Detection of Barrett's Neoplasia with Vibrational Spectroscopy

Early detection of Barrett’s oesophagus and associated neoplasia is key to preventing progression to oesophageal adenocarcinoma. Improving surveillance and introducing population screening for Barrett’s are major goals of current research: this project aimed to apply emerging techniques in vibrational spectroscopy to these problems. Fourier transform infrared (FTIR) mapping was used to develop an automated histology tool for detection of Barrett’s and Barrett’s neoplasia in tissue biopsies. 45 FTIR maps were measured from 22 tissue samples from 19 patients. Principal component analysis (PCA) fed linear discriminant analysis (LDA) was used to build classification models based on spectral differences, tested using leave one sample out cross validation (LOSOCV). Classification of normal squamous samples versus ‘abnormal’ samples (any stage of Barrett’s) was performed with 100% sensitivity and specificity. Using a 3-group model to differentiate normal squamous, non-dysplastic Barrett’s and neoplastic Barrett’s (dysplasia or adenocarcinoma), neoplastic Barrett’s was identified with 95.6% sensitivity and 86.4% specificity. Non-endoscopic cell collection devices have recently been developed for population screening for Barrett’s oesophagus. A further aim of this project was to evaluate FTIR for classification of oesophageal cells. Cytology brushings were collected at endoscopy, cytospun onto slides and FTIR maps measured. Cytology review and contemporaneous histology was used to inform a training dataset containing 141 cells from 17 patients. A classification model was constructed using PCA-fed LDA. Applying this training model to the entire dataset of 115 FTIR maps from 66 patients, whole samples were classified with sensitivity and specificity respectively as follows: normal squamous 79.0% and 77.0%, non-dysplastic Barrett’s 31.3% and 100%, and neoplastic Barrett’s 83.3% and 54.2%. Raman spectroscopy was also evaluated as a tool for tissue diagnosis, but several strands of enquiry were limited by instrument problems. FTIR mapping could be used as an accurate, automated tool for processing biopsies in Barrett’s surveillance. Analysis of oesophageal cell samples can be performed using FTIR with reasonable sensitivity for Barrett’s neoplasia, though poor specificity with the current technique.Royal College of Surgeons of Englan

Cks1 Is Required for Tumor Cell Proliferation but Not Sufficient to Induce Hematopoietic Malignancies

The Cks1 component of the SCFSkp2 complex is necessary for p27Kip1 ubiquitylation and degradation. Cks1 expression is elevated in various B cell malignancies including Burkitt lymphoma and multiple myeloma. We have previously shown that loss of Cks1 results in elevated p27Kip1 levels and delayed tumor development in a mouse model of Myc-induced B cell lymphoma. Surprisingly, loss of Skp2 in the same mouse model also resulted in elevated p27Kip1 levels but exhibited no impact on tumor onset. This raises the possibility that Cks1 could have other oncogenic activities than suppressing p27Kip1. To challenge this notion we have targeted overexpression of Cks1 to B cells using a conditional retroviral bone marrow transduction-transplantation system. Despite potent ectopic overexpression, Cks1 was unable to promote B cell hyperproliferation or B cell malignancies, indicating that Cks1 is not oncogenic when overexpressed in B cells. Since Skp2 overexpression can drive T-cell tumorigenesis or other cancers we also widened the quest for oncogenic activity of Cks1 by ubiquitously expressing Cks1 in hematopoetic progenitors. At variance with c-Myc overexpression, which caused acute myeloid leukemia, Cks1 overexpression did not induce myeloproliferation or leukemia. Therefore, despite being associated with a poor prognosis in various malignancies, sole Cks1 expression is insufficient to induce lymphoma or a myeloproliferative disease in vivo

Potential of FX06 to prevent disease progression in hospitalized non-intubated COVID-19 patients — the randomized, EU-wide, placebo-controlled, phase II study design of IXION

Background: More than 2.7 million hospitalizations of COVID-19-infected patients have occurred in Europe alone since the outbreak of the coronavirus in 2020. Interventions against SARS-CoV-2 are still in high need to prevent admissions to ICUs worldwide. FX06, a naturally occurring peptide in humans and other mammals, has the potential to reduce capillary leak by improving endothelial dysfunction and thus preventing the deterioration of patients. With IXION, we want to investigate the potential of FX06 to prevent disease progression in hospitalized, non-intubated COVID-19 patients. Methods: IXION is an EU-wide, multicentre, placebo-controlled, double-blinded, parallel, randomized (2:1) phase II clinical study. Patient recruitment will start in September 2022 (to Q2/2023) in Germany, Italy, Lithuania, Spain, Romania, Portugal, and France. A total of 306 hospitalized patients (>= 18 years and < 75 years) with a positive SARS-CoV-2 PCR test and a COVID-19 severity of 4-6 according to the WHO scale will be enrolled. After randomization to FX06 or placebo, patients will be assessed until day 28 (and followed up until day 60). FX06 (2 x 200 mg per day) or placebo will be administered intravenously for 5 consecutive days. The primary endpoint is to demonstrate a difference in the proportion of patients with progressed/worsened disease state in patients receiving FX06 compared to patients receiving placebo. Secondary endpoints are lung function, oxygen saturation and breathing rate, systemic inflammation, survival, capillary refill time, duration of hospital stay, and drug accountability. Discussion: With IXION, the multidisciplinary consortium aims to deliver a new therapy in addition to standard care against SARS-CoV-2 for the clinical management of COVID-19 during mild and moderate stages. Potential limitations might refer to a lack of recruiting and drop-out due to various possible protocol violations. While we controlled for drop-outs in the same size estimation, recruitment problems may be subject to external problems difficult to control for

Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma

Abstract: The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Characteristics and mortality of 561,379 hospitalized COVID-19 patients in Germany until December 2021 based on real-life data

The ongoing SARS-CoV-2 pandemic is characterized by poor outcome and a high mortality especially in the older patient cohort. Up to this point there is a lack of data characterising COVID-19 patients in Germany admitted to intensive care (ICU) vs. non-ICU patients. German Reimbursement inpatient data covering the period in Germany from January 1st, 2020 to December 31th, 2021 were analyzed. 561,379 patients were hospitalized with COVID-19. 24.54% (n = 137,750) were admitted to ICU. Overall hospital mortality was 16.69% (n = 93,668) and 33.36% (n = 45,947) in the ICU group. 28.66% (n = 160,881) of all patients suffer from Cardiac arrhythmia and 17.98% (n = 100,926) developed renal failure. Obesity showed an odds-ratio ranging from 0.83 (0.79–0.87) for WHO grade I to 1.13 (1.08–1.19) for grade III. Mortality-rates peaked in April 2020 and January 2021 being 21.23% (n = 4539) and 22.99% (n = 15,724). A third peak was observed November and December 2021 (16.82%, n = 7173 and 16.54%, n = 9416). Hospitalized COVID-19 patient mortality in Germany is lower than previously shown in other studies. 24.54% of all patients had to be treated in the ICU with a mortality rate of 33.36%. Congestive heart failure was associated with a higher risk of death whereas low grade obesity might have a protective effect on patient survival. High admission numbers are accompanied by a higher mortality rate