Hemato-oncological Malignancies Research Articles

The Efficacy of Three Different Oral Hygiene Regimens in Preventing Chemotherapy-Induced Oral Mucositis in Pediatric Patients Receiving Hematopoietic Stem Cell Transplantation.

Oral mucositis is one of the side effects developed post-hematopoietic stem cell transplant. This retrospective study aimed to assess the efficacy of a mouthwash mixture (lidocaine, sodium alginate, sucralfate, pheniramine) versus hyaluronic acid and a solution of sodium bicarbonate in terms of healing time and weight gain in the treatment of oral mucositis in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation with hemato-oncological malignancies. A total of 171 patients that received chemotherapy for the hematopoietic stem cell transplant were divided into three groups; group 1, treated with a mixed mouthwash of lidocaine, sodium alginate, sucralfate, and pheniramine; group 2, treated with hyaluronic acid; and group 3, treated with an aqueous solution of 5% sodium bicarbonate. Weight and mucositis scale scores derived from medical records of patients. There was a statistically significant difference in the mucositis scale scores between the groups on the transplant day and days 5, 10, 15 and 20 after the transplantation. At these measurement points, Group 2 (receiving hyaluronic acid) had a lower score, and Group 3 (who received sodium bicarbonate) had a higher score, especially on days 5 and 10 after the transplantation. The results suggest that hyaluronic acid is a more effective treatment option than the other oral care solutions that are frequently used for prophylaxis and treatment of oral mucositis.

Evaluation of Clinical and Etiological Characteristics of Cases with Pediatric Lymphadenopathy

Lymphadenopathies are among the common causes of frequent hospital admissions in childhood.Lymphadenopathy (LAP) may be most frequently seen during the follow-up of infectious diseases, but some chronic, malignant, and autoimmune diseases may also be encountered in the etiology of lymphadenopathy.In this study we aimed to investigate the clinical, epidemiologic, and etiological characteristics of pediatric patients presenting with lymphadenopathy.A total of 380 pediatric patients with lymphadenopathy who were followed up in the Eskisehir Osmangazi University Pediatric Infectious Diseases Clinic between January 2015 and January 2023 were included in the study.The mean age of the patients was 84 months and 65% of the patients were male.According to etiologic characteristics; 359(94%) cases had infectious and 21(6) cases had non-infectious LAP.Most frequently nonspecific lymphadenitis (68%), Epstein-Barr Virus (12.8%), cytomegalovirus (3.6%), suppurative lymphadenitis (1.9%) and tuberculous lymphadenitis (1.8%) were observed in cases with LAP. Cases with non-infectious LAP had rheumatologic diseases (n:11), hemato-oncologic malignancies (n: 6), and congenital cysts (n:4). When infectious and non-infectious LAP cases were compared, involved lymph nodes were larger (p:0.04) in the non-infectious group.In the non-infectious group,lymph nodes were relatively harder and conglomerated(p:0.03, p:0.04).Computed tomography scan was more frequently performed in the non-infectious group(p:0.01).Although lymphadenopathy in childhood is mostly due to infectious causes, rheumatologic diseases, hemato-oncologic malignancies, and congenital cysts should be kept in mind, especially in prolonged, treatment-refractory cases. Detailed history and physical examination are the first and the most important steps in the differential diagnosis of cases presenting with lymphadenopathy to prevent the application of unnecessary tests and investigations

Pre-Exposure Prophylaxis and Treatment with Tixagevimab/Cilgavimab for COVID-19 among Immunocompromised Pediatric Patients.

Background: Patients treated with hemato-oncological malignancies (HO) or undergoing cellular therapies such as hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T cells (CAR-T) were significantly affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the success of SARS-CoV-2 vaccination, immunocompromised patients remain at increased risk for severe coronavirus disease (COVID-19), rendering this group of population a high priority for additional prevention and treatment options. Tixagevimab and Cilgavimab (TIXA/CILGA, AZD7442, Evusheld®) is a combination of two fully human, long-acting monoclonal antibodies. TIXA/CILGA have been approved as pre-exposure prophylaxis and treatment in patients at risk of severe disease with impaired vaccine response. Our objective was to describe the efficacy and safety among immunocompromised pediatric patients. Methods: This was an observational multicenter cohort study of immunocompromised pediatric patients receiving TIXA/CILGA conducted at nine Polish centers of Pediatric Oncology, Hematology and Bone Marrow Transplantation. We analyzed patients in two groups; those treated with HO and those undergoing cellular therapies: HSCT or CAR-T cells. In addition, two other cohorts were identified: patients given TIXA/CILGA as pre-exposure prophylactic and therapeutic intervention. Results: A total of 78 patients were evaluated during the study period: 69 (88.5%) received TIXA/CILGA as pre-exposure prophylaxis and 9 (11.5%) as a treatment strategy. A total of 52 (66.6%) patients were treated with standard chemotherapy at HO departments; 21 (27%) underwent HSCT, and 5 (6.4%) received CAR-T cell therapy. All children with COVID-19 receiving TIXA/CILGA presented a mild degree of severity. The most common clinical manifestations were fever, cough and coryza. At least one adverse event (AE) was reported in two (3.8%) patients excluding standard injection site reactions. Reported AEs were mild or moderate in intensity. One child reported mild myalgia and one reported moderate bone pain and weakness. Conclusions: In our observational multicenter cohort study, we explored the use of TIXA/CILGA as pre-exposure prophylaxis and treatment for COVID-19 among immunocompromised pediatric patients. While our findings suggest a potential benefit in preventing and managing COVID-19 in this vulnerable population, it is important to note the study's non-comparative design. Our results highlight the need for well-designed clinical trials to confirm these observations and further assess the efficacy and safety of TIXA/CILGA in immunocompromised children.

The Frequency, Severity, and Risk Factors of Hickman CatheterRelated Complications in Pediatric Cancer Patients: A Single-Center Experience from Bosnia and Herzegovina.

This study aimed to identify the frequency, severity, and risk factors associated with Hickman catheter-related complications in children with hemato-oncological malignancies at the largest pediatric tertiary care unit in Bosnia and Herzegovina. A cross-sectional study was conducted on a cohort of pediatric cancer patients who underwent Hickman central venous catheters (CVCs) between January 2019 and December 2022. Mechanical, infectious, and thrombotic Hickman catheter-related complications were evaluated and analyzed. We also investigated possible risk factors associated with these complications. Seventy-one Hickman CVCs were inserted in 68 children (44 boys and 24 girls) at a mean age of 6.9 ± 4.6. Forty (58.8%) children had hematological malignancies and 28 (41.2%) solid cancers. The median follow-up after Hickman CVC insertion was 190 days (95% CI [160-212]) for 12 644 catheter days. During follow-up, 10 (14.1%) mechanical, 7 (9.9%) infectious, and 1 (1.4%) thrombotic complications were recorded (0.8, 0.48, and 0.08 for mechanical, infectious, and thrombotic complications per 1000 catheter days, respectively). A slightly higher incidence of complications was recorded in children with hematological malignancies (1.59 per 1000 catheter days) compared with children with solid cancers (1.22 complications per 1000 catheter days). Using Hickman CVCs for long-term venous access in infusional chemotherapy for pediatric cancer patients is safe but is associated with significant morbidity.

Increasing insight in the value of repetitive COVID-19 vaccination in patients with haematological malignancies in the Omicron era.

The study by Kevlicius etal. from Lithuania gives further confirmation of the efficacy of booster mRNA COVID-19 vaccination for patients with haemato-oncological malignancies in the Omicron era. The risk of COVID-19 and mortality was considerably reduced when patients received the booster vaccination. The threshold of the humoral response to vaccination that was protective for haemato-oncological patients was defined. In particular, ruxolitinib and anti-CD20 treatments limited the humoral response to the third booster vaccination. These data may influence the clinical management of haemato-oncological patients in future waves of the COVID-19 pandemic, regarding for example the selection of patients for passive immunization against SARS-CoV-2. Commentary on: Kevličius etal. Immunogenicity and clinical effectiveness of mRNA vaccine booster against SARS-CoV-2 Omicron in patients with haematological malignancies: A national prospective cohort study. Br J Haematol 2024;204:497-506.

Longitudinal development of fatigue after treatment for childhood cancer: a national cohort study

Background Fatigue is a distressing and prevalent long-term sequela of treatment for childhood cancer, and there is a need for longitudinal studies to investigate the development of fatigue over time. The objective of this study was to calculate growth-curves for the longitudinal development of fatigue after treatment for childhood cancer, and to investigate the effects of biopsychosocial predictors. Materials and methods Participants were recruited from a patient monitoring program and data extracted from medical records. Parent-proxy and self-report versions of PedsQLTM Multidimensional Fatigue Scale were used to repeatedly assess fatigue up to 5 years after the end of treatment for childhood cancer. Fatigue was assessed 2440 times for 761 participants (median:3) with proxy-reports (age 2–8 years) and 2657 times for 990 participants with self-reports (above 8 years) (median:2). Mixed models were used to establish growth-curves and to analyze the effect of predictors separately for participants with solid tumors (ST), hemato-oncological malignancies and central nervous system-tumors (CNS). Results CNS-tumors were associated with more cognitive fatigue than ST at the end of treatment, for both proxy-reports (−11.30, p<.001) and self-reports (−6.78, p=.002), and for proxy-reports of general fatigue (−6.78, p=.002). The only significant difference in change over time was for self-reports of sleep-rest fatigue. The raw scores for the CNS-group decreased with −0.87 per year (95% CI −1.64; −0.81, p=.031) compared to the ST-group. Parental distress was overall the variable most associated with increased fatigue, while immunotherapy was the most frequent medical predictor. National centralization of childhood cancer care decreased fatigue for the CNS-group, but not for other diagnoses. Discussion Children and adolescents treated for CNS-tumors reported more fatigue than other participants after the end of treatment, and this difference remained over time. Results from this study may help to facilitate the early recognition of children with insufficient recovery of fatigue symptoms.

Timely course of SARS-CoV-2 infections and vaccinations in patients with hemato-oncological diseases: analysis of a real-life cohort

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has particularly impacted patients with hemato-oncological malignancies, as they showed not only a higher propensity for severe courses but also weaker immune responses after vaccination. Still, data on the influence of pandemic waves and vaccinations on outcomes are rare. This study aimed to analyze the timely course of infections and vaccinations in a real-life cohort of patients with hemato-oncological diseases. In this cohort study, 1817 patients with hemato-oncological diseases from 1 February 2020 to 15 December 2022 at the 'Franz Tappeiner' Hospital in Merano/Meran, Italy, were followed for SARS-CoV-2 infections and vaccinations. Of 1817 patients with hemato-oncological malignancies, 735 (40.5%) were infected at least once with SARS-CoV-2, and 1614 (88.8%) received one or more doses of the approved vaccinations. Patients receiving antineoplastic treatment had a lower SARS-CoV-2 infection rate [35.1% versus 41.0%; odds ratio (OR) 0.78, 95% confidence interval (CI) 0.64-0.95], but higher risk of hospitalization (13.4% versus 6.9%; OR 2.11, 95% CI 1.25-3.69) compared with untreated patients. Overall, the case fatality rate (CFR) was 3.4%. Unvaccinated patients were more prone to severe coronavirus disease 2019 (COVID-19) courses requiring hospitalization (OR 2.34, 95% CI 1.25-4.36) and had a higher CFR (7.3% versus 1.6%; OR 4.98, 95% CI 2.16-12.98) than their vaccinated counterparts. In the Delta wave, patients with two vaccinations had a lower infection risk (OR 0.18, 95% CI 0.10-0.35) and tendentially lower hospitalization rates (OR 0.25, 95% CI 0.05-1.29) than unvaccinated patients. In the Omicron wave, 345/1198 (28.8%) patients with three or more vaccinations had breakthrough infections, resulting in a similar risk for infection (OR 0.88, 95% CI 0.60-1.30) but numerically lower risk for hospitalization (24/345, 7.0%) than unvaccinated individuals (4/40, 10.0%). Scheduled visits were postponed in 128/335 (38.2%) patients due to COVID-19, and deferrals correlated with pandemic wave (P= 0.002) and vaccination status (P < 0.001). SARS-CoV-2 infections and outcomes differ between distinct phases of the pandemic. Vaccination with variant-specific vaccines should be prioritized as general protective measures are increasingly lifted.

Targeted-Lymphoma Drug Delivery System Based on the Sgc8-c Aptamer.

Aptamers are emerging as a promising new class of functional nucleic acids because they can specifically bind to any target with high affinity and be easily modified chemically with different pharmacophoric subunits for therapy. The truncated aptamer, Sgc8-c, binds to tyrosine-protein kinase-like 7 receptor, a promising cancer therapeutic target, allowing the recognition of haemato-oncological malignancies, among others. We have previously developed aptamer-drug conjugates by chemical synthesis, hybridizing Sgc8-c and dasatinib, a drug proposed for lymphoma chemotherapy. One of the best-characterised Sgc8-c-dasatinib hybrids, namely Sgc8-c-carb-da, was capable of releasing dasatinib at an endosomal-pH. Herein, we probed the therapeutic potential of this aptamer-drug conjugate. Sgc8-c-carb-da specifically inhibited murine A20 B lymphocyte growth and produced cell death, mainly by late apoptosis and necrosis. In addition, Sgc8-c-carb-da generated an arrest in cell proliferation, with a cell cycle arrest in the Sub-G1-peak. The mitochondrial potential was altered accordingly to these pathways. Moreover, using an in vitro cell-targeting assay that mimics in vivo conditions, we showed that Sgc8-c-carb-da displayed higher (2.5-fold) cytotoxic effects than dasatinib. These findings provide proof-of-concept of the therapeutic value of Sgc8-c-carb-da for lymphoma, creating new opportunities for the chemical synthesis of targeted biotherapeutics.

Real-World Comparison of Isavuconazole and Voriconazole in Terms of the Need for Dosage Adjustments Guided by Clinical Pharmacological Advice During Primary Prophylaxis of Invasive Fungal Infections in Pediatric Patients with Hemato-Oncological Malignancies.

Limited evidence concerning optimal azole dosing regimens currently exists for antifungal prophylaxis in hemato-oncological pediatric patients. Hemato-oncological children receiving intravenous or oral isavuconazole or voriconazole for primary antifungal prophylaxis at IRCCS Azienda Ospedaliero-Universitaria of Bologna during November 2020 to October 2021 and undergoing CPA programs based on real-time therapeutic drug monitoring (TDM) were retrospectively analyzed. CPAs for isavuconazole and voriconazole and the number of dosage adjustments were collected. Normalized trough concentrations [(C min )/dose/kg] were calculated for both drugs at each TDM assessment, and the coefficient of variation was determined. The efficacy and safety of the drugs were evaluated. Sixteen hemato-oncological pediatric patients received azole prophylaxis (mean age and weight: 9.1 ± 4.9 years and 32.6 ± 16.0 kg; 6 isavuconazole and 10 voriconazole). Sixty and 89 CPAs were delivered as isavuconazole and voriconazole, respectively. Dosage adjustments were needed in 3.3% of cases for isavuconazole and 53.9% of cases for voriconazole ( P < 0.001). At first TDM, achievement of the desired target during standard dosing regimens was higher for isavuconazole (83.3%) than for voriconazole (10.0%; P = 0.008). Dispersion of normalized concentrations was higher for voriconazole (CV = 139.1% vs. CV = 79.4%). Elevation of ALT and aspartate aminotransferase levels between baseline and the third month was higher in patients receiving voriconazole (median, 28 vs. 90 U/L; P = 0.038, and 19 vs. 65.5 U/L; P = 0.002). Our findings suggest that there is limited variability in isavuconazole exposure in hemato-oncological pediatric patients receiving azole prophylaxis , resulting in a low need for CPA-guided dosage adjustments.

S2.5a Magnusiomyces spp.

S2.5 Rare yeasts, September 21, 2022, 3:00 PM - 4:30 PM Magnusiomyces clavatus and Magnusiomyces capitatus are emerging yeasts with intrinsic resistance to many commonly used antifungal agents. Identification is difficult, and the determination of susceptibility patterns with commercial and reference methods is equally challenging. For this reason, few data on invasive infections by Magnusiomyces spp. are available. We, therefore, determined the epidemiology and susceptibility of Magnusiomyces isolates from bloodstream infections (BSI) isolated in Germany and Austria from 2001 to 2020. A total of 34 Magnusiomyces BSI were analyzed; isolates were identified by internal transcribed spacer (ITS) sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Antifungal susceptibility was determined by EUCAST broth microdilution and gradient tests. Of the 34 isolates, M. clavatus was more common (n = 24) than M. capitatus (n = 10). BSI by Magnusiomyces spp. were more common in men (62%) and mostly occurred in patients with hemato-oncological malignancies (79%). The highest in vitro antifungal activity against M. clavatus/M. capitatus was observed for voriconazole (MIC50, 0.03/0.125 mg/l), followed by posaconazole (MIC50, 0.125/0.25 mg/l). M. clavatus isolates showed overall lower MICs than M. capitatus. With the exception of amphotericin B, a low essential agreement between gradient test and microdilution was recorded for all antifungals (0%-70%). Both species showed distinct morphologic traits on ChromAgar Orientation medium and Columbia blood agar, which can be used for differentiation if no MALDI-TOF MS or molecular identification is available. In conclusion, most BSI were caused by M. clavatus. The lowest MICs were recorded for voriconazole. Gradient tests demonstrated unacceptably low agreement and should preferably not be used for susceptibility testing of Magnusiomyces spp.

Real-World Evidence of Epidemiology and Clinical Outcomes in Multiple Myeloma, Findings from the Registry of Hemato-Oncologic Malignancies in Colombia, Observational Study

Multiple Myeloma (MM) is a plasma cell derived clonal disorder that represents around 1% of all newly diagnosed neoplasms. Limited data regarding MM treatment in Latin America is available, and access to novel agents for a substantial portion of the population is limited by their high costs. RENEHOC is a bidirectional (retrospective and prospective) multicenter observational registry of hematological malignancies in Colombia. MM patients included up to July 2020 were analyzed on this report. 890 are reported with a median follow-up of 18 months (IQR: 7-42 months). Patients were classified by age group (≤ or > 65 years). Median age at diagnosis was 67 years (IQR: 59-75 years) and 47.1% of patients were women. 709 patients (79.6%) received Bortezomib-based schemes as part of the first line. Two hundred and fifty-two patients (28.3%) were consolidated with Autologous Stem Cell Transplantation (ASCT) in first-line. ASCT consolidation and age were the main independent factors influencing outcomes; in the non-ASCT cohort, 5-year overall survival was 48.7% (CI 41.8-55.2) compared to 80.7% (CI 73-86.4) in ASCT patients. This data depicts the reality of MM in Colombia, which likely reflects other Latin American countries, where access barriers to diagnosis and treatment are echoed in advanced stage diagnosis and a low rate of transplants. These seem to negatively impact survival despite the availability of most novel drugs approved for this disease. Thus, emphasizing the paradox that prevails in most of the region: availability without equitable access.

Safety and Efficacy of Single-Dose Intravenous Fosaprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients with Hematooncological Malignancies after Moderate and High Emetogenic Chemotherapy

IntroductionChemotherapy induced nausea and vomiting (CINV) belongs to the most feared and burdensome side effects and poses a substantial impairment of the quality of life, especially in pediatric patients. In adults, antiemetic prophylaxis with a combination of ondansetron, corticosteroids and aprepitant has shown favorable results as compared to ondansetron and corticosteroids alone. Valuable data on aprepitant or its water-soluble derivative fosaprepitant is scarce for pediatric patients.Patients and MethodsThis retrospective single-center analysis enrolled 79 pediatric patients with a median age of 8 years (range 0.8 - 18 years) who received either fosaprepitant (3.5 - 4 mg per kg bodyweight (maximum 150 mg))/ondansetron combination prophylaxis (n=40; fosaprepitant group, 112 chemotherapy cycles analyzed), or ondansetron only (n=39; control group, 116 chemotherapy cycles analyzed). Antiemesis was performed according to the current antiemesis guidelines (NCCN Clinical Practice guidelines in Oncology): Intravenous Ondansetron was started at least 30 minutes prior to start of chemotherapy and administered throughout the chemotherapy cycle (bodyweight adapted; max. 32 mg per 24 hours). Fosaprepitant single-dose administration was started at least one hour before the first application of chemotherapy at a dosage of 3.5 - 4 mg per kg bodyweight (maximum 150 mg) as intravenous infusion within 30 minutes. The groups were comparatively analyzed for occurrence and frequency of vomiting, additional need for dimenhydrinate medication and drug-related clinical (exanthema, sweating, fever, loss of appetite, diarrhea and constipation) and laboratory (increases of ALT, AST, bilirubin, creatinine, urea; decreases of calcium, potassium, sodium) side effects during the acute (<24h) and delayed (>24h) CINV phases of moderate (CINV risk 30%-59%) and high (CINV risk ≥60%) emetogenic chemotherapy. Exclusion criteria were vomiting or administration of antiemetic medication until 48 hours prior to the start of emetogenic chemotherapy, and chemotherapy with ifosfamide.ResultsIn the acute CINV phase, the number of patients experiencing vomiting (33.3% of the patients; Fig. a) and the total number of vomiting events (n=44; Fig. b) was significantly higher (p=0.02449 and p<0.0001, respectively) in the control group when compared to the fosaprepitant group (10.0% of the patients, n=4 events). Even more pronounced were the results for the delayed CINV phase with a significantly higher (p<0.0001) number of patients experiencing vomiting (69.2% vs. 22.5%) and a significantly higher (p<0.0001) number of vomiting events (n=131 vs. n=33 events). The number of patients needing additional medication with dimenhydrinate and more importantly the total number of administered dimenhydrinate doses was significantly higher in the control group (69.2% vs. 47.5% of the patients, p=0.04884; n=416 vs. n=92 doses, p<0.0001) (Fig. c). Differences of all clinical side effects and changes of laboratory parameters were not significantly different between both study groups.ConclusionTaken together, our findings are consistent with previous randomized trials with adult hemato-oncological patients and a retrospective chart analysis with pediatric patients in terms of safety, efficacy and feasibility of fosaprepitant as antiemetic prophylaxis during moderate and high emetogenic chemotherapy (Grunberg et al., 2011, Saito et al., 2013, Okumura et al., 2017, Shillingburg and Biondo, 2014). This is the first available data on the administration of single dose intravenous fosaprepitant in pediatric patients under the age of 12 years. In comparison to antiemesis with ondansetron only, a combination prophylaxis with fosaprepitant proved to be clearly superior with fewer pediatric patients experiencing vomiting, distinctly fewer vomiting events in the acute (11.0 -fold) and delayed (4-fold) CINV phase and an overall 4.5-fold reduction of administered dimenhydrinate doses. However, larger randomized prospective trials with pediatric patients are needed to evaluate our findings. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of COVID-19 on Cancer Care: One Year Retrospective Study of Cancer Patients Affected With COVID-19 at a Tertiary Cancer Care Hospital in Eastern India

Aims and Objectives: The information regarding the nature of the novel corona virus, its spread, implications and treatment were controversial from the very beginning. Whether Cancer patients would do worse was not known to us, although the common belief was that they were high risk group considering the low immunity. To know these we have looked into our data over last one year. Materials and Methods: After Ethical committee permission we have done a retrospective analysis of our data from April, 2020 to March, 2021. The following were looked into- the footfall of new and follow up cases and compared them with the number of the preceding year.We also looked into the age, sex, type of cancer, stages at presentation, symptomatology, time to recovery, complications, delay in treatment and outcome. Results: There was 50% reduction in the number of new and follow up cases combined compared to the previous year. Majority of the 420 cancer patients who were infected were in the fifth decade, the commonest site being Head neck & haematological malignancies. Most of the cancer patients were asymptomatic. There was an average delay in treatment of 5 to 6 weeks. Only 1.67% succumbed to Covid before being referred outside, most of whom had haematological malignancies with multiple comorbidities. Conclusions: The pandemic has significantly affected the care of Cancer patients with less footfall, late presentation, delayed treatment with potentially worse outcome. Interestingly, although they have decreased immunity, majority were asymptomatic. Most of the fatalities were in the haemato-oncological malignancies with multiple co-morbidities. Funding Information: None. Declaration of Interests: None. Ethics Approval Statement: Clearance received from the Institute Ethics committee.

Detection of systemic immunosuppressants in autologous serum eye drops (ASED) in patients with severe chronic ocular graft versus host disease

PurposeChronic graft versus host disease is a major consequence after allogeneic stem cell transplantation (allo-SCT) and has great impact on patients’ morbidity and mortality. Besides the skin, liver, and intestines, the eyes are most commonly affected, manifesting as severe ocular surface disease. Treatment protocols include topical steroids, cyclosporine, tacrolimus, and ASED. Since these patients often receive systemic immunosuppressant therapy from their oncologists, a topical re-administration of these drugs via ASED with potentially beneficial or harmful effects is possible. The purpose of the study was to determine whether and to which extent systemic immunosuppressants are detectable in ASED.MethodsA total of 34 samples of ASED from 16 patients with hemato-oncological malignancies after allo-SCT were collected during the manufacturing process and screened for levels of cyclosporine, mycophenolic acid, everolimus, and tacrolimus via liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The study followed the tenets of the Declaration of Helsinki and informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study.ResultsCyclosporine was found in 18 ASED samples in concentrations ranging from 6.5–105.0 ng/ml (32.0 ± 22.8 ng/ml, mean ± SD). The concentration range of mycophenolic acid in 19 samples was 0.04–25.0 mg/l (4.0 ± 5.4 mg/l, mean ± SD). Everolimus and tacrolimus concentrations were well below the respective limits of quantification (< 0.6 and < 0.5 ng/ml) of the established LC-MS/MS method in all samples.ConclusionsOur study suggests that orally administered cyclosporine and mycophenolic acid for the treatment of systemic GvHD, but not everolimus and tacrolimus, are distinctly detectable in ASED in relevant concentrations. It is highly likely that these agents affect topical therapy of ocular GvHD. However, the extent of this effect needs to be evaluated in further studies.

Program on high value cost-conscious education in intensive care: Educational program on prediction of outcome and cost awareness on Intensive Care admission

BackgroundIntensive Care (ICU) involves extended and long lasting support of vital functions and organs. However, current training programs of ICU residents mainly focus on extended support of vital functions and barely involve training on cost-awareness and outcome. We incorporated an educational program on high-value cost-conscious care for residents and fellows on our ICU and measured the effect of education.MethodsA cohort study with factorial survey design, in which ICU residents and fellows were asked to evaluate clinical vignettes, was performed on the mixed surgical-medical ICU of the Amsterdam University Medical Centre. Residents were offered an educational program focusing on outcome and costs of ICU care. Before and after the program they filled out a questionnaire, which consisted of 23 vignettes, in which known predictors of outcome of community acquired pneumonia (CAP), pancreatitis, acute respiratory distress syndrome (ARDS) and cardiac arrest were presented, together with varying patient factors (age, body mass index (BMI), acute kidney failure (AKI) and haemato-oncological malignancy). Participants were asked to either admit the patient or estimate mortality.ResultsBMI, haemato-oncological malignancy and severity of pancreatitis were discriminative for admission to ICU in clinical vignettes on pancreatitis and CAP. After education, only severity of pancreatitis was judged as discriminative. Before the intervention only location of cardiac arrest (in- vs out of hospital) was distinctive for mortality, afterwards this changed to presence of haemato-oncological malignancy.ConclusionWe incorporated an educational program on high-value cost-conscious care in the training of ICU physicians. Based on our vignette study, we conclude that the improvement of knowledge of costs and prognosis after this program was limited.

Sgc8-c Aptamer as a Potential Theranostic Agent for Hemato-Oncological Malignancies.

Background: Aptamers represent an emerging class of oligonucleotides that have the ability to bind ligands with high affinity. Sgc8-c aptamer recognizes PTK7, a member of the catalytically defective receptor protein tyrosine kinase family that is upregulated in various cancers, including hemato-oncological malignancies. Herein, an Sgc8-c-NOTA-radiolabeled probe was prepared for theranostic purpose. Materials and Methods: In this work, an Sgc8-c-radiolabeled probe against PTK7 was prepared, and biological evaluations-pharmacokinetic studies, biodistribution analysis, and in vivo molecular imaging-were performed. To obtain the radiolabeled probe, a modified 5'-amino-derivative of the Sgc8-c aptamer was bound to the metal chelator NOTA, and subsequently labeled with 67Ga with high yield and radiochemical purity. The precursor, Sgc8-c-NOTA, the radio probe Sgc8-c-NOTA-67Ga, and its nonradioactive complex, Sgc8-c-NOTA-69/71Ga, were purified by reverse-phase high-performance liquid chromatography and characterized by electrospray ionization mass spectrometry. The binding ability of Sgc8-c-NOTA-67Ga was studied in vitro against purified PTK7 receptor. In addition, the binding was also evidenced against the hemato-oncological A20 cell line, derived from B lymphocytes, and the corresponding A20-green fluorescent protein (GFP)-transfected cells. The proof of concept was performed on A20-GFP tumor-bearing mice, in which the biodistribution of the radiolabeled probe was evaluated through imaging, using X-ray, fluorescence, and γ modalities. The specific uptake of the probe was confirmed by blocking with the Sgc8-c aptamer in an in vivo competition assay. Results: The biodistribution results showed considerable uptake in tumor since 2 h, with highest at 48 h postinjection. However, the blood and muscle ID/g (injected dose per gram of tissue) activities were decreasing with time and tumor/no-target ratios increasing to 20 at 24 h postinjection. These results are consistent with the in vivo images. Conclusions: This study supports the utility of Sgc8-c-NOTA radiolabeled as a theranostic agent.

Burkitt Leukemia in a 5-Year-Old Girl with Williams–Beuren Syndrome: Review of the Literature

AbstractWilliams–Beuren syndrome (WBS) is a rare neurodevelopmental genetic disorder associated with microdeletion at the long arm of chromosome 7 (7q11.23). Few cases have been reported with WBS with hemato oncological malignancies. Herein, we report Burkitt leukemia in a 5 year old girl with WBS. We like to call attention to the management of this rare combination.

The role of a critical care outreach service in the management of patients with haematological malignancy.

Although improvement in survival from haematological malignancies has been reported, a substantial number of these patients develop life threatening complications. Critical care outreach services (CCOS) aim to avert inappropriate ICU admissions, while ensuring timely patient review. We retrospectively analysed patients with haematological malignancy reviewed by an outreach service between January 2014 and December 2015 at a single institution. The aim of our study was to describe the patient population assessed by a well-established outreach team, identify predictors of ICU admission, as well as ICU and hospital mortality. Sixty of 126 patients reviewed (47.6%) were admitted to ICU. ICU and hospital mortality were 25.3% and 45.2%, respectively. The odds of being admitted to ICU was 13 times higher (p = 0.013) if the patient was referred for hypoxia, 20 times higher (p = 0.006) if they were referred for sepsis or 14 times higher (p = 0.027) if they were referred to CCOS for hypotension, compared to when the team was automatically alerted. The odds of not surviving hospital admission increased 1.27 times for every extra day of CCOS review (p = 0.02). When a patient was referred having a refractory or progressive haematological condition, the odds of not surviving to hospital discharge increased by four or 12 times, respectively, compared to when the referred patient was in remission. Receiving high flow nasal cannula oxygen (HFNCO) was associated with a reduction in ICU admission (p = 0.03), irrespective of the underlying diagnosis, performance status or location of delivery. The CCOS participated in end-of-life discussions in 29% patients. ICU and hospital mortality of patients with haemato-oncological malignancy continue to improve. CCOS are heavily involved in the recognition and management of these patients, as well as in the facilitation of end-of-life discussions. Sepsis was associated with increased risk of ICU admission and mortality. Initiation of HFNCO outside ICU appears to be feasible and safe and was not associated with increasing risk in this single centre study.

Procalcitonin and C-Reactive Protein during Transplant-Related Adverse Events after Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients

BackgroundEarly diagnosis and treatment interventions of transplant-related adverse events (TRAE) such as sepsis, fungal, bacterial and viral infection, graft-versus-host disease (GvHD), veno-occlusive disease (VOD), and graft rejection is crucial for the patient outcome. The predictive value of a multitude of serum biomarkers their specific patterns in occurring TRAE have been widely investigated. Procalcitonin (PCT) is a precursor molecule of the hormone calcitonin that regulates calcium homeostasis and is elevated for example during systemic infection, thermal injury or septic shock. A discriminative value of PCT during adverse events after HSCT has been described for adult patients. There is currently no data available concerning PCT in the context of TRAE in children.Material and MethodsIn this single-center retrospective analysis, serum PCT and CRP levels of pediatric patients who underwent allogeneic HSCT for the treatment of hemato-oncological malignancies and non-malignancies were analyzed and correlated to TRAE (graft rejection, VOD, GvHD, sepsis, and viral or fungal infection). Primary objective of this work was to evaluate a predictive and discriminative value of serum PCT and CRP in the early identification of transplant-related complications in these patients. The observation period included the time of measurement directly before start of conditioning, until the day of clinical discharge. Serum PCT and CRP values were analyzed daily during the occurrence of fever or at least 3 times per week.ResultsThe patient group consisted of 124 male and 87 female pediatric patients (n=211) with a median age of 9.0 years (range 0.5-17.8 years) undergoing HSCT for hemato-oncological malignancies and inborn errors of metabolism. Patients received grafts from mismatched unrelated donors (n=66), matched unrelated donors (n=118) or matched family donors (n=27). The patients underwent HSCT for the treatment of acute leukemia (AML, ALL, AML relapse and ALL relapse; 50.7% of the patients), myelodysplastic syndromes (5.2%), anemia (severe aplastic anemia, beta thalassemia, sickle cell anemia; 16.1%), or solid tumors (28.0%). The median observation period was 76 days (range 31-245 days). Graft rejection occurred in 9 patients (4.3%), VOD in 4 patients (1.9%), acute skin GvHD grade II-IV in 31 patients (14.7%), acute intestinal GvHD grade II-IV in 10 patients (4.7%), sepsis in 24 patients (11.4%), viremia in 22 patients (10.4%), and fungemia in 7 patients (3.3%).PCT values were significantly and relevantly elevated (>0.5 ng/mL) during graft rejection (median 1.43 ng/mL, range 1.04-5.46 ng/mL), skin GvHD (median 0.90 ng/mL, range 0.02-4.34 ng/mL), intestinal GvHD (median 1.01 ng/mL, range 0.30-3.05 ng/mL), and sepsis (median 3.09 ng/mL, range 0.57-37.32 ng/mL). CRP values were significantly and relevantly elevated (>0.5 mg/dL) during graft rejection (median 10.34 mg/dL, range 5.45-30.19 mg/dL), skin GvHD (median 1.85 mg/dL, range 0.04-21.63 mg/dL), intestinal GvHD (median 8.73 mg/dL, range 1.05-24.2 mg/dL), sepsis (median 10.26 mg/dL, range 2.67-49.47 mg/dL), viremia (median 1.80 mg/dL, range 0.06-14.04 mg/dL), and fungemia (median 5.10 mg/dL, range 2.30-11.60 mg/dL). A simultaneous significant and relevant elevation of both PCT and CRP values was observed during graft rejection, skin and intestinal GvHD, and sepsis (Fig. 1).ConclusionsEspecially during acute skin and intestinal GvHD, PCT and CRP values strongly and significantly increased beyond the upper normal limits. Simultaneous elevations of PCT and CRP occurred during graft rejection, skin and intestinal GvHD, and sepsis. Taken together, laboratory-chemical analyses of serum PCT in combination with CRP could be a useful discriminative biomarker in the detection of TRAE. Larger, prospective trials are needed, to evaluate these findings.FigureFig. 1. PCT and CRP serum concentrations during acute GvHD, graft rejection, VOD, sepsis, viremia and fungemia. Dotted horizontal lines indicate normal PCT and CRP values (PCT: 0.5 ng/mL | CRP: 0.5 mg/dL). Symbols indicate *: p<0.05; **:p<0.01; ***: p<0.001; ****: p<0.0001; tested by Wilcoxon matched-pairs signed rank test.AcknowledgmentsThis work was supported by the Stefan-Morsch-Stiftung, Birkenfeld, Germany and the Bettina-Bräu-Stiftung, Fürstenfeldbruck, Germany. [Display omitted] DisclosuresLang:Miltenyi Biotec: Patents & Royalties, Research Funding. Handgretinger:Miltenyi Biotec: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding.

Where to "cut-off"?

Where to "cut-off"?