Impaired coronary flow reserve in metastatic cancer patients treated with sunitinib.

PURPOSE: Hypertension is one of the major side effects of sunitinib, an angiogenesis inhibitor used in the treatment of metastatic renal cell carcinomas (mRCC) and gastrointestinal stromal tumors (GIST). Endothelial dysfunction, an early and reversible event in the pathogenesis of atherosclerosis, is suggested to be one of the possible underlying mechanisms of hypertension caused by angiogenesis inhibitors. Coronary flow reserve (CFR) measurement by trans-thoracic Doppler echocardiography (TTDE) reflects coronary microvascular and endothelial functions, as a cheaper and an easy screening test. We have used TTDE to evaluate endothelial function and coronary microvascular function in mRCC and GIST patients under sunitinib treatment. METHODS: Eighteen metastatic cancer patients (16 mRCC and 2 GIST) on sunitinib treatment and 27 healthy subjects were enrolled in this cross-sectional study. Thyroid stimulating hormone (TSH), lipid profile, creatinine, hemoglobin, glucose, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anthropometric and physical parameters of patients were recorded. CFR recordings were performed by the Vivid 7 echocardiography device. RESULTS: CFR was significantly lower in patients when compared with controls (1.82±0.4 vs 2.71±0.8, respectively; p < 0.001). Impaired CFR was found in 13 (72%) patients whereas all controls had normal CFR values. CFR was inversely correlated with the duration of sunitinib treatment (r=-0.36, p =0.01), high sensitivite (hs) CRP (r = -0.574, p =0.01) and ESR (r = - 0.5, p = 0.02). CONCLUSION: Our findings indicate that CFR is significantly impaired in cancer patients on sunitinib treatment. There is an inverse correlation between CFR and duration of sunitinib treatment and inflammation markers.

Prognostic significance of the metastatic lymph node ratio for survival in colon cancer.

PURPOSE: The metastatic lymph node ratio (LNR) is defined as the number of metastatic lymph nodes divided by the total number of lymph nodes removed. The aim of this study was to investigate the prognostic significance of the metastatic LNR in patients with colon cancer. METHODS: One-hundred twenty-five patients with stage III colon cancer admitted to the Istanbul University Oncology Institute between 1995 and 2005 were retrospectively evaluated. The median LNR was 0.2, and this figure was accepted as cut-off value in the present study. Overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. Log-rank test was used for intergroup comparisons. The significance level was put at p<0.05. RESULTS: Of the 125 patients, 58 (46.4%) were males and 67 (53.6%) females with median age 57 years. The mean OS in patients with a LNR <0.2 was 120.5±7.3 months, with a LNR ≥0.2 was 92.8±9.0 months Although clinically significant, the difference between the groups was statistically insignificant (p=0.074). The mean duration of DFS in patients with a LNR <0.2 was 100.6±8.6 months and for those with a LNR ≥0.2 it was 71.7±8.3 months (p=0.017). The 5-year DFS rate in patients with a LNR ≥0.2 was 42.3%; it was 64.1% in those with LNR<0.2. The difference between the groups was statistically significant (p=0.017). CONCLUSION: The determination of the optimal cut-off value for the LNR in future prospective studies will help defining prognosis with better accuracy in colon cancer patients.

Glutathione S-transferase P1 polymorphisms are associated with time to tumor progression in small cell lung cancer patients.

PURPOSE: Many of commonly used chemotherapeutics in lung cancer treatment are metabolized by glutathione-S transferases (GSTs). The placental isoform of GST (GSTP1) is the most abundant isoform in the lung. Polymorphisms within the GSTP1 may result in alterations in enzyme activity and change sensitivity to platinum-based chemotherapy. We investigated whether the polymorphism within the exons 5 and 6 of GSTP1 gene may change response to therapy, time to tumor progression (TTP) and overall survival in small cell lung cancer (SCLC) patients. METHODS: Ninety-four histologically confirmed patients with SCLC were enrolled in this study during 1995-2006. GSTP1 Ile105Val polymorphism in exon 5 and GSTP1 Ala- 114Val polymorphism in exon 6 were determined by using PCR-RFLP techniques. Associations between the GSTP1 polymorphisms and treatment response were evaluated using the chi-square test. Associations between the GSTP1 polymorphisms and TTP and overall survival were compared using Kaplan-Meier survival curves. RESULTS: We found no significant associations between exon 5 and exon 6 GSTP1 gene polymorphisms and response to therapy or overall survival. Patients carrying both variant exon 5 (Ile/Val or Val/Val) and variant exon 6 (Ala/Val) genotypes had significantly shorter TTP (5 vs. 8 months, p = 0.04). Moreover, patients with heterozygote exon 6 variant had presented with extensive-stage disease. CONCLUSION: No individual effect of variant alleles was found in relation to chemotherapy response, median TTP and overall survival. The carriage of both types of variant alleles may predict worse outcome.

L-myc gene polymorphism and risk of thyroid cancer.

UNLABELLED: L-myc gene polymorphism is a representative genetic trait responsible for an individual's susceptibility to several cancers. However, there have been no reports concerning the association between thyroid cancer and L-myc gene polymorphism. AIM: To analyze the distribution of L-myc gene polymorphism in Turkish patients with thyroid disorders and thyroid cancers. METHODS: We used a molecular genotyping method, polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). We studied 138 patients of whom 47 had multinodular goiter, 13 had follicular cancer and 69 had papillar cancer, in comparison with control group of 109 healthy individuals. RESULTS: No significant difference in the distribution of genotypes was observed between thyroid patients and controls. Carrying SS or LS genotype revealed a 1.96-fold (95% CI 0.573-6.706) risk for the occurrence of follicular cancer when compared with controls, and 3.11-fold (95% CI 0.952-10.216), when compared with multinodular goiter patients (p=0.04). CONCLUSION: We suggest that L-myc genotype profiling together with other susceptibility factors, may be useful in the screening for thyroid nodular malignancy.

Adjuvant chemoradiation for patients with adenocarcinoma of the pancreas: an expirence of single institute.

Only a small percentage of patients with pancreatic cancer have limited disease suitable for curative resection. Even with surgery, patients often have poor long-term survival due to relapse of the disease. There are controversies about the adjuvant treatment of these patients. We reported the survival of resected pancreatic cancer from a single institute. About 128 consecutive patients who had complete resection of the pancreatic ductal adenocarcinoma were evaluated, retrospectively. Chemoradiotherapy (45 Gy plus 5-fluorouracil) was given to 63 patients. Fifty-five patients declined to take chemoradiotherapy or with poor performance status were observed without additional treatment. Eight patients took only chemotherapy and two patients took only radiotherapy. The median survival of chemoradiotherapy group was significantly higher than the observation group (13 months vs. 4 months, respectively; P < 0.001). In multivariate analyses the most important factors improving survival were the application of chemoradiation (P < 0.001), low-level serum LDH (P = 0.026), good performance status (P = 0.033) and low serum CA19-9 (P = 0.037). Although adjuvant chemoradiotherapy has a significant survival benefit when compared with the observation group, the survival data are still poor for pancreatic cancer. Therefore, we need more effective additional or adjuvant treatment modalities.

Effect of pre-emptive ketamine on sensory changes and postoperative pain after thoracotomy: comparison of epidural and intramuscular routes.

BACKGROUND: In this study we have evaluated the efficacy of ketamine via i.m. and epidural routes for the control of post-thoracotomy pain. METHODS: The study was randomized, double blinded and placebo controlled. With the approval of the Faculty Ethics Committee, 60 patients undergoing elective thoracotomy were randomized into three equal groups. Group IM had i.m. ketamine 1 mg kg(-1) in 2 ml plus epidural normal saline; Group EPI had epidural ketamine 1 mg kg(-1) in 10 ml plus i.m. normal saline; Group C had epidural normal saline 10 ml plus i.m. normal saline 10 ml. Anaesthesia was standardized. Postoperative analgesia was maintained with epidural patient-controlled analgesia using bupivacaine and morphine. Visual analogue scale values and analgesic consumption were evaluated at 2, 4, 6, 8, 10, 12, 24 and 48 h after surgery. The areas of allodynia, pin-prick hyperalgesia and pressure hyperalgesia were measured at 48 h, and days 15 and 30 in all groups. RESULTS: Intraoperative fentanyl requirement was significantly lower in Group EPI than Group C. The morphine and bupivacaine requirements were significantly lower in Group EPI than the other two groups in the postoperative period. There was reduced pin-prick hyperalgesia and touch allodynia in the EPI group. There were no side-effects attributable to ketamine. CONCLUSION: The results of the present study demonstrate that pre-emptive epidural ketamine is effective in reducing intra- and postoperative analgesic requirements, hyperalgesia and touch allodynia.

Combination chemotherapy with docetaxel and irinotecan in metastatic malignant melanoma.

AIM: The aim of the current trial was to assess the efficacy and toxicity of 3-weekly intravenous docetaxel and irinotecan in the treatment of patients with metastatic malignant melanoma. MATERIALS AND METHODS: Sixteen patients with no history of previous cytotoxic agents or immunological treatment for advanced disease were treated with docetaxel 50 mg/m2 and irinotecan 150 mg/m2 intravenously over 60 min every 21 days. Prior immunotherapy with interferon and chemotherapy for adjuvant therapies were accepted provided there was a minimum 4-week treatment-free interval. Response evaluation was performed after two cycles. RESULTS: None of the patients had chemotherapy-induced tumour response. Eight patients achieved stable disease and others had progression of disease. The median survival time was 136 days (95% CI: 30.2-241.8), and the 3-month survival rate was 62.5%. Patients with stable disease (n = 8) had a longer survival than non-responders (P = 0.023, Breslow test). Generally side effects were mild and tolerable. Grade III-IV haematological toxicity occurred in approximately 10%. Severe emesis, stomatitis and diarrhoea was seen in less than 20% of the patients. Alopecia was observed in all patients. CONCLUSION: A 3-weekly intravenous docetaxel and irinotecan combination appears to be inactive in the treatment of patients with malignant melanoma and has not been recommended.

Prognostic significance of melanoma inhibiting activity levels in malignant melanoma.

This analytic (phase II) study aimed to investigate the hypothesis that the decline in serum melanoma-inhibiting activity (MIA) levels following initiation of treatment might have prognostic value. The mean serum lactate dehydrogenase (LDH), MIA and S100 levels in patients with malignant melanoma before treatment were higher than in the control group. Patients with visceral dissemination had much higher mean serum MIA levels than patients with nodal spread only. A regression model was constructed to analyse the prognostic factors in patients with advanced stage malignant melanoma. Therapy included surgical excision or lymph node dissection, hypofractionated radiotherapy, and immunotherapy or chemotherapy. Blood samples were collected within 24 h before the initiation of systemic treatment and two or three times more at 20-28 day intervals. Overall survival was investigated by univariate analysis, and correlation with clinical factors was compared using the log-rank test. Gender, primary tumour site, surgery, radiation therapy, serum S100 levels before systemic treatment and choice of chemotherapy were not correlated with the outcome. In addition to the stage of disease, low serum LDH levels before systemic treatment and a decline in serum MIA levels following initiation of systemic treatment predicted a favourable outcome. Metastasis to visceral organs was associated with higher serum MIA levels. Persistence of high serum MIA levels despite systemic treatment predicts an unfavourable prognosis.

Treatment of aggressive non-Hodgkin's lymphoma with dose-intensified epirubicin in combination of cyclophosphamide, vincristine, and prednisone (CEOP-100): a phase II study.

Epirubicin is an agent with a lower incidence of cardiotoxicity and myelotoxicity compared with doxorubicin; and it is active in patients with non-Hodgkin's lymphoma (NHL). Our aim was to define the therapeutic efficacy and toxicity of dose-intensified epirubicin in combination with cyclophosphamide, vincristine, and prednisone (CEOP) in patients with diffuse large-cell NHL. Previously untreated patients aged between 15 and 75 years, with at least one measurable lesion, adequate liver, renal, cardiac functions, and no central nervous system involvement were included in the study. The planned chemotherapy regimen CEOP consisted of cyclophosphamide 750 mg/m2, epirubicin 100 mg/m2, and vincristine 1.4 mg/m2 intravenously on day 1 and 100 mg prednisone taken orally on days 1 to 5. Courses were repeated every 21 days. Patients with stage I and II received four cycles of chemotherapy followed by involved-field radiotherapy, and patients with stage III and IV received six cycles of chemotherapy followed by radiotherapy to bulky lymph node sites. Seventy-five patients were enrolled in the study. The complete response rate was 83.8%, and 72 patients were assessable for toxicity. The most common toxicity was myelosuppression; 13.9% of the patients had grade III-IV neutropenia. Severe mucositis, diarrhea, and emesis were uncommon (<10%). At a median follow-up period of 41 months, the 5-year progression-free survival and overall survival rates were 63.5% and 65.3%, respectively. Increasing the dose intensity of epirubicin can yield a similar complete response rate compared with the regimens used in NHL without significantly increasing the toxicity rate associated with chemotherapy. The role of dose-intensive epirubicin should be investigated further in future randomized trials.

Serum levels of the soluble adhesion molecules in patients with malignant melanoma.

The incidence of malignant melanoma has been steadily increasing over the past decades. CD 44 is a transmembrane glycoprotein which is implicated in a number of adhesive and migratory events. Downregulation of CD 44 is implicated in the metastatic process. P-Selectin is a member of the selectin family of cell surface molecules. The levels of P-Selectin in biological fluids may be elevated in subjects with a variety of pathological conditions. In malignant melanoma, elevation of the plasma level of soluble intercellular adhesion molecule-1 (sICAM-1) has been associated with a reduction in disease-free survival. This study was performed to investigate the differences in the serum concentrations of the adhesion molecules in patients with malignant melanoma. The study group consisted of 52 patients with malignant melanoma and 20 healthy subjects. No meaningful difference was observed for P-selectin and sICAM 1 levels. A statistically significant decrease was observed in the cancer patients for serum CD 44 levels.

The roles of chemotherapy and surgery in gastric carcinoma and the influence of prognostic factors on survival.

In this study, we present the results of surgery and chemotherapy and the impact of various prognostic factors on survival in patients with gastric carcinoma with a follow-up of 6 years. All of the 328 cases were adenocarcinoma histologically and had a median age of 55 years. Median survival was 11 months, and the 5-year survival rate was 18%. Nonmetastatic cases were associated with improved survival as compared with the cases with metastatic disease (p<0.001). Patients with gastrectomy had improved survival (p<0.001). Subtotal gastrectomized patients had better survival rates in comparison to the total gastrectomized patients (p = 0.03). Addition of splenectomy to total gastrectomy and adjuvant chemotherapy did not influence survival rates (p>0.05). In metastatic patients, we determined beneficial effects of gastrectomy and chemotherapy on survival. The benefit was most predominant in chemoresponsive patients (p<0.001). Higher serum CA 19.9 levels in patients without metastases, higher serum lactate dehydrogenase and carcinoembryonic antigen levels in patients with metastases, and lower serum albumin levels in both stages were determined as significant predictors of poor survival. On multivariate analysis, only higher serum CA 19.9 level was the independent unfavorable prognostic factor of survival time in nonmetastatic patients (p = 0.008). In metastatic disease, older age (p = 0.03) and male gender (p = 0.05) were associated with poorer survival. In conclusion, gastric cancer is a great health problem, especially in developing countries, and we need more optimal approaches and treatment modalities for gastric cancer.

Factors influencing the distribution of metastases and survival in extensive disease small cell lung cancer.

This study was conducted to investigate the distribution of metastatic lesions and their influence on survival, as well as other prognostic factors previously shown to have an impact on the outcome of patients with extensive small cell lung cancer (SCLC). Of the 207 patients were included and retrospectively analyzed; 124 patients had extended disease at initial presentation and the remaining 83 developed metastatic disease during follow-up. Patients who relapsed presented most frequently with distant metastases. The brain was the most frequent organ targeted for metastatic disease following the completion of chemotherapy (p<0.05). Serum LDH levels correlated significantly with the presence of liver metastasis (p<0.001). The site of involvement did not seem to have an impact on survival. Nevertheless, patients with multiple metastatic sites had a significantly poor survival rate (p = 0.001). Weight loss, performance status, gender, clinical stage, serum LDH and albumin levels were all shown to correlate with survival (p<0.05). Response to chemotherapy was determined to be the most important prognostic factor.

Prognostic value of proliferating cell nuclear antigen immunostaining in pediatric rhabdomyosarcomas.

BACKGROUND: The levels of proliferating cell nuclear antigen (PCNA) are almost negligible in long-term quiescent cells and increase dramatically during the cell cycle. Recently, the monoclonal antibodies to PCNA have been used to demonstrate the proliferative component of paraffin-embedded tumor tissues. It has been shown to be available as a simple histological marker of proliferative activity and the PCNA labeling index has been correlated with the prognosis of several malignant neoplasms. METHODS: Formalin fixed, paraffin embedded tissue specimens of 29 primary pediatric rhabdomyosarcomas were immunostained by using an anti-PCNA monoclonal antibody (DAKO PCNA PC10). The relationship between the PCNA index and prognosis, clinicopathological features and survival were assessed retrospectively. RESULTS: The mean PCNA index for the whole series was 54%. There was no correlation between PCNA index and any of the clinicopathological characteristics. However, patients having tumors with a high (> 54%) PCNA index demonstrated significantly lower survival rates than tumors with a low (< 54%) PCNA index (P = 0.01). Moreover, there were significantly more patients with relapse or progressive disease in the high PCNA index group (P = 0.005). CONCLUSION: The PCNA labeling index can be a useful prognostic factor and a good indicator of recurrence and/or survival in patients with rhabdomyosarcoma.

Utility of CA 15-3 and CEA in monitoring breast cancer patients with bone metastases: special emphasis on "spiking" phenomena.

OBJECTIVES: CA 15-3 and CEA are considered useful tumor markers in monitoring breast cancer patients. This study was undertaken to specifically evaluate the transient elevations in these markers that are observed during systemic treatment for metastatic disease. This phenomenon has been termed "spiking." DESIGN AND MATERIALS: Serum tumor marker levels were investigated by enzyme immunoassay in 20 breast cancer patients without metastases and in 20 patients with bone metastases receiving systemic treatment. RESULTS: Both CEA and CA 15-3 levels were significantly elevated in the patients with bone metastases. Serum CEA and CA 15-3 levels in patients with metastases displayed a transient, but significant, elevation days 15 and 30, respectively, after commencing systemic treatment, which returned to pretreatment levels on the 60th day. CONCLUSIONS: The spiking effect observed in the tumor marker levels should be carefully evaluated, and not be misdiagnosed as disease progression.

Evaluation of phosphohexose isomerase as a metastasis marker in breast cancer patients.

In this study the value of PHI serum measurements in breast cancer as an index of metastases was investigated. Serum CA 15-3 and CEA tumor marker and gamma-glutamyltranspeptidase (gamma-GT) levels were also determined in groups of patients with established distant metastases or in patients on follow-up with no evidence of disease. Fifty-one female breast cancer patients were included in the study. The mean values for each parameter were higher when metastases were present. However, the difference was mostly not meaningful. The only significant difference was observed for CA 15-3. Our data do not support the usefulness of the PHI assay for early detection of the metastases in breast cancer.