The stroma in solid tumors contains a variety of cellular phenotypes and signaling pathways associated with wound healing, leading to the concept that a tumor behaves as a wound that does not heal. Similarities between tumors and healing wounds include fibroblast recruitment and activation, extracellular matrix (ECM) component deposition, infiltration of immune cells, neovascularization, and cellular lineage plasticity. However, unlike a wound that heals, the edges of a tumor are constantly expanding. Cell migration occurs both inward and outward as the tumor proliferates and invades adjacent tissues, often disregarding organ boundaries. The focus of our review is cancer associated fibroblast (CAF) cellular heterogeneity and plasticity and the acellular matrix components that accompany these cells. We explore how similarities and differences between healing wounds and tumor stroma continue to evolve as research progresses, shedding light on possible therapeutic targets that can result in innovative stromal-based treatments for cancer.

To determine whether the routine use of surgical exploration for gastrinoma resection/cure in 160 patients with Zollinger-Ellison syndrome (ZES) altered survival compared with 35 ZES patients who did not undergo surgery. The role of routine surgical exploration for resection/cure in patients with ZES has been controversial since the original description of this disease in 1955. This controversy continues today, not only because medical therapy for acid hypersecretion is so effective, but also in large part because no studies have shown an effect of tumor resection on survival. Long-term follow-up of 160 ZES patients who underwent routine surgery for gastrinoma/resection/cure was compared with 35 patients who had similar disease but did not undergo surgery for a variety of reasons. All patients had preoperative CT, MRI, ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994 to determine resectability. At surgery, all had the same standard ZES operation. All patients were evaluated yearly with imaging studies and disease activity studies. The 35 nonsurgical patients did not differ from the 160 operated in clinical, laboratory, or tumor imaging results. The 2 groups did not differ in follow-up time since initial evaluation (range, 11.8–12 years). At surgery, 94% had a tumor removed, 51% were cured immediately, and 41% at last follow-up. Significantly more unoperated patients developed liver metastases (29% vs. 5%, P = 0.0002), died of any cause (54 vs. 21%, P = 0.0002), or died a disease-related death (23 vs. 1%, P < 0.00001). Survival plots showed operated patients had a better disease-related survival (P = 0.0012); however, there was no difference in non-disease-related survival. Fifteen-year disease-related survival was 98% for operated and 74% for unoperated (P = 0.0002). These results demonstrate that routine surgical exploration increases survival in patients with ZES by increasing disease-related survival and decreasing the development of advanced disease. Routine surgical exploration should be performed in ZES patients.

Highlight unresolved controversies in the management of Zollinger-Ellison syndrome (ZES). Recent studies have resolved some of the previous controversies including the surgical cure rate in patients with and without Multiple Endocrine Neoplasia-type1 (MEN1), the biological behavior of duodenal and pancreatic gastrinomas, role of imaging studies to localize tumor, and gastrectomy to manage acid output. Review of the literature based on computer searches in Index Medicus, Pubmed and Ovid. Current controversies as identified in the literature include the role of endoscopic ultrasound (EUS), surgery in ZES patients with MEN1, pancreaticoduodenectomy (Whipple procedure), lymph node primary gastrinoma, parietal cell vagotomy, reoperation and surgery for metastatic tumor, and the use of minimally invasive surgical techniques to localize and remove gastrinoma. It is hoped that future studies will focus on these issues to improve the surgical management of ZES patients.

Objective: To determine whether routine use of duodenotomy (DUODX) alters cure rate, survival, or development of liver metastases in 143 patients (162 operations) with Zollinger-Ellison syndrome (ZES) without MEN1. Summary Background Data: DUODX has been shown to increase the detection of duodenal gastrinomas, but it is unknown if it alters rate of cure, liver metastases, or survival. Data from our prospective studies of surgery in ZES allow us to address this issue because DUODX was not performed before 1987, whereas it was routinely done after 1987. Methods: All patients with sporadic ZES (non-MEN1) undergoing surgery for possible cure without a prior DUODX from November 1980 to June 2003 were included. Patients had preoperative computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994. At surgery, all had the same standard ZES operation and were assessed immediately postoperatively, at 3 to 6 months, and yearly for cure (fasting gastrin, secretin test. and imaging studies). Results: A DUODX was performed in 79 patients (94 operations), and no DUODX was performed in 64 patients (68 operations), with 10 patients having both (no DUODX, then a DUODX later). Gastrinoma was found in 98% with DUODX compared with 76% with no DUODX (P < 0.00001). Duodenal gastrinomas were found more frequently with DUODX (62% vs. 18%; P < 0.00001), whereas pancreatic, lymph node, and other primary gastrinomas occurred similarly. Six of the 10 patients with 2 operations had a duodenal tumor found with DUODX during a second operation that was missed in the first operation without DUODX. Both the immediate postoperative cure rate (65% vs. 44%; P = 0.010) and long-term cure rate at last follow-up (8.8 ± 0.4 years; range, 0.1 to 21.5) (52% vs. 26%; P = 0.0012) were significantly greater with a DUODX than without. In patients without pancreatic tumors or liver metastases at surgery, both the rate of developing liver metastases (6% vs. 9.5%) and the disease-related death rate (0% vs. 2%) were low and not significantly different in patients with or without a DUODX. Conclusions: These results demonstrate that routine use of DUODX increases the short-term and long-term cure rate due to the detection of more duodenal gastrinomas. The rate of development of hepatic metastases and/or disease-related mortality in patients without pancreatic tumors is low, and no effect of DUODX on these parameters was seen. Duodenotomy (DUODX) should be routinely performed during all operations for cure of sporadic ZES.

Approximately 1% to 3% of all gastric cancers are associated with families exhibiting an autosomal dominant pattern of susceptibility. E-cadherin (CDH1) truncating mutations have been shown to be present in approximately 30% of families with hereditary diffuse gastric cancer (HDGC) and are associated with a significantly increased risk of gastric cancer and lobular breast cancer. Individuals from a large kindred with HDGC who were identified to have a CDH1 mutation prospectively underwent comprehensive screening with stool occult blood testing, standard upper gastrointestinal endoscopy with random gastric biopsies, high-magnification endoscopy with random gastric biopsies, endoscopic ultrasonography, CT, and PET scans to evaluate the stomach for occult cancer. Subsequently, they each underwent total gastrectomy with d-2 node dissection and Roux-en-y esophagojejunostomy. The stomach and resected lymph nodes were evaluated pathologically. Six patients were identified as CDH1 carriers from a single family. There were 2 men and 4 women. The mean age was 54 years (range, 51–57 years). No patient had any signs or symptoms of gastric cancer. Exhaustive preoperative stomach evaluation was normal in each case, and the stomach and adjacent lymph nodes appeared normal at surgery. However, each patient (6 of 6, 100%) was found to have multiple foci of T1 invasive diffuse gastric adenocarcinoma (pure signet-ring cell type). No patient had lymph node or distant metastases. Each was staged as T1N0M0. Each patient recovered uneventfully without morbidity or mortality. CDH1 mutations in individuals from families with HDGC are associated with gastric cancer in a highly penetrant fashion. CDH1 mutations are an indication for total gastrectomy in these patients. This mutation will identify patients with cancer before other detectable symptoms or signs of the disease.