Prognostic Value of Systemic Inflammatory Response Markers in Patients Undergoing Neoadjuvant Chemotherapy and Gastrectomy for Advanced Gastric Cancer in the Eastern European Population.

The prognostic value of the systemic inflammatory response markers, namely neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) has not yet been clarified in patients undergoing neoadjuvant chemotherapy (NAC) and gastrectomy for advanced gastric cancer (GC) in the Eastern European population. This study aimed to verify the prognostic value of NLR, PLR, and LMR in GC patients undergoing multimodal treatment. One hundred six GC patients undergoing NAC and gastrectomy between 2012 and 2020 were included. Analysed blood samples were obtained prior to NAC (pre-NAC group) and before surgical treatment (post-NAC group). To evaluate the prognostic value of the NLR, LMR, and PLR, univariable and multivariable overall survival (OS) analyses were performed. In the pre-NAC group, elevated NLR and PLR were associated with significantly higher risk of death (mOS: 36 vs. 87 months; HR = 2.21; p = 0.0255 and mOS: 30 vs. 87 months; HR = 2.89; p = 0.0034, respectively). Additionally, a significantly higher risk of death was observed in patients with elevated NLR in the post-NAC group (mOS: 35 vs. 87 months; HR = 1.94; p = 0.0368). Selected systemic inflammatory response markers (NLR, PLR) are significant prognostic factors in patients with advanced GC treated with NAC and gastrectomy, as shown in the Eastern European population.

The importance of Epstein-Barr virus infection in the systemic treatment of patients with gastric cancer.

The Epstein-Barr virus (EBV) may directly cause the development of EBV-associated gastric cancer (EBVaGC). The prevalence of EBVaGC ranges from 4% to 18%, with a 2-fold higher frequency in males, and in tumors arising in the gastric cardia or corpus and 4 times higher frequency in gastric stump carcinoma. The vast majority of EBVaGC are lymphoepithelioma-like carcinomas. Despite extensive nodal involvement and distant metastases at initial diagnosis, EBVaGC seems to be a distinct etiologic entity with a favorable prognosis. However, the lymphoepithelioma-like carcinomas subtype in EBVaGC cannot be recognized in the current molecular classifications. Neither is there an association between EBV positivity and survival of patients after curative gastrectomy if they received standard adjuvant chemotherapy, nor EBV positivity and prediction of response to neoadjuvant platinum/5-FU-based chemotherapy. Alterations in chemokines and PD-L1 provide theoretical justification for clinical evaluation of immune checkpoint therapy in EBVaGC. Moreover, a higher degree of host immune response was demonstrated in EBVaGC. The current histologic and molecular GC classification does not influence clinical practice. Further research is expected to find convenient methods to assess gastric subtypes in day-to-day practice and to tailor therapy to improve overall survival.

Neoadjuvant chemotherapy with or without oxaliplatin after short-course radiotherapy in high-risk rectal cancer: A subgroup analysis from a prospective study.

AIM: To evaluate the role of oxaliplatin in neoadjuvant chemotherapy delivered after short-course irradiation. BACKGROUND: Using oxaliplatin in the above setting is uncertain. PATIENTS AND METHODS: A subgroup of 136 patients managed by short-course radiotherapy and 3 cycles of consolidation chemotherapy within the framework of a randomised study was included in this post-hoc analysis. Sixty-seven patients received FOLFOX4 (oxaliplatin group) while oxaliplatin was omitted in the second period of accrual in 69 patients because of protocol amendment (fluorouracil-only group). RESULTS: Grade 3+ acute toxicity from neoadjuvant treatment was observed in 30% of patients in the oxaliplatin group vs. 16% in the fluorouracil-only group (p = 0.053). The corresponding proportions of patients having radical surgery or achieving complete pathological response were 72% vs. 77% (odds ratio [OR] = 0.88; 95% confidence interval [CI]: 0.39-1.98; p = 0.75) and 15% vs. 7% (OR = 2.25; 95% CI: 0.83-6.94; p = 0.16), respectively. The long-term outcomes were similar in the two groups. Overall and disease-free survival rates at 5 years were 63% vs. 56% (p = 0.78) and 49% vs. 44% (p = 0.59), respectively. The corresponding numbers for cumulative incidence of local failure or distant metastases were 33% vs. 38% (hazard ratio [HR] = 0.89; 95% CI: 0.52-1.52; p = 0.68) and 33% vs. 33% (HR = 0.78; 95% CI: 0.43-1.40; p = 0.41), respectively. CONCLUSION: Our findings do not support adding oxaliplatin to three cycles of chemotherapy delivered after short-course irradiation.

Proximal Gastric Resection with Posterior Esophago-Gastrostomy and Partial Neo-Fundoplication in the Treatment of Advanced Upper Gastric Carcinoma.

BACKGROUND: Proximal gastric resection (PGR) is rarely used in western countries because of frequent postoperative reflux and uncommon diagnosis of early gastric cancer (GC). OBJECTIVES: We hypothesized that the PGR with an anti-reflux procedure may be an attractive option even in advanced proximal GC after downstaging with the neo-adjuvant chemotherapy. METHOD: A novel technique of end-to-side esophago-gastrostomy with the posterior wall of the gastric stump and partial neo-fundoplication to prevent reflux symptoms has been introduced. An observational retrospective study was undertaken to evaluate early and late outcomes of the innovative technique in patients with advanced proximal GC after neoadjuvant chemotherapy. RESULTS: Twenty consecutive patients with the diagnosis of loco-regionally advanced GC, localized in the subcardiac region or proximal upper third of the stomach, were selected for the study. Eleven (55%) patients completed preoperative neo-adjuvant chemotherapy. The mean postoperative hospitalization time was 13.3 (± 8.3) days. There was one postoperative in-hospital death due to acute circulatory insufficiency. The mean comprehensive complication index was 11.94 (±24.82). Two patients were diagnosed with a complete pathological response (ypT0N0). Median survival was 41.8 (95% CI 27.9-41.8) months. The 5-year survival rate was 42%. At a median follow-up of 26 months, reflux symptoms were present in 7 (35%) patients who had to use antireflux medication. Anastomotic stenosis was observed in 1 patient during the follow-up. Mean scores of reflux symptoms on medication were not significantly different to those in patients without medication. The Overall Satisfaction Score for patients on medication was 7.57 ± 1.92, whereas it was 8.83 ± 1.34 (p = 0.2; Student t test) for those with no medication. CONCLUSIONS: Proximal gastrectomy is feasible and may be safely used in patients with advanced GC after neo-adjuvant chemotherapy with acceptable survival. Posterior esophago-gastrostomy with partial neo-fundoplication reduces the postoperative reflux, while patients with persistent reflux symptoms can be effectively treated with an antireflux therapy.

The Role of the Lymph Node Ratio in Advanced Gastric Cancer After Neoadjuvant Chemotherapy.

The ratio of positive lymph nodes (LNs) to the total LN harvest is called the LN ratio (LNR). It is an independent prognostic factor in gastric cancer (GC). The aim of the current study was to evaluate the impact of neoadjuvant chemotherapy (NAC) on the LNR (ypLNR) in patients with advanced GC. We retrospectively analysed the data of patients with advanced GC, who underwent gastrectomy with N1 and N2 (D2) lymphadenectomy between August 2011 and January 2019 in the Department of Surgical Oncology at the Medical University of Lublin. The exclusion criteria were a lack of preoperative NAC administration, suboptimal lymphadenectomy (

Conversion Surgery with HIPEC for Peritoneal Oligometastatic Gastric Cancer.

Peritoneal metastases (PM) of gastric cancer (GC) are characterized by a particularly poor prognosis, with median survival time of 6 months, and virtually no 5-year survival reported. Conversion therapy for GC is defined as a surgical treatment aiming at an R0 resection after systemic chemotherapy for tumours that were originally unresectable (or marginally resectable) for technical and/or oncological reasons. The aim of the present study was to evaluate early and late outcomes in GC patients with PM who underwent the cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) after neoadjuvant (conversion) chemotherapy. Thirty patients with stage IV GC underwent CRS plus HIPEC. Severe grade III/IV (Clavien-Dindo classification) complications occurred in 13 (43%) patients. The Comprehensive Complication Index (CCI) ranged from 8.7 to 100 (median, 42.4). In the multivariate survival analysis, ypT2 and P3 (according to the Japanese classification of the PM severity) were favourable and adverse prognostic factors p = 0.031 and o = 0.035, respectively. Estimated 1- and 3-year survival was 73.9% and 36.6%, respectively. The median survival was 19.3 months. Conclusion: Conversion surgery, including extended gastrectomy and multi-organ resections followed by HIPEC performed after systemic chemotherapy therapy for GC with PM is justified in downstaged patients with ypT2 and limited (less than P3) PM.

Blast from the past: Perioperative use of the Maruyama computer program for prediction of lymph node involvement in the surgical treatment of gastric cancer following neoadjuvant chemotherapy.

BACKGROUND: Surgical quality assurance is a key element of gastric cancer treatment. The Maruyama Computer Program (MCP) allows to predict lymph node involvement in stations no. 1-16. The aim of the current study was to evaluate the accuracy of the MCP predictions in GC patients treated with neoadjuvant chemotherapy (nCTH) followed by gastrectomy with adequate lymphadenectomy. METHODS: 101 patients who underwent preoperative nCTH followed by D2 gastrectomy with curative intent were analysed. The response to nCTH was measured using the tumour regression grade system. RESULTS: Test sensitivity, specificity, PPV, NPV and accuracy of the MCP were 92%, 33%, 41%, 89%, and 53%, respectively. In patients with response to nCTH, number of false positive (FP) results was significantly higher than in patients who did not respond to nCTH both in the N1 (56.3% vs 28.9%, p < 0.0001) and in the N2 (59% vs 41%, p < 0.0001) trier. The risk for FP results was 6 times higher in N1 (OR = 6.50, 95%CI: 3.91-10.82,; p < 0.0001) and N2 (OR = 5.84, 95%CI: 2.85-11.96; p < 0.0001) triers. In patients with intestinal type GC, the risk for FP results was 4 times higher than in other histologic types of GC in both N1 (OR = 4.23, 95%CI: 2.58-6.95; p < 0.0001) and N2 (OR = 4.23, 95%CI: 2.02-9.62; p = 0.0002) triers. CONCLUSIONS: MCP predictions in the GC patients treated with nCTH have low specificity due to significantly high number of FP results. Noticeably low accuracy level of predictions indicate a need for new prediction models, based on Laurén classification, since it may provide some information on expected regression grade.

Current challenges in gastric cancer surgery: European perspective.

Gastric cancer (GC) remains one of the most common causes of cancer death worldwide with expected 5-year survival rates around 25% in Western countries. In order to improve treatment strategy, a most effective staging process should be completed. A novel TNM staging for GC has been proposed recently, along with a separate staging system for GC patients who underwent preoperative therapy (ypStage). Availability of high-quality imaging and access to diagnostic laparoscopy with lavage cytology should be applied while planning the multimodal therapy. In the European setting, GC treatment is based on a combination of surgery and perioperative chemotherapy. However, in selected groups of patients with high risk of locoregional recurrence, adjuvant chemoradiotherapy should be considered. New epidemiological trends of GC in the Western countries include an upward shift in the location of the primary tumour and a relative increase of advanced and diffuse type tumours. These trends dictate modification of surgical techniques towards a more individualized GC treatment approach.

Distinct molecular subtypes of gastric cancer: from Laurén to molecular pathology.

In Western countries the majority of gastric cancers (GC) are usually diagnosed in advanced stages reporting a 5-year survival rate of only 26%. The Laurén classification of GC was most widely used in clinical practice since it reflects GC morphology, epidemiology, tumor biology, clinical management and outcome. Despite the initial promise of individualizing antitumor treatment, the management of GC still remains relatively broad and general. Apart from clinical staging, molecular profiling enables targeting of the identified underlying alterations, rather than histology. In contrast to breast carcinoma, molecular classification of GC does not yet imply treatment modality. Molecular classifications of GC and their therapeutic implications are therefore extensively studied. The current proposed molecular divisions of GC come from three different parts of the world where different standard treatment modalities for advanced GC are recommended. Wider use of GC molecular subtyping may solve problems, such as susceptibility to novel systemic therapy regimens or selection of patients for aggressive surgery and targeted adjuvant/conversion therapy. In any case, the rapid entry of novel molecular targeted therapies into routine oncology practice clearly underscores the urgent need for clinicians to be aware of these new possibilities.

Liver metastases from gastric carcinoma: A Case report and review of the literature.

Gastric carcinoma (GC) is the fifth most common malignancy worldwide but the third leading cause of cancer death, and surgery remains the only curative treatment option. Prognosis of patients with liver metastases from gastric carcinoma (LMGC) is poor, and the optimal treatment of metastatic gastric cancer remains a matter of debate. In 2002, a 53-year-old male patient with GC and synchronous oligometastatic lesion in liver VIII segment underwent a total gastrectomy combined with metastasectomy. The pathologic diagnosis was stage IV gastric adenocarcinoma (pT3N2M1), which was treated with adjuvant chemotherapy (cisplatin, epirubicin, leucovorin, and 5-fluorouracil). In 2012, abdominal ultrasound and percutaneous liver biopsy revealed recurrence of the metastasis in the right liver lobe. Progression of the disease was observed after palliative chemotherapy (epirubicin, oxaliplatin, and capecitabine). Nevertheless, an extended right hemihepatectomy, with excision of segments 1, 4A, 5, 6, 7, and 8, was still performed. Pathologic examination confirmed large KRAS- and HER2-negative LMGC. The patient is alive and free of disease 47 months after the repeated hepatectomy and 13 years after removal of the primary GC and synchronous liver metastasis. Based on review of 27 articles, 5-year overall survival rate following gastrectomy and liver metastasectomy may reach 60%, with median survival time up to 74 months. Although the combination of aggressive surgical approach with systemic therapy for LMGC is controversial, it may allow favorable outcome. Careful selection of patients based on evaluable predictive factors for R0 surgical resection of both primary tumor and liver metastases can lead to cure, as shown in our case presentation, where a 10-year relapse-free survival was observed, followed by successful repeated hepatectomy due to liver metastases.

Guilty bystanders: nurse-like cells as a model of microenvironmental support for leukemic lymphocytes.

B-cell chronic lymphocytic leukemia (B-CLL) is one of the most common leukemias among the elderly and, despite many efforts, still stays incurable. Recent studies point to the microenvironment as the critical factor providing leukemic lymphocytes with pro-survival signals. Thus, the neighboring cells appear to be a perfect target for antileukemic therapy. Nurse-like cells (NLCs) largely contribute to CLL microenvironmental support. We developed the CLL lymphocyte/NLC co-culture model for the investigation of microenvironmental interactions. Viability and apoptosis were investigated in CLL lymphocytes treated with dexamethasone (DEX) and chlorambucil (CLB), with and without NLCs' support. For the first time, the capacity of DEX and CLB to affect NLCs viability was also evaluated. Apoptosis-associated gene expression profiles of leukemic lymphocytes ex vivo and cultured with NLCs were assessed by expression arrays. CLL lymphocytes escaped spontaneous apoptosis for several months when cultured with NLCs. The presence of NLCs significantly reduced apoptosis induced with DEX and CLB (p < 0.001; p = 0.012, respectively), and their protective effect was more evident than the effect of recombinant SDF1. Both DEX and CLB also decreased NLCs viability, but to a lesser extent (mean viability in DEX-treated cultures was 37.79% in NLCs compared to 29.24% in lymphocytes). NLCs induced the expression of important anti-apoptotic genes in cultured CLL lymphocytes; median expression of BCL2, SURVIVIN, BCL2A1, and XIAP was significantly higher as compared to ex vivo status. The CLL lymphocyte/NLC co-culture makes up the convenient and close to the natural-state model for studying the relationship between leukemic cells and the microenvironment. Direct cell-to-cell contact with NLCs increases the expression of anti-apoptotic genes in CLL lymphocytes, thus protecting them against induced apoptosis. As the effect of antileukemic drugs is not so apparent in NLCs, the combined therapy targeted at both lymphocytes and the microenvironment should be considered for CLL patients. Simultaneous aiming at the disruption of several different signaling pathways and/or anti-apoptotic proteins may further improve treatment efficiency.

Circulating microenvironment of CLL: are nurse-like cells related to tumor-associated macrophages?

B-cell chronic lymphocytic leukemia (B-CLL) is one of the most common hematologic malignancies in Western countries. Accumulation of leukemic lymphocytes in peripheral blood, bone marrow and secondary lymphatic organs of CLL patients is due to decreased apoptosis rather than to increased proliferation. The former is driven by signals from a specific microenvironment, created by stromal cells of mesenchymal origin, follicular dendritic cells, T lymphocytes and others. Nurse-like cells (NLCs) were first described to differentiate from peripheral blood mononuclear cells of CLL patients in vitro, then they have been also found in proliferation centers of their lymphatic tissues. Like tumor-associated macrophages (TAMs) in solid tumors, nurse-like cells promote survival of CLL lymphocytes. NLC gene expression patterns suggest their similarity to TAMs and differ between patients depending on ZAP70 protein expression status. NLC number in vitro corresponds with CD14 expressing cell count and beta-2-microglobulin serum level, and positively correlates with leukemic lymphocyte viability. As NLCs strongly express genes for adhesion molecules and secrete chemokines of antiapoptotic activity, they should be considered as a target for anti-microenvironment therapy of this incurable disease.