Follow-up after curative resection for gastric cancer. Is it time to tailor it?

There is still no consensus on the follow-up frequency and regimen after curative resection for gastric cancer. Moreover, controversy exists regarding the utility of follow-up in improving survival, and the recommendations of experts and societies vary considerably. The main reason to establish surveillance programs is to diagnose tumor recurrence or metachronous cancers early and to thereby provide prompt treatment and prolong survival. In the setting of gastric malignancies, other reasons have been put forth: (1) the detection of adverse effects of a previous surgery, such as malnutrition or digestive sequelae; (2) the collection of data; and (3) the identification of psychological and/or social problems and provision of appropriate support to the patients. No randomized controlled trials on the role of follow-up after curative resection of gastric carcinoma have been published. Herein, the primary retrospective series and systematic reviews on this subject are analyzed and discussed. Furthermore, the guidelines from international and national scientific societies are discussed. Follow-up is recommended by the majority of institutions; however, there is no real evidence that follow-up can improve long-term survival rates. Several studies have demonstrated that it is possible to stratify patients submitted to curative gastrectomy into different classes according to the risk of recurrence. Furthermore, promising studies have identified several molecular markers that are related to the risk of relapse and to prognosis. Based on these premises, a promising strategy will be to tailor follow-up in relation to the patient and tumor characteristics, molecular marker status, and individual risk of recurrence

Influence of perineural invasion in predicting overall survival and disease-free survival in patients With locally advanced gastric cancer

Background The aim of the present study was to evaluate the prognostic significance of perineural invasion (PNI) in locally advanced gastric cancer patients who underwent D2 gastrectomy and adjuvant chemotherapy. Methods The records of a series of 103 patients undergoing D2 gastrectomy with curative intent combined with adjuvant chemotherapy from January 2004 to December 2014 were retrospectively reviewed. Results PNI was positive in 47 (45.6%) specimens. The 1-, 3-, and 5-year overall survival rates were 81%, 55%, and 42%, respectively. The 1-, 3-, and 5-year disease-free survival (DFS) rates were 76%, 57%, and 49%, respectively. A multivariate analysis showed that age number of positive lymph nodes, T stage, and PNI were independently associated with overall survival. Regarding DFS, the multivariate analysis showed that only PNI was independently associated with DFS. Conclusions PNI and T stage and positive lymph nodes are independent markers of poor prognosis in patients with gastric cancer. PNI should be incorporated in the postoperative staging system for planning follow-up after surgery and in our opinion to propose more aggressive postoperative therapies in PNI-positive patients

The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma

Cholangiocarcinoma (CCA) is an aggressive cancer with high resistance to chemotherapeutics. CCA is enriched in cancer stem cells, which correlate with aggressiveness and prognosis. FXR, a member of the metabolic nuclear receptor family, is markedly down-regulated in human CCA. Our aim was to evaluate, in primary cultures of human intrahepatic CCA (iCCA), the effects of the FXR agonist obeticholic acid (OCA), a semisynthetic bile acid derivative, on their cancerogenic potential. Primary human iCCA cell cultures were prepared from surgical specimens of mucinous or mixed iCCA subtypes. Increasing concentrations (0–2.5 μM) of OCA were added to culture media and, after 3–10 days, effects on proliferation (MTS assay, cell population doubling time), apoptosis (annexin V-FITC/propidium iodide), cell migration and invasion (wound healing response and Matrigel invasion assay), and cancerogenic potential (spheroid formation, clonogenic assay, colony formation capacity) were evaluated. Results: FXR gene expression was downregulated (RT-qPCR) in iCCA cells vs normal human biliary tree stem cells (p < 0.05) and in mucinous iCCA vs mixed iCCA cells (p < 0.05) but was upregulated by addition of OCA. OCA significantly (p < 0.05) inhibited proliferation of both mucinous and mixed iCCA cells, starting at a concentration as low as 0.05 μM. Also, CDCA (but not UDCA) inhibited cell proliferation, although to a much lower extent than OCA, consistent with its different affinity for FXR. OCA significantly induced apoptosis of both iCCA subtypes and decreased their in vitro cancerogenic potential, as evaluated by impairment of colony and spheroid formation capacity and delayed wound healing and Matrigel invasion. In general, these effects were more evident in mixed than mucinous iCCA cells. When tested together with Gemcitabine and Cisplatin, OCA potentiated the anti-proliferative and pro-apoptotic effects of these chemotherapeutics, but mainly in mixed iCCA cells. OCA abolished the capacity of both mucinous and mixed iCCA cells to form colonies when administered together with Gemcitabine and Cisplatin. In subcutaneous xenografts of mixed iCCA cells, OCA alone or combined with Gemcitabine or Cisplatin markedly reduced the tumor size after 5 weeks of treatment by inducing necrosis of tumor mass and inhibiting cell proliferation. In conclusion, FXR is down-regulated in iCCA cells, and its activation by OCA results in anti-cancerogenic effects against mucinous and mixed iCCA cells, both in vitro and in vivo. The effects of OCA predominated in mixed iCCA cells, consistent with the lower aggressiveness and the higher FXR expression in this CCA subtype. These results, showing the FXR-mediated capacity of OCA to inhibit cholangiocarcinogenesis, represent the basis for testing OCA in clinical trials of CCA patients

c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability

c-FLIP (cellular FLICE-like inhibitory protein) protein is mostly known as an apoptosis modulator. However, increasing data underline that c-FLIP plays multiple roles in cellular homoeostasis, influencing differently the same pathways depending on its expression level and isoform predominance. Few and controversial data are available regarding c-FLIP function in autophagy. Here we show that autophagic flux is less effective in c-FLIP−/− than in WT MEFs (mouse embryonic fibroblasts). Indeed, we show that the absence of c-FLIP compromises the expression levels of pivotal factors in the generation of autophagosomes. In line with the role of c-FLIP as a scaffold protein, we found that c-FLIPL interacts with Beclin-1 (BECN1: coiled-coil, moesin-like BCL2-interacting protein), which is required for autophagosome nucleation. By a combination of bioinformatics tools and biochemistry assays, we demonstrate that c-FLIPL interaction with Beclin-1 is important to prevent Beclin-1 ubiquitination and degradation through the proteasomal pathway. Taken together, our data describe a novel molecular mechanism through which c-FLIPL positively regulates autophagy, by enhancing Beclin-1 protein stability

Cognitive level and adaptive behaviour in the Klippel-Trenaunay-Weber Syndrome. An example of the potentials of an early intervention model applied to a complex pathology

PURPOSE: The Klippel-Trenaunay-Weber syndrome is a rare, congenital disorder characterized by benign excessive growth of blood vessels on the skin. Little is still known about its cognitive development and adaptive behaviour functioning. CASE STUDY: This case study describes the clinical history of a female child suffering from this rare syndrome and admitted to our Pediatric Unit in order to provide motor rehabilitation, speech therapy and psychoanalytic psychotherapy following an early intervention model program. After five years of treatment her clinical picture witnessed a considerable improvement. CONCLUSIONS: Patients with Klippel-Trenaunay-Weber Syndrome are best served by a multidisciplinary approach, and this case study shows the effectiveness of an early intervention program on the cognitive development and adaptive behaviour functioning

Impact of anastomotic leakage on overall and disease-free survival after surgery for gastric carcinoma. a systematic review

BACKGROUND/AIM: Gastric cancer is the fifth most frequently diagnosed cancer and the second most common cause of cancer-related death. The only potentially curative treatment is surgical resection, which is associated with potentially severe complications, such as anastomotic leakage. The aim of this systematic review was to evaluate the relationship between anastomotic leakage and overall and disease-free survival after surgery for gastric cancer. MATERIALS AND METHODS: A systematic literature search was performed and 7 articles published between 2010 and 2019 were included, including a total of 7,167 patients. RESULTS: Among the included studies the frequency of anastomotic leakage ranged from 6 to 41%. Patients affected by anastomotic leakage had an overall survival ranging between 4.1 and 97.6 months, whereas patients who did not experience anastomotic leakage had an overall survival between 23 and 109.5 months. CONCLUSION: Closer follow-up or even more aggressive oncological therapy may be considered for patients affected by anastomotic leakage after surgery for gastric cancer

Tumor-Stroma Ratio is an independent predictor for overall survival and disease free survival in gastric cancer patients

Background Despite different prognostic factors have been already studied, patients undergoing potentially curative resection for gastric cancer, still have a poor outcome. There is therefore the need to identify novel prognostic factors. Recently, Tumor-Stroma Ratio (TSR) was proven to be associated with prognosis in different types of cancers. Aim of this study was to evaluate the prognostic value of TSR in gastric cancer patients. Methods 106 patients underwent gastrectomy between January 2004 and December 2015. Demographics and histopathological characteristics were collected. We considered a 50% TSR cutoff value to divide patients in Stroma-Rich (≥50%) and Stroma-Poor (<50%) groups. Results Forty-one (38.7%) patients were classified as Stroma-Poor while 65 (61.3%) as Stroma-Rich (61.3%). The Stroma-Rich patients had a higher number of positive lymph-nodes, lymph node ratio (LNR), a higher percentage of T3/T4 local invasion and N2/N3, and a more advanced TNM. Moreover, these patients showed a higher percentage of lymphovascular and perineural invasion. With a median FU of 38 months Stroma-Rich patients had a significantly worse 5-years actuarial overall survival (OS) and disease free survival (DFS) compared to Stroma-Poor patients. Moreover, the multivariate analysis showed that Stroma-Rich was the only independent factor associated with OS and DFS together with TNM-Stage. Conclusions TSR is an independent marker of poor prognosis in patients with gastric cancer that should be readily incorporated into routine clinical pathology reporting. Identification of sensitive markers for patients who had undergone curative gastrectomy and who are at high risk of recurrence could provide useful information for planning follow-up after surgery or intensive and or/targeting adjuvant chemotherapy

Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with marked resistance to chemotherapeutics without therapies. The tumour microenvironment of iCCA is enriched of Cancer-Stem-Cells expressing Epithelial-to-Mesenchymal Transition (EMT) traits, being these features associated with aggressiveness and drug resistance. Treatment with the anti-diabetic drug Metformin, has been recently associated with reduced incidence of iCCA. We aimed to evaluate the anti-cancerogenic effects of Metformin in vitro and in vivo on primary cultures of human iCCA. Our results showed that Metformin inhibited cell proliferation and induced dose- and time-dependent apoptosis of iCCA. The migration and invasion of iCCA cells in an extracellular bio-matrix was also significantly reduced upon treatments. Metformin increased the AMPK and FOXO3 and induced phosphorylation of activating FOXO3 in iCCA cells. After 12&nbsp;days of treatment, a marked decrease of mesenchymal and EMT genes and an increase of epithelial genes were observed. After 2&nbsp;months of treatment, in order to simulate chronic administration, Cytokeratin-19 positive cells constituted the majority of cell cultures paralleled by decreased Vimentin protein expression. Subcutaneous injection of iCCA cells previously treated with Metformin, in Balb/c-nude mice failed to induce tumour development. In conclusion, Metformin reverts the mesenchymal and EMT traits in iCCA by activating AMPK-FOXO3 related pathways suggesting it might have therapeutic implications