Pathologic Lymph Node Regression After Neoadjuvant Chemotherapy Predicts Recurrence and Survival in Esophageal Adenocarcinoma: A Multicenter Study in the United Kingdom.

PURPOSE: There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma. METHODS: Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index. RESULTS: In total, 17,930 LNs from 763 patients were examined. LN response classified as complete LN response (LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%), partial LN response (LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%), poor/no LN response (LNRS 4-5; n = 303, 39.7%), or LN negative (no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio [HR], 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%). CONCLUSION: Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.

Real world outcomes in cancer patients with COVID-19 infection: Northern Ireland experience.

Background: Cancer has been assumed to be associated with a high-risk of morbidity and mortality from COVID-19. Protective measures have incorporated modifications in cancer treatments. There are conflicting data about the impact of COVID-19 infection and outcomes in cancer patients. We aim to describe the impact of demographic and clinical characteristics on COVID-19 outcomes in patients with cancer in Northern Ireland reported within the UK Coronavirus Cancer Monitoring Project (UKCCMP). Method: Prospective data collection including demographics, cancer stage and type, treatment and outcomes occurred for all Northern Irish patients enrolled in the UKCCMP. The primary endpoint was all-cause mortality. Descriptive statistics and logistic regression analysis were performed using SPSSv25. Results: Between March 2020 and March 2021, 110 cases were registered. Median age was 63 years (range 27 to 87). Seventy patients (63.6%) were >60 years and 59 (53.8%) were females. Co-morbidities were reported in 83 patients (72.7%). Most patients had metastatic disease (64, 58.2%). Sixty-seven patients (60.9%) received anticancer treatment in the 4 weeks prior to COVID-19 infection. Of those patients, 35 (52.2%) received chemotherapy. Thirty-nine patients (58.2%) continued treatment as planned; 24 (36.9%) stopped treatment due to SARS-CoV-2 infection. The majority of patients were asymptomatic or experienced mild symptoms (67, 60.9%). Fifty-one (46.3%%) were admitted to hospital for COVID-19. Risk of severe/critical COVID-19 disease was significantly associated with age (OR 1.07 [95% CI 1.03-1.11); p=0.004), pre-existing hypertension (OR 3.29 [95% CI 1.42-7.62]; p=0.02) and thoracic primary malignancy (OR 4.41 [95% CI 1.52-12.74]; p=0.042). Twenty-nine patients (26.3%) died of whom 15 (57.7%) died of COVID-19 and 13 (44.8%) died due to cancer. Risk of death was significantly associated with age (OR 1.05 [95% CI 1.01-1.09]; p=0.014), male sex (OR 3.76 [95% CI 1.51-9.34]; p=0.008) and thoracic primary malignancy (OR 5.35 [95% CI 1.88-15.25]; p=0.014). When corrected for age, gender and co-morbidities, chemotherapy within the past 4 weeks was not significantly associated with mortality (OR 0.65 [95% CI 0.20-2.11]; p=0.476). Conclusion: Age and thoracic cancer diagnosis correlated with survival. Comparison of performance during the pandemic with national benchmarks can inform how regional services should be adapted in preparation for future healthcare crises.

A DNA-damage immune response assay combined with PET biomarkers predicts response to neo-adjuvant chemotherapy and survival in oesophageal adenocarcinoma.

18F-fluorodeoxyglucose PET-CT may guide treatment decisions in patients with oesophageal adenocarcinoma (OAC). This study evaluated the added value of maximum standardised uptake value (SUVmax) to a novel DNA-damage immune response (DDIR) assay to improve pathological response prediction. The diagnostic accuracy of PET response and the prognostic significance of PET metrics for recurrence-free survival (RFS) and overall survival (OS) were assessed. This was a retrospective, single-centre study of OAC patients treated with neo-adjuvant chemotherapy from 2003 to 2014. SUVmax was recorded from baseline and repeat PET-CT after completion of pre-operative chemotherapy. Logistic regression models tested the additional predictive value of PET metrics combined with the DDIR assay for pathological response. Cox regression models tested the prognostic significance of PET metrics for RFS and OS. In total, 113 patients were included; 25 (22.1%) were DDIR positive and 88 (77.9%) were DDIR negative. 69 (61.1%) were PET responders (SUVmax reduction of 35%) and 44 (38.9%) were PET non-responders. After adding PET metrics to DDIR status, post-chemotherapy SUVmax (hazard ratio (HR) 0.75, p = 0.02), SUVmax change (HR 1.04, p = 0.003) and an optimum SUVmax reduction of 46.5% (HR 4.36, p = 0.021) showed additional value for predicting pathological response. The optimised SUVmax threshold was independently significant for RFS (HR 0.47, 95% CI 0.26-0.85, p = 0.012) and OS (HR 0.51, 95% CI 0.26-0.99, p = 0.047). This study demonstrated the additional value of PET metrics, when combined with a novel DDIR assay, to predict pathological response in OAC patients treated with neo-adjuvant chemotherapy. Furthermore, an optimised SUVmax reduction threshold for pathological response was calculated and was independently significant for RFS and OS.

An overview of acute gastrointestinal side effects of systemic anti-cancer therapy and their management.

Treatment-related acute gastrointestinal toxicities are a common and often debilitating hurdle encountered in the treatment of cancer patients. While the introduction of targeted therapies such as tyrosine kinase inhibitors has led to improvements in survival outcomes, their use has also been complicated by a high frequency of clinically important adverse effects. Gastrointestinal toxicities such as nausea, vomiting, diarrhoea and hepatotoxicity represent potentially serious adverse events that may necessitate dose reductions, treatment interruptions and cessation of treatment. An improved knowledge of the incidence, pathophysiology, management and prophylaxis of these toxicities is crucial in order to reduce patient morbidity and mortality. In this review, we discuss the main gastrointestinal toxicities associated with chemotherapy and targeted therapies in oncology, outlining their incidence, pathophysiology and expert management guidelines.

Transcriptomic biomarkers for predicting response to neoadjuvant treatment in oesophageal cancer.

Oesophageal cancer is a devastating disease with poor outcomes and is the sixth leading cause of cancer death worldwide. In the setting of resectable disease, there is clear evidence that neoadjuvant chemotherapy and chemoradiotherapy result in improved survival. Disappointingly, only 15%-30% of patients obtain a histopathological response to neoadjuvant therapy, often at the expense of significant toxicity. There are no predictive biomarkers in routine clinical use in this setting and the ability to stratify patients for treatment could dramatically improve outcomes. In this review, we aim to outline current progress in evaluating predictive transcriptomic biomarkers for neoadjuvant therapy in oesophageal cancer and discuss the challenges facing biomarker development in this setting. We place these issues in the wider context of recommendations for biomarker development and reporting. The majority of studies focus on messenger RNA (mRNA) and microRNA (miRNA) biomarkers. These studies report a range of different genes involved in a wide variety of pathways and biological processes, and this is explained to a large extent by the different platforms and analysis methods used. Many studies are also vastly underpowered so are not suitable for identifying a candidate biomarker. Multiple molecular subtypes of oesophageal cancer have been proposed, although little is known about how these relate to clinical outcomes. We anticipate that the accumulating wealth of genomic and transcriptomic data and clinical trial collaborations in the coming years will provide unique opportunities to stratify patients in this poor-prognosis disease and recommend that future biomarker development incorporates well-designed retrospective and prospective analyses.

Plasma levels of intermedin (adrenomedullin-2) in healthy human volunteers and patients with heart failure.

Intermedin/adrenomedullin-2 (IMD) is a member of the adrenomedullin/CGRP peptide family. Less is known about the distribution of IMD than for other family members within the mammalian cardiovascular system, particularly in humans. The aim was to evaluate plasma IMD levels in healthy subjects and patients with chronic heart failure. IMD and its precursor fragments, preproIMD(25-56) and preproIMD(57-92), were measured by radioimmunoassay in 75 healthy subjects and levels of IMD were also compared to those of adrenomedullin (AM) and mid-region proadrenomedullin(45-92) (MRproAM(45-92)) in 19 patients with systolic heart failure (LVEF<45%). In healthy subjects, plasma levels (mean+SE) of IMD (6.3+0.6 pg ml(-1)) were lower than, but correlated with those of AM (25.8+1.8 pg ml(-1); r=0.49, p<0.001). Plasma preproIMD(25-56) (39.6+3.1 pg ml(-1)), preproIMD(57-92) (25.9+3.8 pg ml(-1)) and MRproAM(45-92) (200.2+6.7 pg ml(-1)) were greater than their respective bioactive peptides. IMD levels correlated positively with BMI but not age, and were elevated in heart failure (9.8+1.3 pg ml(-1), p<0.05), similarly to MRproAM(45-92) (329.5+41.9 pg ml(-1), p<0.001) and AM (56.8+10.9 pg ml(-1), p<0.01). IMD levels were greater in heart failure patients with concomitant renal impairment (11.3+1.8 pg ml(-1)) than those without (6.5+1.0 pg ml(-1); p<0.05). IMD and AM were greater in patients receiving submaximal compared with maximal heart failure drug therapy and were decreased after 6 months of cardiac resynchronization therapy. In conclusion, IMD is present in the plasma of healthy subjects less abundantly than AM, but is similarly correlated weakly with BMI. IMD levels are elevated in heart failure, especially with concomitant renal impairment, and tend to be reduced by high intensity drug or pacing therapy.

The South Asian genome.

The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.