Generation of two iPSC lines (MHHi001-A-12 and MHHi001-A-13) carrying biallelic truncating mutations at the 3'-end of SRCAP using CRISPR/Cas9.

Non-Floating Harbour Syndrome (FLHS) neurodevelopmental disorder (NDD) is a recently described disorder caused by mutations in certain regions of the SRCAP gene. We generated two iPSC lines that contain truncating mutation on both alleles at the 3'-end of SRCAP using CRISPR/Cas9 technology. Both cell lines are pluripotent, differentiate into the 3 germ layers and contain no genomic aberrations or off-target modifications. The cell lines form part of a human disease model to investigate the effects of truncating mutations in different regions of SRCAP.

A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202).

BACKGROUND: Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC. PATIENTS AND METHODS: Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class. CONCLUSIONS: Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.

Severity and 1-month outcome of SARS-CoV-2 infection in patients with solid cancers: a Danish nationwide cohort study.

BACKGROUND: Cancer patients are vulnerable to infections, are older and often have comorbidities in comparison to the general population, which increases the risk for severe outcomes related to COVID-19 diagnosis. METHODS: This study is a prospective, nationwide study in patients with solid cancer and SARS-CoV-2 infection included between 10 March to 15 June 2020. Patient's baseline characteristics were collected. The study's primary outcome was overall survival within 30 days of verified SARS-CoV-2 infection. Secondary outcomes were hospital admission, admission to an ICU, and need for supplemental oxygen. RESULTS: A total of 112 patients with a cancer diagnosis and verified SARS-CoV-2 infection were identified. After one month of follow up, hospitalization was required for 54% (n = 61) and 21% of the patients had died and 14 of the 23 deceased cancer patients were ≥70 years. Most patients were classified with mild COVID-19 symptoms (66%, n = 74); however, 48% (n = 23) of the ≥70-year-olds patients were classified with severe or critical COVID-19 symptoms. Among the total study population, 61% (n = 68) had comorbidities and comorbidity were more frequently observed among the deceased (91%, n = 21) and older cancer patients (≥70 years, 81%, n = 39). CONCLUSIONS: Acknowledging the low sample size in this study, our work shows that age and comorbidities, but not recent cytotoxic therapy, are associated with adverse outcomes of SARS-CoV-2 infection for patients with solid cancer. Particularly, patients with progressive disease seem to be at greater risk of a fatal outcome from COVID-19.HighlightsAge, performance status, and comorbidities are strong predictors of adverse outcome in cancer patients with SARS-CoV-2 infection.Patients with progressive cancer disease seem to be at greater risk of a fatal outcome from COVID-19.Recent cytotoxic therapy, however, did not seem to be associated with increased risk for adverse outcomes of SARS-CoV-2 infection for patients with solid cancer.

Generation of an iPSC line (UMGWi001-B) from a patient with Floating-Harbor Syndrome (FLHS) carrying a heterozygous SRCAP mutation (p.Arg2444).

Floating-Harbor syndrome (FLHS) is a rare genetic disease caused by mutations in the SRCAP gene. Here, we generated an induced pluripotent stem cell line from gingival fibroblasts of a male patient with a heterozygous mutation in exon 34 of the SRCAP gene (c.7330C > T, p.Arg2444*). The iPSC colonies have an atypical morphology with diffuse borders and disintegrate quickly upon touch. Still, the cell line expresses pluripotency markers and differentiates into three germ layers. The cell line can be used as patient-specific disease model and help elucidate the molecular mechanisms involving SRCAP in the context of FLHS.

Receptor Activator of Nuclear Factor kappa-B Ligand is Not Regulated During Chronic Osteomyelitis in Pigs.

Bone loss is a major complication of osteomyelitis and from numerous in-vitro studies, it has been concluded that the bone lysis is caused by elevated expression of the receptor activator of nuclear factor κB ligand (RANKL), leading to increased osteoclast activity. However, we failed to find any relationship between bone loss and osseous RANKL expression in a porcine model of acute and chronic implant-associated osteomyelitis (IAO) due to Staphylococcus aureus or in chronic osteomyelitis lesions in slaughter pigs. Surprisingly, we found that the expression of RANKL was reduced during chronic bone infections. This is in line with the few studies conducted on human samples. A significant bone loss was observed in IAO lesions and in lesions from slaughter pigs, but with no indication of osteoclast involvement using histochemistry, immunohistochemistry for RANKL, receptor activator of nuclear factor kappa-B, osteoprotegerin and cathepsin K, and high-throughput quantitative real-time polymerase chain reaction on bone tissue from osteomyelitic lesions. A strong inflammatory response was seen in the infected animals and, therefore, we propose proteolytic enzymes induced by inflammation to be a major component of the bone loss. Furthermore, we found a significant upregulation of the IL26 gene in infected animals, which can inhibit RANKL-induced osteoclastogenesis, but has no homologue in mice. This finding emphasises that neither murine models nor in-vitro studies can mirror human disease development completely. The present study emphasises that the interactions between microorganisms, the immune system and bone cells in osteomyelitis are too complex to be accurately represented by an in-vitro model.

Guideline for Preclinical Studies of Bone Infections in Large Animals Based on a Systematic Review of 316 Non-Rodent Models.

BACKGROUND: In recent years, animal models of bone infections have been used with increased frequency in order to evaluate novel diagnostic and anti-infective technologies, like antibacterial coating of bone implants or local antibiotic carrier products. Therefore, it is highly relevant to evaluate the scientific quality of existing bone infection models. METHODS: We conducted a systematic review of 316 studies of large non-rodent animal models of bone infection (254 rabbit, 16 pig, 23 dog, 11 goat, and 12 sheep) and extracted data on study design, methodological quality, and postmortem evaluation of infection with respect to reporting and quantification of pathology and microbiology. RESULTS: The review demonstrated a substantial lack of study-design information, which hampers reproducibility and continuation of the established work. Furthermore, the methodological study quality was found to be low, as the definition of infection, randomization, power analysis, and blinding were only seldomly reported. The use of histology increased in recent years, but a semi-quantitative scoring of the lesions was often missing, i.e. no objective quantification of outcome. Most of the studies focused on whether the inoculated bacteria were present within the bone tissue post mortem or not. However, very often the bacterial burden was not quantified. In many of the models, different antimicrobial interventions were examined and, although antimicrobial effects were commonly described, a lack of complete sterile outcome was observed in many models. On the basis of the systematic review, we established a study template providing a guideline for the standard reporting of animal models of bone infections, including details related to the animal, pathogen, infected animal, and postmortem analysis that are of crucial importance for validation of results and reproducibility. CONCLUSIONS: As the aim of many bone infection models is to examine the effect of an intervention, the guideline emphasizes the importance of objective quantification of outcome, e.g., blinded quantitative scoring of histological findings and quantification of bacterial burden within tissue and on inserted implants. Less than 5% of the analyzed studies adhered completely to the ideal form presented in the study template. CLINICAL RELEVANCE: Anti-infective interventions must be tested in preclinical animal models before implementation in human patients, and optimal design and validation is essential for a high translational value.

International comparison of treatment strategy and survival in metastatic gastric cancer.

Background: In the randomized Asian REGATTA trial, no survival benefit was shown for additional gastrectomy over chemotherapy alone in patients with advanced gastric cancer with a single incurable factor, thereby discouraging surgery for these patients. The purpose of this study was to evaluate treatment strategies for patients with metastatic gastric cancer in daily practice in five European countries, along with relative survival in each country. Methods: Nationwide population-based data from Belgium, Denmark, the Netherlands, Norway and Sweden were combined. Patients with primary metastatic gastric cancer diagnosed between 2006 and 2014 were included. The proportion of gastric resections performed and the administration of chemotherapy (irrespective of surgery) within each country were determined. Relative survival according to country was calculated. Results: Overall, 15 057 patients with gastric cancer were included. The proportion of gastric resections varied from 8·1 per cent in the Netherlands and Denmark to 18·3 per cent in Belgium. Administration of chemotherapy was 39·2 per cent in the Netherlands, compared with 63·2 per cent in Belgium. The 6-month relative survival rate was between 39·0 (95 per cent c.i. 37·8 to 40·2) per cent in the Netherlands and 54·1 (52·1 to 56·9) per cent in Belgium. Conclusion: There is variation in the use of gastrectomy and chemotherapy in patients with metastatic gastric cancer, and subsequent differences in survival.

Vibrio coralliilyticus infection triggers a behavioural response and perturbs nutritional exchange and tissue integrity in a symbiotic coral.

Under homoeostatic conditions, the relationship between the coral Pocillopora damicornis and Vibrio coralliilyticus is commensal. An increase in temperature, or in the abundance of V. coralliilyticus, can turn this association pathogenic, causing tissue lysis, expulsion of the corals' symbiotic algae (genus Symbiodinium), and eventually coral death. Using a combination of microfluidics, fluorescence microscopy, stable isotopes, electron microscopy and NanoSIMS isotopic imaging, we provide insights into the onset and progression of V. coralliilyticus infection in the daytime and at night, at the tissue and (sub-)cellular level. The objective of our study was to connect the macro-scale behavioural response of the coral to the micro-scale nutritional interactions that occur between the host and its symbiont. In the daytime, polyps enhanced their mucus production, and actively spewed pathogens. Vibrio infection primarily resulted in the formation of tissue lesions in the coenosarc. NanoSIMS analysis revealed infection reduced 13C-assimilation in Symbiodinium, but increased 13C-assimilation in the host. In the night incubations, no mucus spewing was observed, and a mucus film was formed on the coral surface. Vibrio inoculation and infection at night showed reduced 13C-turnover in Symbiodinium, but did not impact host 13C-turnover. Our results show that both the nutritional interactions that occur between the two symbiotic partners and the behavioural response of the host organism play key roles in determining the progression and severity of host-pathogen interactions. More generally, our approach provides a new means of studying interactions (ranging from behavioural to metabolic scales) between partners involved in complex holobiont systems, under both homoeostatic and pathogenic conditions.

North European comparison of treatment strategy and survival in older patients with resectable gastric cancer: A EURECCA upper gastrointestinal group analysis.

BACKGROUND: As older gastric cancer patients are often excluded from randomized clinical trials, the most appropriate treatment strategy for these patients remains unclear. The current study aimed to gain more insight in treatment strategies and relative survival of older patients with resectable gastric cancer across Europe. METHODS: Population-based cohorts from Belgium, Denmark, The Netherlands, Norway, and Sweden were combined. Patients ≥70 years with resectable gastric cancer (cT1-4a, cN0-2, cM0), diagnosed between 2004 and 2014 were included. Resection rates, administration of chemotherapy (irrespective of surgery), and relative survival within a country according to stage were determined. RESULTS: Overall, 6698 patients were included. The percentage of operated patients was highest in Belgium and lowest in Sweden for both stage II (74% versus 56%) and stage III disease (57% versus 25%). For stage III, chemotherapy administration was highest in Belgium (44%) and lowest in Sweden (2%). Three year relative survival for stage I, II, and III disease in Belgium was 67.8% (95% CI:62.8-72.6), 41.2% (95% CI:37.3-45.2), 17.8% (95% CI:12.5-24.0), compared with 56.7% (95% CI:51.5-61.7), 31.3% (95% CI:27.6-35.2), 8.2% (95% CI:4.4-13.4) in Sweden. There were no significant differences in treatment strategies of patients with stage I disease. CONCLUSION: Substantial treatment differences are observed across North European countries for patients with stages II and III resectable gastric cancer aged 70 years or older. In the present comparison, treatment strategies with a higher proportion of patients undergoing surgery seemed to be associated with higher survival rates for patients with stages II or III disease.

Administration of platelets to ruptured abdominal aortic aneurysm patients before open surgery: a prospective, single-blinded, randomised study.

BACKGROUND: In patients undergoing open surgery for a ruptured abdominal aortic aneurysm (rAAA), survivors demonstrate a high platelet count, and proactive administration of platelets (and fresh frozen plasma) appears to influence mortality. OBJECTIVES: This trial investigated the effect of platelets administered before transport to surgery. METHODS: In a prospective study design, patients were randomised to receive platelets (intervention; n = 61) or no platelets (control; n = 61) before transport to vascular surgery from 11 local hospitals. The study was terminated when one of the vascular surgical centres implemented endovascular repair for rAAA patients. RESULTS: Thirty days after surgery, mortality was 36% for patients with intervention vs 31% for controls (P = 0·32). Post-operative thrombotic events (14 vs 15; P = 0·69), renal failure (11 vs 10; P = 0·15) and pulmonary insufficiency (34 vs 39; P = 0·15) were similar in the two groups of patients. No adverse reactions to platelet administration were observed. In addition, length of stay in the intensive care unit was unaffected by intervention. CONCLUSIONS: For patients planned for open repair of a rAAA, we observed no significant effect of early administration of platelets with regard to post-operative complications and stay in the ICU or in hospital and also no significant effect on mortality.

Monitoring the effect of first line treatment in RAS/RAF mutated metastatic colorectal cancer by serial analysis of tumor specific DNA in plasma.

BACKGROUND: Precision medicine calls for an early indicator of treatment efficiency. Circulating tumor DNA (ctDNA) is a promising marker in this setting. Our prospective study explored the association between disease development and change of ctDNA during first line chemotherapy in patients with RAS/RAF mutated metastatic colorectal cancer (mCRC). METHODS: The study included 138 patients with mCRC receiving standard first line treatment. In patients with RAS/RAF mutated tumor DNA the same mutation was quantified in the plasma using droplet digital PCR. The fractional abundance of ctDNA was assessed in plasma before treatment start and at every treatment cycle until radiologically defined progressive disease. RESULTS: RAS/RAF mutations were detected in the plasma from 77 patients. Twenty patients progressed on treatment and 57 stopped treatment without progression. The presence of mutated DNA in plasma was correlated with poor overall survival. A low level of ctDNA after the first cycle of chemotherapy was associated with a low risk of progression. On the other hand, a significant increase of ctDNA at any time during the treatment course was associated with a high risk of progression on continuous treatment. The first increase in ctDNA level occurred at a median of 51 days before radiologically confirmed progression. CONCLUSIONS: The results indicate that the ctDNA level holds potential as a clinically valuable marker in first line treatment of mCRC. A rapid decrease was associated with a prolonged progression free interval, whereas a significant increase gave notice of early progression with a relevant lead time.

Nitrogen mineralisation and greenhouse gas emission from the soil application of sludge from reed bed mineralisation systems.

A sludge treatment reed bed system (STRB) is a technology used for dewatering and stabilising sewage sludge via assisted biological mineralisation, which creates a sludge residue suitable for use as fertiliser on agricultural land. We evaluated the effect of sludge residue storage time (stabilisation time) for three STRBs on soil N mineralisation and CO2 and N2O emissions in soil. The experiment revealed that the N mineralisation rate and emissions of CO2 and N2O decreased as a function of treatment time in the STRBs. Mixed sludge residue (sludge residue subjected to different treatment times) for the three STRBs resulted in N mineralisation rates similar to the sludge residue subjected to a shorter treatment time but lower N2O emissions similar to the values of the older sludge residue. This finding reveals that combining fresh and more stabilised sludge residue ensures high N availability and reduces N2O emissions when applied to land.

Changes in treatment and outcome of oesophageal cancer in Denmark between 2004 and 2013.

BACKGROUND: Since 2003, care for patients with oesophageal cancer has been centralized in a few dedicated centres in Denmark. The aim of this study was to assess changes in the treatment and outcome of patients registered in a nationwide database. METHODS: All patients diagnosed with oesophageal cancer or cancer of the gastro-oesophageal junction who underwent oesophagectomy in Denmark between 2004 and 2013, and who were registered in the Danish clinical database of carcinomas in the oesophagus, gastro-oesophageal junction and stomach (DECV database) were included. Quality-of-care indicators, including number of lymph nodes removed, anastomotic leak rate, 30- and 90-day mortality, and 2- and 5-year overall survival, were assessed. To compare quality-of-care indicators over time, the relative risk (RR) was calculated using a multivariable log binomial regression model. RESULTS: Some 6178 patients were included, of whom 1728 underwent oesophagectomy. The overall number of patients with 15 or more lymph nodes in the resection specimen increased from 38·1 per cent in 2004 to 88·7 per cent in 2013. The anastomotic leak rate decreased from 14·8 to 7·6 per cent (RR 0·66, 95 per cent c.i. 0·43 to 1·01). The 30-day mortality rate decreased from 4·5 to 1·7 per cent (RR 0·51, 0·22 to 1·15) and the 90-day mortality rate from 11·0 to 2·9 per cent (RR 0·46, 0·26 to 0·82). There were no statistically significant changes in 2- or 5-year survival rates over time. CONCLUSION: Indicators of quality of care have improved since the centralization of oesophageal cancer treatment in Denmark.

Muscular response to the first three months of deflazacort treatment in boys with Duchenne muscular dystrophy.

OBJECTIVE: Duchenne muscular dystrophy (DMD) patients are often treated with glucocorticoids; yet their precise molecular action remains unknown. METHODS: We investigated muscle biopsies from nine boys with DMD (aged: 7,6±2,8 yrs.) collected before and after three months of deflazacort treatment and compared them to eight healthy boys (aged: 5,3±2,4 yrs.). mRNA transcripts involved in activation of satellite cells, myogenesis, regeneration, adipogenesis, muscle growth and tissue inflammation were assessed. Serum creatine kinase (CK) levels and muscle protein expression by immunohistochemistry of selected targets were also analysed. RESULTS: Transcript levels for ADIPOQ, CD68, CDH15, FGF2, IGF1R, MYF5, MYF6, MYH8, MYOD, PAX7, and TNFα were significantly different in untreated patients vs. normal muscle (p⟨0.05). Linear tests for trend indicated that the expression levels of treated patients were approaching normal values (p⟨0.05) following treatment (towards an increase; CDH15, C-MET, DLK1, FGF2, IGF1R, MYF5, MYF6, MYOD, PAX7; towards a decrease: CD68, MYH8, TNFα). Treatment reduced CK levels (p⟨0.05), but we observed no effect on muscle protein expression. CONCLUSIONS: This study provides insight into the molecular actions of glucocorticoids in DMD at the mRNA level, and we show that multiple regulatory pathways are influenced. This information can be important in the development of new treatments.

Editor's Choice - Factors Associated with Long-Term Outcome in 191 Patients with Ilio-Femoral DVT Treated With Catheter-Directed Thrombolysis.

OBJECTIVE: To identify factors associated with long-term treatment success after catheter-directed thrombolysis (CDT) for acute deep venous thrombosis (DVT) involving the ilio-femoral vein. MATERIAL AND METHODS: This was a non-randomised observational cohort study. From 1999 to 2013, 191 consecutive patients (203 limbs) attending a tertiary vascular centre at Gentofte University Hospital, Denmark underwent CDT. All patients had ultrasonically verified acute ilio-femoral DVT with open distal popliteal vein and calf veins. Patients were seen in the outpatient clinic 6 weeks, 3, 6, and 12 months, and annually thereafter following the DVT. Successful outcome was defined as patent deep veins without reflux on Duplex ultrasound scanning (DUS). Data were collected prospectively as per protocol and analysed retrospectively. RESULTS: Median age was 27 years (range 14-74 years) and overall median lysis time was 56 h (range 22-146 h). A stent was placed in 106 limbs (52%). Six patients had major bleeding. The median follow-up was 5 years (range 1 month-14.3 years). The cumulative rate of patients with deep patent veins without reflux at 7 years was 79%. Multivariate Cox regression analyses showed that symptom duration >2 weeks (hazard ratio (HR) 2.78, 95% CI 1.14-6.73) and chronic post-thrombotic lesions (HR 19.3, 95% CI 7.29-51.2) were significantly associated with poorer outcome, while the pulse-spray technique (HR 0.15, 95% CI 0.05-0.48) was associated with better outcome. Age, gender, side, IVC atresia, stenting, and lysis duration did not affect outcome. CONCLUSION: In this observational study of CDT for ilio-femoral DVT it was demonstrated that symptom duration less than 2 weeks, absence of chronic post-thrombotic lesions and use of the pulse-spray technique for CDT resulted in better primary patency including normal valve function in the long term.

A bridging stent to surgery in patients with esophageal and gastroesophageal junction cancer has a dramatic negative impact on patient survival: A retrospective cohort study through data acquired from a prospectively maintained national database.

This study aimed to assess the impact of esophageal stenting on postoperative complications and survival in patients with obstructing esophageal and gastroesophageal junction (GEJ) cancer. All patients treated without neoadjuvant therapy that had an R0-resection performed for esophageal and GEJ cancer between January 2003 and December 2010 were identified from a prospectively maintained database. Data on stenting, postoperative mortality, morbidity, recurrence-free survival, complications, and length of hospital stay were collected. Kaplan-Meier plots for survival and recurrence-free survival curves were constructed for R0 resected patients. Data were compared between the stent and no-stent group by nonparametric tests. Two hundred seventy three consecutive R0 resected patients with esophageal or GEJ cancer were identified. Of these patients, 63 had a stent as a bridge to surgery. The male/female ratio was 2.64 (198/75) with a median age in the stent group (SG) of 65.1 versus 64.3 in the no stent group (NSG). Patients were comparable with respect to gender, age, smoking, TNM-classification, oncological treatment, hospital stay, tumor location, and histology. The median survival in the SG was 11.6 months compared with 21.3 months for patients treated without a bridging stent (P < 0.001). There were no statistically significant differences in 30-day mortality between the two groups, but NSG patients exhibited a significantly better two-year survival (P = 0.017). The median recurrence-free survival was 9.1 months for the SG compared with 15.2 months for the NSG. The use of a stent as a bridging procedure to surgery in patients treated without neaoadjuvant therapy for an esophageal or GEJ cancer that later underwent R0 resection decreased the two year survival and the recurrence-free survival.

Skeletal Muscle Remodelling as a Function of Disease Progression in Amyotrophic Lateral Sclerosis.

Muscle weakness is considered the pivotal sign of amyotrophic lateral sclerosis (ALS). Knowledge about the skeletal muscle degeneration/regeneration process and the myogenic potential is limited in ALS patients. Therefore, we investigate these processes in a time course perspective by analysing skeletal muscle biopsies from ALS patients collected before and after a 12-week period of normal daily activities and compare these with healthy age-matched control tissue. We do this by evaluating mRNA and protein (immunohistochemical) markers of regeneration, neurodegeneration, myogenesis, cell cycle regulation, and inflammation. Our results show morphological changes indicative of active denervation and reinnervation and an increase in small atrophic fibres. We demonstrate differences between ALS and controls in pathways controlling skeletal muscle homeostasis, cytoskeletal and regenerative markers, neurodegenerative factors, myogenic factors, cell cycle determinants, and inflammatory markers. Our results on Pax7 and MyoD protein expression suggest that proliferation and differentiation of skeletal muscle stem cells are affected in ALS patients, and the myogenic processes cannot overcome the denervation-induced wasting.

Description and analysis of clinical pathways for oesophago-gastric adenocarcinoma, in 10 European countries (the EURECCA upper gastro intestinal group - European Registration of Cancer Care).

AIMS: Outcomes for patients with oesophago-gastric cancer are variable across Europe. The reasons for this variability are not clear. The aim of this study was to describe and analyse clinical pathways to understand differences in service provision for oesophageal and gastric cancer in the countries participating in the EURECCA Upper GI group. METHODS: A questionnaire was devised to assess clinical presentation, diagnosis, staging, treatment, pathology, follow-up and service frameworks across Europe for patients with oesophageal and gastric cancer. The questionnaire was issued to experts from 14 countries. The responses were analysed quantitatively and qualitatively and compared. RESULTS: The response rate was (10/14) 71.4%. The approach to diagnosis was similar. Most countries established a diagnosis within 3 weeks of presentation. However, there were different approaches to staging with variable use of endoscopic ultrasound reflecting availability. There has been centralisation of treatments in most countries for oesophageal surgery. The most consistent area was the approach to pathology. There were variations in access to specialist nurse and dietitian support. Although most countries have multidisciplinary teams, their composition and frequency of meetings varied. The two main areas of significant difference were research and audit and overall service provision. Observations on service framework indicated that limited resources restricted many of the services. CONCLUSION: The principle approaches to diagnosis, treatment and pathology were similar. Factors affecting the quality of patient experience were variable. This may reflect availability of resources. Standard pathways of care may enhance both the quality of treatment and patient experience.

Comparative Investigation of Postoperative Complications in Patients With Gastroesophageal Junction Cancer Treated With Preoperative Chemotherapy or Surgery Alone.

BACKGROUND AND AIM: Gastroesophageal junction cancer is one of the leading causes to cancer-related death and the prognosis is poor. However, progress has been made over the last couple of decades with the introduction of multimodality treatment and optimized surgery. Three-year survival rates have improved to 50% in patients receiving neoadjuvant therapy. Only a few studies have focused on the difference of postoperative complications in patients receiving neoadjuvant therapy in relation to a comparative surgery-only group. The aim of this study was to compare the prevalence of postoperative complications of patients with cancer at the gastroesophageal junction treated with either neoadjuvant chemotherapy or surgery alone in patients from "The Danish Clinical Registry of Carcinomas of the Esophagus, the Gastro-Esophageal Junction and the Stomach." MATERIALS AND METHODS: A historical follow-up study, comparing postoperative complications between two cohorts before and after implementation of chemotherapy was completed. RESULTS: In all, 180 consecutive patients treated with perioperative chemotherapy and a comparative surgery-only group of patients were identified from The Danish Clinical Registry of Carcinomas of the Esophagus, the Gastro-Esophageal Junction and the Stomach. No difference was found in demographics between the two groups, except for alcohol consumption and a lower T and N stage in the surgery-only group, and no difference in complication rates was found. Furthermore, no variable in the multivariate analysis was significantly associated with anastomotic leakage which was considered the most severe complication. CONCLUSION: Since perioperative chemotherapy does not appear to increase surgical complications, the future challenges include defining the optimal combination of chemo- and/or radiotherapy, but more importantly also to select the patients who will benefit the most from the different neoadjuvant strategies.

Prognostic factors for progression-free and overall survival in advanced biliary tract cancer.

BACKGROUND: Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic outcome characteristics for patients with advanced disease. METHODS: Multivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset. RESULTS: A total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.20-2.02]} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival [HR 2.24 (95% CI 1.53-3.28)]. In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value [6-month PFS: area under the curve (AUC) 62% (95% CI 57-68); 1-year OS: AUC 64% (95% CI 58-69)]. CONCLUSION: These data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers.