Vascular challenges from pancreatoduodenectomy in the setting of coeliac artery stenosis

Coeliac artery stenosis due to median arcuate ligament compression or atherosclerotic disease is a frequently unrecognised challenge to recovery after pancreatoduodenectomy. The described case illustrates management with intraoperative superior mesenteric artery to hepatic artery bypass graft that led to haemorrhagic challenges postoperatively but ultimately a good recovery. Aspects of preoperative diagnosis, preoperative intervention and intraoperative management options are reviewed. Surgeons need to possess these tools to prevent complications from coeliac artery stenosis when pancreatoduodenectomy is required

Ideal Outcome After Pancreatoduodenectomy:A Transatlantic Evaluation of a Harmonized Composite Outcome Measure

OBJECTIVE: The aim of this study is to define and assess Ideal Outcome in the national or multicenter registries of North America, Germany, the Netherlands, and Sweden. BACKGROUND: Assessing outcomes after pancreatoduodenectomy among centers and countries requires a broad evaluation that cannot be captured by a single parameter. Previously, 2 composite outcome measures (textbook outcome and optimal pancreatic surgery) for pancreatoduodenectomy have been described from Europe and the United States. These composites were harmonized into ideal outcome (IO). METHODS: This analysis is a transatlantic retrospective study (2018-2020) of patients after pancreatoduodenectomy within the registries from North America, Germany, The Netherlands, and Sweden. After 3 consensus meetings, IO for pancreatoduodenectomy was defined as the absence of all 6 parameters: (1) in-hospital mortality, (2) severe complications-Clavien-Dindo ≥3, (3) postoperative pancreatic fistula-International Study Group of Pancreatic Surgery (ISGPS) grade B/C, (4) reoperation, (5) hospital stay &gt;75th percentile, and (6) readmission. Outcomes were evaluated using relative largest difference (RLD) and absolute largest difference (ALD), and multivariate regression models. RESULTS: Overall, 21,036 patients after pancreatoduodenectomy were included, of whom 11,194 (54%) reached IO. The rate of IO varied between 55% in North America, 53% in Germany, 52% in The Netherlands, and 54% in Sweden (RLD: 1.1, ALD: 3%, P &lt;0.001). Individual components varied with an ALD of 2% length of stay, 4% for in-hospital mortality, 12% severe complications, 10% postoperative pancreatic fistula, 11% reoperation, and 9% readmission. Age, sex, absence of chronic obstructive pulmonary disease, body mass index, performance status, American Society of Anesthesiologists (ASA) score, biliary drainage, absence of vascular resection, and histologic diagnosis were associated with IO. In the subgroup of patients with pancreatic adenocarcinoma, country, and neoadjuvant chemotherapy also was associated with improved IO. CONCLUSIONS: The newly developed composite outcome measure "Ideal Outcome" can be used for auditing and comparing outcomes after pancreatoduodenectomy. The observed differences can be used to guide collaborative initiatives to further improve the outcomes of pancreatic surgery.</p

Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC)

INTRODUCTION: Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC. METHODS: One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at \u3c40 or breast cancer \u3c50 years of age). RESULTS: Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants. CONCLUSION: Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies

Ideal Outcome After Pancreatoduodenectomy: A Transatlantic Evaluation of a Harmonized Composite Outcome Measure

Objective: The aim of this study is to define and assess Ideal Outcome in the national or multicenter registries of North America, Germany, the Netherlands, and Sweden. Background: Assessing outcomes after pancreatoduodenectomy among centers and countries requires a broad evaluation that cannot be captured by a single parameter. Previously, 2 composite outcome measures (textbook outcome and optimal pancreatic surgery) for pancreatoduodenectomy have been described from Europe and the United States. These composites were harmonized into ideal outcome (IO). Methods: This analysis is a transatlantic retrospective study (2018-2020) of patients after pancreatoduodenectomy within the registries from North America, Germany, The Netherlands, and Sweden. After 3 consensus meetings, IO for pancreatoduodenectomy was defined as the absence of all 6 parameters: (1) in-hospital mortality, (2) severe complications - Clavien-Dindo ≥3, (3) postoperative pancreatic fistula - International Study Group of Pancreatic Surgery (ISGPS) grade B/C, (4) reoperation, (5) hospital stay >75th percentile, and (6) readmission. Outcomes were evaluated using relative largest difference (RLD) and absolute largest difference (ALD), and multivariate regression models. Results: Overall, 21,036 patients after pancreatoduodenectomy were included, of whom 11,194 (54%) reached IO. The rate of IO varied between 55% in North America, 53% in Germany, 52% in The Netherlands, and 54% in Sweden (RLD: 1.1, ALD: 3%, P<0.001). Individual components varied with an ALD of 2% length of stay, 4% for in-hospital mortality, 12% severe complications, 10% postoperative pancreatic fistula, 11% reoperation, and 9% readmission. Age, sex, absence of chronic obstructive pulmonary disease, body mass index, performance status, American Society of Anesthesiologists (ASA) score, biliary drainage, absence of vascular resection, and histologic diagnosis were associated with IO. In the subgroup of patients with pancreatic adenocarcinoma, country, and neoadjuvant chemotherapy also was associated with improved IO. Conclusions: The newly developed composite outcome measure "Ideal Outcome"can be used for auditing and comparing outcomes after pancreatoduodenectomy. The observed differences can be used to guide collaborative initiatives to further improve the outcomes of pancreatic surgery

The State of Immunotherapy in Hepatobiliary Cancers

Hepatobiliary cancers, including hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder carcinoma (GBC), are lethal cancers with limited therapeutic options. Curative-intent treatment typically involves surgery, yet recurrence is common and many patients present with advanced disease not amenable to an operation. Immunotherapy represents a promising approach to improve outcomes, but the immunosuppressive tumor microenvironment of the liver characteristic of hepatobiliary cancers has hampered the development and implementation of this therapeutic approach. Current immunotherapies under investigation include immune checkpoint inhibitors (ICI), the adoptive transfer of immune cells, bispecific antibodies, vaccines, and oncolytic viruses. Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two ICIs that have demonstrated utility in HCC, and newer immune checkpoint targets are being tested in clinical trials. In advanced CCA and GBC, PD-1 ICIs have resulted in antitumor responses, but only in a minority of select patients. Other ICIs are being investigated for patients with CCA and GBC. Adoptive transfer may hold promise, with reports of complete durable regression in metastatic CCA, yet this therapeutic approach may not be generalizable. Alternative approaches have been developed and promising results have been observed, but clinical trials are needed to validate their utility. While the treatment of hepatobiliary cancers involves unique challenges that these cancers present, the progress seen with ICIs and adoptive transfer has solidified immunotherapy as an important approach in these challenging patients with few other effective treatment options

Morbidity and Mortality after Surgery for Retroperitoneal Sarcoma

Retroperitoneal sarcoma (RPS) is a rare disease with over 100 histologic types and accounts for 10–15% of all soft tissue sarcomas. Due to the rarity of RPS, sarcoma centers in Europe and North America have created the Transatlantic RPS Working Group (TARPSWG) to study this disease and establish best practices for its management. Current guidelines dictate complete resection of all macro and microscopic disease as the gold standard for patients with RPS. Complete extirpation often requires a multi-visceral resection. In addition, recent evidence suggests that en bloc compartmental resections are associated with reduced rates of local recurrence. However, this approach must be balanced by the potential for added morbidity. Strategies to mitigate postoperative complications include optimization of the patient through improved preoperative nutrition and pre-habilitation therapy, referral to a high-volume sarcoma center, and implementation of enhanced recovery protocols. This review will focus on the factors associated with perioperative complications following surgery for RPS and outline approaches to mitigate poor surgical outcomes in this patient population

Is American College of Surgeons NSQIP organ space infection a surrogate for pancreatic fistula?

BACKGROUND: In the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP), pancreatic fistula has not been monitored, although organ space infection (OSI) data are collected. Therefore, the purpose of this analysis was to determine the relationship between ACS NSQIP organ space infection and pancreatic fistulas. STUDY DESIGN: From 2007 to 2011, 976 pancreatic resection patients were monitored via ACS NSQIP at our institution. From this database, 250 patients were randomly chosen for further analysis. Four patients were excluded because they underwent total pancreatectomy. Data on OSI were gathered prospectively. Data on pancreatic fistulas and other intra-abdominal complications were determined retrospectively. RESULTS: Organ space infections (OSIs) were documented in 22 patients (8.9%). Grades B (n = 26) and C (n = 5) pancreatic fistulas occurred in 31 patients (12.4%); grade A fistulas were observed in 38 patients (15.2%). Bile leaks and gastrointestinal (GI) anastomotic leaks each developed in 5 (2.0%) patients. Only 17 of 31 grade B and C pancreatic fistulas (55%), and none of 38 grade A fistulas were classified as OSIs in ACS NSQIP. In addition, only 2 of 5 bile leaks (40%) and 2 of 5 GI anastomotic leaks (40%) were OSIs. Moreover, 3 OSIs were due to bacterial peritonitis, a chyle leak, and an ischemic bowel. CONCLUSIONS: This analysis suggests that the sensitivity (55%) and specificity (45%) of organ space infection (OSI) in ACS NSQIP are too low for OSI to be a surrogate for grade B and C pancreatic fistulas. We concluded that procedure-specific variables will be required for ACS NSQIP to improve outcomes after pancreatectomy

26. The Role of Macrophages In Mediating Radiation-induced Fibrosis

Purpose: Radiation-induced fibrosis (RIF) remains a clinically challenging problem in cancer patients without effective treatment or prevention. To elucidate the mechanisms of RIF, we investigated the role of macrophages as mediators of fibrosis, and the reciprocal signaling that occurs between macrophages and fibroblasts. Methods: Bone marrow-derived macrophages and dermal fibroblasts were isolated from C57BL/6 mice. Cells were co-cultured in a three-dimensional collagen gel system and subjected to radiation. Gel contracture was measured over time. Flow cytometry was utilized to analyze macrophage polarization towards inflammatory and anti-inflammatory phenotypes using cell surface markers such as CD38 and CD206, respectively. Macrophages from both radiated and non-radiated co-cultures were subjected to RNA sequencing to investigate radiation induced phenotypic and functional changes. Results: Co-culturing fibroblasts and macrophages led to pronounced collagen gel contraction compared to fibroblasts alone, highlighting the essential role of macrophages. In addition, radiated macrophages had a significantly increased effect on gel contracture compared to non-radiated controls indicating a changed phenotype promoting contraction. Since macrophage involvement was found to be critical for radiation-induced functional alteration in collagen gels, we investigated macrophage phenotypes in response to radiation. Flow cytometry analysis revealed that radiation-induced alternate activation (M2) of macrophages, as shown by increased CD206 expression. Similarly, RNA sequencing data showed increased expression of interferon response genes such as Ifi206 and chemokines including c-c motif chemokine ligand 7 (ccl7) suggesting a distinct inflammatory response to radiation. Furthermore, we analyzed the impact of radiation on macrophage plasticity. Interestingly, when macrophages were polarized to M2 phenotype and then radiated, their potential to repolarize to M1 was lost, as opposed to non-radiated macrophages suggesting potential loss of macrophage plasticity during radiation. Conclusion: Our study highlights the crucial role of macrophages in early RIF and their potential as a therapeutic target to mitigate the negative side effects of radiation therapy. We observed that radiation exposure induces an M2 phenotype, upregulates interferon response genes in macrophages, and impairs plasticity. These findings suggest that radiation may contribute to the pro-fibrotic environment by activating macrophages in a physiologically distinct manner. Our study offers insights into the underlying mechanisms of RIF and the role of macrophages in this process