Investigating the prevalence of pathogenic variants in Saudi Arabian patients with familial cancer using a multigene next generation sequencing panel.

Family history is an important factor in determining hereditary cancer risk for many cancer types. The emergence of next-generation sequencing (NGS) has expedited the discovery of many hereditary cancer susceptibility genes and the development of rapid, affordable testing kits. Here, a 30-gene targeted NGS panel for hereditary cancer risk assessment was tested and validated in a Saudi Arabian population. A total of 310 subjects were screened, including 57 non-cancer patients, 110 index patients with cancer and 143 of the cancer patients' family members, 16 of which also had cancer. Of the 310 subjects, 119 (38.4%) were carriers of pathogenic or likely pathogenic variants (PVs) affecting one or more of the following genes: TP53, ATM, CHEK2, CDH1, CDKN2A, BRCA1, BRCA2, PALB2, BRIP1, RAD51D, APC, MLH1, MSH2, MSH6, PMS2, PTEN, NBN/NBS1 and MUTYH. Among 126 patients and relatives with a history of cancer, 49 (38.9%) were carriers of PVs or likely PVs. Two variants in particular were significantly associated with the occurrence of a specific cancer in this population (APC c.3920T>A - colorectal cancer/Lynch syndrome (p = 0.026); TP53 c.868C>T; - multiple colon polyposis (p = 0.048)). Diverse variants in BRCA2, the majority of which have not previously been reported as pathogenic, were found at higher frequency in those with a history of cancer than in the general patient population. There was a higher background prevalence of genetic variants linked to familial cancers in this cohort than expected based on prevalence in other populations.

Healthcare Professionals' Culture Toward Reporting Errors in the Oncology Setting.

INTRODUCTION:  Reporting an error during a hospital journey is crucial to reduce such errors' recurrence and to learn from events. Therefore, this study aimed to investigate oncology staff's attitudes, perceived barriers, and strategy towards reporting incidents and errors. METHODS:  A cross-sectional online survey was conducted among health professionals providing care to cancer patients in a tertiary healthcare hospital in Saudi Arabia in 2019. Data were collected using an online self-administered questionnaire distributed to the targeted population. RESULTS:  A total of 211 participated in this study. Sixty-five percent of responders reported that they felt a need to reveal errors. The leading perceived barrier to reporting the events was that the staff wanted to avoid getting into trouble (60%), followed by worries about legal action (59.2%). The top-ranking strategy to improve reporting by nurses was to have clear guidelines to report errors, education and feedback by doctors, and further education and training by allied healthcare. CONCLUSION:  The study revealed that healthcare professionals do possess a favorable attitude toward reporting errors. However, a major gap is still a barrier between attitude and practice, and this need creating a safe atmosphere where every healthcare professional feels safe and comfortable with reporting incidents is required to build a non-punitive environment to enhance the safety culture. On the other hand, the respondents listed different strategies to enhance reporting events and errors.

Papillary Tumor of the Pineal Region Rare Pediatric CNS Tumor Case Series Treated in King Fahad Medical City (KFMC).

The clinical behaviors, prognosis, and appropriate treatments of papillary tumors of the pineal region (PTPR) are not fully defined due to the rarity of these tumors. At diagnosis, PTPR may present with clinical symptoms, including headache with obstructive hydrocephalus, diplopia, vomiting, and lethargy, as well as neurological signs, including Argyll Robertson pupils and Parinaud's syndrome due to compression of the dorsal midbrain, specifically the periaqueductal region with horizontal nystagmus. Radiological assessment of pineal region lesions is challenging, with a wide range of potential differential diagnoses. PTPR typically presents as a heterogeneous, well-circumscribed mass in the pineal region, which might contain cystic areas, calcifications, hemorrhages, or protein accumulations. Here, we report three female pediatric patients with PTPR treated in King Fahad Medical City (KFMC) in Saudi Arabia. Histological and immunohistochemical diagnosis was confirmed by analysis of genome-wide DNA methylation profiles. This case series expands on the available reports on the clinical presentations of PTPR and provides important information on the responses to different treatment modalities.

The Effect of Video-Assisted Education Prior Intrathecal Chemotherapy on Anxiety and Knowledge Enhancement.

Intrathecal chemotherapy procedures are stressful to patients and caregivers, especially the first time. Providing the patient and caregiver with sufficient information to address their concerns before the scheduled procedure is necessary. This study aims to determine whether the use of video instructions could enhance learning outcomes and decrease anxiety levels in patients' caregivers. A prospective trial was conducted in pediatric hematology for 1 year. Thirty-seven respondents were randomly assigned to two groups wherein one group was given conventional educational leaflets and verbal instructions, while the other group received the same information through an educational video presentation before the intrathecal chemotherapy procedure. Knowledge enhancement in the two groups was evaluated using the summative assessment method and measured by a 10-point Likert scale. The validated Arabic version of the Beck Anxiety Inventory (BAI) scale was used to assess anxiety levels. The anxiety level (12.31 ± 8.84) in the video presentation group was significantly higher than that in the conventional group (6.16 ± 5.91). Similarly, the overall Beck scale score revealed that palpitation, frightening, lightheadedness, and hot/cold sweat levels were decreased in the video presentation group. Additionally, a significant difference in knowledge enhancement was noted between the two groups, as knowledge enhancement in the video presentation group (7.61 ± 1.88) was better than that in the conventional group (6.00 ± 1.00). This produced a domino effect on the anxiety level scores of both groups. An educational video presentation before the intrathecal chemotherapy procedure is effective since both visual and auditory senses are involved. This could be considered a good source of an interventional approach before a therapeutic procedure.

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Epigenomics and immunotherapeutic advances in pediatric brain tumors.

Brain tumors are the leading cause of childhood cancer-related deaths. Similar to adult brain tumors, pediatric brain tumors are classified based on histopathological evaluations. However, pediatric brain tumors are often histologically inconsistent with adult brain tumors. Recent research findings from molecular genetic analyses have revealed molecular and genetic changes in pediatric tumors that are necessary for appropriate classification to avoid misdiagnosis, the development of treatment modalities, and the clinical management of tumors. As many of the molecular-based therapies developed from clinical trials on adults are not always effective against pediatric brain tumors, recent advances have improved our understanding of the molecular profiles of pediatric brain tumors and have led to novel epigenetic and immunotherapeutic treatment approaches currently being evaluated in clinical trials. In this review, we focus on primary malignant brain tumors in children and genetic, epigenetic, and molecular characteristics that differentiate them from brain tumors in adults. The comparison of pediatric and adult brain tumors highlights the need for treatments designed specifically for pediatric brain tumors. We also discuss the advancements in novel molecularly targeted drugs and how they are being integrated with standard therapy to improve the classification and outcomes of pediatric brain tumors in the future.

Stress Reactions and Coping Strategy among Healthcare Professionals during COVID-19 Outbreak.

BACKGROUND: Psychological impacts among healthcare professionals have increased significantly due to the increasing number of COVID-19 cases. This study aimed to identify stress and coping strategies among healthcare professionals in Saudi Arabia during the COVID-19 outbreak. SUBJECTS AND METHODS: A cross-sectional study online survey was conducted for health care professionals during a peak of COVID-19 from March to June 2020 at different healthcare institutions at KSA (n=342). RESULTS: Sixty-five percent of responders often and always feel fears about infection and subsequent effects on themselves, the patient, and the family. 57% of them stated that they felt sometimes depressed mode and 47% anxiety during the outbreak. Eighty-four percent of the respondent always focusing on prevention as the first biosecurity measures such as hand-washing habits and using hand sanitizer, and 38.3% of them make sometimes relax and rest. While half of the responses (50%) sometimes had physical exercise. Also, thirty-eight percent joined sometimes community and/or group online chat groups, and 56.1% always keep contact with family and friends through social messaging or phone calls. CONCLUSION: Understanding this topic is important for healthcare organizations, effective strategies, and programs is needed to provide holistic staff care and wellbeing during outbreaks that focus on the value of mental and emotional support.

Survival after therapy for pediatric ependymoma in a tertiary care center in Saudi Arabia.

BACKGROUND: There is limited data from Saudi Arabia on the demographic characteristics, outcomes and effectiveness of different treatment modalities in children with intracranial ependymoma. OBJECTIVE: Study the characteristics of pediatric ependymoma and outcomes of treatment modalities in Saudi Arabia. DESIGN: Retrospective. SETTING: Tertiary care center. PATIENTS AND METHODS: Children with intracranial ependymoma who were younger than 14 years of age and treated between 2006 and 2015 were included in the study. Patients with prior radiation, chemo-therapy, or surgical resection at other centers were excluded. MAIN OUTCOME MEASURES: Kaplan-Meier survival curves were used to estimate the event-free (EFS) and overall survival (OS) rates of the patients. SAMPLE SIZE: 22. RESULTS: Of the 22 children, 4 (18.2%) were less than three years old. All intracranial ependymomas had upfront surgical resection of the primary tumor. Gross total resection was achievable in 9 (42.9%) cases and subtotal resection in another 9 (42.9%). Near-total resection was done in 3 (14.3%) cases. Median time from surgery to start of radiotherapy was 62 days. RT was given to 17 (77.3%) patients. Both mean and median RT dose was 55.8 Gy. Only 5 (22.7%) of the children received chemotherapy. The median duration of follow-up was 5.38 years and the median time for EFS was 2.27 years. The cumulative OS rate of the study was 44.5%. The cumulative EFS survival rate of the study was 18.6%. Among demographic, pathological, radiological features, none had a statistically significant effect on the survival. CONCLUSIONS: The outcomes are comparable to those reported by international investigators for similar populations. Further improvements can be achieved by avoiding delays in radiation therapy and adding molecular staging. LIMITATIONS: The limited number of cases, retrospective nature, lack of molecular biology and size of the tumors. CONFLICT OF INTEREST: None.

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.

Frequency of pathogenic/likely pathogenic germline variants in cancer-related genes among children with acute leukemia in Saudi Arabia.

BACKGROUND: The frequency of pathogenic/likely pathogenic (P/LP) germline mutations in cancer-related genes among children with cancer in highly consanguineous populations is not well studied. METHODS: Whole-exome sequencing of germline DNA was performed in 60 children with acute leukemia. We used the St. Jude Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE) data portal for the classification of germline variants by the St. Jude Medal Ceremony pipeline. RESULTS: Fifty-seven patients had acute lymphoblastic leukemia (ALL) and three patients had acute myeloid leukemia. Parental consanguinity was present in 27 (45%) patients. All patients were of Arab ancestry. Three patients (5%) had a history of cancer in their siblings. Five patients (8.3%) had P/LP germline mutations in cancer-related genes. Three patients with B-ALL had heterozygous pathogenic mutations in TP53, BRCA1, and BRCA2; one patient with B-ALL had homozygous pathogenic mutation in PMS2; and one patient with T-ALL had LP homozygous mutation in AK2 that was associated with reticular dysgenesis. Among patients who had history of parental consanguinity, three (11%) had P/LP germline mutations compared with two (8%) in the absence of parental consanguinity. Fourteen (23%) patients had gold medal variants in cancer-related genes, 13 were heterozygous, and one was homozygous. Silver medal variants were present in 35 (58%) patients; all were heterozygous except one homozygous. CONCLUSIONS: Children with acute leukemia in Saudi Arabia had low frequency of P/LP mutations in cancer-related genes despite the high rate of consanguinity. Larger studies using whole-genome sequencing are needed to further explore the heritability of childhood leukemia.

Methylation Profiling of Medulloblastoma in a Clinical Setting Permits Sub-classification and Reveals New Outcome Predictions.

Medulloblastoma (MB) is the most common childhood malignant brain tumor and is a leading cause of cancer-related death in children. DNA methylation profiling has rapidly advanced our understanding of MB pathogenesis at the molecular level, but assessments in Saudi Arabian (SA)-MB cases are sparse. MBs can be sub-grouped according to methylation patterns from FPPE samples into Wingless (WNT-MB), Sonic Hedgehog (SHH-MB), Group 3 (G3), and Group 4 (G4) tumors. The WNT-MB and SHH-MB subgroups are characterized by gain-of function mutations that activate oncogenic cell signaling, whilst G3/G4 tumors show recurrent chromosomal alterations. Given that each subgroup has distinct clinical outcomes, the ability to subgroup SA-FPPE samples holds significant prognostic and therapeutic value. Here, we performed the first assessment of MB-DNA methylation patterns in an SA cohort using archival biopsy material (FPPE n = 49). Of the 41 materials available for methylation assessments, 39 could be classified into the major DNA methylation subgroups (SHH, WNT, G3, and G4). Furthermore, methylation analysis was able to reclassify tumors that could not be sub-grouped through next-generation sequencing, highlighting its superior accuracy for MB molecular classifications. Independent assessments demonstrated known clinical relationships of the subgroups, exemplified by the high survival rates observed for WNT tumors. Surprisingly, the G4 subgroup did not conform to previously identified phenotypes, with a high prevalence in females, high metastatic rates, and a large number of tumor-associated deaths. Taking our results together, we demonstrate that DNA methylation profiling enables the robust sub-classification of four disease sub-groups in archival FFPE biopsy material from SA-MB patients. Moreover, we show that the incorporation of DNA methylation biomarkers can significantly improve current disease-risk stratification schemes, particularly concerning the identification of aggressive G4 tumors. These findings have important implications for future clinical disease management in MB cases across the Arab world.

Religious Belief and Social Support Among Cancer Patients in Saudi Arabia.

Background People with cancer usually experience some degree of depression, anxiety, and fear, as if embracing the fact that cancer has become part of their lives. Additionally, religious beliefs can influence a patient's support system, as well as the patient's own emotional response, behavior, and decision-making, which can create a conflict with medical treatment. The objective of this study was to assess cancer patients' religious beliefs and social support. Methods A cross-sectional study was conducted in 294 adult patients at the Comprehensive Cancer Center of King Fahad Medical City in Riyadh, Saudi Arabia. Patients were interviewed using the System of Belief Inventory (SBI-15R) questionnaire, and responses were noted in the survey form. Results The majority (82.3%) of patients were newly diagnosed with cancer and in the treatment phase, whereas 9.9% were in the metastatic phase. The total mean score of the SBI-15R scale was 27.9. The mean score of the social support subscale was 13.1 ± 1.68, whereas the mean score for the beliefs and practice subscale was 29.7 ± 0.81. For the social support subscale, a statistically significant difference was found in age (P < 0.001), gender (P < 0.001), and occupation (P = 0.009). However, for the beliefs and practice subscale, a statistically significant difference was found only with gender (P = 0.001).  Conclusions This study concluded that social support is important for the study participants, and they were attached to their beliefs and cultural practices, as indicated by the high total mean score on the SBI-15R. Understanding this topic is important in order for healthcare organizations to provide holistic patient care.

Clinical management and genomic profiling of pediatric low-grade gliomas in Saudi Arabia.

Pediatric Low Grade Gliomas (PLGGs) display heterogeneity regarding morphology, genomic drivers and clinical outcomes. The treatment modality dictates the outcome and optimizing patient management can be challenging. In this study, we profiled a targeted panel of cancer-related genes in 37 Saudi Arabian patients with pLGGs to identify genetic abnormalities that can inform prognostic and therapeutic decision-making. We detected genetic alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient. The KIAA1549-BRAF fusion was the most common alteration (21/37 patients) followed by AFAP1-NTRK2 (2/37) and TBLXR-PI3KCA (2/37) fusions that were observed at much lower frequencies. The most frequently mutated) genes were NOTCH1-3 (7/37), ATM (4/37), RAD51C (3/37), RNF43 (3/37), SLX4 (3/37) and NF1 (3/37). Interestingly, we identified a GOPC-ROS1 fusion in an 8-year-old patient whose tumor lacked BRAF alterations and histologically classified as low grade glioma. The patient underwent gross total resection (GTR). The patient is currently disease free. To our knowledge this is the first report of GOPC-ROS1 fusion in PLGG. Taken together, we reveal the genetic characteristics of pLGG patients can enhance diagnostics and therapeutic decisions. In addition, we identified a GOPC-ROS1 fusion that may be a biomarker for pLGG.

Burnout Among Healthcare Providers in a Comprehensive Cancer Center in Saudi Arabia.

Background Overwork has grave consequences for staff health, either physically or psychologically. Burnout has an impact on health care turnover, patient safety, patient satisfaction, and patient perception towards health professionals. This study aims to assess the prevalence of burnout, psychosocial distress, occupational predictors, perceived causes, and suggested strategies for preventing or reducing its impact of burnout on oncology healthcare workers. Materials and methods A cross-sectional survey was conducted among various oncology healthcare professionals using the Maslach Burnout and Kessler-10 Inventory tools to derive the data. Results A total of 157 participants represented with an overall response rate of 62.8%. Among all the respondents, it showed that 28.7% of them reported moderate to severe burnout. Moreover, 32.9% of the participants with patient contact had experienced moderate to severe burnout, and the same burnout level was reported by 55% of the respondents with no patient contact. Physicians (35.1%) were recorded to have the highest rate of burnout, followed by nurses (29%) and allied healthcare professionals (27%). Also, exhaustion and emotional exhaustion subscales were higher to those samples without patient contact (33.3%) compared to samples with patient contact (25.5%). On the other hand, 28.7% of those samples with patient contact exhibited a high level of depersonalization, while 42.9% of non-patient contact samples recorded a high level of cynicism. Both sub-samples scored more than half in personal accomplishment (73.4%) and the related professional efficacy (57%), merging the average and high-level scores. The proportion of non-patient contact respondents who had experienced psychiatric symptoms was 10%. Conclusions There was a significant number of King Fahad Medical City Comprehensive Cancer Center healthcare professionals who experienced a substantial level of burnout. On the other hand, the respondents listed different strategies to reduce the level of burnout. These strategies are self-defined, such as improved access to leave, attention to staff psychosocial and training needs, and emphasizing the importance of regular communication skills training. The management needs to take action for the area of improvement based on the results.

Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue.

PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family.

Li-Fraumeni syndrome (LFS) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors at an early age. Approximately 70% of families with classic LFS have pathogenic variants in the tumor suppressor gene TP53 that disrupt protein function or stability. While more than 70% of pathogenic variants in TP53 are missense variants, the vast majority occur very infrequently, and thus their clinical significance is uncertain or conflicting. Here, we report an extremely rare TP53 missense variant, c.799C > T (p.Arg267Trp), identified in a 2-year-old Saudi proband diagnosed with choroid plexus carcinoma (CPC) and six of his first- and second-degree relatives. CPC is frequently found in families with LFS, and this is the first detailed report of a family with this variant. Intriguingly, the proband's father is homozygous for TP53 c.799C > T and phenotypically normal at 39 years of age. While loss of TP53 heterozygosity is often observed in tumors from individuals with LFS, homozygous germline TP53 pathogenic variants are rare. Based on our analysis of this single family, we hypothesize that TP53 c.799C > T has low or variable penetrance for LFS, with predisposition to the development of CPC. The observations from this family have furthered our understanding of the phenotypic variability that may be caused by one variant of TP53, even in the same family, and suggest that other factors (genetic and/or environmental) may play a role in mechanism of disease manifestation in LFS.

Durable Response to Nivolumab in a Pediatric Patient with Refractory Glioblastoma and Constitutional Biallelic Mismatch Repair Deficiency.

Primary brain tumors are a leading cause of cancer-related morbidity and mortality in children. Glioblastoma (GBM) is a high-grade astrocytoma that occurs in both children and adults and is associated with a poor prognosis. Despite extensive study in recent years, the clinical management of these tumors has remained largely unchanged, consisting of surgical resection, conventional chemotherapy, and radiotherapy. Although the etiology and genomic drivers in GBM are diverse, constitutional mismatch repair-deficiency (CMMRD) syndrome is a rare, recessively inherited disease with a predisposition to gliomagenesis. CMMRD results from biallelic mutations in one of the mismatch repair genes including mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and post-meiotic segregation increased 2 (PMS2). In this report, we present the case of a 5-year-old female with GBM and CMMRD due to an MSH6 homozygous c.1883G>A mutation, who continues to experience an exceptional and durable response (9 months) to the immune checkpoint inhibitor (ICPI) nivolumab. Our patient presented with acute neurologic decline and increased intracranial pressure. Neuroimaging studies revealed a large left frontoparietal mass requiring neurosurgical decompression and resection. Histopathologic analyses resulted in a diagnosis of de novo GBM that was BRAF wild type and negative for programmed death-ligand 1 protein expression. She received standard-of-care treatment with surgery, radiation therapy, and temozolomide; however, the tumor recurred 3 months after the initial diagnosis. Molecular analyses of tumor and blood tissues revealed an MSH6 homozygous c.1883G>A mutation consistent with CMMRD. Given her CMMRD status, she was treated with nivolumab (3 mg/kg doses every 2 weeks for 36 weeks) and showed a 60% reduction in tumor size, improved clinical symptoms, and an ongoing durable response lasting 10 months to date. Our study highlights a durable response to the ICPI nivolumab in a pediatric patient with recurrent/refractory CMMRD-associated GBM. We show that incorporating genomic and/or molecular testing for CMMRD into routine pediatric oncology clinical care can identify a subset of patients likely to benefit from ICPI. KEY POINTS: Constitutional mismatch repair-deficiency (CMMRD) syndrome, alternatively known as biallelic mismatch repair deficiency syndrome, occurs in subset of pediatric cancer patients, including those with primary brain tumors.Patients from Arab and other developing countries are predicted to have higher incidence of CMMRD due to high prevalence of consanguinity.Integration of molecular and/or genomic testing into routine clinical care for pediatric cancer patients is important to identify patients with CMMRD syndrome.Patient with CMMRD-associated cancers may show increased responsiveness to immune checkpoint inhibitors.To the authors' knowledge, this is the first report in the Arab world of a durable response to immune checkpoint inhibitors in a pediatric glioblastoma patient.

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.

The Effect of Satellite Laboratory Installation on Chemotherapy Waiting Time in an Oncology Treatment Unit.

Background Timely treatment is a patient's right. Increasing the efficiency of laboratory testing could potentially improve hospital operations, provide quicker access to health services, and have a positive impact on patient experience. Installation of a satellite laboratory may shorten laboratory turnaround time (TAT) and chemotherapy waiting time. Method The laboratory TAT and chemotherapy waiting time were analyzed and compared before and three years after the establishment of the satellite laboratory. Result The mean laboratory TAT decreased from one hour and 30 minutes at baseline in 2012 to 43, 43, and 37 minutes in 2013, 2014, and 2015, respectively; a reduction rate of 59%. Mean chemotherapy waiting time also reduced, from a 2012 baseline of 252 minutes to 170, 157, and 146 minutes in 2013, 2014, and 2015, respectively; a reduction rate of 42%. Conclusion The reduced chemotherapy waiting time after the installation of a satellite laboratory had a positive impact on patient care. It also reduced employee workload and maximized the utilization of hospital resources.