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BACKGROUND: Heart transplantation (HTx) after donation after circulatory death (DCD) is an expanding practice but is associated with increased warm ischemic time. The impact of DCD HTx on cardiac mechanics and myocardial fibrosis has not been reported. We aimed to compare cardiac mechanics and myocardial fibrosis using cardiovascular magnetic resonance (CMR) imaging in donation after brain death (DBD) and DCD HTx recipients and healthy controls. METHODS AND RESULTS: Consecutive HTx recipients between March 2015 and March 2021 who underwent routine surveillance CMR imaging were included. Cardiac mechanics were assessed using CMR feature tracking to compute global longitudinal strain, global circumferential strain, and right ventricular free-wall longitudinal myocardial strain. Fibrosis was assessed using late gadolinium enhancement imaging and estimation of extracellular volume. There were 82 (DBD n = 42, DCD n = 40) HTx recipients (aged 53 years, interquartile range 41-59 years, 24% female) who underwent CMR imaging at median of 9 months (interquartile range 6-14 months) after transplantation. HTx recipients had increased extracellular volume (29.7 ± 3.6%) compared with normal ranges (25.9%, interquartile range 25.4-26.5). Myocardial strain was impaired after transplantation compared with controls (global longitudinal strain -12.6 ± 3.1% vs -17.2 ± 1.8%, P < .0001; global circumferential strain -16.9 ± 3.1% vs -19.2 ± 2.0%, P = .002; right ventricular free-wall longitudinal strain -15.7 ± 4.5% vs -21.6 ± 4.7%, P < .0001). There were no differences in fibrosis burden (extracellular volume 30.6 ± 4.4% vs 29.2 ± 3.2%; P = .39) or cardiac mechanics (global longitudinal strain -13.1 ± 3.0% vs -12.1 ± 3.1%, P = .14; global circumferential strain -17.3 ± 2.9% vs -16.6 ± 3.1%, P = .27; right ventricular free-wall longitudinal strain -15.9 ± 4.9% vs -15.5 ± 4.1%, P = .71) between DCD and DBD HTx. CONCLUSIONS: HTx recipients have impaired cardiac mechanics compared with controls, with increased myocardial fibrosis. There were no differences in early CMR imaging characteristics between DBD and DCD heart transplants, providing further evidence that DCD and DBD HTx outcomes are comparable.

Background: Heterozygous hotspot mutations in the RNA splicing factor SF3B1, occur in 3% of unselected breast cancers and are associated with oestrogen receptor (ER+) breast cancer (BC) where they are enriched in metastatic disease and are associated with a poor clinical outcome. SF3B1 mutations drive distinct signatures of alternative splicing through cryptic 3’ splice site selection leading to global transcriptomic and proteomic changes. The functional consequences of the mis-splicing events and resultant genetic vulnerabilities are poorly understood and precision medicine approaches that exploit these characteristics are not clinically available (Table 1). Methods: To understand the role of SF3B1 mutations in ER+ BC, we generated a series of SF3B1 mutant (SF3B1MUT) isogenic cell lines which were characterised using RNA-sequencing and high content mass-spectrometry proteomic profiling. SF3B1 interactome analysis was also performed using immunoprecipitation of SF3B1 followed by mass-spectrometry. The molecular consequences of aberrant splicing were investigated using a targeted screening approach of 280 genes predicted to be alternatively spliced in SF3B1MUT BC, while high-throughput drug screens were used to identify novel therapeutic options for patients with SF3B1MUT breast cancer using isogenic cells. Hits were validated in vitro and in vivo using cell line and patient derived xenografts. Results: Transcriptomic and proteomic profiling of SF3B1MUT cells identified global alternative 3’ splice site selection and subsequent proteomic changes induced by the mutations. Investigation of the SF3B1K700E interactome identified an enrichment of SF3B1K700E binding with ER, aberrant splicing of ER target genes, global rewiring of ER chromatin binding and resistance to endocrine therapy. Silencing of the aberrantly spliced candidate genes PPIH, TRIM37, HIGD1A, BRD9, and PHKG2 significantly enhanced the growth of the SF3B1 mutant cells, suggestive of a dose dependent tumour suppressive effect. Through synthetic-lethal drug screens we found that SF3B1MUT cells are selectively sensitive to PARP inhibitors. SF3B1MUT cells display a defective response to PARPi induced replication stress. Mechanistically, this occurs via defective ATR signalling in SF3B1MUT cells, which upon PARPi exposure leads to increased replication origin firing and loss of pChk1 (S317) induction. The resultant replication stress leads to failure to resolve DNA replication intermediates via the endonuclease MUS81 and cell cycle stalling at the G2/M checkpoint. These defects can be further targeted by ATM, CDK7 or FACT inhibition, when used in combination with PARPi treatment. This SF3B1MUT selective PARPi sensitivity is preserved across multiple cell lines and patient derived tumour models. In vivo, PARPi produce profound anti-tumour effects in multiple SF3B1MUT cancer models and eliminate distant metastases. Conclusions: Our integrative analysis reveals mechanistic insight into the role of SF3B1 mutations in endocrine therapy response in ER+ breast cancers, where altered SF3B1 induces ER-transcriptional re-programming. We further identified a robust synthetic-lethal relationship of mutant SF3B1 with PARP inhibition that is caused by a defective response to PARPi induced replication stress. Furthermore, we identified several potential selective combination strategies together with PARPi that are selective for SF3B1MUT cells. Together, these data provide the pre-clinical and mechanistic rationale for assessing already-approved PARPi in a biomarker-defined subset of advanced ER+ BC. Table 1. Identified potential therapies for SF3B1 mutant cancers from this study and the literature Citation Format: Phil Bland, Harry Saville, Abigail Read, Patty Wai, Gareth Muirhead, Lucinda Curnow, Jadwiga Nieminuszczy, Nivedita Ravindran, Marie John, Somaieh Hedayat, Holly Barker, James Wright, Lu Yu, Ioanna Mavrommati, Barrie Peck, Mark Allen, Patrycja Gazinska, Helen Pemberton, Aditi Gulati, Sarah Nash, Farzana Noor, Naomi Guppy, Ioannis Roxanis, Samantha Barlow, Helen Kalirai, Sarah Coupland, Ronan Broderick, Samar Alsafadi, Alexandre Houy, Marc-Henri Stern, Stephen Pettit, Jyoti Choudhary, Syed Haider, Wojciech Niedzwiedz, Christopher Lord, Rachael Natrajan. Mutations in the RNA Splicing Factor SF3B1 drive endocrine therapy resistance and confer a targetable replication stress response defect through PARP inhibition. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-05.

Ex-situ heart perfusion (ESHP) is commonly used for the reanimation and preservation of hearts following donation after circulatory determined death (DCD). The only commercially available existing ESHP device promotes perfusate lactate levels for assessment of heart viability. The reliability of this marker is yet to be confirmed for DCD heart transplantation.This is a single center, retrospective study examining DCD heart transplants from March 1, 2015 to June 30, 2020. Recipients were divided into 2 groups dependent upon their requirement for or absence of mechanical circulatory support post-transplant. Lactate profiles obtained during ESHP were analyzed. Hearts were procured using the direct procurement and perfusion (DPP) method.Fifty-one DCD heart transplant recipients were studied, of which 20 (39%) were dependent on mechanical circulatory support (MCS) following transplantation, (2% Ventricular Assist Device (VAD), 16% Extra Corporeal Membrane Oxygenation (ECMO) and 21% Intra-aortic balloon pumps (IABP). There was no difference in arterial lactate profiles on ESHP at any time point for those dependent upon MCS support (MCS) and those that were not (no MCS) post-transplant. After 3 hours of ESHP, the arterial lactate was5mmol/L in 80% upon MCS vs 62% no MCS, p = .30. There was also no difference in ESHP rising arterial lactate concentrations, (15% MCS vs 13% non MCS, p = 1.00).For DCD hearts transplants retrieved using the DPP technique, lactate profiles do not seem to be a reliable predictor of mechanical circulatory support requirement post-transplant.

Predicted heart mass (PHM) equations may be used in donor-recipient size matching in heart transplantation. We compared PHM and actual heart mass in 25 consecutive DBD heart transplants. There was a moderate positive correlation between actual heart mass and PHM. There was a similar moderate correlation between actual heart mass and donor weight or donor body surface area but not donor height. PHM was lower than actual heart mass for all donor hearts. Bland-Altman analysis showed a systematic bias between PHM and actual heart mass, with a mean difference of 190.9 ± 66.4 g. The utility of PHM equations is likely to be part of a multi-parametric assessment of the relative differences between donor and recipient, so the absolute difference is likely to be unimportant.

Mechanical circulatory support (MCS) describes the use of mechanical pumps to maintain blood flow around the body when the heart is unable to meet this need. MCS may be appropriate in cardiogenic shock, either as a bridge to decision, recovery, heart transplantation, or for long-term support (destination therapy). There are various techniques by which MCS may be delivered and the most appropriate technique will vary depending on the patient, pathology, clinical situation, and experience of the hospital. Adverse events during MCS are frequent despite advances in blood pump technology. Careful patient selection and meticulous care are essential to achieve acceptable long-term survival and quality of life.

Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of solid-organ transplantation (SOT). We present the incidence and outcomes of PTLD in a cohort of 5365 SOT recipients over a 20-year period at two UK transplant centres. With a median follow-up of 7.7 years, 142 of 5365 patients have developed PTLD. Cumulative incidence was 18% at five years after multivisceral transplant and 1%-3% at five years following the other SOT types. Twenty-year cumulative incidence was 2%-3% following liver and heart transplantation and 10% following kidney transplantation. Median overall survival (OS) following SOT was 16 years, which is significantly reduced compared with the age-adjusted UK population. There is relatively high early mortality following diagnosis of PTLD and only patients surviving two years regained a longer-term survival approaching the non-PTLD SOT cohort. Of 90 patients with monomorphic PTLD, diffuse large B-cell lymphoma, 66 were treated with first-line rituximab monotherapy and 24 received first-line rituximab plus chemotherapy. Up-front rituximab monotherapy does not appear to compromise OS, but the number of patients dying from non-lymphoma causes before and after treatment remains high with both treatment approaches. Multivariate analysis of all 90 monomorphic PTLD patients identified an International Prognostic Index (IPI) of 3+ as the strongest pretreatment variable associating with inferior one-year OS.

Advanced chronic kidney disease (CKD) frequently aggravates heart failure (HF). However, these patients have inherently been excluded from most HF trials. We aim to provide updated estimates of the representation of patients with advanced CKD and the provision of baseline renal function indices in HF trials with a focused interest on the landmark trials. Updated systematic review was performed from the inception of MEDLINE to 31 December 2019 to identify all chronic HF randomized trials published in the three major cardiology and medical journals, respectively, which included mortality endpoint. The included studies were analysed based on the representativeness of the advanced CKD population and the reporting of baseline renal function. A total of 187 eligible randomized trials with 322,374 participants were included in our analysis. One hundred and six trials (56.7%) had exclusion criteria related to renal function, which remained a continuing trend-55.1% (27/49) from inception-2000, 53.4% (39/73) from 2001-2010 and 61.5% (40/65) from 2011 (P = 0.64). The exclusion criteria, however, have become less restrictive. There was a temporal improvement in the likelihood of HF trials in providing baseline renal function indices (28.6% from inception-2000 versus 53.4% from 2001-2010 and 83.1% from 2011, P 0.001). Concordant findings were observed in the landmark trials. Patients with advanced CKD remain underrepresented in HF trials in the contemporary era, even though the exclusion criteria have become less restrictive, and the quality of renal function monitoring has improved. The continued underrepresentation of patients with advanced CKD in HF trials merits measured broadening of eligibility in further trial studies.

Aims The CardioMEMS HF System Post‐Market Study (COAST) was designed to evaluate the safety, effectiveness, and feasibility of haemodynamic‐guided heart failure (HF) management using a small sensor implanted in the pulmonary artery of New York Heart Association (NYHA) Class III HF patients in the UK, Europe, and Australia. Methods and results COAST is a prospective, international, multicentre, open‐label clinical study (NCT02954341). The primary clinical endpoint compares annualized HF hospitalization rates after 1 year of haemodynamic‐guided management vs. the year prior to sensor implantation in patients with NYHA Class III symptoms and a previous HF hospitalization. The primary safety endpoints assess freedom from device/system‐related complications and pressure sensor failure after 2 years. Results from the first 100 patients implanted at 14 out of the 15 participating centres in the UK are reported here. At baseline, all patients were in NYHA Class III, 70% were male, mean age was 69 ± 12 years, and 39% had an aetiology of ischaemic cardiomyopathy. The annualized HF hospitalization rate after 12 months was 82% lower [95% confidence interval 72–88%] than the previous 12 months (0.27 vs. 1.52 events/patient‐year, respectively, P

The identification of molecularly defined subgroups of Pancreatic ductal Adenocarcinoma (PDAC) has the potential to transform clinical practice. There is now a growing consensus that PDAC can be divided into transcriptomic subtypes with 2 broad linages referred to as Classical (Pancreatic) and Squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal linage specification, HNF4A and GATA6, switch metabolic profiles from Classical (Pancreatic) to predominantly Squamous, with GSK3B a key regulator of glycolysis. Pharmacological inhibition of GSK3B results in selective sensitivity in the Squamous subtype, however a subset of these Squamous PDCLs acquired rapid drug tolerance. Using chromatin accessibility maps, we identify subtype specific chromatin landscapes and unique promoter usage between subpopulations of Squamous PDCLs can affect drug tolerance. Our findings demonstrate that a chromatin-based framework can be used to identify subtypes of PDAC that are indistinguishable by gene expression profiles which could refine patient selection for precision medicine.

The symptomatic repertoire of cardiac disease is relatively narrow and most conditions will present with one or more of chest pain, dyspnoea, palpitation, syncope, or presyncope. On the other hand, the differential diagnosis of each of these symptoms is broad and includes both cardiac and non-cardiac disorders. Certain features of acute chest pain alter the likelihood of acute coronary syndrome but, in isolation, the history is usually insufficient to rule in or rule out the diagnosis. Intermittent chest pain can be categorized as typical angina, atypical angina, or non-anginal based on three symptom characteristics; this classification has substantial diagnostic value and helps to determine the need for and the most appropriate mode of further investigation. Orthopnoea and paroxysmal nocturnal dyspnoea are more specific for heart failure than other forms of dyspnoea. However, it is not possible to diagnose either acute or chronic heart failure by the history alone. For both angina and chronic heart failure, the European Society of Cardiology recommends objective assessment of symptom severity using the Canadian Cardiovascular Society and New York Heart Association classifications respectively. Definitive diagnosis of palpitation usually requires documentation of the cardiac rhythm during symptoms but a clear description of the symptom may suggest the likely diagnosis and guide the optimal approach to rhythm monitoring. The history is invaluable in differentiating syncope and presyncope from other causes of transient loss of consciousness and dizziness. Beyond this, clinical features such as prodromal symptoms or precipitation of episodes by exposure to pain can help to distinguish cardiac from reflex syncope.

A 48-year-old non-smoking man underwent laparotomy for peritonitis immediately after taking ibuprofen 800 mg 6 hourly for 14 days for back pain. His only other medication was long-term omeprazole 20 mg per day. At operation he had three separate perforations in his proximal jejunum. Fifteen centimetres of jejunum were resected with primary anastomosis. Histology showed focal mucosal ischaemic changes with normal mucosa between. There was no vasculitis. The perforations were attributed to ibuprofen intake. He made an uneventful recovery and was instructed to refrain from non-steroidal anti-inflammatory drug (NSAID) intake. He was readmitted …

Non-steroidal anti-inflammatory drugs (NSAIDs) can produce diaphragm disease where multiple strictures develop in the small bowel. This typically presents with anaemia and symptoms of small bowel obstruction. The strictures develop as a result of circumferential mucosal ulceration with subsequent contraction of rings of scar tissue. We report a case of a 47-year-old woman with a 6-month history of NSAIDs abuse who presented with subacute small bowel obstruction 1 year after stopping NSAIDs. CT and MRI showed multiple ileal strictures with florid locoregional lymphadenopathy. A malignant diagnosis such as lymphoma was considered likely as florid mesenteric lymphadenopathy has not been previously reported in diaphragm disease. Laparotomy with small bowel resection was therefore performed. Histology showed diaphragm disease with the enlarged mesenteric nodes having reactive features. Gross locoregional lymphadenopathy should not deter a diagnosis of diaphragm disease in cases of multiple small bowel strictures where there is a strong history of NSAIDs use.

The finding of unusual contents within hernias merits publication so as to raise surgeons’ awareness of the structures that could be encountered during hernia repair.1 ,2 We describe a case of a 66-year-old man who underwent elective transabdominal preperitoneal bilateral inguinal hernia repair. At laparoscopy, a large cystic structure was seen arising from the pelvis (figure 1). The hernias were repaired and the patient was informed of the abdominal finding before being discharged home later the …

A 35-year-old man was admitted following daily vomiting for 2 weeks. He reported bouts of unexplained vomiting over the preceding 10 years. Gastroscopy showed obstruction in the second part of the duodenum with normal mucosa on biopsy (figure 1). CT demonstrated dilation of the first part of the duodenum caused by narrowing of the second part (figure 2). There was no pancreatic mass. At laparotomy, a ring of pancreatic tissue was found encircling the second part of the duodenum causing obstruction (figure 3). This is …

Using feeding catheters to maintain gut function and optimise nutrition is commonplace. We highlight the pitfall of inadequate monitoring of catheters when used in stomas. A 44-year-old woman initially presented with intestinal obstruction; at laparotomy she underwent a 25 cm proximal jejunal resection, with the creation of a jejunostomy and mucous fistula. Postoperatively nutrition optimisation became paramount. Initially feeding was wholly parenteral. Progressively enteral nutrition was initiated, yet due to the difficulty with tolerance and fistula output; a 22F catheter was placed in …

We describe two cases of recurrent major umbilical bleeding in male patients with Childs A liver cirrhosis and portal hypertension. Both patients had umbilical hernias with omentum incarcerated in the hernial sac. In both cases, portosystemic abdominopelvic CT scan had shown omental varices without significant paraumbilical cutaneous varices. Previous reports have shown that venous communication can develop between omental varices and overlying abdominal wall scars, resulting in spontaneous cutaneous bleeding. We concluded that there was a similar mechanism for the umbilical bleeding in our cases and both were successfully treated by excising the umbilicus, ligating the omental varices within the hernia sac, returning the omentum to the abdominal cavity and repairing the hernia defect. This cause for umbilical bleeding has not been previously reported. We advise that with similar cases, excision of the umbilicus and ligation of the omental varices is safe and effective treatment. Umbilical bleeding is a well recognised but rare complication of portal hypertension. In previously reported cases, it has arisen from rupture of umbilical varices that have developed due to portosystemic communication between the recanalised umbilical vein and the periumbilical veins of the abdominal wall.1–8 We present two cases of recurrent major umbilical bleeding from omental varices incarcerated within an umbilical hernia. Both cases were treated successfully with excision of the umbilicus and ligation of the omental varices. This is the first report of umbilical bleeding from omental varices in patients with umbilical hernias and portal hypertension. We wished to raise awareness of this potentially life-threatening condition and have discussed its pathogenesis, investigation and surgical management. ### Case 1 A 51-year-old man presented with spontaneous bleeding from his umbilicus. He described blood pouring out of his umbilicus as if a tap had been turned on (figure 1). His clothes had become soaked with blood. He had Childs A …

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