Surgery during holiday periods and prognosis in oesophageal cancer: a population-based nationwide Swedish cohort study

OBJECTIVE: Previous studies indicate an increased short-term and long-term mortality from major cancer surgery performed towards the end of the working week or during the weekend. We hypothesised that the prognosis after major cancer surgery is also negatively influenced by surgery conducted during holiday periods. SETTING: Population-based nationwide Swedish cohort study. PARTICIPANTS: Patients undergoing oesophagectomy for oesophageal cancer between 1987 and 2010. Among 1820 included patients, 206 (11.3%) and 373 (20.5%) patients were operated on during narrow and wide holiday periods, respectively. INTERVENTIONS: Narrow (7 weeks) and wide (14 weeks) Swedish holiday periods. PRIMARY AND SECONDARY OUTCOME MEASURES: 90-day all-cause, 5-year all-cause and 5-year disease-specific mortality. RESULTS: Narrow holiday period did not increase all-cause 90-day (HR=0.84, 95% CI 0.53 to 1.33), all-cause 5-year (HR=1.01, 95% CI 0.85 to 1.21) or disease-specific 5-year mortality (HR=1.04, 95% CI 0.87 to 1.26). Similarly, wide holiday period did not increase the risk of 90-day (HR=0.79, 95% CI 0.55 to 1.13), all-cause 5-year (HR=0.96, 95% CI 0.84 to 1.1) or disease-specific 5-year mortality (HR=1.03, 95% CI 0.89 to 1.19). CONCLUSIONS: No measurable effects of holiday periods on short-term or longer term mortality following surgery for oesophageal cancer were observed in this population-based study, indicating that an adequate surgical experience was maintained during holiday periods

The Charlson comorbidity index in registry-based research : which version to use?

Background: Comorbidities may have an important impact on survival, and comorbidity scores are often implemented in studies assessing prognosis. The Charlson Comorbidity index is most widely used, yet several adaptations have been published, all using slightly different conversions of the International Classification of Diseases (ICD) coding. Objective: To evaluate which coding should be used to assess and quantify comorbidity for the Charlson Comorbidity Index for registry-based research, in particular if older ICD versions will be used. Methods: A systematic literature search was used to identify adaptations and modifications of the ICD-coding of the Charlson Comorbidity Index for general purpose in adults, published in English. Back-translation to ICD version 8 and version 9 was conducted by means of the ICD-code converter of Statistics Sweden. Results: In total, 16 studies were identified reporting ICD-adaptations of the Charlson Comorbidity Index. The Royal College of Surgeons in them United Kingdom combined 5 versions into, an adapted and updated version which appeared appropriate for research purposes. Their ICD-10 codes were back-translated into ICD-9 and ICD-8 according to their Proposed adaptations, and verified with previous versions of the Charlson Comorbidity Index. Conclusion: Many versions of the Charlson Comorbidity Index are used in parallel, so clear reporting of the version, exact ICD-coding and weighting is necessary to obtain transparency and reproducibility in research. Yet, the version of the Royal College of Surgeons is up-to-date and easy-to-use, and therefore an acceptable co-morbidity score to be used in registry-based research especially for surgical patients

Weekday of oesophageal cancer surgery in relation to early postoperative outcomes in a nationwide Swedish cohort study

Objectives: Later weekday of surgery for oesophageal cancer seems to increases 5-year mortality, but the mechanisms are unclear. We hypothesised that early postoperative reoperations and mortality might explain this association, since reoperation after oesophagectomy decreases long-term prognosis and later weekday of elective surgery increases 30-day mortality. Design: This was a population-based cohort study during the study period 1987-2014. Setting: All Swedish hospitals conducting elective surgery for oesophageal cancer in Sweden. Participants: Included were 1,748 patients, representing almost all (98%) patients who underwent elective surgery for oesophageal cancer in Sweden during 1987-2010, with follow-up until 2014. Primary and secondary outcome measures: The risk of reoperation or mortality within 30 days of oesophageal cancer surgery was assessed in relation to weekday of surgery by calculating odds ratios (ORs) with 95% confidence intervals (CIs) using multivariable logistic regression. ORs were adjusted for age, co-morbidity, tumour stage, histology, neoadjuvant therapy, and surgeon volume. Results: Surgery Wednesday-Friday did not increase the risk of reoperation or mortality compared to surgery Monday-Tuesday (OR=0.99, 95% CI 0.75-1.31). A decreased point estimate of reoperation (OR=0.88, 95% CI 0.64-1.21) was counteracted by an increased point estimate of mortality (OR=1.28, 95% CI 0.83-1.99). ORs did not increase from Monday to Friday when each weekday was analysed separately. There was no association between weekday of surgery and reoperation specifically for anastomotic leak, laparotomy, or wound infection. Stratification for surgeon volume did not reveal any clear associations between weekday of surgery and risk of 30-day reoperation or mortality. Conclusions: Weekday of oesophageal cancer surgery does not seem to influence the risk of reoperation or mortality within 30 days of surgery, and thus cannot explain the association between weekday of surgery and long-term prognosis.The Swedish Research CouncilThe Swedish Cancer SocietyAccepte

Iran-United States Claims Tribunal

On 1 July 1981, at the Peace Palace in The Hague, I had the privilege of declaring open the Iran-United States Claims Tribunal, which had been constituted in accordance with the Declarations made by the Government of the Democratic and Popular Republic of Algeria, on 19 January 1981, and adhered to by Iran and the United States of America. As I observed at that time, two great nations had, by agreeing to peaceful settlement of their differences through arbitration, brought to an end a crisis of unique complexity which might well have become a threat to world peace

Acute myeloid leukemia : apoptotic signalling and gene expression associated with treatment response

Acute myeloid leukemia (AML) is a severe, life threatening malignancy characterized by a clonal expansion of immature myeloid cells in the bone marrow, resulting in severe infections and bleedings. High dose chemotherapy is able to normalize the blood and bone marrow morphology (complete remission, CR) in a majority of treated patients, but recurrent disease, typically occurs within 1-2 years. Since further intensification of chemotherapeutic regimens is usually ineffective and accompanied by excess toxicity, novel approaches using better-targeted drugs are now being assessed. We have analysed the effects of one such new agent, gemtuzumab ozogamicin (GO) on AML cells and have also looked for biomarkers of clinical response and the role of multidrug resistance (MDR) expression utilizing biobanked cells from an AML cohort with known long-term therapuetic outcome. In paper I we analysed apoptotic signalling in response to GO, a monoclonal CD33 antibody conjugated to the DNA-double strand break-inducing toxin calicheamicin. The CD33 antigen is typically expressed on AML blast cells, but not on e.g. normal gut cells. We found that GO could induce mitochondrial depolarisation, activation of caspase-3 and decreased viability of primary cells from AML patients and AML cell lines. Moreover, we showed that GO activated the proapoptotic proteins Bak and Bax, regulators of mitochondria-mediated apoptotic signalling. Importantly, none of the above events could be observed in GO-resistant AML cells. In paper II, we looked at the role of caspase-2 in GO- or daunorubicin-induced apoptotic signalling. We noted that both drugs caused cleavage of caspase-2 into its active form. A selective caspase-2 inhibitor prevented GO-induced caspase-3 activation, yet did not influence the activation of Bak and Bax. All in all, our data indicate that both mitochondria-dependent and independent routes to caspase-3 activation are involved in GO-induced apoptotic signalling, findings that may lead to novel future therapeutic approaches for AML. Improved predictive biomarkers for treatment response are clearly needed to enable more personalized and effective therapeutic options in AML. In paper III we studied peripheral blood cells from 42 patients diagnosed with AML and subjected to induction chemotherapy, aiming to identify biomarkers of CR duration using global gene expression analysis (Affymetrix®). Prominent differences in gene expression were found with a remarkable up-regulation of the transcription factor RUNX1T1 in patients with short vs. those with long subsequent CR duration. Network analyses (Oncomine®) revealed multiple transcription factors as interactors to RUNX1T1, out of which TCF3 was also significantly up-regulated in patients with short CR duration. An in silico validation, taking advantage of previously published data from two other independent AML cohorts revealed 52 genes to be regulated in all three cohorts. Among these genes CXCL3, ZMIZ1 and PRDX2 attracted a special interest due to their reported involvement in cancer, leukemia, apoptosis and proliferation. Thus, CXCL3 and ZMIZ1, with known involvement in tumorgenesis, had increased expression in poor responders whereas PRDX2, a tumour suppressor gene, instead showed a decreased expression. In paper IV we investigated the clinical relevance of 380 genes, reported to have a role in multidrug resistance (MDR) and analyzed 11 paired sampled from AML patients, collected at diagnosis and at time of relapse. Unsupervised hierarchical clustering showed that half of the cases had a similar expression pattern at both time points, whereas in the remaining patients the MDR genes became altered, suggesting clonal evolution. Patient-by-patient analyses showed signs of unique individual patient gene signatures and in 10 out of 11 patients an increase of at least one ABC transporter was observed at relapse. These findings call for a more broad signalling analysis of diagnostic and relapse AML blasts in order to improve chemotherapy response and thereby overall survival of the individual AML patient

The male predominance in esophageal adenocarcinoma

The incidence of esophageal adenocarcinoma (EAC) has increased rapidly during the past four decades in many Western populations, including North America and Europe. The established etiological factors for EAC include gastro-esophageal reflux and obesity, Helicobacter pylori infection, tobacco smoking, and consumption of fruit and vegetables. There is a marked male predominance of EAC with a male-to-female ratio in incidence of up to 9-to-1. This review evaluates the available literature on the reasons for the male predominance, particularly an update on epidemiologic evidence from human studies during the past decade. The striking sex difference does not seem to be explained by established risk factors, given that the prevalence of the etiological factors and the strengths of associations between these factors and EAC risk are similar between the sexes. Sex hormonal factors may play a role in the development of EAC; estrogenic exposures may prevent such development, while androgens might increase the risk of EAC. However, continuing research efforts are still in need to fully understand the reasons for the male predominance of EAC.Swedish Research CouncilSwedish Cancer SocietyAccepte

A global assessment of the male predominance in esophageal adenocarcinoma

Background: Esophageal adenocarcinoma (EAC) is characterized by a male predominance. However, variations in the sex difference across populations and over time have not previously been thoroughly investigated. Results: The male-to-female ratio in EAC incidence varied greatly across continents, ranging from 1.03 in Africa to 7.64 in Northern America during 2003– 2007. The ratio was high in Europe (6.04) and Oceania (6.24), and lower in Asia (4.37) and Latin America and the Caribbean (3.94). The sex ratio remained relatively stable over time in most populations. In absolute terms, the sex difference in EAC incidence increased over time in populations of higher incidence, while it remained stable or slightly decreased in low-incidence populations. Materials and Methods: We used data from the Cancer Incidence in Five Continents series to compute sex-specific age-standardized rates of EAC by population. The sex difference in incidence was evaluated on both absolute and relative scales, measured by the absolute difference and ratio between sexes, respectively. Conclusions: This first global assessment of the sex ratio in EAC shows that the male predominance is particularly strong in developed countries. The underlying reasons remain to be identified, but the emerging EAC burden in men merits consideration for targeted prevention and early detection.Swedish Research Council (SIMSAM)Swedish Cancer SocietyPublishe

A model for predicting individuals' absolute risk of esophageal adenocarcinoma : moving toward tailored screening and prevention

Esophageal adenocarcinoma (EAC) is characterized by rapidly increasing incidence and poor prognosis, stressing the need for preventive and early detection strategies. We used data from a nationwide population-based case-control study, which included 189 incident cases of EAC and 820 age- and sex-matched control participants, from 1995 through 1997 in Sweden. We developed risk prediction models based on unconditional logistic regression. Candidate predictors included established and readily identifiable risk factors for EAC. The performance of model was assessed by the area under receiver operating characteristic curve (AUC) with cross-validation. The final model could explain 94% of all case patients with EAC (94% population attributable risk) and included terms for gastro-esophageal reflux symptoms or use of antireflux medication, body mass index (BMI), tobacco smoking, duration of living with a partner, previous diagnoses of esophagitis and diaphragmatic hernia and previous surgery for esophagitis, diaphragmatic hernia or severe reflux or gastric or duodenal ulcer. The AUC was 0.84 (95% confidence interval [CI] 0.81-0.87) and slightly lower after cross-validation. A simpler model, based only on reflux symptoms or use of antireflux medication, BMI and tobacco smoking could explain 91% of the case patients with EAC and had an AUC of 0.82 (95% CI 0.78-0.85). These EAC prediction models showed good discriminative accuracy, but need to be validated in other populations. These models have the potential for future use in identifying individuals with high absolute risk of EAC in the population, who may be considered for endoscopic screening and targeted prevention.Swedish Research Council, D0547801Swedish Cancer Society, 14 0322Accepte