Microsatellite Instability and Mismatch Repair Deficiency Define a Distinct Subset of Lung Cancers Characterized by Smoking Exposure, High Tumor Mutational Burden, and Recurrent Somatic MLH1 Inactivation.

INTRODUCTION: Microsatellite instability (MSI) and mismatch repair (MMR) deficiency represent a distinct oncogenic process and predict response to immune checkpoint inhibitors (ICIs). The clinicopathologic features of MSI-high (MSI-H) and MMR deficiency (MMR-D) in lung cancers remain poorly characterized. METHODS: MSI status from 5171 patients with NSCLC and 315 patients with SCLC was analyzed from targeted next-generation sequencing data using two validated bioinformatic pipelines. RESULTS: MSI-H and MMR-D were identified in 21 patients with NSCLC (0.41%) and six patients with SCLC (1.9%). Notably, all patients with NSCLC had a positive smoking history, including 11 adenocarcinomas. Compared with microsatellite stable cases, MSI-H was associated with exceptionally high tumor mutational burden (37.4 versus 8.5 muts/Mb, p < 0.0001), MMR mutational signatures (43% versus 0%, p < 0.0001), and somatic biallelic alterations in MLH1 (52% versus 0%, p < 0.0001). Loss of MLH1 and PMS2 expression by immunohistochemistry was found in MLH1 altered and wild-type cases. Similarly, the majority of patients with MSI-H SCLC had evidence of MLH1 inactivation, including two with MLH1 promoter hypermethylation. A single patient with NSCLC with a somatic MSH2 mutation had Lynch syndrome as confirmed by the presence of a germline MSH2 mutation. Among patients with advanced MSI-H lung cancers treated with ICIs, durable clinical benefit was observed in three of eight patients with NSCLC and two of two patients with SCLC. In NSCLC, STK11, KEAP1, and JAK1 were mutated in nonresponders but wild type in responders. CONCLUSIONS: We present a comprehensive clinicogenomic landscape of MSI-H lung cancers and reveal that MSI-H defines a rare subset of lung cancers associated with smoking, high tumor mutational burden, and MLH1 inactivation. Although durable clinical benefit to ICI was observed in some patients, the broad range of responses suggests that clinical activity may be modulated by co-mutational landscapes.

Hypoglossal Nerve Transfer for Facial Nerve Paralysis: A Systematic Review and Meta-Analysis.

Background: Hypoglossal-facial nerve (12-7) anastomosis can restore symmetry and voluntary movement on the face in patients with facial nerve paralysis. Traditional 12-7 transfer includes direct end-to-end nerve anastomosis, sacrificing the entire hypoglossal nerve. Contemporary, end-to-side anastomosis, or split anastomosis techniques limit tongue morbidity by preserving some hypoglossal nerve. Direct outcome comparisons between these techniques are limited. Objective: To compare reported outcomes of facial movement, tongue, speech, and swallow outcomes among the different types of hypoglossal-facial nerve anastomosis schemes. Evidence Review: For this systematic review and meta-analysis, a comprehensive strategy was designed to search PubMed, Scopus, and the Cochrane Database from inception to January 2021, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis, reporting guideline yielding 383 results. Any participant who underwent 12-7 transfer using any of the three techniques, with or without an interposition graft, and had documented preoperative and postoperative evaluation of facial nerve function with a validated instrument such as House-Brackmann (HB), was considered for inclusion. Secondary outcomes of synkinesis, tongue atrophy, and speech or swallowing dysfunction were also compared. Forty-nine studies met inclusion criteria, representing data from 961 total patients who underwent 12-7 transfer. Results: The proportion of good HB outcomes (HB I-III) did not differ by anastomosis type: End-to-side and end-to-end anastomosis (73% vs. 59%, p = 0.07), split and end-to-end anastomosis (62% vs. 59%, p = 0.88), and end-to-side anastomosis and split anastomosis (73% vs. 62%, p = 0.46). There was no difference in reported synkinesis rates between the anastomosis types. However, end-to-side anastomosis (z = 6.55, p < 0.01) and split anastomosis (z = 3.58, p < 0.01) developed less tongue atrophy than end-to-end anastomosis. End-to-side anastomosis had less speech/swallowing dysfunction than end-to-end anastomosis (z = 3.21, p < 0.01). Conclusion: End-to-side and split anastomoses result in similar HB facial nerve outcomes as the traditional end-to-end 12-7 anastomosis. End-to-side anastomosis has decreased complications of tongue atrophy and speech/swallow dysfunction compared to end-to-end anastomosis. In addition, split anastomosis has decreased rates of tongue atrophy compared to end-to-end anastomosis.

Advances and Challenges of the Decade: The Ever-Changing Clinical and Genetic Landscape of Immunodeficiency.

In the past 10 years, we have witnessed major advances in clinical immunology. Newborn screening for severe combined immunodeficiency has become universal in the United States and screening programs are being extended to severe combined immunodeficiency and other inborn errors of immunity globally. Early genetic testing is becoming the norm for many of our patients and allows for informed selection of targeted therapies including biologics repurposed from other specialties. During the COVID-19 pandemic, our understanding of essential immune responses expanded and the discovery of immune gene defects continued. Immunoglobulin products, the backbone of protection for antibody deficiency syndromes, came into use to minimize side effects. New polyclonal and monoclonal antibody products emerged with increasing options to manage respiratory viral agents such as SARS-CoV-2 and respiratory syncytial virus. Against these advances, we still face major challenges. Atypical is becoming typical as phenotypes of distinct genetic disease overlap whereas the clinical spectrum of the same genetic defect widens. Therefore, clinical judgment needs to be paired with repeated deep immune phenotyping and upfront genetic testing, as technologies rapidly evolve, and clinical disease often progresses with age. Managing patients with organ damage resulting from immune dysregulation poses a special major clinical challenge and management often lacks standardization, from autoimmune cytopenias, granulomatous interstitial lung disease, enteropathy, and liver disease to endocrine, rheumatologic, and neurologic complications. Clinical, translational, and basic science networks will continue to advance the field; however, cross-talk and education with practicing allergists/immunologists are essential to keep up with the ever-changing clinical and genetic landscape of inborn errors of immunity.

Preserving Nasal Tip Rotation and Projection in Open Septorhinoplasty.

Background: Open septorhinoplasty is a common facial plastic surgery procedure that requires extensive planning and knowledge to achieve predictable outcomes. Many patients want to keep their nasal tip characteristics, and the surgeon's task is to reliably meet this expectation and provide stable long-term results. Techniques used to reconstruct nasal tip support include the tongue-in-groove, caudal septal extension graft, and caudal septal replacement graft procedures. Methods: We assessed the 1-year reliability of tongue-in-groove, caudal septal extension graft, and caudal septal replacement graft procedures in maintaining nasal tip rotation and projection in open septorhinoplasty. We conducted a retrospective case series review of septorhinoplasty cases between 2015 and 2019 at the Medical University of South Carolina. Cases with intention to change nasal tip rotation or projection were excluded. Two blinded reviewers analyzed standardized preoperative and 1-year postoperative photographs. Results: Fifty-seven patients fit the inclusion criteria and were included in the analysis. Mean preoperative and postoperative nasal tip rotations and projection ratios were similar (P=0.62, P=0.22, respectively). Twenty-six patients underwent a tongue-in-groove procedure, 24 had a caudal septal extension graft, and 7 had a caudal septal replacement graft with preoperative nasal tip rotations of 98.93°, 99.35°, and 96.89°, respectively (P=0.73). At 1 year, patients who received a tongue-in-groove procedure had a significant increase in nasal tip rotation to 101.24° (P=0.013), while patients who received a caudal septal extension graft had a significant decrease in nasal tip rotation to 97.25° (P=0.009). Patients who received a caudal septal replacement graft had no significant change in nasal tip rotation (P=0.117). The preoperative and postoperative projection ratios were not significantly different among the 3 techniques. Conclusion: Tongue-in-groove, caudal septal extension graft, and caudal septal replacement graft are reliable techniques for maintaining nasal tip projection in open septorhinoplasty. In our experience, when attempting to maintain preoperative nasal tip rotation, the tongue-in-groove technique resulted in a significant increase in tip rotation of 2.31°, while the caudal septal extension graft resulted in a significant decrease of 2.1° at 1 year postoperatively.

Masseteric-to-facial nerve transfer for treatment of pediatric facial paralysis: An initial report.

OBJECTIVES: The indications and outcomes of masseteric-to-facial nerve transfer in pediatric patients with short-term facial paralysis is incompletely understood as compared to its use in adult patients. This report aims to retrospectively quantify outcomes with both clinician-based measurements and objective facial analysis software. METHODS: Retrospective case series at a single institution. The Sunnybrook Facial Grading System was used for clinician-based measurements and Emotrics software for objective measurements. RESULTS: Four pediatric patients underwent masseteric-to-facial nerve transfers from 2016 to 2018. The mean patient age at the time of surgery was 4.5 years (range = 2-7) and the mean time from paralysis onset to surgical intervention was 12.9 months (range = 10.0-16.2). The mean follow-up was 18.3 months (range = 14.5-23.6). With regards to the Sunnybrook resting nasolabial fold symmetry, 3 of the 4 patients improved from 2 (absent nasolabial fold) to 1 (less pronounced nasolabial fold). Per the Emotrics analysis, the pre- and post-operative mean absolute differences for commissure excursion between the normal functioning and paralyzed sides were 11.8 mm and 6.7 mm, respectively (p = 0.04). CONCLUSION: The masseteric-to-facial nerve transfer technique leads to an objective improvement in dynamic smile function in select pediatric patients.

SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression.

Sterile α motif domain-containing protein 9-like (SAMD9L) is encoded by a hallmark interferon-induced gene with a role in controlling virus replication that is not well understood. Here, we analyze SAMD9L function from the perspective of human mutations causing neonatal-onset severe autoinflammatory disease. Whole-genome sequencing of two children with leukocytoclastic panniculitis, basal ganglia calcifications, raised blood inflammatory markers, neutrophilia, anemia, thrombocytopaenia, and almost no B cells revealed heterozygous de novo SAMD9L mutations, p.Asn885Thrfs*6 and p.Lys878Serfs*13. These frameshift mutations truncate the SAMD9L protein within a domain a region of homology to the nucleotide-binding and oligomerization domain (NOD) of APAF1, ∼80 amino acids C-terminal to the Walker B motif. Single-cell analysis of human cells expressing green fluorescent protein (GFP)-SAMD9L fusion proteins revealed that enforced expression of wild-type SAMD9L repressed translation of red fluorescent protein messenger RNA and globally repressed endogenous protein translation, cell autonomously and in proportion to the level of GFP-SAMD9L in each cell. The children's truncating mutations dramatically exaggerated translational repression even at low levels of GFP-SAMD9L per cell, as did a missense Arg986Cys mutation reported recurrently as causing ataxia pancytopenia syndrome. Autoinflammatory disease associated with SAMD9L truncating mutations appears to result from an interferon-induced translational repressor whose activity goes unchecked by the loss of C-terminal domains that may normally sense virus infection.

Integrated digital pathology at scale: A solution for clinical diagnostics and cancer research at a large academic medical center.

OBJECTIVE: Broad adoption of digital pathology (DP) is still lacking, and examples for DP connecting diagnostic, research, and educational use cases are missing. We blueprint a holistic DP solution at a large academic medical center ubiquitously integrated into clinical workflows; researchapplications including molecular, genetic, and tissue databases; and educational processes. MATERIALS AND METHODS: We built a vendor-agnostic, integrated viewer for reviewing, annotating, sharing, and quality assurance of digital slides in a clinical or research context. It is the first homegrown viewer cleared by New York State provisional approval in 2020 for primary diagnosis and remote sign-out during the COVID-19 (coronavirus disease 2019) pandemic. We further introduce an interconnected Honest Broker for BioInformatics Technology (HoBBIT) to systematically compile and share large-scale DP research datasets including anonymized images, redacted pathology reports, and clinical data of patients with consent. RESULTS: The solution has been operationally used over 3 years by 926 pathologists and researchers evaluating 288 903 digital slides. A total of 51% of these were reviewed within 1 month after scanning. Seamless integration of the viewer into 4 hospital systems clearly increases the adoption of DP. HoBBIT directly impacts the translation of knowledge in pathology into effective new health measures, including artificial intelligence-driven detection models for prostate cancer, basal cell carcinoma, and breast cancer metastases, developed and validated on thousands of cases. CONCLUSIONS: We highlight major challenges and lessons learned when going digital to provide orientation for other pathologists. Building interconnected solutions will not only increase adoption of DP, but also facilitate next-generation computational pathology at scale for enhanced cancer research.

Prelaminated paramedian forehead flap for subtotal nasal reconstruction using three-dimensional printing.

Nasal reconstruction following a total or subtotal resection presents a challenging clinical scenario. Ample external skin coverage is readily available using the paramedian forehead flap (PMFF), but restoring adequate internal lining of sufficient size and pliability is a major limitation. Intranasal mucosal flaps or free tissue transfer is often employed for this purpose, each with their own sets of limitations. Prelamination of the PMFF with a skin graft prior to transfer is a method to create a composite flap with both internal and external lining. Another challenge in subtotal nasal reconstruction centres around restoring adequate dimensions to the nose without an existing template to work from. Three-dimensional (3D) printing has become an increasingly popular tool in reconstructive surgery as it captures precise patient-specific dimensions to guide reconstruction. Herein, we describe a case of subtotal nasal reconstruction using a prelaminated PMFF using a patient-specific 3D printed model as a template for reconstruction.

Characterization of dysphagia following anterior cervical spine surgery.

BACKGROUND: Post-operative dysphagia is one of the most common complications of anterior cervical spine surgery (ACSS). OBJECTIVE: Examine post-operative structural and physiologic swallowing changes in patients with dysphagia following ACSS as compared with healthy age and gender matched controls. METHODS: Videofluoroscopic swallow studies of adults with dysphagia after ACSS were retrospectively reviewed. Seventy-five patients were divided into early (≤2 months) and late (> 2 months) post-surgical groups. Modified Barium Swallow Impairment Profile (MBSImP), Penetration-Aspiration Scale (PAS) scores, and pharyngeal wall thickness (PWT) metrics were compared. RESULTS: Significant differences were identified for all parameters between the control and early post-operative group. MBSImP Pharyngeal Total (PT) scores were greater in the early group (Interquartile Range (IQR) = 9-14, median = 12) versus controls (4-7, 5, P < 0.001) and late group (0.75-7.25, 2, P < 0.001). The early group had significantly higher maximum PAS scores (IQR = 3-8, median = 7) than both the control group (1-2, 1, P < 0.001) and late post-operative group (1-1.25, 1, P < 0.001). PWT was significantly greater in the early (IQR = 11.12-17.33 mm, median = 14.32 mm) and late groups (5.31-13.01, 9.15 mm) than controls (3.81-5.41, 4.68 mm, P < 0.001). CONCLUSION: Dysphagic complaints can persist more than two months following ACSS, but often do not correlate with validated physiologic swallowing dysfunction on VFSS. Future studies should focus on applications of newer technology to elucidate relevant deficits.

Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency.

Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.

Giant cell myocarditis causing sudden death in a patient with sarcoidosis.

Giant cell myocarditis (GCM) is a rare and rapidly fatal cardiovascular condition most often seen in young adults. It is characterized microscopically by myocardial necrosis with multinucleated giant cells in the absence of well-defined granulomas. This disorder has typically been attributed to manifest as heart failure, but in some individuals, GCM may present as sudden cardiac death. Herein, we present a fatal case of GCM in a 36-year-old male with a history of autoimmune disorders. The decedent presented to the emergency room due to vomiting and was treated for nausea due to suspected dehydration. He was discharged that night and found dead on his bathroom floor the following day. Postmortem examination revealed psoriasis and granulomatous lesions in the lungs consistent with sarcoidosis, further supporting circumstantial evidence existing between GCM and autoimmune disorders. Additionally, this case provides an opportunity to distinguish GCM from the distinct clinical entity of cardiac sarcoidosis (CS), especially in the setting of systemic sarcoidosis. We hope to raise awareness of this rare disease process and its potential to cause sudden cardiac death so that it may be considered in a differential diagnosis as immunosuppression and early cardiac transplantation largely determine the prognosis.

Giant cell myocarditis causing sudden death in a patient with sarcoidosis

Giant cell myocarditis (GCM) is a rare and rapidly fatal cardiovascular condition most often seen in young adults. It is characterized microscopically by myocardial necrosis with multinucleated giant cells in the absence of well-defined granulomas. This disorder has typically been attributed to manifest as heart failure, but in some individuals, GCM may present as sudden cardiac death. Herein, we present a fatal case of GCM in a 36-year-old male with a history of autoimmune disorders. The decedent presented to the emergency room due to vomiting and was treated for nausea due to suspected dehydration. He was discharged that night and found dead on his bathroom floor the following day. Postmortem examination revealed psoriasis and granulomatous lesions in the lungs consistent with sarcoidosis, further supporting circumstantial evidence existing between GCM and autoimmune disorders. Additionally, this case provides an opportunity to distinguish GCM from the distinct clinical entity of cardiac sarcoidosis (CS), especially in the setting of systemic sarcoidosis. We hope to raise awareness of this rare disease process and its potential to cause sudden cardiac death so that it may be considered in a differential diagnosis as immunosuppression and early cardiac transplantation largely determine the prognosis.

Molecular Analysis of Goodpasture's Disease Following Hematopoietic Stem Cell Transplant in a Pediatric Patient, Recalls the Conformeropathy of Wild-Type Anti-GBM Disease.

Background: Goodpasture's disease (GP) is mediated by autoantibodies that bind the glomerular and alveolar basement membrane, causing rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. The autoantibodies bind neoepitopes formed upon disruption of the quaternary structure of α345NC1 hexamer, a critical structural domain of α345 collagen IV scaffolds. Hexamer disruption leads to a conformational changes that transitions α3 and α5NC1 subunits into immunogens, however, the trigger remains unknown. This contrasts with another anti-GBM disease, Alports' post-transplant nephritis (APTN), where the pathogenic alloantibody binds directly to native NC1 hexamer. The current report includes the first study of antigenic specificity and allo-incompatability in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). Results: The anti-GBM antibodies were found to be directed predominantly against the EA epitope of the α3 NC1 monomer of collagen IV and developed rapidly in patient serum reaching peak level within 5 weeks. Autoantibody binding to native α345NC1 hexamer was minimal; however, binding was greatly increased upon dissociation of the native hexamer. There were no polymorphic genetic differences between donor and recipient collagen IV genes which would be predicted to cause a significant NC1 conformational change or to provide a target for antibody binding. Both patient and donor possessed the Goodpasture's susceptibility HLA-allele DRB1*1501. Conclusions: The current report includes the first in-depth study of allo-incompatability and antigenic specificity in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). No polymorphic genetic differences were identified between donor and recipient collagen IV genes which would be predicted to provide a target for antibody binding. Furthermore, autoantibody binding to native α345NC1 hexamer was minimal, increasing greatly upon dissociation of the native hexamer, resembling wild-type GP diseases and marking this as the first example of a post-HSCT conformeropathy.

Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity.

Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.

Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients.

Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αß T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency.

BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival.

Haematopoietic stem cell transplantation for primary immunodeficiency syndromes: A 5-year single-centre experience.

AIM: Haematopoietic stem cell transplantation (HSCT) is a central therapy in the treatment of primary immunodeficiency diseases (PIDs). Over the past 5 years, outcomes have been greatly improved due to earlier diagnosis, improved donor availability, advancements in graft manipulation and the use of less toxic preparative regimens. We present a 5-year audit of HSCT for PID at a single Australian tertiary hospital. METHODS: Retrospective case note review identified diagnosis, pre-transplant medical morbidity, transplant protocol, engraftment, adverse events, post-transplant immune reconstitution and general health. RESULTS: A total of 22 patients with PID underwent 24 HSCTs at our institution between 2012 and 2016. The most common indications were severe combined immunodeficiency, chronic granulomatous disease and familial haemophagocytic lymphohistiocytosis, with a genetic diagnosis in all but two patients. Reduced intensity or reduced toxicity conditioning was used in 91% of cases, and 75% of the donors were unrelated. Transplant-related mortality at day +100 was 9.5%, and cumulative overall survival was 86%. There were three mortalities, all secondary to viral infection, one of which occurred in the context of graft failure. Two patients remained on immune support, with the remainder achieving adequate immune reconstitution. CONCLUSIONS: The outcomes for HSCT for PIDs performed at Sydney Children's Hospital were in line with the world's best practice. HSCT should be considered a potential therapeutic option for all Australian PID patients with a valid disease indication.

Haematopoietic stem cell transplantation for severe combined immunodeficiency: Long-term health outcomes and patient perspectives.

AIM: To examine the long-term follow-up and health outcomes of patients who have undergone haematopoietic stem cell transplant (HSCT) for severe combined immunodeficiency (SCID). METHODS: Through a structured questionnaire, we examined follow-up arrangements and long-term health outcomes in 22 children who have had a successful HSCT for SCID during the period of 1984-2012 at the Sydney Children's Hospital, Sydney, Australia. RESULTS: Most children considered themselves healthy and 'cured' from SCID. Whilst many children enjoy relatively good bio-social health outcomes, specific negative health outcomes and absenteeism from school were perceived negatively. Two-thirds of children see their general practitioner or specialist regularly; however, there did not appear to be consistency with the nature of this follow-up. CONCLUSION: The findings from our study highlight the complex bio-psychosocial health needs of post-HSCT SCID children and encourage SCID centres to consider a multidisciplinary approach to their follow-up. Further studies into the determinants of patients' perceptions of their health are needed.

Early infant male circumcision: Systematic review, risk-benefit analysis, and progress in policy.

AIM: To determine whether recent evidence-based United States policies on male circumcision (MC) apply to comparable Anglophone countries, Australia and New Zealand. METHODS: Articles in 2005 through 2015 were retrieved from PubMed using the keyword "circumcision" together with 36 relevant subtopics. A further PubMed search was performed for articles published in 2016. Searches of the EMBASE and Cochrane databases did not yield additional citable articles. Articles were assessed for quality and those rated 2+ and above according to the Scottish Intercollegiate Grading System were studied further. The most relevant and representative of the topic were included. Bibliographies were examined to retrieve further key references. Randomized controlled trials, recent high quality systematic reviews or meta-analyses (level 1++ or 1+ evidence) were prioritized for inclusion. A risk-benefit analysis of articles rated for quality was performed. For efficiency and reliability, recent randomized controlled trials, meta-analyses, high quality systematic reviews and large well-designed studies were used if available. Internet searches were conducted for other relevant information, including policies and Australian data on claims under Medicare for MC. RESULTS: Evidence-based policy statements by the American Academy of Pediatrics (AAP) and the Centers for Disease Control and Prevention (CDC) support infant and later age male circumcision (MC) as a desirable public health measure. Our systematic review of relevant literature over the past decade yielded 140 journal articles that met our inclusion criteria. Together, these showed that early infant MC confers immediate and lifelong benefits by protecting against urinary tract infections having potential adverse long-term renal effects, phimosis that causes difficult and painful erections and "ballooning" during urination, inflammatory skin conditions, inferior penile hygiene, candidiasis, various sexually transmissible infections in both sexes, genital ulcers, and penile, prostate and cervical cancer. Our risk-benefit analysis showed that benefits exceeded procedural risks, which are predominantly minor, by up to 200 to 1. We estimated that more than 1 in 2 uncircumcised males will experience an adverse foreskin-related medical condition over their lifetime. Wide-ranging evidence from surveys, physiological measurements, and the anatomical location of penile sensory receptors responsible for sexual sensation strongly and consistently suggested that MC has no detrimental effect on sexual function, sensitivity or pleasure. United States studies showed that early infant MC is cost saving. The evidence supporting early infant MC has further strengthened since the positive AAP and CDC reviews. CONCLUSION: Affirmative MC policies are needed in Australia and New Zealand. Routine provision of accurate, unbiased education, and access in public hospitals, will maximize health and financial benefits.