ScribbleDom: using scribble-annotated histology images to identify domains in spatial transcriptomics data.

MOTIVATION: Spatial domain identification is a very important problem in the field of spatial transcriptomics. The state-of-the-art solutions to this problem focus on unsupervised methods, as there is lack of data for a supervised learning formulation. The results obtained from these methods highlight significant opportunities for improvement. RESULTS: In this article, we propose a potential avenue for enhancement through the development of a semi-supervised convolutional neural network based approach. Named "ScribbleDom", our method leverages human expert's input as a form of semi-supervision, thereby seamlessly combines the cognitive abilities of human experts with the computational power of machines. ScribbleDom incorporates a loss function that integrates two crucial components: similarity in gene expression profiles and adherence to the valuable input of a human annotator through scribbles on histology images, providing prior knowledge about spot labels. The spatial continuity of the tissue domains is taken into account by extracting information on the spot microenvironment through convolution filters of varying sizes, in the form of "Inception" blocks. By leveraging this semi-supervised approach, ScribbleDom significantly improves the quality of spatial domains, yielding superior results both quantitatively and qualitatively. Our experiments on several benchmark datasets demonstrate the clear edge of ScribbleDom over state-of-the-art methods-between 1.82% to 169.38% improvements in adjusted Rand index for 9 of the 12 human dorsolateral prefrontal cortex samples, and 15.54% improvement in the melanoma cancer dataset. Notably, when the expert input is absent, ScribbleDom can still operate, in a fully unsupervised manner like the state-of-the-art methods, and produces results that remain competitive. AVAILABILITY AND IMPLEMENTATION: Source code is available at Github (https://github.com/1alnoman/ScribbleDom) and Zenodo (https://zenodo.org/badge/latestdoi/681572669).

NoVaTeST: identifying genes with location-dependent noise variance in spatial transcriptomics data.

MOTIVATION: Spatial transcriptomics (ST) can reveal the existence and extent of spatial variation of gene expression in complex tissues. Such analyses could help identify spatially localized processes underlying a tissue's function. Existing tools to detect spatially variable genes assume a constant noise variance across spatial locations. This assumption might miss important biological signals when the variance can change across locations. RESULTS: In this article, we propose NoVaTeST, a framework to identify genes with location-dependent noise variance in ST data. NoVaTeST models gene expression as a function of spatial location and allows the noise to vary spatially. NoVaTeST then statistically compares this model to one with constant noise and detects genes showing significant spatial noise variation. We refer to these genes as "noisy genes." In tumor samples, the noisy genes detected by NoVaTeST are largely independent of the spatially variable genes detected by existing tools that assume constant noise, and provide important biological insights into tumor microenvironments. AVAILABILITY AND IMPLEMENTATION: An implementation of the NoVaTeST framework in Python along with instructions for running the pipeline is available at https://github.com/abidabrar-bracu/NoVaTeST.

Chloro-aluminum phthalocyanine-mediated photodynamic therapy improves peri-implant parameters and crevicular fluid cytokine levels in cigarette smokers with chronic hyperglycemia.

PURPOSE: This clinical trial aimed to evaluate the effectiveness of chloroaluminum phthalocyanine-mediated photodynamic therapy (CAPC-PDT) as an adjunct to peri­implant mechanical debridement (PID) in the treatment of peri­implantitis in patients with chronic hyperglycemia and cigarette smoking. METHODS: The selected participants with peri­implantitis were divided into two groups: Group I (n = 15) included hyperglycemic patients with no history of smoking and Group II (n = 15) included hyperglycemic patients with a history of smoking cigarettes. Both groups were further divided into two subgroups based on the type of therapy provided: PDT+PID and PID alone. Peri-implant bleeding on probing (PiBOP), peri­implant pocket depth (PiPD), peri­implant plaque scores (PiPS), and crestal bone loss (CBL) were assessed. Peri-implant crevicular fluid (PICF) was sampled for quantification of interleukin (IL)-1ß and tumor necrosis factor-alpha (TNF-α) using an enzyme-linked immunosorbent assay. All assessments were performed at baseline and at three and six months. RESULTS: PDT+PID showed a higher reduction in PiBOP than PID alone in hyperglycemic/non-smoking participants (p<0.01). PDT+PID and PID show a significant reduction in PiBOP in smokers only at 6 months (p<0.05), with comparable differences between PDT+PID and PID (p>0.05). PDT+PID significantly reduced PiPD hyperglycemic/smoking patients at 3 and 6 months (p<0.05), whereas PID only produced a significant reduction in PiPD at 6 months in smoking patients (p<0.05). CBL alone with PDT+PID in both smokers and non-smokers showed a statistically significant reduction at 6 months follow-up (p<0.05). IL-1ß was significantly reduced in hyperglycemic/non-smoking participants at 6 months follow-up with both PDT+PID and PID alone (p<0.01). This trend was also observed in cigarette smokers, with an additional short-term reduction in IL-1ß at 3 months with PDT+PID (p<0.05). Only the PDT+PID group showed a significant reduction in TNF-a among cigarette smoking patients with chronic hyperglycemia at 6 months follow-up (p<0.05) CONCLUSION: Chloroaluminum phthalocyanine-mediated PDT proved effective in improving peri­implant clinical outcomes and reducing cytokine levels in smoking patients with chronic hyperglycemia.

Availability of comprehensive emergency obstetric and neonatal care in developing regions in Ethiopia: lessons learned from the USAID transform health activity.

BACKGROUND: In collaboration with its partners, the Ethiopian government has been implementing standard Emergency Obstetric and Neonatal Care Services (CEmONC) since 2010. However, limited studies documented the lessons learned from such programs on the availability of CEmONC signal functions. This study investigated the availability of CEmONC signal functions and described lessons learned from Transform Health support in Developing Regional State in Ethiopia. METHOD: At baseline, we conducted a cross-sectional study covering 15 public hospitals in four developing regions of Ethiopia (Somali, Afar, Beneshangul Gumz, and Gambella). Then, clinical mentorship was introduced in ten selected hospitals. This was followed by reviewing the clinical mentorship program report implemented in all regions. We used the tool adapted from an Averting Maternal Death and Disability tools to collect data through face-to-face interviews. We also reviewed maternal and neonatal records. We then descriptively analyzed the data and presented the findings using text, tables, and graphs. RESULT: At baseline, six out of the 15 hospitals performed all the nine CEmONC signal functions, and one-third of the signal functions were performed in all hospitals. Cesarean Section service was available in eleven hospitals, while blood transfusion was available in ten hospitals. The least performed signal functions were blood transfusion, Cesarean Section, manual removal of placenta, removal of retained product of conceptus, and parenteral anticonvulsants. After implementing the clinical mentorship program, all CEmONC signal functions were available in all hospitals selected for the mentorship program except for Abala Hospital; the number of Cesarean Sections increased by 7.25% at the last quarter of 2021compared to the third quarter of 20,219; and the number of women referred for blood transfusions and further management of obstetric complications decreased by 96.67% at the last quarter of 2021 compared to the third quarter of 20,219. However, the number of women with post-cesarean Section surgical site infection, obstetric complications, facility maternal deaths, neonatal deaths, and stillbirths have not been changed. CONCLUSION: The availability of CEmONC signal functions in the supported hospitals did not change the occurrence of maternal death and stillbirth. This indicates the need for investigating underlying and proximal factors that contributed to maternal death and stillbirth in the Developing Regional State of Ethiopia. In addition, there is also the need to assess the quality of the CEmONC services in the supported hospitals, institutionalize reviews, surveillance, and response mechanism for maternal and perinatal or neonatal deaths and near misses.

Effect of USAID-funded obstetric ultrasound service interventions on maternal and perinatal health outcomes at primary healthcare facilities in Ethiopia: a propensity score matching analysis.

OBJECTIVE: A dimensional shift in the health service delivery in the primary healthcare setting is required to raise maternal and child well-being. This study aimed to evaluate the effect of US Agency for International Development-funded obstetric ultrasound service on maternal and perinatal health outcomes at Ethiopia's primary healthcare facilities. DESIGN: We employed a quasi-experimental study design. SETTING: The study was conducted in primary health centres located in four regions of Ethiopia. PARTICIPANTS: We used 2 years' data of 1568 mothers from 13 intervention and 13 control primary health centres. Data were obtained from Vscan, antenatal care (ANC), delivery and postnatal care registers. INTERVENTION: Use of portable obstetric ultrasound service during pregnancy. OUTCOME MEASURES: The primary outcome variables include complete four ANC visits, referral during ANC, delivery in a health facility and having postnatal care and continuum of care. The secondary outcome variable was perinatal death. RESULTS: With the kernel matching approach, we have found that having four or more ANC visits was decreased after the intervention (average treatment effect (ATE): -0.20; 95% CI: -0.23 to -0.09), and the rest of the indicators, including referral during ANC (ATE: 0.01; 95% CI: 0.15 to 0.34), institutional delivery (ATE: 0.24; 95% CI: 0.15 to 0.34) and postnatal care (ATE: 0.26; 95% CI: 0.10 to 0.37), were significantly raised because of the intervention. Similarly, we have found that perinatal death dropped considerably due to the intervention. CONCLUSION: The findings show a consistent increase in maternal health service use because of the introduction of obstetric ultrasound services at the primary health centre level. Furthermore, early detection of complications and following referral for specialty care were found to be high. The consistent rise in maternal health service use indicators calls for additional trial to test the effect of obstetric ultrasound service in other locations of the country. Furthermore, evaluating the predictive values, sensitivity and specificity of the obstetric ultrasound service is important.

Multinomial Convolutions for Joint Modeling of Regulatory Motifs and Sequence Activity Readouts.

A common goal in the convolutional neural network (CNN) modeling of genomic data is to discover specific sequence motifs. Post hoc analysis methods aid in this task but are dependent on parameters whose optimal values are unclear and applying the discovered motifs to new genomic data is not straightforward. As an alternative, we propose to learn convolutions as multinomial distributions, thus streamlining interpretable motif discovery with CNN model fitting. We developed MuSeAM (Multinomial CNNs for Sequence Activity Modeling) by implementing multinomial convolutions in a CNN model. Through benchmarking, we demonstrate the efficacy of MuSeAM in accurately modeling genomic data while fitting multinomial convolutions that recapitulate known transcription factor motifs.

Cytomegalovirus pneumonitis amid COVID-19 chaos: the hidden enemy-a case report.

BACKGROUND: The effect of coronavirus disease 2019 on the immune system is increasingly recognized. When severe, it causes immune dysregulation that may favor other infections, including Herpesviridae. Cytomegalovirus shares many innate immune pathways with severe acute respiratory syndrome coronavirus 2, which may potentiate each other. We describe a case of cytomegalovirus pneumonitis complicating the course of coronavirus disease 2019 in a patient with systemic lupus erythematosus/systemic sclerosis overlap and usual interstitial pneumonia, mimicking interstitial lung disease exacerbation. To the best of the authors' knowledge, this is the first case to be reported worldwide in the setting of connective tissue disease-associated interstitial lung disease. CASE DESCRIPTION: We describe the case of a 47-year-old white/Yemeni female who is known to have systemic lupus erythematosus/scleroderma overlap and usual interstitial pneumonia who was initially admitted with severe coronavirus disease 2019 pneumonia mandating intensive care. After initial improvement, it was later complicated with cytomegalovirus pneumonitis, mimicking interstitial lung disease exacerbation. The case was successfully treated with ganciclovir. CONCLUSION: Intriguingly, severe acute respiratory syndrome coronavirus 2 and cytomegalovirus may potentiate each other, since they share some innate immune pathways. Subjects with severe coronavirus disease 2019 and underlying connective tissue diseases and those who are immunosuppressed carry higher risk compared with other cohorts, which may mandate active surveillance for cytomegalovirus coinfection or reactivation. Among various immunosuppressive therapies that has been tried for cytokine storm, use of anti-interleukin-6 inhibitors in the aforementioned population may carry more harm than previously thought, which may suggest that is reasonable to omit its use in treating this group with coronavirus disease 2019. This case underlines an underrecognized and underreported cause of morbidity and mortality during the course of severe coronavirus disease 2019 and will help to alert clinicians of its occurrence.

Relationship between urinary nitrate concentrations and cognitive function in older adults: findings from the NHANES survey.

This study evaluated the association of urinary nitrate concentrations with cognition in older subjects enrolled in the NHANES study. We also explored whether associations between urinary nitrate and cognition were modified by cardiovascular risk, vitamin D status and vitamin C intake. Two NHANES cycles were merged (2011-2012 and 2013-2014) and a total of 1,015 adults aged 60-80 (69.4 ± 0.3) years were included. Cognition was assessed using the Word List Learning, Word List Recall, Animal Fluency and the Digit Symbol Substitution tests. Urinary nitrate was analysed using electrospray tandem mass spectrometry. Urinary nitrate concentrations were not associated with cognitive performance on any of the cognitive tests. Associations were also not significant in subjects at greater risk for cognitive impairment (i.e. high cardiovascular risk and non-optimal vitamin D status). Longitudinal analyses are needed to explore the associations of urinary nitrate concentrations with dietary nitrate intake and cognitive function.

The prevalence of masked hypertension in a group of young healthy soldiers.

BACKGROUND: To assess the prevalence of masked hypertension (MH) in young Saudi National Guard soldiers based on 24h ambulatory blood pressure monitoring (ABPM). METHODS: A prospective study of 196 soldiers, aged between 21-50 years, without a history of hypertension or antihypertensive medication use. Each participant was fitted with a 24h-ABPM. Patients were considered to have MH if the office blood pressure (OBP) was <140/90 mm Hg and the 24h-ABPM average was ≥130/80 mmHg. RESULTS: The mean age of the MH group was 34.5 years compared to 32.4 years of the normotensive group. By pairing the average OBP with the 24h-ABPM, the prevalence of MH was estimated to be 29/196 (14.8%), with the SBP (systolic blood pressure) and DPB MH (diastolic BP) prevalence 12.8% and 7.7%, respectively. For the systolic BP, the OBP compared with the 24h-ABPM was 120.0±8.1 vs. 134.7±4.5 (P<0.001) and for the diastolic BP, 70.7±7.0 vs. 79.9±4.2 (P<0.001). CONCLUSIONS: The prevalence of MH among this sample of healthy military soldiers was 14.8%. It is important not to rely solely on the OBP and to consider MH when screening for hypertension in apparently healthy individuals.

Travel burden and geographic access to health care among children with cancer in Saudi Arabia.

BACKGROUND: Travel burden has a substantial psychosocial impact and financial strain on childhood cancer patients and their families. AIMS: To study the geographic distribution of childhood cancer and assess the travel burden for care in Saudi Arabia. METHODS: This was a cross-sectional multi-institutional study that enrolled 1657 children with cancer who were diagnosed between 2011 and 2014. Cancer type/stage, city/region of residence, and city/region of treating centre were recorded. Travel burden was measured based on a 1-way distance in kilometres from the city centre to the treatment institution. This study was supported by Sanad Children's Cancer Support Association. RESULTS: Diagnosis was leukaemia (45.2%), non-CNS solid tumours (30.2%), lymphoma (12.3%), CNS tumours (11.8%) and histiocytosis (0.5%). Childhood cancer centres were in the same city as where the patients lived in 652 (39.3%) cases, same region but different city in 308 (18.6%), different regions in 613 (37%), and not known in 84 (5.1%). The mean 1-way travel distance for patients who lived in different regions was 790 (range, 116-1542) km. A total of 536 (32%) patients lived ≥ 400 km and 216 (13%) > 1000 km from the treatment centre. Among 642 patients with acute lymphoblastic leukaemia who required 2-3 years of therapy, 197 (31%) lived ≥ 400 km and 94 (15%) >1000 km from the treatment centre. CONCLUSIONS: Nearly two thirds of patients with childhood cancer lived in different cities than the treatment centres, including one third of patients who lived ≥ 400 km away. There is a need to develop strategies to improve access to childhood cancer care.

The validity of a daytime ambulatory blood pressure to diagnose masked hypertension.

Masked hypertension (MH) is traditionally diagnosed with 24-hour ambulatory blood pressure monitoring (24-ABPM). This is relatively costly and could cause discomfort during the night. We studied the validity of daytime ABP (DT-ABPM) in young National Guard soldiers and determined the prevalence in comparison to the standard 24-ABPM. A prospective study of 196 soldiers aged 21-50 years, without a history of hypertension or antihypertensive medication use. Each participant was fitted with a 12h-ABPM. Patients were diagnosed with MH if the office blood pressure (OBP) was <140/90 mmHg and the average DT-ABPM was ≥135/85 mmHg. By pairing the average OBP with the 12 h-ABPM, the prevalence of MH was estimated as 18/196 (9.2%), the SBP MH (systolic blood pressure) of 8.2% and the DPB MH (diastolic blood pressure) of 3.1%.  When we compared the daytime prevalence with the 24 h-ABPM, and the average OBP, the prevalence of MH was 29/196 (14.8%). No statistically significant difference was noted (kappa=0.74; 95% CI: 0.59 to 0.88). We conclude that DT-ABPM is a good method and convenient to detect MH, with no statistically significant difference when compared to the 24 h-ABPM. The prevalence of MH in young healthy soldiers was unexpectedly high.

Evaluation of a Multidisciplinary Antimicrobial Stewardship Program in a Saudi Critical Care Unit: A Quasi-Experimental Study.

Background: Antimicrobial stewardship programs (ASPs) are collaborative efforts to optimize antimicrobial use in healthcare institutions through evidence-based quality improvement strategies. With regard to critically ill patients, appropriate antimicrobial usage is of significance, and any delay in therapy increases their risk of mortality. Therefore, the implementation of structured multidisciplinary ASPs in critical care settings is of the utmost importance to promote the judicious use of antimicrobials. Methods: This quasi-experimental study evaluating a multidisciplinary ASP in a 20-bed critical care setting was conducted from January 1, 2016 to July 31, 2017. Outcomes were compared nine months before and after ASP implementation. The national antimicrobial stewardship toolkit by Ministry of health was reviewed and the hospital antibiotic prescribing policy was accordingly modified. The antimicrobial stewardship algorithm (Start Smart and Then Focus) and an ASP toolkit were distributed to all intensive care unit staff. Prospective audit and feedback, in addition to prescribing forms for common infectious diseases and education, were the primary antimicrobial strategies. Results: We found that the mean total monthly antimicrobial consumption measured as defined daily dose per 100 bed days was reduced by 25% (742.86 vs. 555.33; p = 0.110) compared to 7% in the control condition (tracer medications) (35.35 vs. 38.10; p = 0.735). Interestingly, there was a negative impact on cost in the post-intervention phase. Interestingly, the use of intravenous ceftriaxone measured as defined daily dose per 100 bed days was decreased by 82% (94.32 vs. 16.68; p = 0.008), whereas oral levofloxacin use was increased by 84% (26.75 vs. 172.29; p = 0.008) in the intensive care unit. Conclusion: Overall, involvement of higher administration in multidisciplinary ASP committees, daily audit and feedback by clinical pharmacists and physicians with infectious disease training, continuous educational activities about antimicrobial use and resistance, use of local antimicrobial prescribing guidelines based on up-to-date antibiogram, and support from the intensive care team can optimize antibiotic use in Saudi healthcare institutions.

Diagnostic Comparability and Interchangeability Between Daytime Ambulatory Blood Pressure Monitoring and 24-Hour Ambulatory Blood Pressure Monitoring in Detecting Masked Hypertension.

Background The primary aim of this study was to evaluate the level of diagnostic overlap between daytime ambulatory blood pressure (BP) monitoring (DT-ABPM) and 24-hour ambulatory BP monitoring (24-h ABPM) in detecting masked hypertension (MH). Methods This is a prospective study that was performed in a sample of 196 soldiers aged between 21 and 50 years (without a history of hypertension) undergoing ABPM testing. The diagnosis of MH based on DT-ABPM defined as (office blood pressure (OBP) <140/90 and DT-ABPM ≥135/85) was compared with the 24-h ABPM defined as (OBP <140/90 mm Hg and 24-h ABPM ≥130/80 mm Hg). We critically analyzed the results to see the agreement between the two methods. Results The number of subjects classified as having MH based on both DT-ABPM and 24-h ABPM, only on 24-h ABPM, and only on DT-ABPM were 11 (5.6%), 29 (14.8%), and 18 (9.2%), respectively. The sensitivity, specificity, and positive and negative predictive values for DT-ABPM in detecting MH were: sensitivity = 100% (95% CI: 97.82% - 100%), specificity = 62.07% (95% CI: 42.26% - 79.31%), PPV = 93.82% (95% CI: 90.50% - 96.03%), and NPV = 100%, respectively. The level of agreement between DT-ABPM and 24-h ABPM in diagnosing MH was 94.4% and discordance in 5.6% (11/196); (kappa=0.736, p < 0.001). Conclusion The sensitivity, specificity, positive and negative predictive values all showed agreement between the two BP methods to confirm the diagnoses of MH. DT-ABPM can be used as an alternative to the 24-h ABPM. DT-ABPM eliminates sleep disturbance attributable to ABPM and maximizes patient compliance with the ABPM test. A further larger trial is needed for more confirmation and to affect the guidelines for using daytime ABPM.

FLAG/FLAG-IDA regimen for children with relapsed/refractory acute leukemia in the era of targeted novel therapies.

BACKGROUND: Outcomes of relapsed/refractory childhood acute leukemia remain poor. We analyzed the safety/efficacy of fludarabine, cytarabine, and granulocyte colony stimulating factor, with/without idarubicin (FLAG ± IDA) as salvage therapy compared with recent published results of novel therapies. METHODS: This retrospective study included children aged 1 to 15 years with relapsed/refractory acute leukemia who received FLAG ± IDA salvage therapy from January 2000 to December 2014. Patients with infant leukemia, mixed lineage leukemia, Philadelphia-positive acute leukemia, or secondary leukemia were excluded. RESULT: Fifty patients were identified: 25 with acute lymphoblastic leukemia and 25 with acute myeloid leukemia. The median age at initiation of FLAG ± IDA was seven years. Site of relapse was the bone marrow in 29, isolated central nervous system in 11, and combined in 10 patients. FLAG ± IDA was used after first relapse in 68% and after multiple relapses in 32%. Complete remission was achieved in 34 (68%) patients. No variables predictive of complete remission were identified. Grade 3 or greater toxicity was observed in 96% and 6% died from toxicity. Toxicities included hematologic toxicity (96%), infection (52%), and enterocolitis (28%). Twenty-four of 50 (48%) patients achieved a sustained complete remission and survived to bone marrow transplantation. The five-year overall survival was 23.9% ± 6.9%. Patients achieving second complete remission and patients proceeding to bone marrow transplantation following second complete remission demonstrated significantly improved overall survival (p = 0.001). CONCLUSION: Despite a 68% complete remission rate using FLAG ± IDA, only 48% of patients survived to bone marrow transplantation. The regimen was associated with 96% toxicity and only one in four patients was alive at five years. This underscores the need to find more effective lower toxicity salvage regimens.

First dental visit: Age, reason, and experiences of Saudi children.

OBJECTIVE: A study was conducted among parents/guardians of children attending the Outpatient Department of King Khalid University College of Dentistry, Abha, to assess the attitude and knowledge regarding children's first dental visit and related aspects. MATERIALS AND METHODS: A cross-sectional questionnaire-based study was conducted among a convenient sample of 320 parents/guardians. All the parents/guardians willing to participate in the study and whose children visiting the dentist for the first time were included in the study. Children's behavior was assessed using Frankl's scale. RESULTS: Majority (29%) of the children visited the dentist for the first time at the age of 3-6 years, while the least percentage (8%) visited the dentist for the first time at the age of 0-1 year. A statistically significant difference was found between the responses (P ≤ 0.05). Most (72.67%) of the children were being accompanied by parents during their first dental visit. About 40.33% of the parents said that overall experience of the first visit of their children was good. About 39.67% of the children had positive behavior during their first dental visit. About 37.33% of the participants said that pain was the main reason for them to get their children to dentist. CONCLUSION: It was concluded that bulk of the parents were unaware about the appropriate age of their children's first dental visit. Most of the parents brought their children to dentist after their children experienced pain or suffered from dental caries. There is a need to raise awareness among masses regarding the importance of taking oral health care of their children quite seriously at the earliest budding stage of their life.

Identifying Prognostic Factors That Influence Outcome of Childhood Acute Myeloid Leukemia in First Relapse in Saudi Arabia: Results of the Multicenter SAPHOS Study.

BACKGROUND: The outcome of childhood acute myeloid leukemia (AML) in first relapse (rAML) remains poor. Reported overall survival (OS) rates vary between high-income developed countries and those with fewer resources. The OS of rAML in high-income developing countries (HIDCs) has not been reported. PATIENTS AND MATERIALS: A multicenter study was performed in an HIDC. The outcome of patients with relapsed non-M3/non-Down syndrome AML was evaluated. Three-year OS was computed using the Kaplan-Meier method, and predictors of OS were analyzed using a Cox proportional hazards model. RESULTS: A total of 88 patients with non-M3/non-Down syndrome AML diagnosed between January 2005 and December 2012 with a first relapse were identified. Their 3-year OS was 22.6% ± 5.4%. Patients with inv(16) and t(8;21) had an OS of 75.0% ± 21.7% and 36.0% ± 16.1%, respectively. Worse outcomes were associated with "other intermediate" and 11q23 rearrangement AML (OS of 9.4% ± 8.7% and 10.7% ± 9.6%, respectively). Patients experiencing time to relapse (TTR) less than 1 year had shorter OS than those with a longer TTR (14.6% ± 5.4% vs. 41.1% ± 11.5%; P = .006). The outcome of patients after stem cell transplantation (SCT) in second complete remission (CR2) was superior compared with no SCT (50.9% ± 11.2% vs. 7.7% ± 4.6%; P = .001). TTR, risk group, CR2, and SCT in CR2 were the most significant predictors for survival. CONCLUSIONS: rAML remains a clinical challenge. Genetic variability in outcomes was observed. A majority of patients with inv(16) were successfully salvaged post-relapse, whereas patients with 11q23 rearrangement had a poor prognosis. Only one-third of those with t(8;21) rAML survived. Better access to SCT in HIDCs is needed.

Prevalence of hereditary cancer susceptibility syndromes in children with cancer in a highly consanguineous population.

BACKGROUND & AIM: Hereditary cancer susceptibility syndromes (HCSS) are reported in up to one-third of children with cancer. Diagnosis of HCSS is crucial for implementation of surveillance protocols. We identified children who fulfilled criteria for HCSS in Saudi Arabia using the American College of Medical Genetics and Genomics (ACMG) guidelines, addressing the utility of these guidelines in a highly consanguineous population. METHODS: This multi-center cross-sectional study recruited 1858 children with cancer between January 2011 and December 2014. HCSS criteria were based on the ACMG guidelines. RESULTS: Seven hundred and four (40.4%) out of 1742 eligible patients fulfilled criteria for HCSS. Consanguinity was reported in 629 (38%) patients, with 50 (2.9%) first-degree, 535 (30.7%) second-degree, and 272 (15.6%) third-degree relatives affected with cancer. Two hundred and eighty eight (17.4%) leukemia and 87 (5.3%) brain tumour patients fulfilled HCSS criteria, with parental consanguinity being the most frequent criterion in both (leukemia 85.4%, brain tumors 83.9%). However, leukemia was less frequent in patients of consanguineous parents (p = 0.023). CONCLUSION: Four out of 10 children with cancer fulfilled criteria for HCSS, most often due to consanguinity. This higher than expected prevalence suggests the need to validate consanguinity as a criterion for HCSS in highly consanguineous populations.

Challenges in the management of childhood low-grade glioma in a developing country.

BACKGROUND: Treatment modality impacts outcome of childhood low-grade glioma (LGG). Optimizing management in developing countries can be challenging. This study evaluates the clinical characteristics, treatment, and factors influencing outcome of childhood LGG in Saudi Arabia. PATIENTS AND METHODS: This study retrospectively evaluated 59 children consecutively diagnosed with LGG between January 2001 and June 2016. RESULTS: Median age at diagnosis was 6.0 years. Pilocytic astrocytoma represented 64.9% of cases. The anatomic site was cerebellar in 23.7%, cerebral in 18.6%, hypothalamic-optic pathway in 33.9%, and midline in 23.7%. The 5-year overall survival (OS) and progression-free survival (PFS) were 90.6 ± 4.7 and 54.3 ± 8.4%, respectively. Initial treatment was observation in 28.8%, surgery alone in 35.6%, chemotherapy in 13.6%, radiotherapy in 5.1%, and combined in 16.9% of cases. The corresponding 5-year PFS was 56.3 ± 15.6, 53.3 ± 14.0, 22.9 ± 19.7, 33.3 ± 27.2, and 88.9 ± 10.5%, respectively (p = 0.006). Among the 61% who had surgical intervention (either alone or in combination with other therapies), 22% achieved complete resection with 5-year radiation/progression-free survival (RPFS) of 87.5 ± 11.7% compared to 27.6 ± 10.8% for subtotal resection/biopsy and 62.2 ± 17.0% for no surgery (p = 0.013). Adjuvant therapy for residual tumor improved survival with 5-year PFS of 66.7 ± 19.2% for chemotherapy and 100% for radiotherapy compared to 12.5 ± 11.4% for observation (p = 0.033). CONCLUSIONS: We identified variability in the outcomes of LGG. Fewer surgeries with lower rates of total resection were noted, compared to reports from international cooperative groups. The extent of resection was predictive of RPFS. Adjuvant therapy improved the outcome of patients with residual disease, resulting in PFS rates comparable to international data.

Clinical characteristics and outcome of childhood acute promyelocitic leukemia (APL) in Saudi Arabia: a multicenter SAPHOS leukemia group study.

BACKGROUND: Acute promyelocytic leukemia (APL) is a rare form of acute myelogenous leukemia (AML). Survival rates exceed 80% in developed countries. Successful treatments rely on all-trans retinoic acid with anthracycline-based chemotherapy. Availability of modern care and public knowledge play important roles in pediatric APL survival. METHOD: A cytogenetic diagnosis of APL was confirmed in 30 (14.5%) out of 207 children consecutively diagnosed with de novo AML between January 2005 and December 2012 at nine cancer care centers in Saudi Arabia. Patients were treated based on the standard protocol used by the center following the PETHEMA or the C9710 treatment protocols. We modeled 5-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) vs. treatment and potential covariates of age at diagnosis, involvement of central nervous system (CNS), and white blood cell (WBC) levels. RESULTS: The median age was 10.4 years with a male:female ratio of 1.9. WBC was 10 × 109/l or greater in 57% and CNS involvement was confirmed in 13%. OS, EFS, and CIR were 74 ± 12%, 55 ± 19%, and, 36 ± 17% respectively. No significant difference was found by treatment protocol. WBC levels were significantly prognostic for all negative events, but treatment with C9710 significantly ameliorated negative WBC effects. Overall outcomes were comparable to those reported in developed countries. CONCLUSIONS: Access to modern care is likely to be a critical factor in successful and comparable outcomes of childhood APL across the globe. In the present study, utilizing a cytarabine-containing protocol improved outcome of high-risk pediatric patients with APL.

Prophylactic use of carvedilol to prevent ventricular dysfunction in patients with cancer treated with doxorubicin.

OBJECTIVE: Deterioration in ventricular function is often observed in patients treated with anthracyclines for cancer. There is a paucity of evidence on interventions that might provide cardio-protection. We investigated whether prophylactic use of carvedilol can prevent doxorubicin-induced cardiotoxicity and whether any observed effect is dose related. METHODS: A prospective, randomized, double-blind study in patients treated with doxorubicin, comparing placebo (n = 38) with different doses of carvedilol [6.25 mg/day (n = 41), 12.5 mg/day (n = 38) or 25 mg/day (n = 37)]. The primary endpoint was the measured change in left ventricular ejection fraction (LVEF) from baseline to 6 months. RESULTS: LVEF decreased from 62 ±â€¯5% at baseline to 58 ±â€¯7% at 6-months (p = 0.002) in patients assigned to placebo but no statistically significant changes were observed in any of the 3 carvedilol groups. At 6 months, only one of 116 patients (1%) assigned to carvedilol had an LVEF < 50% compared to four of the 38 assigned to placebo (11%), (p = 0.013). No significant differences were noted between carvedilol and placebo in terms of the development of diastolic dysfunction, clinically overt heart failure or death. CONCLUSIONS: Carvedilol might prevent deterioration in LVEF in cancer patients treated with doxorubicin. This effect may not be dose related within the studied range.