EBV persistence in gastric cancer cases conventionally classified as EBER-ISH negative.

BACKGROUND: The Epstein-Barr virus (EBV) causes various B-cell lymphomas and epithelial malignancies, including gastric cancer (GC) at frequencies ranging from 5 to 10% in adenocarcinomas (ADK) to 80% in GC with lymphoid stroma (GCLS). Using high-sensitivity methods, we recently detected EBV traces in a large cohort of EBV-negative B-cell lymphomas, suggesting a hit-and-run mechanism. METHODS: Here, we used routine and higher-sensitivity methods [droplet digital PCR (ddPCR) for EBV segments on microdissected tumour cells and RNAscope for EBNA1 mRNA] to assess EBV infection in a cohort of 40 GCs (28 ADK and 12 GCLS). RESULTS: ddPCR documented the presence of EBV nucleic acids in rare tumour cells of several cases conventionally classified as EBV-negative (ADK, 8/26; GCLS, 6/7). Similarly, RNAscope confirmed EBNA1 expression in rare tumour cells (ADK, 4/26; GCLS, 3/7). Finally, since EBV induces epigenetic changes that are heritable and retained after complete loss of the virus from the host cell, we studied the methylation pattern of EBV-specifically methylated genes (Timp2, Eya1) as a mark of previous EBV infection. Cases with EBV traces showed a considerable level of methylation in Timp2 and Eya1 genes that was similar to that observed in EBER-ISH positive cases and greater than cases not featuring any EBV traces. CONCLUSIONS: These findings suggest that: (a) EBV may contribute to gastric pathogenesis more widely than currently acknowledged and (b) indicate the methylation changes as a mechanistic framework for how EBV can act in a hit-and-run manner. Finally, we found that the viral state was of prognostic significance in univariate and multivariate analyses.

Open versus laparoscopic gastrectomy for advanced gastric cancer: a propensity score matching analysis of survival in a western population-on behalf of the Italian Research Group for Gastric Cancer.

BACKGROUND: Oncologic outcomes after laparoscopic gastrectomy for advanced gastric cancer in the West have been poorly investigated. The aim of the present study was to compare survival outcomes in patients undergoing curative-intent laparoscopic and open gastrectomy for advanced gastric cancer in several centres belonging to the Italian Research Group for Gastric Cancer. METHODS: Data of patients operated between 2015 and 2018 were retrospectively analysed. Propensity Score Matching was performed to balance baseline characteristics of patients undergoing laparoscopic and open gastrectomy. The primary endpoint was 3-year overall survival. Secondary endpoints were 3-year disease-free survival and short-term outcomes. Multivariable regression analyses for survival were conducted. RESULTS: Data were retrieved from 20 centres. Of the 717 patients included, 438 patients were correctly matched, 219 per group. The 3-year overall survival was 73.6% and 68.7% in the laparoscopic and open group, respectively (p = 0.40). When compared with open gastrectomy, laparoscopic gastrectomy showed comparable 3-year disease-free survival (62.8%, vs 58.9%, p = 0.40), higher rate of return to intended oncologic treatment (56.9% vs 40.2%, p = 0.001), similar 30-day morbidity/mortality. Prognostic factors for survival were ASA Score ≥ 3, age-adjusted Charlson Comorbidity Index ≥ 5, lymph node ratio ≥ 0.15, p/ypTNM Stage III and return to intended oncologic treatment. CONCLUSIONS: Laparoscopic gastrectomy for advanced gastric cancer offers similar rates of survival when compared to open gastrectomy, with higher rates of return to intended oncologic treatment. ASA score, age-adjusted Charlson Comorbidity Index, lymph node ratio, return to intended oncologic treatment and p/ypTNM Stage, but not surgical approach, are prognostic factors for survival.

Global Forum of Cancer Surgeons: Cancer Surgery During the COVID-19 Pandemic: Impact and Lessons Learned.

BACKGROUND: The purpose of this article is to summarize the opinions of the surgical oncology leaders from the Global Forum of Cancer Surgeons (GFCS) about the global impact of COVID-19 pandemic on cancer surgery. METHODS: A panel session (virtual) was held at the annual Society of Surgical Oncology 2021 International Conference on Surgical Cancer Care to address the impact of COVID-19 on cancer surgery globally. Following the virtual meeting, a questionnaire was sent to all the leaders to gather additional opinions. The input obtained from all the leaders was collated and analyzed to understand how cancer surgeons from across the world adapted in real-time to the impact of COVID-19 pandemic. RESULTS: The surgical oncology leaders noted that the COVID-19 pandemic led to severe disruptions in surgical cancer care across all domains of clinical care, education, and research. Several new changes/protocols associated with increased costs were implemented to deliver safe care. Leaders also noted that preexisting disparities in care were exacerbated, and the pandemic had a detrimental effect on well-being and financial status. CONCLUSIONS: The COVID-19 pandemic has led to severe disruptions in surgical cancer care globally. Leaders of the GFCS opined that new strategies need to be implemented to prepare for any future catastrophic events based on the lessons learned from the current events. The GFCS will embark on developing such a roadmap to ensure that surgical cancer care is preserved in the future regardless of any catastrophic global events.

Mid-transverse colon cancer and extended versus transverse colectomy: Results of the Italian society of surgical oncology colorectal cancer network (SICO CCN) multicenter collaborative study.

INTRODUCTION: Transverse colon cancer (TCC) is poorly studied, and TCC cases are often excluded from large prospective randomized trials because of their complexity and their potentially high complication rate. The best surgical approach for TCC has yet to be established. The aim of this large retrospective multicenter Italian series is to investigate the advantages and disadvantages of both hemicolectomy and transverse colectomy in order to identify the best surgical approach. MATERIALS AND METHODS: This was a retrospective cohort study of patients with mid-transverse colon cancer treated with a segmental colon resection or an extended hemicolectomy (right or left) between 2006 and 2016 in 28 high-volume (more than 70 procedures/year) Italian referral centers for colorectal surgery. RESULTS: The study included 1529 patients, 388 of whom underwent a segmental resection while 1141 underwent an extended resection. A higher number of complications has been reported in the segmental group than in the extended group (30.1% versus 23.6%; p 0.010). In 42 cases the main complication was the anastomotic leak (4.4% versus 2.2%; p 0.020). Recovery outcomes also showed statistical differences: time to first flatus (p 0.014), time to first mobilization (p 0.040), and overall hospital stay (p < 0.001) were significantly shorter in the extended group. Even if overall survival were similar between the groups (95.1% versus 97%; p 0.384), 3-year disease-free survival worsened after segmental resection (78.1% versus 86.2%; p 0.001). CONCLUSIONS: According to our results, an extended right colon resection for TCC seems to be surgically safer and more oncologically valid.

Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer.

BACKGROUND: Several associations between microsatellite instability (MSI) and other clinicopathological factors have been reported in gastric cancer, but the results have been ambiguous. This systematic review and meta-analysis investigated the relationship between MSI and overall survival and clinicopathological characteristics of patients with gastric cancer. METHODS: A systematic literature search of the PubMed, Cochrane and Ovid databases until 31 January 2016 was performed in accordance with the PRISMA statement. The articles were screened independently according to PICO (population, intervention, comparator, outcome) eligibility criteria. All eligible articles were evaluated independently by two reviewers for risk of bias according to the Quality In Prognosis Study tool. RESULTS: Overall, 48 studies with a total of 18 612 patients were included. MSI was found in 9·2 per cent of patients (1718 of 18 612), and was associated with female sex (odds ratio (OR) 1·57, 95 per cent c.i. 1·31 to 1·89; P < 0·001), older age (OR 1·58, 2·20 to 1·13; P < 0·001), intestinal Laurén histological type (OR 2·23, 1·94 to 2·57; P < 0·001), mid/lower gastric location (OR 0·38, 0·32 to 0·44; P < 0·001), lack of lymph node metastases (OR 0·70, 0·57 to 0·86, P < 0·001) and TNM stage I-II (OR 1·77, 1·47 to 2·13; P < 0·001). The pooled hazard ratio for overall survival of patients with MSI versus those with non-MSI gastric cancer from 21 studies was 0·69 (95 per cent c.i. 0·56 to 0·86; P < 0·001). CONCLUSION: MSI in gastric cancer was associated with good overall survival, reflected in several favourable clinicopathological tumour characteristics.

Validation of two prognostic models for recurrence and survival after radical gastrectomy for gastric cancer.

BACKGROUND: Prognostic models from Korea and Italy have been developed that predict overall survival and cancer recurrence respectively after radical gastrectomy for gastric cancer. The aim of this study was to validate the two models in independent patient cohorts, and to evaluate which factors may explain differences in prognosis between Korean and Italian patients with gastric cancer. METHODS: Patients who underwent radical gastrectomy for gastric cancer between January 2000 and December 2004 at Seoul National University Hospital and at eight centres in Italy were included. Discrimination of the models was tested with receiver operating characteristic (ROC) curves and calculation of area under the curve (AUC). Calibration was evaluated by plotting actual survival probability against predicted survival probability for the Korean nomogram, and actual against predicted risk of recurrence for the Italian score. RESULTS: Some 2867 and 940 patients from Korea and Italy respectively were included. The Korean nomogram achieved good discrimination in the Italian cohort (AUC 0·80, 95 per cent c.i. 0·77 to 0·83), and the Italian model performed well in the Korean cohort (AUC 0·87, 0·85 to 0·89). The Korean nomogram also achieved good calibration, but this was not seen for the Italian model. Multivariable analyses confirmed that Italian ethnicity was an independent risk factor for cancer recurrence (odds ratio (OR) 1·72, 1·31 to 2·25; P < 0·001), but not for overall survival (OR 1·20, 0·95 to 1·53; P = 0·130). CONCLUSION: Both prognostic models performed fairly well in independent patient cohorts. Differences in recurrence rates of gastric cancer may be partially explained by ethnicity.

Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with T2 to T4, N0 and N1 breast cancer.

BACKGROUND: Histological status of axillary lymph nodes is an important prognostic factor in patients receiving surgery for breast cancer (BC). Sentinel lymph node (SLN) biopsy (B) has rapidly replaced axillary lymph node dissection (ALND), and is now the standard of care for axillary staging in patients with clinically node-negative (N0) operable BC. The aim of this study is to compare pretreatment lymphoscintigraphy with a post primary systemic treatment (PST) scan in order to reduce the false-negative rates for SLNB. METHODS: In this single-institution study we considered 170 consecutive T2-4 N0-1 M0 BC patients treated with anthracycline-based PST. At the time of incisional biopsy, we performed sentinel lymphatic mapping. After PST, all patients repeated lymphoscintigraphy with the same methodology. During definitive surgery we performed further sentinel lymphatic mapping, SLNB and ALND. RESULTS: The SLN was removed in 158/170 patients giving an identification rate of 92.9% (95% confidence interval (CI) = 88.0-96.3%) and a false-negative rate of 14.0% (95% CI = 6.3-25.8%). SLNB revealed a sensitivity of 86.0% (95% CI = 74.2-93.7%), an accuracy of 94.9% (95% CI = 90.3-97.8%) and a negative predictive value of 92.7% (95% CI = 86.1-96.8%). CONCLUSION: Identification rate, sensitivity and accuracy are in accordance with other studies on SLNB after PST, even after clinically negative node conversion following PST. This study confirms that diagnostic biopsy and neoadjuvant chemotherapy maintain breast lymphatic drainage unaltered.

Extended lymphadenectomy in elderly and/or highly co-morbid gastric cancer patients: A retrospective multicenter study.

BACKGROUND: Gastrectomy with extended lymphadenectomy is considered the gold standard treatment for advanced gastric cancer, with no age- or comorbidity-related limitations. We evaluated the safety and efficacy of curative gastrectomy with extended nodal dissection, verifying survival in elderly and highly co-morbid patients. METHODS: In a retrospective multicenter study, we examined 1322 non-metastatic gastric-cancer patients that underwent curative gastrectomy with D2 versus D1 lymphadenectomy from January 2000 to December 2009. Postoperative complications, overall survival (OS), and disease-specific survival (DSS) according to age and the Charlson Comorbidity Score were analyzed in relation to the extent of lymphadenectomy. RESULTS: Postoperative morbidity was 30.4%. Complications were more frequent in highly co-morbid elderly patients, and, although general morbidity rates after D2 and D1 lymphadenectomy were similar (29.9% and 33.2%, respectively), they increased following D2 in highly co-morbid elderly patients (39.6%). D2-lymphadenectomy significantly improved 5-year OS and DSS (48.0% vs. 37.6% in D1, p < 0.001 and 72.6% vs. 58.1% in D1, p < 0.001, respectively) in all patients. In elderly patients, this benefit was present only in 5-year DSS. D2 nodal dissection induced better 5-year OS and DSS rates in elderly patients with positive nodes (29.7% vs. 21.2% in D1, p = 0.008 and 47.5% vs. 30.6% in D1, p = 0.001, respectively), although it was present only in DSS when highly co-morbid elderly patients were considered. CONCLUSION: Extended lymphadenectomy confirmed better survival rates in gastric cancer patients. Due to high postoperative complication rate and no significant improvement of the OS, D1 lymphadenectomy should be considered in elderly and/or highly co-morbid gastric cancer patients.

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients - A GIRCG study.

BACKGROUND: Gastric gastrointestinal stromal tumors (GISTs) represent a subgroup of GISTs with a better prognosis than those located in other areas. In this retrospective study we performed a molecular characterization of a large series of patients with gastric GISTs in relation to clinical-pathological characteristics and prognosis. METHODS: DNA was extracted from paraffin-embedded sections from 221 gastric GIST patients submitted to surgery. Exons 9, 11, 13 and 17 of KIT, exons 12 and 18 of PDGFRA and exons 11 and 15 of BRAF were analyzed by direct sequencing. Cox regression analysis adjusted for clinical-pathological factors was performed to evaluate KIT and PDGFRA mutations in relation to the composite endpoint of relapse or death. RESULTS: KIT and PDGFRA mutations were observed in 119 (53.8%) and 56 (25.3%) patients, respectively, whereas 46 (20.8%) patients had wild type (wt) disease. Univariable analyses showed that a high Miettinen risk category and the presence of ulceration and KIT deletions were associated with increased risk of relapse or death (p < 0.001; p = 0.0389 and p = 0.002, respectively). After adjusting for Miettinen risk score, KIT deletions remained an independent prognostic factor (HRadj = 2.65, 95% CI [1.15-6.13], p = 0.023). Moreover, KIT deletions in exon 11 codons 557, 558 or 559 were associated with a higher risk of relapse or death than wt tumors (HRadj = 3.29 95% CI [1.64-6.64], p = 0.001). CONCLUSIONS: KIT deletions in exon 11, especially those involving codons 557, 558 or 559, were correlated with a more aggressive gastric GIST phenotype and increased risk of relapse or death.

Factors influencing survival after hepatectomy for metastases from gastric cancer.

PURPOSE: To investigate clinical factors influencing the prognosis of patients submitted to hepatectomy for metastases from gastric cancer and their clinical role. METHODS: Retrospective multi-center chart review. We evaluated how survival from surgery was influenced by patient-related, gastric cancer-related, metastasis-related and treatment-related candidate prognostic factors. RESULTS: One hundred and five patients submitted to hepatectomy for metastases from gastric cancer, in the synchronous and metachronous setting of the disease. In 89 cases a R0 resection was achieved, while in 16 a R+ hepatic resection was performed. Adjuvant chemotherapy was administered to 29 patients. Surgical mortality was 1% and morbidity 13.3%. Median disease-free survival was 10 months, median overall survival was 14.6 months. Overall 1, 3, and 5-year survival rates were 58.2%, 20.3%, and 13.1%, respectively. Survival was influenced independently by the factor T of the gastric primary (p < 0.001), by the curativity of surgical procedure (p = 0.001), by the timing of hepatic involvement (p < 0.001) and by adjuvant chemotherapy (p < 0.001). T4 gastric cancer, R+ resection, synchronous metastases, and abstention from adjuvant chemotherapy were associated with a worse prognosis; T4 gastric cancer and R+ resections displayed a cumulative effect (p < 0.001). CONCLUSIONS: Our data show that R0 resection must be pursued whenever possible. Furthermore, in the synchronous setting, the coexistence of T4 gastric primaries and R+ resections suggests prudence and probably abstention from hepatectomy. Finally, a multimodal treatment associating surgery and chemotherapy offers the best survival results.

Nipple-areola complex reconstruction techniques: A literature review.

Many techniques for nipple-areola complex (NAC) reconstruction are described. Clarity is required on the currently available options. Since a complete list of all the techniques described until now is not available, a possibly comprehensive literature overview was carried out from 75 papers (years 1946-2015). The local flap was the most frequently described technique for the nipple reconstruction with no significant difference in complications' rate among the various types of techniques. Complications in nipple reconstruction were 46.9% after graft, 7.9% after local flap, and 5.3% in case of flaps with autologous graft/alloplastic/allograft augmentation, while complications in areola reconstruction were 10.1% after graft, and 1.6% after areola tattoo. Flaps appear to be more reliable than grafts in nipple reconstruction, while tattoo is thought to be safer than graft in areola reconstruction. The loss of projection, although considerable (45%-75%), had not significant impact on patients' satisfaction. Due to contraction, overcorrection of 25-50% of the desired result is advisory when adopting local flaps, in order to prevent loss of projection. The use of flaps with autologous graft/alloplastic/allograft augmentation (cartilage, fat, calcium hydroxylapatite, acellular dermal matrix, polymethylmethacrylate, biologic collagen) showed a minor loss of nipple projection but may expose to a relative increased number of postoperative flap necrosis.

Description and analysis of clinical pathways for oesophago-gastric adenocarcinoma, in 10 European countries (the EURECCA upper gastro intestinal group - European Registration of Cancer Care).

AIMS: Outcomes for patients with oesophago-gastric cancer are variable across Europe. The reasons for this variability are not clear. The aim of this study was to describe and analyse clinical pathways to understand differences in service provision for oesophageal and gastric cancer in the countries participating in the EURECCA Upper GI group. METHODS: A questionnaire was devised to assess clinical presentation, diagnosis, staging, treatment, pathology, follow-up and service frameworks across Europe for patients with oesophageal and gastric cancer. The questionnaire was issued to experts from 14 countries. The responses were analysed quantitatively and qualitatively and compared. RESULTS: The response rate was (10/14) 71.4%. The approach to diagnosis was similar. Most countries established a diagnosis within 3 weeks of presentation. However, there were different approaches to staging with variable use of endoscopic ultrasound reflecting availability. There has been centralisation of treatments in most countries for oesophageal surgery. The most consistent area was the approach to pathology. There were variations in access to specialist nurse and dietitian support. Although most countries have multidisciplinary teams, their composition and frequency of meetings varied. The two main areas of significant difference were research and audit and overall service provision. Observations on service framework indicated that limited resources restricted many of the services. CONCLUSION: The principle approaches to diagnosis, treatment and pathology were similar. Factors affecting the quality of patient experience were variable. This may reflect availability of resources. Standard pathways of care may enhance both the quality of treatment and patient experience.

Surgical management of advanced gastric cancer: An evolving issue.

Worldwide, gastric cancer represents the fifth most common cancer and the third leading cause of cancer deaths. Although the overall 5-year survival for resectable disease was more than 70% in Japan due to the implementation of screening programs resulting in detection of disease at earlier stages, in Western countries more than two thirds of gastric cancers are usually diagnosed in advanced stages reporting a 5-year survival rate of only 25.7%. Anyway surgical resection with extended lymph node dissection remains the only curative therapy for non-metastatic advanced gastric cancer, while neoadjuvant and adjuvant chemotherapies can improve the outcomes aimed at the reduction of recurrence and extension of survival. High-quality research and advances in technologies have contributed to well define the oncological outcomes and have stimulated many clinical studies testing multimodality managements in the advanced disease setting. This review article aims to outline and discuss open issues in current surgical management of advanced gastric cancer.

Predicting recurrence after curative resection for gastric cancer: External validation of the Italian Research Group for Gastric Cancer (GIRCG) prognostic scoring system.

BACKGROUND: Most nomograms for Gastric Cancer (GC) were developed to predict overall survival (OS) after curative resection. The Italian Research Group for Gastric Cancer (GIRCG) prognostic scoring system (PSS) was designed to predict the recurrence risk after curative treatment based on pathologic tumor stage and treatment performed (D1-D2/D3 lymphadenectomy). This study was carried out to externally validate the GIRCG's PSS. PATIENTS AND METHODS: Adopting the same criteria used by GIRCG to build the PSS, 185 patients with GC operated with curative intention were selected. The median follow-up period was 77.8 months (1.93-150.8) for all patients and 102.5 months (60.9-150.8) for patients free of disease. The NRI (net reclassification improvement) was calculated to estimate the overall improvement in the reclassification of patients using the PSS in place of the TNM stage system. RESULTS: GC recurrence occurred in 70 (37.8%) patients. The mean time to recurrence was 22.2 (range 1.9-98.1) months. For patients with recurrence, the gain in the proportion of reclassification was 0.257 (p < 0.001), indicating an improvement of 26%. For patients without recurrence, the gain in the proportion of reclassification was -0.122 (p < 0.001), indicating a worsening of 12%. The NRI calculated was 0.135 (p = 0.0527). CONCLUSION: The GIRCG's PSS, which predicts the likelihood of recurrence after radical surgical treatment for GC, is more accurate than TNM system to predict recurrence mainly for high-risk patients. Yet, the PSS does not have the same effectiveness for low-risk patients, overestimating the chance of recurrence occurs even for disease-free patients.

Duodenal gastrointestinal stromal tumor: From clinicopathological features to surgical outcomes.

Duodenal gastrointestinal tumors represent an extremely rare subset of stromal tumors arising from interstitial cells of Cajal. In the last 30 years the comprehension of the pathophysiology and natural history of this previously misunderstood clinical entity, in association with developments in endoscopy, imaging technology, and immunohistochemistry has resulted in novel diagnostic and treatment approaches. This is a comprehensive review of the current data of the literature on the various aspects of the diagnosis and treatment of these tumors. The duodenum is the less commonly involved site for these tumors in the digestive tract. Endoscopy and computed tomography can usually establish the diagnosis, confirmed by immunohistochemical staining and occasionally molecular genetic analysis. Endoscopic ultrasound with fine needle aspiration has been recently found to be the gold diagnostic standard with high sensitivity and specificity rates, diagnosing GIST in up to 80% of patients. Due to the complex anatomy of the pancreatico-duodenal region optimal therapeutic strategy of duodenal GISTs are challenging. Nevertheless surgical resection with microscopically clear resection margins seems to be the only potentially curative treatment for non-metastatic primary GISTs of the duodenum. Imatinib mesylate plays a key role in the management of GISTs both as neoadjuvant therapy and in patients with recurrent and metastatic disease. Meanwhile, the advances in the comprehension of the pathophysiology and natural history of this previously misunderstood clinical entity as well as the treatment of these tumors may render feasible, in the near future, the advent of newer and more effective treatment options.

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.