Erythroblastosis Transformation-Specific Regulated Gene 1 (ERG) Immunohistochemistry in the Diagnosis of Acute Myeloid Leukemia.

INTRODUCTION: The erythroblastosis transformation-specific regulated gene 1 (ERG) is a transcription factor that can be used as an immunohistochemical (IHC) marker in the diagnosis and prognostication of malignancy. ERG was initially used in prostate cancer; however, it is a useful marker in extramedullary myeloid disease. Patients with acute myeloid leukemia (AML), dry bone marrow aspirate, and CD34, CD117-negative blast cells can be in a diagnostic dilemma. This audit aimed to (a) validate ERG IHC in bone marrow trephine samples, (b) quantify ERG IHC positivity in an AML cohort, and correlate concordance with CD34 and CD117 IHC, when available, and (c) to see whether ERG is a useful adjunct in the diagnosis of cases of AML. METHODS: A retrospective audit was completed of all new and relapsed cases of AML over one year at a single center. For inclusion, patients needed a trephine specimen at presentation, and all had a hematoxylin and eosin(H&E) specimen, ERG IHC, and at least one or both of CD34 and CD117 IHC. Four pathologists independently assessed the stains quantitatively and qualitatively in comparison to the morphology seen on the H&E sample. The kappa value was used to assess agreement. RESULTS: Seventeen patients with AML met the inclusion criteria. All specimens had H&E, CD34, and ERG stains; 9/17 (53%) had CD117 IHC. ERG demonstrated high concordance with blast cells on H&E morphology, with a high agreement among pathologists. Qualitatively, pathologists recognized that ERG spared lymphoid nodules; however, it also stained granulocytes at various maturation stages. CONCLUSION: ERG is a sensitive marker for the diagnosis of AML. ERG can help visualize blast cells that have been confirmed by ancillary tests. More research into the utility of ERG in AML diagnostics is recommended.

Impact of patient and public (PPI) involvement in the Life After Prostate Cancer Diagnosis (LAPCD) study: a mixed-methods study.

OBJECTIVES: Standardised reporting of patient and public involvement (PPI) in research studies is needed to facilitate learning about how to achieve effective PPI. The aim of this evaluation was to explore the impact of PPI in a large UK study, the Life After Prostate Cancer Diagnosis (LAPCD) study, and to explore the facilitators and challenges experienced. DESIGN: Mixed-methods study using an online survey and semistructured interviews. Survey and topic guide were informed by systematic review evidence of the impact of PPI and by realist evaluation. Descriptive analysis of survey data and thematic analysis of interview data were conducted. Results are reported using the GRIPP2 (Guidance for Reporting Involvement of Patients and the Public, Version 2) reporting guidelines. SETTING: LAPCD study, a UK-wide patient-reported outcome study. PARTICIPANTS: User Advisory Group (UAG) members (n=9) and researchers (n=29) from the LAPCD study. RESULTS: Impact was greatest on improving survey design and topic guides for interviews, enhancing clarity of patient-facing materials, informing best practices around data collection and ensuring steering group meetings were grounded in what is important to the patient. Further impacts included ensuring patient-focused dissemination of study findings at conference presentations and in lay summaries.Facilitating context factors included clear aims, time to contribute, confidence to contribute, and feeling valued and supported by researchers and other UAG members. Facilitating mechanisms included embedding the UAG within the study as a separate workstream, allocating time and resources to the UAG reflecting the value of input, and putting in place clear communication channels. Hindering factors included time commitment, geographical distance, and lack of standardised feedback mechanisms. CONCLUSION: Including PPI as an integral component of the LAPCD study and providing the right context and mechanisms for involving the UAG helped maximise the programme's effectiveness and impact.

Collection of cancer Patient Reported Outcome Measures (PROMS) to link with primary and secondary electronic care records to understand and improve long term cancer outcomes: A protocol paper.

INTRODUCTION: More people are living with and beyond a cancer diagnosis. There is limited understanding of the long-term effects of cancer and cancer treatment on quality of life and personal and household finances when compared to people without cancer. In a separate protocol we have proposed to link de-identified data from electronic primary care and hospital records for a large population of cancer survivors and matched controls. In this current protocol, we propose the linkage of Patient Reported Outcomes Measures data to the above data for a subset of this population. The aim of this study is to investigate the full impact of living with and beyond a cancer diagnosis compared to age and gender matched controls. A secondary aim is to test the feasibility of the collection of Patient Reported Outcomes Measures (PROMS) data and the linkage procedures of the PROMs data to electronic health records data. MATERIALS AND METHODS: This is a cross-sectional study, aiming to recruit participants treated at the Leeds Teaching Hospitals National Health Service Trust. Eligible patients will be cancer survivors at around 5 years post-diagnosis (breast, colorectal and ovarian cancer) and non-cancer patient matched controls attending dermatology out-patient clinics. They will be identified by running a query on the Leeds Teaching Hospitals Trust patient records system. Approximately 6000 patients (2000 cases and 4000 controls) will be invited to participate via post. Participants will be invited to complete PROMs assessing factors such as quality of life and finances, which can be completed on paper or online (surveys includes established instruments, and bespoke instruments (demographics, financial costs). This PROMs data will then be linked to routinely collected de-identified data from patient's electronic primary care and hospital records. DISCUSSION: This innovative work aims to create a truly 'comprehensive patient record' to provide a broad picture of what happens to cancer patients across their cancer pathway, and the long-term impact of cancer treatment. Comparisons can be made between the cases and controls, to identify the aspects of life that has had the greatest impact following a cancer diagnosis. The feasibility of linking PROMs data to electronic health records can also be assessed. This work can inform future support offered to people living with and beyond a cancer diagnosis, clinical practice, and future research methodologies.

eIF6 rebinding dynamically couples ribosome maturation and translation.

Protein synthesis is a cyclical process consisting of translation initiation, elongation, termination and ribosome recycling. The release factors SBDS and EFL1-both mutated in the leukemia predisposition disorder Shwachman-Diamond syndrome - license entry of nascent 60S ribosomal subunits into active translation by evicting the anti-association factor eIF6 from the 60S intersubunit face. We find that in mammalian cells, eIF6 holds all free cytoplasmic 60S subunits in a translationally inactive state and that SBDS and EFL1 are the minimal components required to recycle these 60S subunits back into additional rounds of translation by evicting eIF6. Increasing the dose of eIF6 in mice in vivo impairs terminal erythropoiesis by sequestering post-termination 60S subunits in the cytoplasm, disrupting subunit joining and attenuating global protein synthesis. These data reveal that ribosome maturation and recycling are dynamically coupled by a mechanism that is disrupted in an inherited leukemia predisposition disorder.

A data flow process for confidential data and its application in a health research project.

BACKGROUND: The use of linked healthcare data in research has the potential to make major contributions to knowledge generation and service improvement. However, using healthcare data for secondary purposes raises legal and ethical concerns relating to confidentiality, privacy and data protection rights. Using a linkage and anonymisation approach that processes data lawfully and in line with ethical best practice to create an anonymous (non-personal) dataset can address these concerns, yet there is no set approach for defining all of the steps involved in such data flow end-to-end. We aimed to define such an approach with clear steps for dataset creation, and to describe its utilisation in a case study linking healthcare data. METHODS: We developed a data flow protocol that generates pseudonymous datasets that can be reversibly linked, or irreversibly linked to form an anonymous research dataset. It was designed and implemented by the Comprehensive Patient Records (CPR) study in Leeds, UK. RESULTS: We defined a clear approach that received ethico-legal approval for use in creating an anonymous research dataset. Our approach used individual-level linkage through a mechanism that is not computer-intensive and was rendered irreversible to both data providers and processors. We successfully applied it in the CPR study to hospital and general practice and community electronic health record data from two providers, along with patient reported outcomes, for 365,193 patients. The resultant anonymous research dataset is available via DATA-CAN, the Health Data Research Hub for Cancer in the UK. CONCLUSIONS: Through ethical, legal and academic review, we believe that we contribute a defined approach that represents a framework that exceeds current minimum standards for effective pseudonymisation and anonymisation. This paper describes our methods and provides supporting information to facilitate the use of this approach in research.

Early detection of T-cell lymphoma with T follicular helper phenotype by RHOA mutation analysis.

Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma with T follicular helper phenotype (PTCL-TFH) are a group of complex clinicopathological entities that originate from T follicular helper cells and share a similar mutation profile. Their diagnosis is often a challenge, particularly at an early stage, because of a lack of specific histological and immunophenotypic features, paucity of neoplastic T cells and prominent polymorphous infiltrate. We investigated whether the lymphoma-associated RHOA Gly17Val (c.50G>T) mutation, occurring in 60% of cases, is present in the early "reactive" lesions, and whether mutation analysis could help to advance the early diagnosis of lymphoma. The RHOA mutation was detected by quantitative polymerase chain reaction with a locked nucleic acid probe specific to the mutation, and a further peptide nucleic acid clamp oligonucleotide to suppress the amplification of the wild-type allele. The quantitative polymerase chain reaction assay was highly sensitive and specific, detecting RHOA Gly17Val at an allele frequency of 0.03%, but not other changes in Gly17, nor in 61 controls. Among the 37 cases of AITL and PTCL-TFH investigated, RHOA Gly17Val was detected in 62.2% (23/37) of which 19 had multiple biopsies including preceding biopsies in ten and follow-up biopsies in 11 cases. RHOA Gly17Val was present in each of these preceding or follow-up biopsies including 18 specimens that showed no evidence of lymphoma by combined histological, immunophenotypic and clonality analyses. The mutation was seen in biopsies 0-26.5 months (mean 7.87 months) prior to the lymphoma diagnosis. Our results show that RHOA Gly17Val mutation analysis is valuable in the early detection of AITL and PTCL-TFH.

Stability of health-related quality of life and morbidity burden from 18 months after diagnosis of prostate cancer: results of a UK-wide population-based outcome cohort.

OBJECTIVE: To evaluate the dynamic nature of self-reported health-related quality of life (HRQL) and morbidity burden in men diagnosed with prostate cancer, we performed a follow-up study of the Life After Prostate Cancer Diagnosis (LAPCD) study cohort 12 months after initial survey. METHODS: The LAPCD study collected information from 35,823 men across the UK who were 18-42 months post-diagnosis of prostate cancer. Men who were still alive 12 months later were resurveyed. Generic HRQL (EQ-5D-5L plus self-assessed health rating) and prostate cancer-specific outcomes (EPIC-26) were assessed. Treatment(s) received was self-reported. Previously defined clinically meaningful differences were used to evaluate changes in outcomes over time. RESULTS: A total of 28,450 men across all disease stages completed follow-up surveys (85.8% response). Of the 21,700 included in this study, 89.7% reported no additional treatments since the first survey. This group experienced stable urinary and bowel outcomes, with good function for most men at both time points. On-going poor (but stable) urinary issues were associated with previous surgery. Sexual function scores remained low (mean: 26.8/100). Self-assessed health ratings were stable over time. The largest declines in HRQL and functional outcomes were experienced by men reporting their first active treatment between surveys. DISCUSSION: The results suggest stability of HRQL and most specific morbidities by 18-42 months for men who report no further treatment in the subsequent 12 months. This is reassuring for those with good function and HRQL but re-enforces the need for early intervention and support for men who experience poor outcomes.

SETBP1 overexpression acts in the place of class-defining mutations to drive FLT3-ITD-mutant AML.

Advances in cancer genomics have revealed genomic classes of acute myeloid leukemia (AML) characterized by class-defining mutations, such as chimeric fusion genes or in genes such as NPM1, MLL, and CEBPA. These class-defining mutations frequently synergize with internal tandem duplications in FLT3 (FLT3-ITDs) to drive leukemogenesis. However, ∼20% of FLT3-ITD-positive AMLs bare no class-defining mutations, and mechanisms of leukemic transformation in these cases are unknown. To identify pathways that drive FLT3-ITD mutant AML in the absence of class-defining mutations, we performed an insertional mutagenesis (IM) screening in Flt3-ITD mice, using Sleeping Beauty transposons. All mice developed acute leukemia (predominantly AML) after a median of 73 days. Analysis of transposon insertions in 38 samples from Flt3-ITD/IM leukemic mice identified recurrent integrations at 22 loci, including Setbp1 (20/38), Ets1 (11/38), Ash1l (8/38), Notch1 (8/38), Erg (7/38), and Runx1 (5/38). Insertions at Setbp1 led exclusively to AML and activated a transcriptional program similar, but not identical, to those of NPM1-mutant and MLL-rearranged AMLs. Guide RNA targeting of Setbp1 was highly detrimental to Flt3ITD/+/Setbp1IM+, but not to Flt3ITD/+/Npm1cA/+, AMLs. Also, analysis of RNA-sequencing data from hundreds of human AMLs revealed that SETBP1 expression is significantly higher in FLT3-ITD AMLs lacking class-defining mutations. These findings propose that SETBP1 overexpression collaborates with FLT3-ITD to drive a subtype of human AML. To identify genetic vulnerabilities of these AMLs, we performed genome-wide CRISPR-Cas9 screening in Flt3ITD/+/Setbp1IM+ AMLs and identified potential therapeutic targets, including Kdm1a, Brd3, Ezh2, and Hmgcr. Our study gives new insights into epigenetic pathways that can drive AMLs lacking class-defining mutations and proposes therapeutic approaches against such cases.

Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.

Epstein-Barr Virus-associated Diffuse Large B-cell Lymphoma Identified in a Breast Implant Capsule: A New Breast Implant-Associated Lymphoma?

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma is a relatively uncommon T-cell lymphoma with about 900 reported cases worldwide to April 2020 according to the American Society of Plastic Surgeons Breast Implant-Associated Anaplastic Large Cell Lymphoma Physician Resources information. CASE PRESENTATION: A 51-year old woman was found to have an Epstein-Barr virus-related diffuse large B-cell lymphoma (EBV-DLCBCL) in her left breast periimplant capsule at the time of a second revision breast implant surgery for recurrent severe capsular contractures following cosmetic breast augmentation 21 years previously. The first revision operation, 15 years earlier, had comprised simple implant exchange from smooth-saline to textured-silicone gel prostheses. RESULTS: Histopathological and immunohistochemical analyses of the periimplant capsulectomy specimen confirmed a B cell lymphoma which was, in addition, positive for EBV-encoded RNA on in-situ hybridization. Staging investigations including positron emission tomography-computed tomography did not reveal any metastatic disease. DISCUSSION AND CONCLUSION: Despite recommendations to the contrary (by 2 independent hematological malignancy multidisciplinary teams), the patient has declined explantation of her new breast implants choosing instead to be observed under a watch-and-wait protocol. She remains disease-free 2 years postdiagnosis. To date, a diffuse B-cell lymphoma has never been documented as arising in a breast implant capsule or in association with breast augmentation whether associated with EBV or not. This is the first such report in the world.

Experiences of Support for Sexual Dysfunction in Men With Prostate Cancer: Findings From a U.K.-Wide Mixed Methods Study.

BACKGROUND: Men with prostate cancer (PCa) often experience sexual dysfunction following diagnosis and treatment, yet little is known about the support they receive to deal with this. AIM: To explore men's experiences of support for sexual dysfunction following PCa diagnosis. METHODS: This study included a U.K.-wide survey of men 18-42 months post-diagnosis of PCa, identified through cancer registries. The survey measured sexual function and the extent to which men perceived sexual dysfunction to be a problem (Expanded Prostate Cancer Index Composite-26), access to and experience of medications, devices, and specialist services for sexual dysfunction, and included a free-text question for further comments. Analysis focussed on men who reported poor sexual function, which they considered a moderate or big problem. Descriptive statistics explored the characteristics of men offered intervention and those that found this helpful. Free-text responses were analyzed using thematic analysis. OUTCOME: The main outcome of this study was to assess access to and experience of medications, devices, and specialist services for sexual dysfunction. RESULTS: 39.0% of all survey respondents (13,978/35,823) reported poor sexual function, which they considered a moderate or big problem. 51.7% of these men were not offered any intervention to aid sexual functioning. 71.9% of those offered an intervention reported trying it, of whom 48.7% found the intervention helpful. Men treated with surgery or brachytherapy were most likely to be offered an intervention. Medication was the most commonly offered intervention and 39.3% of those who tried medication found this helpful. Although offered less often, approximately half of the men who tried devices or attended specialist services found the intervention helpful. Free-text responses indicated that barriers to accessing support included inadequate information and support from healthcare professionals, embarrassment, negative views about treatment options, concerns about side effects and safety, and inconsistencies between secondary and primary care. Barriers to continuing use included limited effectiveness of treatments, inadequate ongoing support, and funding constraints. Drivers of sexual recovery included patient proactivity and persistence with trying different treatment options and ongoing support from health professionals. CLINICAL IMPLICATIONS: There is an urgent need to ensure that all men are offered, and have equal access to, sexual care support, with referral to specialist services when required. STRENGTHS & LIMITATIONS: This study presents data from a large, U.K.-wide, population-based study of men with PCa and includes quantitative and qualitative findings. The possibility of non-response bias should, however, be considered. CONCLUSION: There are significant shortcomings in the support offered to U.K. men with sexual dysfunction following diagnosis and treatment for PCa which need to be addressed. Watson E, Wilding S, Matheson L, et al. Experiences of Support for Sexual Dysfunction in Men With Prostate Cancer: Findings From a U.K.-Wide Mixed Methods Study. J Sex Med 2021;18:515-525.

Quality of Life After Bladder Cancer: A Cross-sectional Survey of Patient-reported Outcomes.

BACKGROUND: Little is known about health-related quality of life (HRQOL) following treatment for bladder cancer (BC). OBJECTIVE: To determine this, we undertook a cross-sectional survey covering 10% of the English population. DESIGN, SETTING, AND PARTICIPANTS: Participants 1-10 yr from diagnosis were identified through national cancer registration data. INTERVENTION: A postal survey was administered containing generic HRQOL and BC-specific outcome measures. Findings were compared with those of the general population and other pelvic cancer patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Generic HRQOL was measured using five-level EQ-5D (EQ-5D-5L) and European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ)-C30. BC-specific outcomes were derived from EORTC QLQ-BLM30 and EORTC QLQ-NMIBC24. RESULTS AND LIMITATIONS: A total of 1796 surveys were completed (response rate 55%), including 868 (48%) patients with non-muscle-invasive BC, 893 (50%) patients who received radiotherapy or radical cystectomy, and 35 (1.9%) patients for whom treatment was unknown. Most (69%) of the participants reported at least one problem in any EQ-5D dimension. Age/sex-adjusted generic HRQOL outcomes were similar across all stages and treatment groups, whilst problems increased with age (problems in one or more EQ-5D dimensions: <65 yr [67% {95% confidence interval or CI: 61-74}] vs 85+ yr [84% {95% CI: 81-89}], p = 0.016) and long-term conditions (no conditions [53% {95% CI: 48-58}] vs more than four conditions [94% {95% CI: 90-97}], p < 0.001). Sexual problems were reported commonly in men, increasing with younger age and radical treatment. Younger participants (under 65 yr) reported more financial difficulties (mean score 20 [95% CI: 16-25]) than those aged 85+ yr (6.8 [4.5-9.2], p < 0.001). HRQOL for BC patients (for comparison, males with problems in one or more EQ-5D dimensions 69% [95% CI: 66-72]) was significantly worse than what has been found after colorectal and prostate cancers and in the general population (51% [95% CI: 48-53], all p < 0.05). CONCLUSIONS: HRQOL following BC appears to be relatively independent of disease stage, treatment, and multimodal care. Issues are reported with sexual function and financial toxicity. HRQOL after BC is worse than that after other pelvic cancers. PATIENT SUMMARY: Patients living with bladder cancer often have reduced quality of life, which may be worse than that for other common pelvic cancer patients. Age and other illnesses appear to be more important in determining this quality of life than the treatments received. Many men complain of sexual problems. Younger patients have financial worries.

Strategies for living well with hormone-responsive advanced prostate cancer-a qualitative exploration.

PURPOSE: Due to recent treatment advances, men are increasingly living longer with advanced prostate cancer (PCa). This study sought to understand men's experiences of living with and adjusting to advanced hormone-responsive PCa and how this influenced their quality of life (QoL), in order to highlight how support could be optimized. METHODS: Participants were recruited through a UK wide survey-the 'Life After Prostate Cancer Diagnosis' study. In-depth telephone interviews were conducted with 24 men (aged 46-77 years) with advanced (stage IV) hormone-responsive PCa diagnosed 18-42 months previously. Thematic analysis was undertaken using a framework approach. RESULTS: Most participants perceived their QoL to be relatively good, which was influenced by the following factors (enablers to 'living well' with PCa): a sense of connectedness to others, engagement in meaningful activities, resources (social, cognitive, financial), ability to manage uncertainty, utilization of adjustment strategies and support, communication and information from health professionals. Barriers to 'living well' with PCa were often the converse of these factors. These also included more troublesome PCa-related symptoms and stronger perceptions of loss and restriction. CONCLUSIONS: In our study, men living with advanced hormone-responsive PCa often reported a good QoL. Exploring the influences on QoL in men with advanced PCa indicates how future interventions might improve the QoL of men who are struggling. Further research is required to develop and test interventions that enhance QoL for these men.

Influence of deprivation and rurality on patient-reported outcomes of men living with and beyond prostate cancer diagnosis in the UK: A population-based study.

BACKGROUND: In the UK, inequalities exist in prostate cancer incidence, survival and treatment by area deprivation and rurality. This work aimed to identify variation in patient-reported outcomes of men with prostate cancer by area type. METHODS: A population-based survey of men 18-42 months after prostate cancer diagnosis (N = 35608) measured self-assessed health (SAH) using the EQ-5D and five functional domains using the Expanded Prostate Cancer Index Composite (EPIC-26). RESULTS: Mean SAH was higher for men in least deprived areas compared to most deprived (difference 6.3 (95 %CI 5.6-7.2)). SAH scores were lower for men in most urban areas compared to most rural (difference 2.4 (95 %CI 1.8-3.0)). Equivalent estimates in the general population reported a 13 point difference by deprivation and a 4 point difference by rurality. For each EPIC-26 domain, functional outcomes were better for men in the least deprived areas, with clinically meaningful differences observed for urinary incontinence and hormonal function. There were no clinically meaningful differences in EPIC-26 outcomes by rurality with less than a three point difference in scores for each domain between urban and rural areas. CONCLUSION: In men 18-42 months post diagnosis of prostate cancer in the UK, impacts of area deprivation and rurality on self-assessed health related quality of life were not greater than would be expected in the general population. However, clinically meaningful differences were identified for some prostate functional outcomes (urinary and hormonal function) by deprivation. No impact by rurality of residence was identified.

Achieving margin clearance following oncoplastic breast surgery in comparison with simple wide local excision: a three-dimensional specimen assessment.

BACKGROUND: Pre-operative breast tumour radial dimensions often determine the choice between simple wide local excision (WLE) and oncoplastic breast surgery (OBS). We reviewed the three-dimensional interplay between tumour and surgical specimen dimensions in the two cohorts. METHODS: Demographic, tumour and treatment data were collected for all patients undergoing OBS by a single surgeon and compared with a randomly selected cohort of WLE patients treated. The relationship between tumour and specimen medio-lateral, supero-inferior and antero-posterior dimensions were explored in both groups. Subgroup analyses were performed in the OBS cohort (parenchymal displacement versus replacement). RESULTS: We identified 60 OBS patients (63 breasts), comparing them with 60 WLE patients. Pre-operative tumour estimated size was significantly larger in the OBS cohort and concordant with macroscopic tumour radial dimensions and final microscopic tumour size. Surgical specimen weight was more than 3.5 times higher in the OBS group and its radial dimensions were almost double. No significant difference was observed for the antero-posterior dimensions. The rate of margin re-excisions and completion mastectomies were lower in the OBS cohort. WLE patients with positive margins had a lower tumour-to-specimen ratio, whereas, the requirement for further surgery in the OBS cohort was associated with larger tumour dimensions. CONCLUSION: Despite larger tumour dimensions, OBS is not inferior to WLE in providing clear surgical margins. Our analysis of the three-dimensional spatial relationship between cancer and surgical specimen, although not completely conclusive, can be helpful in the selection of the most appropriate surgical approach for every patient.

ADA2 deficiency complicated by EBV-driven lymphoproliferative disease.

A 29-year old male with recurrent respiratory and skin infections, anaemia and neutropaenia during childhood required immunoglobulin replacement for antibody deficiency from age 16. He remained relatively well until age 28 when he presented with a two-week history of fatigue, sore throat, fever and productive cough. He was found to have EBV viraemia and splenomegaly and a diagnosis of EBV-driven lymphoproliferative disease was made following bone marrow trephine. Family history was notable with three siblings: a healthy sister and two brothers with anaemia and neutropaenia; one who succumbed to septicaemia secondary to neutropaenic enterocolitis age 5 and another who developed intestinal vasculitis and antibody deficiency and had a successful haemopoetic stem cell transplant. The proband's DNA underwent targeted sequencing of 279 genes associated with immunodeficiency (GRID panel). The best candidates were two ADA2 variants, p.Arg169Gln (R169Q) and p.Asn370Lys (N370K). Sanger sequencing and co-segregation of variants in the parents, unaffected sister and all three affected brothers was fully consistent with compound heterozygous inheritance. Subsequent whole genome sequencing of the proband identified no other potential causal variants. ADA2 activity was consistent with a diagnosis of ADA2 deficiency in affected family members. This is the first description of EBV-driven lymphoproliferative disease in ADA2 deficiency. ADA2 deficiency may cause susceptibility to severe EBV-induced disease and we would recommend that EBV status and viral load is monitored in patients with this diagnosis and allogeneic SCT is considered at an early stage for patients whose ADA2 deficiency is associated with significant complications.

A Qualitative Exploration of Prostate Cancer Survivors Experiencing Psychological Distress: Loss of Self, Function, Connection, and Control.

PURPOSE: To explore the experiences of men with prostate cancer identified as having psychological distress and to identify factors influencing distress. PARTICIPANTS & SETTING: 28 men with prostate cancer diagnosed 18-42 months earlier, identified as having psychological distress on survey measures. METHODOLOGIC APPROACH: Semistructured telephone interviews were conducted. Thematic analysis using a framework approach was used. FINDINGS: Men with psychological distress had strong perceptions of loss toward self (identity, sexuality/masculinity, self-confidence), function (physical activities), connection (relational, social, community), and control (future, emotional). Psychological vulnerability appeared heightened in particular groups of men. Maladaptive strategies of emotional concealment, help-seeking avoidance, and withdrawal appeared to contribute to distress. IMPLICATIONS FOR NURSING: Distress in men with prostate cancer is multifaceted. Men with distress should be identified and offered support. Nurse- or peer-led interventions are required.

Decision regret in men living with and beyond nonmetastatic prostate cancer in the United Kingdom: A population-based patient-reported outcome study.

OBJECTIVE: Clinical options for managing nonmetastatic prostate cancer (PCa) vary. Each option has side effects associated with it, leading to difficulty in decision-making. This study aimed to assess the relationship between patient involvement in treatment decision-making and subsequent decision regret (DR), and quantify the impact of health-related quality of life (HRQL) outcomes on DR. METHODS: Men living in the United Kingdom, 18 to 42 months after diagnosis of PCa, were identified from cancer registration data and sent a questionnaire. Measures included the Decision Regret Scale (DRS), Expanded Prostate cancer Index Composite short form (EPIC-26), EQ-5D-5L, and an item on involvement in treatment decision-making. Multivariable ordinal regression was utilized, with DR categorized as none, mild, or moderate/severe regret. RESULTS: A total of 17 193 men with stage I-III PCa completed the DRS: 36.6% reported no regret, 43.3% mild regret, and 20.0% moderate/severe regret. The odds of reporting DR were greater if men indicated their views were not taken into account odds ratio ([OR] = 6.42, 95% CI: 5.39-7.64) or were involved "to some extent" in decision-making (OR = 4.63, 95% CI: 4.27-5.02), compared with men who were "definitely" involved. After adjustment, including for involvement, men reporting moderate/big problems with urinary, bowel, or sexual function were more likely to experience regret compared with men with no/small problems. Better HRQL scores were associated with lower levels of DR. CONCLUSIONS: This large-scale study demonstrates the benefit of patient involvement in treatment decision-making for nonmetastatic PCa. However, men experiencing side effects and poorer HRQL report greater DR. Promoting engagement in clinical decision-making represents good practice and may reduce the risk of subsequent regret.

Angioimmunoblastic T-cell lymphoma contains multiple clonal T-cell populations derived from a common TET2 mutant progenitor cell.

Angioimmunoblastic T-cell lymphoma (AITL) is a neoplastic proliferation of T follicular helper cells with clinical and histological presentations suggesting a role of antigenic drive in its development. Genetically, it is characterized by a stepwise acquisition of somatic mutations, with early mutations involving epigenetic regulators (TET2, DNMT3A) and occurring in haematopoietic stem cells, with subsequent changes involving signaling molecules (RHOA, VAV1, PLCG1, CD28) critical for T-cell biology. To search for evidence of potential oncogenic cooperation between genetic changes and intrinsic T cell receptor (TCR) signaling, we investigated somatic mutations and T-cell receptor ß (TRB) rearrangement in 119 AITL, 11 peripheral T-cell lymphomas with T follicular helper phenotype (PTCL-TFH), and 25 PTCL-NOS using Fluidigm polymerase chain reaction (PCR) and Illumina MiSeq sequencing. We confirmed frequent TET2, DNMT3A, and RHOA mutations in AITL (72%, 34%, 61%) and PTCL-TFH (73%, 36%, 45%) and showed multiple TET2 mutations (2 or 3) in 57% of the involved AITL and PTCL-TFH. Clonal TRB rearrangement was seen in 76 cases with multiple functional rearrangements (2-4) in 18 cases (24%). In selected cases, we confirmed bi-clonal T-cell populations and further demonstrated that these independent T-cell populations harboured identical TET2 mutations by using BaseScope in situ hybridization, suggesting their derivation from a common TET2 mutant progenitor cell population. Furthermore, both T-cell populations expressed CD4. Finally, in comparison with tonsillar TFH cells, both AITL and PTCL-TFH showed a significant overrepresentation of several TRB variable family members, particularly TRBV19*01. Our findings suggest the presence of parallel neoplastic evolutions from a common TET2 mutant haematopoietic progenitor pool in AITL and PTCL-TFH, albeit to be confirmed in a large series of cases. The biased TRBV usage in these lymphomas suggests that antigenic stimulation may play an important role in predilection of T cells to clonal expansion and malignant transformation. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.