Maria Bencivenga

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.

Short-term and long-term risk factors in gastric cancer

While in chronic diseases, such as diabetes, mortality rates slowly increases with age, in oncological series mortality usually changes dramatically during the follow-up, often in an unpredictable pattern. For instance, in gastric cancer mortality peaks in the first two years of follow-up and declines thereafter. Also several risk factors, such as TNM stage, largely affect mortality in the first years after surgery, while afterward their effect tends to fade. Temporal trends in mortality were compared between a gastric cancer series and a cohort of type 2 diabetic patients. For this purpose, 937 patients, undergoing curative gastrectomy with D1/D2/D3 lymphadenectomy for gastric cancer in three GIRCG (Gruppo Italiano Ricerca Cancro Gastrico = Italian Research Group for Gastric Cancer) centers, were compared with 7148 type 2 diabetic patients from the Verona Diabetes Study. In the early/advanced gastric cancer series, mortality from recurrence peaked to 200 deaths per 1000 person-years 1 year after gastrectomy and then declined, becoming lower than 40 deaths per 1000 person-years after 5 years and lower than 20 deaths after 8 years. Mortality peak occurred earlier in more advanced T and N tiers. At variance, in the Verona diabetic cohort overall mortality slowly increased during a 10-year follow-up, with ageing of the type 2 diabetic patients. Seasonal oscillations were also recorded, mortality being higher during winter than during summer. Also the most important prognostic factors presented a different temporal pattern in the two diseases: while the prognostic significance of T and N stage markedly decrease over time, differences in survival among patients treated with diet, oral hypoglycemic drugs or insulin were consistent throughout the follow-up. Time variations in prognostic significance of main risk factors, their impact on survival analysis and possible solutions were evaluated in another GIRCG series of 568 patients with advanced gastric cancer, undergoing curative gastrectomy with D2/D3 lymphadenectomy. Survival curves in the two different histotypes (intestinal and mixed/diffuse) were superimposed in the first three years of follow-up and diverged thereafter. Likewise, survival curves as a function of site (fundus vs body/antrum) started to diverge after the first year. On the contrary, survival curves differed among age classes from the very beginning, due to different post-operative mortality, which increased from 0.5% in patients aged 65-74 years to 9.9% in patients aged 75-91 years; this discrepancy later disappeared. Accordingly, the proportional hazards assumption of the Cox model was violated, as regards age, site and histology. To cope with this problem, multivariable survival analysis was performed by separately considering either the first two years of follow-up or subsequent years. Histology and site were significant predictors only after two years, while T and N, although significant both in the short-term and in the long-term, became less important in the second part of follow-up. Increasing age was associated with higher mortality in the first two years, but not thereafter. Splitting survival time when performing survival analysis allows to distinguish between short-term and long-term risk factors. Alternative statistical solutions could be to exclude post-operative mortality, to introduce in the model time-dependent covariates or to stratify on variables violating proportionality assumption.

Western strategy for EGJ carcinoma

In this paper, the epidemiological and clinicobiological behavior of esophagogastric junction (EGJ) adenocarcinoma in the West is compared and contrasted to that in the East, and an overview is provided of current therapeutic strategies employed for this type of tumor in Western countries. It is well known that multimodal treatment is the therapeutic standard in locally advanced EGJ adenocarcinoma, but whether neoadjuvant/perioperative chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT) is the optimal approach is still debated. Neoadjuvant CRT improves local control in locally advanced Siewert type I and II tumors, so it should be considered the treatment of choice. In the subset of these patients with microscopic systemic disease at diagnosis, more intensive exclusive chemotherapy protocols could be of benefit. Therefore, there is an urgent need to identify these patients before planning the treatment. For Siewert type III tumors, perioperative chemotherapy is the standard. While there is general agreement on the optimal surgical approach for Siewert types I and III (a two-field Ivor Lewis operation and a total gastrectomy with distal esophagectomy, respectively), no standard surgical treatment has been defined for Siewert type II tumors. When data from Western series on proximal and circumferential resection margins and on nodal spread in Siewert type II tumors are taken into account, the optimal surgical approach appears to be Ivor Lewis esophagectomy. Whether the extent of esophageal invasion can correctly predict nodal involvement in middle–upper mediastinal stations as a means to restrict indications for transthoracic esophagectomy requires further investigation in the West.

Enhanced recovery after surgery protocol in patients undergoing esophagectomy for cancer: a single center experience

This article is about an emerging issue in esophageal surgery: enhanced recovery after surgery (ERAS) Few data are published in literature and its safety and feasibility is still debated. The focus of our paper is on the feasibility of an ERAS protocol for esophagectomy (including both the Ivor-Lewis and McKeown procedure) in a high volume center comparing to a standard perioperative protocol. We introduced a novelty item on this type of surgery: resume of oral feeding in the first postoperative day. We analyzed the dropout rate for each item and the postoperative morbidity. We studied 39 patients operated in the Upper GI division of Verona University Hospital between January 2013 and August 2014; 22 patients (ERAS group) were studied in a perspective way while 17 patients (standard group) were studied retrospectively. The enhanced recovery protocol included intraoperative fluid management, time of extubation after surgery, intensive care unit discharge, drains and nasogastric tube management, mobilization of the patient, oral food intake. We compared the results between the two groups in term of hospital stay, postoperative morbidity and mortality. We also calculated the percentage completion of the protocol, evaluating patient drop-out rates for each of the items. Patients showed an improvement in the ERAS group in terms of earlier extubation, earlier intensive care unit discharge (p < 0.01), earlier thoracic drain, urinary catheter (p < 0.01) and nasogastric tube removal (p = 0.02), earlier mobilization (p < 0.01), and resume of oral feeding (p < 0.01). Median length of hospital stays in the ERAS group was 9 days while in the standard group was 10 days (p = 0.23). Postoperative morbidity and mortality were comparable between the two groups. This study shows the feasibility and safety of an ERAS protocol for esophageal surgery in a high-volume center. These data strengthen the literature results on this argument calling for larger sample size studies.

Complications after gastrectomy for cancer: Italian perspective

Surgery for gastric cancer is associated with significant major morbidity and an estimated mortality rate of about 5%. A reliable comparison of post-operative outcomes is hampered by the lack of a clear, universally recognized, definition of the most frequent complications. This paper reports the final results of a project launched by the Italian Research Group for Gastric Cancer in September 2015, whose goal was to propose a comprehensive list of surgical-related, gastric cancer-specific complications, with their definitions. The project was carried out through a multicentric, mainly web-based, consensus of experts. The proposed list, following assessment and validation by a group of experts of the European Chapter of the International Gastric Cancer Association, will form the basis for implementing a “Complications Recording Sheet” that can be disseminated worldwide for proper and reliable post-operative assessment.

On the road to standardization of D2 lymph node dissection in a European population of patients with gastric cancer

The amount of lymph node dissection (LD) required during surgical treatment of gastric cancer surgery has been quite controversial. In the 1970s and 1980s, Japanese surgeons developed a doctrine of aggressive preventive gastric cancer surgery that was based on extended (D2) LD volumes. The West has relatively lower incidence rates of gastric cancer, and in Europe and the United States the most common LD volume was D0-1. This eventually caused a scientific conflict between the Eastern and Western schools of surgical thought: Japanese surgeons determinedly used D2 LD in surgical practice, whereas European surgeons insisted on repetitive clinical trials in the European patient population. Today, however, one can observe the results of this complex evolution of views. The D2 LD is regarded as an unambiguous standard of gastric cancer surgical treatment in specialized European centers. Such a consensus of the Eastern and Western surgical schools became possible due to the longstanding scientific and practical search for methods that would help improve the results of gastric cancer surgeries using evidence-based medicine. Today, we can claim that D2 LD could improve the prognosis in European populations of patients with gastric cancer, but only when the surgical quality of LD execution is adequate.

hERG1 behaves as biomarker of progression to adenocarcinoma in Barrett’s esophagus and can be exploited for a novel endoscopic surveillance

Barretts esophagus (BE) is the only well-known precursor lesion of esophageal adenocarcinoma (EA). The exact estimates of the annual progression rate from BE to EA vary from 0.07% to 3.6%. The identification of BE patients at higher risk to progress to EA is hence mandatory, although difficult to accomplish. In search of novel BE biomarkers we analyzed the efficacy of hERG1 potassium channels in predicting BE progression to EA. Once tested by immunohistochemistry (IHC) on bioptic samples, hERG1 was expressed in BE, and its expression levels increased during progression from BE to esophageal dysplasia (ED) and EA. hERG1 was also over-expressed in the metaplastic cells arising in BE lesions obtained in different BE mouse models, induced either surgically or chemically. Furthermore, transgenic mice which over express hERG1 in the whole gastrointestinal tract, developed BE lesions after an esophago-jejunal anastomosis more frequently, compared to controls. A case-control study was performed on 104 bioptic samples from newly diagnosed BE patients further followed up for at least 10 years. It emerged a statistically significant association between hERG1 expression status and risk of progression to EA. Finally, a novel fluorophore- conjugated recombinant single chain variable fragment antibody (scFv-hERG1-Alexa488) was tested on freshly collected live BE biopsies: it could recognize hERG1 positive samples, perfectly matching IHC data. Overall, hERG1 can be considered a novel BE biomarker to be exploited for a novel endoscopic surveillance protocol, either in biopsies or through endoscopy, to identify those BE patients with higher risk to progress to EA.

Proton magnetic resonance spectroscopy: ex vivo study to investigate its prognostic role in colorectal cancer.

BACKGROUND Proton Magnetic Resonance Spectroscopy (1H MRS) is used for clinical diagnosis in some tumours. The aim of this study is to explore ex vivo the potential of 1H MRS in identifying malignancy through metabolic markers in the perspective of its application in all cases of difficult diagnosis and after neoadjuvant treatment. METHODS Spectroscopy was performed ex vivo on 29 colorectal specimens. All patients were staged with imaging, underwent radical surgery and then followed-up. Spectral quantification analysis of components expressed in colorectal tumours and in healthy mucosa were evaluated. The MRS-tumour marker (MRS-tm) was calculated for each case. The U-test was used to compare MRS-tm in tumours and in healthy mucosa. In order to select a cut-off for MRS-tm in the tumour and healthy mucosa and to distinguish patients who were disease-free or with recurrence-progression, we performed the ROC curve analysis. RESULTS In the 24 subjects without neoadjuvant treatment, it was found that MRS-tm is able to discriminate healthy and neoplastic tissue and can discriminate patients with risk of recurrence/progression CONCLUSION Our data seem to show that 1H MRS may be successfully applied in vivo non-invasively to differentiate tumours from healthy mucosa and could also distinguish patients with different prognoses.

Il PDTA del paziente con adenocarcinoma gastrico: analisi organizzativa di cinque centri del Veneto

Il cancro gastrico e il quinto tumore per incidenza e la terza causa di morte a livello mondiale. Si tratta di una patologia maggiormente diffusa in Giappone e in Corea mentre in Europa l’incidenza varia notevolmente tra i Paesi. L’incidenza in Italia varia tra 10 e 20 casi su 100.000 abitanti. L’obiettivo principale del lavoro consiste nel disegnare un Percorso Diagnostico Terapeutico Assistenziale (PDTA) ottimizzato, che sia applicabile alla Rete Regionale Veneta, in grado di garantire al paziente una elevata qualita della prestazione assistenziale e al sistema sanitario un maggiore livello di efficienza sia organizzativa che economica. Il percorso ottimizzato e frutto dell’analisi organizzativa dei percorsi e delle criticita di cinque centri clinici veneti. Il PDTA ottimizzato definisce un modello strutturato di comunicazione nella fase della diagnosi e rafforza la gestione multidisciplinare del paziente con adenocarcinoma gastrico.