Initial Leukocyte Research Articles

Prognostic value of leukocytosis in pediatric traumatic brain injury.

The purpose of this study was to assess leukocytosis and its prognostic value in pediatric isolated traumatic brain injury (TBI). Two hundred one children with isolated TBI admitted to the authors' institution between June 2006 and June 2018 were prospectively followed and their data retrospectively analyzed. Initial blood leukocyte count (i.e., white cell count [WCC]), Glasgow Coma Scale (GCS) score, CT scans, duration of hospital stay, and Pediatric Cerebral Performance Category Scale (PCPCS) scores were analyzed. The mean age was 4.2 years (range 0.2-16 years). Seventy-four, 70, and 57 patients had severe (GCS score 3-8), moderate (GCS score 9-13), and mild (GCS score 14-15) TBI, respectively, with associated WCC of 20, 15.9, and 10.7 × 109/L and neutrophil counts of 15.6, 11.3, and 6.1 × 109/L, respectively (p < 0.01). Higher WCC and neutrophil counts were demonstrated in patients with increased intracranial mass effect on CT, longer hospital stay, and worse 6-month PCPCS score (p < 0.05). Multivariate regression revealed a cutoff leukocyte count of 16.1 × 109/L, neutrophil count of 11.9 × 109/L, and neutrophil-to-lymphocyte ratio (NLR) of 5.2, above which length of hospital stay and PCPCS scores were less favorable. Furthermore, NLR was the second most important independent risk factor for a poor outcome (after GCS score). The IMPACT (International Mission for Prognosis and Analysis of Clinical Trials in TBI) adult TBI prediction model applied to this pediatric cohort demonstrated increased accuracy when WCC was incorporated as a risk factor. In the largest and first prospective study of isolated pediatric head injury to date, the authors have demonstrated that WCC > 16.1 × 109/L, neutrophil count > 11.9 × 109/L and NLR > 5.2 each have predictive value for lengthy hospital stay and poor PCPCS scores, and NLR is an independent risk factor for poor outcome. Incorporating the initial leukocyte count into TBI prediction models may improve prognostication.

Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups: Presented in part at the 41st meeting of the American Society of Hematology, New Orleans, LA, December 3-7, 1999.

AbstractPreliminary independent reports of the Italian GIMEMA and the Spanish PETHEMA trials for newly diagnosed acute promyelocytic leukemia (APL) indicated a similarly high antileukemic efficacy in terms of complete remission and disease-free survival rates. To better investigate these studies and the prognostic factors influencing relapse risk, this study analyzed the updated results of 217 patients with PML/RARα-positive APL enrolled in GIMEMA (n = 108) and PETHEMA (n = 109). All patients received identical induction (AIDA schedule) and maintenance. For consolidation, GIMEMA patients received 3 courses including idarubicin/cytarabine, mitoxantrone/etoposide, and idarubicin/cytarabine/thioguanine, whereas PETHEMA patients received the same drugs and dose schedule of idarubicin and mitoxantrone with the omission of nonintercalating agents. Depending on whether molecular relapses were classified as censored or uncensored events, the 3-year Kaplan-Meier estimates of relapse-free survival (RFS) for the combined series were 90 ± 2% and 86 ± 2%, respectively. Minor differences observed between the 2 patient cohorts were negligible. Multivariate regression analysis of RFS showed that initial leukocyte (WBC) and platelet counts were the only variables with independent prognostic value. The resulting predictive model for RFS demonstrated its capability of segregating patients into low-risk (WBC count ≤ 10 × 109/L, platelet count > 40 × 109/L), intermediate-risk (WBC count ≤ 10 × 109/L, platelets ≤ 40 × 109/L), and high-risk (WBC count > 10 × 109/L) groups, with distinctive RFS curves (P < .0001). The conclusions are that omission of nonanthracycline drugs from the AIDA regimen is not associated with reduced antileukemic efficacy and a simple predictive model may be used for risk-adapted therapy in this disease.

Response Adapted Therapy in ETV6/RUNX1-Positive Childhood Acute Lymphoblastic Leukemia Treated per Modified St Jude Total XV Study

Introduction: ETV6-RUNX1 is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of cases with a precursor-B phenotype. The presence of ETV6-RUNX1 has been associated with a relatively low rate of relapse in multiple studies. Relapses tend to occur late and have a better salvage rate than other ALL subtypes. Moreover, conflicting data in literature regarding the prognostic significance of ETV6-RUNX1 after accounting for age, initial count and treatment intensity. We sought to study the clinical features, therapy response in newly diagnosed ETV6-RUNX1-positive treated at King Hussein Cancer Center. Methods: Patients were treated per modified St Jude Total (XV) study, risk stratification was further refined by including minimal residual disease (MRD)measurements on day 15 and day 46 of remission induction therapy. Patients with the ETV6- RUNX1 fusion or hyperdiploidy without CNS or testicular disease and a satisfactory early MRD decline (&amp;lt;1% on day 15 and &amp;lt;0.01% on day 46) were classified as being low-risk for relapse and were treated on lower -risk arm regardless of age and leukocyte count. Results: Seventy patients (n=70) with ETV6-RUNX1-positive treated at our institution between May 2006 to October 2017. The median age at diagnosis, 5.8 years (range, 1.5-10.8). ETV6-RUNX1 was associated with favorable age between 1- and 6-years in 55 patients (79%), male gender in 41 patients (59%), initial leukocyte count &amp;lt;10 in 39 patients (56%), CNS status 1 in 100% of patients. The majority, n= 58 (83%) of patients had NCI standard risk (SR) and n=12 (17%) had NCI high risk (HR). Sixty-six patients (94%) had MRD &amp;lt;1% at day 15 and all patients achieved remission with MRD&amp;lt;0.01% at day 46 of remission induction. All patients were treated as LR ALL per modified St Jude total XV protocol. At median follow up of (36 months; range, 26 to 154), in the subgroups of ETV6-RUNX1-positive patients classified as NCI standard risk (SR)and NCI high risk (HR) the 5-year EFS estimates were 94.1% ± 3.2 and 82%±1(P=.13), 5-year OS estimates were 100% and 92% ± 8 (p=0.31) respectively. Conclusion: MRD treatment schema in ETV6/RUNX1 -positive patients have excellent outcomes if they achieved favorable response at day 15 and end of remission induction regardless of the age and Initial leukocyte count. Treatment reduction is feasible and declared safe for children with NCI-HR who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD post remission induction therapy. Disclosures No relevant conflicts of interest to declare.

Outcome of Core Binding Factor Acute Myeloid Leukemia by Receptor Tyrosine Kinase Mutation

BackgroundCore binding factor acute myeloid leukemia (CBF-AML) encodes 2 recurrent cytogenetic abnormalities, t(8;21) and inv(16), which carries an overall good prognosis. However, some patients will develop a relapse. We sought define the unfavorable group of CBF-AML by analysis of (c-KIT and FLT3-ITD) and to correlate them with treatment outcome. Patients and MethodsWe performed a prospective study of 70 patients with CBF-AML diagnosed and managed at the medical oncology department of the (National Cancer Institute), Cairo University, with analysis of c-KIT and FLT3 mutations. All patients had received “3 + 7” induction, followed by 3 to 4 courses of high-dose cytarabine consolidation. The institutional review board approved the present study. ResultsThe median patient age was 31 years (range, 18-60 years), with a male/female ratio of 4:3. Of the 70 patients, 42 (60%) had t(8;21) and 28 had inv(16) (40%). c-KIT mutations (exons 8 and 17) were detected in 10 of 52 tested patients, and FLT3-ITD was detected in 3 of 70 patients. Patients with inv(16) experienced more lymphadenopathy and splenomegaly, had a higher median initial leukocyte count. Hepatitis C antibody positivity (8 of 42) was exclusively present in patients with t(8;21). The median overall survival (OS) was 19.5 months, and the median disease-free survival (DFS) was not reached. Patients with inv(16) had near-significant (P = .07) better DFS than patients with t(8;21). c-KIT mutations had no significant effect on OS or DFS. However, reverse tyrosine kinase mutations had a negative effect on DFS but not OS (P = .04). ConclusionCBF-AML with reverse tyrosine kinase mutation conveys a worse prognosis. Hepatitis C virus antibody positivity might be associated with t(8;21) AML and inv(16) with more extramedullary disease.

Factors Predicting the Need for Early Surgical Intervention for Small Bowel Obstruction.

Purpose Small bowel obstruction (SBO) is a common disease that requires hospitalization. The most common cause of SBO is postoperative adhesion. Delayed timing of operations in patients who need surgical intervention results in mortality or morbidity. A number of studies on SBO have established criteria for emergency surgery. However, few objective clinical parameters are available for screening patients who need a delayed operation. Therefore, we analyzed factors that affect the clinical course of SBO to select appropriate therapeutic plans for reducing the risk of complications in these patients.Methods We investigated the clinical characteristics of patients admitted to the surgery department of our hospital between January 1, 2015, and December 31, 2016, who were diagnosed with SBO. Patients were divided into an operative treatment group (n = 12) and a conservative treatment group (n = 96). We compared clinical characteristics between the 2 groups.Results The operative treatment group underwent more operations before SBO than the conservative treatment group (P = 0.007). Initial leukocyte counts (P = 0.004) and C-reactive protein (CRP) levels (P = 0.028) were elevated in the operative group. Body mass index (BMI) was lower in the operative group (P = 0.013).Conclusion The number of operations before SBO, leukocyte counts, CRP levels, and BMI were useful parameters for selecting patients who needed an urgent operation for SBO.

The Outcome of Modified St. Jude Total XV Protocol in Turkish Children with Newly Diagnosed Acute Lymphoblastic Leukemia

Introduction: Childhood acute lymphoblastic leukemia (ALL) treatment with St. Jude Total therapies showed superior outcome with event-free and overall survival rates 85.6 ± 2.9% and 93.5 ± 1.9%, respectively. Here, we studied prognostic features and the outcome of Turkish children with newly diagnosed ALL treated with modified St. Jude Total Therapy XV Protocol. Patients and methods: There were 182 newly diagnosed ALL patients aged 1-18 years old and treated with modified Total Therapy XV between 1 January 2008 and 30 January 2016. According to our previous successful results with high dose methylprednisolone (HDMP), each patient received 7 days of HDMP as an initial treatment and randomized at doses of 20 mg/kg/d or 10mg/kg/d HDMP, not exceeding at maximum 1000 mg MP. After the first 7-day steroid treatment, concomitant chemotherapy was given and the steroid doses were tapered to 10mg/kg/d and 5mg/kg/d during the next week in each group, respectively. Afterwards, the whole group received 2 mg/kg/d MP for the following two weeks. Also, there were a third group received lower doses (&lt;10 mg/kg/d) of MP because of the hyperleukocytosis for the first 7 days. Results: Out of 182 patients, 174 completed the treatment and 1 patient experienced induction failure, 4 patients died during remission induction, 3 patients abandoned treatment during maintenance. 97.2% of the children entered complete remission after remission induction. 16 patients (8.9%) had relapses during follow-up, 9 isolated bone marrow, 7 isolated CNS and 3 of 7 patients who had CNS relapse experienced a second relapse (bone marrow) afterwards. The five-year event-free survival (EFS) and overall survival (OS) were 85.6±2.6 % and 89.2±2.3%, respectively. There was no significant difference according to the survival rates between different MP doses (10 and 20mg/kg/d) which were given before induction. Moreover, difference in frequency of infection between patient groups treated with different steroid doses during induction period was not found statistically significant. Univarite analysis showed that age ≥ 10 years at the time of diagnosis, initial leukocyte count ≥50x109/L, low MP doses (&lt;10mg/kg/d) and infection with gram negative bacteria during remission induction were associated with inferior EFS. Multivariate analysis revealed lower EFS rates with an initial leukocyte count ≥50x109/L [HR=5.58, 95% CI: 1.99-15.64, p&lt;0.001], age ≥ 10 years at the time of diagnosis [HR=3.81, 95% CI: 1.65-8.81, p=0.002], infection with gram negative bacteria during remission induction [HR=3.71, 95% CI: 1.55-8.88, p=0.003] and CD20 positivity (&gt;20%) at diagnosis [HR=2.49, 95% CI: 1.08-5.73, p=0.031]. Response to MP measured as &lt;1000/mm3absolute blast count in peripheral blood sample after first 7 days did not have statistically significant influence on survival in comparison with poor MP response (&lt;1000/mm3absolute blast count in peripheral blood). Conclusion: Our encouraging EFS result with modified St. Jude Total XV in childhood ALL patients is comparable with the one in original protocol. Favorable effect of higher doses of MP (20 mg/kg/d) on survival could not be demonstrated when compared with 10mg/kg/d. Disclosures No relevant conflicts of interest to declare.

The atherogenic role of immune cells in familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism that mainly occurs due to mutations in the low-density lipoprotein receptor gene and is characterized by increased levels of low-density lipoprotein cholesterol, leading to accelerated atherogenesis and premature coronary heart disease. Both innate and adaptive immune responses, which mainly include monocytes, macrophages, neutrophils, T lymphocytes, and B lymphocytes, have been shown to play a key role for the initiation and progression of atherogenesis in the general population. In FH patients, these immune cells have been suggested to play specific pro-atherosclerotic activities, from the initial leukocyte recruitment to plaque rupture. In fact, the accumulation of cholesterol crystals and oxLDL in the vessels in FH patients is particularly high, with consequent abnormal mobilization of immune cells and secretion of various pro-inflammatory and chemokines. In addition, cholesterol accumulation in immune cells is exaggerated with chronic exposure to relevant pro-atherosclerotic triggers. The topics considered in this review may provide a more specific focus on the immune system alterations in FH and open new insights toward immune cells as potential therapeutic targets in FH.

Long-term follow-up of children with acute promyelocytic leukemia treated with Beijing Children’s Hospital APL 2005 protocol (BCH-APL 2005)

We studied the outcomes of children with APL treated by the Beijing Children’s Hospital’s (BCH) acute promyelocytic leukemia (APL) 2005 protocol (BCH-APL2005). The clinical data of 77 patients enrolled from January 2005 to June 2015 were analyzed retrospectively. The hematologic complete remission (CR) rate and overall survival (OS) rate were evaluated between standard-risk (SR) and high-risk (HR) groups. Prognostic factors and complications were investigated in these two groups. CR in the SR and HR groups was 96.4% (54/56) and 85.7% (18/21), respectively, while the 10-year OS was 94.6% (53/56) and 76.2% (16/21), respectively. The cumulative incidence of early death was 6.5% (5/77), and the SR and HR groups were 1.8% (1/56) and 19.0% (4/21), respectively. Only two patients relapsed, and the relapse rate was 2.6% (2/77). According to Kaplan–Meier analysis, the SR group had a significantly better long-term survival than HR counterparts (p= .016). Initial leukocyte count was the only prognostic factor (p= .016) by univariate analysis, while other factors, such as FLT3-ITD and platelet count, had no correlation with prognosis. In addition, early deaths were mainly due to intracranial hemorrhage. Although the combination of all-trans retinoic acid (ATRA) and chemotherapy can improve the outcome of APL patients, the early deaths and anthracycline-related cardiac toxicity were relatively higher in our study. Current efforts focus on reducing or even avoiding chemotherapy in APL children and rest on the frontline regimen of intravenous arsenic trioxide or oral realgar-indigo naturalis formula plus ATRA, which is the direction for APL treatment.

Prognostic Value of Leucocytosis in Paediatric Traumatic Brain Injury

Abstract INTRODUCTION Prognostic factors in paediatric traumatic brain injury (TBI) remain unclear. This study assessed the prognostic value of leucocytosis in paediatric isolated TBI METHODS A total of 106 paediatric isolated TBI patients treated at our institution between June 2008 and June 2016 were retrospectively analysed. Data collected included initial blood leucocyte count (WCC), presenting Glasgow Coma Score (GCS), computed tomography (CT), hospital stay, and Paediatric Cerebral Performance Category Scale (PCPCS), and their relationship with WCC were statistically evaluated. RESULTS A total of 39, 37, and 30 patients had severe, moderate, and mild TBI, respectively. For patients with GCS 3-8, 9-13, and 14-15, WCC was 20, 15.9, and 10.7 × 109/L, respectively. Differences in WCC were significant between the different GCS groups (P &lt; .01). WCC was greatest and smallest in patients with CT findings demonstrating significant mass effect (Marshall grading V-VI) and minimal mass effect (Marshall grading I-II), respectively (P &lt; .05). Length of hospital stay and extent of midline shift on CT each significantly correlated with WCC (P &lt; .05). In addition, higher WCC counts were associated with a poorer 6-mo PCPCS rating (P &lt; .05). Multivariate regression analysis revealed a cut-off leucocyte count of 16.1 × 109/L, and Neutrophil-to-Lymphocyte ratio (NLR) of 5.2, above which GCS, CT findings, length of hospital stay and PCPCS were less favourable. Application of the International Mission on Prognosis and Analysis of randomized Controlled Trials in TBI (IMPACT) adult TBI prediction model to our paediatric cohort, using area under the operating curve (AUROC) and coefficient analyses, demonstrated increased accuracy with incorporation of WCC count as a risk factor. CONCLUSION High leucocyte count (&gt;16.1 × 109/L) and NLR &gt; 5.2 each have a predictive value for poor GCS, severe CT findings, lengthy hospital stay and poor PCPCS in isolated paediatric TBI. Incorporating initial leucocyte count into TBI prediction models may increase the accuracy of prognostication.

Demographics and Outcome of Philadelphia-positive ALL in a Pediatric Population in North India: a Single-center Experience.

Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) in children had a worse outcome before the use of tyrosine kinase inhibitors. We have evaluated the demographics and outcome of Ph+ ALL patients treated with imatinib without blood marrow transplantation. Of the 206 children with ALL registered for treatment, the demographic data of 15 Ph+ ALL patients were compared with the remaining Ph- patients. Imatinib (340 mg/m) was started on day 5 (D5) of induction in Ph+ patients, and their overall survival was compared with Ph- high-risk patients treated on similar protocols. Statistical analysis was carried out by the Fisher exact test and the t test. The Kaplan-Meier test was used for survival analysis. Philadelphia positivity noted in 15/206 (7.28%) ALL patients was higher than reported earlier. Median initial total leukocyte count and central nervous system positivity were significantly higher in Ph+ patients. Myeloid markers, CD13 and CD33, were also positive in 33.3% Ph+ patients. D15 and D35 marrow showed remissions in a larger proportion of Ph+ ALL, as compared with Ph- patients, but chemotherapy interruptions and neutropenic deaths were significantly higher after starting imatinib, as compared with Philadelphia high-risk patients. Overall survival was similar in Ph+ and Ph- high-risk ALL patients. Ph+ ALL, noted in 7.28%, presented with high initial white blood cell counts, high central nervous system positivity, poor steroid response, and higher induction deaths, as compared with high-risk Ph- ALL, and raised the question about the appropriate dose and time of introduction of imatinib to prevent toxicity.

Evaluation of Systemic Effects of Negative Pressure Wound Therapy in Open Wound Treatment in Dogs

Objectives The aim of this study was to evaluate the systemic effect of negative pressure wound therapy (NPWT) on the treatment of complicated wounds in dogs. Materials and Methods Dogs undergoing open wound treatment were randomly assigned to one of two groups: NPWT (n = 11) or polyurethane foam dressing (n = 11). Rectal temperature, heart rate as well as haematocrit, thrombocytes, leucocyte count, band neutrophils, C-reactive protein (CrP), total protein and albumin were recorded daily from the beginning of therapy (day 0) until day 5, as well as on day 10. The effect of treatment on systemic parameters was evaluated as well as the prognostic power of the individual parameters with regard to successful wound closure. Results A more profound systemic decrease was found in total protein under NPWT. This difference was non-significant. Patients with non-successful closure displayed a non-significant trend towards lower initial leukocyte and thrombocyte counts and significantly higher CrP values on days 4, 5 and 10 (p &lt; 0.05) compared with successfully treated patients. Receiver operating characteristic analysis revealed an optimal cutoff value of 70.2 mg/L at day 4 (sensitivity 80; specificity of 85.7). Conclusion There might be an increased loss of protein in NPWT-treated patients, which does not affect albumin levels, otherwise no systemic effects were detected compared with the control treatment. The parameter with the best sensitivity and specificity to detect serious complications (no wound closure achieved) was CrP at day 4.

Long-Term Outcomes of Modified St Jude Children’s Research Hospital Total Therapy XIIIB and XV Protocols for Thai Children With Acute Lymphoblastic Leukemia

BackgroundWe studied long-term outcomes and prognostic features of Thai children with acute lymphoblastic leukemia treated with modified St Jude Children’s Research Hospital (SJCRH) protocols. Patients and MethodsPediatric patients newly diagnosed with acute lymphoblastic leukemia were included. From 1997 to 2003, the first group received modified Total Therapy XIIIB (previous protocol). From 2004 to 2014, the latter had modified Total Therapy XV (current protocol). ResultsIn 250 patients, the event-free survival rates (± standard error) of the previous protocol (n = 95) were 82.8 ± 3.9%, 81.7 ± 4.0%, and 81.7 ± 4.0% at 5, 10, and 15 years, respectively; current protocol event-free survival rates (n = 155) were 84 ± 3.0%, 80.8 ± 3.4%, and 80.8 ± 3.4%, respectively. Previous protocol overall survival rates for the same years were 89.2 ± 3.2%, 84.8 ± 3.8%, and 84.8 ± 3.8%, and for the current protocol were 90 ± 2.5%, 86.9 ± 3.2%, and 83.7 ± 4.4%. Previous protocol relapses were 10.5% (10 patients), with 7 having isolated hematologic and 3 isolated/combined central nervous system relapses. Current protocol relapses were 9.7% (15 patients), with 7 having isolated hematologic, 6 isolated/combined central nervous system, and 2 extramedullary relapses. Patients with leukocyte counts over 100 × 109/L and who had disease classified as high risk had worse event-free survival using the previous protocol. However, only initial leukocyte counts of ≥ 100 × 109/L predicted adverse outcomes under the current protocol. Minimal residual disease positivity was a prognostic factor of worse overall survival only for previous protocol patients. ConclusionFavorable outcomes of childhood acute lymphoblastic leukemia occurred using adapted SJCRH protocols, perhaps because of multidisciplinary care teams and improved parent advocacy. Inferior outcomes might be prevented by addressing predictive factors to ameliorate monitoring and care.

Leucocyte Trafficking via the Lymphatic Vasculature- Mechanisms and Consequences.

The lymphatics fulfill a vital physiological function as the conduits through which leucocytes traffic between the tissues and draining lymph nodes for the initiation and modulation of immune responses. However, until recently many of the molecular mechanisms controlling such migration have been unclear. As a result of careful research, it is now apparent that the process is regulated at multiple stages from initial leucocyte entry and intraluminal crawling in peripheral tissue lymphatics, through to leucocyte exit in draining lymph nodes where the migrating cells either participate in immune responses or return to the circulation via efferent lymph. Furthermore, it is increasingly evident that most if not all leucocyte populations migrate in lymph and that such migration is not only important for immune modulation, but also for the timely repair and resolution of tissue inflammation. In this article, I review the latest research findings in these areas, arising from new insights into the distinctive ultrastructure of lymphatic capillaries and lymph node sinuses. Accordingly, I highlight the emerging importance of the leucocyte glycocalyx and its novel interactions with the endothelial receptor LYVE-1, the intricacies of endothelial chemokine secretion and sequestration that direct leucocyte trafficking and the significance of the process for normal immune function and pathology.

Diagnostic Value of Platelet and Leukocyte Counts in the Differential Diagnosis of Fever in the Returning Traveler.

Malaria, arbovirus infection and travelers' diarrhea are among the most common etiologies of fever after a stay in the tropics. Because the initial symptoms of these diseases often overlap, the differential diagnostic remains a challenge. The aim of this study was to establish the effectiveness of platelet and leukocyte counts in the differential diagnosis of fever in the returning traveler. Between 2013 and 2016, patients with a clinical suspicion of malaria, who had thick blood smears performed were retrospectively included. The microbiological etiology of each episode was established based on molecular detection in the case of arbovirus infection, the detection of pathogens in stool samples for diarrhea and other gastrointestinal symptoms and the thick and thin blood smear results for malaria. A total of 1,218 episodes were included. Malaria, arbovirus infection, and diarrhea and other gastrointestinal symptoms caused 102 (8.4%), 68 (5.6%), and 72 (5.9%) episodes, respectively. The median platelet counts in malaria episodes were 89 × 109/L and thrombocytopenia (< 150,000 × 109 platelets/L) yielded a 98% negative predictive value to predict malaria. The median leukocyte counts in arbovirus infection episodes were 3.19 × 109/L and leucopenia (< 4 × 109 leukocytes/L) yielded a 97.9% negative predictive value to predict arbovirus infections. Platelet and leukocyte counts were not significantly altered in episodes caused by diarrhea and other gastrointestinal symptoms. Initial platelet and leukocyte counts might be useful for the clinical differential diagnosis of fever in the returning traveler. Although these results are insufficient to establish a diagnosis, they should be considered in the initial clinical assessment.

Sobrevida global de pacientes con leucemia aguda en el Hospital de Especialidades Pediátricas de Chiapas, México

At the 10th anniversary of the Hospital de Especialidades Pediátricas in Chiapas, Mexico, it was important to assess the 5-year acute leukemia overall survival under the Seguro Popular program (Popular Insurance). A descriptive and survival study of 210 acute leukemia patients diagnosed and treated during 2008-2012 was performed. Kaplan-Meier survival curves were developed for all patients, each leukemia type (B, T and myeloid) and for B type related to risk group, age, sex, leukocytes, cell markers, DNA index, karyotype, and translocations. Age, gender and proportion of leukemia types (B = 85%; M = 10%; T = 5%), were similar to other parts of the country. At the end of the 5-year treatment, 20% of the patients were alive, 53% had died and 27% had abandoned the treatment. Global survival was 42% (B = 45%; T = 20%; M = 10%) (median: 38.8 months; confidence interval of 95% = 28.9-48.7). Very high-risk median survival was 7.7 versus 47 months. There was no difference between standard and high-risk groups. The initial leukocyte count < 50,000/mL and CD10 positive were related to better B survival; no other variables were related. At the time of death, 29% of patients were in remission. Global survival of acute leukemia at Hospital de Especialidades Pediátricas under the Seguro Popular during its first 5 years was surprisingly poor given the medical resources available through the insurance. Early mortality, death during remission and high desertion rates contributed to these results. A detailed revision of treatment protocols and reasons for abandoning treatment is mandatory.

Different Treatment Regimens, Optimal Time Points and Threshold Level While Minimal Residual Disease Evaluation in AML Patients

Introduction. Minimal residual disease (MRD) detection by multicolor flow cytometry (MFC) after early induction or consolidation AML therapy is a well known factor of adverse prognosis, especially in intermediate risk group. New assessment of response in AML is complete remission with MRD-negative status. However, there is still no standardization of MFC method for AML patients (pts). Optimal time point for MRD status and its threshold value vary in different studies.Aim. To study different consolidation treatment regimens in AML pts by measuring of MRD reduction, to determine optimal time point and threshold level for additional risk stratification.Patients and methods. From March 2016 to February 2018 42 pts (younger than 60 y.o.) with newly diagnosed AML were included in prospective MRD study in hematology department of National Research Center for hematology. Initial leukemia-associated immunophenotype was analysed before any treatment, and bone marrow assessment for MRD detection was performed in CR pts after 1st and 2nd chemotherapy courses. The standard antibody panel included CD19, CD7, CD2, CD38, CD65, CD66b, CD99 (FITC); CD56, CD15, CD11b, CD13 (PE); CD33 (APC); HLA-DR, CD14, CD16, CD117 (PerCP-Cy 5.5); CD45 (APC-H7) and CD34(PE-Cy7). For results record BD FACSCanto II (Becton Dickinson) machine was used. The first course for all pts was the standard «7+3». Before March 2017 the second course was also «7+3» and included 25 pts, after March 2017 - 17 pts received intensive «Flarida» regimen (Fludarabine 30mg/m2 1-4, Ara-C 1g/m2 1-4, Idarubicin 8mg/m2 1,3). The 2nd MRD test was compared in these two groups. There was no difference between the two groups by pts in CR after the first «7+3», ELN status and age.Results. By using of special mathematical and statistical method the threshold value of 0,01% was estimated for long-term prognosis. Two years relapse-free survival (RFS) in MRD-positive (MRD+) and MRD-negative (MRD-) groups after the 1st induction was 23% and 87%, respectively (p<0,01). Probability of relapse (PoR) during the first year of observation in these two groups was 72% and 10%, respectively (p<0,01). After the second course 9 more pts in two groups became MRD-negative and 6 of them developed a relapse. RFS in MRD+ and MRD- after the 2nd course was 36% and 65% (p<0,01), and PoR - 71% and 34%, respectively (p<0,01). Multivariate analysis showed MRD factor as the only important in RFS compared to cytogenetic, molecular status, age and initial leukocyte count. OS and RFS in «7+3» and «Flarida» regimens during the first year were 100% vs 80% (p=0,27) and 74% vs 76% (p=0,63), respectively. MRD level reduction after different consolidation regimens («7+3» vs «Flarida») didn't show any variation (p=0,14) and there was no association between MRD status after induction in different ELN groups (p=0,52).Conclusion. MRD threshold value of 0,01% allows to distinguish the two cohorts of AML pts groups: with different prognosis even in any ELN risk subgroups. The RFS was reliably higher in pts with CR and MRD-negative status right after the first induction, which reflected the chemo sensitivity of the tumor. After the consolidation course MRD detection still has a prognostic value. MRD level reduction was not associated with intensification of chemotherapy. There is a great need to achieve MRD negative status in AML pts after the 1st induction course so new therapy approaches are pending. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hematologic Adverse Effects of Prolonged Piperacillin-Tazobactam Use in Adults

Objective:We aimed to find the incidence and risk factors of hematologic adverse effects of piperacillin-tazobactam (TZP).Materials and Methods:Adult patients who used TZP for more than 10 days were included in the study.Results:The incidence of leukopenia, neutropenia, and eosinophilia in 110 TZP therapy episodes was found to be 16.3%, 10%, and 10%, respectively. Lower Charlson Comorbidity Index score, lower initial leukocyte count, combination of TZP with another antibiotic, and total duration of TZP therapy were found to be independent risk factors for leukopenia, while initial higher eosinophil count (IHEC) and usage of TZP for >20 days were independent risk factors for neutropenia and IHEC and total duration of TZP therapy were independent risk factors for eosinophilia.Conclusion:Longer duration of therapy, combination with other antibiotics, younger age with fewer comorbidities, and IHEC could result in hematologic adverse effects in patients treated with TZP. Patients with IHEC may be more prone to allergic reactions, so immunological mechanisms may facilitate the development of hematological adverse effects of TZP.

Acute promyelocytic leukemia: state-of-the-art management

Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML) -retinoic acid receptor (RAR) α fusion protein generated by the chromosomal translocation t (15;17) which affects both nuclear receptor signaling and PML nuclear body (NB) assembly. The advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as molecular targeted therapies directed against PML-RARα has been a major breakthrough in APL treatment. ATRA and ATO target RARα and PML, respectively, and elicit PML-RARα degradation, leading to the reformation of normal NBs and cell differentiation. In several multicenter trials, more than 90% of newly diagnosed APL patients treated with ATRA and chemotherapy achieved complete remission, of whom 20%-30% subsequently relapsed; the overall survival was approximately 80% in these studies. However, several major clinical problems continue to account for treatment failure including early death due to hemorrhage, infection during consolidation, disease relapse, and secondary malignancies. These issues are associated mainly with anticancer agents used in combination with ATRA. Combination therapy using ATRA and ATO is the current standard therapy for untreated patients with APL in Western countries. The current problems in patients with APL treated with ATRA and ATO are APL differentiation syndrome and high risk of relapse in patients with an initial leukocyte count of more than 10×109/l.

Factors associated with non-response to lactulose therapy in cirrhotic patients with minimal hepatic encephalopathy

Background and objectives: Minimal hepatic encephalopathy (MHE) impairs health related quality of life and predicts overt hepatic encephalopathy (HE) in cirrhotic patients. Lactulose is effective in the treatment of MHE. But the response to lactulose treatment depends on several factors. This study was aimed to find out the contributing factors to non-response to lactulose therapy.Materials and methods: The study was carried out at the BIRDEM general hospital from September, 2013 to March, 2015. Sixty patients were enrolled to assess the response of lactulose therapy in cirrhotic patients with MHE. MHE was diagnosed based on abnormal psychometric tests namely, number connection test (NCT), digit symbol test (DST) and high serum ammonia level. A daily dose of 30-60 ml of lactulose was given to all patients for one month. The response to treatment with regard to MHE was determined after one month using defined criteria. The response was graded as responder and non-responder.Results: The mean age of the study population was 57.0±10.3 years. Out of 60 cases, 46 (77%) were male and 39 (65%) had diabetes. Out of 60 enrolled MHE cases, 16 (27%) had Child-Turcotte-Pugh-A (CTP-A) score and 44 (73%) belonged to CTP-B &amp; C category. Out of 60 MHE cases, 23 (38.3%) showed improvement in their MHE status based on normalization of psychometric tests and reduction of serum ammonia level to ≤32 μmol/L. Age, gender and diabetes were not associated with the response to lactulose therapy. Low baseline arterial pressure was significantly (p=0.003) associated with non-response to lactulose treatment. The mean baseline ammonia level was higher significantly among the nonresponders compared to the responders (83.6±21.4 μmol/L vs 58.8±19.8 μmol/L, p&lt;0.001). Compared to responders, low serum sodium and potassium and raised serum bilirubin levels of non-responders at baseline were found significantly (p&lt;0.05) associated with non-response to one month of lactulose treatment. Initial hemoglobulin, peripheral leucocyte and platelet counts did not have any effect on the response to lactulose treatment in MHE cases.Conclusions: The status of MHE in patients with cirrhosis improved by one-month treatment with lactulose. Baseline low arterial pressure, hyperammonemia, hypokalemia and hyponatremia were major contributors to non-response to lactulose therapy. The findings of the study would be useful in treating patients of cirrhosis with MHE.IMC J Med Sci 2018; 12(1): 15-21

Tamibarotene As Maintenance Therapy for Acute Promyelocytic Leukemia Improved Long Term Relapse-Free Survival: 7-Year Results from a Randomized Controlled Trial, JALSG-APL204

Background: Tamibarotene, a new synthetic retinoid, displays (i) approximately 10-fold increased potency over ATRA at inducing in vitro differentiation of NB-4 cells (ii) enhanced chemical stability compared with ATRA (iii) low affinity for cellular RA-binding protein. The clinical efficacy of tamibarotene for the treatment of acute promyelocytic leukemia (APL) has also been reported. A prospective randomized controlled study to evaluate tamibarotene by comparison to ATRA was carried out for maintenance therapy of APL in JALSG APL204 (Shinagawa et al, 2014). The 4-year-relapse free survival (RFS) did not differ between patients treated with ATRA or tamibarotene. However, an improved efficacy of tamibarotene in high-risk patients was suggested, which warrants further investigation. Here, we evaluate the long-term outcome of the study. Patients and Methods: Patients enrolled in this study were newly diagnosed with APL and documented cytogenetic and/or molecular evidence of t(15;17)/ PML-RARA . The age of the patients ranged between 15 and 70 years and the ECOG performance status was between 0 and 3. For remission induction therapy, ATRA was administered to all patients at a daily dose of 45 mg/m2 until complete remission (CR). The chemotherapy protocol varied depending on the initial leukocyte count and blast count in the peripheral blood. In brief, patient groups were defined as: leukocytes Results: A total of 347 patients were enrolled in the study. Of the 344 eligible patients, 319 (93%) achieved CR. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment; 135 patients were assigned to ATRA, and 134 patients were assigned to tamibarotene. The mean follow-up of patients alive and relapse-free at the date of last contact was 7 years. The 7-year RFS rate was 84% for the ATRA arm and 93% for the tamibarotene arm (p=0.031) (Fig.1). When the analysis was restricted to 52 high-risk patients with an initial leukocyte count ≥ 10,000/µl, the difference was more prominent (62% vs 89%, p=0.034) (Fig.2). The 7-year RFS of induction treatment for Group A (92 cases) was 91%, Group B (38 cases) 92%, Group C (52 cases) 75% and Group D (87 cases) 91% (p=0.005). Both treatments were generally well tolerated. Secondary hematopoietic disorders were observed in 12 cases, malignancies in 9 cases, late cardiac complications (grade 3 or more) in 5 cases. However, there was no significant difference in terms of these complications between the two treatment groups. Conclusions: Maintenance therapy with tamibarotene was effective at decreasing the relapse rate in APL patients by comparison to ATRA at the 7-year observation point. In particular, tamibarotene was significantly more effective than ATRA for high risk patients with leukocytes ≧10,000/μl. These results could lead to a new strategy for the treatment of high risk patients, which is one of the recent priority issues in the treatment of APL. Disclosures Takeshita: Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Phizer Japan Inc.: Research Funding; Takeda Pharmaceutical Co Ltd: Research Funding. Asou: Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding. Ueda: KAINOS LABORATORIES INC: Membership on an entity9s Board of Directors or advisory committees; Abrynx nv: Membership on an entity9s Board of Directors or advisory committees; Elli LiLLY Japan KK: Other: Clinical Trial; Takeda PharmaceuticalCompany Limited: Other: Clinical TRial; Otsuka Pharmaceutical Co Ltd: Other: Clinical Trial; Celgene KK: Other: Clinical Trial; Symbio Pharmaceutical Limited: Other: Clinical Trial; AstellasPharma Inc: Other: Clinical Trial; Eisai Co. Ltd: Other: Clinical Trial. Fujita: Chugai Pharmaceutical: Honoraria. Usui: Nippon Shinyaku Pharmaceutical Co: Research Funding. Kobayashi: Pfizer, Ohtsuka, Astellas, Ariad: Research Funding. Kiyoi: Kyowa Hakko Kirin Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; ONO Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Meiji Seika Pharma Co.,Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Eisai Co., Ltd.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Phizer Japan Inc.: Honoraria, Research Funding; MSD K.K.: Research Funding; Novartis Pharma K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; JCR Pharmaceuticals Co.,Ltd.: Research Funding. Atsuta: Otsuka Pharmaceutical Co., Ltd.: Honoraria. Naoe: Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Nippon Boehringer Ingelheim Co.: Honoraria, Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Dainippon Sumitomo Pharma Co.,LTD.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding. Miyazaki: Nippon Shinyaku: Honoraria.