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Pancreatic ductal adenocarcinoma (PDAC) remains to be a therapeutic challenge as only 15%‐20% of all patients present with resectable tumor stages by the time of diagnosis. In the remaining patients, either local tumor extension or systemic spread are obstacles for a surgical therapy as the only chance for long‐term survival. With regard to local tumor extension, PDAC has been classified as resectable, borderline‐resectable (BR) or locally advanced (LA). While there is currently no evidence for neoadjuvant therapy in resectable PDAC, this issue remains controversial in BR‐PDAC. In the case of venous tumor involvement, guidelines mostly recommend upfront resection, when technically possible; whereas arterial involvement is regarded as an indication for chemotherapy or chemoradiotherapy first. Furthermore, in locally advanced PDAC, neoadjuvant treatment approaches have recently resulted in high rates of secondary resection, thus allowing “conversion” surgery in an otherwise palliative treatment situation. The present review gives an overview on the current literature of treatment concepts in these situations and additionally focuses of evaluation of resectability after neoadjuvant therapy as well as technical aspects in this specific situation.

The characteristic desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a key contributor to its lethality. This stromal microenvironment is populated by cancer-associated fibroblasts (CAFs) that interact with cancer cells to drive progression and chemo-resistance. Research has focused on CAFs in the primary tumour but not in metastases, calling into question the role of analogous metastasis-associated fibroblasts (MAFs). We infer a role of MAFs in murine hepatic metastases following untargeted treatment with the anti-angiogenic drug sunitinib in vivo . Treated metastases were smaller and had fewer stromal cells, but were able to maintain angiogenesis and metastasis formation in the liver. Furthermore, sunitinib was ineffective at reducing MAFs alongside other stromal cells. We speculate that cancer cells interact with MAFs to maintain angiogenesis and tumour progression. Thus, we tested interactions between metastatic pancreatic cancer cells and fibroblasts using in vitro co-culture systems. Co-cultures enhanced fibroblast proliferation and induced angiogenesis. We identify carcinoma-educated fibroblasts as the source of angiogenesis via secretions of CXCL8 (aka IL-8) and CCL2 (aka MCP-1). Overall, we demonstrate that metastasis-associated fibroblasts have potential as a therapeutic target and highlight the CXCL8 and CCL2 axes for further investigation.

BackgroundThe optimal surgical strategy for pancreatic neuroendocrine tumors (PNETs) is unknown. However, current guidelines recommend a watch-and-wait strategy for small nonfunctional PNETs (NF-PNETs). The aim of this study is to investigate the risk stratification and prognostic significance of lymph node metastasis (LNM) of PNETs to guide decision-making for lymphadenectomy.Patients and MethodsThe MEDLINE and Web of Science databases were systematically searched for studies reporting either risk factors of LNM in resected PNETs or survival of patients with LNM. The weighted average incidence of LNM was calculated according to tumor characteristics. Random-effects metaanalyses were performed, and pooled hazard ratios (HR) and their 95% confidence intervals (CI) were calculated to determine the impact of LNM on overall survival (OS). In subgroup analyses, NF-PNETs were assessed.ResultsFrom a total of 5883 articles, 98 retrospective studies with 13,374 patients undergoing resection for PNET were included. In all PNETs, the weighted median rates of LNM were 11.5% for small (≤ 2 cm) PNETs and 15.8% for G1 PNETs. In NF-PNETs, the rates were 11.2% for small PNETs and 10.3% for G1 PNETs. LNM of all PNETs (HR 3.87, 95% CI 3.00–4.99, P < 0.001) and NF-PNETs (HR 4.98, 95% CI 2.81–8.83, P < 0.001) was associated with worse OS.ConclusionsLNM is potentially prevalent even in small and well-differentiated PNETs and is associated with worse prognosis. A watch-and-wait strategy for small NF-PNETs should be reappraised, and oncologic resection with lymphadenectomy can be considered. Prospective and controlled studies are needed in the future.

The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5–31·5) compared with 25·5 months (22·7–27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68–0·98], p=0·032). 608 grade 3–4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3–4 adverse events in 196 of 366 patients in the gemcitabine group. The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. Cancer Research UK.

Purpose In pancreatic cancer, genetic markers to aid clinical decision making are still lacking. The present study was designed to determine the prognostic role of perioperative serum tumor marker carbohydrate antigen 19-9 (CA19-9) in pancreatic adenocarcinoma, with a focus on implications for pre- and postoperative therapeutic consequences. Methods Of a total of 1,626 consecutive patients who underwent surgery for primary pancreatic adenocarcinoma, data from 1,543 patients with preoperative serum levels of CA19-9 were evaluated for tumor stage, resectability, and prognosis. Preoperative to postoperative CA19-9 changes were analyzed for long-term survival. A control cohort of 706 patients with chronic pancreatitis was used to assess the predictability of malignancy by CA19-9 and the effects of hyperbilirubinemia on CA19-9 levels. Results The more that preoperative CA19-9 increased, the lower were tumor resectability and survival rates. Resectability and 5-year survival varied from 80 to 38 % and from 27 to 0 % for CA19-9 <37 versus ≥4,000 U/ml, respectively. The R0 resection rate was as low as 15 % in all patients with CA19-9 levels ≥1,000 U/ml. CA19-9 increased with the stage of the disease and was highest in AJCC stage IV. Patients with an early postoperative CA19-9 increase had a dismal prognosis. Hyperbilirubinemia did not markedly affect CA19-9 levels (correlation coefficient ≤0.135). Conclusions In patients with pancreatic adenocarcinoma, CA19-9 predicts resectability, stage of disease, as well as survival. Highly elevated preoperative or increasing postoperative CA19-9 levels are associated with low resectability and poor survival rates, and demand the adjustment of surgical and perioperative therapy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a low survival rate and limited responsiveness to current therapies. The role of hypoxia in the tumor microenvironment is critical, influencing tumor progression and therapy resistance. The aim of this study was to implement the complex dynamics of the hypoxic tumor microenvironment in PDAC in a hypoxia-related prognosis model. We utilized single-cell RNA sequencing (scRNA-seq) data and integrated it with TCGA-PAAD database to identify hypoxia-responsive macrophage subsets and related genes. Kaplan-Meier survival analysis, Cox regression, and Lasso regression methods were employed to construct and validate a hypoxia-related prognostic model. The model's effectiveness was evaluated through its predictive capabilities regarding chemotherapy sensitivity and overall survival. Our research integrated data from scRNA-seq and the TCGA-PAAD database to construct a hypoxia-related prognostic model that encompassed 13 critical genes. This hypoxia model independently predicted chemotherapy response and poor outcomes, outperforming traditional clinicopathologic features. Additionally, a pan-cancer analysis affirmed the relevance of our hypoxia-related genes across multiple malignancies, particularly highlighting KRTCAP2 as a pivotal biomarker associated with worse prognosis and reduced immune infiltration. Our findings underscored the prognostic potential of hypoxia-related model and offered a novel avenue for therapeutic targeting, aiming to ameliorate outcomes in pancreatic cancer.

ObjectiveResection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation.DesignData from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003–2016 were analysed. Age-standardised resection rates for overall and stage I–II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models.ResultsA total of 153 698 records were analysed. In population-based registries in 2012–2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I–II tumours, with great international variations. During 2003–2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I–II tumours: 0.05–0.18 and 0.01–0.06 across countries) and increasing age (ORs for patients 70–79 and ≥80 versus those <60 years: 0.37–0.63 and 0.03–0.16 across countries). Patients with advanced-stage tumours (stage III–IV: 63.8%–81.2%) and at older ages (≥70 years: 52.6%–59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application.ConclusionRates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.

BackgroundPancreatic cancer is associated with high recurrence rates, and any surgery should aim to prevent local recurrence. However, systematic resection of putatively tumor-infiltrated soft tissue adjacent to the celiac branches and superior mesenteric artery has not regularly been applied in pancreatic head resection.ObjectiveWe describe a technique of vessel-oriented pancreatic head resection, allowing for extended removal of lymphatic and neural tissue that is situated in the TRIANGLE in between the celiac trunk, the superior mesenteric artery, and the portal vein.ConclusionsVessel-oriented dissection or vascular resection facilitates complete removal of putatively tumor-infiltrated soft tissue, thus potentially reducing the risk of isolated local recurrence in pancreatic cancer.

BackgroundAcute pancreatitis (AP) is defined as an acute inflammatory attack of the pancreas of sudden onset. Around 25% of patients have either moderately severe or severe disease with a mortality rate of 15–20%.PurposeThe aim of this article was to summarize the advances being made in the understanding of this disease and the important role of surgery.Results and conclusionsAn accurate diagnosis should be made a soon as possible, initiating resuscitation with large volume intravenous fluids and oxygen by mask. Predicted severe disease will require intensive monitoring. Most deaths within the first week are due to multi-organ failure; thus, these patients will require intensive therapy unit management. During the second phase of the disease, death is due to local complications arising from the pancreatic inflammation, requiring accurate identification to determine the correct form of treatment. Acute peripancreatic fluid collections arise < 4 weeks after onset of interstitial edematous pancreatitis, not requiring any treatment. Most pancreatic pseudocysts arise > 4 weeks and largely resolve on conservative management. Necrotizing pancreatitis causing acute necrotic collections and later walled-off necrosis will require treatment if symptomatic or infected. Initial endoscopic transgastric or percutaneous drainage will resolve less serious collections but necrosectomy using minimally invasive approaches will be needed for more serious collections. To prevent recurrent attacks of AP, causative factors need to be removed where possible such as cholecystectomy and cessation of alcohol. Future progress requires improved management of multi-organ failure and more effective minimally invasive techniques for the removal of necrosis.

Metastasis is the leading cause of cancer death, tumor progression proceeding through emigration from the primary tumor, gaining access to the circulation, leaving the circulation, settling in distant organs and growing in the foreign environment. The capacity of a tumor to metastasize relies on a small subpopulation of cells in the primary tumor, so called cancer-initiating cells (CIC). CIC are characterized by sets of markers, mostly membrane anchored adhesion molecules, CD44v6 being the most frequently recovered marker. Knockdown and knockout models accompanied by loss of tumor progression despite unaltered primary tumor growth unraveled that these markers are indispensable for CIC. The unexpected contribution of marker molecules to CIC-related activities prompted research on underlying molecular mechanisms. This review outlines the contribution of CD44, particularly CD44v6 to CIC activities. A first focus is given to the impact of CD44/CD44v6 to inherent CIC features, including the crosstalk with the niche, apoptosis-resistance, and epithelial mesenchymal transition. Following the steps of the metastatic cascade, we report on supporting activities of CD44/CD44v6 in migration and invasion. These CD44/CD44v6 activities rely on the association with membrane-integrated and cytosolic signaling molecules and proteases and transcriptional regulation. They are not restricted to, but most pronounced in CIC and are tightly regulated by feedback loops. Finally, we discuss on the engagement of CD44/CD44v6 in exosome biogenesis, loading and delivery. exosomes being the main acteurs in the long-distance crosstalk of CIC with the host. In brief, by supporting the communication with the niche and promoting apoptosis resistance CD44/CD44v6 plays an important role in CIC maintenance. The multifaceted interplay between CD44/CD44v6, signal transducing molecules and proteases facilitates the metastasizing tumor cell journey through the body. By its engagement in exosome biogenesis CD44/CD44v6 contributes to disseminated tumor cell settlement and growth in distant organs. Thus, CD44/CD44v6 likely is the most central CIC biomarker.