Elisabetta Marino

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.

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.

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.

Unique case of sporadic multiple gastro intestinal stromal tumour

Introduction Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and they derived from transformed neoplastic precursors of Cajal’s interstitial cell (ICC). Presentation of the case We are presenting a sporadic and exemplary case of 42 multiple GISTs in a young female patient. Our patient showed anemia for the gastric GIST bleeding and only after other tumors were instrumentally and intra-surgery discovered. The patient showed genetic mutation V559A/1676 T > C of the juxtamembrane domain of the exon 11 causing the replacement of Valine with Alanine in the 559 codon. Discussion GISTS estimated annual incidence is 12–14 per million. Multiple GISTs associated with familiarity or hereditary syndromes are described only in few case reports and sporadic mGISTs have not been studied yet. Literature review has been done. Conclusion We are presenting a sporadic and exemplary case of 42 multiple GISTs in a young female patient localized trough out all the gastrointestinal tract. This is the only case of sporadic multiple GISTs reported in literature.

Analysis of operative morbidity in a single center initial experience with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Background Peritoneal carcinomatosis has been traditionally considered a rapidly lethal disease and consequently managed by merely palliative options. In the last decade, the clinical interest in the condition has increased because encouraging results have been reported in association with a new treatment strategy that combines cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Relatively high rates of severe complications are generally associated to this complex procedure. Our aim was to analyze treatment-related morbidity in our institutional initial experience. Materials and Methods Since October 2006, 36 hyperthermic intraperitoneal chemotherapy plus cytoreductive surgery procedures have been carried out in our Department. Patients treated showed abdominal malignancies and ovarian cancer with peritoneal carcinomatosis. Only 9 patients were treated with prophylactic treatment for gastric cancer at high risk to develop peritoneal carcinomatosis. Results In 27 patients, a macroscopically complete cytoreduction was done. The overall morbidity was 75%. Grades IV and V represented only 11.1%. Conclusions Rigorous preoperative workup and strict selection criteria allowed a successful safe start of a new program of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in a general surgery unit.

Simultaneous surgical treatment for both colorectal liver metastases and peritoneal carcinomatosis.

We read with interest the paper written by Allard M.A et al. We disagree with the authors assertion that intraperitoneal chemotherapy (HIPEC) does not have a defined role in colorectal peritoneal carcinomatosis (PC) in the presence of liver metastases (LM). Many studies have demonstrated an improved survival in selected patients with both PC and LMs treated with cytoreductive surgery (CRS) and HIPEC. Colorectal PC was previously treated palliatively with a median survival of 6 months. Recently, the introduction of an aggressive approach, which combines complete cytoreductive surgery and intraperitoneal chemotherapy has led to a major improvement in the prognosis e reaching a survival of 20 months. Chua et al. has shown that LMs synchronously observed with PC have not been regarded as an absolute contraindication to CRS plus HIPEC. Chua’s comparative study demonstrated no significant survival difference in the treating of patients with both colorectal cancer PC and LMs compared to patients with isolated PC alone e reaching a 3 y overall survival (OS) of 60%. The number of LMs seems to be the only real prognostic factor. Elias identified three patients groups with a long-term prognosis: Patients with a good prognosis e those with a low PCI (<12), no LM and with an OS of 76 months. Patients with an intermediate prognosis e those with a low PCI (<12), 1 or 2 LMs and with an OS of 40 months. Patients with an impaired prognosis e those with a high PCI ( 12), with 3 LMs or more and with an OS dropping to 27 months. For patients with a PCI less than 12 and 1 or 2 resectable LMs, then complete CRS followed by HIPEC should be proposed. Furthermore, Elias showed a trend toward a higher major-complication rate in patients of the PC and

Prognostic Value of CEA and Ca 19.9/Tumor Markers in Gastric Cancer to Identify Patients with Poor Prognosis after Radical Surgery

Introduction: Although gastric cancer incidence has decreased worldwide, it’ s still the fifth most frequent malignancy and the third leading cause of cancer related mortality. Many prognostic factors have been identified as indicators of gastric cancer prognosis including tumour size, depth, lymph nodes metastasis and microvascular involvement. To date the clinical significance of tumoral markers remains unclear. In our study we would like to investigate the prognostic survival significance of preoperative CEA and CA19.9.Material and Methods: From January 2004 to September 2016, a total of 326 gastric cancer patients were analysed. Of these 260 were enrolled in the study. The two serum tumour markers CEA and CA19.9 were detected within 7 days before surgery. The normal cut off value for serum CEA was 5 ng/ml whereas for CA19.9 was 35 U/ ml. Patients were also dichotomized according to CEA and CA19.9 median value (respectively 2 ng/ml and 9 U/ml).Results: Our results suggest that the optimal application of these common tumour markers could promote the clinical screening and staging of gastric cancer patients. Their evaluation is cheap and easy, allowing a routinely use to identify patients at high risk of death or post-surgical recurrences. Also, we could utilize the optimal cut-off value of CA19.9 for individualizing patients with an early stage but a very bad prognosis.Discussion and Conclusion: We conclude that the combined assessment of CA19.9 and CEA levels could have prognostic value in gastric cancer in particular to identify patients with a poor prognosis after radical surgery, who need an aggressive follow-up and medical treatment.

Inflammatory markers as prognostic factors of survival in patients affected by hepatocellular carcinoma undergoing transarterial chemoembolization

Introduction Transarterial chemoembolization (TACE) is a good choice for hepatocellular carcinoma (HCC) treatment when surgery and liver transplantation are not feasible. Few studies reported the value of prognostic factors influencing survival after chemoembolization. In this study, we evaluated whether preoperative inflammatory factors such as neutrophil to lymphocyte ratio and platelet to lymphocyte ratio affected our patient survival when affected by hepatocellular carcinoma. Methods We retrospectively evaluated a total of 72 patients with hepatocellular carcinoma that underwent TACE. We enrolled patients with different etiopathogeneses of hepatitis and histologically proven HCC not suitable for surgery. The overall study population was dichotomized in two groups according to the median NLR value and was analyzed also according to other prognostic factors. Results The global median overall survival (OS) was 28 months. The OS in patients with high NLR was statistically significantly shorter than that in patients with low NLR. The following pretreatment variables were significantly associated with the OS in univariate analyses: age, Child-Pugh score, BCLC stage, INR, and NLR. Pretreated high NLR was an independently unfavorable factor for OS. Conclusion NLR could be considered a good prognostic factor of survival useful to stratify patients that could benefit from TACE treatment.

Minimally invasive surgery for advanced gastric cancer: are we sure?

We read with particular interest the paper written by Erin K. Greenleaf et al. and published in March 2017 in Gastric Cancer [1]. Their paper reports a comparison of the minimally invasive surgical approach to the open surgical approach in resectable gastric cancer patients with curative intent, focusing on what is currently the largest series of Western gastric cancer patients. We agree with the authors that minimally invasive surgical techniques are an emerging option in the staging and management of both early and advanced gastric cancer. Although much of the current knowledge about these approaches and their outcomes was obtained in Eastern countries, experience of them in the West is growing. Minimally invasive gastrectomy appears to have similar oncologic outcomes to open procedures, as Vivian Strong demonstrated in her recent published meta-analysis [2], and it has therefore become a useful alternative to open precedures that enables patients to return more quickly to their routine activities. However, we dispute the highly encouraging oncological outcomes described by the authors in their work because we note that a relatively high number of patients did not receive the correct treatment in terms of their oncological outcomes, particularly in the minimally invasive groups. Surgeons did not remove lymph nodes in 9.4% of the robotic procedures and 13.4% of the laparoscopic ones; in addition, one-third of the patients (32.7% in the robotic group and 33.3% in the laparoscopic group) who underwent a minimally invasive procedure did not undergo oncological staging because an insufficient number of lymph nodes (\15) were removed. We also note that the percentages of patients with stage III–IV gastric cancer who were treated using robotic, laparoscopic, and open approaches were the same.When the disease is at stage III–IV (particularly stage III), the gastric cancer guidelines state that a good D2 lymphadenectomy is needed to improve overall survival and disease-free survival. Stage III disease includes patients affected by a locally advanced gastric cancer that could benefit from curative surgery as a component of integrated therapy (i.e., with adjuvant or perioperative chemotherapy). Also, according to the 7th UICC Gastric Cancer Staging System, stage IV disease includes patients with positive cytology but without remote metastases and macroscopically evident peritoneal carcinomatosis. A curative D2 gastric resection performed within local and integrated treatment strategies can be carried out in such cases [3]. We believe that robotic and laparoscopic approaches can be applied in gastric cancer cases, but the oncological results obtained when these approaches have been used at an advanced disease stage have so far been poor and inconclusive. Minimally invasive gastric resection is currently the standard method applied in cases of early-stage cancer, as it has significant advantages in relation to shortterm and long-term oncological outcomes. Recently, the indication for a laparoscopic approach has been extended to locally advanced gastric cancer. Large-scale randomized controlled clinical trials are currently underway in Eastern patients to confirm its feasibility and safety in cases of more advanced gastric cancer. The application of a minimally invasive surgical approach could modify the extent of the surgery needed, reduce the risk of perioperative complications, and potentially yield better results in terms & L. Graziosi luiginagraziosi@yahoo.it