The Immune Checkpoint Landscape in Tumor Cells of Pancreatic Ductal Adenocarcinoma

Immune checkpoint therapy (ICT) has shown promising potential in the treatment of multiple solid tumors. However, the role of ICT in pancreatic ductal adenocarcinoma (PDAC) remains limited. Patterns of immune checkpoints (ICs) in PDAC represent the basis for establishing a potent ICT. The aim of this study is to create a profile of IC expression and its prognostic relevance in cancer cells of PDAC. Therefore, tumor cells from peripheral and central tissue microarray (TMA) spots from histologically confirmed PDAC of 68 patients after tumor resection were investigated in terms of expressions of TIM3, IDO, B7H4, LAG3, VISTA, and PD-L1 using immunohistochemistry. The presence of the respective ICs was compared to overall survival (OS). The presence of VISTA and PD-L1 significantly correlates with shorter OS (median OS: 22 months vs. 7 months and 22 months vs. 11 months, respectively, p 0.05). The analysis of OS of combined subgroups for VISTA and PD-L1 (VISTA and PD-L1 neg., VISTA pos. and PD-L1 neg., VISTA neg. and PD-L1 pos., and VISTA and PD-L1 pos.) yielded overall statistical significance difference (p = 0.02). These results suggest that the presence of VISTA and PD-L1 is of prognostic relevance and potentially qualifies them as targets for ICT

Perfusion Visualization during Ileal J-Pouch Formation—A Proposal for the Standardization of Intraoperative Imaging with Indocyanine Green Near-Infrared Fluorescence and a Postoperative Follow-Up in IBD Surgery

Background: An anastomotic leak (AL) after a restorative proctocolectomy and an ileal J-pouch increases morbidity and the risk of pouch failure. Thus, a perfusion assessment during J-pouch formation is crucial. While indocyanine green near-infrared fluorescence (ICG-NIRF) has shown potential to reduce ALs, its suitability in a restorative proctocolectomy remains unclear. We aimed to develop a standardized approach for investigating ICG-NIRF and ALs in pouch surgery. Methods: Patients undergoing a restorative proctocolectomy with an ileal J-pouch for ulcerative colitis at an IBD-referral-center were included in a prospective study in which an AL within 30 postoperative days was the primary outcome. Intraoperatively, standardized perfusion visualization with ICG-NIRF was performed and video recorded for postoperative analysis at three time points. Quantitative clinical and technical variables (secondary outcome) were correlated with the primary outcome by descriptive analysis and logistic regression. A novel definition and grading of AL of the J-pouch was applied. A postoperative pouchoscopy was routinely performed to screen for AL. Results: Intraoperative ICG-NIRF-visualization and its postoperative visual analysis in 25 patients did not indicate an AL. The anastomotic site after pouch formation appeared completely fluorescent with a strong fluorescence signal (category 2) in all cases of ALs (4 of 25). Anastomotic site was not changed. ICG-NIRF visualization was reproducible and standardized. Logistic regression identified a two-stage approach vs. a three-stage approach (Odds ratio (OR) = 20.00, 95% confidence interval [CI] = 1.37-580.18, p = 0.029) as a risk factor for ALs. Conclusion: We present a standardized, comparable approach of ICG-NIRF visualization in pouch surgery. Our data indicate that the visual interpretation of ICG-NIRF alone may not detect ALs of the pouch in all cases-quantifiable, objective methods of interpretation may be required in the future

Peptide Signatures for Prognostic Markers of Pancreatic Cancer by MALDI Mass Spectrometry Imaging

Simple Summary: Pancreatic cancer remains one of the most lethal tumor entities worldwide given its overall 5-year survival after diagnosis of 9%. Thus, further understanding of molecular changes to improve individual prognostic assessment as well as diagnostic and therapeutic advancement is crucial. The aim of this study was to investigate the feasibility of Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify specific peptide signatures linked to established prognostic parameters of pancreatic cancer. In a patient cohort of 18 patients with exocrine pancreatic cancer after tumor resection, MALDI imaging analysis additional to histopathological assessment was performed. Applying this method to tissue sections of the tumors, we were able to identify discriminative peptide signatures corresponding to nine proteins for the prognostic histopathological features lymphatic vessel invasion, lymph node metastasis and angioinvasion. This demonstrates the technical feasibility of MALDI-MSI to identify peptide signatures with prognostic value through the workflows used in this study. Abstract: Despite the overall poor prognosis of pancreatic cancer there is heterogeneity in clinical courses of tumors not assessed by conventional risk stratification. This yields the need of additional markers for proper assessment of prognosis and multimodal clinical management. We provide a proof of concept study evaluating the feasibility of Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify specific peptide signatures linked to prognostic parameters of pancreatic cancer. On 18 patients with exocrine pancreatic cancer after tumor resection, MALDI imaging analysis was performed additional to histopathological assessment. Principal component analysis (PCA) was used to explore discrimination of peptide signatures of prognostic histopathological features and receiver operator characteristic (ROC) to identify which specific m/z values are the most discriminative between the prognostic subgroups of patients. Out of 557 aligned m/z values discriminate peptide signatures for the prognostic histopathological features lymphatic vessel invasion (pL, 16 m/z values, eight proteins), nodal metastasis (pN, two m/z values, one protein) and angioinvasion (pV, 4 m/z values, two proteins) were identified. These results yield proof of concept that MALDI-MSI of pancreatic cancer tissue is feasible to identify peptide signatures of prognostic relevance and can augment risk assessment

Survival rates and prognostic factors in right- and left-sided colon cancer stage I–IV: an unselected retrospective single-center trial

Purpose: Colorectal cancer revealed over the last decades a remarkable shift with an increasing proportion of a right- compared to a left-sided tumor location. In the current study, we aimed to disclose clinicopathological differences between right- and left-sided colon cancer (rCC and lCC) with respect to mortality and outcome predictors. Methods: In total, 417 patients with colon cancer stage I-IV were analyzed in the present retrospective single-center study. Survival rates were assessed using the Kaplan-Meier method and uni/multivariate analyses were performed with a Cox proportional hazards regression model. Results: Our study showed no significant difference of the overall survival between rCC and lCC stage I-IV (p = 0.354). Multivariate analysis revealed in the rCC cohort the worst outcome for ASA (American Society of Anesthesiologists) score IV patients (hazard ratio [HR]: 16.0; CI 95%: 2.1-123.5), CEA (carcinoembryonic antigen) blood level > 100 mu g/l (HR: 3.3; CI 95%: 1.2-9.0), increased lymph node ratio of 0.6-1.0 (HR: 5.3; CI 95%: 1.7-16.1), and grade 4 tumors (G4) (HR: 120.6; CI 95%: 6.7-2179.6) whereas in the lCC population, ASA score IV (HR: 8.9; CI 95%: 0.9-91.9), CEA blood level 20.1-100 mu g/l (HR: 5.4; CI 95%: 2.4-12.4), conversion to laparotomy (HR: 14.1; CI 95%: 4.0-49.0), and severe surgical complications (Clavien-Dindo III-IV) (HR: 2.9; CI 95%: 1.5-5.5) were identified as predictors of a diminished overall survival. Conclusion: Laterality disclosed no significant effect on the overall prognosis of colon cancer patients. However, group differences and distinct survival predictors could be identified in rCC and lCC patients

Rethinking the TNM Classification Regarding Direct Lymph Node Invasion in Pancreatic Ductal Adenocarcinoma

Mechanisms of lymph node invasion seem to play a prognostic role in pancreatic ductal adenocarcinoma (PDAC) after resection. However, the 8th edition of the TNM classification of the American Joint Committee on Cancer (AJCC) does not consider this. The aim of this study was to analyse the prognostic role of different mechanisms of lymph node invasion on PDAC. One hundred and twenty-two patients with resected PDAC were examined. We distinguished three groups: direct (per continuitatem, Nc) from the main tumour, metastasis (Nm) without any contact to the main tumour, and a mixed mechanism (Ncm). Afterwards, the prognostic power of the different groups was analysed concerning overall survival (OS). In total, 20 patients displayed direct lymph node invasion (Nc = 16.4%), 44 were classed as Nm (36.1%), and 21 were classed as Ncm (17.2%). The difference in OS was not statistically significant between N0 (no lymph node metastasis, n = 37) and Nc (p = 0.134), while Nm had worse OS than N0 (p < 0.001). Direct invasion alone had no statistically significant effect on OS (p = 0.885). Redefining the N0 stage by including Nc patients showed a more precise OS prediction among N stages (p = 0.001 vs. p = 0.002). Nc was more similar to N0 than to Nm; hence, we suggest a rethinking of TNM classification based on the mechanisms of lymph node metastases in PDAC. Overall, this novel classification is more precise

The impact of surgical site infection—a cost analysis

Purpose: Surgical site infection (SSI) occurs in up to 25% of patients after elective laparotomy. We aimed to determine the effect of SSI on healthcare costs and patients' quality of life. Methods: In this post hoc analysis based on the RECIPE trial, we studied a 30-day postoperative outcome of SSI in a single-center, prospective randomized controlled trial comparing subcutaneous wound irrigation with 0.04% polyhexanide to 0.9% saline after elective laparotomy. Total medical costs were analyzed accurately per patient with the tool of our corporate controlling team which is based on diagnosis-related groups in Germany. Results: Between November 2015 and May 2018, 456 patients were recruited. The overall rate of SSI was 28.2%. Overall costs of inpatient treatment were higher in the group with SSI: median 16.685 euro; 19.703 USD (IQR 21.638 euro; 25.552 USD) vs. median 11.235 euro; 13.276 USD (IQR 11.564 euro; 13.656 USD); p < 0.001. There was a difference in surgery costs (median 6.664 euro; 7.870 USD with SSI vs. median 5.040 euro; 5.952 USD without SSI; p = 0.001) and costs on the surgical ward (median 8.404 euro; 9.924 USD with SSI vs. median 4.690 euro; 5.538 USD without SSI; p < 0.001). Patients with SSI were less satisfied with the cosmetic result (4.3% vs. 16.2%; p < 0.001). Overall costs for patients who were irrigated with saline were median 12.056 euro; 14.237 USD vs. median 12.793 euro; 15.107 USD in the polyhexanide group (p = 0.52). Conclusion: SSI after elective laparotomy increased hospital costs substantially. This is an additional reason why the prevention of SSI is important. Overall costs for intraoperative wound irrigation with saline were comparable with polyhexanide

Mechanosensitive ACKR4 scavenges CCR7 chemokines to facilitate T cell de-adhesion and passive transport by flow in inflamed afferent lymphatics.

T cell migration via afferent lymphatics to draining lymph nodes (dLNs) depends on expression of CCR7 in T cells and CCL21 in the lymphatic vasculature. Once T cells have entered lymphatic capillaries, they slowly migrate into contracting collecting vessels. Here, lymph flow picks up, inducing T cell detachment and rapid transport to the dLNs. We find that the atypical chemokine receptor 4 (ACKR4), which binds and internalizes CCL19 and CCL21, is induced by lymph flow in endothelial cells lining lymphatic collectors, enabling them to scavenge these chemokines. In the absence of ACKR4, migration of T cells to dLNs in TPA-induced inflammation is significantly reduced. While entry into capillaries is not impaired, T cells accumulate in the ACKR4-deficient dermal collecting vessel segments. Overall, our findings identify an ACKR4-mediated mechanism by which lymphatic collectors facilitate the detachment of lymph-borne T cells in inflammation and their transition from crawling to free-flow toward the dLNs

Mortality and pulmonary complications in patients undergoing surgery with perioperative sars-cov-2 infection: An international cohort study

Background The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (740%) had emergency surgery and 280 (248%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (261%) patients. 30-day mortality was 238% (268 of 1128). Pulmonary complications occurred in 577 (512%) of 1128 patients; 30-day mortality in these patients was 380% (219 of 577), accounting for 817% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 175 [95% CI 128-240], p&lt;00001), age 70 years or older versus younger than 70 years (230 [165-322], p&lt;00001), American Society of Anesthesiologists grades 3-5 versus grades 1-2 (235 [157-353], p&lt;00001), malignant versus benign or obstetric diagnosis (155 [101-239], p=0046), emergency versus elective surgery (167 [106-263], p=0026), and major versus minor surgery (152 [101-231], p=0047). Interpretation Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks