Antoni Czupryna

Efficiency of adjuvant immunochemotherapy following curative resection in patients with locally advanced gastric cancer

BackgroundDespite curative resection, 50%–90% of gastric cancer patients die of disease relapse. Although some clinical trials have indicated that chemotherapy and immunochemotherapy may be effective modalities, more recent studies have not been able to define the standard treatment for advanced gastric cancer. The present study evaluated the effect of adjuvant immunochemotherapy with the use of BCG (bacille Calmette-Guérin) and FAM (5-fluorouracil, adriamycin, mitomycin C) chemotherapy on the survival of patients with locally advanced resectable gastric cancer.MethodsA total of 156 patients with stage III or IV gastric cancer who had undergone curative resection were randomly assigned to three treatment groups: BCG + FAM (immunochemotherapy), FAM (chemotherapy), and control (surgery only). Treatment was continued for 2 years or until death. Further postsurgical follow up was carried on for up to 10 years.ResultsOverall 10-year survival was 47.1% for the immunochemotherapy group (P < 0.037 vs FAM and P < 0.0006 vs control), 30% for the chemotherapy group (vs control, NS), and 15.2% for the control group. In patients with pT2/T3 primary tumors, 10-year survival was 55.3% for BCG + FAM vs 28.2% for FAM (P < 0.01) and 14.6% for the control group (P < 0.00018). BCG + FAM signifi-cantly improved the survival of patients with intestinal-type but not diffuse-type cancer. Immunochemotherapy was well tolerated.ConclusionThis study, based on a limited number of patients, indicates that adjuvant immunochemotherapy (BCG + FAM) may prolong the survival of gastric cancer patients after curative gastrectomy; in particular, in patients with pT2/T3 tumors and intestinal-type primary tumors. There was no survival benefit from FAM adjuvant chemotherapy.

Tumour-cell-induced production of tumour necrosis factor by monocytes of gastric cancer patients receiving BCG immunotherapy

SummaryHuman peripheral blood monocytes cocultured with tumour cells were used as an in vitro model of in situ interactions between tumour-infiltrating macrophages and the tumour. Tumour cells stimulated de novo expression of the human tumour necrosis factor α (TNF) gene in monocytes and caused the release of TNF into the culture supernatant. A group of 14 patients with stage IVA gastric cancer receiving adjuvant chemotherapy (5-FU, Adriamycin, mitomycin C: FAM) or immunochemotherapy (BCG+FAM) was investigated for the ability of monocytes to produce TNF in vitro upon stimulation with tumour cells or purified protein derivative of tuberculin (PPD). Patients were followed at biweekly intervals, i.e. before each instillation of BCG epicutaneously over a period of 10 weeks. It was found that monocytes of some patients receiving BCG at the end of the observation period had an enhanced ability to produce TNF following stimulation with tumour cells. In contrast, such production was not substantially altered during the study period in patients on chemotherapy. PPD-induced TNF production was much weaker and was not significantly changed during this observation time. We infer that BCG immunotherapy may induce the subtle changes in some cancer patients that lead to an increased interaction between monocytes and tumour cells and result in enhanced production of cytokine(s) with antitumour properties.

T-regulatory lymphocytes in peripheral blood of gastric and colorectal cancer patients.

AIM To assess the absolute number of T-regulatory cells (Tregs; CD4+CD25+Foxp3+) in the peripheral blood of gastric and colorectal cancer patients. METHODS We enrolled 70 cancer patients (33 gastric cancer, 37 colorectal cancer) and 17 healthy volunteers. The CD3+CD4+ lymphocytes and CD4+CD25+Foxp3+ Tregs in the peripheral blood were analyzed with flow cytometry. The absolute numbers of Tregs were calculated based on the CD4+CD25+Foxp3+ cells percentage of CD3+CD4+ cells and the absolute numbers of CD3+CD4+ cells per microliter. RESULTS The mean number of CD4+CD25+Foxp3+ cells per microliter in colorectal cancer patients was 15.7 (SD: 21.8), for gastric cancer patients 12.2 (SD: 14.3), and for controls 17.5 (SD: 11.4). The absolute number of Tregs was significantly lower in gastric cancer patients than in controls (P = 0.026). There was no statistically significant difference for gastric vs colorectal cancer or colorectal cancer vs controls. The absolute number of Tregs was also significantly depressed in N+ vs N⁻ cancer patients [22.0 (27.7) vs 10.1 (9.0), P = 0.013], and in the subgroup of gastric cancer patients [30.3 (27.6) vs 9.6 (8.0), P = 0.003]. No statistical difference was observed in the proportion of Tregs in the CD4+ population between the groups. CONCLUSION The absolute number of Tregs in peripheral blood of gastric cancer but not colorectal cancer patients was significantly decreased in comparison with that in healthy controls.

Depressed tumor necrosis factor alpha and interleukin-12p40 production by peripheral blood mononuclear cells of gastric cancer patients: Association with IL-1R-associated kinase-1 protein expression and disease stage

Our study investigated the ability of peripheral blood mononuclear cells (PBMCs) isolated from patients with different clinical stages of gastric cancer to produce proinflammatory (tumor necrosis factor alpha [TNFα], interleukin 12p40 [IL‐12p40] and interleukin 6 [IL‐6]) and antiinflammatory (interleukin‐10 [IL‐10]) cytokines after stimulation with lipopolysaccharide (LPS) or tumor cells, and its correlation with IL‐1R‐associated kinase‐1 (IRAK‐1) protein expression. The data showed that TNF production by tumor cell–stimulated PBMCs obtained from patients with advanced gastric cancer was significantly depressed in comparison to the control group. The response to LPS was less affected. IL‐12p40 production was depressed in all stages of disease, while the release of IL‐10 and IL‐6 remained unchanged. Depressed tumor cell–induced TNF and IL‐12p40 production was associated with diminished IRAK‐1 protein expression in PBMC. These findings may suggest that in advanced gastric cancer (at least in some cancer patients) diminished IRAK‐1 protein expression may be a novel mechanism responsible for or facilitating downregulation of innate immune response to tumor cells.

Cytostatic activity on tumour cells of monocytes from patients with gastrointestinal cancer

SummaryThe ability of monocytes from patients with gastrointestinal cancer to inhibit tumour cell growth and suppress PHA-induced lymphocyte response in vitro was assessed. Isolated monocytes, i.e., adherent Fc+ cells from mononuclear cell suspension, were cytostatic but not cytolytic for both K562 line and L1210 lymphoma cells. Monocytes from the patients showed an increased ability to inhibit the growth of L1210 but not K562 line cells. The increased cytostatic activity of monocytes was associated with their suppressor activity. This suggests that suppressor monocytes are also able to arrest tumour cell growth in vitro.

“Activated” monocytes in gastric cancer patients

SummaryThe Fc receptor expression, antibody-dependent cellular cytotoxicity (ADCC), and nitro-blue tetrazolium (NBT) reduction of peripheral blood monocytes from 150 patients with different stages of gastric cancer was assessed and compared with results obtained in 77 normal persons and 104 patients with non-malignant diseases of the gut. Monocytes of cancer patients showed an increased ability to form rosettes with human 0, Rh+ erythrocytes coated with D-specific antibody. ADCC and NBT reduction were also elevated but no correlation was found with the stage of disease. However, all these phenomena were related to the tumor load as elevated values were the same 4–6 months after surgery in the unresectable-tumor group, while they decreased in patients with resectable tumors. These observations suggest that monocytes of some cancer patients are functionally altered (“activated”) in the course of disease.

The altered expression of MHC-class II determinants on monocytes of cancer patients.

SummaryThe expression of MHC class II determinants Ia.7 (detected by cross reactive mouse anti-Iak antibody) and HLA-DR on monocytes (MO) of gastric and colorectal cancer patients was examined. An increased proportion of MO bearing the Ia.7 determinant was found, while the number of MO expressing DR was not elevated. In gastric cancer patients the increased expression of the Ia.7 determinant was most pronounced in advanced cancer (stage IVA and IVB). The increased expression of this determinant was related to the presence of the tumour as the number of MO expressing Ia.7 decreased 6 months following surgical resection of the tumour. Further, the increased expression of Ia.7 on MO correlated with the tumour infiltration of the serosa. The Ia.7 determinants were mainly expressed on MO which also expressed the receptor for the Fc part of immunoglobulin. Immunostaining in cellular infiltrates surrounding the tumour revealed that Ia.7+ macrophages (MØ) were more numerous than in normal gastric mucosa and severe chronic gastritis and were mostly present in close proximity to tumour cells, while DR+ MØ were mainly localized within the stromal tissue of the tumour and their number was not increased in cancer infiltrates. These observations indicate that the Ia.7+ subpopulation of MØ may be involved in the anti-tumour response of the host.

The recommendations for perioperative pain relief in general surgery

Post-operative pain is caused by intra-operative damage to the tissue/organs; its intensity and range are usually proportional to the extent of surgery. Post-operative pain occurs when intra-operative analgesia stops acting. It is caused by damaged superficial tissues (skin, subcutaneous tissue, mucous membranes), as well as deeper structures (muscles, fascias, ligaments, periosteum). If an injury is large, apart from superficial and deep somatic pain, also a visceral component of post-operative pain appears, resulting from the contraction of smooth muscles, caused by crushing or stretching of visceral structures along with inflammatory changes, pulling or twisting of the mesentery. Post-operative pain is a „self-limiting phenomenon”. It is the most intense on the first and second day after surgery and much smaller on the third or fourth day. Pain is the most irritating in patients after thoracotomy and abdominal surgeries, while the procedures on integuments and limbs are much less painful. The following factors are crucial in patient’s perception of pain: the location of surgery, its extent, a degree of tissue trauma, a direction of skin cutting and perioperative analgesia techniques. Pain relief is a fundamental right of the patient. We know that the proper treatment of postoperative pain (POP) significantly reduces perioperative morbidity, including the number of postoperative complications, the duration and costs of hospitalization, especially in patients at the high risk (ASA III-V), those undergoing extensive surgery and hospitalized at intensive care units. Therefore, relieving acute pain, including post-operative pain must be one of the priority institutional objectives and an integral part of treating a „perioperative disease” covering pain relief, early mobilization and enteral nutrition along with active physiotherapy). In Poland, a team of experts appointed by the Association of Polish Surgeons, Polish Society for the Study of Pain, the Polish Society of Anaesthesiology and Intensive Care, has established the following criteria for proper organizing the system aimed to improve the quality of pain management in the postoperative period: – the assessment of pain intensity in all operated patients, at least 4 times a day, – informing patients before surgery, about the possible methods of postoperative pain management, – recording the measurements of pain and the management in accordance with the recommendations of pain relief, – monitoring possible side effects of the treatment on a special form designed to report adverse drug reactions. Appropriate patient education is a crucial element of pain management in the perioperative period. It involves oral and written information on post-operative pain and its methods of treatment. This information should include the most important data on: – methods of measuring the pain, – methods of pain relief, – the importance of post-operative pain relief for the therapeutic process. Preoperative talk to the patient, his legal guardians or relatives should focus on: – obtaining information on patient’s previous experiences with pain and preferences for analgesic treatment,