Randomized controlled trial of 8 weeks' vs 12 weeks' interval between neoadjuvant chemoradiotherapy and surgery for locally advanced rectal cancer.

AIM: The aim was to compare the pathological complete response (pCR) rate at 8 compared to 12 weeks' interval between completion of neoadjuvant chemoradiotherapy (CRT) and surgery in patients with locally advanced rectal cancer. METHOD: This was a randomized trial which included a total of 330 patients from two institutions. Patients with locally advanced (T3-4N0M0, TxN+M0) rectal cancer were randomized into 8- and 12-week interval groups. All the patients received long-course CRT (45 Gy in 1.8 Gy fractions and concomitant oral capecitabine or 5-fluorouracil infusion). Surgery was performed at either 8 or 12 weeks after CRT. The primary end-point was pCR. Secondary end-points were sphincter preservation, postoperative morbidity and mortality. RESULTS: Two-hundred and fifty-two patients (n = 125 in the 8-week group, n = 127 in the 12-week group) were included. Demographic and clinical characteristics were similar between groups. The overall pCR rate was 17.9% (n = 45): 12% (n = 15) in the 8-week group and 23.6% (n = 30) in the 12-week group (P = 0.021). Sphincter-preserving surgery was performed in 107 (85.6%) patients which was significantly higher than the 94 (74%) patients in the 12-week group (P = 0.016). Postoperative mortality was seen in three (1.2%) patients overall and was not different between groups (1.6% in 8 weeks vs 0.8% in 12 weeks, P = 0.494). Groups were similar in anastomotic leak (10.8% in 8 weeks vs 4.5% in 12 weeks, P = 0.088) and morbidity (30.4% in 8 weeks and 20.1% in 12 weeks, P = 0.083). CONCLUSION: Extending the interval between CRT and surgery from 8 to 12 weeks resulted in a 2-fold increase in pCR rate without any difference in mortality and morbidity.

Preclinical evidence for the antihyperalgesic activity of CDP-choline in oxaliplatin-induced neuropathic pain.

PURPOSE: This study was designed to evaluate the antihyperalgesic effect of CDP-choline (cytidine-5'-diphosphate- choline; citicoline) in a rat model of neuropathic pain produced by oxaliplatin (OXA). METHODS: A single administration of OXA (6 mg/kg intraperitoneally/ ip) was used for induction of neuropathy. We assessed the antihyperalgesic effect of intracerebroventricularly (icv) administered CDP-choline (0.5, 1.0 and 2.0 µmol) using the rat paw pressure test (Randall-Selitto). RESULTS: CDP-choline significantly reduced OXA-induced mechanical hyperalgesia, in a dose- and time-dependent manner. The antihyperalgesic effect of CDP-choline was blocked by the neuronal high affinity choline uptake inhibitor hemicholinium-3 (1 µg; icv), the nonselective nicotinic receptor antagonist mecamylamine (50 µg; icv), the α7 selective nicotinic acetylcholine receptor antagonist α-bungarotoxin (2 µg; icv), and the gamma-amino butyric acid (GABA)-B receptor antagonist CGP-35348 (20 µg; icv), but not by the nonselective opioid receptor antagonist naloxone (10 µg; icv) and the nonselective muscarinic receptor antagonist atropine (10 µg; icv). CONCLUSION: These findings indicate that CDP-choline exerts an antihyperalgesic effect in OXA-induced neuropatic pain and it can be tested in clinical trials.

Prognostic significance of estrogen receptor, progesterone receptor, HER2/neu, Ki-67, and nm23 expression in patients with invasive breast cancer.

PURPOSE: To determine the prognostic significance of estrogen receptor (ER), progesterone receptor (PR), HER2/neu, Ki-67, and nm23 immunohistochemical expression with respect to progression free survival (PFS) and overall survival (OS) in Turkish patients with invasive breast cancer (IBC). METHODS: Patients with IBC (n = 81; mean age = 51.9 ± 11.1 years) were prospectively enrolled at the Department of Oncology, Uludag University Medical Center, Bursa, Turkey. Immunohistochemistry was performed on formalin- fixed, paraffin-embedded tissue sections. RESULTS: We did not find any significant association between immunohistochemical expression of ER, PR, HER2/ neu, Ki-67, and nm23 and the baseline characteristics of IBC patients. The median patient PFS was 30 months (range 22-45), and the median OS was 32 months (range 23-46). Stratification of the patient population according to nm23 immunohistochemical expression revealed a statistically significant difference in terms of both OS (p < 0.05) and DFS (p < 0.05). Multivariate Cox regression analysis indicated that tumor grade, axillary lymph node status, and nm23 immunohistochemical expression were the 3 main independent prognostic factors for PFS and OS in IBC patients. CONCLUSION: Reduced nm23 immunohistochemical expression is an independent negative prognostic factor for OS and PFS. Patients with negative nm23 expression may require a more intensive follow-up.

Comparison of second-line treatment outcomes between sensitive and refractory small cell lung cancer patients: a retrospective analysis

PURPOSE: Small cell lung cancer (SCLC) has a high relapse rate despite being very chemosensitive. The efficacy of second-line treatment is dismal. Our aim was to evaluate the outcome of second-line treatment. METHODS: We retrospectively assessed data of 120 SCLC patients who failed first-line treatment and received second-line treatment at three medical oncology centers. RESULTS: Median age of group was 58. 82 % had an ECOG PS of 0-1 at the time of relapse. 39 % were at limited stage (LS) at the time of diagnosis. Patients who progressed more than 3 months after first-line therapy were categorized as having platinum-sensitive disease (PSD) (64 %). The number of patients who received platin-based combination treatment was 33 (27 %). The median OS time starting from the initiation of second-line treatment was 7 months. Multivariate analysis identified PS (p = 0.006), extent of disease at diagnosis (0.014) and PSD (0.001) as the independent prognostic factors for survival. Subgroup analyses of the patients with PSD indicated platin rechallenge yields higher progression-free survival, overall survival and overall response rate. CONCLUSION: Patients with good ECOG PS,who have PSD or initially presenting with LS, have a good prognosis and in patients with PSD, platinum-based therapy would be more appropriate (AU)

Prognostic significance of c-erbB2 overexpressionin patients with metastatic gastric cancer

BACKGROUND: Overexpression of the gene c-erbB2, which encodes a receptor tyrosine kinase, has been associated with prognosis and response to therapy in several solid tumors. This study was designed to test whether c-erb-B2 overexpression can be related to prognosis of patients with metastatic gastric cancer. METHODS: Between 2005 and 2010, 46 cases of metastatic gastric cancer were evaluated immunohistochemically for c-erb-B2 overexpression. Overall survival (OS) and time-to-progression (TTP) served as the main outcome measures. RESULTS: c-erbB2 was overexpressed in 19 (41.3 %) cases and 8 patients (17.4 %) had a c-erbB2 score of 3+ (a strong complete membrane staining observed in >10 % of the tumor cells). c-erbB2 expression was not associated with the clinicohistological characteristics of the study participants. The mean OS was 11.48 ± 1.03 months, whereas the mean TTP was 8.28 ± 0.8 months. Compared with patients with a score of 2+ or less (n = 38), those with a c-erbB2 score of 3+ (n = 8) had both a significantly lower OS (15.55 ± 1.63 vs. 8.22 ± 0.88 months, respectively, p < 0.05) and TTP (10.72 ± 1.81 vs. 6.11 ± 0.61 months, respectively, p < 0.05). After allowance for potential confounders, Cox regression analysis identified a c-erbB2 score of 3+ as an independent predictor of both OS (hazard ratio = 1.9; 95 % confidence interval = 1.1-3.7, p < 0.05) and TTP (hazard ratio = 1.8; 95 % confidence interval = 1.1-4.1, p < 0.05). CONCLUSION: Our results suggest that c-erbB-2 overexpression may have a prognostic significance in patients with metastatic gastric cancer (AU)

Comparison of second-line treatment outcomes between sensitive and refractory small cell lung cancer patients: a retrospective analysis.

PURPOSE: Small cell lung cancer (SCLC) has a high relapse rate despite being very chemosensitive. The efficacy of second-line treatment is dismal. Our aim was to evaluate the outcome of second-line treatment. METHODS: We retrospectively assessed data of 120 SCLC patients who failed first-line treatment and received second-line treatment at three medical oncology centers. RESULTS: Median age of group was 58. 82 % had an ECOG PS of 0-1 at the time of relapse. 39 % were at limited stage (LS) at the time of diagnosis. Patients who progressed more than 3 months after first-line therapy were categorized as having platinum-sensitive disease (PSD) (64 %). The number of patients who received platin-based combination treatment was 33 (27 %). The median OS time starting from the initiation of second-line treatment was 7 months. Multivariate analysis identified PS (p = 0.006), extent of disease at diagnosis (0.014) and PSD (0.001) as the independent prognostic factors for survival. Subgroup analyses of the patients with PSD indicated platin rechallenge yields higher progression-free survival, overall survival and overall response rate. CONCLUSION: Patients with good ECOG PS,who have PSD or initially presenting with LS, have a good prognosis and in patients with PSD, platinum-based therapy would be more appropriate.

Identification of prognostic factors in patients with metastatic gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumors (GISTs) have a complex biology which is reflected by a marked clinical heterogeneity. Thus, there has been great interest in identifying prognostic factors influencing tumor recurrence and survival. The aim of this study was to identify potential clinical and immunohistochemical prognostic factors that may affect survival and treatment outcomes in patients with metastatic GISTs. METHODS: Between 2000 and September 2011, a total of 41 patients with metastatic GISTs (29 males and 12 females; mean age: 57.4±11.8 years; range 29-74) were referred to the Department of Oncology, Uludag University Medical School. Survival analysis for a number of potential prognostic factors was made with the main outcome results of progression-free survival (PFS) and overall survival (OS7rpar;. RESULTS: The most common sites of isolated metastases comprised the liver (n=18), followed by lymph nodes (n=5), the omentum (n=1), and the mesothelium (n=1). The remaining patients had metastases at multiple sites. Cox regression analysis identified ileal location as the only significant predictor of poor PFS both after first-line (p=0.023) and second-line therapy (p=0.016). Tumor location in the ileum (p=0.025) and S100 immunoreactivity (p=0.041) were both independent predictors of OS. CONCLUSION: Tumor site and S100 positivity were the main significant independent predictors of clinical outcomes in patients with metastatic GISTs treated by standard of care.

Simultaneous occurrence of synchronous and metachronous tumors with gastrointestinal stromal tumors.

OBJECTIVE: To examine the frequency and clinicopathological features of synchronous and metachronous tumors which occur simultaneously with gastrointestinal stromal tumors (GIST). METHODS: Clinical and pathologic records of 78 patients diagnosed with primary GIST and treated at our institution between 1997 and 2009 were reviewed. RESULTS: GIST occurred simultaneously with other primary GI malignancies in 16.1 % (n = 13) of all patients with GIST. Of the simultaneous secondary tumors, 69.2 % (n = 9) were gastrointestinal tumors, and the remaining were biliary system and breast tumors. GIST most frequently had gastric localization (n = 6, 46.1%). CONCLUSION: Although GIST are uncommon neoplasms, their synchronous and metachronous coexistence with other tumors is rather frequent, mostly as incidental tumors accompanying a gastrointestinal neoplasm. Therefore, during surgery on cases with gastrointestinal neoplasms, the surgeon needs to be careful about a synchronous GIST. At the same time, more detailed studies are needed about the carcinogenesis of dual tumors coexisting with GIST (Tab. 1, Ref. 14).

Immunohistochemical expression of excision repair cross-complementing 1 (ERCC1) in non-small-cell lung cancer: implications for patient outcome.

INTRODUCTION The identification of novel prognostic markers may help to better assess survival probability in different subgroups of patients with non-small-cell lung cancer (NSCLC) and to tailor treatment according to the molecular profile of the tumour. AIM We sought to examine whether the immunohistochemical expression of excision repair cross-complementing 1 (ERCC1), an essential component of the nucleotide excision repair pathway, may predict prognosis in NSCLC. MATERIAL AND METHOD Formalin-fixed paraffin-embedded tumour samples from 44 Turkish patients with NSCLC treated by adjuvant platinum-based chemotherapy were included in the study. Immunohistochemical expression levels of ERCC1 were correlated with clinical outcomes by Kaplan-Meier curves and multivariable Cox proportional hazards regression analysis. RESULTS A total of 29 patients had ERCC1-negative tumours while 15 had ERCC1-positive tumours. The mean progression- free survival (PFS) was significantly lower in patients with ERCC1-positive tumours (13±2 months) than in those with ERCC1-negative tumours (27±5 months, p<0.05). Similarly, the mean overall survival (OS) was significantly lower in patients with ERCC1-positive tumours (20±3 months) than in those with ERCC1-negative tumours (33±5 months, p<0.05). After allowance for potential confounders, Cox regression analysis demonstrated that ERCC1 expression was significantly associated with both PFS and OS (both p<0.05). CONCLUSION This study provides support for the prognostic value of ERCC1 immunohistochemical expression in patients with NSCLC treated by adjuvant platinum-based chemotherapy. If independently confirmed, these findings may improve prognostic stratification in this group of patients.

Immunohistochemical expression of excision repair cross-complementing 1 (ERCC1) in non-small-cell lung cancer: implications for patient outcome

INTRODUCTION The identification of novel prognostic markers may help to better assess survival probability in different subgroups of patients with non-small-cell lung cancer (NSCLC) and to tailor treatment according to the molecular profile of the tumour. AIM We sought to examine whether the immunohistochemical expression of excision repair cross-complementing 1 (ERCC1), an essential component of the nucleotide excision repair pathway, may predict prognosis in NSCLC. MATERIAL AND METHOD Formalin-fixed paraffin-embedded tumour samples from 44 Turkish patients with NSCLC treated by adjuvant platinum-based chemotherapy were included in the study. Immunohistochemical expression levels of ERCC1 were correlated with clinical outcomes by Kaplan-Meier curves and multivariable Cox proportional hazards regression analysis. RESULTS A total of 29 patients had ERCC1-negative tumours while 15 had ERCC1-positive tumours. The mean progression- free survival (PFS) was significantly lower in patients with ERCC1-positive tumours (13±2 months) than in those with ERCC1-negative tumours (27±5 months, p<0.05). Similarly, the mean overall survival (OS) was significantly lower in patients with ERCC1-positive tumours (20±3 months) than in those with ERCC1-negative tumours (33±5 months, p<0.05). After allowance for potential confounders, Cox regression analysis demonstrated that ERCC1 expression was significantly associated with both PFS and OS (both p<0.05). CONCLUSION This study provides support for the prognostic value of ERCC1 immunohistochemical expression in patients with NSCLC treated by adjuvant platinum-based chemotherapy. If independently confirmed, these findings may improve prognostic stratification in this group of patients (AU)

Capecitabine-induced cardiotoxicity mimicking myocardial infarction.

Capecitabine, a fluoropyrimidine derivative, is an orally administered drug that delivers 5-fluorouracil (5-FU) selectively to the tumour. The drug has demonstrated activity in metastatic colorectal cancer. We describe a male patient receiving capecitabine therapy with typical chest pain and electrocardiographic changes consistent with STsegment elevation myocardial infarction. Capecitabine-induced cardiotoxicity may develop in patients who have had a previous episode of 5-FU-induced cardiotoxicity. Capecitabine-induced cardiotoxicity is a rare condition that may lead to diagnostic and therapeutic dilemmas. (Neth Heart J 2009;17:277-80.).

Mycobacterium tuberculosis complex DNA does not exist in atheromatous plaques.

The possible potential role of several infectious agents in atherosclerosis has been shown. Several infectious agents DNA in atheromatous plaques have been displayed by PCR. In patients with atheromas antibody levels against Hsp65 were higher. Vaccination of mice with recombinant Hsp65 and Hsp65-rich M. tuberculosis resulted in formation of atheromatous plaques. We attempted to detect M. tuberculosis DNA in atherosclerotic plaque samples by PCR. In endarterectomy tissue samples obtained from patients during coronary artery bypass graft surgery DNA was prepared by proteinase-K digestion, phenol/chloroform extraction and ethanol precipitation. After amplification with M.tuberculosis complex IS6110 region specific primers, the products were analyzed on electrophoresis. M. tuberculosis DNA was negative in all tissue samples. More data on etiological studies with mycobacteriaceae will be yield information on atherosclerosis pathogenesis.

Therapy, outcome and analysis of c-kit expression in patients with extrapulmonary small cell carcinoma.

In this study, we aimed to investigate the clinicopathological characteristics with special emphasis on c-kit expression and the treatment results of patients with extrapulmonary small cell carcinoma (EPSCC). The medical records of the patients with EPSCC were reviewed, and the data regarding patient and tumour characteristics, treatment and clinical outcome were retrieved and analysed. A total of 28 patients with the diagnosis of EPSCC were identified. There were 19 males and 9 females, with a mean age of 56.5 years. Patients with limited disease (LD) (n = 13) were treated with surgery, chemotherapy (CT) and radiotherapy with different sequences. Patients with extensive disease (ED) (n = 15) were mainly treated with combination CT. The median overall survival was 14.5 months in patients with LD compared to 11 months in those with ED (p = 0.029). Ten patients (36%) showed c-kit overexpression. There was no significant difference between the survival of c-kit-positive and c-kit-negative patients (p = 0.367). In conclusion, our study demonstrates that the prognosis of EPSCC is poor despite currently available treatments. C-kit may be considered as a potential target for novel therapeutical approaches.

Comparison of the serum erythropoietin levels in chemotherapy-naive and cisplatin-treated cancer patients.

There are conflicting data about the effects of cisplatin on erythropoietin (EPO) response to anemia. Aim of our study was to investigate whether endogenous EPO response to anemia in cisplatin treated patients was insufficient in comparison to the anemic chemotherapy-naive cancer patients and non cancer patients with iron deficiency anemia. Patients who had hemoglobin (Hb) levels of less than 110 g/l were included in the study. Fifteen chemotherapy- naive cancer patients were enrolled in Group A. Group B consisted of 15 patients who had been treated with three cycles of cisplatin chemotherapy and then became anemic and in Group C were included 15 patients who had iron deficiency anemia, without any malignancy. The mean Hb values were not different between all groups (102.8+/-39.8 g/l, 103.1+/-2.5 g/l and 99.3+/-3.6 g/l in Group A, Group B and Group C, respectively). However, EPO levels were found to be significantly lower in Group A and Group B than Group C (29.63+/-9.09 mU/ml, 20.87+/-2.43 mU/ml and 85.38+/-25.72 mU/ml, respectively; p=0.017 Group A vs. Group C, p=0.005 Group B vs. Group C). No significant difference was found between Group A and B (p=0.917). Opposite the iron deficiency anemia, cancer anemia is associated with an inadequate EPO response to anemia and administration of cisplatin does not lead to it further deterioration.