Impact of disseminated tumor cells in the bone marrow on survival and disease progression in patients with left-sided colorectal cancer.

INTRODUCTION: Disseminated tumor cells (DTCs) are a subset of circulating tumor cells that migrate to the bone marrow. Colorectal cancer is a heterogeneous disease depending on the site of the primary tumor. OBJECTIVES: We aimed to assess the association between the presence of DTCs in the bone marrow and tumor characteristics as well as long­term treatment outcomes in patients with left­sided colorectal cancer. PATIENTS AND METHODS: This prospective study included 91 patients with left­sided colorectal cancer (37 with colon cancer and 54 with rectal cancer) treated between 2007 and 2012 in a single tertiary center. Fifteen patients had stage I cancer; 26, stage II; 26, stage III; and 24, stage IV. Overall survival and cancer relapse rates were compared between patients with different cancer stages and DTC status. RESULTS: Bone marrow DTCs were identified in 42 patients (46.1%). The prevalence of DTCs was not related to tumor infiltration depth, nodal involvement, distant metastasis, tumor stage, or primary tumor site. The 5­year overall survival rates were 59.5% and 53% in the DTC­positive and DTC­negative groups, respectively (P = 0.19). There was a notable trend favoring survival in patients with DTCs with stage II and III disease (both separately and when combined). The number of metachronous distant metastases was significantly lower in DTC­positive patients. CONCLUSIONS: The presence of DTCs in the bone marrow is not associated with primary tumor characteristics and seems to reduce metastasis formation in left­sided colorectal cancer. There is also a trend for improved overall survival in DTC­positive patients. These results are intriguing and warrant further confirmation.

Properties of monocytes generated from haematopoietic CD34(+) stem cells from bone marrow of colon cancer patients.

Monocytes exhibit direct and indirect antitumour activities and may be potentially useful for various forms of adoptive cellular immunotherapy of cancer. However, blood is a limited source of them. This study explored whether monocytes can be obtained from bone marrow haematopoietic CD34(+) stem cells of colon cancer patients, using previously described protocol of expansion and differentiation to monocytes of cord blood-derived CD34(+) haematopoietic progenitors. Data show that in two-step cultures, the yield of cells was increased approximately 200-fold, and among these cells, up to 60 % of CD14(+) monocytes were found. They consisted of two subpopulations: CD14(++)CD16(+) and CD14(+)CD16(-), at approximately 1:1 ratio, that differed in HLA-DR expression, being higher on the former. No differences in expression of costimulatory molecules were observed, as CD80 was not detected, while CD86 expression was comparable. These CD14(+) monocytes showed the ability to present recall antigens (PPD, Candida albicans) and neoantigens expressed on tumour cells and tumour-derived microvesicles (TMV) to autologous CD3(+) T cells isolated from the peripheral blood. Monocytes also efficiently presented the immunodominant HER-2/neu369-377 peptide (KIFGSLAFL), resulting in the generation of specific cytotoxic CD8(+) T lymphocytes (CTL). The CD14(++)CD16(+) subset exhibited enhanced cytotoxicity, though nonsignificant, towards tumour cells in vitro. These observations indicate that generation of monocytes from CD34(+) stem cells of cancer patients is feasible. To our knowledge, it is the first demonstration of such approach that may open a way to obtain autologous monocytes for alternative forms of adaptive and adoptive cellular immunotherapy of cancer.

IL-6 serum levels predict postoperative morbidity in gastric cancer patients.

BACKGROUND: Despite progress in surgical techniques and perioperative care, gastrectomy remains a procedure of significant morbidity. Several scoring systems and clinical measures have been adopted to predict postoperative complications in gastric cancer patients. The aim of this study was to investigate whether high serum levels of interleukin 6 (IL-6) in the early postoperative period may be a prognostic factor of postoperative morbidity. METHODS: A group of 99 consecutive patients with resectable gastric cancer were enrolled. The mean age was 62.9 years and the male/female ratio was 72:27. Subtotal gastric resection was performed in 22 patients and total gastric resection in 77. The IL-6 serum level was measured on the 1st postoperative day (POD). RESULTS: Complications were recorded in 28 patients (28.3%). The observed case-fatality rate was 3.03%. An IL-6 serum level of >288.7 pg/ml on the 1st POD in univariate and multivariate Cox proportional hazard models was an independent prognostic factor for overall complications and infective complications. CONCLUSION: Our study showed an association between perioperative IL-6 serum levels and postoperative morbidity in gastric cancer patients. The IL-6 serum level on the 1st POD was shown to be an independent prognostic factor for both overall complications and infective complications.

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.

[Post transplant lymphoproliferative disorder (PTLD)--10 years follow-up]. / Potransplantacyjna choroba limfoproliferacyjna (PTLD)--obserwacja 10 letnia.

PTLD is a very severe, life threatening complication after organ transplantation. A 17 years old female patient with kidney transplanted (KTx) 7th months ago on immunosuppression therapy: Tacrolimus (TAC), Cell Cept (MMF), Encorton (Enc) was described. She was admitted to the hospital due to: fever, abdominal pain, diarrhea and enlarged cervical and inguinal lymph nodes on palpation. Histopathological diagnosis revealed monomorphic PTLD; diffuse large B cell lymphoma, immunoblastic. Treatment of PTLD was started immediatly after the final diagnosis. MMF was stopped, dose of TAC was reduced (blood level 3-4 ng/ ml), Enc were continued. Anti-CD20 antibodies (Rituximab) were administered. After 7 days of treatment the patient developed signs of diffuse peritonitis. In the course of surgery, perforation in six sites of the small intestine and sigmoid colon were discovered. The Hartman's surgery was performed (sigmoidectomy) with formation of temporary sigmoideostomy. Resected parts of intestine and sigmoid colon were infiltrated by immnunoblasts and revealed diffuse necrosis - the same process was seen in lymph nodes. After the wounds healed, Rituksymab was continued (8 doses) and chemotherapy was started - CHOP - 6 cycles every month. Eight months after surgery, full remission was obtained, TAC was change to rapamycine (RAP) and closure of sigmoideostomy was performed. At present, almost 10 years after first symptoms of PTLD, the patient remains in full remission of the disease.

Circulating tumour-derived microvesicles in plasma of gastric cancer patients.

Cell membrane microfragments called microvesicles (MV) originating from different cells are circulating in the blood of healthy subjects and their elevated numbers are found in different diseases, including cancer. This study was designed to characterise MV present in plasma of gastric cancer patients. Since majority of MV in blood are platelets-derived (PMV), plasma samples deprived of PMV were used. In comparison to control, the number of MV in patients was significantly elevated in all stages, higher in more advanced disease. Patients' MV showed an increased membrane expression of CCR6 and HER-2/neu. The proportion of MV carrying some leucocyte determinants was low and similar in patients and control. Transmission electron microscopy showed their substantial heterogeneity in size and shape. The size determined by dynamic light scattering analysis confirmed this heterogeneity. The MV size distribution in patients was broader within the range of 10-800 nm, while in control MV showed 3-mode distribution within the range of 10-400 nm. Atomic force microscopy confirmed MV size heterogeneity with implication that larger objects represented aggregates of smaller microparticles. Patients' MV exhibited increased absolute values of zeta potential, indicating a higher surface charge. Tumour markers HER-2/neu, MAGE-1, c-MET and EMMPRIN were detected both in control and patients' samples with stronger expression in the latter. Significantly higher expression of MAGE-1 and HER-2/neu mRNA was observed in individual patients. All together, it suggests that at least some MV in plasma of gastric cancer patients are tumour-derived. However, their role in cancer requires further studies.

[The effect of immunomodulating enteral nutrition on postoperative cytokine profile in gastric cancer patients]. / Wplyw immunomodulujacego leczenia zywieniowego na pooperacyjny profil cytokin u chorych na raka zoladka.

UNLABELLED: The operative injury affects the immune system what results in cytokine production--mediators of immune response. Intensity of this reaction depends on the extent of surgery, the time of procedure and actual status of the immune system. In gastric cancer patients malnutrition is diagnosed in as much as 60-80% and increases postoperative morbidity, and the time to functional recovery. The implementation of immunonutrition correlates with the improvement of postoperative course. The aim of this study was to evaluate the influence of immunonutrition on postoperative cytokine (IL-6, IL-10, TNF-alpha) plasma levels in gastric cancer patients. MATERIAL AND METHODS: The group of 99 gastric cancer patients was enrolled. In 54 patients standard postoperative enteral nutrition and in 45 patients immunonutrition was administered. Preoperatively and in 1., 3. and 7. postoperative day plasma levels of IL6, IL10 and TNFalpha were measured. RESULTS: The mean absolute levels of IL-6 and TNF-alpha did not differ statistically between the groups. However, the increment of changes of these cytokines was higher in immunonutrition group reaching statistical significance at day 7 for TNF-alpha (26 pg/ml for immunonutrition vs -10 pg/ml for standard nutrition p = 0.024). IL-10 levels were significantly higher in immunonutrition group at 1. and 3. postoperative days. CONCLUSIONS: The postoperative profile of proinflammatory cytokines did not differ significantly between immunonutrition and standard nutrition groups. The increase of IL-10 plasma levels in early postoperative period in immunonutrition patients may suggest that one of the effects of this therapy is the inhibition of early inflammatory reaction.

Preoperative plasma level of IL-10 but not of proinflammatory cytokines is an independent prognostic factor in patients with gastric cancer.

There have been many discrepant observations on the serum levels of cytokines in cancer patients and their prognostic value. The purpose of this study was to determine the plasma levels of pro- and anti-inflammatory cytokines and their clinical significance in a large group of patients with gastric carcinoma. The levels of tumour necrosis factor alpha (TNF alpha), interleukin-12p40 (IL-12p40), IL-12p70, IL-18, IL-10 and soluble TNF receptors I and II sTNF-Rs were investigated in the plasma of 136 consecutive patients with biopsy proven gastric cancer using specific enzyme-linked immunoabsorbent assays (ELISA). Survival curves were estimated using the method of Kaplan and Meier and the differences in the survival rates were tested by the log-rank test. For multivariate analysis of prognostic factors, the Cox proportional hazard model was used. Proinflammatory cytokines and sTNF-Rs were higher in the whole group of patients in comparison to healthy volunteers. IL-10 was elevated mostly in advanced disease. The increased levels of IL-10 (>10 pg/ml) were associated with significantly poorer survival of patients, while the levels of the other cytokines and sTNF-Rs showed no correlation with prognosis. The increased level of IL-10 is an independent unfavorable prognostic factor in patients with gastric cancer.

Circulating tumour cells and survival of patients with gastric cancer.

BACKGROUND: The prognostic significance of the presence of tumour cells in the blood of gastric cancer patients remains unclear. Their occurrence and its association with the stage of disease and long-term survival was determined. PATIENTS AND METHODS: Fifty-seven patients with stage I-IV gastric cancer were divided into two groups: these with and these without circulating tumour cells that were identified as cytokeratin positive (CK+) cells among CD45- cells (obtained by sorting of CD45+ leukocytes). RESULTS: Tumour cells were detected prior surgery in the peripheral blood of 54.4% patients but no clear association with the stage of disease was observed. After gastrectomy detection rate was 21.1%. There was no significant difference in the 5-year survival of patients, with or without CK+ in the blood. CONCLUSION: The presence of circulating tumour cells is of no prognostic value in patients with resectable gastric cancer.

[Solid and papillary epithelial neoplasm of the pancreas--a rare malignant tumor of pancreas]. / Solid and papillary epithelial neoplasm of the pancreas--rzadki guz nowotworowy trzustki.

The paper presents two cases of solid and papillary epithelial neoplasm of the pancreas (SPENP)--a rare pancreatic neoplasm in a 45-year-old woman admitted to the hospital with the diagnosis of pancreatic tail tumor and 22-year-old woman with the diagnosis of pancreatic head tumor. First patient was subjected to peripheral pancreatic resection; the second patient was subjected to Whipple pancreatoduodenectomy. Histopathological examination confirmed SPENP. The authors present cases and review of the literature on SPENP.

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 [TNFalpha], 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.

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

BACKGROUND: Despite 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-Guerin) and FAM (5-fluorouracil, adriamycin, mitomycin C) chemotherapy on the survival of patients with locally advanced resectable gastric cancer. METHODS: A 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. RESULTS: Overall 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 significantly improved the survival of patients with intestinal-type but not diffuse-type cancer. Immunochemotherapy was well tolerated. CONCLUSION: This 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.

Effect of bowel decontamination with metronidazole and vancomycin on gastroduodenal myoelectric activity.

UNLABELLED: It is well recognized that prolonged antibiotic therapy leading to gut decontamination often results in side effects and may lead to colonization of gut with pathologic bacteria. Changes of a gut microflora could play a role in dysmotility of gastrointestinal tract. The aim of the study was to evaluate influence of intraluminal colon anaerobic and aerobic bacterial flora on myoelectric activity of duodenum and stomach. A myoelectric activity recordings using electrodes implanted on small bowel of the conscious rats were performed. Group I was scheduled for control recording, group II for recordings in 4th day after metronidazole (M) administration (30 mg/kg) and group III for recordings after vancomycin (V) administration (15 mg/kg) respectively. Rat's stools were cultured for confirmation of changes in colon flora composition. Recordings were previously filtered digitally with bandwidth filter 0.01-0.1 Hz and 0.1-1.0 Hz to extract gastric and duodenal slow wave respectively and than analyzed with Fast Fourier Transformation. Baseline duodenal slow wave frequency in control group revealed 0.60 +/- 0.05 Hz. M increased slow waves frequency to 0.64 +/- 0.13 Hz and V did not 0.58 +/- 0.09 Hz (p > 0.05). Slow wave dominant frequency of the stomach showed decrease of frequency from control 0.035 +/- 0.04 to 0.025 +/- 0.06 Hz after M (p < 0.05). Pretreatment with V also did not influence slow wave dominant frequency in comparison to control group (0.036 +/- 0.07 Hz, p > 0.05). CONCLUSION: Only pretreatment with M significantly decreased gastric slow wave frequency. One can speculate that M effects are related not only to gut decontamination but also directly affects ENS. We propose hypothesis that M influence on slow wave frequency may be related not only to its antimicrobial activity but to its potential neurotoxic action on intramural ENS neurons.