CANCER-ASSOCIATED ADIPOCYTES AND PROGNOSTIC VALUE OF PREOPERATIVE NEUTROPHIL-LYMPHOCYTE RATIO IN GASTRIC CANCER.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) turned out to be a routinely available marker capable to reflect the systemic inflammatory response created by a tumor. Gastric cancer (GC) grows in the anatomical vicinity of adipose tissue, which is also associated with low-grade inflammation. AIM: To investigate the usefulness of the combined use of preoperative NLR and density of intratumoral cancer-associated adipocytes (CAAs) for predicting the disease outcome in GC patients. MATERIALS AND METHODS: A total of 151 patients with GC were eligible for retrospective analysis between 2009 and 2015.NLR preoperative values were calculated. Perilipin expression in tumor tissue was examined immunohistochemically. RESULTS: Low preoperative NLR is the most reliable prognostic factor for the favorable outcome for patients with low density of intratumoral CAAs. Patients with a high density of CCAs are at high risk of lethal outcomes independently of the value of preoperative NLR. CONCLUSION: The results have clearly shown an association between preoperative NLR and the density of CAAs in the primary tumor of GC patients. The prognostic value of NLR is essentially modified by means of the individual density of intratumoral CAAs in GC patients.The elevated NLR could be of significant predictive potential for a negative prognosis for patients with tumors characterized by the high density of CAAs independently of BMI.

Tumor microenvironment and metabolic factors: contribution to gastric cancer.

Malignancy may be characterized as a state formed in the setting of specific tumor-host relationships at the molecular and cellular microenvironment levels. R.E. Kavetsky and his collaborators distinctly outlined the concept of tumor-host interaction. Tumor is a complicated biological system closely connected with the organism, where it arises and develops. Tumor cells are in the environment of different factors that form tumor microenvironment playing an active role in the disease progression. There are two types of tumor microenvironment: the metabolic microenvironment mediated by factors of tumor microphysiology (blood flow, vascular permeability, oxygenation, extracellular рН, interstitial fluid pressure, etc.) and the cellular-molecular microenvironment comprising interactions between tumor cells and non-tumor cells and the factors of the stromal compartment. Factors of tumor microphysio-logy can modify the interaction between tumor cells and surrounding non-tumor cells and molecular components and they form the tumor profile that influences the pressure of tumor on the host. The review presents the data concerning the role of metabolic microenvironment of tumor cells from the point of tumor-host interaction in order to employ these parameters to working out the methods of diagnosis and prognosis of disease outcome in patients with gastric cancer. Special attention has been paid to hypoxia as a key factor of metabolic microenvironment that positively affects tumor progression, stimulating its aggressiveness, metastasis and resistance to therapy and is regarded as a factor of unfavorable prognosis. It was shown that there is possible clinical relevance of tumor classification based on the level of tumor oxygenation that may be advantageous for selection of patients for individualized therapy that may give the hope for enhancement of treatment efficacy.

CD8 and CD45RO T lymphocytes in bone marrow of gastric cancer patients: correlation with disseminated tumor cells and disease outcome.

AIM: To evaluate the association between the presence of CD8 and CD45RO T lymphocytes in bone marrow (BM), disseminated tumor cells (DTCs), tumor hypoxia and their impact on disease outcome. MATERIAL AND METHODS: 91 naïve gastric cancer (GC) patients were enrolled into the study. DTCs, CD8- and CD45RO-positive T lymphocytes in BM were detected using immunocytochemistry. All patients were thoroughly informed about the study that was approved by the local ethics committee. Statistical analyses were done using NCSS2000/PASS2000 and Prism, version 4.03 software packages. RESULTS: It was detected that 80.5 and 81.3% of patients had CD8- and CD45RO-positive T cells in BM, respectively. When DTCs were detected in BM, the number of patients with CD8-and CD45RO-positive T cells in BM were 86.1 and 84.4%, respectively. It was also determined that the number of patients with DTCs in BM with categories M0 and M1 and with CD8- and CD45RO-positive T cells in BM were 86.2 and 85.7%, 85.7 and 80.0%, respectively. The association between DTCs in BM and presence of CD8 and CD45RO T cells lymphocytes in BM was not found. At the same time it was shown the association between presence of CD8 and CD45RO T lymphocytes and survival. The presence of CD8- and CD45RO-positive T cells in BM were accompanied with significantly longer overall survival of patients compared to that of patients without CD8- and CD45RO-positive T cells in BM. CONCLUSION: Patients with the presence of CD8- and CD45RO-positive T cells in BM demonstrated better survival of GC patients than those with the absence of these cells in BM. It may be suggested that tumor cells in BM are controlled in a dormant state by T cells in BM, in particular by CD8-positive T cells.

Premorphological alterations in gastric mucosa in patients with gastric cancer: hypoxia level assessed by 31P NMR spectroscopy.

UNLABELLED: The aim of this study was to detect the hypoxic status in adjacent histologically uninvolved gastric mucosa in gastric cancer (GC) patients. PATIENTS AND METHODS: 50 naïve patients with primary GC, and one patient with stomach ulcer (gastric mucosa was used as control) were enrolled into the study. The tumor and mucosa samples of stomach (without muscularis and serosa layers) in patients with GC were obtained immediately after operation. Assessment of the hypoxia level has been provided using (31)P NMR spectroscopy in tissue perchloric acid extracts. Mucosa was examined by convenient histological method. Obtained results were analyzed statistically. RESULTS: It was shown that gastric mucosa in 52% of patients with GC is under different levels of hypoxia, among them 23% of mucosa is under severe hypoxia (PME/Pi < 1.0) with average mean of PME/Pi 0.89 ± 0.04. It was revealed that there are definite associations between the hypoxia in mucosa tissue and pT as well as pN categories and G grade and stage of disease but not with M category. Overall survival of patients with gastric mucosa characterized by severe and mild hypoxia was significantly poorer as compared to that of patients with gastric mucosa with satisfactory oxygenation (p = 0.0035). CONCLUSION: Gastric mucosa uninvolved in tumor process is characterized by hypoxia in 52% of GC patients; severe hypoxia of mucosa was detected in 23% of patients having hypoxic mucosa. It was suggested that biochemical alterations in tissue surrounding tumor node may precede morphological ones.

Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a randomized controlled phase II trial.

BACKGROUND: Paclitaxel embedded in cationic liposomes (EndoTAG™-1; ET) is an innovative agent targeting tumor endothelial cells. This randomized controlled phase II trial evaluated the safety and efficacy of ET in combination with gemcitabine (GEM) in advanced pancreatic cancer (PDAC). PATIENTS AND METHODS: Chemotherapy-naive patients with locally advanced or metastatic disease were randomly assigned to receive weekly GEM 1000 mg/m(2) or GEM plus twice-weekly ET 11, 22 or 44 mg/m(2) for 7 weeks. After a safety run-in of 100 patients, a second cohort continued treatment. End points included overall survival (OS), progression-free survival (PFS), tumor response and safety. RESULTS: Two hundred and twelve patients were randomly allocated to the study and 200 were treated (80% metastatic, 20% locally advanced). Adverse events were manageable and reversible. Transient thrombocytopenia and infusion reactions with chills and pyrexia mostly grade 1 or 2 occurred in the ET groups. Disease control rate after the first treatment cycle was 43% with GEM and 60%, 65% and 52% in the GEM + ET cohorts. Median PFS reached 2.7 compared with 4.1, 4.6 and 4.4 months, respectively. Median OS was 6.8 compared with 8.1, 8.7 and 9.3 months, respectively. CONCLUSIONS: Treatment of advanced PDAC with GEM + ET was generally well tolerated. GEM + ET showed beneficial survival and efficacy. A randomized phase III trial should confirm this positive trend.

Cytoreductive surgery and intraperitoneal chemohyperthermia for peritoneal carcinomatosis arising from gastric cancer.

HYPOTHESIS: The most common cause of palliative resection and recurrence in gastric cancer is peritoneal seeding. This study evaluates the efficacy of intraperitoneal chemohyperthermia after cytoreductive surgery in patients with peritoneal carcinomatosis arising from gastric cancer. DESIGN: Prospective clinical trial. SETTING: Surgical department at a university academic hospital. PATIENTS: Forty-nine consecutive patients with peritoneal carcinomatosis treated between January 1, 1989, and February 29, 2000. INTERVENTIONS: All patients underwent intraperitoneal chemohyperthermia with mitomycin C (40-60 mg); 21 patients had previously undergone extensive cytoreductive surgery. MAIN OUTCOME MEASURES: Clinicopathologic factors that affect overall survival rates. RESULTS: With median follow-up of 99 months, overall median survival was 10.3 months. Two factors were significant independent predictors of survival by multivariate analysis: preoperative ascites (P =.04) and completeness of cancer resection (CCR) by cytoreductive surgery (P<.001). Median survival was 21.3 months for patients with CCR-0 (macroscopic complete resection) or CCR-1 (diameter of residual nodules <5 mm) and 6.1 months for patients with CCR-2 (diameter of residual nodules >5 mm) (P<.001). Four patients survived longer than 5 years. CONCLUSIONS: An aggressive management strategy combining intraperitoneal chemohyperthermia with cytoreductive surgery is effective for patients with peritoneal carcinomatosis arising from gastric cancer. In highly selected patients (good general status, resectable primary tumor, resectable peritoneal carcinomatosis), this therapy may result in long-term survival.

Intraperitoneal chemohyperthermia using a closed abdominal procedure and cytoreductive surgery for the treatment of peritoneal carcinomatosis: morbidity and mortality analysis of 216 consecutive procedures.

BACKGROUND: Peritoneal carcinomatosis has been regarded as a lethal clinical entity. Recently, aggressive treatments combining intraperitoneal chemohyperthermia (IPCH) with cytoreductive surgery have resulted in long-term survival in selected patients. The aim of this trial was to analyze the mortality and morbidity of 216 consecutive treatments of peritoneal carcinomatosis by IPCH by using a closed abdominal procedure combined with cytoreductive surgery. METHODS: Between February 1989 and August 2001, 207 patients who underwent 216 IPCH procedures using a closed abdominal procedure with mitomycin C, cisplatin, or both were prospectively studied. RESULTS: The postoperative mortality and morbidity rates were 3.2% and 24.5%, respectively. The most frequent complications were digestive fistula (6.5%) and hematological toxicity (4.6%). Morbidity was statistically linked with the carcinomatosis stage (P =.016), the duration of surgery (P =.005), and the number of resections and peritonectomy procedures (P =.042). Duration of surgery and carcinomatosis stage were the most common predictors of morbidity. CONCLUSIONS: The frequency of complications after IPCH and cytoreductive surgery was mainly associated with the carcinomatosis stage and the extent of the surgical procedure. The IPCH closed abdominal procedure has shown an acceptable frequency of adverse events.

Surgery combined with peritonectomy procedures and intraperitoneal chemohyperthermia in abdominal cancers with peritoneal carcinomatosis: a phase II study.

PURPOSE: To evaluate the tolerance of peritonectomy procedures (PP) combined with intraperitoneal chemohyperthermia (IPCH) in patients with peritoneal carcinomatosis (PC), a phase II study was carried out from January 1998 to September 2001. PATIENTS AND METHODS: Fifty-six patients (35 females, mean age 49.3) were included for PC from colorectal cancer (26 patients), ovarian cancer (seven patients), gastric cancer (six patients), peritoneal mesothelioma (five patients), pseudomyxoma peritonei (seven patients), and miscellaneous reasons (five patients). Surgeries were performed mainly on advanced patients (40 patients stages 3 and 4 and 16 patients stages 2 and 1) and were synchronous in 36 patients. All patients underwent surgical resection of their primary tumor with PP and IPCH (with mitomycin C, cisplatinum, or both) with a closed sterile circuit and inflow temperatures ranging from 46 degrees to 48 degrees C. Three patients were included twice. RESULTS: A macroscopic complete resection was performed in 27 cases. The mortality and morbidity rates were one of 56 and 16 of 56, respectively. The 2-year survival rate was 79.0% for patients with macroscopic complete resection and 44.7% for patients without macroscopic complete resection (P =.001). For the patients included twice, two are alive without evidence of disease, 54 and 47 months after the first procedure. CONCLUSION: IPCH and PP are able to achieve unexpected long-term survival in patients with bulky PC. However, one must be careful when selecting the patients for such an aggressive treatment, as morbidity rate remains high even for an experienced team.