Background
The aim of this study is to report the experience with conversion surgery from six Gruppo Italiano Ricerca Cancro Gastrico (GIRCG) centers, focusing our analysis on factors affecting ...survival and the risk of recurrence.
Methods
A retrospective, multicenter cohort study was performed in patients who had undergone conversion gastrectomy between 2005 and 2017. Data were extracted from a GIRCG database including all metastatic gastric cancer patients submitted to surgery. Only stage IV unresectable tumors/metastases which became resectable after chemotherapy were included in this analysis.
Results
Forty-five resected M1 patients were included in the analysis. Reasons for being deemed unresectable at diagnosis were peritoneal involvement (PCI > 6) (
n
= 38, 84.4%), distant metastatic nodes (
n
= 3, 6.6%) and extensive liver involvement (
n
= 4, 8.8%). Median follow-up was 25 months (IQR 9-50). Median overall survival from surgery was 15 months and 1-, 3- and 5-year survivals were 57.2, 36.1 and 24%, respectively. Median progression-free survival was 12 months with 1- and 3-year survival of 46.4 and 33.9%, respectively. At cox regression analysis the only independent prognostic factor for OS was the presence of more than one type of metastasis (HR 4.41, 95% CI 1.72–11.3,
p
= 0.002). A positive microscopic resection margin was the only risk factor for recurrence (HR 5.72, 95% CI 1.04–31.4,
p
= 0.045).
Conclusions
Unresectable stage IV GC patients could benefit from radical surgery after chemotherapy and achieve long survivals. The main prognostic factor for these patients was the presence of more than one type of extra-gastric metastatic involvement.
Background and aims
Clinicopathological characteristics of gastric cancer (GC) are changing, especially in the West with a decreasing incidence of distal, intestinal-type tumours and the ...corresponding increasing proportion of tumours with Laurén diffuse or WHO poorly cohesive (PC) including signet ring cell (SRC) histology. To accurately assess the behaviour and the prognosis of these GC subtypes, the standardization of pathological definitions is needed.
Methods
A multidisciplinary expert team belonging to the European Chapter of International Gastric Cancer Association (IGCA) identified 11 topics on pathological classifications used for PC and SRC GC. The topics were debated during a dedicated Workshop held in Verona in March 2017. Then, through a Delphi method, consensus statements for each topic were elaborated.
Results
A consensus was reached on the need to classify gastric carcinoma according to the most recent edition of the WHO classification which is currently WHO 2010. Moreover, to standardize the definition of SRC carcinomas, the proposal that only WHO PC carcinomas with more than 90% poorly cohesive cells having signet ring cell morphology have to be classified as SRC carcinomas was made. All other PC non-SRC types have to be further subdivided into PC carcinomas with SRC component (< 90% but > 10% SRCs) and PC carcinomas not otherwise specified (< 10% SRCs).
Conclusion
The reported statements clarify some debated topics on pathological classifications used for PC and SRC GC. As such, this consensus classification would allow the generation of evidence on biological and prognostic differences between these GC subtypes.
Advanced unresectable gastric cancer has a dismal prognosis. The aim of this study was to evaluate the short- and long-term outcomes of patients who underwent induction chemotherapy ± gastrectomy for ...advanced gastric cancer.
All patients referred to our center with a clinical diagnosis of unresectable locally advanced or stage IV gastric adenocarcinoma between April 2005 and August 2016 were included in the study. Cox regression was performed to find independent prognostic factor among the considered variable.
The cohort included 73 patients: 16 had best supportive care, 35 chemotherapy alone and 22 chemotherapy plus radical surgery. Thirty-three patients underwent surgery after chemotherapy. Twenty-two patients had R0 surgery, while the remaining 11 had only an exploratory procedure. Nine patients (40.9%) underwent gastrectomy plus hyperthermic intraperitoneal chemotherapy. Three patients out of 22 developed postoperative complications with a Clavien-Dindo grade above 2. Median survival was 50 months for patients who had chemotherapy plus surgery while it was 14 and 3 for those who had chemotherapy alone and best supportive care, respectively (p < 0.0001). Cox regression analysis performed on the whole cohort identified only radical conversion surgery as an independent factor positively associated with survival (HR 0.12, 95% CI 0.05–0.29, p < 0.0001).
Conversion gastrectomy, when R0 could be achieved, is associated with long survivals and it is the most important prognostic factor in patients with advanced gastric cancer. Further studies are needed to define the ideal patient who can really benefit from this treatment.
•Unresectable gastric cancer could be associated with a dismal prognosis.•Chemotherapy has offered new perspectives for these patients.•Conversion surgery may offer good survivals after palliative chemotherapy.•Surgery should not be excluded a priori in advanced cases.
Background
The prevention and early diagnosis of gastric cancer permit clinicians to discover the tumor in the initial phase, during which time it can be completely eradicated, endoscopically or ...surgically. Since Murakami gave the definition of early gastric cancer (EGC) in 1971, many authors have identified various subtypes of EGC with different morphological characteristics and clinical behaviour.
Methods
We evaluated retrospectively 530 patients: the median follow-up time was 10.4 months (range 0.3–29.2). All tumors were classified according to the macroscopic and microscopic criteria proposed by the Japanese Society of Gastroenterology and Endoscopy and Lauren, respectively. The infiltrative growth pattern was evaluated according to Kodama’s classification. Only tumor-related death was considered as an endpoint of interest for the survival analysis.
Results
The overall survival rates of our patients were 94 % (95 % CI, 92–96) and 90 % (95 % CI, 87–93) at 5 and 10 years, respectively. Only 44 patients (8.3 %) died of the disease. Kodama’s type (
p
< 0.0001), lymph node status, both for number and pathological stage according to the 7th Edition of TNM (
p
< 0.0001), and depth of infiltration (
p
= 0.0006) were significant prognostic factors in univariate analysis. The multivariate analysis identified Kodama’s PENA type (HR, 3.91; 95 % CI, 2.08–7.33;
p
< 0.0001) and lymph node status for more than three positive nodes versus negative nodes (HR, 12.78; 95 % CI, 5.37–30.43;
p
< 0.0001) as the only independent prognostic factors in our series.
Conclusion
Lymph node status, especially when more than three lymph nodes are involved, is the most important prognostic factor in EGC. However, it is also important to evaluate the infiltrative growth pattern of the cancers in their early phase according to Kodama’s classification, considering PEN A type lesions to be more aggressive than the other EGC types. Then, we propose new elements for an updated definition and classification of EGC, with an important clinical impact on the treatment of patients.
Gastric cancer surgical management differs between Eastern Asia and Western countries. Extended lymphadenectomy(D2) is the standard of care in Japan and South Korea since decades, while the majority ...of United States patients receive at most a limited lymphadenectomy(D1). United States and Northern Europe are considered the scientific leaders in medicine and evidencebased procedures are the cornerstone of their clinical practice. However, surgeons in Eastern Asia are more experienced, as there are more new cases of gastric cancer in Japan(107898 in 2012) than in the entire European Union(81592), or in South Korea(31269) than in the entire United States(21155). For quite a long time evidence-based medicine(EBM) did not solve the question whether D2 improves long-term prognosis with respect to D1. Indeed, eastern surgeons were reluctant to perform D1 even in the frame of a clinical trial, as their patients had a very good prognosis after D2. Evidence-based surgical indications provided by Western trials were questioned, as surgical procedures could not be properly standardized. In the present study we analyzed indications about the optimal extension of lymphadenectomy in gastric cancer according to current scientific literature(2008-2012) and surgical guidelines. We searched PubMed for papers using the key words "lymphadenectomy or D1 or D2" AND "gastric cancer" from 2008 to 2012. Moreover, we reviewed national guidelines for gastric cancer management. The support to D2 lymphadenectomy increased progressively from 2008 to 2012: since 2010 papers supporting D2 have achieved a higher overall impact factor than the other papers. Till 2011, D2 was the procedure of choice according to experts’ opinion, while three meta-analyses found no survival advantage after D2 with respect to D1. In 2012-2013, however, two meta-analyses reported that D2 improves prognosis with respect to D1. D2 lymphadenectomy was proposed as the standard of care for advanced gastric cancer by Japanese National Guidelines since 1981 and was adopted as the standard procedure by the Italian Research Group for Gastric Cancer since the Nineties. D2 is now indicated as the standard of surgical treatment with curative intent by the German, British and ESMO-ESSO-ESTRO guidelines. At variance American NCCN guidelines recommend a D1+ or a modified D2 lymph node dissection. In conclusion, D2 lymphadenectomy, originally developed by Eastern surgeons, is now becoming the procedure of choice also in the West. In gastric cancer surgery EBM is lagging behind national guidelines, rather than preceding and orienting them. To eliminate this lag, EBM should value to a larger extent Eastern Asian literature and should evaluate not only the quality of the study design but also the quality of surgical procedures.
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
TP53
mut/LOH
significantly characterized Pen A.
gene, encoding E-cadherin, is a tumor suppressor gene frequently altered in gastric cancers (GCs) of both diffuse (DGC) and intestinal (IGC) histotypes, albeit through different mechanisms. The study ...aimed to characterize
expression in sporadic IGC and to investigate whether microRNAs (miRs) are involved in its transcriptional control. We evaluated
expression by quantitative real-time PCR (RT-qPCR) in 33 IGC patients and found a significant downregulation in tumor tissues compared to normal counterparts (
-value = 0.025). Moreover, 14 miRs, predicted to be involved in
regulation in both a direct and indirect manner, were selected and analyzed by RT-qPCR in an independent case series of 17 IGCs and matched normal tissues. miR-101, miR-26b, and miR-200c emerged as significantly downregulated and were confirmed in the case series of 33 patients (
-value < 0.001). Finally, we evaluated
expression, a target of both miR-101 and miR-26b, which showed significant upregulation in IGCs (
-value = 0.005). A significant inverse correlation was observed between
overexpression and
, miR-101, and miR-26b levels (
-value < 0.001). Our results reinforce the link between
and IGC, highlighting the role of miRs in its transcriptional control and improving our understanding of GC subtypes and biomarkers.
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.
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.
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.
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 (
= 0.742).
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.
hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behavior. A thorough analysis of the functional role and clinical ...significance of hERG1 channels in gastric cancer is still lacking.
hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected patients with gastric cancer, by immunohistochemistry and real-time quantitative PCR. The functional link between hERG1 and the VEGF-A was studied in different gastric cancer cell lines. The effects of hERG1 and VEGF-A inhibition were evaluated in vivo in xenograft mouse models.
hERG1 was positive in 69% of the patients and positivity correlated with Lauren's intestinal type, fundus localization of the tumor, G1-G2 grading, I and II tumor-node-metastasis stage, and VEGF-A expression. hERG1 activity modulated VEGF-A secretion, through an AKT-dependent regulation of the transcriptional activity of the hypoxia inducible factor. Treatment of immunodeficient mice xenografted with human gastric cancer cells, with a combination of hERG1 blockers and anti-VEGF-A antibodies, impaired tumor growth more than single-drug treatments.
Our results show that hERG1 (i) is aberrantly expressed in human gastric cancer since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a gastric cancer patients' group where a combined treatment with antiangiogenic drugs and noncardiotoxic hERG1 inhibitors could be proposed.
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