Late Effects of Therapy, Stigmatization and Social Reintegration following Childhood Cancer Survival in Kenya: A Case Report

Childhood cancer survival is increasing in low- and middle-income countries like Kenya, which comes with a new healthcare challenge: late effects and quality-of-life of survivors. A case was studied to depict a Kenyan Hodgkin lymphoma survivor, illustrating some of the childhood cancer survivors' difficulties in Kenya. Late effects of therapy, stigmatization and social reintegration were explored. The investigators reviewed medical records and used semi-structured interviews and stigma assessments using the Social Impact Scale. The survivor developed severe pulmonary hypertension during treatment with ABVD and salvage protocols. Three years after treatment, the patient experienced chemotherapy-induced late effects (chronic heart disease) that hindered personal care, social activities and job opportunities and required follow-up. Stigmatization by the community burdened his family life and marital prospects. This case report is one of the first that testifies of combined medical and psychosocial challenges that childhood cancer survivors may face in sub-Saharan Africa and underlines the need for a holistic approach

Socio-economic Status Plays Important Roles in Childhood Cancer Treatment Outcome in Indonesia

Background: The influence of parental socio-economic status on childhood cancer treatment outcome in low-income countries has not been sufficiently investigated. Our study examined this influence and explored parental experiences during cancer treatment of their children in an Indonesian academic hospital. Materials and Methods: Medical charts of 145 children diagnosed with cancer between 1999 and 2009 were reviewed retrospectively. From October 2011 until January 2012, 40 caretakers were interviewed using semi-structured questionnaires. Results: Of all patients, 48% abandoned treatment, 34% experienced death, 9% had progressive/relapsed disease, and 9% overall event-free survival. Prosperous patients had better treatment outcome than poor patients (P<0.0001). Odds-ratio for treatment abandonment was 3.3 (95%CI: 1.4-8.1, p=0.006) for poor versus prosperous patients. Parents often believed that their child's health was beyond doctor control and determined by luck, fate or God (55%). Causes of cancer were thought to be destiny (35%) or God's punishment (23%). Alternative treatment could (18%) or might (50%) cure cancer. Most parents (95%) would like more information about cancer and treatment. More contact with doctors was desired (98%). Income decreased during treatment (55%). Parents lost employment (48% fathers, 10% mothers), most of whom stated this loss was caused by their child's cancer (84% fathers, 100% mothers). Loss of income led to financial difficulties (63%) and debts (55%). Conclusions: Treatment abandonment was most important reason for treatment failure. Treatment outcome was determined by parental socio-economic status. Childhood cancer survival could improve if financial constraints and provision of information and guidance are better addressed

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

Aims/hypothesis Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA(1c), systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA(1c), SBP, weight and intraglomerular pressure is associated with antialbuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent. Methods We examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR=30-300 mg/g; n = 636) or macroalbuminuria (UACR>300 mg/g; n=215) who participated in one of five phase III randomised clinical trials. Primary assessment was defined as percentage change in geometric mean UACR from baseline to week 24. Results After controlling for clinical confounders including baseline log-transformed UACR, HbA(1c), SBP and estimated GFR (according to the Modification of Diet in Renal Disease [MDRD] formula), treatment with empagliflozin significantly reduced UACR in patients with microalbuminuria (-32% vs placebo; p Conclusions/interpretation In patients with type 2 diabetes and either micro-or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount. This effect was largely independent of the known metabolic or systemic haemodynamic effects of this drug class. Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes. Trial registration: Clinicaltrials.gov NCT01177813 (study 1); NCT01159600 (study 2); NCT01159600 (study 3); NCT01210001 (study 4); and NCT01164501 (study 5).Peer reviewe

Infections with Avian Pathogenic and Fecal Escherichia coli Strains Display Similar Lung Histopathology and Macrophage Apoptosis

The purpose of this study was to compare histopathological changes in the lungs of chickens infected with avian pathogenic (APEC) and avian fecal (Afecal) Escherichia coli strains, and to analyze how the interaction of the bacteria with avian macrophages relates to the outcome of the infection. Chickens were infected intratracheally with three APEC strains, MT78, IMT5155, and UEL17, and one non-pathogenic Afecal strain, IMT5104. The pathogenicity of the strains was assessed by isolating bacteria from lungs, kidneys, and spleens at 24 h post-infection (p.i.). Lungs were examined for histopathological changes at 12, 18, and 24 h p.i. Serial lung sections were stained with hematoxylin and eosin (HE), terminal deoxynucleotidyl dUTP nick end labeling (TUNEL) for detection of apoptotic cells, and an anti-O2 antibody for detection of MT78 and IMT5155. UEL17 and IMT5104 did not cause systemic infections and the extents of lung colonization were two orders of magnitude lower than for the septicemic strains MT78 and IMT5155, yet all four strains caused the same extent of inflammation in the lungs. The inflammation was localized; there were some congested areas next to unaffected areas. Only the inflamed regions became labeled with anti-O2 antibody. TUNEL labeling revealed the presence of apoptotic cells at 12 h p.i in the inflamed regions only, and before any necrotic foci could be seen. The TUNEL-positive cells were very likely dying heterophils, as evidenced by the purulent inflammation. Some of the dying cells observed in avian lungs in situ may also be macrophages, since all four avian E. coli induced caspase 3/7 activation in monolayers of HD11 avian macrophages. In summary, both pathogenic and non-pathogenic fecal strains of avian E. coli produce focal infections in the avian lung, and these are accompanied by inflammation and cell death in the infected areas

Population Pharmacokinetics and Pharmacodynamics of Ciprofloxacin Prophylaxis in Pediatric Acute Lymphoblastic Leukemia Patients

Background: Ciprofloxacin is used as antimicrobial prophylaxis in pediatric acute lymphoblastic leukemia (ALL) to decrease infections with gram-negative bacteria. However, there are no clear guidelines concerning prophylactic dose. Aims: To determine the pharmacokinetics and pharmacodynamics (PKPD) of ciprofloxacin prophylaxis in a pediatric ALL population. The effect of patient characteristics and antileukemic treatment on ciprofloxacin exposure, the area under the concentration time curve over minimal inhibitory concentration (AUC24/MIC) ratios, and emergence of resistance were studied. Methods: A total of 615 samples from 129 children (0-18 years) with ALL were collected in a multicenter prospective study. A population pharmacokinetic model was developed. Microbiological cultures were collected prior to and during prophylaxis. An AUC24/MIC of ≥125 was defined as target ratio. Results: A 1-compartment model with zero-order absorption and allometric scaling best described the data. No significant (P <. 01) covariates remained after backward elimination and no effect of asparaginase or azoles were found. Ciprofloxacin AUC24 was 16.9 mg∗h/L in the prednisone prophase versus 29.3 mg∗h/L with concomitant chemotherapy. Overall, 100%, 81%, and 18% of patients at, respectively, MIC of 0.063, 0.125, and 0.25 mg/L achieved AUC24/MIC ≥ 125. In 13% of the patients, resistant bacteria were found during prophylactic treatment. Conclusion: Ciprofloxacin exposure shows an almost 2-fold change throughout the treatment of pediatric ALL. Depending on the appropriateness of 125 as target ratio, therapeutic drug monitoring or dose adjustments might be indicated for less susceptible bacteria starting from ≥ 0.125 mg/L to prevent the emergence of resistance and reach required targets for efficacy

Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of &lt; 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age &lt; 3 or &gt; 10 years (11% v 3% and 33% v 23%, respectively; P &lt; .001) and with longer symptom duration ( P &lt; .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials

Clinical and self-reported markers of reproductive function in female survivors of childhood Hodgkin lymphoma

Purpose: To evaluate the impact of treatment for Hodgkin lymphoma (HL) on clinical reproductive markers and pregnancy outcomes.Methods: This study was embedded within the DCOG LATER-VEVO study; a Dutch, multicenter, retrospective cohort study between 2004 and 2014. Serum anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B, antral follicle count (AFC), and self-reported (first) pregnancy outcomes were evaluated in female childhood HL survivors and controls.Results: 84 HL survivors and 798 controls were included, aged 29.6 and 32.7 years old at time of assessment. Median age at HL diagnosis was 13.4 years. Cyclophosphamide equivalent dose (CED-score) exceeded 6000 mg/m2 in 56 women and 14 survivors received pelvic irradiation.All clinical markers were significantly deteriorated in survivors (odds-ratio for low AMH (&lt; p10) 10.1 [95% CI 4.9; 20.6]; low AFC (&lt; p10) 4.6 [95% CI 2.1; 9.9]; elevated FSH (&gt; 10 IU/l) 15.3 [95% CI 5.7; 41.1], low Inhibin B (&lt; 20 ng/l) 3.6 [95% CI 1.7; 7.7], p &lt; 0.001). Pregnancy outcomes were comparable between survivors and controls (± 80% live birth, ± 20% miscarriage). However, survivors were significantly younger at first pregnancy (27.0 years vs 29.0 years, P = 0.04). Adjusted odds-ratio for time to pregnancy &gt; 12 months was 2.5 [95% CI 1.1; 5.6] in survivors, p = 0.031. Adverse outcomes were specifically present after treatment with procarbazine and higher CED-score.Conclusion: HL survivors appear to have an impaired ovarian reserve. However, chance to achieve pregnancy seems reassuring at a young age. Additional follow-up studies are needed to assess fertile life span and reproductive potential of HL survivors, in particular for current HL treatments that are hypothesized to be less gonadotoxic.</p

Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines

Cell lines are important models for drug resistance in acute lymphoblastic leukaemia (ALL), but are often criticised as being unrepresentative of primary disease. There are also doubts regarding the authenticity of many lines. We have characterised a panel of ALL cell lines for growth and drug resistance and compared data with that published for primary patient specimens. In contrast to the convention that cell lines are highly proliferative, those established in our laboratory grow at rates similar to estimates of leukaemic cells in vivo (doubling time 53–442 h). Authenticity was confirmed by genetic fingerprinting, which also demonstrated the potential stability of long-term cultures. In vitro glucocorticoid resistance correlated well with that measured ex vivo, but all lines were significantly more sensitive to vincristine than primary specimens. Sensitivity to methotrexate was inversely correlated to that of glucocorticoids and L-asparaginase, indicating possible reciprocity in resistance mechanisms. A cell line identified as highly methotrexate resistant (IC50 >8000-fold higher than other lines) was derived from a patient receiving escalating doses of the drug, indicating in vivo selection of resistance as a cause of relapse. Many of these lines are suitable as models to study naturally occurring resistance phenotypes in paediatric ALL