Simone Giacopuzzi

Indexes of Surgical Quality in Gastric Cancer Surgery: Experience of an Italian Network

BackgroundShort-term results of gastric cancer surgery vary remarkably worldwide, and international surgical quality criteria are urgently needed. To contribute to defining these criteria, we reviewed short-term results of gastrectomy for gastric cancer in three centers of the Italian Research Group for Gastric Cancer, with an average of 24.7, 29.5, and 18 gastrectomies per year.MethodsBetween 1988 and 2002, 1,032 patients underwent gastrectomy for gastric cancer in Verona, Siena, and Padua. D1, D2, and D3 lymphadenectomy were performed, respectively, in 228, 584, and 220 cases.ResultsThe median number of retrieved lymph nodes was 14 (interquartile range 9–18.75) after D1, 29 (21–38) after D2, and 46.5 (37–57) after D3. Fewer than 15 nodes were retrieved in 54.5%, 6.2%, and 1.4% of cases undergoing, respectively, D1, D2, and D3. Adjacent organ removal was rare during D1 (splenectomy: 6.1%, splenopancreasectomy: 1.8%), and quite common during D3 (11.4%, 11.4%). Forty patients (3.9%) died postoperatively. Neither postoperative morbidity nor mortality was significantly associated with extension of lymphadenectomy.ConclusionWe conclude that at least D2 lymphadenectomy is necessary to achieve adequate disease staging (≥15 nodes retrieved). Spleen and pancreas tail are more frequently removed during D3, but this removal is not associated with higher postoperative morbidity or mortality.

Super-extended (D3) lymphadenectomy in advanced gastric cancer

PURPOSE To analyze our experience with D3 lymphadenectomy in the treatment of advanced GC with specific reference to post-operative morbidity and mortality, incidence of para-aortic node (PAN) metastases, and long-term prognosis. METHODS Short- and long-term results of D3 lymphadenectomy were analyzed in 286 patients with advanced GC. RESULTS PAN metastases were demonstrated in 37 patients. PAN involvement was significantly higher in upper third tumours (29%) compared to middle and lower third (7%; P < 0.001). Eighty patients developed post-operative complications, being pulmonary disorders (6%), abdominal abscesses (4.5%) and pancreatic fistulas (3%) the most frequently observed. In-hospital mortality was 2%. Overall 5-year survival rate for R0 pT2-4 patients was 52%. When considering survival in relation to nodal involvement, both pN3 and non-regional lymph node metastases (M1a) patients showed a chance of long-term survival: 5-year survival was 31% for pN3 and 17% for M1a cases. Furthermore, the 5-year survival rate was remarkably high (about 60%) even in pN2 and pN3 subsets when no serosal invasion (pT2) was demonstrated. CONCLUSIONS D3 lymphadenectomy could be further explored in specialized centers for curative surgery of advanced GC, especially for upper third tumours, providing that an acceptable morbidity and no increase in mortality can be offered.

METACHRONOUS HEPATIC METASTASES FROM GASTRIC CARCINOMA: A MULTICENTRIC SURVEY.

BACKGROUND The treatment of hepatic metastases from gastric cancer is controversial, due to biologic aggressiveness of the disease. OBJECTIVE To survey the clinical approach to the subset of patients presenting with metachronous hepatic metastases as sole site of recurrence after curative resection of gastric cancer, focusing on the results achieved by different therapies and to investigate the prognostic factors of major clinical relevance. METHODS Retrospective multi-center chart review evaluating 73 patients, previously submitted to D >or= 2 gastrectomy for gastric cancer, who developed exclusive hepatic recurrence. Prognostic factors related to the patient, to the gastric malignancy and its treatment, and to the metastatic disease and its therapy were evaluated. RESULTS Forty-five patients received supportive care, 17 were submitted to chemotherapy, and 11 to hepatic resection. Survival was independently influenced by the variables T (p=0.019), N (p=0.05) and G (p=0.018) of the gastric primary and by the therapeutic approach to the metastases (p<0.005). In particular, T4 gastric cancer, presence of lymph-node metastases and G3 tumor displayed a negative prognostic value. Therapeutic approach to the metastases was the principal prognostic variable: 1, 2, and 3 years survival rates were 22.2%, 4.4% and 2.2%, respectively, for patients without specific treatment; 44.9%, 12.8% and 6.4% after chemotherapy (p=0.08) and 80.8%, 30.3% and 20.2% after surgical resection (p<0.001). CONCLUSIONS Our data suggest some clinical criteria that may facilitate selection of therapy for patients with hepatic recurrence after primary gastric cancer resection. The best survival rates are associated with surgical treatment, which should be chosen whenever possible.

Changing clinical and pathological features of gastric cancer over time

The aim of the present multicentre observational study was to evaluate potential changes in clinical and pathological features of patients with gastric cancer (GC) treated in a 15‐year interval.

Lymph Node Involvement in Gastric Cancer for Different Tumor Sites and T Stage

BackgroundThe aim of lymphadenectomy is to clear all the metastatic nodes achieving a complete removal of the tumor; nevertheless, its role in gastric cancer has been very much debated.Materials and methodsThe frequency of node metastasis in each lymphatic station according to the International Gastric Cancer Association, was studied in 545 patients who underwent D2 or D3 lymphadenectomy from June 1988 to December 2002.ResultsUpper third early cancers have shown an involvement of N2 celiac nodes in 25%. In advanced cancers, there was a high frequency of metastasis in the right gastroepiploic (from 10% in T2 to 50% in T4) and in the paraaortic nodes (26% in T2, 32% in T3, 38 % in T4). N3 left paracardial nodes involvement was observed in an important share of middle third tumors (17% in T3, 36% in T4). Splenic hilum nodes metastasis were common in T3 and T4 cancers located in the upper (39%) and middle (17%) stomach. N2 nodal involvement was frequent in lower third advanced cancers. Metastasis in M left paracardial and short gastric nodes were observed in a small percentage of cases.ConclusionGiven the nodal diffusion in our gastric cancer patients, extended lymphadenectomy is still a rationale to obtain radical resection.

Response to induction therapy in oesophageal and cardia carcinoma using Mandard tumour regression grade or size of residual foci.

Tumour regression grade (TRG) is used to evaluate responses to induction therapy in cancer of the oesophagus or cardia. This study aimed to determine whether inclusion of node category could improve the prognostic accuracy provided by TRG, and explore the prognostic value of an alternative classification based on size of residual foci and node category.

An FGFR3 autocrine loop sustains acquired resistance to trastuzumab in gastric cancer patients

Purpose: The majority of gastric cancer patients who achieve an initial response to trastuzumab-based regimens develop resistance within 1 year of treatment. This study was aimed at identifying the molecular mechanisms responsible for resistance. Experimental Design: A HER2+-trastuzumab sensitive NCI-N87 gastric cancer orthotopic nude mouse model was treated with trastuzumab until resistance emerged. Differentially expressed transcripts between trastuzumab-resistant and sensitive gastric cancer cell lines were annotated for functional interrelatedness by Ingenuity Pathway Analysis software. Immunohistochemical analyses were performed in pretreatment versus posttreatment biopsies from gastric cancer patients receiving trastuzumab-based treatments. All statistical tests were two-sided. Results: Four NCI-N87 trastuzumab-resistant (N87-TR) cell lines were established. Microarray analysis showed HER2 downregulation, induction of epithelial-to-mesenchymal transition, and indicated fibroblast growth factor receptor 3 (FGFR3) as one of the top upregulated genes in N87-TR cell lines. In vitro, N87-TR cell lines demonstrated a higher sensitivity than did trastuzumab-sensitive parental cells to the FGFR3 inhibitor dovitinib, which reduced expression of pAKT, ZEB1, and cell migration. Oral dovitinib significantly (P = 0.0006) reduced tumor burden and prolonged mice survival duration in N87-TR mouse models. A higher expression of FGFR3, phosphorylated AKT, and ZEB1 were observed in biopsies from patients progressing under trastuzumab-based therapies if compared with matched pretreatment biopsies. Conclusions: This study identified the FGFR3/AKT axis as an escape pathway responsible for trastuzumab resistance in gastric cancer, thus indicating the inhibition of FGFR3 as a potential strategy to modulate this resistance. Clin Cancer Res; 22(24); 6164–75. ©2016 AACR.

Impact of super-extended lymphadenectomy on relapse in advanced gastric cancer.

BACKGROUND In gastric cancer the incidence of loco-regional recurrences decreases when lymphadenectomy is expanded from D1 to D2. The present study aimed at evaluating whether the pattern of recurrence in advanced gastric cancer (AGC) is further modified when lymphadenectomy is expanded from D2 to D3. METHODS 568 patients undergoing curative gastrectomy for AGC (274 D2 and 294 D3) were considered; none of them received preoperative chemotherapy. MantelHaenszel test of homogeneity was used to verify whether the relation between extension of lymphadenectomy and recurrence varied as a function of each risk factor considered. The impact of D2 and D3 on relapse was further investigated by multivariable logistic regression model. RESULTS Cumulative incidence of recurrence did not significantly differ after D2 and after D3 in the whole series (45.3% vs 46.3%; p = 0.866). However, the association between recurrence and extension of lymphadenectomy was significantly affected by histology (Mantel-Haenszel test of homogeneity: p = 0.007). The risk of recurrence was higher after D3 than after D2 (45.1% vs 35.3%) in the intestinal histotype while the pattern was reversed in the mixed/diffuse histotype (48.3% vs 61.5%). This pattern was confirmed in multivariable logistic regression: the interaction between histology and extension of lymphadenectomy was highly significant (p = 0.004). In particular, cumulative incidence of locoregional recurrences was higher in the diffuse histotype after D2, while being higher in the intestinal histotype after D3. CONCLUSIONS D3 reverses the negative impact of diffuse histotype on relapses, especially on locoregional recurrences. Therefore D3 could be considered a valid therapeutic option in histotype-oriented tailored treatment of AGC.

TAK1-regulated expression of BIRC3 predicts resistance to preoperative chemoradiotherapy in oesophageal adenocarcinoma patients

Background:About 20% of resectable oesophageal carcinoma is resistant to preoperative chemoradiotherapy. Here we hypothesised that the expression of the antiapoptotic gene Baculoviral inhibitor of apoptosis repeat containing (BIRC)3 induced by the transforming growth factor β activated kinase 1 (TAK1) might be responsible for the resistance to the proapoptotic effect of chemoradiotherapy in oesophageal carcinoma.Methods:TAK1 kinase activity was inhibited in FLO-1 and KYAE-1 oesophageal adenocarcinoma cells using (5Z)-7-oxozeaenol. The BIRC3 mRNA expression was measured by qRT–PCR in 65 pretreatment frozen biopsies from patients receiving preoperatively docetaxel, cisplatin, 5-fluorouracil, and concurrent radiotherapy. Receiver operator characteristic (ROC) analyses were performed to determine the performance of BIRC3 expression levels in distinguishing patients with sensitive or resistant carcinoma.Results:In vitro, (5Z)-7-oxozeaenol significantly reduced BIRC3 expression in FLO-1 and KYAE-1 cells. Exposure to chemotherapeutic agents or radiotherapy plus (5Z)-7-oxozeaenol resulted in a strong synergistic antiapoptotic effect. In patients, median expression of BIRC3 was significantly (P<0.0001) higher in adenocarcinoma than in the more sensitive squamous cell carcinoma subtype. The BIRC3 expression significantly discriminated patients with sensitive or resistant adenocarcinoma (AUC-ROC=0.7773 and 0.8074 by size-based pathological response or Mandards tumour regression grade classifications, respectively).Conclusions:The BIRC3 expression might be a valid biomarker for predicting patients with oesophageal adenocarcinoma that could most likely benefit from preoperative chemoradiotherapy.

Extranodal extension of lymph node metastasis is a marker of poor prognosis in oesophageal cancer: a systematic review with meta-analysis

The extranodal extension (ENE) of nodal metastasis is the extension of neoplastic cells through the nodal capsule into the perinodal adipose tissue. This histological feature has recently been indicated as an important prognostic factor in different types of malignancies; in this manuscript, we aim at defining its role in the prognosis of oesophageal cancer with the tool of meta-analysis. Two independent authors searched SCOPUS and PubMed until 31 August 2015 without language restrictions. The studies with available data about prognostic parameters in subjects with oesophageal cancer, comparing patients with the presence of ENE (ENE+) versus only intranodal extension (ENE−), were considered as eligible. Data were summarised using risk ratios (RRs) for number of deaths/recurrences and HRs together with 95% CIs for time-dependent risk related to ENE+, adjusted for potential confounders. Fourteen studies were selected; they followed-up 1437 patients with oesophageal cancer for a median follow-up of 39.4 months. The presence of ENE was associated with a significantly increased risk of all-cause mortality (RR=1.33; 95% CI 1.18 to 1.50, p<0.0001, I2=49%; HR=2.72, 95% CI 2.03 to 3.64, p<0.0001, I2=0%), cancer-specific mortality (RR=1.35; 95% CI 1.14 to 1.59, p=0.001, I2=57%; HR=1.97, 95% CI 1.41 to 2.75, p<0.0001, I2=41%) and of risk of recurrence (RR=1.50, 95% CI 1.20 to 1.88, p<0.0001, I2=9%; HR=2.27, 95% CI 1.72 to 2.90, p<0.0001, I2=0%). On the basis of these results, in oesophageal cancer, ENE should be considered from the gross sampling to the pathology report, and in future oncological staging system.