (prostaglandin E 2) gel. Findings of a meta-analysis of the results of 3 large, randomised clinical trials were employed in the construction of a decision tree used in the economic analysis. For the intended target population, the primary clinical and economic outcomes of gel pretreatment were shortening of the treatment-to-delivery interval, an increase in the percentage of patients achieving labour and a decrease in the percentage of patients requiring delivery by caesarean section. Application of cost factors associated with these and other variables led to a finding of net savings associated with use of the dinoprostone gel pretreatment, compared with no gel pretreatment, of $US159 to $US214 (1993 prices) per treated patient, corresponding to the maximum and minimum duration of the pre-induction treatment period, respectively.

The Effects of Preinduction Warming on Temperature and Blood Pressure during Propofol/Nitrous Oxide Anesthesia

Core temperature decreases rapidly after induction of anesthesia, largely because heat is redistributed to peripheral tissues. The hypothesis that warming peripheral tissues before induction of general anesthesia (prewarming) minimizes hypothermia was tested. Because circulating blood volume may be greater during exposure to heat compared to cold, the hypothesis that prewarming decreases the amount of hypotension associated with induction of anesthesia was tested also. Finally, the hypothesis that the difference between direct radial arterial blood pressure and blood pressure measured oscillometrically at the brachial artery depends on thermoregulatory and anesthetic conditions was tested. Each of six volunteers underwent general anesthesia (propofol and nitrous oxide) twice on the same day. Each anesthetic lasted 1 h and was preceded by either 2 h of active warming with forced air or 2 h of passive cooling by exposure to a typical operating room environment. After induction of each anesthetic, volunteers were fully exposed to the ambient environment. Volunteers recovered for 2 h before starting the second preinduction treatment. Initial tympanic membrane temperatures were similar before each preinduction treatment: 36.7 +/- 0.4 degrees C when volunteers were not warmed and 36.7 +/- 0.6 degrees C when volunteers were warmed. Tympanic membrane temperature did not change during the preinduction period without warming but increased slightly (delta T = 0.4 +/- 0.2 degree C) during warming. After induction of anesthesia, core temperatures decreased to 36.1 +/- 0.4 degree C over 1 h when volunteers were prewarmed but decreased to 34.9 +/- 0.4 degrees C when they were not. Radial arterial systolic, diastolic, and mean blood pressures were lower before induction of anesthesia when volunteers were warmed compared to when no warming was given. Oscillometric diastolic and mean pressures also were lower during prewarming; however, oscillometric systolic pressure did not differ significantly. Prewarming did not result in less hypotension after induction. Without warming, the difference (radial arterial minus oscillometric) in systolic blood pressure measurements was approximately 17 mmHg. Warming was associated with a reversal of the systolic pressure difference to approximately -6 mmHg. After induction of anesthesia, the differences in systolic and mean pressure measurements became more negative with respect to the preinduction values regardless of preinduction warming treatment. These data confirm our hypothesis that redistribution hypothermia can be minimized by preinduction warming of peripheral tissues. Prewarming decreases blood pressure but does not prevent subsequent hypotension after induction. The difference between radical arterial blood pressure and oscillometric blood pressure depends on thermoregulatory vasomotor changes but also may be influenced by vasodilation associated with administration of propofol and nitrous oxide.

Differential synchronization of leukemic cells in vivo by hydroxyurea

Flow cytometry (FCM) was used to monitor the cell cycle changes which occurred in the bone marrow cells of a patient with acute myeloblastic leukemia following pre-induction treatment with hydroxyurea. Flow cytometric and cytogenetic analysis showed two populations of cells: one hypertetraploid and presumably leukemic, and the other diploid and possibly normal. Sequential FCM monitoring of bone marrow cells after hydroxyurea demonstrated an early rise (after 24 h) in the S-phase component of diploid cells and a rise in the S-phase component of hypertetraploid cells 48–72 h later. Conventional induction therapy timed to coincide with this latter peak resulted in early remission.