Textbook Neoadjuvant Outcome-Novel Composite Measure of Oncological Outcomes among Gastric Cancer Patients Undergoing Multimodal Treatment.

The incidence of gastric cancer (GC) is expected to increase to 1.77 million cases by 2040. To improve treatment outcomes, GC patients are increasingly treated with neoadjuvant chemotherapy (NAC) prior to curative-intent resection. Although NAC enhances locoregional control and comprehensive patient care, survival rates remain poor, and further investigations should establish outcomes assessment of current clinical pathways. Individually assessed parameters have served as benchmarks for treatment quality in the past decades. The Outcome4Medicine Consensus Conference underscores the inadequacy of isolated metrics, leading to increased recognition and adoption of composite measures. One of the most simple and comprehensive is the "All or None" method, which refers to an approach where a specific set of criteria must be fulfilled for an individual to achieve the overall measure. This narrative review aims to present the rationale for the implementation of a novel composite measure, Textbook Neoadjuvant Outcome (TNO). TNO integrates five objective and well-established components: Treatment Toxicity, Laboratory Tests, Imaging, Time to Surgery, and Nutrition. It represents a desired, multidisciplinary care and hospitalization of GC patients undergoing NAC to identify the treatment- and patient-related data required to establish high-quality oncological care further. A key strength of this narrative review is the clinical feasibility and research background supporting the implementation of the first and novel composite measure representing the "ideal" and holistic care among patients with locally advanced esophago-gastric junction (EGJ) and GC in the preoperative period after NAC. Further analysis will correlate clinical outcomes with the prognostic factors evaluated within the TNO framework.

International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape : Bertinoro Workshop, November 2022.

BACKGROUND: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy. Innovative treatments, like targeted therapy or immunotherapy, have recently proved to ameliorate prognosis, but a general agreement on managing oligometastatic disease has yet to be achieved. An international multi-disciplinary workshop was held in Bertinoro, Italy, in November 2022 to verify whether achieving a consensus on at least some topics was possible. METHODS: A two-round Delphi process was carried out, where participants were asked to answer 32 multiple-choice questions about CT, laparoscopic staging and biomarkers, systemic treatment for different localization, role and indication of palliative care. Consensus was established with at least a 67% agreement. RESULTS: The assembly agreed to define oligometastases as a "dynamic" disease which either regresses or remains stable in response to systemic treatment. In addition, the definition of oligometastases was restricted to the following sites: para-aortic nodal stations, liver, lung, and peritoneum, excluding bones. In detail, the following conditions should be considered as oligometastases: involvement of para-aortic stations, in particular 16a2 or 16b1; up to three technically resectable liver metastases; three unilateral or two bilateral lung metastases; peritoneal carcinomatosis with PCI ≤ 6. No consensus was achieved on how to classify positive cytology, which was considered as oligometastatic by 55% of participants only if converted to negative after chemotherapy. CONCLUSION: As assessed at the time of diagnosis, surgical treatment of oligometastases should aim at R0 curativity on the entire disease volume, including both the primary tumor and its metastases. Conversion surgery was defined as surgery on the residual volume of disease, which was initially not resectable for technical and/or oncological reasons but nevertheless responded to first-line treatment.

A pragmatic approach improves the clinical management of stage IV gastric cancer: Comparison between the Meta-Gastro results and the GIRCG's retrospective series.

INTRODUCTION: The Italian Research Group for Gastric Cancer developed a prospective database about stage IV gastric cancer, to evaluate how a pragmatic attitude impacts the management of these patients. MATERIALS AND METHODS: We prospectively collected data about metastatic gastric cancer patients thanks to cooperation between radiologists, oncologists and surgeons and we analyzed survival and prognostic factors, comparing the results to those obtained in our retrospective study. RESULTS: Three-hundred and eighty-three patients were enrolled from 2018 to September 2022. We observed a higher percentage of laparoscopic exploration with peritoneal lavage in the prospective cohort. In the registry only 3.6 % of patients was submitted to surgery without associated chemotherapy, while in the retrospective population 44.3 % of patients were operated on without any chemotherapy. At univariate and multivariate analyses, the different metastatic sites did not show any survival differences among each other (OS 20.0 vs 16.10 vs 16.7 months for lymphnodal, peritoneal and hepatic metastases, respectively), while the number of metastatic sites and the type of treatment showed a statistical significance (OS 16,7 vs 13,0 vs 4,5 months for 1, 2 and 3 different metastatic sites respectively, p < 0.001; 24,2 vs 12,0 vs 2,5 months for surgery with/without chemotherapy, chemotherapy alone and best supportive treatment respectively, p < 0.001). CONCLUSIONS: Our data highlight that the different metastatic sites did not show different survivals, but survival is worse in case of multiple localization. In patients where a curative resection can be achieved, acceptable survival rates are possible. A better diagnostic workup and a more accurate staging impact favorably upon survival.

Association between Pre-Treatment Biological Indicators and Compliance to Neoadjuvant/Perioperative Chemotherapy in Operable Gastric Cancer.

BACKGROUND AND AIMS: Perioperative treatment is currently the gold standard approach in Europe for locally advanced gastric cancer (GC). Unfortunately, the phenomenon of patients dropping out of treatment has been frequently observed. The primary aims of this study were to verify if routine blood parameters, inflammatory response markers, sarcopenia, and the depletion of adipose tissues were associated with compliance to neoadjuvant/perioperative chemotherapy. METHODS AND STUDY DESIGN: Blood samples were considered before the first and second cycles of chemotherapy. Sarcopenia and adipose indices were calculated with a CT scan before starting chemotherapy and before surgery. Odds ratios (OR) from univariable and multivariable models were calculated with a 95% confidence interval (95% CI). RESULTS: A total of 84 patients with locally advanced GC were identified between September 2010 and January 2021. Forty-four patients (52.4%) did not complete the treatment according to the number of cycles planned/performed. Eight patients (9.5%) decided to suspend chemotherapy, seven patients (8.3%) discontinued because of clinical decisions, fourteen patients (16.7%) discontinued because of toxicity and fifteen patients (17.9%) discontinued for miscellaneous causes. Seventy-nine (94%) out of eighty-four patients underwent gastrectomy, with four patients having surgical complications, which led to a suspension of treatment. Sarcopenia was present in 38 patients (50.7%) before chemotherapy began, while it was present in 47 patients (60%) at the CT scan before the gastrectomy. At the univariable analysis, patients with basal platelet to lymphocyte ratio (PLR) ≥ 152 (p = 0.017) and a second value of PLR ≥ 131 (p = 0.007) were more frequently associated with an interruption of chemotherapy. Patients with increased PLR (p = 0.034) compared to the cut-off were associated with an interruption of chemotherapy, while patients with increased monocytes between the first and second cycles were associated with a lower risk of treatment interruption (p = 0.006); patients who underwent 5-fluorouracil plus cisplatin or oxaliplatin had a higher risk of interruption (p = 0.016) compared to patients who underwent a 5-fluorouracil plus leucovorin, oxaliplatin and docetaxel (FLOT) regimen. The multivariable analysis showed a higher risk of interruption for patients who had higher values of PLR compared to the identified cut-off both at pretreatment and second-cycle evaluation (OR: 5.03; 95% CI: 1.34-18.89; p = 0.017) as well as for patients who had a lower PLR than the identified cut-off at pretreatment evaluation and had a higher PLR value than the cut-off at the second cycle (OR: 4.64; 95% CI: 1.02-21.02; p = 0.047). Becker regression was neither affected by a decrease of sarcopenia ≥ 5% (p = 0.867) nor by incomplete compliance with chemotherapy (p = 0.281). CONCLUSIONS: Changes in PLR values which tend to increase more than the cut-off seem to be an immediate indicator of incomplete compliance with neoadjuvant/perioperative treatment. Fat loss and sarcopenia do not appear to be related to compliance. More information is needed to reduce the causes of interruption.

Textbook Oncological Outcome in European GASTRODATA.

OBJECTIVE: To assess the rate of textbook outcome (TO) and textbook oncological outcome (TOO) in the European population based on the GASTRODATA registry. BACKGROUND: TO is a composite parameter assessing surgical quality and strongly correlates with improved overall survival. Following the standard of treatment for locally advanced gastric cancer, TOO was proposed as a quality and optimal multimodal treatment parameter. METHODS: TO was achieved when all the following criteria were met: no intraoperative complications, radical resection according to the surgeon, pR0 resection, retrieval of at least 15 lymph nodes, no severe postoperative complications, no reintervention, no admission to the intensive care unit, no prolonged length of stay, no postoperative mortality and no hospital readmission. TOO was defined as TO with the addition of perioperative chemotherapy compliance. RESULTS: Of the 2558 patients, 1700 were included in the analysis. TO was achieved in 1164 (68.5%) patients. The use of neoadjuvant chemotherapy [odds ratio (OR) = 1.33, 95% CI: 1.04-1.70] and D2 or D2+ lymphadenectomy (OR = 1.55, 95% CI: 1.15-2.10) had a positive impact on TO achievement. Older age (OR = 0.73, 95% CI: 0.54-0.94), pT3/4 (OR = 0.79, 95% CI: 0.63-0.99), ASA 3/4 (OR = 0.68, 95% CI: 0.54-0.86) and total gastrectomy (OR = 0.56, 95% CI: 0.45-0.70), had a negative impact on TO achievement. TOO was achieved in 388 (22.8%) patients. Older age (OR = 0.37, 95% CI: 0.27-0.53), pT3 or pT4 (OR = 0.52, 95% CI: 0.39-0.69), and ASA 3 or 4 (OR = 0.58, 95% CI: 0.43-0.79) had a negative impact on TOO achievement. CONCLUSIONS: Despite successively improved surgical outcomes, stage-appropriate chemotherapy in adherence to the current guidelines for multimodal treatment of gastric cancer remains poor. Further implementation of oncologic quality metrics should include greater emphasis on perioperative chemotherapy and adequate lymphadenectomy.

Frail patients dropping out of neoadjuvant treatment: what should we do?

Perioperative oncological treatment is currently the gold standard approach in Europe for Advanced Gastric Cancer patients. Unfortunately, patients dropping out due to worsening conditions has been frequently observed, but these data are seldomly considered and reported. To analyze frequency and propose solutions to support these patients, we reconsidered our results from the GASTRODOC randomized trial performed by [blinded for reviewers] and GIRCG on 91 patients. Thirty-four patients (37.4%) suspended chemotherapy and five (5.4%) did not reach surgery. Ten patients (11%) presented unacceptable toxicity related to gastrointestinal symptoms, six ended the treatment for investigator decision and six for progression, five patients withdrew their consent, five patients were excluded because of surgical complications and long hospitalization, and two patients died. Even though not significant, survival rates for patients who interrupted treatment in the whole trial were lower (5-year OS completed 64.6 vs. interrupted 41.8 p 0.07). Promptness in giving patient support for gastrointestinal symptoms, careful evaluation of anemia and patient nutritional status, and psychological programs from the beginning of the oncologic treatment may improve the final results.

Clinical outcomes of patients with complicated post-operative course after gastrectomy for cancer: a GIRCG study using the GASTRODATA registry.

Gastrectomy for gastric cancer is still performed in Western countries with high morbidity and mortality. Post-operative complications are frequent, and effective diagnosis and treatment of complications is crucial to lower the mortality rates. In 2015, a project was launched by the EGCA with the aim of building an agreement on list and definitions of post-operative complications specific for gastrectomy. In 2018, the platform www.gastrodata.org was launched for collecting cases by utilizing this new complication list. In the present paper, the Italian Research Group for Gastric Cancer endorsed a collection of complicated cases in the period 2015-2019, with the aim of investigating the clinical pictures, diagnostic modalities, and treatment approaches, as well as outcome measures of patients experiencing almost one post-operative complication. Fifteen centers across Italy provided 386 cases with a total of 538 complications (mean 1.4 complication/patient). The most frequent complications were non-surgical infections (gastrointestinal, pulmonary, and urinary) and anastomotic leaks, accounting for 29.2% and 17.3% of complicated patients, with a median Clavien-Dindo score of II and IIIB, respectively. Overall mortality of this series was 12.4%, while mortality of patients with anastomotic leak was 25.4%. The clinical presentation with systemic septic signs, the timing of diagnosis, and the hospital volume were the most relevant factors influencing outcome.

Consequences of the COVID-19 pandemic on the diagnosis and treatment of gastric cancer in referral centers in Italy.

BACKGROUND: The coronavirus pandemic had a major impact in Italy. The Italian health system's re-organization to face the emergency may have led to significant consequences especially in the diagnosis and treatment of malignancies. This study aimed to assess the impact of the pandemic in the diagnosis and treatment of gastric cancer in nine Gruppo Italiano RIcerca Cancro Gastrico (GIRCG) centers. METHODS: All patients assessed for gastric adenocarcinoma at nine GIRCG centers between January 2019 and November 2020 were included. Patients were grouped according to the date of "patient 1's" diagnosis in Italy: preCOVID versus COVID. Clinico-pathological and outcome differences between the two groups were analyzed. RESULTS: A total of 632 patients were included in the analysis (205 in the COVID group). The cT4 weighted ratios were higher in 2020 from April to September, with the greatest differences in May, August and September. The cM+ weighted ratio was significantly higher in July 2020. The mean number of gastrectomies had the greatest reduction in March and May 2020 compared with 2019. The median times from diagnosis to chemotherapy, to complete diagnostic work-up or to operation were longer in 2019. The median time from the end of chemotherapy to surgery was 17 days longer in the preCOVID group. CONCLUSIONS: A greater number of advanced or metastatic cases were diagnosed after the spread of SARS-CoV-2 infection, especially after the "full lockdown" periods. During the pandemic, once gastric cancer patients were referred to one of the centers, a shorter time to complete the diagnostic work-up or to address them to the best treatment option was required.

Oligometastatic Gastric Cancer: Clinical Data from the Meta-Gastro Prospective Register of the Italian Research Group on Gastric Cancer.

BACKGROUND: Interest in the field of metastatic gastric cancer has grown in recent years, and the identification of oligometastatic patients plays a critical role as it consents to their inclusion in multimodal treatment strategies, which include systemic therapy but also surgery with curative intent. To collect sound clinical data on this subject, The Italian Research Group on Gastric Cancer developed a prospective multicentric observational register of metastatic gastric cancer patients called META-GASTRO. METHODS: Data on 383 patients in Meta-Gastro were mined to help our understanding of oligometastatic, according to its double definition: quantitative/anatomical and dynamic. RESULTS: the quantitative/anatomical definition applies to single-site metastases independently from the metastatic site (p < 0.001) to peritoneal metastases with PCI ≤ 12 (p = 0.009), to 1 or 2 hepatic metastases (p = 0.024) and nodal metastases in station 16 (p = 0.002). The dynamic definition applies to a percentage of cases variable according to the metastatic site: 8%, 13.5 and 23.8% for hepatic, lymphatic and peritoneal sites, respectively. In all cases, the OS of patients benefitting from conversion therapy was similar to those of cases deemed operable at diagnosis and operated after neoadjuvant chemotherapy. CONCLUSIONS: META-GASTRO supports the two-fold definition of oligometastatic gastric cancer: the quantitative/anatomical one, which accounts for 30% of our population, and the dynamic one, observed in 16% of our cases.

Development and Multicenter Validation of a Novel Immune-Inflammation-Based Nomogram to Predict Survival in Western Resectable Gastric and Gastroesophageal Junction Adenocarcinoma (GEA): The NOMOGAST.

Background. More than 50% of operable GEA relapse after curative-intent resection. We aimed at externally validating a nomogram to enable a more accurate estimate of individualized risk in resected GEA. Methods. Medical records of a training cohort (TC) and a validation cohort (VC) of patients undergoing radical surgery for c/uT2-T4 and/or node-positive GEA were retrieved, and potentially interesting variables were collected. Cox proportional hazards in univariate and multivariate regressions were used to assess the effects of the prognostic factors on OS. A graphical nomogram was constructed using R software's package Regression Modeling Strategies (ver. 5.0-1). The performance of the prognostic model was evaluated and validated. Results. The TC and VC consisted of 185 and 151 patients. ECOG:PS > 0 (p < 0.001), angioinvasion (p < 0.001), log (Neutrophil/Lymphocyte ratio) (p < 0.001), and nodal status (p = 0.016) were independent prognostic values in the TC. They were used for the construction of a nomogram estimating 3- and 5-year OS. The discriminatory ability of the model was evaluated with the c-Harrell index. A 3-tier scoring system was developed through a linear predictor grouped by 25 and 75 percentiles, strengthening the model's good discrimination (p < 0.001). A calibration plot demonstrated a concordance between the predicted and actual survival in the TC and VC. A decision curve analysis was plotted that depicted the nomogram's clinical utility. Conclusions. We externally validated a prognostic nomogram to predict OS in a joint independent cohort of resectable GEA; the NOMOGAST could represent a valuable tool in assisting decision-making. This tool incorporates readily available and inexpensive patient and disease characteristics as well as immune-inflammatory determinants. It is accurate, generalizable, and clinically effectivex.

Conversion Surgery in Gastric Cancer Carcinomatosis.

Background: After the REGATTA trial, patients with stage IV gastric cancer could only benefit from chemotherapy (CHT). However, some of these patients may respond extraordinarily to palliative chemotherapy, converting their disease to a radically operable stage. We present a single centre experience in treating peritoneal carcinomatosis from gastric cancer. Methods: All patients with stage IV gastric cancer with peritoneal metastases as a single metastatic site operated at a single centre between 2005 and 2020 were included. Cases were grouped according to the treatment received. Results: A total of 118 patients were considered, 46 were submitted to palliative gastrectomy (11 were considered M1 because of an unsuspected positive peritoneal cytology), and 20 were submitted to Hyperthermic Intraperitoneal Chemotherapy (HIPEC) because of a <6 Peritoneal Cancer Index (PCI). The median overall survival (OS) after surgery plus HIPEC was 46.7 (95% CI 15.8-64.0). Surgery (without HIPEC) after CHT presented a median OS 14.4 (8.2-26.8) and after upfront surgery 14.7 (10.9-21.1). Patients treated with upfront surgery and considered M1 only because of a positive cytology, had a median OS of 29.2 (25.2-29.2). The OS of patients treated with surgery plus HIPEC were 60.4 months (9.2-60.4) in completely regressed cancer after chemotherapy and 31.2 (15.8-64.0) in those partially regressed (p = 0.742). Conclusions: Conversion surgery for peritoneal carcinomatosis from gastric cancer was associated with long survival and it should always be taken into consideration in this group of patients.

Which gastric cancer patients could benefit from staging laparoscopy? A GIRCG multicenter cohort study.

BACKGROUND: This study aimed to investigate which gastric cancer patients could benefit the most from staging laparoscopy. METHODS: A retrospective cohort study was carried out, including 316 (216 cM- and 100 cM+) gastric cancer patients who had undergone staging laparoscopy between 2010 and 2020 in seven GIRCG centers. A model including easily-accessible clinical, biochemical and pathological markers was constructed to predict the risk of carcinomatosis. ROC curve and decision curve analyses were used to verify its accuracy and net benefit. RESULTS: In the cM-population staging laparoscopy could detect 67 cases who had peritoneal carcinomatosis or positive cytology, for a yield of 30.5%. In cM-patients, intestinal type tumors (0.25, 0.12-0.51; p = 0.002), cT4 tumors (2.18, 1.11-4.28; p = 0.023) and cancers of the lower third (0.31, 0.14-0.70; p = 0.004) were associated with the presence of peritoneal carcinomatosis and/or positive cytology. The ROC curve analysis of the model including the three variables showed an AUC of 0.75 (0.68-0.81, p < 0.001). The decision curve analyses showed that the model had a higher net benefit than the treating all strategy between threshold probabilities of 15 and 50%. CONCLUSIONS: Staging laparoscopy is a useful tool to address the patient with gastric cancer to the most adequate treatment. In cM-patients the assessment of the location of the tumor, the Lauren's histotype and the cT status may help in providing additional elements in indicating or not the use of staging laparoscopy.

Structured and shared CT radiological report of gastric cancer: a consensus proposal by the Italian Research Group for Gastric Cancer (GIRCG) and the Italian Society of Medical and Interventional Radiology (SIRM).

OBJECTIVES: Written radiological report remains the most important means of communication between radiologist and referring medical/surgical doctor, even though CT reports are frequently just descriptive, unclear, and unstructured. The Italian Society of Medical and Interventional Radiology (SIRM) and the Italian Research Group for Gastric Cancer (GIRCG) promoted a critical shared discussion between 10 skilled radiologists and 10 surgical oncologists, by means of multi-round consensus-building Delphi survey, to develop a structured reporting template for CT of GC patients. METHODS: Twenty-four items were organized according to the broad categories of a structured report as suggested by the European Society of Radiology (clinical referral, technique, findings, conclusion, and advice) and grouped into three "CT report sections" depending on the diagnostic phase of the radiological assessment for the oncologic patient (staging, restaging, and follow-up). RESULTS: In the final round, 23 out of 24 items obtained agreement ( ≥ 8) and consensus ( ≤ 2) and 19 out 24 items obtained a good stability (p > 0.05). CONCLUSIONS: The structured report obtained, shared by surgical and medical oncologists and radiologists, allows an appropriate, clearer, and focused CT report essential to high-quality patient care in GC, avoiding the exclusion of key radiological information useful for multidisciplinary decision-making. KEY POINTS: • Imaging represents the cornerstone for tailored treatment in GC patients. • CT-structured radiology report in GC patients is useful for multidisciplinary decision making.

Looking for a strategy in treating peritoneal gastric cancer carcinomatosis: an Italian multicenter Gastric Cancer Research group's analysis.

BACKGROUND: The present study provides a snapshot of Italian patients with peritoneal metastasis from gastric cancer treated by surgery in Italian centers belonging to the Italian Research Group on Gastric Cancer. Prognostic factors affecting survival in such cohort of patients were evaluated with the final aim to identify patients who may benefit from radical intent surgery. METHODS: It is a multicentric retrospective study based on a prospectively collected database including demographics, clinical, surgical, pathological, and follow-up data of patients with gastric cancer and synchronous macroscopic peritoneal metastases. Patients were surgically treated from January 2005 to January 2017. We focused on patients with macroscopic peritoneal carcinomatosis (PC) treated with upfront surgery in order to provide homogeneous evidences. RESULTS: Our results show that patients with peritoneal carcinomatosis cannot be considered all lost. Strictly selected cases (R0/R1 and P1 patients) could benefit from an aggressive surgical approach performing an extended lymphadenectomy and HIPEC treatment. CONCLUSION: The main result of the study is that GC patients with limited peritoneal involvement can have a survival benefit from a surgery with "radical oncological intent", that means extended lymphadenectomy and R0 resection. The retrospective nature of this study is an important bias, and for this reason, we have started a prospective multicentric study including Italian stage IV patients that hopefully will give us more answers.

Validating a nodal regression system for gastric cancer: An ancillary cohort study of the GASTRODOC trial.

BACKGROUND: To validate a nodal regression system for gastric cancer and to verify its impact on prognosis. METHODS: This is an ancillary study which included 47 patients of the GASTRODOC trial. The dedicated pathologists of each Institute were invited to revise all the lymph nodes included in the surgical specimens in order to classify the regression according to the grading system proposed by Tsekrekos et al. The association of the nodal regression system and the clinico-pathological characteristics and prognosis were investigated. RESULTS: According to the classification of Tsekrekos et al., there were 19 (40.4%) patients with grade a, 14 (29.8%) with grade b and 14 (29.8%) with grade c nodal regression. This regression system showed significant statistical associations with pathological N status (p < 0.001), residual tumor classification (p = 0.003) and Becker regression system (p = 0.011). At multivariable analysis only Tsekrekos' grading regression system was significantly associated with the PFS (HR 10.1, 95% CI 1.3-75.5; p = 0.025). CONCLUSIONS: The analyzed nodal regression system is significantly associated with Becker's regression system and it has a strong correlation with prognosis.

Genetic and Epigenetic Alterations of CDH1 Regulatory Regions in Hereditary and Sporadic Gastric Cancer.

E-cadherin is a key player in gastric cancer (GC) and germline alterations of CDH1, its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of CDH1 promoter and enhancers in the regulation of gene expression. For this purpose, we analyzed genetic variants of the CDH1 gene through Next-Generation Sequencing (NGS) in a series of GC cell lines (NCI-N87, KATO-III, SNU-1, SNU-5, GK2, AKG, KKP) and the corresponding CDH1 expression levels. By bisulfite genomic sequencing, we analyzed the methylation status of CDH1 regulatory regions in 8 GC cell lines, in a series of 13 sporadic GC tissues and in a group of 20 HDGC CDH1-negative patients and 6 healthy controls. The NGS analysis on CDH1 coding and regulatory regions detected genetic alterations in 3 out of 5 GC cell lines lacking functional E-cadherin. CDH1 regulatory regions showed different methylation patterns in patients and controls, GC cell lines and GC tissues, expressing different E-cadherin levels. Our results showed that alterations in terms of genetic variants and DNA methylation patterns of both promoter and enhancers are associated with CDH1 expression levels and have a role in its regulation.

Delta-radiomics and response to neoadjuvant treatment in locally advanced gastric cancer-a multicenter study of GIRCG (Italian Research Group for Gastric Cancer).

BACKGROUND: To predict response to neoadjuvant chemotherapy (NAC) of gastric cancer (GC), prior to surgery, would be pivotal to customize patient treatment. The aim of this study is to investigate the reliability of computed tomography (CT) texture analysis (TA) in predicting the histo-pathological response to NAC in patients with resectable locally advanced gastric cancer (AGC). METHODS: Seventy (40 male, mean age 63.3 years) patients with resectable locally AGC, treated with NAC and radical surgery, were included in this retrospective study from 5 centers of the Italian Research Group for Gastric Cancer (GIRCG). Population was divided into two groups: 29 patients from one center (internal cohort for model development and internal validation) and 41 from other four centers (external cohort for independent external validation). Gross tumor volume (GTV) was segmented on each pre- and post-NAC multidetector CT (MDCT) image by using a dedicated software (RayStation), and 14 TA parameters were then extrapolated. Correlation between TA parameters and complete pathological response (tumor regression grade, TRG1), was initially investigated for the internal cohort. The univariate significant variables were tested on the external cohort and multivariate logistic analysis was performed. RESULTS: In multivariate logistic regression the only significant TA variable was delta gray-level co-occurrence matrix (GLCM) contrast (P=0.001, Nagelkerke R2: 0.546 for the internal cohort and P=0.014, Nagelkerke R2: 0.435 for the external cohort). Receiver operating characteristic (ROC) curves, generated from the logistic regression of all the patients, showed an area under the curve (AUC) of 0.763. CONCLUSIONS: Post-NAC GLCM contrast and dissimilarity and delta GLCM contrast TA parameters seem to be reliable for identifying patients with locally AGC responder to NAC.

The effect of learning curve on perioperative outcomes of robotic gastrectomy in two western high-volume centers.

INTRODUCTION: To compare outcomes of robotic gastrectomy (RG) performed during the learning curve (P1) with those after its completion (P2). METHODS: In this retrospective study, all consecutive RG patients (n = 92) performed between 2008 and 2018 were included. Primary outcome was conversion rate. RESULTS: D2 lymphadenectomies were more common in P2 (41, 97.6%) than P1 (41, 82.0%) (p = 0.019). Conversions were 11 (22%) in P1 versus 2 (4.8%) in P2 (p = 0.006). Postoperative morbidity was comparable between the groups. Median hospital stay was significantly shorter in P2. The only factor significantly associated with conversion was P2 (odds ratio = 0.18; 95% confidence interval, 0.04-0.85; p = 0.039). The 5-year overall survival in P1 was 79.6% versus 79.7% in P2 (p = 0.373). CONCLUSIONS: The learning curve affected operative and postoperative outcomes: during the learning curve, conversion to open surgery was significantly more frequent, the number of D2 was higher and patients were discharged earlier.

Early Gastric Cancer: identification of molecular markers able to distinguish submucosa-penetrating lesions with different prognosis.

BACKGROUND: Early Gastric Cancer (EGC) reaches 25% of the gastric cancers surgically treated in some areas of Northeastern Italy and is usually characterized by a good prognosis. However, among EGCs classified according to Kodama's criteria, Pen A subgroup is characterized by extensive submucosal invasion, lymph node metastases and worse prognosis, whereas Pen B subgroup by better prognosis. The aim of the study was to characterize the differences between Pen A, Pen B and locally advanced gastric cancer (T3N0) in order to identify biomarkers involved in aggressiveness and clinical outcome. METHODS: We selected 33 Pen A, 34 Pen B and 20 T3N0 tumors and performed immunohistochemistry of mucins, copy number variation analysis of a gene panel, microsatellite instability (MSI), TP53 mutation and loss of heterozygosity (LOH) analyses. RESULTS: Pen A subgroup was characterized by MUC6 overexpression (p = 0.021). Otherwise, the Pen B subgroup was significantly associated with the amplification of GATA6 gene (p = 0.002). The higher percentage of MSI tumors was observed in T3N0 group (p = 0.002), but no significant differences between EGC types were found. Finally, TP53 gene analysis showed that 32.8% of Pen tumors have a mutation in exons 5-8 and 50.0% presented LOH. Co-occurrence of TP53 mutation and LOH mainly characterized Pen A tumors (p = 0.022). CONCLUSIONS: Our analyses revealed that clinico-pathological parameters, microsatellite status and frequency of TP53 mutations do not seem to distinguish Pen subgroups. Conversely, the amplification of GATA6 was associated with Pen B, as well as the overexpression of MUC6 and the TP53mut/LOH significantly characterized Pen A.

Preoperative or Perioperative Docetaxel, Oxaliplatin, and Capecitabine (GASTRODOC Regimen) in Patients with Locally-Advanced Resectable Gastric Cancer: A Randomized Phase-II Trial.

Docetaxel associated with oxaliplatin and 5-fluorouracil (FLOT) has been reported as the best perioperative treatment for gastric cancer. However, there is still some debate about the most appropriate number and timing of chemotherapy cycles. In this randomized multicenter phase II study, patients with resectable gastric cancer were staged through laparoscopy and peritoneal lavage cytology, and randomly assigned (1:1) to either four cycles of neoadjuvant chemotherapy (arm A) or two preoperative + two postoperative cycles of docetaxel, oxaliplatin, and capecitabine (DOC) chemotherapy (arm B). The primary endpoint was to assess the percentage of patients receiving all the planned preoperative or perioperative chemotherapeutic cycles. Ninety-one patients were enrolled between September 2010 and August 2016. The treatment was well tolerated in both arms. Thirty-three (71.7%) and 24 (53.3%) patients completed the planned cycles in arms A and B, respectively (p = 0.066), reporting an odds ratio for early interruption of treatment of 0.45 (95% confidence interval (CI): 0.18-1.07). Resection was curative in 39 (88.6%) arm A patients and 35 (83.3%) arm B patients. Five-year progression-free survival (PFS) was 51.2% (95% CI: 34.2-65.8) in arm A and 40.3% (95% CI: 28.9-55.2) in arm B (p = 0.300). Five-year survival was 58.5% (95% CI: 41.3-72.2) and 53.9% (95% CI: 35.5-69.3) (p = 0.883) in arms A and B, respectively. The planned treatment was more frequently completed and was more active, albeit not significantly, in the neoadjuvant arm than in the perioperative group.