Spatial heterogeneity of immune regulators drives dynamic changes of local immune responses, affecting disease outcomes in pancreatic cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is considered a low immunogenic tumor with "cold" tumor microenvironment (TME) and is mostly unresponsive to immune checkpoint blockade therapies. Here we decipher the impact of intratumoral heterogeneity of immune determinants on antitumor response. EXPERIMENTAL DESIGN: We performed spatial proteomic and transcriptomic analyses and multiplexed immunofluorescence on multiple tumor regions, including tumor center (TC) and invasive front (IF), from 220 PDAC-patients, classified according to their transcriptomic immune signaling into high-immunogenic (HI-PDACs, n=54) and low-immunogenic tumors (LI-PDACs, n=166). Spatial compartments (tumor: Pancytokeratin+/CD45- and leukocytes: Pancytokeratin-/CD45+) were defined by fluorescent imaging. RESULTS: HI-PDACs exhibited higher densities of cytotoxic T lymphocytes with upregulation of T-cell priming-associated immune determinants, including CD40, ITGAM, GITR, CXCL10, GZMB, IFNG and HLA-DR, which was significantly more prominent at the IF than the TC. In contrast, LI-PDACs exhibited immune evasive TMEs with downregulation of immune determinants and a negative gradient from TC to IF. Patients with HI-PDACs had significantly better outcomes; however, they showed more frequently exhausted immune phenotypes. CONCLUSIONS: Our results indicate strategic differences in the regulation of immune determinants, which lead to different levels of effectiveness of antitumor responses between high- and low-immunogenic tumors and dynamic spatial changes, which affect the evolution of immune evasion and patient outcomes. This supports coevolution of tumor and immune cells and may help define therapeutic vulnerabilities to improve antitumor immunity and harness the responsiveness to immune checkpoint inhibitors in PDAC patients.

Low-pressure versus standard-pressure pneumoperitoneum in minimally invasive colorectal surgery: a systematic review, meta-analysis, and meta-regression analysis.

Background: We aimed to assess the efficacy and safety of low-pressure pneumoperitoneum (LPP) in minimally invasive colorectal surgery. Methods: A PRISMA-compliant systematic review/meta-analysis was conducted, searching PubMed, Scopus, Google Scholar, and clinicaltrials.gov for randomized-controlled trials assessing outcomes of LPP vs standard-pressure pneumoperitoneum (SPP) in colorectal surgery. Efficacy outcomes [pain score in post-anesthesia care unit (PACU), pain score postoperative day 1 (POD1), operative time, and hospital stay] and safety outcomes (blood loss and postoperative complications) were analyzed. Risk of bias2 tool assessed bias risk. The certainty of evidence was graded using GRADE. Results: Four studies included 537 patients (male 59.8%). LPP was undertaken in 280 (52.1%) patients and associated with lower pain scores in PACU [weighted mean difference: -1.06, 95% confidence interval (CI): -1.65 to -0.47, P = 0.004, I 2 = 0%] and POD1 (weighted mean difference: -0.49, 95% CI: -0.91 to -0.07, P = 0.024, I 2 = 0%). Meta-regression showed that age [standard error (SE): 0.036, P < 0.001], male sex (SE: 0.006, P < 0.001), and operative time (SE: 0.002, P = 0.027) were significantly associated with increased complications with LPP. In addition, 5.9%-14.5% of surgeons using LLP requested pressure increases to equal the SPP group. The grade of evidence was high for pain score in PACU and on POD1 postoperative complications and major complications, and blood loss, moderate for operative time, low for intraoperative complications, and very low for length of stay. Conclusions: LPP was associated with lower pain scores in PACU and on POD1 with similar operative times, length of stay, and safety profile compared with SPP in colorectal surgery. Although LPP was not associated with increased complications, older patients, males, patients undergoing laparoscopic surgery, and those with longer operative times may be at risk of increased complications.

Trans­anal minimally invasive surgery (TAMIS) versus rigid platforms for local excision of early rectal cancer: a systematic review and meta-analysis of the literature.

BACKGROUND: Available platforms for local excision (LE) of early rectal cancer are rigid or flexible [trans­anal minimally invasive surgery (TAMIS)]. We systematically searched the literature to compare outcomes between platforms. METHODS: PRISMA-compliant search of PubMed and Scopus databases until September 2022 was undertaken in this random-effect meta-analysis. Statistical heterogeneity was assessed using I2 statistic. Studies comparing TAMIS versus rigid platforms for LE for early rectal cancer were included. Main outcome measures were intraoperative and short-term postoperative outcomes and specimen quality. RESULTS: 7 studies were published between 2015 and 2022, including 931 patients (423 females); 402 underwent TAMIS and 529 underwent LE with rigid platforms. Techniques were similar for operative time (WMD 11.1, 95%CI - 2.6 to 25, p = 0.11), percentage of defect closure (OR 0.7, 95%CI 0.06-8.22, p = 0.78), and peritoneal violation (OR 0.41, 95%CI 0.12-1.43, p = 0.16). Rigid platforms had higher rates of short-term complications (19.1% vs 14.2, OR 1.6, 95%CI 1.07-2.4, p = 0.02), although no significant differences were seen for major complications (OR 1.41, 95%CI 0.61-3.23, p = 0.41). Patients in the rigid platforms group were 3-times more likely to be re-admitted within 30 days compared to the TAMIS group (OR 3.1, 95%CI 1.07-9.4, p = 0.03). Rates of positive resection margins (rigid platforms: 7.6% vs TAMIS: 9.34%, OR 0.81, 95%CI 0.42-1.55, p = 0.53) and specimen fragmentation (rigid platforms: 3.3% vs TAMIS: 4.4%, OR 0.74, 95%CI 0.33-1.64, p = 0.46) were similar between the groups. Salvage surgery was required in 5.5% of rigid platform patients and 6.2% of TAMIS patients (OR 0.8, 95%CI 0.4-1.8, p = 0.7). CONCLUSION: TAMIS or rigid platforms for LE seem to have similar operative outcomes and specimen quality. The TAMIS group demonstrated lower readmission and overall complication rates but did not significantly differ for major complications. The choice of platform should be based on availability, cost, and surgeon's preference.

Predictors of nodal positivity in clinically under-staged patients with colon cancer: A National Cancer Database study and proposal of a predictive scoring system.

BACKGROUND: Colon cancer pathological and clinical staging may be disoncordant. This study assessed patients with colon cancer in whom the nodal status was clinically understaged. METHODS: Patients with stage I-III clinical node-negative colon cancer from the National Cancer Database were included. Regression analyses were conducted to elucidate risk factors for clinical nodal understaging and a scoring system was developed to identify high-risk patients. RESULTS: The study included 94,945 patients with 78.4 â€‹% of patients correctly staged and 21.6 â€‹% clinically understaged. The predictors of nodal positivity in clinically understaged patients were age <65 (OR 1.43), left-sided tumors (OR 1.41), elevated CEA (OR 2.03), moderately (OR 1.81) or poorly/undifferentiated tumors (OR 3.76), T1 tumors (OR 1.29), signet-ring cell histology (OR 2.26), and microsatellite-stable tumors (OR 1.4). CONCLUSION: Patients with colon cancer and the above factors are more likely to have their nodal status clinically understaged. A scoring system has been developed to identify high-risk patients.

Obesity and overweight are associated with worse survival in early-onset colorectal cancer.

BACKGROUND: Obesity and its associated lifestyle are known risk factors for early-onset colorectal cancer and are associated with poor postoperative and survival outcomes in older patients. We aimed to investigate the impact of obesity on the outcomes of early-onset colorectal cancers. METHODS: Retrospective review of all patients undergoing primary resection of colon or rectal adenocarcinoma at our institution between 2015-2022. Patients who had palliative resections, resections performed at another institution, appendiceal tumors, and were underweight were excluded. The primary endpoint was survival according to the patient's body mass index: normal weight (18-24.9 kg/m2), overweight (25-29.9 kg/m2), and obesity (≥30 kg/m2). Patient and tumor characteristics and survival were compared between the three groups. RESULTS: A total of 279 patients aged <50 years with colorectal cancer were treated at our hospital; 120 were excluded from the analysis for the following reasons: main treatment or primary resection performed at another hospital (n = 97), no resection/palliative resection (n = 23), or body mass index <18 kg/m2 (n = 2). Of these, 157 patients were included in the analysis; 61 (38.9%) were overweight and 45 (28.7%) had obesity. Except for a higher frequency of hypertension in the overweight (P = .062) and obese (P = .001) groups, no differences in patient or tumor characteristics were observed. Mean overall survival was 89 months with normal weight, 92 months with overweight, and 65 months with obesity (P = .032). Mean cancer-specific survival was 95 months with normal weight, 94 months with overweight, and 68 months with obesity (P = .018). No statistically significant difference in disease-free survival (75 vs 70 vs 59 months, P = .844) was seen. CONCLUSION: Individuals with early-onset colorectal cancer who are overweight or obese present with similar tumor characteristics and postoperative morbidity to patients with normal weight. However, obesity may have a detrimental impact on their survival. Addressing obesity as a modifiable risk factor might improve early-onset colorectal cancer prognosis.

The feasibility and outcomes of metabolic and bariatric surgery prior to neoplastic therapy.

BACKGROUND: Metabolic and bariatric surgery (MBS) is a potent intervention for addressing obesity-related medical conditions and achieving sustainable weight loss. Beyond its conventional role, MBS has demonstrated potential to serve as a transitional step for patients requiring various interventions. However, the implications of MBS in the context of neoplasia remain understudied. OBJECTIVES: To explore the feasibility of MBS as a possible attempt to reduce surgical and treatment risks in patients with benign tumors or low-grade cancers. SETTING: Multicenter review from twelve tertiary referral centers spanning 8 countries. METHODS: A retrospective review of patients with a diagnosis of primary neoplasia, deemed inoperable or high-risk due to obesity, and receiving primary MBS prior to neoplastic therapy. Data encompassed baseline characteristics, neoplasia characteristics, MBS outcomes, and neoplastic therapy outcomes. RESULTS: Thirty-seven patients (median age 52 years, 75.7% female, median BMI of 49.1 kg/m2) were included. There were 9 distinct organs of origin of primary neoplasia, with the endometrium (43.2%) being the most common, followed by the pancreas, colon, kidney and breast. Sleeve gastrectomy (SG) was the most commonly performed MBS procedure (78.4%), with no MBS-related complications or mortalities reported over an average of 4.3 ± 3.9 years. Thirty-one patients (83.8%) eventually underwent neoplastic surgery, with a mean BMI decrease from 49.9 kg/m2 to 39.7 kg/m2 at surgery over an average of 5.8 ± 4.8 months. There were 2 (6.7%) documented mortalities associated with neoplastic surgical intervention. CONCLUSIONS: This study highlights the potential feasibility of employing MBS prior to neoplastic therapy in patients with low-grade, less aggressive neoplasms in the context of obesity. This underscores the importance of providing a personalized, case-to-case multidisciplinary approach in the management of these patients.

Ostomy continence devices: a systematic review of the literature and meta-analysis.

AIM: Colostomy complication rates range widely from 10% to 70%. The psychological burden on patients, leading to lifestyle changes and decreased quality of life (QoL), is one of the largest factors. The aim of this work was to assess the history and efficacy of ostomy continence devices in improving continence and QoL. METHOD: In this PRISMA-compliant systematic review and meta-analysis, we searched PubMed, Scopus, Google Scholar and clinicaltrials.gov for studies on continence devices for all ostomies up to April 2023. Primary outcomes were continence and improvement in QoL. Secondary outcomes were leakage, patient's device preference and complications. Risk of Bias 2 and the revised tool to assess risk of bias in non-randomized studies of interventions (ROBINS-1) were used to assess risk of bias. Certainty of evidence was graded using GRADE. RESULTS: Twenty-two studies assessed devices from 1978 to 2022. The two main types identified were ball-valve devices and plug systems. Conseal and Vitala were the two main devices with significant evidence allowing for pooled analyses. Conseal, the only currently marketed device, had a pooled rate of continence of 67.4%, QoL improvement was 74.9%, patient preference over a traditional appliance was 69.1%, leakage was 10.1% and complications was 13.7%. Since 2011, five studies have investigated experimental devices on both human and animal models. CONCLUSION: Ostomy continence has been a long-standing goal without a consistently reliable solution. We propose that selective and short-term usage of continence devices may lead to improved continence and QoL in ostomy patients. Further research is needed to develop a reliable daily device for ostomy continence. Future investigation should include the needs of ileostomates.

Endorectal advancement flap compared to ligation of inter-sphincteric fistula tract in the treatment of complex anal fistulas: A meta-analysis of randomized clinical trials.

BACKGROUND: Rectal advancement flap and ligation of intersphincteric fistula tract are common procedures for treating complex anal fistula. The present meta-analysis aimed to compare the surgical outcomes of advancement flap and ligation of intersphincteric fistula tract. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review of randomized clinical trials comparing the ligation of intersphincteric fistula tract and advancement flap was conducted. PubMed, Scopus, and Web of Science were searched through January 2023. The risk of bias was assessed using the Risk of Bias 2 tool and certainty of evidence with the Grading of Recommendations Assessment, Development and Evaluation approach. The primary outcomes were healing and recurrence of anal fistulas, and secondary outcomes were operative time, complications, fecal incontinence, and early pain. RESULTS: Three randomized clinical trials (193 patients, 74.6% male) were included. The median follow-up was 19.2 months. Two trials had a low risk of bias, and 1 had some risk of bias. The odds of healing (odds ratio: 1.363, 95% confidence interval: 0.373-4.972, P = .639), recurrence (odds ratio: 0.525, 95% confidence interval: 0.263-1.047, P = .067), and complications (odds ratio: 0.356, 95% confidence interval: 0.085-1.487, P = .157) were similar between the 2 procedures. Ligation of intersphincteric fistula tract was associated with a significantly shorter operation time (weighted mean difference: -4.876, 95% confidence interval: -7.988 to -1.764, P = .002) and less postoperative pain (weighted mean difference: -1.030, 95% confidence interval: -1.418 to -0.641, 0.198, P < .001, I2 = 3.85%) than advancement flap. Ligation of intersphincteric fistula tract was associated with marginally lower odds of fecal incontinence than advancement flap (odds ratio: 0.27, 95% confidence interval: 0.069-1.06, P = .06). CONCLUSION: Ligation of intersphincteric fistula tract and advancement flap had similar odds of healing, recurrence, and complications. The odds of fecal incontinence and extent of pain after ligation of intersphincteric fistula tract were lower than after advancement flap.

Resection margin status at the portomesenteric axis may not determine oncologic outcome after pancreaticoduodenectomy for lymph node-positive pancreatic ductal adenocarcinoma.

BACKGROUND: Lymph node and resection margin status are associated with oncologic outcomes after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. However, surgical radicality at the portomesenteric axis in case of suspected infiltration remains controversial. METHODS: Clinicopathological data of patients who underwent a partial or total pancreaticoduodenectomy for PDAC between 2012 to 2019 in 2 major hepato-pancreato-biliary centers in Germany and Switzerland were assessed. We evaluated the impact of positive resection margins at the vascular, parenchymal, and retropancreatic surfaces on overall survival in patients with and without lymph node involvement. Margin-positive vascular resection included both patients with positive margins at the vascular groove and the resected venous wall. RESULTS: During the study period, 217 patients underwent partial/total pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. After excluding 7 patients suffering postoperative complications resulting in mortality within 90 days after surgery (3%), 169 patients had lymph node involvement (80%). In the entire study cohort, margin-positive resection (33%) was significantly associated with worse overall survival (3-year overall survival: margin-positive resection: 27% vs margin-negative resection: 43%, P = .014). Among patients with positive lymph nodes, margin-positive vascular resection (n = 48, 28%) was not significantly associated with impaired overall survival (3-year overall survival: margin-positive vascular resection: 28% vs margin-negative vascular resection: 36%, P = .065). On the contrary, margin-positive parenchymal resection (n = 7, 4%) (3-year overall survival: margin-positive parenchymal resection: 0% vs margin-negative parenchymal resection: 35%, P < .0001) and margin-positive retropancreatic resection (n = 21, 12%) (3-year overall survival: margin-positive retropancreatic resection: 6% vs margin-negative retropancreatic resection: 39%, P < .0001) significantly diminished overall survival in univariate and multivariate analysis in all patients. Among patients without lymph node involvement (n = 41, 20%), there were no margin-positive parenchymal or margin-positive retropancreatic resections. In contrast, only 5 patients had margin-positive vascular resection (12%), with overall survival compared to those with margin-negative vascular resection. CONCLUSIONS: In patients with pancreatic ductal adenocarcinoma and lymph nodal positivity, resection status at the parenchymal and retropancreatic surface but probably not at the portal and/or superior mesenteric vein is a determinant of survival. Therefore, margin-negative resection should be pursued during pancreaticoduodenectomy. However, radical venous resection and/or reconstruction for suspected tumor infiltration may not be necessary for patients with intraoperatively detected lymph node metastases.

Spatially restricted tumour-associated and host-associated immune drivers correlate with the recurrence sites of pancreatic cancer.

OBJECTIVE: Most patients with pancreatic ductal adenocarcinoma (PDAC) will experience recurrence after resection. Here, we investigate spatially organised immune determinants of PDAC recurrence. DESIGN: PDACs (n=284; discovery cohort) were classified according to recurrence site as liver (n=93/33%), lung (n=49/17%), local (n=31/11%), peritoneal (n=38/13%) and no-recurrence (n=73/26%). Spatial compartments were identified by fluorescent imaging as: pancytokeratin (PanCK)+CD45- (tumour cells); CD45+PanCK- (leucocytes) and PanCK-CD45- (stromal cells), followed by transcriptomic (72 genes) and proteomic analysis (51 proteins) for immune pathway targets. Results from next-generation sequencing (n=194) were integrated. Finally, 10 tumours from each group underwent immunophenotypic analysis by multiplex immunofluorescence. A validation cohort (n=109) was examined in parallel. RESULTS: No-recurrent PDACs show high immunogenicity, adaptive immune responses and are rich in pro-inflammatory chemokines, granzyme B and alpha-smooth muscle actin+ fibroblasts. PDACs with liver and/or peritoneal recurrences display low immunogenicity, stemness phenotype and innate immune responses, whereas those with peritoneal metastases are additionally rich in FAP+ fibroblasts. PDACs with local and/or lung recurrences display interferon-gamma signalling and mixed adaptive and innate immune responses, but with different leading immune cell population. Tumours with local recurrences overexpress dendritic cell markers whereas those with lung recurrences neutrophilic markers. Except the exclusive presence of RNF43 mutations in the no-recurrence group, no genetic differences were seen. The no-recurrence group exhibited the best, whereas liver and peritoneal recurrences the poorest prognosis. CONCLUSIONS: Our findings demonstrate distinct inflammatory/stromal responses in each recurrence group, which might affect dissemination patterns and patient outcomes. These findings may help to inform personalised adjuvant/neoadjuvant and surveillance strategies in PDAC, including immunotherapeutic modalities.

The impact of bariatric and metabolic surgery on cancer development.

Obesity (BMI ≥ 30 kg/m2) with related comorbidities such as type 2 diabetes mellitus, cardiovascular disease, sleep apnea syndrome, and fatty liver disease is one of the most common preventable risk factors for cancer development worldwide. They are responsible for at least 40% of all newly diagnosed cancers, including colon, ovarian, uterine, breast, pancreatic, and esophageal cancer. Although various efforts are being made to reduce the incidence of obesity, its prevalence continues to spread in the Western world. Weight loss therapies such as lifestyle change, diets, drug therapies (GLP-1-receptor agonists) as well as bariatric and metabolic surgery are associated with an overall risk reduction of cancer. Therefore, these strategies should always be essential in therapeutical concepts in obese patients. This review discusses pre- and post-interventional aspects of bariatric and metabolic surgery and its potential benefit on cancer development in obese patients.

Surgical Site Infections Are Associated With Higher Blood Loss and Open Access in General Thoracic Practice.

Background: Surgical site infections (SSIs) are the most costly and second most frequent healthcare-associated infections in the Western world. They are responsible for higher postoperative mortality and morbidity rates and longer hospital stays. The aim of this study is to analyze which factors are associated with SSI in a modern general thoracic practice. Methods: Data were collected from our department's quality database. Consecutive patients operated between January 2014 and December 2018 were included in this retrospective study. Results: A total of 2430 procedures were included. SSIs were reported in 37 cases (1.5%). The majority of operations were video-assisted (64.6%). We observed a shift toward video-assisted thoracic surgery in the subgroup of anatomical resections during the study period (2014: 26.7%, 2018: 69.3%). The multivariate regression analysis showed that blood loss >100 ml (p = 0.029, HR 2.70) and open surgery (p = 0.032, HR 2.37) are independent risk factors for SSI. The latter was higher in open surgery than in video-assisted thoracic procedures (p < 0.001). In the subgroup of anatomical resection, we found the same correlation (p = 0.043). SSIs are also associated with significantly longer mean hospital stays (17.7 vs. 7.8 days, p < 0.001). Conclusion: As SSIs represent higher postoperative morbidity and costs, efforts should be made to maintain their rate as low as possible. In terms of prevention of SSIs, video-assisted thoracic surgery should be favored over open surgery whenever possible.

The Impact of Patient Age ≥80 Years on Postoperative Outcomes and Treatment Costs Following Pancreatic Surgery.

As life expectancy is increasing, elderly patients are evaluated more frequently for resection of benign or malignant pancreatic lesions. However, the impact of age on postoperative morbidity, mortality, and treatment costs in octogenarian patients (≥80 years) undergoing major pancreatic surgery needs further investigation. The clinicopathological data of patients who underwent pancreatic surgery between January 2015 and March 2019 in a major hepatopancreatobiliary center in Switzerland were assessed. Postoperative outcomes and hospital costs of octogenarians and younger patients were compared in univariate and multivariate regression analysis. During the study period, 346 patients underwent pancreatic resection. Pancreatoduodenectomy, distal pancreatectomy, total pancreatectomy, and other procedures were performed in 54%, 20%, 13%, and 13% of patients, respectively. The major postoperative morbidity rate and postoperative mortality rate were 25% and 3.5%, respectively. A total of 39 patients (11%) were ≥80 years old, and 307 patients were <80 years old. The majority of octogenarians suffered from ductal adenocarcinoma, whereas among younger patients, other indications for a pancreatic resection were predominant (ductal adenocarcinoma 64% vs. 41%, p = 0.006). Age ≥80 was associated with more frequent postoperative medical (pulmonary, cardiovascular) and surgical (high-grade pancreatic fistula, postoperative hemorrhage) complications. Postoperative mortality was significantly higher in octogenarians (15.4% vs. 2%, p < 0.0001). This finding may be explained by the higher rate of type C pancreatic fistula (13% vs. 5%), resulting more frequently in postoperative hemorrhage (18% vs. 5%, p = 0.002) among patients ≥80 years old. In the multivariate logistic regression analysis, patient age ≥80 years predicted postoperative mortality independently of the tumor entity and surgical technique (p = 0.013, OR 6.71, 95% CI [1.5-30.3]). Increased major postoperative morbidity was responsible for lower cost recovery in octogenarians (94% vs. 102%, p = 0.046). In conclusion, patient age ≥80 years is associated with increased postoperative medical and surgical morbidity after major pancreatic surgery leading to lower cost recovery and a lower chance for successful resuscitation in patients requiring revisional surgery for postoperative hemorrhage and/or pancreatic fistula. In octogenarian patients suffering from pancreatic tumors, careful selection, and thorough prehabilitation is crucial to achieve the best postoperative and long-term oncologic outcomes.