Improved transplant survival and long-term disease outcome in children with MHC class II deficiency.

MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.

Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.

Postsurgical geometrical variations of tumor bed and brainstem during photon and proton therapy for pediatric tumors of the posterior fossa: dosimetric impact and predictive factors.

PURPOSE: Brainstem radionecrosis is an important issue during the irradiation of tumors of the posterior fossa. The aim of the present study is to analyze postsurgical geometrical variations of tumor bed (TB) and brainstem (BS) and their impact on dosimetry. METHODS: Retrospective collection of data from pediatric patients treated at a single institution. Availability of presurgical magnetic resonance imaging (MRI) was verified; availability of at least two postsurgical MRIs was considered a further inclusion criterion. The following metrics were analyzed: total volume, Dice similarity coefficient (DSC), and Haudsdorff distances (HD). RESULTS: Fourteen patients were available for the quantification of major postsurgical geometrical variations of TB. DSC, HD max, and HD average values were 0.47 (range: 0.08;0.76), 11.3 mm (7.7;24.5), and 2.6 mm (0.7;6.7) between the first and the second postoperative MRI, respectively. Postsurgical geometrical variations of the BS were also observed. Coverage to the TB was reduced in one patient (D95: -2.9 Gy), while D2 to the BS was increased for the majority of patients. Overall, predictive factors for significant geometrical changes were presurgical gross tumor volume (GTV) > 33 mL, hydrocephaly at diagnosis, Luschka foramen involvement, and younger age (≤ 8 years). CONCLUSION: Major volume changes were observed in this cohort, with some dosimetric impact. The use of a recent co-registration MRI is advised. The 2-3 mm HD average observed should be considered in the planning target volume/planning organ at risk volume (PTV/PRV) margin and/or robust optimization planning. Results from wider efforts are needed to verify our findings.

A RAB27A duplication in several cases of Griscelli syndrome type 2: An explanation for cases lacking a genetic diagnosis.

Griscelli syndrome type 2 (GS2) is a rare and often fatal autosomal recessive, hyperinflammatory disorder. It is associated with hypopigmentation of the skin and the hair, resulting in the characteristic pigment accumulation and clumping in the hair shaft. Loss-of-function mutations in RAB27A, resulting from point mutations, short indel, or large deletions, account for all the cases reported to date. However, several GS2 cases originating from Saudi Arabia lack a genetic diagnosis. Here, we report on a new RAB27A genetic anomaly observed in seven Saudi Arabia families that had remained negative after extensive molecular genomic DNA testing. Linkage analysis and targeted sequencing of the RAB27A genomic region in several of these patients led to the identification of a common homozygous tandem duplication of 38 kb affecting exon 2-5 and resulting in a premature stop codon. The pathogenic effect of this duplication was confirmed by a cDNA analysis and functional assays. The identification of microhomology flanking the breakpoint site suggests a possible underlying mechanism.

The Effect of Food Allergen Exclusion on the Growth of Saudi Children.

With a variety of symptoms that can impede children's development, food allergies are an important public health concern. With the help of information from the King Fahad Medical City Hospital in Riyadh, we looked at how restricting certain foods affected the growth of Saudi children who had food allergies. An anonymous self-administered questionnaire asking about the individuals' demographics and their restricted eating habits was completed by 72 children (48 boys and 24 girls) between the ages of 2 and 14. The sensitivity of six allergens (hen eggs, cow milk, fish, wheat, peanuts, and soybeans), anthropometric indices, specific Immunoglobulin E (IgE) levels, and sensitivity were examined. The Statistical Package for Social Science (SPSS), version 26, was used to analyze the data. Chi-square and t-tests were used to examine the relationships between various category variables. According to the findings, most of the mothers of the children were between the ages of 30 and 40 (80.6%), had a college degree (72.3%), were unemployed (59.7%), and had a monthly family income between 5000 and 15,000 SAR (69.4%). Both sexes had specific IgE antibodies for allergens in classes 2 and 3, with boys having noticeably (p ≤ 0.05) higher quantities than girls. While females were more sensitive to fish and peanuts, boys were more likely than girls to show specific IgE sensitivity to egg white, cow milk, wheat, and soybeans. Both sexes' allergy levels were considerably (p ≤ 0.01) higher in children aged 5.01 to 10 than in other age groups. In terms of classifications of thinness, overweightness, and obesity, boys were slenderer than girls, and a greater percentage of boys than girls were overweight or obese. The exclusion of hen eggs, cow milk, wheat, and peanuts from the diet had a significant and detrimental effect on body mass index (BMI) and height-for-age ratio among children with impaired growth, in contrast to the demographic factors, which had a significant and favorable effect on the growth of other children. In conclusion, restrictions on food allergens impairs growth in Saudi children, particularly boys' growth.

Atypical presentation of adenosine deaminase 2 deficiency with bi-allelic ADA2 mutation.

Herein, we report a case of VAIHS with atypical clinical presentation of perianal abscess, fistula fever, and bi-cytopenia including pathogenic ADA2 mutation suggesting that ADA2 deficiency be considered as a differential diagnosis of enlarging cutaneous abscess with no evidence of wound healing in the setting of leukopenia and neutropenia.

Disseminated Pulmonary Mycosis Caused by Candida tropicalis in an 11-Year-Old Male Patient with Chronic Granulomatous Disease.

Invasive fungal infection is a major threat to chronic granulomatous disease (CGD) patients. We present a rare case of invasive mycosis in a CGD boy. An 11-year-old preadolescent boy presented with fever, hypoxia, and dyspnea. Physical examination revealed left neck enlarged lymph nodes with healed scars. The chest revealed bilateral diminished air entry with bilateral coarse crackles. Peripheral blood leukocyte count was 28.260/µL with 84% neutrophil, 11% lymphocyte, and 4.4% monocyte. The patient's condition deteriorated regardless of the empirical antibacterial against MRSA and suspected tuberculosis. A sputum sample was submitted for mycological investigation, and budding yeasts with pseudohyphae were detected in the direct smear and were isolated in pure culture using Sabouraud agar. Candida tropicalis was identified from cultural and microscopic features and confirmed by the Vitek 2 automated system. This result confirmed the invasive mycosis, obviously due to the underlying primary immunodeficiency, chronic granulomatous disease (CGD). Amphotericin was added, and he also received IV methylprednisolone for seven days. The patient improved and was weaned off oxygen with no fever. However, the patient was referred to a higher center for further workup, which confirmed CGD's diagnosis. He is on the list for HLA-identical bone marrow transplantation (BMT).

The Road to Dissemination: The Concept of Oligometastases and the Barriers for Widespread Disease.

Over the last years, the oligometastatic disease state has gained more and more interest, and randomized trials are now suggesting an added value of stereotactic radiotherapy on all macroscopic disease in oligometastatic patients; but what barriers could impede widespread disease in some patients? In this review, we first discuss the concept of oligometastatic disease and some examples of clinical evidence. We then explore the route to dissemination: the hurdles a tumoral clone has to overtake before it can produce efficient and widespread dissemination. The spectrum theory argues that the range of metastatic patterns encountered in the clinic is the consequence of gradually obtained metastatic abilities of the tumor cells. Tumor clones can obtain these capabilities by Darwinian evolution, hence early in their genetic progression tumors might produce only a limited number of metastases. We illustrate selective dissemination by discussing organ tropism, the preference of different cancer (sub)types to metastasize to certain organs. Finally we discuss biomarkers that may help to distinguish the oligometastatic state.

Peanut-Induced Anaphylaxis in Children: A Literature Review.

Peanut allergy has become more common among children and is considered one of the most common triggers for fatal anaphylaxis. Treatment of symptoms during a reaction is only one aspect of managing anaphylaxis; other elements include rigorous dietary avoidance and education about settings that could put the patient at a high risk of unintentional exposure. We aimed to review the prevalence, mechanism, diagnosis, treatment, and emergency action of peanut-induced anaphylaxis among children. We used a web-based literature search using the advanced features of databases such as PubMed, Scopus, Directory of Open Access Journals (DOAJ), Embase, Google Scholar, and Cochrane electronic databases. The most common food to cause fatal anaphylaxis and a common cause of food allergies is peanuts. Over the past two years, our knowledge improved more about peanut allergens, their prevalence, causes, diagnoses, and treatments. The research cited in this review demonstrates that the peanut allergens are most closely associated with disease differ across cultures, that early oral peanut exposure may reduce the occurrence of peanut allergy while early non-oral exposure may have the opposite effect, that complement activation by peanut constituents appears to promote peanut-induced anaphylaxis, and that oral immunotherapy, anti-IgE antibody, and a herbal formulation are all demonstrating promise as treatments. To conclude, peanut allergies have increased frequently during the past 10 years, especially in Westernized nations. Given that peanut allergy poses a danger for fatal anaphylaxis, response management is crucial. The current standard of care for those with nut allergies comprises complete food avoidance and the administration of injectable epinephrine to treat systemic symptoms.

Anatomically consistent CNN-based segmentation of organs-at-risk in cranial radiotherapy.

Planning of radiotherapy involves accurate segmentation of a large number of organs at risk (OAR), i.e., organs for which irradiation doses should be minimized to avoid important side effects of the therapy. We propose a deep learning method for segmentation of OAR inside the head, from magnetic resonance images (MRIs). Our system performs segmentation of eight structures: eye, lens, optic nerve, optic chiasm, pituitary gland, hippocampus, brainstem, and brain. We propose an efficient algorithm to train neural networks for an end-to-end segmentation of multiple and nonexclusive classes, addressing problems related to computational costs and missing ground truth segmentations for a subset of classes. We enforce anatomical consistency of the result in a postprocessing step. In particular, we introduce a graph-based algorithm for segmentation of the optic nerves, enforcing the connectivity between the eyes and the optic chiasm. We report cross-validated quantitative results on a database of 44 contrast-enhanced T1-weighted MRIs with provided segmentations of the considered OAR, which were originally used for radiotherapy planning. In addition, the segmentations produced by our model on an independent test set of 50 MRIs were evaluated by an experienced radiotherapist in order to qualitatively assess their accuracy. The mean distances between produced segmentations and the ground truth ranged from 0.1 to 0.7 mm across different organs. A vast majority (96%) of the produced segmentations were found acceptable for radiotherapy planning.

Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies.

BACKGROUND: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test. METHODS: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors. RESULTS: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%). CONCLUSION: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.

A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations.

Primary immunodeficiencies are often monogenic disorders characterized by vulnerability to specific infectious pathogens. Here, we performed whole-exome sequencing of a patient with disseminated Mycobacterium abscessus, Streptococcus viridians bacteremia, and cytomegalovirus (CMV) viremia and identified mutations in 2 genes that regulate distinct IFN pathways. The patient had a homozygous frameshift deletion in IFNGR2, which encodes the signal transducing chain of the IFN-γ receptor, that resulted in minimal protein expression and abolished downstream signaling. The patient also harbored a homozygous deletion in IFNAR1 (IFNAR1*557Gluext*46), which encodes the IFN-α receptor signaling subunit. The IFNAR1*557Gluext*46 resulted in replacement of the stop codon with 46 additional codons at the C-terminus. The level of IFNAR1*557Gluext*46 mutant protein expressed in patient fibroblasts was comparable to levels of WT IFNAR1 in control fibroblasts. IFN-α-induced signaling was impaired in the patient fibroblasts, as evidenced by decreased STAT1/STAT2 phosphorylation, nuclear translocation of STAT1, and expression of IFN-α-stimulated genes critical for CMV immunity. Pretreatment with IFN-α failed to suppress CMV protein expression in patient fibroblasts, whereas expression of WT IFNAR1 restored IFN-α-mediated suppression of CMV. This study identifies a human IFNAR1 mutation and describes a digenic immunodeficiency specific to type I and type II IFNs.

Pancreatic cancer in Saudi patients treated at tertiary institution. Ten years retrospective study.

OBJECTIVES: To describe presentation, management, and outcome, and determine prognostic factors for pancreatic cancer patients. METHODS: A retrospective review of patients diagnosed with pancreatic cancer at King Abdulaziz Medical City, Riyadh, Saudi Arabia during the period from January 2000 to December 2010. Descriptive statistics were conducted on the collected data and survival was estimated using the Kaplan Meier estimate. Univariate and multiple regression analyses were carried out. RESULTS: The medical records of 179 patients were reviewed. The patients' median age was 63 years ranging from 15-96 years, and 116 (64.8%) of them were male. The one-year survival rate was 39% and the 5-year survival was 10%. The median overall survival (OS) was 6.9 months. Age at diagnosis, grade, T stage, N stage, M stage, TNM stage group, and the combined stage group (stage III/IV versus others), site of distant metastasis, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9, surgery and chemotherapy were significant predictors for OS on an univariate Cox proportional hazards regression analysis. A multiple regression model including all the significant predictors was conducted. Age at the time of diagnosis and M stage were significant variables. CONCLUSION: Our patients present at a younger age and have better 5-year survival compared with the United States Surveillance Epidemiology and End Results data, which deserves further evaluation. Age and disease stage were identified as independent prognostic factors for survival in this patient population.