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Introduction: RCTs support neoadjuvant chemoradiotherapy (nCRT) followed by surgery in locally advanced esophago-gastric junction (LA-EGJ) adenocarcinoma. However, RCTs are performed in highly controlled settings with limited representativeness of real-life patients (RLS). The aim of the study was to compare the outcomes in RLS and clinical trial settings., Methods: The outcomes of RLS, which comprised 125 patients consequently treated for LA-EGJ adenocarcinoma between 2012 and 2017, were compared with the phase II trial (PIIS), performed on 65 patients from 2003 to 2011., Results: About half of RLS (51.2%) were treated with nCRT according to VR protocol, 20.8% with standard CRT according to CROSS/Al-Sarraf, 20% with chemotherapy (CT) alone. pCR was 36.8%, 28.6%, and 9.1% after VR protocol, standard CRT, and CT, respectively (p = 0.082), while 3-year overall survival (OS) was 58.6% (95% CI 43.2-71.1%), 32.8% (14.6-52.4%), and 44.8% (21.3-65.9%), respectively (p = 0.030). With respect to PIIS, RLS had a higher proportion of cN+ (94% vs. 54%; p < 0.001) and a lower proportion of pCR after CT/CRT (23% vs. 39%; p = 0.041). Three-year OS was slightly higher, although not significantly, in PIIS (58.9%, 45.1-70.2%) than RLS (47.9%, 37.4-57.7%) and nearly identical to 3-year OS in RLS treated with VR protocol., Conclusion: Real-life patients with EGJ adenocarcinoma have more advanced cancer at baseline, lower pathologic response to neoadjuvant treatment than patients enrolled in clinical trials, but similar survival., (© 2023 S. Karger AG, Basel.)

Purpose: The impact of acute histopathological changes (HC) of the rectum on development of late clinical proctitis (LCP) after external radiotherapy (RT) for prostate cancer is poorly explored and was the primary end point of this prospective study., Methods: In 70 patients, 15 HC of early rectal biopsies after RT were identified, whereby RT was conventional 2D RT in 41 cases and conformational 3D RT in 29. Associations of HC in anterior and posterior rectal walls (ARW, PRW) with LCP, acute endoscopic (AEP) and acute clinical proctitis (ACP) were statistically evaluated considering as explicative variables the patient general characteristics and the HC., Results: The mean patients' follow-up was 123.5 months (24-209). The median prostatic dose was 72 Gy (2 Gy/fraction). For the 41 and 29 patients the ARW and PRW doses were 64 and 49 Gy vs. 63 and 50 Gy, respectively. The incidence of LCP ≥ grade 2 at 10 years was 12.9%. The univariate (p = 0.02) and Kaplan-Meyer methods (p = 0.007) showed that the gland (or crypts) loss in the ARW was significantly associated with LCP. AEP and ACP occurred in 14.3 and 55.7% of cases. At multivariate level AEP significantly correlated with hemorrhoids (p = 0.014) and neutrophilia in ARW (p = 0.042)., Conclusions: Early after RT, substantial gland loss in ARW is predictive of LCP. To reduce this complication with conventional fractionation, we suggest keeping the mean dose to ARW ≤48-52 Gy.

Background: The incidence of cholelithiasis has been shown to be higher for patients after gastrectomy than for the general population, due to vagal branch damage and gastrointestinal reconstruction. The aim of this trial was to evaluate the need for routine concomitant prophylactic cholecystectomy (PC) during gastrectomy for cancer., Methods: A multicenter, randomized, controlled trial was conducted between November 2008 and March 2017. Of the total 130 included patients, 65 underwent PC and 65 underwent standard gastric surgery only for curable cancers. The primary endpoint was cholelithiasis-free survival after gastrectomy for gastric adenocarcinoma. Cholelithiasis was detected by ultrasound exam., Results: After a median follow-up of 62 months, eight patients (12.3%) in the control group developed biliary abnormalities (four cases of gallbladder calculi and four cases of biliary sludge), with only three (4.6%) being clinically relevant (two cholecystectomies needed, one acute pancreatitis). One patient in the PC group had asymptomatic biliary dilatation during sonography after surgery. The cholelithiasis-free survival did not show statistical significance between the two groups (P = 0.267). The number needed to treat with PC to avoid reoperation for cholelithiasis was 1:32.5., Conclusions: Concomitant PC during gastric surgery for malignancies, although reducing the absolute number of biliary abnormalities, has no significant impact on the natural course of patients.

Siewert III cancers were classified as esophageal cancers by the TNM 7th edition (TNM7), while being defined as gastric cancers by the new TNM 8th edition (TNM8). Aim of this study was to compare previous and present TNM classifications of Siewert III. From 2000 to 2015, 309 patients with Siewert III adenocarcinoma were treated at ten high-volume centers, belonging to the GIRCG (Italian Research Group for Gastric Cancer). We retrospectively analyzed overall survival according to TNM classifications: gastric TNM8 was compared with either gastric TNM7 or esophageal TNM7. Median number of lymph nodes harvested was 31 (interquartile range 22-44). Agreement between gastric TNM7 and TNM8 was very good (weighted kappa 92.3%, IC 95% 90.3-94.1%). Accordingly, stage migration was observed in 54 of 309 patients (17.5%), with 12 patients upstaged (3.9%) and 42 downstaged (13.6%). Cox models including either gastric TNM7 or TNM8 achieved similar goodness-of-fit and c-index. Differences were much larger, when shifting from esophageal TNM7 to gastric TNM8: the agreement was much lower (weighted kappa 69.1%, 65.2-73.2%), with 196 of 309 patients (63.4%) downstaging. The corresponding Cox model presented the lowest goodness-of-fit and discrimination ability. Gastric TNM7 and TNM8 were largely superimposable, so that stage migration was minor and prognostic significance was similar. At variance, stage migration was substantial when shifting from esophageal TNM7 to TNM8. Moreover, survival models with esophageal TNM7 presented the worst goodness-of-fit and the lowest discrimination ability. This further supports placing Siewert III among gastric cancers, as done in TNM8.

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.

Background: ypN0 following induction treatment for advanced esophageal cancer improves survival. Importance of how ypN0 is achieved is unknown. This study evaluates survival in "natural" N0 (cN0/ypN0) and "downstaged" N0 (cN+/ypN0) patients., Methods: Among patients treated with induction treatment and surgery, 83 CT scans were retrieved in digital format and re-evaluated by a radiologist, blinded to pathological nodal status: 28 natural N0, 37 downstaged N0, and 18 ypN+. Impact of N0 classification on survival and associations with survival were identified., Results: Survival varied with ypN: 3-year survival was 84 % for natural N0 patients, 59 % for downstaged N0, and 20 % for ypN+ (p < .001). Compared with natural N0 patients, risk of cancer mortality was 3.8 for downstaged N0 and 7.6 for ypN+ (p = .01). Survival was also stratified by ypT: compared with ypT0 natural N0, who had the best survival, intermediate survival was seen in ypT+ natural N0 [hazard ratio (HR), 1.3] and ypT0 downstaged N0 (HR, 1.8), and poor survival in ypT+ downstaged N0 (HR, 9.5) and ypN+ (HR, 12.0) (p = .026)., Conclusions: Natural N0 and downstaged N0 patients are different clinical entities: downstaging cN+ with induction treatment producing downstaged N0 improves survival only if there is concomitant primary cancer downstaging to ypT0. Intermediate survival is seen in downstaged N0 patients with complete tumor response. Natural N0 patients experience intermediate survival with incomplete response (ypT+). Complete response in natural N0 patients produces the best survival. Means of obtaining ypN0 status matters and requires a complete response for downstaged N0 patients to benefit from induction treatment.

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 Mandard's 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.

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Neoadjuvant chemoradiotherapy (CRT) is now considered the standard of care by many centers in the treatment of both squamous cell carcinoma (SCC) and adenocarcinoma of the esophagus. This study evaluates the effectiveness of a neoadjuvant CRT protocol, as regards pathological complete response (pCR) rate and long-term survival., Methods: From 2003 to 2011, at Upper G.I. Surgery Division of Verona University, 155 consecutive patients with locally advanced esophageal cancers (90 SCC, 65 adenocarcinoma) were treated with a single protocol of neoadjuvant CRT (docetaxel, cisplatin, and 5-fluorouracil with 50.4 Gy of concurrent radiotherapy). Response to CRT was evaluated through percentage of pathological complete response (pCR or ypT0N0), overall (OS) and disease-related survival (DRS), and pattern of relapse., Results: One hundred thirty-one patients (84.5 %) underwent surgery. Radical resection (R0) was achieved in 123 patients (79.3 %), and pCR in 65 (41.9 %). Postoperative mortality was 0.7 % (one case). Five-year OS and DRS were respectively 43 and 49 % in the entire cohort, 52 and 59 % in R0 cases, and 72 and 81 % in pCR cases. Survival did not significantly differ between SCC and adenocarcinoma, except for pCR cases. Forty-nine patients suffered from relapse, which was mainly systemic in adenocarcinoma. Only three out of 26 pCR patients with previous adenocarcinoma developed relapse, always systemic., Conclusions: This study suggests that patients treated with the present protocol achieve good survival and high pCR rate. Further research is necessary to evaluate whether surgery on demand is feasible in selected patients, such as pCR patients with adenocarcinoma.

Background: This study was designed to identify pathological predictors of para-aortic nodal invasion in advanced gastric cancer., Methods: Between 1990 and 2007, 294 patients with advanced gastric cancer underwent gastrectomy with D2 lymphadenectomy + para-aortic nodal dissection in Siena and Verona, Italy., Results: Forty-seven (16%) patients had para-aortic node metastases. Of these, 91%, 88%, and 74%, respectively, also had metastases at stations No. 3, No. 1, and No. 7. Para-aortic node metastases were never observed when stations No. 1 and No. 3 were both negative. Patients were divided into three groups, according to the risk of para-aortic node invasion: (1) high-risk group (n = 24, 8.2%), presenting a 42% risk and comprising T3/T4 cancers with mixed/nonintestinal histology, arising from the upper third; (2) low-risk group (n = 138, 46.9%), presenting a 0-10% risk and including middle-lower third tumors-either T2 irrespective of histology, or T3/T4 with intestinal histology; (3) intermediate-risk group, comprising all other patients (n = 132, 44.9%). Their risk ranged between 16% and 30%, but increased up to 21-37.5% after excluding 33 patients with negative No. 1 and No. 3 stations., Conclusions: The combination of tumor site, histology, and T stage with perigastric nodal status allowed identification of patients at higher risk of para-aortic nodal invasion who could benefit from para-aortic nodal dissection.

Objective: To evaluate the prognostic significance of different clinico-pathological and molecular factors, and to compare survival after standard and extended pancreaticoduodenectomy (PD) in ampulla of Vater adenocarcinoma (AVAC). There are discordant data on factors affecting prognosis, and hence therapeutic choices, in AVAC., Patients and Methods: Clinical-pathological factors were evaluated in 59 patients, subjected to PD for AVAC; in 42 subjects information on chromosome 17p and 18q allelic losses (LOH) and microsatellite instability (MSI) was also available. The association between survival and type of PD was investigated in the 25 patients operated between 1990 and 2001 (16 standard and nine extended)., Results: The overall 5- and 10-year tumor-related survival rates were 46% and 33%, respectively. Sixteen patients had T-stages 1-2, 14 T-stage 3, and 29 T-stage 4 cancers. Chromosome 17p and 18q LOH were detected in 23 (55%) and 15 cases (36%), respectively, and in 12 cases (29%) coexisted. Five cases were MSI-positive (12%). At univariate analysis, poor survival was associated with cancer ulceration (P = 0.051), poor differentiation (P = 0.008), T-stage 4 (P < 0.001), nodal metastases (P = 0.004), chromosome 17p (P < 0.001) and 18q LOH (P = 0.002), and absence of MSI (P = 0.009). At multivariate analysis, only T-stage (P = 0.002) and 17p LOH (P = 0.001) were independent predictors of survival. All patients with MSI-positive cancers were long-survivors (>12 yrs), whereas only 30% of MSI-negative cancer patients survived at 5 years. Extended pancreaticoduodenectomy was associated with a 3-year disease-related survival higher than standard resection (83% vs 31%; P = 0.018)., Conclusion: MSI and chromosome 17p status allow to better define prognosis within ampullary cancers at the same stage. Surgery alone resulted curative in MSI-positive cancer patients, whereas it was inadequate in patients showing allelic losses, who might benefit from adjuvant therapy. In this observational study, extended PD was associated with increased survival compared to standard procedures.

Background: Adenocarcinoma of the gastro-oesophageal junction is considered a distinct clinical entity, although the current pathological tumour node metastasis (pTNM) classification does not consider this tumour specifically. A prospective study was undertaken to determine the prognostic importance of lymph node involvement in adenocarcinoma of the gastro-oesophageal junction, analysing both a number- and site-based classification, in order to develop a clinically useful nodal staging system., Methods: Two classification systems were analysed in 116 patients who underwent resection for adenocarcinoma of the gastro-oesophageal junction from January 1988 to August 2001. The Cox regression model was used to evaluate the prognostic significance of the site and number of positive nodes., Results: The number- and site-based staging systems coincided only in 42 (56 per cent) of 75 patients; in particular, the old pN1 classification was upstaged in 13 of 41 patients and the old pN2 was downstaged in 13 of 34 patients. Lymph node involvement was the most important prognostic factor in both classifications (P < 0.001). The risk of death was significantly influenced by the site of nodal metastasis among patients with a similar number of involved nodes (relative risk with respect to pN0: 2.18 for pN1 with one to six nodes; 6.53 for pN2 with one to six nodes; 7.53 for pN1 with more than six nodes; 39.13 for pN2 with more than six nodes)., Conclusion: Adenocarcinoma of the gastro-oesophageal junction requires a specific lymph node classification which should take into account both the number and site of nodal metastases., (Copyright 2004 British Journal of Surgery Society Ltd.)

Background: The role of subtotal or total gastrectomy in the treatment of advanced gastric cancer of the antrum with serosal invasion was investigated., Methods: The investigation involved 117 patients with a cancer of the lower third of the stomach invading the serosa (pT3) who underwent R0 resection with at least D2 lymphadenectomy between 1988 and 1998 at three different Italian centers. The choice of surgical procedure (40 total gastrectomies and 77 subtotal gastrectomies) was based on the preference of the surgeon; none of the patients underwent splenectomy. The Cox regression model was used to evaluate the prognostic significance of the type of surgery (subtotal versus total gastrectomy), controlling for age, sex, histology, nodal involvement, and surgical center., Results: The morbidity and mortality rates did not vary significantly according to the type of surgery. Patients undergoing subtotal gastrectomy presented a better disease-related survival than patients undergoing total gastrectomy ( P = 0.011): the median survival times were, respectively, 38 months and 23 months, and the overall cumulative 5-year survival rates (95% confidence intervals [CI]) were, respectively, 36% (22%-50%) and 22% (11%-37%). On univariate analysis, the relative risk (RR) of disease-related death was 1.84 (1.14-2.97) after total gastrectomy, with respect to subtotal gastrectomy. This difference was blunted on multivariate analysis (RR, 1.66; 0.99-2.78): in the final model, only nodal metastasis was a significant prognostic factor, while type of surgery had a borderline significance ( P = 0.057)., Conclusions: Survival after subtotal gastrectomy is not lower than that after total gastrectomy in patients with tumor of the antrum invading the serosa. The role of subtotal or total gastrectomy in the treatment of advanced gastric cancer of the antrum with serosal invasion was investigated.

The present study aimed at investigating whether in gastric cancer patients stage migration occurs with extension of lymphadenectomy, when node metastases are staged according to the new pN classification (UICC 1997). The investigation involved 921 patients, who underwent R0 gastric resection for gastric cancer between 1988 and 1998 in three different Italian centres: Verona (n=236), Forlì (n=409), Siena (n=276). The relation among lymphadenectomy and pN category was assessed by Kendall's partial rank-order correlation coefficient, controlling for depth of tumour invasion. A direct evaluation of the Will Rogers phenomenon was accomplished in the Verona series, by comparing the number of positive nodes actually observed with the number of positive nodes which would have been retrieved by a less extended lymphadenectomy (D1). The number of positive nodes increased remarkably with the enlargement of lymphadenectomy, especially in pT2 patients (from 2.2+/-3.9 in D1 to 3.9+/-5.0 in D3) and in pT3/pT4 patients (from 5.1+/-5.9 in D1 to 11.3+/-12.6 in D3). Non-parametric statistics highlighted a weak (Kendall's partial T=0.128) but significant (P<0.001) correlation between pN category and extension of lymphadenectomy. In the direct analysis of the Verona series, 22 patients out of 230 (9.6%) migrated to a lower pN tier when ignoring positive nodes retrieved from the second and third level. This percentage increased to 39.1% (90 out of 230) when adopting the TNM 87 classification. In conclusion stage migration is of minor importance in gastric cancer patients, staged according to the new pN classification.