Upskilling haematological services for WGS and germline assessments through a regional skin biopsy training programme

NHS England Genomics introduced whole genome sequencing (WGS) with standard-of- care (SoC) genetic testing for haemato-oncology patients who meet eligibility criteria, including patients with acute leukaemia across all ages, and exhausted SoC testing. Alongside, the role of germline mutations in haematological cancers is becoming increasingly recognised. DNA samples are required from the malignant cells (somatic sample) via a bone marrow aspirate, and from non-malignant cells (germline sample) for comparator analysis. Skin biopsy is considered the gold-standard tissue to provide a source of fibroblast DNA for germline analysis. Performing skin punch biopsies is not within the traditional skillset for haematology teams and upskilling is necessary to deliver WGS/germline testing safely, independently and sustainably. A teaching programme was designed and piloted by the dermatology and haematology teams in Sheffield and delivered throughout the NHS trusts in North East & Yorkshire Genomic Laboratory Hub. The training programme consisted of a 90-min session, slides, video and practical biopsy on pork belly or synthetic skin, designed to teach up to six students at one time. To disseminate best practice, the standard operating procedure and patient information used routinely in Sheffield were shared, to be adapted for local service delivery. From January 2021 to December 2022, 136 haematology staff from 11 hospitals, including 34 consultants, 41 registrars, 34 nurses and 8 physician associates, across the NEY GLH region completed the skin biopsy training programme. Feedback from the course was outstanding, with consistently high scores in all categories. Practical components of the course were especially valued;98.6% (71/72) trainees scored the practical element of the programme a top score of 5 out of 5, highlighting that despite the challenges of delivering face-to- face teaching due to COVID-19, teaching of practical skills was highly valued;training in this way could not have been replicated virtually. Costs of the programme have been approximately 16 000, including consultant input and teaching/educational materials. Recent support has been provided by a separately funded Genomic Nurse Practitioner (GNP), with succession planning for the GNP to take over leadership from the consultant dermatologist. Plans are in place to use the remaining budget to disseminate the programme nationally. Our training programme has shown that skin biopsy can be formally embedded into training for haematology consultants, trainees, nursing team, and physician associates. Delivery of training can be effective and affordable across regional GLHs with appropriate leadership and inter-speciality coordination, and ultimately sustainable with specialist nursing staff, including GNPs.

Neoadyuvant Treatment in the Covid Era

Since Coronavirus Disease 2019 (COVID-19) was declared pandemic in March 2020, there have been 545.226.550 cases up to 4 July 2022 (1). Several studies concluded that patients (pts) with cancer are at increased risk of COVID-19 infection, morbidity and mortality. Those undergoing neoadyuvant treatment are at particularly risk of disease progression if chemotherapy or surgery are delayed. Also, is known that a higher NLR (neutrophil to limphocyte ratio) is related to worse outcomes (3). Our hospital is located at the Northwest of Spain and in the last months we noticed a never seen number of infections in cancer population. The aim of this study is to evaluate the severity of COVID19 and its impact on chemotherapy and surgery delay in pts undergoing neoadjuvant chemotherapy breast cancer. METHOD(S): We conducted a ambispective, unicenter, observational study of breast cancer pts, treated with neoadjuvant chemotherapy, between March 2020 and May 2022 at University Hospital A Coruna (Spain). We analyzed type of infection, need of hospitalization, chemotherapy and surgical delay, and its association with tumor type;BRCA germline mutation;clinical stage;treatment;vaccination status;and neutrophils, lymphocytes, and NLR before COVID-19 disease. RESULT(S): During the study period, from 1 March 2020 to 31 May 2022, 183 pts underwent neoadjuvant chemotherapy. A total of 23 (12.5%) pts experienced COVID-19 infection, of which 21 were diagnosed between January and May 2022. The median age was 47,91 years [range 33 - 69 years]. Luminal B HER 2 negative comprised the most common molecular subtype (40.9%), followed by Triple Negative (36.4%), Luminal B HER 2 positive (13.6%), and HER 2 enriched (9.1%). Germline mutations in BRCA account for 13.6% pts. At diagnosis, 4.5%, 72.7%, and 22.7% had stages I, II, and III respectively. Chemotherapy treatments included: paclitaxel followed by AdryamicineCyclophosphamide (AC) (45.4%);carboplatin - paclitaxel - trastuzumab - pertuzumab (18,2%);carboplatin - paclitaxel followed by AC (18,2%);KEYNOTE-756: pembrolizumab/placebo - paclitaxel followed by AC (13.7%);and paclitaxel - trastuzumab - pertuzumab followed by myocet - cyclophosphamide - trastuzumab - pertuzumab (4.5%). The association of G-CSF ocurred in 9 pts (40.9%). 22 pts were fully vaccinated, 8 pts (36.4%) with two doses and 13 pts (59.1%) with three doses. 77.3% pts experienced mild respiratory symptoms with 9.1% hospitalizations. The median duration of delays was 15 days for chemotherapy and 29,58 days for surgery. NLR percentil 25 was associated with COVID-19 type of infection. For those pts with a lower rate, infection was asymptomatic and for those with a higher rate symptoms were moderate (X2= 5,119, p = 0,024). CONCLUSION(S): COVID-19 disease become a high prevalent infection in pts undergoing neoadjuvant breast cancer chemotherapy. Most pts are fully vaccinated and experienced an indolent infection. NLR is an easily measurable and cost-effective parameter that could be useful as a prognostic marker of severity in COVID-19. We will continue to follow-up these pts to see the impact of chemotherapy or surgery delay in pathological complete response and disease-free survival until the congress in December 2022.

GATA2 deficiency presenting as fever and rash

Case Report: Our patient is an 8-year-old Caucasian female with a history of choanal atresia, first degree heart block, recurrent urinary tract infections, and recent COVID-19 infection, who initially presented with an episode of syncope and vomiting. By history, she had two weeks of daily fever and an intermittent nonspecific rash. She was diagnosed with a UTI 5 days prior to presentation but had not defervesced despite treatment. Shewas initially found to be in shock with tachycardia and poor perfusion and was treated with fluid resuscitation, antipyretics, and empiric antibiotics. Labs were significant for leukopenia, elevated inflammatory markers, lactic acidosis, coagulopathy, and mildly elevated troponin. Chest x-ray showed abnormal but non-specific widespread infiltrates. She was initially treated with IVIG and pulse steroids for a working diagnosis of MIS-C, however she did not improve and a more extensive infectious, oncologic, and rheumatologic work-up was performed. Her workup revealed a disseminated Mycobacterium abscessus infection. Bone marrow biopsy revealed myelodysplasia with monosomy 7. Her buccal swab testing revealed a heterozygous germline mutation in the GATA2 gene, a variant that is predicted to cause loss of normal protein function. She is presently on multidrug regimen for her mycobacterial infection. Her myelodysplasia evolved into an acute leukemia, and she is undergoing chemotherapy for that at this time. Discussion(s): GATA2 deficiency, first identified in 2011, is a rare immune disorder resulting in a wide variety of clinical presentations. It is caused by a germline mutation of the GATA2 gene that disrupts blood cell differentiation, resulting in decreased or absent monocytes, B cells, NK cells, and dendritic cells1. This case presented multiple challenges due to the broad range of differential diagnoses. This patient was ultimately diagnosed with myelodysplastic syndrome associated with monosomy 7 and GATA2 deficiency, confirmed by FISH testing. Due to the presentation and lab derangements this patient had, there was a delay in targeted treatment while managing her cytopenias and presumed pulmonary infection. GATA2 deficiency carries a high risk of progression from myelodysplastic syndrome to acute myelogenous leukemia. The best long-term treatment for GATA2 deficiency is hematopoietic stem cell transplant, which is the ultimate goal for our patient. Copyright © 2023 Southern Society for Clinical Investigation.

Roles of Genetic Predisposition in the Sex Bias of Pulmonary Pathophysiology, as a Function of Estrogens : Sex Matters in the Prevalence of Lung Diseases.

In addition to studies focused on estrogen mediation of sex-different regulation of systemic circulations, there is now increasing clinical relevance and research interests in the pulmonary circulation, in terms of sex differences in the morbidity and mortality of lung diseases such as inherent-, allergic- and inflammatory-based events. Thus, female predisposition to pulmonary artery hypertension (PAH) is an inevitable topic. To better understand the nature of sexual differentiation in the pulmonary circulation, and how heritable factors, in vivo- and/or in vitro-altered estrogen circumstances and changes in the live environment work in concert to discern the sex bias, this chapter reviews pulmonary events characterized by sex-different features, concomitant with exploration of how alterations of genetic expression and estrogen metabolisms trigger the female-predominant pathological signaling. We address the following: PAH (Sect.7.2) is characterized as an estrogenic promotion of its incidence (Sect. 7.2.2), as a function of specific germline mutations, and as an estrogen-elicited protection of its prognosis (Sect.7.2.1). More detail is provided to introduce a less recognized gene of Ephx2 that encodes soluble epoxide hydrolase (sEH) to degrade epoxyeicosatrienic acids (EETs). As a susceptible target of estrogen, Ephx2/sEH expression is downregulated by an estrogen-dependent epigenetic mechanism. Increases in pulmonary EETs then evoke a potentiation of PAH generation, but mitigation of its progression, a phenomenon similar to the estrogen-paradox regulation of PAH. Additionally, the female susceptibility to chronic obstructive pulmonary diseases (Sect. 7.3) and asthma (Sect.7.4), but less preference to COVID-19 (Sect. 7.5), and roles of estrogen in their pathogeneses are briefly discussed.