Management of children and adults with all stages of nodular lymphocyte predominant Hodgkin lymphoma - All StAGEs: A consensus-based position paper from the Hodgkin lymphoma subgroup of the UK National Cancer Research Institute.

A consensus statement for the management for patients of all ages with all stages of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) - All StAGEs - is proposed by representatives of the UK National Cancer Research Institute (NCRI) Hodgkin lymphoma study group and the Children's Cancer & Leukaemia Group. Based on current practices and published evidence, a consensus has been reached regarding diagnosis, staging and risk-ik7 stratified management which includes active surveillance, low- and standard-dose immunochemotherapy and radiotherapy.

Bi-allelic mutation of CTNNB1 causes a severe form of syndromic microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia.

BACKGROUND: Inherited vitreoretinopathies arise as a consequence of congenital retinal vascularisation abnormalities. They represent a phenotypically and genetically heterogeneous group of disorders that can have a major impact on vision. Several genes encoding proteins and effectors of the canonical Wnt/ß-catenin pathway have been associated and precise diagnosis, although difficult, is essential for proper clinical management including syndrome specific management where appropriate. This work aimed to investigate the molecular basis of disease in a single proband born to consanguineous parents, who presented with microphthalmia, persistent foetal vasculature, posterior lens vacuoles, vitreoretinal dysplasia, microcephaly, hypotelorism and global developmental delay, and was registered severely visually impaired by 5 months of age. METHODS: Extensive genomic pre-screening, including microarray comparative genomic hybridisation and sequencing of a 114 gene panel associated with cataract and congenital ophthalmic disorders was conducted by an accredited clinical laboratory. Whole exome sequencing (WES) was undertaken on a research basis and in vitro TOPflash transcriptional reporter assay was utilised to assess the impact of the putative causal variant. RESULTS: In the proband, WES revealed a novel, likely pathogenic homozygous mutation in the cadherin-associated protein beta-1 gene (CTNNB1), c.884C>G; p.(Ala295Gly), which encodes a co-effector molecule of the Wnt/ß-catenin pathway. The proband's parents were shown to be heterozygous carriers but ophthalmic examination did not detect any abnormalities. Functional assessment of the missense variant demonstrated significant reduction of ß-catenin activity. CONCLUSIONS: This is the first report of a biallelic disease-causing variation in CTNNB1. We conclude that this biallelic, transcriptional inactivating mutation of CTNNB1 causes a severe, syndromic form of microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia that results in serious visual loss in infancy.

Arterial malformations leading to bilateral spontaneous renal hemorrhage in a dog.

OBJECTIVE: To describe the clinical presentation, diagnostic imaging, management, and follow-up of a dog that presented with sequential, bilateral, spontaneous, subcapsular and perirenal hemorrhage (Wunderlich syndrome) due to bilateral renal arterial malformations. CASE SUMMARY: A 9-year-old intact male Field Spaniel presented for acute onset abdominal pain following a possible syncopal episode. Abdominal ultrasonography, contrast-enhanced ultrasound, and computed tomography (CT) revealed right-sided perirenal hemorrhage that extended into the peritoneum. The dog was discharged following stabilization with analgesia, fluid therapy, and tranexamic acid. One month later, the patient presented with identical clinical signs. A CT scan at this stage revealed bilateral kidney infarcts with new left-sided perirenal hemorrhage. Abdominal ultrasound and contrast-enhanced ultrasound were repeated and showed similar findings. Follow up with four-dimensional CT angiography revealed bilateral renal arterial malformations, likely causing spontaneous renal hemorrhage and secondary subcapsular hematomas , retroperitoneal and peritoneal hemorrhage. UNIQUE INFORMATION PROVIDED: This is the first reported case of both bilateral renal arterial malformations and bilateral spontaneous subcapsular and perirenal hemorrhage in the absence of neoplasia, coagulopathy, or trauma in a dog. Advanced imaging modalities, including selective angiography, were required to diagnose this condition successfully. Arterial malformations should be considered as a differential diagnosis in cases of hemoretroperitoneum. Nephrectomy due to perirenal hemorrhage should be cautiously considered, especially in the absence of angiography, because of the sequential bilateral nature of this case. Conservative management in this case resulted in a good long-term outcome 10 months later.

Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia.

Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We, therefore, investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of cell state accounts for a significant component of bottleneck selection during induction chemotherapy.

Retrospective evaluation of refeeding syndrome in cats: 11 cases (2013-2019).

OBJECTIVES: The aim of this study was to describe the clinicopathological findings, management and outcome of cats with refeeding syndrome (RS) following prolonged starvation. METHODS: Records from four referral hospitals were searched between May 2013 and November 2019 and retrospectively evaluated. Inclusion criteria were the presence of a risk factor for RS, such as severe weight loss or emaciation following a period of presumed starvation, hypophosphataemia or a delta phosphorous exceeding 30% reduction following refeeding, being treated on the basis of a clinical diagnosis of RS and one or more derangement of hypokalaemia, hypoglycaemia or hyperglycaemia. RESULTS: Eleven cats were identified, which had been missing for a median of 6 weeks (range 3-104 weeks). Mean ± SD percentage weight loss was 46% ± 7% (n = 8). Eight of 11 cats developed hypophosphataemia with a mean delta phosphorous of -47% ± 9%. All cats were documented to be hypokalaemic. During hospitalisation, 10/11 cats developed hyperglycaemia and 7/11 cats developed hypoglycaemia. Cardiovascular, gastrointestinal and neurological signs were common. Eight of 11 cats displayed new or progressive neurological deficits after refeeding, including mentation changes and cerebellar dysfunction. All cats became anaemic and seven cats required a blood transfusion. Eight cats survived to discharge after a mean of 14 ± 4 days of hospitalisation. Six cats developed acute kidney injury (AKI; International Renal Interest Society stage 1). The presence of AKI (P = 0.024) was associated with non-survival and maximum bilirubin concentration was significantly higher in non-survivors (P = 0.018). CONCLUSIONS AND RELEVANCE: Cats with RS in this cohort had been missing, presumed starved, for more than 3 weeks. In addition to hypophosphataemia and hypokalaemia, altered glucose homeostasis and organ damage involving the liver and kidneys were common. Cats with RS appear to have a good prognosis, but prolonged intensive care is required.

CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing.

BACKGROUND: Identification of CNVs through chromosomal microarray (CMA) testing is the first-line investigation in individuals with learning difficulties/congenital abnormalities. Although recognised that CMA testing may identify CNVs encompassing a cancer predisposition gene (CPG), limited information is available on the frequency and nature of such results. METHODS: We investigated CNV gains and losses affecting 39 CPGs in 3366 pilot index case individuals undergoing CMA testing, and then studied an extended cohort (n=10 454) for CNV losses at 105 CPGs and CNV gains at 9 proto-oncogenes implicated in inherited cancer susceptibility. RESULTS: In the pilot cohort, 31/3366 (0.92%) individuals had a CNV involving one or more of 16/39 CPGs. 30/31 CNVs involved a tumour suppressor gene (TSG), and 1/30 a proto-oncogene (gain of MET). BMPR1A, TSC2 and TMEM127 were affected in multiple cases. In the second stage analysis, 49/10 454 (0.47%) individuals in the extended cohort had 50 CNVs involving 24/105 CPGs. 43/50 CNVs involved a TSG and 7/50 a proto-oncogene (4 gains, 3 deletions). The most frequently involved genes, FLCN (n=10) and SDHA (n=7), map to the Smith-Magenis and cri-du-chat regions, respectively. CONCLUSION: Incidental identification of a CNV involving a CPG is not rare and poses challenges for future cancer risk estimation. Prospective data collection from CPG-CNV cohorts ascertained incidentally and through syndromic presentations is required to determine the risks posed by specific CNVs. In particular, ascertainment and investigation of adults with CPG-CNVs and adults with learning disability and cancer, could provide important information to guide clinical management and surveillance.

Exploring the feasibility of delivering standardized genomic care using ophthalmology as an example.

PURPOSE: Broadening access to genomic testing and counseling will be necessary to realize the benefits of personalized health care. This study aimed to assess the feasibility of delivering a standardized genomic care model for inherited retinal dystrophy (IRD) and of using selected measures to quantify its impact on patients. METHODS: A pre-/post- prospective cohort study recruited 98 patients affected by IRD to receive standardized multidisciplinary care. A checklist was used to assess the fidelity of the care process. Three patient-reported outcome measures-the Genetic Counselling Outcome Scale (GCOS-24), the ICEpop CAPability measure for Adults (ICECAP-A), and the EuroQol 5-dimension questionnaire (EQ-5D)-and a resource-use questionnaire were administered to investigate rates of missingness, ceiling effects, and changes over time. RESULTS: The care model was delivered consistently. Higher rates of missingness were found for the genetic-specific measure (GCOS-24). Considerable ceiling effects were observed for the generic measure (EQ-5D). The ICECAP-A yielded less missing data without significant ceiling effects. It was feasible to use telephone interviews for follow-up data collection. CONCLUSION: The study highlighted challenges and solutions associated with efforts to standardize genomic care for IRD. The study identified appropriate methods for a future definitive study to assess the clinical effectiveness and cost-effectiveness of the care model.Genet Med advance online publication 02 March 2017.

Advanced stage nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents: clinical characteristics and treatment outcome - a report from the SFCE & CCLG groups.

Advanced stage nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) is extremely rare in children and as a consequence, optimal treatment for this group of patients has not been established. Here we retrospectively evaluated the treatments and treatment outcomes of 41 of our patients from the UK and France with advanced stage nLPHL. Most patients received chemotherapy, some with the addition of the anti CD20 antibody rituximab or radiotherapy. Chemotherapy regimens were diverse and followed either classical Hodgkin lymphoma or B non-Hodgkin lymphoma protocols. All 41 patients achieved a complete remission with first line treatment and 40 patients are alive and well in remission. Eight patients subsequently relapsed and 1 patient died of secondary cancer (9 progression-free survival events). The median time to progression for those who progressed was 21 months (5·9-73·8). The median time since last diagnosis is 87·3 months (8·44-179·20). Thirty-six (90%), 30 (75%) and 27 (68%) patients have been in remission for more than 12, 24 and 36 months, respectively. Overall, the use of rituximab combined with multi-agent chemotherapy as first line treatment seems to be a reasonable therapeutic option.

Relapsed or poorly responsive nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents - a report from the United Kingdom's Children's Cancer and Leukaemia Study Group.

There is a paucity of data on the treatment outcome in children with relapsed or poorly responsive nodular lymphocyte predominant Hodgkin lymphoma (nLPHL). This retrospective report evaluates the treatment outcome in a national cohort of children with relapsed or poorly responsive nLPHL. A total of 37 patients, 22 with relapsed and 15 with poorly responding disease, are the subjects of this report. Of the 22 patients with relapsed nLPHL, 11 had relapsed after primary excision biopsy, 10 after chemotherapy and 1 after chemotherapy and involved field radiotherapy. The majority had localized disease at relapse. The median time to relapse was 8 months after chemotherapy and 11 months after excision biopsy. Seven of the 15 patients with poorly responding nLPHL had variant histology. Three patients with initial poor response did not receive any further treatment and have had no disease progression. Transformation to diffuse large B cell lymphoma, in addition to evolution from typical to variant nLPHL occurred in one patient each. Thirty-four patients have been successfully re-treated with second chemotherapy or radiotherapy. Multiple relapses were uncommon but treatable. Relapse or poorly responsive nLPHL is fully salvageable with either additional chemotherapy and or radiotherapy.

Childhood and Adolescent nodular lymphocyte predominant Hodgkin lymphoma - A review of clinical outcome based on the histological variants.

Nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) comprises approximately 10-12% of all childhood Hodgkin lymphoma. As the majority have low stage disease recent years have seen a de-escalation of treatment intensity to avoid treatment-related morbidity. This report evaluates treatment outcome in children with histopathological variants of nLPHL after therapy de-escalation. Biopsies from 60 patients were reviewed and histology categorized as typical (n = 47; 78%) or variant nLPHL (n = 13; 22%). Furthermore, presence of immunoglobulin D (IgD) expression by the lymphocyte predominant (LP) cells was assessed in 41 patients. Treatment outcomes were compared according to treatment received and histopathology of nLPHL. Compared to typical nLPHL, children with variant nLPHL had higher stage disease at diagnosis (stage III: 3/13; 23% vs. 3/47; 6%, P = 0·11), lower complete response rates (6/13; 46% vs. 38/47; 81%, P = 0·029) and higher relapse rates (2/13; 15% vs. 2/47; 4%, P = 0·20). Additionally, IgD expression by LP cells was associated with poorer treatment response and was more commonly seen in patients with variant nLPHL. (11/13; 85% vs. 15/28; 54%, P = 0·08). Variant histology appears to be indicative of a poorer prognosis in patients with early stage disease, and may be an important factor to take into account when moving towards reduced intensity treatment for nLPHL.

Incidence, management, and outcome of high-grade transformation of nodular lymphocyte predominant Hodgkin lymphoma: long-term outcomes from a 30-year experience.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare form of Hodgkin lymphoma that typically presents as early stage, indolent disease in young adult males. The relationship between NLPHL and DLBCL is incompletely understood, and there remains a paucity of data with regard the incidence and management of high-grade transformation. We report the largest study to date describing the incidence, management and long-term outcome of 26 cases of high-grade transformation of NLPHL over a 30-year period. We report a transformation incidence of 17.0%. Bone marrow, splenic, and liver infiltration with DLBCL was frequent. Patients with an aa-IPI 2-3 have poorer OS and PFS (P = 0.034 and P = 0.009, respectively). Although the approach to treatment was somewhat variable, typically young, otherwise fit patients received anthracycline-based induction, platinum-based consolidation with stem cell harvesting, followed by autologous SCT with BEAM conditioning. Long-term (5 year) PFS was over 60% with this approach, and comparable to our de novo DLBCL historical age and time period-matched cohort largely treated with CHOP-like chemotherapy alone. The transformation rate of 17.0% highlights the importance of accurate initial diagnosis, long-term follow-up, and re-biopsy at relapse.

Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: current and future perspectives in adult and paediatric disease.

Anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma seen in both adults and children. ALCL is associated with a characteristic chromosomal translocation, t(2;5)(p23;35) which fuses the anaplastic lymphoma kinase (ALK) gene on chromosome 2 with the nucleophosmin (NPM) gene on chromosome 5, resulting in a NPM-ALK fusion protein, ALK over-expression and constitutive tyrosine kinase activity. This aggressive lymphoma is more prevalent in males and can present with extranodal involvement (lung, skin and marrow infiltration) and haemophagocytic lymphohistocytosis. The long-term overall survival is approximately 70-90% in children and over 70% in adults. Staging systems and prognostic risk factors are different in both childhood and adult ALCL. Treatment in adults is typically anthracycline-based, with autologous stem cell transplantation (ASCT) salvaging patients in relapsed disease. There is evidence for ALL-like therapy or intensive, pulsed anthracycline-based induction in children. ASCT, allogeneic SCT and vinblastine maintenance are all considered reasonable options in relapsed childhood disease. The anti-CD30 immunoconjugate Brentuximab Vedotin and the specific ALK inhibitor Crizotinib are changing the treatment paradigm in ALCL (ALK-positive or negative) and ALK-positive ALCL respectively. Both agents have shown encouraging responses in relapsed ALCL. It remains to be seen how these novel agents are used, but it is very possible that they may improve overall responses and survival in both children and adults. This review highlights the presentation, histopathological features, prognostic factors, and evidence-based treatment approaches in the first line and relapsed setting in ALK-positive ALCL. The review concludes by discussing the novel approaches using Brentuximab and Crizotinib which are being tested in clinical trials.

GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia.

Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity ∼0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones.

Understanding the expectations of patients with inherited retinal dystrophies.

BACKGROUND: UK genetic ophthalmology services for patients with retinal dystrophy (RD) are variable. Little research exists to define service requirements, or expectations, of patients and their families. This study aimed to explore the views and perceived benefits of genetic ophthalmology services among members of families with RD. METHODS: Twenty participants with known RD mutations were recruited through UK genetic ophthalmic clinics. Semistructured qualitative interviews explored interviewees' perceptions of the role of these services. Interviews were transcribed verbatim and analysed using inductive thematic analysis. RESULTS: Interviewees' expectations and requirements of genetic ophthalmology services were wide-ranging and often perceived to be unmet. Participant expectations were classified in three groups: (1) Medical expectations included obtaining a diagnosis and information about disease/prognosis, genetic risks and research (2) Psychosocial expectations related to participants' need for support in adjusting to RD (3) Practical expectations included the desire for information about welfare and support. CONCLUSIONS: Expectations of RD families for clinical services are complex, encompassing a range of healthcare specialties. Services that align to these expectations will need to reach beyond the diagnostic arena and provide practical and psychosocial support. The identification of measurable outcomes will facilitate future development and evaluation of service delivery models. Many of the expectations identified here map to an existing, previously validated, outcomes framework for clinical genetic services. However, an additional outcome domain, labelled 'Independence' was also identified; this could either be specific to vision loss or relate generally to disability caused by genetic conditions.

Guideline for the diagnosis and management of myelofibrosis.

The guideline group regarding the diagnosis and management of myelofibrosis was selected to be representative of UK-based medical experts, together with a contribution from a single expert from the USA. MEDLINE and EMBASE were searched systematically for publications in English from 1966 until August 2011 using a variety of key words. The writing group produced the draft guideline, which was subsequently revised by consensus of the members of the General Haematology and Haemato-oncology Task Forces of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The criteria used to state levels and grades of evidence are as outlined in the Procedure for Guidelines commissioned by the BCSH; the 'GRADE' system was used to score strength and quality of evidence. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of primary myelofibrosis, as well as post-polycythaemic myelofibrosis (post-PV MF) and post-thrombocythemic myelofibrosis (post-ET MF) in both adult and paediatric patients.