Impact of splenectomy on long-term outcomes after gastrectomy for gastric cancer: a population-based study.

BACKGROUND: No national studies comparing long-term survival after total or partial gastrectomy with splenectomy due to injury or oncologic reasons or spleen preservation exist. This study aimed to examine the 5-year overall survival (OS) of patients with gastric adenocarcinoma who underwent total or partial gastrectomy with splenectomy due to injury or oncologic reasons or spleen preservation in a population-based nationwide setting. METHODS: This study included all patients undergoing total or partial gastrectomy with splenectomy or spleen preservation for gastric adenocarcinoma in Finland from 2005 to 2016, with follow-up until December 31, 2019. A total of 2196 patients with gastric cancer diagnosis and total or partial gastrectomy were identified in the registries. Of these patients, 2118 were applicable for this study. Cox proportional hazard models provided hazard ratios (HRs) with 95% CIs of 5-year OS. The results were adjusted for age, sex, year of operation, comorbidities, tumor location, pathologic stage, and neoadjuvant therapy. RESULTS: The observed 5-year OS rates were 38.7% in patients with no or minor spleen injury, 39.7% in patients with splenectomy due to injury, and 30.8% in patients with splenectomy due to oncologic reasons (P = .032). Patients who underwent R0 gastrectomy with splenectomy due to oncologic reasons had higher 5-year mortality (the adjusted model HR, 1.26; 95% CI, 1.01-1.56) than patients who underwent spleen preservation. CONCLUSION: The OS was worst in patients who underwent gastrectomy with splenectomy due to oncologic reasons, highlighting the poor prognosis in patients with advanced gastric cancer. Splenectomy due to injury does not compromise the prognosis.

Risk of Second Primary Cancer Among Patients with Cardio-Esophageal Cancer in Finland: A Nationwide Population-Based Study.

Purpose: The occurrence of a second primary cancer (SPC) after primary esophageal carcinoma (EC) or gastric cardia carcinoma(GCC) is well acknowledged. However, previous research on the risk of SPC among these patients has been predominantly conducted in Asian countries. Yet, notable population-dependent variation in histological types and risk profiles exists. This register-based study assesses the histology-specific risk of SPC among individuals initially diagnosed with a first primary EC or GCC. Patients and Methods: We obtained data on 7197 patients diagnosed with EC/GCC in Finland between 1980 and 2022 from the Finnish Cancer Registry. Standardized incidence ratios (SIR) of SPC were subsequently calculated relatively to the cancer risk of the general population. Results: The average and median follow-up times were 2.8 years and 10.5 months. Adenocarcinomas and squamous cell carcinomas comprised 57.8% (n = 4165) and 36.6% (n = 2631) of all cases, respectively. An increased SIR was noted among EC/GCC patients after 15-20 years of follow-up (SIR 1.49, 95% CI: 1.01-2.11). Among adenocarcinoma patients, an increased SIR for SPCs of the digestive organs was seen in the 40-54-year-old group (SIR 9.86, 95% CI: 3.62-21.45). Squamous cell carcinoma patients displayed increased SIRs for cancer of the mouth/pharynx (SIR 3.20, 95% CI: 1.17-6.95) and respiratory organs (1.77, 1.07-2.76). Conclusion: Healthcare professionals should be aware of the increased risk of SPCs occurring in the mouth/pharynx, respiratory and digestive organs in survivors of EC/GCC. Patients should be advised about this risk and remain alert for symptoms, even beyond the standard 5-year follow-up period.

Comparison of Postoperative Complications After Gastrectomy for Gastric Cancer with Antecolic Versus Retrocolic Reconstruction: A Population-Based Study.

BACKGROUND: The purpose of this study was to examine the rates of 90-day anastomotic complications and other postoperative complications after total or partial gastrectomy with antecolic versus retrocolic reconstruction in a population-based setting. METHODS: This population-based nationwide retrospective cohort study included all patients undergoing total or partial gastrectomy for gastric adenocarcinoma in Finland in 2005-2016, with follow-up until 31 December 2019. Logistic regression provided odds ratios (ORs) with 95% confidence intervals (CIs) of 90-day mortality. Results were adjusted for age, sex, year of the surgery, comorbidities, tumor locations, pathological stage, and neoadjuvant therapy. RESULTS: A total of 2063 patients having gastrectomy with antecolic (n = 814) or retrocolic (n = 1249) reconstruction were identified from the registries. The anastomotic complication rate was 3.8% with antecolic reconstruction and 5.0% with retrocolic reconstruction. Antecolic reconstruction was not associated with a higher risk of anastomotic complications compared with retrocolic reconstruction in the adjusted analysis (OR 0.69, 95% CI 0.44-1.09) of the whole cohort or in the predefined subgroups. The reoperation rate was 8.2% with antecolic reconstruction and 7.7% with retrocolic reconstruction, without statistical significance. In subgroup analysis of total gastrectomy patients, the risk of major complications was lower with antecolic reconstruction compared with retrocolic reconstruction (OR 0.62, 95% CI 0.45-0.86). CONCLUSIONS: The rate of anastomotic complications did not differ after antecolic versus retrocolic reconstruction after total or partial gastrectomy. In total gastrectomies, the risk of major complications was lower after antecolic compared with retrocolic reconstruction.

Postoperative delayed emptying after total, subtotal, or distal gastrectomy for gastric cancer: a population-based study.

BACKGROUND: This study aimed to examine the rate of delayed emptying and other 90-day postoperative complications after total, subtotal, and distal gastrectomies for gastric adenocarcinoma in a population-based setting. METHODS: This study included all patients who underwent total, subtotal, or distal gastrectomy for gastric cancer in Finland in 2005-2016, with follow-up until December 31, 2019. Logistic regression provided the odds ratios with 95% CIs of 90-day mortality. The results were adjusted for age, sex, year of surgery, comorbidities, pathologic stage, and neoadjuvant therapy. RESULTS: A total of 2058 patients underwent total (n = 1227), subtotal (n = 450), or distal (n = 381) gastrectomy. In the total, subtotal, and distal gastrectomy groups, the rates of 90-day delayed emptying were 1.7%, 1.3%, and 2.1% in the whole cohort and 1.6%, 1.8%, and 3.5% in the subgroup analysis of R0 resections, respectively. The resection type was not associated with the risk of delayed emptying. Subtotal gastrectomy was associated with a lower risk of major complications and reoperations, whereas distal gastrectomy was associated with a lower risk of anastomotic complications. CONCLUSION: The extent of resection did not affect delayed emptying, whereas fewer postoperative complications were observed after subtotal or distal gastrectomy than after total gastrectomy.

Stapled vs handsewn anastomosis and anastomotic leaks in gastric cancer surgery-a population-based nationwide study in Finland.

BACKGROUND: There is a lack of evidence regarding anastomotic technique and postoperative complications in gastric cancer surgery. This study aimed to evaluate whether there are differences between stapled and handsewn anastomosis and anastomotic leaks. METHODS: This was a population-based, retrospective, nationwide cohort study in Finland using the Finnish National Esophago-Gastric Cancer Cohort. Patients undergoing gastrectomy with available postoperative complication data were included. Logistic regression analysis was used to calculate the odds ratios with 95% CIs, adjusted for calendar period of surgery, age at surgery, sex, comorbidity, tumor stage, neoadjuvant therapy, minimally invasive surgery, type of gastrectomy, radical resection, and type of anastomosis. RESULTS: Of the 2164 patients, 472 of all patients (21.8%) had handsewn anastomosis and 1692 of all patients (78.2%) had stapled anastomosis. In the unadjusted analysis, anastomotic leaks were significantly lower in the handsewn group (hazard ratio [HR], 0.42; 95% CI, 0.22-0.79) than the stapled group, but after adjustment for known prognostic factors, this association was no longer significant (HR, 0.57; 95% CI, 0.27-1.21). In the analysis stratified by gastrectomy type (distal or total), no differences in anastomotic leaks were observed between anastomotic techniques. CONCLUSION: In this population-based nationwide study, anastomotic technique (stapled or handsewn) was not associated with anastomotic leaks in any, distal or total, gastrectomy.

Western European Variation in the Organization of Esophageal Cancer Surgical Care.

Reasons for structural and outcome differences in esophageal cancer surgery in Western Europe remain unclear. This questionnaire study aimed to identify differences in the organization of esophageal cancer surgical care in Western Europe. A cross-sectional international questionnaire study was conducted among upper gastrointestinal (GI) surgeons from Western Europe. One surgeon per country was selected based on scientific output and active membership in the European Society for Diseases of the Esophagus or (inter)national upper GI committee. The questionnaire consisted of 51 structured questions on the structural organization of esophageal cancer surgery, surgical training, and clinical audit processes. Between October 2021 and October 2022, 16 surgeons from 16 European countries participated in this study. In 5 countries (31%), a volume threshold was present ranging from 10 to 26 annual esophagectomies, in 7 (44%) care was centralized in designated centers, and in 4 (25%) no centralizing regulations were present. The number of centers performing esophageal cancer surgery per country differed from 4 to 400, representing 0.5-4.9 centers per million inhabitants. In 4 countries (25%), esophageal cancer surgery was part of general surgical training and 8 (50%) reported the availability of upper GI surgery fellowships. A national audit for upper GI surgery was present in 8 (50%) countries. If available, all countries use the audit to monitor the quality of care. Substantial differences exist in the organization and centralization of esophageal cancer surgical care in Western Europe. The exchange of experience in the organizational aspects of care could further improve the results of esophageal cancer surgical care in Europe.

Upper gastrointestinal endoscopy procedure volume trends, perioperative mortality, and malpractice claims: Population-based analysis.

Background and study aims Upper gastrointestinal endoscopy (EGD) is one of the most common diagnostic procedures done to examine the foregut, but it can also be used for therapeutic interventions. The main objectives of this study were to investigate trends in EGD utilization and mortality related to it in a national low-threshold healthcare system, assess perioperative safety, and identify and describe patient-reported malpractice claims from the national database. Patients and methods We retrospectively identified patients from the Finnish Patient Care Registry who underwent diagnostic or procedural EGD between 2010 and 2018. In addition, patient-reported claims for malpractice were analyzed from the National Patient Insurance Center (PIC) database. Patient survival data were gathered collectively from the National Death Registry from Statistics Finland. Results During the study period, 409,153 EGDs were performed in Finland for 298,082 patients, with an annual rate of 9.30 procedures per 1,000 inhabitants, with an annual increase of 2.6%. Thirty-day all-cause mortality was 1.70% and 90-day mortality was 3.84%. For every 1,000 patients treated, 0.23 malpractice claims were filed. Conclusions The annual rate of EGD increased by 2.6% during the study, while the rate of interventional procedures remained constant. Also, while the 30-day mortality rate declined over the study period, it is an unsuitable quality metric for EGDs in comprehensive centers because a patient's underlying disease plays a larger role than the procedure in perioperative mortality. Finally, there were few malpractice claims, with self-evident causes prevailing.

miRNA-221 and miRNA-483-3p Dysregulation in Esophageal Adenocarcinoma.

Alterations in microRNA (miRNA) expression have been reported in different cancers. We assessed the expression of 754 oncology-related miRNAs in esophageal adenocarcinoma (EAC) samples and evaluated their correlations with clinical parameters. We found that miR-221 and 483-3p were consistently upregulated in EAC patients vs. controls (Wilcoxon signed-rank test: miR-221 p < 0.0001; miR-483-3p p < 0.0001). Kaplan-Meier analysis showed worse cancer-related survival among all EAC patients expressing high miR-221 or miR-483-3p levels (log-rank p = 0.0025 and p = 0.0235, respectively). Higher miR-221 or miR-483-3p levels also correlated with advanced tumor stages (Mann-Whitney p = 0.0195 and p = 0.0085, respectively), and overexpression of miR-221 was associated with worse survival in low-risk EAC patients. Moreover, a significantly worse outcome was associated with the combined overexpression of miR-221 and miR-483-3p (log-rank p = 0.0410). To identify target genes affected by miRNA overexpression, we transfected the corresponding mimic RNA (miRVANA) for either miR-221 or miR-483-3p in a well-characterized esophageal adenocarcinoma cell line (OE19) and performed RNA-seq analysis. In the miRNA-overexpressing cells, we discovered a convergent dysregulation of genes linked to apoptosis, ATP synthesis, angiogenesis, and cancer progression, including a long non-coding RNA associated with oncogenesis, i.e., MALAT1. In conclusion, dysregulated miRNA expression, especially overexpression of miR-221 and 483-3p, was found in EAC samples. These alterations were connected with a lower cancer-specific patient survival, suggesting that these miRNAs could be useful for patient stratification and prognosis.

Malpractice claims after antireflux surgery and paraesophageal hernia repair: a population-based analysis.

BACKGROUND: The complication rate of modern antireflux surgery or paraesophageal hernia repair is unknown, and previous estimates have been extrapolated from institutional cohorts. METHODS: A population-based retrospective cohort study of patient injury cases involving antireflux surgery and paraesophageal hernia repair from the Finnish National Patient Injury Centre (PIC) register between Jan 2010 and Dec 2020. Additionally, the baseline data of all the patients who underwent antireflux and paraesophageal hernia operations between Jan 2010 and Dec 2018 were collected from the Finnish national care register. RESULTS: During the study period, 5734 operations were performed, and the mean age of the patients was 54.9 ± 14.7 years, with 59.3% (n = 3402) being women. Out of all operations, 341 (5.9%) were revision antireflux or paraesophageal hernia repair procedures. Antireflux surgery was the primary operation for 79.9% (n = 4384) of patients, and paraesophageal hernia repair was the primary operation for 20.1% (n = 1101) of patients. A total of 92.5% (5302) of all the operations were laparoscopic. From 2010 to 2020, 60 patient injury claims were identified, with half (50.0%) of the claims being related to paraesophageal hernia repair. One of the claims was made due to an injury that resulted in a patient's death (1.7%). The mean Comprehensive Complication Index scores were 35.9 (± 20.7) and 47.6 (± 20.8) (p = 0.033) for antireflux surgery and paraesophageal hernia repair, respectively. Eleven (18.3%) of the claims pertained to redo surgery. CONCLUSIONS: The rate of antireflux surgery has diminished and the rate of paraesophageal hernia repair has risen in Finland during the era of minimally invasive surgery. Claims to the PIC remain rare, but claims regarding paraesophageal hernia repairs and redo surgery are overrepresented. Additionally, paraesophageal hernia repair is associated with more serious complications.

Postoperative Complications After Neoadjuvant Chemotherapy Versus Upfront Surgery in Gastric Adenocarcinoma: A Population-Based Nationwide Study in Finland.

BACKGROUND: To date, no large population-based studies have compared complications and short-term outcomes between neoadjuvant chemotherapy and upfront surgery in gastric cancer. More nationwide studies with standardized reporting on complications are needed to enable international comparison between studies. This study aimed to compare postoperative complications between neoadjuvant therapy and upfront surgery after gastrectomy for gastric adenocarcinoma in a population-based setting. METHODS: This population-based study based on the Finnish National Esophago-Gastric Cancer Cohort included all patients 18 years of age or older undergoing gastrectomy for gastric adenocarcinoma in Finland during 2005-2016. Logistic regression provided odds ratios (ORs) with 95% confidence intervals (CIs), both crude and adjusted for key confounders. Different types of complications were graded based on the Esophagectomy Complications Consensus Group definitions, and major complications were assessed by the Clavien-Dindo scale. RESULTS: This study analyzed 769 patients. Neoadjuvant chemotherapy did not increase major postoperative complications after gastrectomy for gastric cancer compared with upfront surgery (OR, 1.12; 95% CI 0.81-1.56). Furthermore, it did not increase pneumonia, anastomotic complications, wound complications, or other complications. CONCLUSIONS: Neoadjuvant therapy is not associated with increased postoperative complications, reoperations, or short-term mortality compared with upfront surgery in gastric adenocarcinoma.

Development of mesothelioma-specific oncolytic immunotherapy enabled by immunopeptidomics of murine and human mesothelioma tumors.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. As the available therapeutic options show a lack of efficacy, novel therapeutic strategies are urgently needed. Given its T-cell infiltration, we hypothesized that MPM is a suitable target for therapeutic cancer vaccination. To date, research on mesothelioma has focused on the identification of molecular signatures to better classify and characterize the disease, and little is known about therapeutic targets that engage cytotoxic (CD8+) T cells. In this study we investigate the immunopeptidomic antigen-presented landscape of MPM in both murine (AB12 cell line) and human cell lines (H28, MSTO-211H, H2452, and JL1), as well as in patients' primary tumors. Applying state-of-the-art immuno-affinity purification methodologies, we identify MHC I-restricted peptides presented on the surface of malignant cells. We characterize in vitro the immunogenicity profile of the eluted peptides using T cells from human healthy donors and cancer patients. Furthermore, we use the most promising peptides to formulate an oncolytic virus-based precision immunotherapy (PeptiCRAd) and test its efficacy in a mouse model of mesothelioma in female mice. Overall, we demonstrate that the use of immunopeptidomic analysis in combination with oncolytic immunotherapy represents a feasible and effective strategy to tackle untreatable tumors.

Population-based nationwide incidence of complications after gastrectomy for gastric adenocarcinoma in Finland.

BACKGROUND: The incidence of postoperative complications after gastrectomy for gastric cancer is not well known. More population-based studies using established complication classifications are needed for international comparison. The aim of this study was to evaluate the population-based incidence of postoperative complications after gastrectomy for gastric cancer. METHODS: This population-based study based on the Finnish National Esophago-Gastric Cancer Cohort included all patients at least 18 years of age undergoing gastrectomy for gastric adenocarcinoma in Finland during 2005-2016. The occurrence of complications 30 and 90 days after surgery was graded based on the Esophagectomy Complications Consensus Group definitions and the severity of complications was assessed using the Clavien-Dindo scale. RESULTS: This study included a total of 2196 patients. Postoperative complications occurred in 906 (41.3 per cent) of patients during 30 days after surgery and in 946 (43.1 per cent) during 90 days after surgery. Clavien-Dindo grade III or higher complications occurred in 375 (17.1 per cent) of patients. The most common complications 90 days after surgery by Esophagectomy Complications Consensus Group upper-level categories were gastrointestinal (n = 438; 19.9 per cent), including anastomotic leak, infectious (n = 377; 17.2 per cent) and pulmonary (n = 335; 15.3 per cent) complications. Postoperative mortality rate was occurred in 72 (3.3 per cent) patients within 30 days and in 161 (7.3 per cent) patients within 90 days after surgery. The median duration of postoperative hospital stay was 9 days (interquartile range 4-14). CONCLUSIONS: Postoperative complications are common across all types of gastrectomy and the majority occur during the first 30 postoperative days. This study informs the patients and caregivers of the expected outcomes of gastrectomy.

Effective intravenous delivery of adenovirus armed with TNFα and IL-2 improves anti-PD-1 checkpoint blockade in non-small cell lung cancer.

Lung cancer remains among the most difficult-to-treat malignancies and is the leading cause of cancer-related deaths worldwide. The introduction of targeted therapies and checkpoint inhibitors has improved treatment outcomes; however, most patients with advanced-stage non-small cell lung cancer (NSCLC) eventually fail these therapies. Therefore, there is a major unmet clinical need for checkpoint refractory/resistant NSCLC. Here, we tested the combination of aPD-1 and adenovirus armed with TNFα and IL-2 (Ad5-CMV-mTNFα/mIL-2) in an immunocompetent murine NSCLC model. Moreover, although local delivery has been standard for virotherapy, treatment was administered intravenously to facilitate clinical translation and putative routine use. We showed that treatment of tumor-bearing animals with aPD-1 in combination with intravenously injected armed adenovirus significantly decreased cancer growth, even in the presence of neutralizing antibodies. We observed an increased frequency of cytotoxic tumor-infiltrating lymphocytes, including tumor-specific cells. Combination treatment led to a decreased percentage of immunosuppressive tumor-associated macrophages and an improvement in dendritic cell maturation. Moreover, we observed expansion of the tumor-specific memory T cell compartment in secondary lymphoid organs in the group that received aPD-1 with the virus. However, although the non-replicative Ad5-CMV-mTNFα/mIL-2 virus allows high transgene expression in the murine model, it does not fully reflect the clinical outcome in humans. Thus, we complemented our findings using NSCLC ex vivo models fully permissive for the TNFα and IL-2- armed oncolytic adenovirus TILT-123. Overall, our data demonstrate the ability of systemically administered adenovirus armed with TNFα and IL-2 to potentiate the anti-tumor efficacy of aPD-1 and warrant further investigation in clinical trials.

Chemoradiation for oesophageal cancer: the choice of treatment modality.

BACKGROUND: Locally advanced oesophageal cancer can be treated with definitive chemoradiation (dCRT) or with neoadjuvant chemoradiation followed by surgery (nCRT + S), but treatment modality choice is not always clear. The aim of this study was to investigate the factors associated with the choice of treatment modality in locally advanced oesophageal cancer. METHODS: This was a retrospective cohort study of 149 patients treated with dCRT(n = 85) or nCRT + S (n = 64) for oesophageal cancer in Helsinki University Hospital in 2008-2018. Logistic regression was used to analyse factors associated with choice of treatment modality and to compare dosimetric factors with postoperative complications. Multivariate analyses identified factors associated with survival. RESULTS: Surgery was performed after chemoradiation as planned on 64/91 patients (70%). 28/64 had pathological complete response (44%). Probability of nCRT + S was higher in stages I-III versus IV (OR 3.62, 95% CI 1.53-8.53; P = .003), ECOG 0-1 versus 2 (OR 6.99, 95% CI 1.81-26.96; P = .005) or in the middle/lower vs upper oesophageal tumours (OR 5.61, 95% CI 1.83-17.16, P = .003). Probability for surgery was lower, if patient had lost > 10% of body weight (OR 0.46, 95% CI 0.21-0.98, P = 0.043). Patients in the nCRT + S group had significantly better median overall survival (mOS) and local control than the dCRT group (60 vs. 10 months, P < .001 and 53 vs. 6 months, P < 0.0001, respectively). 10/85 (12%) patients died within three months after dCRT. In multivariate analysis, nCRT + S was associated with improved mOS (HR 0.28, 95% CI 0.17-0.44, P < .001). Current smokers had worse mOS (HR 2.02, 95% CI 1.04-3.92, P = .037) compared to never-smokers. No significant dosimetric factor associated with postoperative complications was found. CONCLUSION: The overall clinical status of the patients and the stage of the cancer guide the choice of treatment modalities, leading to overtreatment. Patients with better prognoses were more likely operated after chemoradiation, although there is no evidence of OS benefit in previous randomized trials. On the other hand, the prognosis was poor for patients with poor general health and advanced cancers, despite the chemoradiation. Thus, there are signs of overtreatment. MDT practice should be recommended to optimise the choice of treatment modalities. Smoking status is an independent factor associated with survival.

Time trends in mortality of oesophageal cancer in Finland over 30 years.

INTRODUCTION: Oesophageal cancer survival is reported by epidemiological studies, but knowledge on survival trends regarding different histologies and operative treatment status is lacking. MATERIALS AND METHODS: Data from all patients diagnosed with oesophageal cancer in Finland in 1987-2016 was collected from national registries. 1-, 3- and 5-year survival rates were examined stratified by histology (adenocarcinoma (OAC) and squamous cell carcinoma (OSCC)) and treatment strategy (surgery, no surgery). Hazard ratios (HR) with 95% confidence intervals (CI) for death were provided by multivariable Cox regression, adjusted for confounders. RESULTS: Of the 9102 patients, 3140 had OAC (1074 [34%] oesophagectomies), and 3778 had OSCC (870 [23%] oesophagectomies). Men were overrepresented in both OAC (77%) and OSCC (55%). The proportion of oesophagectomies decreased in both histologies. From 1987 to 1991 to 2012-2016, 5-year survival increased from 11% to 22% in OAC and from 7% to 13% in OSCC. For patients undergoing oesophagectomy, the corresponding increases were from 20% to 49% in OAC and from 11% to 54% in OSCC, and non-operated patients from 5% to 8% and from 5% to 7%, respectively. Earlier calendar period, older age and comorbidity were associated with mortality in both histologies. Female sex was a protective factor for patients operated for OSCC (HR 1.56 (95% CI 1.33-1.83), men versus women). CONCLUSIONS: The prognosis of oesophageal cancer has improved in Finland over the last 30 years in both main histological types. The survival of patients undergoing oesophagectomy has drastically improved, while the prognosis of patients not undergoing surgery is slowly improving but remains poor.

Correlations between Molecular Alterations, Histopathological Characteristics, and Poor Prognosis in Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a severe malignancy with increasing incidence, poorly understood pathogenesis, and low survival rates. We sequenced 164 EAC samples of naïve patients (without chemo-radiotherapy) with high coverage using next-generation sequencing technologies. A total of 337 variants were identified across the whole cohort, with TP53 as the most frequently altered gene (67.27%). Missense mutations in TP53 correlated with worse cancer-specific survival (log-rank p = 0.001). In seven cases, we found disruptive mutations in HNF1alpha associated with other gene alterations. Moreover, we detected gene fusions through massive parallel sequencing of RNA, indicating that it is not a rare event in EAC. In conclusion, we report that a specific type of TP53 mutation (missense changes) negatively affected cancer-specific survival in EAC. HNF1alpha was identified as a new EAC-mutated gene.

Preoperative Esophageal Stenting and 5-Year Survival in Patients Undergoing Esophagectomy for Esophageal Cancer: a Population-Based Nationwide Study from Finland.

BACKGROUND: Preoperative esophageal stenting is proposed to have a negative effect on outcomes. The aim was to compare a 5-year survival in patients undergoing esophagectomy for esophageal cancer with and without preoperative esophageal stent in a population-based nationwide cohort from Finland. The secondary outcome was 90-day mortality. METHODS: This study included curatively intended esophagectomies for esophageal cancer in Finland between 1999 and 2016, with follow-up until December 31, 2019. Cox proportional hazards models provided hazard ratios (HRs) with 95% confidence intervals (CIs) of overall 5-year and 90-day mortality. Model 1 was adjusted for age, sex, year of the surgery, comorbidities, histology, pathological stage, and neoadjuvant therapy. Model 2 included also albumin level and BMI. RESULT: Of 1064 patients, a total of 134 patients underwent preoperative stenting and 930 did not. In both adjusted models 1 and 2, higher 5-year mortality was seen in patients with preoperative stent with HRs of 1.29 (95% CI 1.00-1.65) and 1.25 (95% CI 0.97-1.62), respectively, compared to no stenting. The adjusted HR of 90-day mortality was 2.49 (95% CI 1.27-4.87) in model 1 and 2.49 (95% CI 1.25-4.99) in model 2. When including only neoadjuvant-treated patients, those with preoperative stent had a 5-year survival of 39.2% compared to 46.4% without stent (adjusted HR 1.34, 95% CI 1.00-1.80), and a 90-day mortality rate of 8.5% and 2.5% (adjusted HR 3.99, 95% CI 1.51-10.50). DISCUSSION: This nationwide study reports worse 5-year and 90-day outcomes in patients with preoperative esophageal stent. Since residual confounding remains possible, observed difference could be only an association rather than the cause.

Paraconduit hernia after minimally invasive esophagectomy - incidence and risk factors.

BACKGROUND: Paraconduit hernia is a relatively common long-term complication after esophagectomy which has the potential to cause great morbidity and even mortality. The aim of this study is to examine the risk factors and incidence of paraconduit hernia after minimally invasive esophagectomy (MIE) in esophageal adenocarcinoma patients who have received neoadjuvant treatment. METHODS: Minimally invasive esophagectomies done for patients with neoadjuvant-treated esophageal or esophagogastric junction adenocarcinoma at our institution between 2008 and 2018 were included in this study. All patients with symptomatic or incidentally found paraconduit hernias on computed tomography scans were identified. Patient demographics were analyzed using logistic and Cox regression. RESULTS: The incidence of paraconduit hernia was 14 out of 171 patients (8.2%). The hernia was surgically repaired in 10 (71.4%) of patients. Laparoscopic approach was used in 90% of the repairs, with one (11.1%) conversion to laparotomy. Emergency operations accounted for three (30%) of the operations. The complication rate was 10% (n = 1) and 90-day mortality was 10% (n = 1). Neither sarcopenia nor muscle mass loss was not associated with paraconduit hernia development, whereas preoperative radiotherapy (OR = 8.57, CI = 1.98-33.8, p = .002) was a strong risk factor for paraconduit hernia. Higher BMI had a protective effect (OR = 0.83 per point, 95% CI = 0.69-0.97, p = .027). CONCLUSIONS: Paraconduit hernia is a relatively common complication after MIE for neoadjuvant-treated adenocarcinoma patients. Preoperative radiotherapy was associated with a higher risk of paraconduit hernia. Minimally invasive repair of paraconduit hernia after esophagectomy is efficient and has a low complication rate both in elective and emergency cases.

Five-year Survival after McKeown Compared to Ivor-Lewis Esophagectomy for Esophageal Cancer: A Population-based Nationwide Study in Finland.

OBJECTIVE: The aim of study was to compare overall 5-year survival of esophageal cancer patients undergoing transthoracic esophagectomy with either neck or intrathoracic anastomosis, that is, McKeown and Ivor-Lewis esophagectomy. BACKGROUND: No national studies comparing long-term survival after McKeown and ivor-Lewis esophagectomies in the West exist. METHODS: This population-based nationwide study included all curatively intended transthoracic esophagectomies for esophageal adenocarcinoma or squamous cell carcinoma in Finland in 1987 to 2016, with follow-up until December 31, 2019. Cox proportional hazard models provided hazard ratios (HR) with 95% confidence intervals (ci) of all-cause 5-year mortality. The results were adjusted for age, sex, year of the operation, comorbidities, histology, stage, and neoadjuvant treatment. Adjusted model 2 included also tumor location and lymph node yield. RESULTS: A total of 990 patients underwent McKeown (n = 278) or Ivor-Lewis (n = 712) esophagectomy The observed overall 5-year survival was 43.1% after McKeown, and 45.9% after Ivor-Lewis esophagectomy. McKeown esophagectomy was not associated with the overall 5-year mortality (adjusted HR 1.11, 95% CI: 0.89-1.38), compared to Ivor-Lewis esophagectomy. Additional adjustment for tumor location and lymphadenectomy further attenuated the point estimate (HR 1.06, 95% CI: 0.85-1.33). Surgical approach was not associated with 90-day mortality rate (adjusted HR 1.15, 95% CI: 0.67-1.97). CONCLUSIONS: This population-based nationwide study suggests that overall 5-year survival or 90-day survival with McKeown and Ivor-Lewis esopha-gectomy for esophageal cancer are comparable.

PI3Kß inhibition enhances ALK-inhibitor sensitivity in ALK-rearranged lung cancer.

Treatment with anaplastic lymphoma kinase (ALK) inhibitors significantly improves outcome for non-small-cell lung cancer (NSCLC) patients with ALK-rearranged tumors. However, clinical resistance typically develops over time and, in the majority of cases, resistance mechanisms are ALK-independent. We generated tumor cell cultures from multiple regions of an ALK-rearranged clinical tumor specimen and deployed functional drug screens to identify modulators of ALK-inhibitor response. This identified a role for PI3Kß and EGFR inhibition in sensitizing the response regulating resistance to ALK inhibition. Inhibition of ALK elicited activation of EGFR, and subsequent MAPK and PI3K-AKT pathway reactivation. Sensitivity to ALK targeting was enhanced by inhibition or knockdown of PI3Kß. In ALK-rearranged primary cultures, the combined inhibition of ALK and PI3Kß prevented the EGFR-mediated ALK-inhibitor resistance, and selectively targeted the cancer cells. The combinatorial effect was seen also in the background of TP53 mutations and in epithelial-to-mesenchymal transformed cells. In conclusion, combinatorial ALK- and PI3Kß-inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.