Multicentre validation of CT grey-level co-occurrence matrix features for overall survival in primary oesophageal adenocarcinoma.

BACKGROUND: Personalising management of primary oesophageal adenocarcinoma requires better risk stratification. Lack of independent validation of proposed imaging biomarkers has hampered clinical translation. We aimed to prospectively validate previously identified prognostic grey-level co-occurrence matrix (GLCM) CT features for 3-year overall survival. METHODS: Following ethical approval, clinical and contrast-enhanced CT data were acquired from participants from five institutions. Data from three institutions were used for training and two for testing. Survival classifiers were modelled on prespecified variables ('Clinical' model: age, clinical T-stage, clinical N-stage; 'ClinVol' model: clinical features + CT tumour volume; 'ClinRad' model: ClinVol features + GLCM_Correlation and GLCM_Contrast). To reflect current clinical practice, baseline stage was also modelled as a univariate predictor ('Stage'). Discrimination was assessed by area under the receiver operating curve (AUC) analysis; calibration by Brier scores; and clinical relevance by thresholding risk scores to achieve 90% sensitivity for 3-year mortality. RESULTS: A total of 162 participants were included (144 male; median 67 years [IQR 59, 72]; training, 95 participants; testing, 67 participants). Median survival was 998 days [IQR 486, 1594]. The ClinRad model yielded the greatest test discrimination (AUC, 0.68 [95% CI 0.54, 0.81]) that outperformed Stage (ΔAUC, 0.12 [95% CI 0.01, 0.23]; p = .04). The Clinical and ClinVol models yielded comparable test discrimination (AUC, 0.66 [95% CI 0.51, 0.80] vs. 0.65 [95% CI 0.50, 0.79]; p > .05). Test sensitivity of 90% was achieved by ClinRad and Stage models only. CONCLUSIONS: Compared to Stage, multivariable models of prespecified clinical and radiomic variables yielded improved prediction of 3-year overall survival. CLINICAL RELEVANCE STATEMENT: Previously identified radiomic features are prognostic but may not substantially improve risk stratification on their own. KEY POINTS: • Better risk stratification is needed in primary oesophageal cancer to personalise management. • Previously identified CT features-GLCM_Correlation and GLCM_Contrast-contain incremental prognostic information to age and clinical stage. • Compared to staging, multivariable clinicoradiomic models improve discrimination of 3-year overall survival.

Digital Informed Consent: Modernising Information Sharing in Surgery to Empower Patients.

BACKGROUND: Despite the 2015 Montgomery Ruling highlighting key requisites for informed consent, little has changed to modernise data-sharing and documentation of the consent process. It can be difficult to gauge patient understanding and address all patient concerns in time-limited appointments. We aimed to assess the feasibility of a digital information-sharing platform to support a move towards a digital informed consent process. METHODS: All adult patients referred to a single centre with symptomatic gallstones were invited to use a digital information-sharing platform to support the informed consent process prior to their first surgical clinic appointment. The platform provided patients with multimedia information on gallstones and available treatment options. It recorded the time spent accessing information, asked patients multiple choice questions (MCQs) to allow a self-test of understanding, documented a summary medical history, and allowed free text for patient questions. This information was summarised into a clinical report to support outpatient clinic consultations. RESULTS: Of the 349 patients registered to use the digital platform, 203 (58.2%) [165 (81.3%) female, mean age 47.6 years (range 19-84 years)] completed all modules necessary to generate a clinical report. Some 130 patients (64.0%) answered all 10 MCQs correctly and spent a mean of 18.7 min (range 3-88 min) reading the consent information. Most patient-reported medical histories were deemed to be accurate. CONCLUSION: Despite difficulties with access, resulting in drop-outs, patients welcomed the opportunity to receive information digitally, prior to their consultation. Patients described feeling empowered and better informed to be involved in decision-making.

Digital Follow-Up After Elective Laparoscopic Cholecystectomy: A Feasibility Study.

BACKGROUND: Although recommendations exist for patients to be offered a post-operative helpline or telephone follow-up appointment at discharge after cholecystectomy, implementation of these is resource-intensive. Whilst the benefits of telephone follow-up are well documented, the use of digital modalities is less so. We aimed to identify if digital follow-up (DFU) was equivalent to routine care with telephone follow-up (TFU), for patients undergoing elective laparoscopic cholecystectomy. METHODS: All patients listed for elective laparoscopic cholecystectomy between August 2016 and March 2018 were offered routine post-operative care (TFU or no follow-up) or DFU at a tertiary referral centre in Nottingham. RESULTS: Of 597 patients undergoing laparoscopic cholecystectomy, 199 (33.3%) opted for TFU, and 98 (16.4%) for DFU. DFU was completed for 85 (86.7%) participants and TFU for 125 (62.8%), p < 0.0001. Over 5 times as many patients who chose TFU missed their appointment compared to DFU (5.6% vs. 30.9%, p < 0.001). At 30-days post-operatively, patients undergoing TFU had significantly more post-operative wound infections identified then those undergoing DFU (17.6% vs 5.9%, p = 0.01). However, this did not impact the incidence of 30-day readmissions between groups (7.2% TFU vs. 7.1% DFU). No complications were missed by either the DFU or TFU modalities. DFU was completed significantly earlier than TFU (median 6 days vs. 13.5 days, p = 0.001) with high patient acceptability, identifying complications and alerting clinicians to those patients requiring an early review. CONCLUSION: This feasibility study has demonstrated that digital follow-up is an acceptable alternative to telephone follow-up after elective laparoscopic cholecystectomy.

Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts.

The chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.

Utilising Electronic PROMs to Measure a Change in Health Following Elective Laparoscopic Cholecystectomy: A Feasibility Study.

BACKGROUND: The collection of patient-reported outcome measures (PROMs) has many benefits for clinical practice. However, there are many barriers that prevent them from becoming a part of routine clinical care. The aim of this feasibility study was to pilot the use of a digital platform to facilitate the routine collection of pre- and post-operative electronic PROMs (ePROMs) in participants undergoing elective laparoscopic cholecystectomy and to validate the use of existing patient-reported outcomes for our population. METHODS: Participants scheduled for elective laparoscopic cholecystectomy were asked to complete digital versions of the Otago gallstones Condition-Specific Questionnaire (CSQ), and the RAND 36-item health survey (SF36). An assessment of methodological quality of ePROM questionnaires was also performed. RESULTS: Preoperative ePROMs were completed by 200 participants undergoing laparoscopic cholecystectomy. Post-operatively attrition was high (completion at 30 days, 3 months, and 6months: n = 61, 54, and 38, respectively) due to difficulties accessing our ePROMs portal. Of those able to complete, a significant improvement in quality of life was seen across all health domains post-operatively when compared with baseline preoperative values for both disease-specific and generic PROMs. Methodological quality was assessed as good to excellent in both digital questionnaires. CONCLUSION: The collection of ePROMs is possible with current technological advances. Although it may be an acceptable, and convenient process for patients, and a useful measure of quality-of-life trends for clinicians, further developmental work is necessary to improve accessibility for patients, improve compliance, and reduce reporting bias from high attrition rates.

Risk Prediction Model of 90-Day Mortality After Esophagectomy for Cancer.

Importance: Ninety-day mortality rates after esophagectomy are an indicator of the quality of surgical oncologic management. Accurate risk prediction based on large data sets may aid patients and surgeons in making informed decisions. Objective: To develop and validate a risk prediction model of death within 90 days after esophagectomy for cancer using the International Esodata Study Group (IESG) database, the largest existing prospective, multicenter cohort reporting standardized postoperative outcomes. Design, Setting, and Participants: In this diagnostic/prognostic study, we performed a retrospective analysis of patients from 39 institutions in 19 countries between January 1, 2015, and December 31, 2019. Patients with esophageal cancer were randomly assigned to development and validation cohorts. A scoring system that predicted death within 90 days based on logistic regression ß coefficients was conducted. A final prognostic score was determined and categorized into homogeneous risk groups that predicted death within 90 days. Calibration and discrimination tests were assessed between cohorts. Exposures: Esophageal resection for cancer of the esophagus and gastroesophageal junction. Main Outcomes and Measures: All-cause postoperative 90-day mortality. Results: A total of 8403 patients (mean [SD] age, 63.6 [9.0] years; 6641 [79.0%] male) were included. The 30-day mortality rate was 2.0% (n = 164), and the 90-day mortality rate was 4.2% (n = 353). Development (n = 4172) and validation (n = 4231) cohorts were randomly assigned. The multiple logistic regression model identified 10 weighted point variables factored into the prognostic score: age, sex, body mass index, performance status, myocardial infarction, connective tissue disease, peripheral vascular disease, liver disease, neoadjuvant treatment, and hospital volume. The prognostic scores were categorized into 5 risk groups: very low risk (score, ≥1; 90-day mortality, 1.8%), low risk (score, 0; 90-day mortality, 3.0%), medium risk (score, -1 to -2; 90-day mortality, 5.8%), high risk (score, -3 to -4: 90-day mortality, 8.9%), and very high risk (score, ≤-5; 90-day mortality, 18.2%). The model was supported by nonsignificance in the Hosmer-Lemeshow test. The discrimination (area under the receiver operating characteristic curve) was 0.68 (95% CI, 0.64-0.72) in the development cohort and 0.64 (95% CI, 0.60-0.69) in the validation cohort. Conclusions and Relevance: In this study, on the basis of preoperative variables, the IESG risk prediction model allowed stratification of an individual patient's risk of death within 90 days after esophagectomy. These data suggest that this model can help in the decision-making process when esophageal cancer surgery is being considered and in informed consent.

Outcomes Following an Index Emergency Admission With Cholecystitis: A National Cohort Study.

OBJECTIVE: The objective of this study was to evaluate the differences between patients who undergo cholecystectomy following index admission for cholecystitis, and those who are managed nonoperatively. SUMMARY BACKGROUND DATA: Index emergency cholecystectomy following acute cholecystitis is widely recommended by national guidelines, but its effect on clinical outcomes remains uncertain. METHODS: Data collected routinely from the Hospital Episode Statistics database (all admissions to National Health Service organizations in England and Wales) were extracted between April 1, 2002 and March 31, 2015. Analyses were limited to patients aged over 18 years with a primary diagnosis of cholecystitis. Exclusions included records with missing or invalid datasets, patients who had previously undergone a cholecystectomy, patients who had died without a cholecystectomy, and those undergoing cholecystectomy for malignancy, pancreatitis, or choledocholithiasis. Patients were grouped as either "no cholecystectomy" where they had never undergone a cholecystectomy following discharge, or "cholecystectomy." The latter group was then subdivided as "emergency cholecystectomy" when cholecystectomy was performed during their index emergency admission, or "interval cholecystectomy" when a cholecystectomy was performed within 12 months following a subsequent (emergency or elective) admission. Propensity Score Matching was used to match emergency and interval cholecystectomy groups. Main outcome measures included 1) One-year total length of hospital stay due to biliary causes following an index emergency admission with cholecystitis. 2) One-year mortality; defined as death occurring within 1 year following the index emergency admission with acute cholecystitis. RESULTS: Of the 99,139 patients admitted as an emergency with acute cholecystitis, 51.1% (47,626) did not undergo a cholecystectomy within 1 year of index admission. These patients were older, with more comorbidities (Charlson Comorbidity Score ≥ 5 in 23.5% vs. 8.1%, P < 0.001) when compared to patients who did have a cholecystectomy. While all-cause 1-year mortality was higher in the nonoperated versus the operated group (12.2% vs. 2.0%, P < 0.001), gallbladder-related deaths were significantly lower than all other causes of death in the non-operated group (3.3% vs. 8.9%, P < 0.001). Following matching, 1-year total hospital admission time was significantly higher following emergency compared with interval cholecystectomy (17.7 d vs. 13 d, P < 0.001). CONCLUSIONS: Over 50% of patients in England did not undergo cholecystectomy following index admission for acute cholecystitis. Mortality was higher in the nonoperated group, which was mostly due to non-gallbladder pathologies but total hospital admission time for biliary causes was lower over 12 months. Increasing the numbers of emergency cholecystectomy may risk over-treating patients with acute cholecystitis and increasing their time spent admitted to hospital.

The management and long-term outcomes of endoscopic and surgical treatment of early esophageal adenocarcinoma.

Endoscopic resection (ER) for early (pT1) esophageal adenocarcinoma can be justified if the rate of coexisting lymph node (LN) metastasis is less than the mortality rate from esophagectomy. This study examines endoscopic and surgical outcomes, histological assessment of submucosal (sm) disease, factors influencing LN metastasis, and the safety of treating pT1b disease endoscopically. Histopathological reexamination recorded thickness, width and depth of sm invasion, grade, presence of lymphovascular invasion (LVI), resection margin status and tumor stage. Multivariate analysis was employed to evaluate the factors influencing survival and LN metastasis. Rate of LN metastasis for pT1 low-risk (LR: sm invasion < 500 µm, G1-2, no LVI) or high-risk (HR: sm invasion >500 µm, G3-4 or LVI) disease were analyzed. Ninety three patients underwent ER and 96 underwent esophagectomy. We demonstrate conflicting histological methods of sm disease reporting, which may explain the difference in LN metastasis rate between reported surgical & endoscopic series. Multivariate analysis confirmed age, T stage, and presence of LN metastases were the independent factors predicting poor prognosis. Tumor thickness as well as grade, T stage, LVI were predictors of LN metastasis. Rates of LN metastasis are <2% in LR sm1 disease, and >15% in HR sm1 disease. Pathological reporting of sm invasion should be updated for uniform analysis of endoscopic and surgical specimens. Following rigorous histopathological examination and within a close endoscopic follow-up regimen, pT1a and pT1b LRsm1 disease may be treated with curative intent endoscopically, whereas pT1b HRsm1-sm3 disease should be offered surgery.

Winter cancellations of elective surgical procedures in the UK: a questionnaire survey of patients on the economic and psychological impact.

OBJECTIVES: To quantify the economic and psychological impact of the cancellation of operations due to winter pressures on patients, their families and the economy. DESIGN: This questionnaire study was designed with the help of patient groups. Data were collected on the economic and financial burden of cancellations. Emotions were also quantified on a 5-point Likert scale. SETTING: Five NHS Hospital Trusts in the East Midlands region of England. PARTICIPANTS: We identified 796 participants who had their elective operations cancelled between 1 November 2017 and 31 March 2018 and received responses from 339 (43%) participants. INTERVENTIONS: Participants were posted a modified version of a validated quality of life questionnaire with a prepaid return envelope. MAIN OUTCOME MEASURES: The primary outcome measures were the financial and psychological impact of the cancellation of elective surgery on patients and their families. RESULTS: Of the 339 respondents, 163 (48%) were aged <65 years, with 111 (68%) being in employment. Sixty-six (19%) participants had their operations cancelled on the day. Only 69 (62%) of working adults were able to return to work during the time scheduled for their operation, with a mean loss of 5 working days (SD 10). Additional working days were lost subsequently by 60 (54%) participants (mean 7 days (SD 10)). Family members of 111 (33%) participants required additional time off work (mean 5 days (SD 7)). Over 30% of participants reported extreme levels of sadness, disappointment, anger, frustration and stress. At least moderate concern about continued symptoms was reported by 234 (70%) participants, and 193 (59%) participants reported at least moderate concern about their deteriorating condition. CONCLUSIONS: The cancellation of elective surgery during the winter had an adverse impact on patients and the economy, including days of work lost and health-related anxiety. We recommend better planning, and provision of more notice and better support to patients.

A systematic review of patient reported outcome measures (PROMs) and quality of life reporting in patients undergoing laparoscopic cholecystectomy.

Patient reported outcome measures (PROMs) provide a valuable means of measuring outcomes subjectively from a patient's perspective, facilitating the assessment of service quality across healthcare providers, and assisting patients and clinicians in shared decision making. The primary aim of this systematic review was to critically appraise all historic studies evaluating patient reported quality of life, in adult patients undergoing laparoscopic cholecystectomy for symptomatic gallstones. The secondary aim was to perform a quality assessment of cholecystectomy-specific PROM-validation studies. A literature review was performed in PubMed, Google ScholarTM, the Cochrane Library, Medline, CINAHL, EMBASE and PsychINFO databases up to September 2017. Study characteristics, PROM-specific details and a bias assessment were summarised for non-validation studies. A COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) analysis was performed to assess the methodological quality of identified PROM-validation studies. Fifty one studies were found to evaluate health-related quality of life (HRQoL) after laparoscopic cholecystectomy. Although 94.1% of these studies included PROMs as a primary outcome measure, <20% provided level 1 evidence through randomised controlled trials (RCTs). There was significant variation in the selection and reporting of PROMs, with no studies declaring patient involvement in PROM selection, and 88.2% of studies failing to document the management of missing data points, or non-returned surveys (33.3%). In the 6 PROM-validation studies identified, only 5 psychometric properties were evaluated, the findings of which were limited due to the small number of studies. This systematic review identifies a lack in consistency of study design and PRO reporting in clinical trials. Whilst an increasing number of studies are being performed to evaluate PROs, a lack of adherence to existing PRO administration and reporting guidelines is continuing to negatively affect study quality. We recommend that future clinical trials utilizing PROs should adhere to established comprehensive guidelines as described.

Comparison of Outcomes with Semi-mechanical and Circular Stapled Intrathoracic Esophagogastric Anastomosis following Esophagectomy.

BACKGROUND: Several techniques have been described for esophagogastric anastomosis following esophagectomy. This study compared the outcomes of circular stapled anastomoses with semi-mechanical technique using a linear stapler. METHODS: Perioperative data were extracted from a contemporaneously collected database of all consecutive esophagectomies for cancer with intrathoracic anastomoses performed in the Trent Oesophago-Gastric Unit between January 2015 and April 2018. Anastomotic techniques: circular stapled versus semi-mechanical, were evaluated and outcomes were compared. The primary outcome was anastomotic leak rate. Secondary outcomes included anastomotic stricture, overall complication rates, length of stay (LOS) and 30 day all-cause mortality. RESULTS: One hundred and fifty-nine consecutive esophagectomies with intrathoracic anastomosis were performed during the study period. There were no significant differences between the two groups in terms of age, American Society of Anaesthesiologists score, Charlson comorbidity index and neoadjuvant therapies received. Circular stapled anastomoses were performed in 85 patients, while 74 patients received a semi-mechanical anastomosis. Clavien-Dindo complications II or more were higher in the circular stapled group (p = 0.02). There were 16 (10%) anastomotic leaks overall, three (4%) in semi-mechanical group versus 13 (15%) in the circular stapled group (p < 0.019). There was no statistically significant difference between the two groups in terms of LOS, 30-day mortality or the need for endoscopic dilatation of the anastomosis at 3 months follow-up. CONCLUSION: The move from a circular stapled to a semi-mechanical intrathoracic anastomosis has been associated with a reduced postoperative anastomotic leak rate following esophagectomy for esophageal cancer.

Anaemia and its effects on tumour regression grade and survival following chemotherapy in adenocarcinoma of the oesophagus.

BACKGROUND: Anaemia reduces the efficacy of chemotherapy in gastric cancer. However, it has not been studied in oesophageal cancer. We investigated whether anaemia impacts on survival and the efficacy of chemotherapy, in adenocarcinoma of the oesophagus for those undergoing neoadjuvant chemotherapy and then surgical resection. METHODS: This prospective study included 268 patients who received neoadjuvant chemotherapy for oesophageal adenocarcinoma. Patient clinical data as well as Mandard's tumor regression grading (TRG), haemoglobin pre-chemotherapy and during the chemotherapy were compiled. The association between anaemia and TRG was tested using Chi-squared analysis, whilst survival outcomes were investigated by Kaplan-Meier and Cox regression. RESULTS: One hundred participants were anaemic before chemotherapy whilst 224 were anaemic during chemotherapy cycles. Survival analyses found a significant association between lower haemoglobin levels and decreased overall survival (P=0.048). Comparing those without anaemia against those with moderate -severe anaemia (<10.9 g/dL) found a statistically significant association in overall survival (P=0.026). Multivariate cox regression showed those with anaemia were statistically more likely to have decreased overall survival (HR 1.735, 95% CI, 1.050-2.867, P=0.032). No statistical association was seen between those with pre-chemotherapy anaemia and TRG (OR 0.675, 95% CI, 0.420-1.161, P=0.130) or those with anytime anaemia (OR 0.881, 95% CI, 0.406-1.914, P=0.931). CONCLUSIONS: These results suggest that anaemia is associated with poorer overall survival time, with lower haemoglobin levels reducing prognosis. However, there does not appear to be an association between anaemia and chemotherapy response in oesophageal adenocarcinoma.

Development of a telehealth monitoring service after colorectal surgery: A feasibility study.

AIM: To evaluate the feasibility of a text-messaging system to remotely monitor and support patients after discharge following elective colorectal surgery, within an enhanced recovery protocol. METHODS: Florence (FLO) is a National Health Service telehealth solution utilised for monitoring chronic health conditions, such as hypertension, using text-messaging. New algorithms were designed to monitor the well-being, basic physiological observations and any patient-reported symptoms, and provide support messages to patients undergoing colorectal surgery within an enhanced recovery after surgery protocol for 30 d after discharge. All interactions with FLO and physiological readings were recorded and patients were invited to provide feedback. RESULTS: Over a four-week period, 16 out of 17 patients used the FLO telehealth service at home. These patients did not receive telephone follow-up at three days, as per our standard protocol, unless they reported being unwell or did not make use of the technology. Three patients were readmitted within 30 d, and two of these were identified as being unwell by FLO prior to readmission. No adverse events attributable to the use of the technology were encountered. CONCLUSION: The utilisation of telehealth in the early follow-up of patients who have undergone major colorectal surgery after discharge is feasible. The use of this technology may assist in the early recognition and management of complications after discharge.

The role of adjuvant platinum-based chemotherapy in esophagogastric cancer patients who received neoadjuvant chemotherapy prior to definitive surgery.

BACKGROUND AND OBJECTIVES: For patients with operable esophagogastric cancer, peri-operative chemotherapy confers a significant overall survival benefit compared to surgery alone, however only 30-40% of patients demonstrate histopathological response. It is unclear whether those with no neoadjuvant chemotherapy response should go onto receive adjuvant chemotherapy, as no further benefit may be conferred. METHODS: Esophagogastric cancers were prospectively captured with associated histopathological tumor regression grades following neoadjuvant chemotherapy. This cohort was then interrogated for clinico-pathological and survival outcomes. RESULTS: Following neoadjuvant chemotherapy and surgery, patients with chemotherapy responsive cancers, who were administered adjuvant chemotherapy gained a significant overall survival benefit. Multivariate Cox analysis, demonstrated a final adjusted hazard ratio for adjuvant therapy of 0.509; (95%CI 0.28-0.93); P = 0.028. In contrast, patients with non-responsive tumors, who underwent adjuvant chemotherapy, did not show any survival benefit. Chemotherapy toxicity was prevalent and contributed to only half of patients receiving adjuvant chemotherapy. CONCLUSIONS: These results suggest the benefit of the adjuvant portion of chemotherapy is limited to those who demonstrate a histopathological response to neoadjuvant chemotherapy. The administration of the adjuvant portion of chemotherapy to patients without a response to neoadjuvant chemotherapy may not provide any survival benefit, while potentially causing increased morbidity.

Individual patient oesophageal cancer 3D models for tailored treatment.

BACKGROUND: A model to predict chemotherapy response would provide a marked clinical benefit, enabling tailored treatment of oesophageal cancer, where less than half of patients respond to the routinely administered chemotherapy. METHODS: Cancer cells were established from tumour biopsies taken from individual patients about to undergo neoadjuvant chemotherapy. A 3D-tumour growth assay (3D-TGA) was developed, in which cancer cells were grown with or without supporting mesenchymal cells, then subjected to chemo-sensitivity testing using the standard chemotherapy administered in clinic, and a novel emerging HDAC inhibitor, Panobinostat. RESULTS: Individual patient's cancer cells could be expanded and screened within a clinically applicable timescale of 3 weeks. Incorporating mesenchymal support within the 3D-TGA significantly enhanced both the growth and drug resistance profiles of the patient's cancer cells. The ex vivo drug response in the presence, but not absence, of mesenchymal cells accurately reflected clinical chemo-sensitivity, as measured by tumour regression grade. Combination with Panobinostat enhanced response and proved efficacious in otherwise chemo-resistant tumours. CONCLUSIONS: This novel method of establishing individual patient oesophageal cancers in the laboratory, from small endoscopic biopsies, enables clinically-relevant chemo-sensitivity testing, and reduces use of animals by providing more refined in vitro models for pre-screening of drugs. The 3D-TGA accurately predicted chemo-sensitivity in patients, and could be developed to guide tailored patient treatment. The incorporation of mesenchymal cells as the stromal cell component of the tumour micro-environment had a significant effect upon enhancing chemotherapy drug resistance in oesophageal cancer, and could prove a useful target for future drug development.

3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors.

There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor-derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay. A study of 30 early-stage non-small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standard-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers. Mol Cancer Ther; 15(4); 753-63. ©2016 AACR.

The role of relative lymphocyte count as a biomarker for the effect of catumaxomab on survival in malignant ascites patients: results from a phase II/III study.

PURPOSE: We report the role of relative lymphocyte count (RLC) as a potential biomarker with prognostic impact for catumaxomab efficacy and overall survival (OS) based on a post hoc analysis of the pivotal phase II/III study of intraperitoneal catumaxomab treatment of malignant ascites. EXPERIMENTAL DESIGN: The impact of treatment and RLC on OS was evaluated using multivariate Cox models. Kaplan-Meier and log-rank tests were used for group comparisons. Survival analyses were performed on the safety population [patients with paracentesis plus ≥ 1 dose of catumaxomab (n = 157) and paracentesis alone (n = 88)]. Determination of the optimal cutoff value for RLC was based on five optimality criteria. RESULTS: OS was significantly longer with catumaxomab versus paracentesis alone (P = 0.0219). The 6-month OS rate with catumaxomab was 28.9% versus 6.7% with paracentesis alone. RLC had a positive impact on OS and was an independent prognostic factor (P < 0.0001). In patients with RLC > 13% (n = 159: catumaxomab, 100 and control, 59), catumaxomab was associated with a favorable effect on OS versus paracentesis alone (P = 0.0072), with a median/mean OS benefit of 41/131 days and an increased 6-month survival rate of 37.0% versus 5.2%, respectively. In patients with RLC ≤ 13% at screening (n = 74: catumaxomab, 50 and control, 24), the median (mean) OS difference between the catumaxomab and the control group was 3 (16) days, respectively (P = 0.2561). CONCLUSIONS: OS was significantly improved after catumaxomab treatment in patients with malignant ascites. An RLC > 13% at baseline was a significant prognostic biomarker.

British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus.

These guidelines provide a practical and evidence-based resource for the management of patients with Barrett's oesophagus and related early neoplasia. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was followed to provide a methodological strategy for the guideline development. A systematic review of the literature was performed for English language articles published up until December 2012 in order to address controversial issues in Barrett's oesophagus including definition, screening and diagnosis, surveillance, pathological grading for dysplasia, management of dysplasia, and early cancer including training requirements. The rigour and quality of the studies was evaluated using the SIGN checklist system. Recommendations on each topic were scored by each author using a five-tier system (A+, strong agreement, to D+, strongly disagree). Statements that failed to reach substantial agreement among authors, defined as >80% agreement (A or A+), were revisited and modified until substantial agreement (>80%) was reached. In formulating these guidelines, we took into consideration benefits and risks for the population and national health system, as well as patient perspectives. For the first time, we have suggested stratification of patients according to their estimated cancer risk based on clinical and histopathological criteria. In order to improve communication between clinicians, we recommend the use of minimum datasets for reporting endoscopic and pathological findings. We advocate endoscopic therapy for high-grade dysplasia and early cancer, which should be performed in high-volume centres. We hope that these guidelines will standardise and improve management for patients with Barrett's oesophagus and related neoplasia.

Thioredoxin interacting protein and its association with clinical outcome in gastro-oesophageal adenocarcinoma.

The overall prognosis for operable gastro-oesophageal adenocarcinoma remains poor and therefore neoadjuvant chemotherapy has become the standard of care, in addition to radical surgery. Certain anticancer agents (e.g. anthracyclines and cisplatin) generate damaging reactive oxygen species as by-products of their mechanism of action. Drug effectiveness can therefore depend upon the presence of cellular redox buffering systems that are often deregulated in cancer. The expression of the redox protein, thioredoxin interacting protein, was assessed in gastro-oesophageal adenocarcinomas. Thioredoxin interacting protein expression was assessed using conventional immunohistochemistry on a tissue microarray of 140 adenocarcinoma patients treated by primary surgery alone and 88 operable cases treated with neoadjuvant chemotherapy. In the primary surgery cases, high thioredoxin interacting protein expression associated with a lack of lymph node involvement (p=0.005), no perineural invasion (p=0.030) and well/moderate tumour differentiation (p=0.033). In the neoadjuvant tumours, high thioredoxin interacting protein expression was an independent marker for improved disease specific survival (p=0.002) especially in cases with anthracycline-based regimes (p=0.008). This study highlights the potential of thioredoxin interacting protein as a biomarker for response in neoadjuvant treated gastro-oesophageal adenocarcinoma and may represent a useful therapeutic target due to its association with tumour progression.