Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance. PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51. RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient. CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

Expert consensus on the systemic treatment of atopic dermatitis in special populations.

With the increasing number of options for the treatment of moderate-to-severe atopic dermatitis, clinicians need guidance on a practical approach to selecting a systemic agent for specific patient populations. We convened an expert panel consisting of 12 members to conduct a literature review and summarize relevant data related to six scenarios of clinical interest: comorbid asthma, ocular surface disease, history of cancer, past and ongoing infections of interest (including herpes simplex virus, herpes zoster, hepatitis B, and tuberculosis), pregnancy and lactation, and the elderly. We performed a literature search and examined each clinical scenario with respect to three major categories of available systemic agents: traditional systemics (azathioprine, cyclosporine A, methotrexate, and mycophenolate mofetil), Janus kinase inhibitors (abrocitinib, baricitinib, and upadacitinib), and biologics (dupilumab, lebrikizumab, and tralokinumab). The expert panel and steering committee met virtually to review the data and discuss the drafted consensus statements. A modified Delphi process was used to arrive at a set of final consensus statements related to the systemic treatment of AD in these specific patient populations. To provide practical guidance on the choice of systemic therapy for atopic dermatitis in these six topics of clinical interest, 25 expert consensus statements and a summary of the supporting data are presented herein.

Clinical manifestations and treatment outcomes in degos disease: a systematic review.

Degos disease (atrophic papulosis) is a rare vasculopathy with cutaneous and systemic manifestations. Although potentially fatal, the characteristics of and treatments for Degos disease variants are not adequately described. We conducted a systematic review to summarize cutaneous and systemic presentations, treatments and outcomes of malignant (MAP) and benign (BAP) variants of Degos disease. A comprehensive search was conducted on Embase, MEDLINE, CINAHL and CENTRAL on 27 October 2020, which yielded 254 original studies reporting cases of Degos disease. A total of 357 patients were included in the analysis. Mean age of onset was 33.9 years. MAP was most commonly reported (63.8%, n = 228/357), with 56.6% (n = 129/228) mortality. Cutaneous lesions were usually asymptomatic (26.3%, n = 81/308) and localized to the trunk (57.7%, n = 206/357) and extremities (56.8%, n = 203/357). Systemic involvement developed within 2 years on average, ranging from 0 to 28 years. Anti-platelet monotherapy had a complete resolution rate of 42.3% (n = 11/26) in BAP and 20.0% (n = 7/35) in MAP. Based on the findings of the study, most cases of Degos disease are malignant with high mortality, and even benign cutaneous cases may develop systemic disease in as late as 28 years. Anti-platelet monotherapies may prove effective against both variants. Further studies are needed to confirm these findings.

Contrast enhanced ultrasound of carotid plaque in acute ischemic stroke (CUSCAS study).

INTRODUCTION: Carotid atherosclerosis represents 8 to 15% of ischemic strokes in relation to the concept of "vulnerable" plaque. Contrast enhanced ultrasound (CEUS) can detect moving microbubbles within the plaque corresponding to neovessels that constitute "precursors" of vulnerable plaque and intraplaque hemorrhage. CEUS was not studied specifically in acute ischemic strokes. The aim of this study is to analyse the prevalence of CEUS carotid plaque ipsilateral at the ischemic stroke as well as the main characteristics of contrast-plaques. METHOD: A single-centre prospective pilot study involving 33 consecutive patients with a stroke ≤10 days, diagnosed by an MRI with positive diffusion sequence and having a carotid plaque thickness ≥2.5mm with low or heterogeneous echogenicity, located in the ipsilateral carotid territory at the stroke. Plaque echogenicity was done by visual analysis and by measurement of the gray scale median (GSM). A transcranial Doppler monitoring was carried out in search of HITS. The contrast ultrasound was performed after 2.5 cc IV injection of SonoVue®. A video clip was recorded after injection which was used for interpretation by visual analysis in 3 grades, provided by two independent expert readers. RESULTS: The population consisted of 10 women and 23 men aged 73 on average. The topography of strokes in the carotid territory was located on the right in 11 (33%) cases and on the left in 22 (67%) cases. Seventeen patients had carotid stenosis between 0 and 49% according to the Nascet method and 16 patients had stenosis of 50 to 99%. The visual characterisation of the plaques had echolucent dominance (Type 1-2) in 18 cases and echogenic dominance (Type 3-4a) in 15 cases. Cardiovascular risk factors were common with no difference by sex. The inter-observer agreement of plaque enhancement was moderate in first reading (k=0.48) and excellent at consensus (k=0.91). Only one disagreement was found. Contrast agent enhancement of carotid plaque was observed in 11/32 patients, representing a prevalence of 34.4% - CI95% [17.9-50.9]. Variables associated with contrast plaque included the absence of antiplatelet drug (63.6% vs. 23.8%, P=0.05) and the presence of a regular edge on the plaque (91% vs. 48%, P=0.04). There was no difference in contrast enhancement for stenosis>or<50% in diameter and neither for the type of plaque. CONCLUSION: In a consecutive cohort of 33 patients, the prevalence of CEUS from an ipsilateral carotid plaque to a recent acute ischemic stroke was 34.4%. There was a statistically significant association between the contrast enhancement of the plaque and the absence of antiplatelet drug (P=0.05) and also the presence of a regular edge on the plaque (P=0.04). There was no correlation between plaque contrast and clinical and biological characteristics of patients or the presence of HITS.

The effect of intravenous iron on erythropoiesis in older people with hip fracture.

BACKGROUND: anaemia following hip fracture is common and associated with worse outcomes. Intravenous iron is a potential non-transfusion treatment for this anaemia and has been found to reduce transfusion rates in previous observational studies. There is good evidence for its use in elective surgical populations. OBJECTIVE: to examine the impact of intravenous iron on erythropoiesis following hip fracture. DESIGN: two-centre, assessor-blinded, randomised, controlled trial of patients with primary hip fracture and no contra-indications to intravenous iron. METHOD: the intervention group received three doses of 200 mg iron sucrose over 30 min (Venofer, Vifor Pharma, Bagshot Park, UK) on three separate days. Primary outcome was reticulocyte count at day 7 after randomisation. Secondary outcomes included haemoglobin concentration, complications and discharge destination. Eighty participants were randomised. RESULTS: there was a statistically significantly greater absolute final reticulocyte count in the iron group (89.4 (78.9-101.3) × 109 cells l-1 (n = 39) vs. the control (72.2 (63.9-86.4)) × 109 cells l-1 (n = 41); P = 0.019; (mean (95% confidence intervals) of log-transformed data). There were no differences in final haemoglobin concentration (99.9 (95.7-104.2) vs. 102.0 (98.7-105.3) P = 0.454) or transfusion requirements in the first week (11 (28%) vs. 12 (29%); P = 0.899). Functional and safety outcomes were not different between the groups. CONCLUSIONS: although intravenous iron does stimulate erythropoiesis following hip fracture in older people, the effect is too small and too late to affect transfusion rates. Trial Registry Numbers: ISRCTN:76424792; EuDRACT: 2011-003233-34.

Treatment choices and outcomes of patients with manometrically diagnosed achalasia.

This prospective population-based study was designed to evaluate treatment choices in patients with new manometrically diagnosed achalasia and their outcomes. Patients referred to the esophageal function laboratory were enrolled after a new manometric diagnosis of achalasia. Patients completed an initial achalasia symptom score validated questionnaire on their symptom severity, duration, treatment pre-diagnosis and Medical Outcomes Study 36-item Short-Form (SF-36) survey. Treatment decisions were made by the referring physician and the patient. Follow-up questionnaires were completed every 3 months for 1 year. Patients who chose not to undergo treatment at 1-year follow-up completed another questionnaire after 5 years. Between January 2004 and January 2005, 83 of 124 eligible patients were enrolled. Heller myotomy was performed on 31 patients, three patients received botulinum toxin injections, and 25 patients received 29 pneumatic balloon dilatations. Twenty-four patients chose to receive no treatment. Following treatment, patients treated with surgery, dilatation and botulinum toxin had an average improvement in achalasia symptom score of 23 +/- 12.2, 17 +/- 10.9, and 9 +/- 14, respectively. Patients receiving no treatment had worsening symptoms with a symptom score change of -3.5 +/- 11.4. Surgery and dilatation resulted in significant improvement (P < 0.01) relative to no treatment. In univariate logistic regression, symptom severity score (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.00 to 1.08), sphincter tone (OR 1.04, 95% CI 1.00 to 1.09), difficulty swallowing liquids (OR 3.21, 95% 1.15 to 8.99), waking from sleep (OR 2.75, 95% 1.00 to 7.61), and weight loss (OR 5.99, 95% CI 1.93 to 18.58) were all significant in predicting that patients would select treatment. In the multivariate analysis, older age (OR 1.05, 95% CI 1.01 to 1.09) and weight loss (OR 3.91, 95% CI 1.02 to 15.2) were statistically significant for undergoing treatment. At 5 years, five (21%) of those who had initially declined treatment at 1 year ultimately chose a treatment. Patients who finally chose Heller myotomy had lower mental component dimension scores on the SF-36 at 1 year than those who did not. This study shows that almost one third of patients with manometrically diagnosed achalasia choose not to undergo treatment within 1 year of their diagnosis. Patients who are more symptomatic appear to be more likely to undergo treatment by univariate analysis. In multivariate analysis, increasing age and weight loss are predictive of those who will undergo treatment, with weight loss having the greatest influence. Patients who choose not to undergo treatment make lifestyle changes to maintain their quality of life, and only a minority of them ultimately undergo treatment.

Lung transplantation with donation after circulatory determination of death donors and the impact of ex vivo lung perfusion.

The growing demand for suitable lungs for transplantation drives the quest for alternative strategies to expand the donor pool. The aim of this study is to evaluate the outcomes of lung transplantation (LTx) with donation after circulatory determination of death (DCDD) and the impact of selective ex vivo lung perfusion (EVLP). From 2007 to 2013, 673 LTx were performed, with 62 (9.2%) of them using DCDDs (seven bridged cases). Cases bridged with mechanical ventilation/extracorporeal life support were excluded. From 55 DCDDs, 28 (51%) underwent EVLP. Outcomes for LTx using DCDDs and donation after neurological determination of death (DNDD) donors were similar, with 1 and 5-year survivals of 85% and 54% versus 86% and 62%, respectively (p = 0.43). Although comparison of survival curves between DCDD + EVLP versus DCDD-no EVLP showed no significant difference, DCDD + EVLP cases presented shorter hospital stay (median 18 vs. 23 days, p = 0.047) and a trend toward shorter length of mechanical ventilation (2 vs. 3 days, p = 0.059). DCDDs represent a valuable source of lungs for transplantation, providing similar results to DNDDs. EVLP seems an important technique in the armamentarium to safely increase lung utilization from DCDDs; however, further studies are necessary to better define the role of EVLP in this context.

Evaluation of a Clostridium difficile infection management policy with clinical pharmacy and medical microbiology involvement at a major Canadian teaching hospital.

WHAT IS KNOWN AND OBJECTIVE: Clostridium difficile infection (CDI) represents a spectrum of disease and is a significant concern for healthcare institutions. Our study objective was to assess whether implementation of a regional CDI management policy with Clinical Pharmacy and Medical Microbiology and Infection Control involvement would lead to an improvement in concordance in prescribing practices to an evidence-based CDI disease severity assessment and pharmacological treatment algorithm. METHODS: Conducted at a tertiary care teaching hospital, this two-phase quality assurance study consisted of a baseline retrospective healthcare record review of patients with CDI prior to the implementation of a regional CDI management policy followed by a prospective evaluation post-implementation. RESULTS AND DISCUSSION: One hundred and forty-one CDI episodes in the pre-implementation group were compared to 283 episodes post-implementation. Overall treatment concordance to the CDI treatment algorithm was achieved in 48 of 141 cases (34%) pre-implementation compared with 136 of 283 cases (48·1%) post-implementation (P = 0·01). The median time to treatment with vancomycin was reduced from five days to one day (P < 0·01), with median length of hospital stay decreasing from 30 days to 21 days (P = 0·01) post-implementation. There was no difference in 30-day all-cause mortality. WHAT IS NEW AND CONCLUSION: A comprehensive approach with appropriate stakeholder involvement in the development of clinical pathways, education to healthcare workers and prospective audit with intervention and feedback can ensure patients diagnosed with CDI are optimally managed and prescribed the most appropriate therapy based on CDI disease severity.

Early onset metastatic colorectal cancer in Australia.

BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates have been increasing among young patients (YP), for uncertain reasons. It is unclear whether YP have a distinct tumor biology or merit a different treatment approach to older patients (OP). METHODS: We reviewed prospectively collected data from consecutive patients with metastatic CRC (MCRC) enrolled in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australian registry. Clinicopathological features, treatment and survival outcomes were compared between YP (<50 years) and OP (≥50 years). RESULTS: Of 3692 patients diagnosed August 2009 - March 2023, 14 % (513) were YP. YP were more likely than OP to be female (52% vs. 40 %, P < 0.0001), have ECOG performance status 0-1 (94% vs. 81 %, P < 0.0001), to have a left-sided primary (72% vs. 63 %, P = 0.0008) and to have fewer comorbidities (90% vs. 60 % Charleston score 0, P < 0.0001). There were no differences in the available molecular status, which was more complete in YP. YP were more likely to have de novo metastatic disease (71% vs. 57 %, P < 0.0001). YP were more likely to undergo curative hepatic resection (27% vs. 17 %, P < 0.0001), to receive any chemotherapy (93% vs. 78 % (P < 0.0001), and to receive 3+ lines of chemotherapy (30% vs. 24 % (P < 0.0034)). Median first-line progression free survival (10.2 versus 10.6 months) was similar for YP vs OP, but overall survival (32.1 versus 25.4 months, HR = 0.745, P < 0.0001) was longer in YP. CONCLUSION: Known prognostic variables mostly favored YP versus OP with newly diagnosed mCRC, who were also more heavily treated. Consistent with this, overall survival outcomes were improved. This data does not support that CRC in YP represent a distinct subset of mCRC patients, or that a modified treatment approach is warranted.