Robot-assisted esophagectomy may improve perioperative outcome in patients with esophageal cancer - a single-center experience.

Background: Although the introduction of minimally invasive surgical techniques has improved surgical outcomes in recent decades, esophagectomy for esophageal cancer is still associated with severe complications and a high mortality rate. Robot-assisted surgery is already established in certain fields and robot-assisted esophagectomy may be a possible alternative to the standard minimally invasive esophagectomy. The goal of this study was to investigate whether robot assistance in esophagectomy can improve patient outcome while maintaining good oncological control. Material and methods: Data of all patients who underwent minimally invasive esophagectomy between January 2018 and November 2021 at University Hospital Mannheim was collected retrospectively. Patients were divided into two cohorts according to operative technique (standard minimally invasive (MIE) vs. robot-assisted esophagectomy (RAMIE), and their outcomes compared. In a separate analysis, patients were propensity score matched according to age, gender and histological diagnosis, leading to 20 matching pairs. Results: 95 patients were included in this study. Of those, 71 patients underwent robot-assisted esophagectomy and 24 patients underwent standard minimally invasive esophagectomy. Robot-assisted esophagectomy showed a lower incidence of general postoperative complications (52.1% vs. 79.2%, p=0.0198), surgical complications (42.3% vs. 75.0%, p=0.0055), a lower rate of anastomotic leakage (21.1% vs. 50.0%, p=0.0067), a lower Comprehensive Complication Index (median of 20.9 vs. 38.6, p=0.0065) as well as a shorter duration of hospital stay (median of 15 vs. 26 days, p=0.0012) and stay in the intensive care unit (median of 4 vs. 7 days, p=0.028) than standard minimally invasive surgery. After additionally matching RAMIE and MIE patients according to age, gender and diagnosis, we found significant improvement in the RAMIE group compared to the MIE group regarding the Comprehensive Complication Index (median of 20.9 vs. 38.6, p=0.0276), anastomotic leakage (20% vs. 55%, p=0.0484) and severe toxicity during neoadjuvant treatment (0 patients vs. 9 patients, p=0.005). Conclusion: Robot-assisted surgery can significantly improve outcomes for patients with esophageal cancer. It may lead to a shorter hospital stay as well as lower rates of complications, including anastomotic leakage.

Prognostic value of disease-free interval in colorectal cancer: Is it time?

BACKGROUND: Previous studies have outlined that the onset of synchronous colorectal cancer (CRC) metastases is associated with poor overall survival (OS) compared to patients with metachronous disease. The aim of this study was to evaluate the association of disease-free interval with newly diagnosed CRC scheduled for primary tumor resection. METHODS: Patients who underwent primary CRC resection over an 18-year period were identified from a prospective database at a tertiary-care hospital. In this observational study, the cohort was stratified for the onset of metastases, i.e. synchronous, early-onset and late-onset metachronous disease. The OS was compared using Kaplan-Meier estimators and stratified Cox hazard regression analysis. RESULTS: Of 360 patients, 204 (57%) had synchronous, 61 (17%) had early metachronous, and 95 (26%) had late metachronous metastases, respectively. The onset of synchronous metastases was not associated with worse OS compared to early and late metachronous disease. ASA level > II (P = 0.011), right-sided compared to left-sided cancer (P = 0.032) or rectal cancer (P < 0.001), and high-grade tumors (P = 0.022) were identified as independent predictors of poor OS, whereas the only favorable prognostic factor was surgical resection of metastases (P = 0.047). Additionally, ASA level < III (P = 0.003) and low-grade tumors (P = 0.032) were found to predict resection of metastases. CONCLUSION: Individual patients' and tumor characteristics rather than the timing of metastases are associated with OS in newly diagnosed CRC. These data support curative treatment strategies even in patients with synchronous metastases.

Using a Reinforced Stapler Decreases the Incidence of Postoperative Pancreatic Fistula After Distal Pancreatectomy: A Systematic Review and Meta-Analysis.

BACKGROUND: There is no consensus on the pancreatic transection during distal pancreatectomy (DP) to reduce postoperative pancreatic fistula (POPF). This meta-analysis aimed to evaluate the effects of a reinforced stapler on the postoperative outcomes of DP. METHODS: We systematically searched electronic databases and bibliographic reference lists in The PubMed/MEDLINE, Google Scholar, Cochrane Library's Controlled Trials Registry and Database of Systematic Reviews, Embase, and Scopus. Review Manager Software was used for pooled estimates. RESULTS: Seven eligible studies published between 2007 and 2021 were included with 553 patients (267 patients in the reinforced stapler group and 286 patients in the standard stapler group). The reinforced stapler reduced the POPF grade B and C (OR = 0.33; 95% CI [0.19, 0.57], p < 0.01). There was no difference between the reinforced stapler group and standard stapler group in terms of mortality rate (OR = 0.39; 95% CI [0.04, 3.57], p = 0.40), postoperative haemorrhage (OR = 0.53; 95% CI [0.20, 1.43], p = 0.21), and reoperation rate (OR = 0.91; 95% CI [0.40, 2.06], p = 0.82). CONCLUSIONS: Reinforced stapling in DP is safe and seems to reduce POPF grade B/C with similar mortality rates, postoperative bleeding, and reoperation rate. The protocol of this systematic review with meta-analysis was registered in PROSPERO (ID: CRD42021286849).

Patient-Tailored Approach for Enhanced Recovery after Surgery.

Background: Enhanced recovery after surgery (ERAS®) is increasingly finding its way into clinical practice. ERAS® protocols have not been universally adopted, and they have often been criticized for being difficult to implement. So, the question for more tailor-made approaches arises. Methods: We conducted a literature search on March 16, 2022, using the following search string, which was modified to fit the input of each of the queried databases: ("ERAS®" or "enhanced recovery after surgery" or "fast recovery" or "fast track") and ("tailored" or "individual"). Results: Despite the massive increase in general hits on the subject, stratification according to phenotypic characteristics such as age or a classification according to disease patterns in the sense of specific guidelines is still fundamentally apparent. Evidence suggests that generic protocols can be followed by almost all patients. Prehabilitation, in particular, can be used as an adaptive tool. Conclusion: ERAS® works only in the totality of its tools and can be followed by almost all patients. Prehabilitation is more adaptive and can also increase adherence to ERAS® protocols. A tailored program outside of disease-specific pathways does not seem to be useful.

Differential Effects of Trp53 Alterations in Murine Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC. METHODS: Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing. RESULTS: The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC. CONCLUSIONS: This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.

[Initial experiences with the implementation of the enhanced recovery after surgery (ERAS®) protocol]. / Erste Erfahrungen in der Umsetzung eines ERAS®("enhanced recovery after surgery")-Konzepts.

BACKGROUND: To further improve treatment quality and patient orientation, a multiprofessional enhanced recovery after surgery (ERAS®) transformation program was initiated in our clinic in January 2020. The ERAS® treatment pathway for colorectal surgery was established in October 2020. OBJECTIVE: The aim of the study was to show that the perioperative treatment quality can be increased by implementing a certified ERAS® program in the setting of a fast-track pathway that has been established since 2008. MATERIAL AND METHODS: The first ERAS® patients from October/November 2020 (ERAS®) were compared with those of a representative consecutive control cohort (pre-ERAS®) who had undergone interventions from August to December 2019. Patient care and data collection of the ERAS® patients were ensured by an ERAS® nurse in daily visits. For the comparison cohorts, the electronic patient files were analyzed and historical colon pathway data from our clinic from 2008 were used. RESULTS AND CONCLUSION: A total of 10 ERAS® and 50 pre-ERAS® patients were included. After the ERAS® transformation, an increase in overall compliance with ERAS® guideline recommendations from 45% (pre-ERAS®) to 75% (ERAS®) was achieved. The number of days to tolerance of solid food decreased from 2 days (pre-ERAS®) to 1 day (ERAS®). The general postoperative complication rate was comparable (22% pre-ERAS® vs. 20% ERAS®). Most noticeable was the reduction of the median hospital stay of 9 days in the historical cohort to 3 days after ERAS® implementation. We attribute the necessary high ERAS® pathway compliance of 75% to a successful combination of process standards and multiprofessional ERAS® teams.

Isolation of Circulating Tumor Cells in an Orthotopic Mouse Model of Colorectal Cancer.

Despite the advantages of easy applicability and cost-effectiveness, subcutaneous mouse models have severe limitations and do not accurately simulate tumor biology and tumor cell dissemination. Orthotopic mouse models have been introduced to overcome these limitations; however, such models are technically demanding, especially in hollow organs such as the large bowel. In order to produce uniform tumors which reliably grow and metastasize, standardized techniques of tumor cell preparation and injection are critical. We have developed an orthotopic mouse model of colorectal cancer (CRC) which develops highly uniform tumors and can be used for tumor biology studies as well as therapeutic trials. Tumor cells from either primary tumors, 2-dimensional (2D) cell lines or 3-dimensional (3D) organoids are injected into the cecum and, depending on the metastatic potential of the injected tumor cells, form highly metastatic tumors. In addition, CTCs can be found regularly. We here describe the technique of tumor cell preparation from both 2D cell lines and 3D organoids as well as primary tumor tissue, the surgical and injection techniques as well as the isolation of CTCs from the tumor-bearing mice, and present tips for troubleshooting.

A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer.

Despite the advantages of easy applicability and cost-effectiveness, colorectal cancer mouse models based on tumor cell injection have severe limitations and do not accurately simulate tumor biology and tumor cell dissemination. Genetically engineered mouse models have been introduced to overcome these limitations; however, such models are technically demanding, especially in large organs such as the colon in which only a single tumor is desired. As a result, an immunocompetent, genetically engineered mouse model of colorectal cancer was developed which develops highly uniform tumors and can be used for tumor biology studies as well as therapeutic trials. Tumor development is initiated by surgical, segmental infection of the distal colon with adeno-cre virus in compound conditionally mutant mice. The tumors can be easily detected and monitored via colonoscopy. We here describe the surgical technique of segmental adeno-cre infection of the colon, the surveillance of the tumor via high-resolution colonoscopy and present the resulting colorectal tumors.

Clinical impact of duodenal pancreatic heterotopia - Is there a need for surgical treatment?

BACKGROUND: Pancreatic heterotopia (PH) is defined as ectopic pancreatic tissue outside the normal pancreas and its vasculature and duct system. Most frequently, PH is detected incidentally by histopathological examination. The aim of the present study was to analyze a large single-center series of duodenal PH with respect to the clinical presentation. METHODS: A prospective pancreatic database was retrospectively analyzed for cases of PH of the duodenum. All pancreatic and duodenal resections performed between January 2000 and October 2015 were included and screened for histopathologically proven duodenal PH. PH was classified according to Heinrich's classification (Type I acini, ducts, and islet cells; Type II acini and ducts; Type III only ducts). RESULTS: A total of 1274 pancreatic and duodenal resections were performed within the study period, and 67 cases of PH (5.3%) were identified. The respective patients were predominantly male (72%) and either underwent pancreatoduodenectomy (n = 60); a limited pancreas resection with partial duodenal resection (n = 4); distal pancreatectomy with partial duodenal resection (n = 1); total pancreatectomy (n = 1); or enucleation (n = 1). Whereas 65 patients (83.5%) were asymptomatic, 11 patients (18.4%) presented with symptoms related to PH (most frequently with abdominal pain [72%] and duodenal obstruction [55%]). Of those, seven patients (63.6%) had chronic pancreatitis in the heterotopic pancreas. The risk of malignant transformation into adenocarcinoma was 2.9%. CONCLUSIONS: PH is found in approximately 5% of pancreatic or duodenal resections and is generally asymptomatic. Chronic pancreatitis is not uncommon in heterotopic pancreatic tissue, and even there is a risk of malignant transformation. PH should be considered for the differential diagnosis of duodenal lesions and surgery should be considered, especially in symptomatic cases.

LDB1 overexpression is a negative prognostic factor in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in western countries and is driven by the Wnt signaling pathway. LIM-domain-binding protein 1 (LDB1) interacts with the Wnt signaling pathway and has been connected to malignant diseases. We therefore aimed to evaluate the role of LDB1 in CRC. RESULTS: Overexpression of LDB1 in CRC is associated with strikingly reduced overall and metastasis free survival in all three independent patient cohorts. The expression of LDB1 positively correlates with genes involved in the Wnt signaling pathway (CTNNB1, AXIN2, MYC and CCND1). Overexpression of LDB1 in CRC cell lines induced Wnt pathway upregulation as well as increased invasivity and proliferation. Upon separate analysis, the role of LDB1 proved to be more prominent in proximal CRC, whereas distal CRC seems to be less influenced by LDB1. MATERIALS AND METHODS: The expression of LDB1 was measured via RT-qPCR in 59 clinical tumor and normal mucosa samples and correlated to clinical end-points. The role of LDB1 was examined in two additional large patient cohorts from publicly available microarray and RNAseq datasets. Functional characterization was done by lentiviral overexpression of LDB1 in CRC cell lines and TOP/FOP, proliferation and scratch assays. CONCLUSIONS: LDB1 has a strong role in CRC progression, confirmed in three large, independent patient cohorts. The in vitro data confirm an influence of LDB1 on the Wnt signaling pathway and tumor cell proliferation. LDB1 seems to have a more prominent role in proximal CRC, which confirms the different biology of proximal and distal CRC.

Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer.

The prognosis of colorectal cancer (CRC) is closely linked to the occurrence of distant metastases, which putatively develop from circulating tumor cells (CTCs) shed into circulation by the tumor. As far more CTCs are shed than eventually metastases develop, only a small subfraction of CTCs harbor full tumorigenic potential. The aim of this study was to further characterize CRC-derived CTCs to eventually identify the clinically relevant subfraction of CTCs.We established an orthotopic mouse model of CRC which reliably develops metastases and CTCs. We were able to culture the resulting CTCs in vitro, and demonstrated their tumor-forming capacity when re-injected into mice. The CTCs were then subjected to qPCR expression profiling, revealing downregulation of epithelial and proliferation markers. Genes associated with cell-cell adhesion (claudin-7, CD166) were significantly downregulated, indicating a more metastatic phenotype of CTCs compared to bulk tumor cells derived from hepatic metastases. The stem cell markers DLG7 and BMI1 were significantly upregulated in CTC, indicating a stem cell-like phenotype and increased capacity of tumor formation and self-renewal. In concert with their in vitro and in vivo tumorigenicity, these findings indicate stem cell properties of mouse-derived CTCs.In conclusion, we developed an orthotopic mouse model of CRC recapitulating the process of CRC dissemination. CTCs derived from this model exhibit stem-cell like characteristics and are able to form colonies in vitro and tumors in vivo. Our results provide new insight into the biology of CRC-derived CTCs and may provide new therapeutic targets in the metastatic cascade of CRC.

Metastatic Spread Emerging From Liver Metastases of Colorectal Cancer: Does the Seed Leave the Soil Again?

OBJECTIVE: To investigate whether liver metastases contribute to metastatic spread of colorectal cancer (CRC) by shedding intact tumor cells. BACKGROUND: Metastases represent the primary cause of death in CRC. Understanding the metastatic activity of metastases and which patients are at high risk for tumor cell dissemination may, therefore, have significant influence on cancer care in the future. METHODS: Circulating tumor cells (CTCs) were detected in the hepatic inflow (portal venous blood [PVB]) and outflow compartment (hepatic venous blood [HVB]) of a training (n = 55) and validation (n = 50) set using the CellSearch system. Isolated CTC from the HVB were subjected to gene expression analyses by quantitative polymerase chain reaction. RESULTS: CTC detection rate (37.2% vs 19.6%; P = 0.04) and count (mean: 12.7, SEM: ±â€Š5.9 vs 1.9; ±â€Š1.2; P = 0.01) were significantly higher in HVB compared to PVB. The increased CTC detection rate (54% vs 11.4%; P < 0.001) and CTC count (14.7 ±â€Š5.1 vs 1.1 ±â€Š0.6; P < 0.001) in the HVB compared to the PVB compartment was confirmed in the validation cohort. Expression of epithelial markers and genes involved in cell-to-cell and cell-to-matrix adhesion was reduced in CTC compared to tumor cells in liver metastases. Metastasis size greater than 5 cm was associated with CTC shedding from established liver metastases in the training and validation cohorts. CONCLUSIONS: Colorectal liver metastases shed intact tumor cells with an invasive phenotype. Metastasis size serves as a surrogate marker for metastatic activity of colorectal liver metastases.