Differential dignosis: „primary“ or secondary diabetes - should Cushing´s syndrome be routinely screened in the patients with type 2 diabetes mellitus?

Cushing´s syndrome is a rare disease with the population prevalence about 40 patients per 1 million inhabitants, the number among patients with diabetes mellitus (DM) is probably higher. The screening of CS among the DM patients showed the prevalence between 0-2.9% in the groups of outpatients and 2-2.9% among the patients admitted to the hospital at the time of randomization. The routine screening of CS among patients with type 2 DM is not recommended at the moment. Nevertheless, the possibility of CS should be taken into the account mainly in patients with hypertension, obesity, microvascular complications, bad level of metabolic control or high insulin doses, especially, if more of these features are present. A hormonal profile of patients with adrenal incidentaloma should be evaluated.

Serum homocysteine, cholesterol, retinol, alpha-tocopherol, glycosylated hemoglobin and inflammatory response during therapy with bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin.

BACKGROUND: Targeted agents present with a new spectrum of side-effects, including toxicities that negatively impact the risk of atherosclerosis. The aim of the present study was to evaluate the effect of the combination of targeted therapy and chemotherapy on serum homocysteine and other laboratory parameters of cardiovascular risk in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS: Thirty-one patients with metastatic colorectal carcinoma treated with the combination of bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin were studied before and during the therapy. RESULTS: Serum homocysteine decreased significantly throughout the course of treatment. Total cholesterol and low-density lipoprotein cholesterol also decreased significantly during the first month of therapy. In contrast, serum retinol significantly increased during the second and third months of treatment. A significant increase in glycosylated hemoglobin was also observed. After an initial rise, serum C-reactive protein (CRP) and carcinoembryonic antigen (CEA) were significantly lower compared to baseline throughout the course of treatment. Serum ferritin increased throughout most of the course of treatment. A significant correlation was observed between CRP and high-density lipoprotein cholesterol, retinol, ferritin, and CEA. CEA correlated with hemoglobin, retinol, and ferritin. Retinol correlated significantly with hemoglobin. CONCLUSION: Tumor control, reflected in lower CEA, resulted in suppression of the acute phase response and generally in favorable effects on laboratory parameters indicative of risk factors of atherosclerosis, including lower homocysteine concentrations, and lower total and LDL cholesterol.

Effect of aromatase inhibitors on lipid metabolism, inflammatory response and antioxidant balance in patients with breast carcinoma.

BACKGROUND: Aromatase inhibitors may affect lipid metabolism, inflammatory response and antioxidant balance. PATIENTS AND METHODS: One hundred and eighty-six post-menopausal patients with breast carcinoma underwent evaluation of parameters of lipid metabolism, inflammatory response and antioxidant balance immediately before as well as 2 and 4 months after the start of therapy with aromatase inhibitors. RESULTS: A significant increase in total, very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, lipoprotein (a), retinol, C-reactive protein and fibrinogen was observed. The changes of serum lipid concentrations were restricted mostly to the patients pre-treated with tamoxifen who had significantly lower baseline levels of these parameters. CONCLUSION: An increase of serum cholesterol, lipoprotein (a), C-reactive protein and fibrinogen in patients treated with aromatase inhibitors is the result of tamoxifen withdrawal rather than a direct effect of therapy. No significant changes in serum lipids were observed in patients treated with aromatase inhibitors in the first-line setting.

Urinary neopterin, hemoglobin and peripheral blood cell counts in breast carcinoma patients treated with dose-dense chemotherapy.

BACKGROUND: Among other actions, chemotherapy may induce an activation of systemic inflammatory and immune response. PATIENTS AND METHODS: Urinary neopterin was evaluated, using high-performance liquid chromatography, before and during dose-dense combination chemotherapy with doxorubicin, cyclophosphamide and sequential paclitaxel (neoadjuvant or adjuvant) in 194 patients with breast carcinoma. Hemoglobin, peripheral blood cell count and, in a subgroup of patients, iron metabolism were also evaluated. RESULTS: Urinary neopterin increased significantly during the chemotherapy. The increase in urinary neopterin was accompanied by a gradual decrease of hemoglobin. A marked increase in serum ferritin concentration was observed during the chemotherapy, along with fluctuations of iron concentrations. Among 161 patients treated with primary chemotherapy, the pathological response was evaluable in 150. Pathological complete response was observed in 37 cases (25%). In patients with pathological complete response, significantly lower serum ferritin concentrations were observed. CONCLUSION: Present data demonstrate the presence of systemic immune activation, reflected in increased urinary neopterin concentrations, in breast carcinoma patients treated with dose-dense chemotherapy. Lower ferritin concentrations were predictive of pathological complete response.

Expression of CD40 and growth-inhibitory activity of CD40 ligand in ovarian cancer cell lines.

OBJECTIVE: Soluble recombinant human CD40 ligand trimer (rhuCD40Lt) has shown antitumor activity in preclinical and clinical studies. We evaluated the effect of rhuCD40Lt on epithelial ovarian carcinoma (EOC) cell lines. METHODS: Expression of the receptor, CD40, was determined by reverse transcriptase-polymerase chain reaction and flow cytometry, and antiproliferative effects of rhuCD40Lt, either alone or in combination with recombinant interferon-gamma (rIFN-gamma), were examined in 8 EOC lines. RESULTS: Expression of CD40 was elevated in 5 out of 8 EOC cell lines examined by flow cytometry, and the presence of CD40 transcripts was detected by RT-PCR in all 8 cell lines. CD40 expression was increased by rIFN-gamma, but treatment with rhuCD40Lt decreased CD40 expression in 4 of the 5 lines that had shown elevated CD40 expression. rhuCD40Lt had a growth-inhibitory effect on 2774 cells, which also exhibited the highest level of CD40 expression. Growth-inhibitory effect of rhuCD40Lt was additive with rIFN-gamma on 2774, NMP-1, a cisplatin-resistant subline of OVCAR3, and HEY cell lines. The number of apoptotic tumor cells was increased following treatment with rhuCD40Lt. CONCLUSIONS: CD40 is expressed on EOC cell lines, and expression was found at the transcript level in all of the EOC lines examined. rIFN-gamma enhances CD40 expression, though a decrease in CD40 expression was observed following treatment with rhuCD40Lt. Growth-inhibitory activity of rhuCD40Lt on EOC lines that express CD40 could be enhanced when rhuCD40Lt treatment was combined with rIFN-gamma. These results suggest that future studies of the combination of rhuCD40Lt and rIFN-gamma might warrant consideration.

Urinary neopterin in patients with liver tumors.

AIMS AND BACKGROUND: Primary and secondary liver tumors are associated with poor prognosis. Neopterin is an indicator of systemic immune activation, and increased neopterin concentrations have been associated with poor prognosis in a wide range of malignant tumors. METHODS: Urinary neopterin was determined by high-performance liquid chromatography in 154 patients with primary and secondary liver tumors. The survival of different groups of patients was compared by log-rank test, and Cox regression was used for multivariate analysis. RESULTS: Urinary neopterin was significantly increased in patients compared to controls. A statistically significant correlation was observed between urinary neopterin and age of the patients, hemoglobin concentration, mean erythrocyte volume and peripheral blood leukocyte or platelet count. In univariate analysis, urinary neopterin below 214 micromol/mol creatinine, peripheral blood leukocytes below 8 x 10(9)/L, hemoglobin equal to or above 125 g/L, no extrahepatic tumor, stage of liver involvement, and colorectal, breast or ovarian primary were significant prognostic factors for survival. In multivariate analysis, Bengtsson stage, presence of extrahepatic involvement, primary other than colorectal, breast or ovarian carcinoma, peripheral blood leukocyte count and urinary neopterin were independent prognostic factors. Increased urinary neopterin during and at the end of follow-up was also associated with poor prognosis. CONCLUSIONS: Urinary neopterin is increased in patients with liver tumors. Neopterin is an independent prognostic indicator in patients with liver tumors along with Bengtsson stage, presence of extrahepatic disease, primary site and peripheral blood leukocyte count.

Survival of patients with colorectal cancer liver metastases treated by regional chemotherapy.

BACKGROUND/AIMS: Liver is the most common site of metastatic disease in colorectal cancer. Superior response rate was demonstrated in trials comparing hepatic arterial administration of cytotoxic agents with systemic chemotherapy. METHODOLOGY: Records of 109 consecutive patients with colorectal carcinoma metastatic to the liver treated by regional chemotherapy, who underwent implantation of a port system into hepatic artery or portal vein tributaries between 1991 and 1999, were reviewed and survival was evaluated using the log-rank test and multivariate analysis (Cox's proportional hazard regression). RESULTS: The median survival from diagnosis was 24 months. Survival was significantly longer for patients treated by radical resection, and patients treated in 1997-1999. On multivariate analysis, treatment by 6 or more chemotherapy cycles, stage 1 liver metastases, treatment with irinotecan and radical resection were associated with better survival, while the presence of extrahepatic disease had an adverse effect on the risk of death. Extrahepatic spread was subsequently detected in almost half of the patients who had originally isolated liver metastases. CONCLUSIONS: Patients treated by liver resection had the best outcome, while patients with extrahepatic diseases had poor prognosis. The prognosis of patients treated by regional chemotherapy improved significantly with the advent of irinotecan and better selection.

Regional chemotherapy in patients with breast carcinoma liver metastases.

BACKGROUND/AIMS: Although liver is a common site of metastases in breast cancer, isolated liver metastases in patients with disseminated breast cancer are rare. The role of liver-directed therapies in these patients is based on data derived from retrospective analysis of case series. METHODOLOGY: We have reviewed the records of 8 patients with liver metastases and a history of breast cancer treated at our institution over a period of 11 years with regional chemotherapy administered through surgically implanted port systems. RESULTS: Three of the patients also had a history of second primary colorectal carcinoma. One patient had evidence of extrahepatic spread. All patients were treated by regimens based on the combination of 5-fluorouracil and folinic acid. Three patients were also treated by cytoreductive procedures. The median survival times from the diagnosis and port systems implantation were 34 months and 31 months, respectively. CONCLUSIONS: Our data support the use of regional intraarterial chemotherapy in patients with metastatic breast cancer limited to the liver.

Neopterin in renal cell carcinoma: inhalational administration of interleukin-2 is not accompanied by a rise of urinary neopterin.

Inhalational administration of interleukin-2 (IL-2) is effective in controlling renal cell carcinoma (RCC) lung metastases with minimal toxicity. Neopterin is an indicator of systemic immune activation in metastatic cancer and is increased after systemic IL-2 administration. Urinary neopterin was investigated in 13 patients with metastatic RCC and 18 controls. In seven patients, urinary neopterin was followed before and after treatment with inhalational IL-2. Neopterin was measured by high-performance liquid chromatography and creatinine was determined by Jaffé reaction. Urinary neopterin was significantly increased in patients with metastatic RCC compared to controls (257 +/- 263 micromol/mol creatinine vs. 110 +/- 41 micromol/mol creatinine; Mann-Whitney U-test, p < 0.05). Median survival was significantly longer in patients with urinary neopterin <173 micromol/mol creatinine compared to patients with neopterin > or = 173 micromol/mol creatinine (698 vs. 245 days; log-rank test, p < 0.05). No significant increase was observed after inhalational IL-2 therapy (147 +/- 101 vs. 153 +/- 54 micromol/mol creatinine). We conclude that urinary neopterin is increased in patients with metastatic RCC, and higher neopterin concentrations are indicative of poor prognosis. The absence of an increase in urinary neopterin after inhalational IL-2 therapy is in accord with the lack of significant systemic toxicity.

Hepatic arterial infusion chemotherapy in sarcoma liver metastases: a report of 6 cases.

AIMS AND BACKGROUND: Liver metastases in patients with sarcoma are rare and associated with a poor prognosis. The experience with liver-directed therapies, eg hepatic arterial infusion, in these patients is limited. METHODS: Six patients with sarcoma metastatic to the liver (4 patients with gastrointestinal stromal tumors and 2 patients with leiomyosarcoma) were treated by hepatic arterial infusion in our center over a 12-year period. Since the experience was limited, a pooled analysis of reports with data on survival of 22 individual patients was performed. RESULTS: None of the 5 assessable patients responded to the therapy, and liver metastases progressed in all patients. The median survival was 20 months. In the pooled analysis, partial response was observed in 10 of 21 assessable patients (48%) and median survival was 20 months. The survival was significantly longer in responding patients compared to nonresponders (35 vs 14 months; logrank test, P = 0.009). CONCLUSIONS: Hepatic arterial infusion has little efficacy in the treatment of sarcoma metastatic to the liver. More promising results have been reported for chemoembolization. The survival of responding patients seems to be better compared to non-responders.

Hepatic arterial infusion chemotherapy in gastric cancer: a report of four cases and analysis of the literature.

AIMS AND BACKGROUND: Gastric cancer is associated with high mortality. Although the liver is a common site of metastases in this tumor, the experience with liver-directed therapies is limited. METHODS: We report a single-center experience involving four patients with liver metastases from gastric cancer treated by hepatic arterial infusion (HAI). In addition, we performed a search for reports on HAI in gastric cancer metastatic to the liver and used the studies with data on survival of individual patients for a pooled analysis. RESULTS: Among three valuable patients, one had a complete response, one had stable disease and one had progressive disease. The patient with complete response is still alive 41 months after the diagnosis of liver metastases, while the other patients died 6, 22 and 31 months after the diagnosis. Objective responses were observed in 48% of the 25 patients in the pooled analysis. Objective response and limited hepatic involvement were independent predictors of survival in these patients. CONCLUSIONS: Although isolated liver involvement in metastatic gastric cancer is rare, HAI seems to be similarly effective in these patients as in patients with liver metastases from colorectal cancer. The prognosis is significantly better in gastric cancer patients who have limited hepatic involvement and attain an objective response after HAI.

Growth-inhibitory effect of a novel synthetic triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, on ovarian carcinoma cell lines not dependent on peroxisome proliferator-activated receptor-gamma expression.

OBJECTIVES: Despite the advent of new chemotherapeutic drugs in recent decades, epithelial ovarian carcinoma (EOC) remains the leading cause of death from gynecologic cancers, and new therapeutic targets and agents are urgently needed. 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a novel synthetic triterpenoid with anti-tumor activity against a wide range of tumors in vitro and in vivo. CDDO is a ligand for the peroxisome proliferator-activated receptor-gamma (PPARgamma). The aim of the present study was to evaluate CDDO activity in EOC cell lines in vitro. METHODS: The expression of PPARgamma was examined by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) in eight EOC cell lines (2774, SKOV3, CAOV3, OVCAR3, NMP-1, HEY, 2008 and 2008.C13), and the growth inhibitory activity of CDDO was assessed using the MTT assay. RESULTS: PPARgamma RNA was expressed in all eight cell lines examined, but the expression varied widely among cell lines. In contrast, CDDO showed a similar degree of activity in different EOC cell lines independent of cisplatin sensitivity, with 50% inhibitory concentrations ranging from 1 to 4 microM. Experiments combining CDDO with cisplatin and paclitaxel indicated weak antagonism. The growth-inhibitory activity of CDDO was unaffected by PPARgamma antagonist T007. CONCLUSIONS: Although differences were observed in PPARgamma expression in EOC cell lines, CDDO had similar growth-inhibitory activity in all cell lines examined, indicating that the antitumor activity of CDDO in vitro is mediated by a mechanism independent of PPARgamma. The activity of CDDO in platinum-resistant cell lines is encouraging with respect to the potential clinical use of the drug.

rIFN-gamma-mediated growth suppression of platinum-sensitive and -resistant ovarian tumor cell lines not dependent upon arginase inhibition.

BACKGROUND: Arginine metabolism in tumor cell lines can be influenced by various cytokines, including recombinant human interferon-gamma (rIFN-gamma), a cytokine that shows promising clinical activity in epithelial ovarian cancer (EOC). METHODS: We examined EOC cell lines for the expression of arginase in an enzymatic assay and for transcripts of arginase I and II, inducible nitric oxide synthase (iNOS), and indoleamine 2,3-dioxygenase (IDO) by reverse transcription-polymerase chain reaction. The effects of rIFN-gamma on arginase activity and on tumor cell growth inhibition were determined by measuring [3H]thymidine uptake. RESULTS: Elevated arginase activity was detected in 5 of 8 tumor cell lines, and analysis at the transcriptional level showed that arginase II was involved but arginase I was not. rIFN-gamma reduced arginase activity in 3 EOC cell lines but increased activity in the 2008 cell line and its platinum-resistant subline, 2008.C13. iNOS transcripts were not detected in rIFN-gamma-treated or untreated cell lines. In contrast, IDO activity was induced or increased by rIFN-gamma. Suppression of arginase activity by rIFN-gamma in certain cell lines suggested that such inhibition might contribute to its antiproliferative effects. However, supplementation of the medium with polyamine pathway products did not interfere with the growth-inhibitory effects of rIFN-gamma EOC cells. CONCLUSIONS: Increased arginase activity, specifically identified with arginase II, is present in most of the tested EOC cell lines. rIFN-gamma inhibits or stimulates arginase activity in certain EOC cell lines, though the decrease in arginase activity does not appear to be associated with the in vitro antiproliferative activity of rIFN-gamma. Since cells within the stroma of EOC tissues could also contribute to arginine metabolism following treatment with rIFN-gamma or rIFN-gamma-inducers, it would be helpful to examine these effects in vivo.

Intraperitoneal fluid neopterin, nitrate, and tryptophan after regional administration of interleukin-12.

Activated monocytes-macrophages may be associated with antitumor activity, and activation of these cells by certain cytokines, primarily interferon gamma (IFN-gamma), can be indicated by alterations in the concentrations of neopterin, nitrate, or tryptophan. Specimens of peritoneal fluid were obtained from patients with intra-abdominal neoplasia who were undergoing treatment in a phase I trial of weekly intraperitoneal recombinant interleukin-12 (rhIL-12), an inducer of IFN-gamma. Concentrations of neopterin, nitrate, tryptophan, IFN-gamma, and tumor necrosis factor alpha (TNF-alpha) were determined at various times during the first 48 hours in 11 patients who received intraperitoneal rhIL-12 in doses ranging from 100 to 1,500 ng/kg. An increase in peritoneal fluid nitrate concentrations was observed in nine of these patients. Increased concentrations of TNF-alpha and IFN-gamma were detected in 3 of 9 and 8 of 11 patients, respectively. Increased peritoneal fluid neopterin concentrations were detected by 24 hours after the injection in all patients studied. A significant increase in the ascitic fluid neopterin level could still be detected after 1 or 2 weeks of treatment (mean +/- standard error, 7.8 +/- 1.5 nM vs. 4.6 +/- 0.3 nM; Wilcoxon test, p = 0.0019), which is consistent with monocyte-macrophage activation. In contrast, the tryptophan concentration was lower (4.7 +/- 1.1 microM vs. 6.1 +/- 1.2 microM; p = 0.0428) after 1 or 2 weeks of treatment. There was a significant correlation between the dose of rhIL-12 and posttreatment neopterin concentrations (r(s) = 0.559, p = 0.0102). The intraperitoneal delivery of rhIL-12 appears to be associated with an immediate, sustained, and dose-dependent increase in peritoneal fluid neopterin, associated in most patients by an increase in IFN-gamma and in certain patients by an increase in nitrate and a decrease in tryptophan concentrations.

Regional chemotherapy in biliary tract cancers--a single institution experience.

BACKGROUND/AIMS: The prognosis of biliary tract cancers is poor. The aim of the present report was to analyze retrospectively the effectiveness of regional chemotherapy in patients with biliary tract cancers treated at a single institution. METHODOLOGY: Thirty-two patients with biliary tract cancers, 17 patients with cholangiocarcinoma and 15 patients with gallbladder carcinoma, were treated by regional administration of the chemotherapy, usually the combination of 5-fluorouracil, cisplatin and folinic acid. Eighteen patients with inoperable tumors received no surgical treatment, 10 patients were treated by palliative resection (cohort B), and 4 patients received radical surgery (cohort C). RESULTS: The median survival of the patients is (mean +/- standard deviation) 14 +/- 17+ (median 7+) months for cohort A patients, 22 +/- 17+ (median 17+) months for cohort B patients, and 32 +/- 4+ (median 33+) months for cohort C patients. One-year survival was 38% (6 out of 16 patients) for cohort A, 80% (8 out of 10 patients) for cohort B, and 100% (4 out of 4 patients for cohort C). Two-year survival was 15% (2 out of 13) for cohort A, 30% (3 out of 10) for cohort B, and 100% (4 out of 4) for cohort C. One out of 12 patients (8%) in cohort A and 1 out of 10 patients (10%) in cohort B survived more than 5 years. After intraarterial chemotherapy, a significant increase was observed in the absolute numbers of CD3+, CD3+CD8+ and CD8+CD28+ lymphocytes, as well as an increase in CD3+CD4+ and natural killer lymphocytes. CONCLUSIONS: Regional chemotherapy is active in controlling the disease, and seems to result in prolongation of survival in patients with biliary tract cancer. Administration of regional chemotherapy is also associated with a rise of circulating lymphocyte numbers.