Luigina Graziosi

Malignant ascites: pathophysiology and treatment

Malignant ascites (MA) accompanies a variety of abdominal and extra-abdominal tumors. It is a primary cause of morbidity and raises several treatment challenges. MA has several symptoms, producing a significant reduction in the patient’s quality of life: loss of proteins and electrolyte disorders cause diffuse oedema, while the accumulation of abdominal fluid facilitates sepsis. Treatment options include a multitude of different procedures with limited efficacy and some degree of risk. A Pubmed, Medline, Embase, and Cochrane Library review of medical, interventional and surgical treatments of MA has been performed. Medical therapy, primarily paracentesis and diuretics, are first-line treatments in managing MA. Paracentesis is widely adopted but it is associated with significant patient discomfort and several risks. Diuretic therapy is effective at the very beginning of the disease but efficacy declines with tumor progression. Intraperitoneal chemotherapy, targeted therapy, immunotherapy and radioisotopes are promising medical options but their clinical application is not yet completely elucidated, and further investigations and trials are necessary. Peritoneal–venous shunts are rarely used due to high rates of early mortality and complications. Laparoscopy and hyperthermic intraperitoneal chemotherapy (HIPEC) have been proposed as palliative therapy. Literature on the use of laparoscopic HIPEC in MA includes only reports with small numbers of patients, all showing successful control of ascites. To date, none of the different options has been subjected to evidence-based clinical trials and there are no accepted guidelines for the management of MA.

Dissociation of Intestinal and Hepatic Activities of FXR and LXRα Supports Metabolic Effects of Terminal Ileum Interposition in Rodents

The farnesoid X receptor (FXR) and the liver x receptors (LXRs) are bile acid–activated receptors that are highly expressed in the enterohepatic tissues. The mechanisms that support the beneficial effects of bariatric surgery are only partially defined. We have investigated the effects of ileal interposition (IT), a surgical relocation of the distal ileum into the proximal jejunum, on FXR and LXRs in rats. Seven months after surgery, blood concentrations of total bile acids, taurocholic acid, an FXR ligand, and taurohyocholic acid, an LXRα ligand, were significantly increased by IT (P < 0.05). In contrast, liver and intestinal concentrations of conjugated and nonconjugated bile acids were decreased (P < 0.05). These changes were associated with a robust induction of FXR and FXR-regulated genes in the intestine, including Fgf15, a negative regulator of bile acid synthesis. IT repressed the liver expression of glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase (Pepck), two gluconeogenetic genes, along with the expression of LXRα and its target genes sterol regulatory element-binding protein (Srebp) 1c and fatty acid synthase (Fas) in the liver. Treating IT rats with chenodeoxycholic acid ameliorated insulin signaling in the liver. Whether confirmed in human settings, these results support the association of pharmacological therapies with bariatric surgeries to exploit the selective activation of intestinal nuclear receptors.

Successful palliation of malignant ascites from peritoneal mesothelioma by laparoscopic intraperitoneal hyperthermic chemotherapy.

A variety of options have been proposed to treat malignant ascites but most of them have failed to reach a significant impact in terms of palliation. Laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC) could represent a good therapeutic tool for patients in whom medical therapies have failed and peritoneovenous shunting is contraindicated. Here we present a case of a 49-year-old woman with malignant ascites secondary to peritoneal spreading of a right pleural mesothelioma. After failure of medical therapy, the patient underwent LHIPEC with Cisplatin 25 mg/m2/L and Doxorubicin 7 mg/m2/L. A dramatic reduction of ascites was documented in the postoperative period and the patient experienced complete abdominal symptom relief. Ascites did not recur during a follow-up period of 6 months. LHIPEC could be a good therapeutic option to palliate malignant ascites from mesothelioma in cases not eligible for a radical treatment. Further studies are needed to standardize dosage and perfusion parameters.

Prognostic value of the seventh AJCC/UICC TNM classification of non-cardia gastric cancer

BackgroundThe TNM staging criteria for gastric carcinoma have seen numerous revisions, the most recent of which are reflected in the seventh edition AJCC TNM cancer staging manual.MethodsA retrospective evaluation of the sixth and seventh TNM classification of gastric cancer on a prospective database, regarding patients operated on for primary gastric cancer, was conducted. The end point of the study was prognosis evaluation in terms of overall survival.Patients operated on for primary gastric cancer between September 2003 and March 2012 at our Department of Emergency and General Surgery, were consecutively retrieved in this study; a total of 114 patients were considered. Cardia gastric cancers, gastric lymphomas and gastrointestinal stromal tumors (GIST) were excluded. Median and mean follow-up periods were 22.5 and 27.7 months (range 15 days to 5 years). Both TNM6 and TNM7 were used to evaluate our patients. Overall survival and survival rates at different stages were analyzed using the Kaplan-Meier method and differences were determined using a log-rank test. Cox’s proportional hazard model was used to identify significant factors related to prognosis in a multivariate analysis.ResultsOverall survival between the sixth and seventh TNM classification was not significantly different. Both the Kaplan-Meier analysis and the multivariate analysis showed that the major negative prognostic factor was lymphovascular invasion (P < 0.001 in the univariate analysis and P = 0.035 to 0.048 in the multivariate analysis). Stage distribution and stage-related survival changed from the sixth to the seventh edition, especially in T3 stage where median survival for the sixth edition was 720 days versus 1,200 days for the seventh edition. Moreover, differences were shown in the survival rate of N1 versus N2 stages within the seventh TNM.ConclusionsEven though further studies are needed in order to increase the number of patients studied, the seventh edition seems to provide a more accurate prognosis, especially regarding N1 and N2 tumors, showing that the most important prognostic factor is lymphovascular invasion.

Mechanistic role of p38 MAPK in gastric cancer dissemination in a rodent model peritoneal metastasis.

Peritoneal dissemination is a highly frequent complication of poorly differentiated gastric cancers for which no effective therapies are available. Constitutive activation of mitogen-activated protein kinases (MAPKs) signaling cascades is recognized as a causative factor in the malignant transformation of several carcinoma cell types. In the present study we provide evidence that p38 MAPK inhibition protects against gastric cancer cells dissemination in a mouse model of peritoneal carcinomatosis. Administering mice with ML3403 and SB203580, potent and selective p38 MAPK inhibitors, attenuate the formation of neoplastic foci induced by intraperitoneal inoculation of gastric cancer cells. By gene array analysis we found that such a protective effect correlates with a robust downregulation in the expression of CXC chemokine receptor-4, Fms-related tyrosine kinase 4 (FLT4), the non-receptor spleen tyrosine kinase (SYK) and the collagen α2(IV) (COL4A2) in neoplasic foci. Inhibition of p38 MAPK in vivo increased the sensitivity of tumor cells to cisplatin and associated with a robust downregulation in the expression of the multidrug resistance (MDR)-1, a well defined marker of resistance to chemotherapy. In summary, p38 MAPK inhibition by a small molecule is beneficial in preventing the peritoneal dissemination of poorly differentiated gastric cancer cells by acting at multiple check-points in the process of attachment and diffusion of tumor cells in the peritoneum.

Epigenetic Modulation by Methionine Deficiency Attenuates the Potential for Gastric Cancer Cell Dissemination

IntroductionMethionine dependency occurs frequently in tumor cells. Here we have investigated the effect of methionine deficiency on metastatic potential of gastric cancer cells in vitro and in vivo.Materials and MethodsModel of peritoneal carcinomatosis and xenograft was generated by intraperitoneal or subcutaneous implantation of gastric cancer cells in NOD-SCID mice. In comparison to control medium, 3-day culture of MKN45, MKN74, and KATOIII cells in a methionine-deficient medium inhibited cell proliferation, increased the rate of cell apoptosis, and reduced cell adhesion and migration. In the xenograft model induced by implantation of MNK45 and MNK74 cells, two cycles of methionine-deficient diet reduced the tumor growth. Further on, a 10-day cycle of methionine-deficient diet reduced the number of peritoneal nodules in the model of peritoneal carcinomatosis induced by MKN45 cells injection. Finally, a microarray analysis of the methylation of promoter CpG islets demonstrated that methionine deficiency reduced the promoter methylation of E-cadherin whose expression was markedly increased in vivo and in vitro.ResultsIn summary, we have provided evidence that a methionine-deficient diet modulates the growth of gastric tumor cells and in vitro deficiency of methionine increased apoptosis and decreased cellular adhesion and migration associated to epigenetic change of E-cadherin gene, in vivo and in vitro.

The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines

GPBAR1 (also known as TGR5) is a bile acid activated receptor expressed in several adenocarcinomas and its activation by secondary bile acids increases intestinal cell proliferation. Here, we have examined the expression of GPBAR1 in human gastric adenocarcinomas and investigated whether its activation promotes the acquisition of a pro-metastatic phenotype. By immunohistochemistry and RT-PCR analysis we found that expression of GPBAR1 associates with advanced gastric cancers (Stage III-IV). GPBAR1 expression in tumors correlates with the expression of N-cadherin, a markers of epithelial-mesenchymal transition (EMT) (r=0.52; P<0.01). Expression of GPBAR1, mRNA and protein, was detected in cancer cell lines, with MKN 45 having the higher expression. Exposure of MKN45 cells to GPBAR1 ligands, TLCA, oleanolic acid or 6-ECDCA (a dual FXR and GPBAR1 ligand) increased the expression of genes associated with EMT including KDKN2A, HRAS, IGB3, MMP10 and MMP13 and downregulated the expression of CD44 and FAT1 (P<0.01 versus control cells). GPBAR1 activation in MKN45 cells associated with EGF-R and ERK1 phosphorylation. These effects were inhibited by DFN406, a GPBAR1 antagonist, and cetuximab. GPBAR1 ligands increase MKN45 migration, adhesion to peritoneum and wound healing. Pretreating MKN45 cells with TLCA increased propensity toward peritoneal dissemination in vivo. These effects were abrogated by cetuximab. In summary, we report that GPBAR1 is expressed in advanced gastric cancers and its expression correlates with markers of EMT. GPBAR1 activation in MKN45 cells promotes EMT. These data suggest that GPBAR1 antagonist might have utility in the treatment of gastric cancers.

Late Migration of a Covered Stent into the Stomach after Repair of a Splenic Artery Pseudoaneurysm.

We would like to report our experience of a rather rare complication that occurred in a 76-year old patient tree years after endovascular repair of a splenic artery pseudoaneurysm with a covered stent. Three years after stent insertion, the patient complained of mild abdominal pain and melena; it was revealed endoscopically that the covered stent has eroded the stomach wall and migrated into the stomach. The splenic artery is the most common location among the spectrum of potential presentation sites of visceral arteries aneurysms and pseudoaneurysms. Endovascular treatment with the use of coils or stents is the first option due to lower morbidity and mortality than open surgery. Endovascular repair may also lead to complications and patients need to be followed up in order to confirm aneurysm sealing, and exclude late complication. Minor stent graft migration may occur in the long term, however extra vascular migration is extremely rare.

Role of CRS plus HIPEC in gastric cancer peritoneal carcinomatosis.

Dear Editor, I read with interest the paper written by Rudloff U. entitled “Impact of Maximal Cytoreductive Surgery Plus Regional Heated Intraperitoneal Chemotherapy (HIPEC) on Outcome of Patients With Peritoneal Carcinomatosis of Gastric Origin: Results of the GYMSSA Trial” [1]. Peritoneal dissemination (PC) is the most frequent metastatic pattern in GC especially in diffuse Lauren histological subtype (most gastric cancer patients enrolled in this study have diffuse type GC). Traditionally, there is an agreementwithin the oncologist community that patients with gastric PC are incurable. Despite improvements in systemic chemotherapy, there have been no large phase III studies that demonstrated the real benefit of one regimen that could change PC prognosis. On the contrary, lately hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) reported encouraging survival results in treatment of GC PC. Recently, French surgeons collected data from 159 patients and it represents the largest experience of GC PC treatment with CRS and HIPEC [2]. This study shows that HIPEC survival results are less encouraging than those obtained for other peritoneal surface malignancies, reflecting a more aggressive disease less responsive to this multimodal treatment and thus the need for a better patient selection. However, the combination of CRS with HIPEC was the only therapeutic strategy that reported long‐term survivors at 5 years if a strictly patient selection was performed. CRS plus HIPEC obtains better survival results in a limited peritoneal cancer index (PCI) and if a complete cytoreduction (CC0) is achieved. Yang et al. [3], Yonemura et al. [4], and Fujimoto [5] also show similar results. Rudloff enrolled in the GYMS arm metastastic GC patients with a median PCI too high that needed an extensive surgery with an elevated complication and re‐operation rate and no real survival benefit. Probably, for this post‐surgical morbidity, only few patients were able to start adjuvant chemotherapy, useful in controlling the systemic disease. In addition, authors did not describe PCI distribution of patients enrolled in SA arm to better see survival effect of systemic chemotherapy against PC and to compare it to CRS and HIPEC procedure. Moreover, we do not understand why patients with a PCI1⁄4 0 underwent peritonectomies and HIPEC as illustrated in Table II. We agree with HIPEC associated to gastric resection and D2 lymphadenectomy, in positive peritoneal cytology, being it a IVth stage disease. We indeed sustain that aggressive CRS/HIPEC may be selectively offered to GC patients with low peritoneal tumor burden in whom CC0 can be achieved. CRS/HIPEC may be most beneficial in a prophylactic setting for patients with locally advancedGCwithout macroscopic PC and possibly those with positive peritoneal cytology or serosal invasion who are at high risk of developing PC.

Retrospective analysis of short term outcomes after spleen-preserving distal pancreatectomy for sodid pseudopapillary tumours

Solid pseudopapillary pancreatic tumour (SPN) is a rare pancreatic tumour representing 0.1%-3% of all exocrine pancreatic tumours. Most SPN show benign and low-grade malignant behaviour; malignant degeneration is observed in 10-15% of the patients. More than 40% of SPN involve the tail of the pancreas leading to a minimal invasive distal pancreatectomy approach. In this report we present the case of a young 22 Caucasian woman suffering from SPN who successfully underwent laparoscopic spleen-preserving distal pancreatectomy. Postoperative course was uneventful. A CT scan control at six months was negative for recurrences. We have also made an analysis of all the laparoscopic treatment of SPN reported in English literature.