The role of the PTEN/mTOR axis in clinical response of rectal cancer patients.

BACKGROUND: Preoperative chemoradiotherapy has long been accepted as a method to improve survival and lifetime quality of rectal cancer patients. However, physiologic effects of these therapies largely depend on the resistance of cells to the radiation, type of chemotherapeutic agents and individual responses. As one of the signaling cascades involved in chemo- or radiation- resistance, the present study focused on several proteins involved in pTEN/Akt/mTOR pathway to explore their prognostic significance. MATERIALS AND METHODS: Samples from advanced stage rectal cancer patients were analyzed to detect expression levels of pTEN/Akt/mTOR pathway related proteins pTEN, mLST8, REDD1, BNIP3, SAG and NOXA, together with p53, by RT-qPCR. Kaplan-Meier analysis was used to assess expression-survival relation and correlations among all proteins and clinicopathological features were statistically analyzed. RESULTS: Except p53, none of the proteins showed prognostic significance. High p53 expression presented clear impact on overall survival and disease free survival. It was also significantly related to pathologic complete response. p53 showed high correlation to local recurrence as well. On the other hand, strong correlation was observed with PTEN expression and tumor response, but not with survival. High associations were also observed between mLST8/REDD1, PTEN and NOXA, confirming their role in the same cascade. CONCLUSION: The contentious role of p53 as a prognostic biomarker in colorectal cancer was further affirmed, while PTEN and REDD1 could be suggested as potential candidates. Additionally, NOXA emerges as a conjunctive element for different signaling pathways.

Is there any role of intravenous iron for the treatment of anemia in cancer?

BACKGROUND: Anemia is a major cause of morbidity in patients with cancer resulting in poor physical performance, prognosis and therapy outcome. The aim of this study is to assess the efficacy of intravenous (iv) iron administration for the correction of anemia, for the prevention of exacerbation of anemia, for decreasing blood transfusion rates, and for the survival of cancer patients. METHODS: Patients with different solid tumor diagnosis who received iv iron during their cancer treatment were evaluated retrospectively. Sixty-three patients with hemoglobin (Hgb) levels between ≥ 9 g/dL, and ≤ 10 g/dL, and no urgent need for red blood cell transfusion were included in this retrospective analysis. The aim of cancer treatment was palliative for metastatic patients (36 out of 63), or adjuvant or curative for patients with localized disease (27 out of 63). All the patients received 100 mg of iron sucrose which was delivered intravenously in 100 mL of saline solution, infused within 30 min, 5 infusions every other day. Complete blood count, serum iron, and ferritin levels before and at every 1 to 3 months subsequently after iv iron administration were followed regularly. RESULTS: Initial mean serum Hgb, serum ferritin and serum iron levels were 9.33 g/dL, 156 ng/mL, and 35.9 µg/dL respectively. Mean Hgb, ferritin, and iron levels 1 to 3 months, and 6 to 12 months after iv iron administration were 10.4 g/dL, 11.2 g/dL, 298.6 ng/mL, 296.7 ng/mL, and 71.6 µg/dL, 67.7 µg/dL respectively with a statistically significant increase in the levels (p < 0.001). Nineteen patients (30 %) however had further decrease in Hgb levels despite iv iron administration, and blood transfusion was necessary in 18 of these 19 patients (28.5 %). The 1-year overall survival rates differed in metastatic cancer patients depending on their response to iv iron; 61.1 % in responders versus 35.3 % in non-responders, (p = 0.005), furthermore response to iv iron correlated with tumor response to cancer treatment, and this relation was statistically significant, (p < 0.001). CONCLUSIONS: Iv iron administration in cancer patients undergoing active oncologic treatment is an effective and safe measure for correction of anemia, and prevention of worsening of anemia. Amelioration of anemia and increase in Hgb levels with iv iron administration in patients with disseminated cancer is associated with increased tumor response to oncologic treatment and overall survival. Response to iv iron may be both a prognostic and a predictive factor for response to cancer treatment and survival.

Expression of TRF2 and its prognostic relevance in advanced stage cervical cancer patients.

BACKGROUND: Telomeres are protective caps consisted of specific tandem repeats (5'-TTAGGG-3'). Shortening of telomeres at each cell division is known as "mitotic clock" of the cells, which renders telomeres as important regulators of lifespan. TRF2 is one of the critical members of shelterin complex, which is a protein complex responsible from the preservation of cap structure, and loss or mutation of TRF2 results in DNA damage, senescence or apoptosis. Since cancer is frequently associated with aberrant cell cycle progression, defective DNA repair or apoptosis pathways, TRF2 could be one likely candidate for cancer therapy. Here we investigated the prognostic role of TRF2 levels in cervical cancer patients. Fold-induction rates were evaluated with respect to median values after real-time PCR analysis. Overall survival, distant disease-free and local recurrence-free survival rates were calculated using Kaplan-Meier long rank test. RESULTS: Both five year overall- and disease-free survival rates were longer in patients with higher TRF2 expression compared to lower expression, but results were not statistically significant (69.2% vs 28.9%, respectively). Mean local recurrence-free survivals (LRF) were very close ( 58.6, CI: 44.3-72.9 vs 54.5, CI: 32.1-76.9 months) for high and low expressions, respectively. Cumulative proportion of LRF at the end of five year period was 76.9% for high and 57.1% for low TRF2 expression (P = 0.75). Statistically significant difference was found between survival ratios and Bcl-xL and p53 gene expressions, but not with TRF2. A respectable correlation between TRF2 expression and apoptosis along with distant metastasis was noted (P = 0.045 and 0.036, respectively). Additionally, high TRF2 expression levels had a positive impact in five year survival rate of stage IIIB-IVA patients (P = 0.04). CONCLUSIONS: Our results support the role of TRF2 in apoptosis and imply a positive relation with distant metastases and survival in advanced stage patients. The remarkable difference in survival periods of patients with different TRF2 expressions suggest that TRF2 may be a candidate factor to estimate survival for cervical cancer, a preliminary observation which should further be verified with a larger cohort.

Health-related quality of life during postoperative chemoradiotherapy with oral uracil-tegafur and leucovorin in rectal cancer patients.

BACKGROUND/AIMS: The objective of this study was to report on the quality of life of locally advanced rectal cancer patients that were treated with uracil-tegafur (UFT)/leucovorin (LV)-based concurrent chemoradiotherapy. METHODOLOGY: Twenty-five patients were enrolled into this prospective study. Radiotherapy (50.4Gy) was given with concurrent UFT (300mg/m2/day) and LV (30mg/day). Turkish versions of EORTC-QLQC30 and EORTC QLQCR38 were applied at the beginning (HRQoL-1) and at the end (HRQoL-2) of chemoradiotherapy. Paired samples t-test was used to compare the difference of means for each scale between HRQoL1 and HRQoL2 and p values <0.05 were considered statistically significant. RESULTS: Study compliance was 80.6%. From baseline to the end of chemoradiotherapy, the mean scores of dyspnea (p=0.006) diarrhea (p=0.005) and micturition (p=0.005) increased significantly. Chemotherapy side effects also increased at the end of therapy (p=0.07). Seventy-six percent (76%) of male patients replied to questions related to sexual problems and functions, whereas no female patients replied. CONCLUSIONS: Although, diarrhea and micturition are the major problems, quality of life scores indicate that concurrent oral fluoropyrimidine-based chemoradiotherapy is a feasible treatment.

Escitalopram co-prescription in anastrozole-treated breast cancer patients.

OBJECTIVE: The purpose of the study was to evaluate the impact of escitalopram co-prescription on plasma anastrozole levels in post-menopausal breast cancer patients. METHODS: A total of 24 post-menopausal operated breast cancer patients co-prescribed with escitalopram and anastrozole were included. Blood samples were collected, before and 1-month after the onset of escitalopram to analyze plasma anastrozole and estradiol levels. RESULTS: No significant difference was noted in basal plasma anastrozole levels with respect to age, body mass index (BMI), tumor stage, previous antineoplastic treatments, concomitant medications, and serum estradiol levels. Overall, 17 patients completed the 1-month escitalopram treatment, while 7 patients discontinued escitalopram within the 1st week of the treatment. Basal anastrozole levels of 24 patients were 26.1±2.4 ng/mL. Among 17 patients who continued 1-month escitalopram treatment was associated with significant increase in plasma anastrozole levels (24.5±2.3 ng/mL to 32.2±3.2 ng/mL, p<0.05). Notably, 1-month escitalopram use was associated with significant increase in plasma anastrozole levels only in the subgroup of obese (BMI >29 kg/m2) patients (23.1±2.8 to 35.9±4.7 ng/mL, p<0.01), while no such interaction was noted among non-obese patients. The estradiol levels of the patients were below ≤10 pg/mL in 75% of patients and no change occurred after escitalopram administration. CONCLUSION: Escitalopram co-prescription resulted in significant increase in plasma anastrozole levels without affecting the serum estradiol levels. Our findings emphasize the need for close monitoring in case of concomitant use of anastrozole and escitalopram, especially in obese patients and the potential role of therapeutic drug monitoring.

Long-term effects of neoadjuvant chemoradiotherapy followed by sphincter-preserving resection on anal sphincter function in relation to quality of life among locally advanced rectal cancer patients: a cross-sectional analysis.

BACKGROUND: There is growing recognition for the consequences of rectal cancer treatment to maintain an adequate functional sphincter in the long-term rather than preserving the anal sphincter itself. This study aims to evaluate long-term effects of neoadjuvant chemoradiotherapy (nCRT) followed by sphincter-preserving resection on anal sphincter function in relation to quality of life (QoL) among locally advanced rectal cancer patients. METHODS: Twenty-nine patients treated with nCRT followed by low anterior resection surgery were included in this study. Data on patient demographics, tumor location and symptoms of urgency and fecal soiling were recorded and evaluated with respect to Wexner Fecal Incontinence Scoring Scale, European Organization for Research and Cancer (EORTC) cancer-specific (EORTC QLQ-C30) and colorectal cancer-specific (EORTC QLQ-CR38) questionnaires and anorectal manometrical findings. Correlation of manometrical findings with Wexner Scale, EORTC QLQ-CR38 scores and EORTC QLQ-C30 scores was also evaluated. RESULTS: Median follow-up was 45.6 months (ranged 7.5-98 months. Higher scores for incontinence for gas (p = 0.001), liquid (p = 0.048) and solid (p = 0.019) stool, need to wear pad (p = 0.001) and alteration in life style (p = 0.004) in Wexner scale, while lower scores for future perspective (p = 0.010) and higher scores for defecation problems (p = 0.001) in EORTC QLQ-CR38 were noted in patients with than without urgency. Manometrical findings of resting pressure (mmHg) was positively correlated with body image (r = 0.435, p = 0.030) and sexual functioning (r = 0.479, p = 0.011) items of functional scale, while rectal sensory threshold (RST) volume (mL) was positively correlated with defecation problems (r = 0.424, p = 0.031) items of symptom scale in EORTC QLQ-CR38 and negatively correlated with social function domain (r = -0.479, p = 0.024) in EORTC QLQ-C30. RST volume was also positively correlated with Wexner scores including incontinence for liquid stool (r = 0.459, p = 0.024), need to wear pad (r = 0.466, p = 0.022) and alteration in lifestyle (r = 0.425, p = 0.038). CONCLUSION: The high risk of developing functional anal impairment as well as the systematic registration of not only oncological but also functional and QoL related outcomes seem important in rectal cancer patients in the long-term disease follow-up.

Survival in gastric cancer in relation to postoperative adjuvant therapy and determinants.

AIM: To evaluate survival data in patients with gastric cancer in relation to postoperative adjuvant therapy and survival determinants METHODS: A total of 201 patients (mean±SD age: 56.0±11.9 years, 69.7% were males) with gastric carcinoma who were operated and followed up at Lutfi Kirdar Kartal Training and Research Hospital between 1998 and 2010 were included in this retrospective study. Follow up was evaluated divided into two consecutive periods (before 2008 and 2008-2010, respectively) based on introduction of 3-D conformal technique in radiotherapy at our clinic in 2008. Data on patient demographics, clinical and histopathological characteristics of gastric carcinoma and the type of treatment applied after surgery [postoperative adjuvant treatment protocols including chemoradiotherapy (CRT) and chemotherapy (CT), supportive therapy or follow up without any treatment] were recorded. The median duration and determinants of local recurrence free (LRF) survival, distant metastasis free (DMF) survival and overall survival were evaluated in the overall population as well as with respect to follow up years [1998-2008 (n=127) vs 2008-2010 (n=74)]. RESULTS: Median duration for LRF survival, DMF survival and overall survival were 31.9, 24.1 and 31.9 mo, respectively in patients with postoperative adjuvant CRT. No significant difference was noted in median duration for LRF survival, DMF survival and overall survival with respect to treatment protocols in the overall population and also with respect to followed up periods. In the overall population, CT protocols FUFA [5-fluorouracil (400 mg/m2) and leucovorin-folinic acid (FA, 20 mg/m2)] (29.9 mo) and UFT®+Antrex® [a fixed combination of the oral FU prodrug tegafur (flouroprymidine, FT, 300 mg/m2 per day) with FA (Antrex®), 15 mg tablet, two times a day] (42.5 mo) was significantly associated with longer LRF survival times than other CT protocols (P=0.036), while no difference was noted between CT protocols in terms of DMF survival and overall survival. Among patients received CRT, overall survival was significantly longer in patients with negative than positive surgical margin (27.7 mo vs 22.4 mo, P=0.016) in the overall study population, while time of radiotherapy initiation had no significant impact on survival times. Nodal stage was determined to be independent predictor of LRF survival in the overall study population with 4.959 fold (P=0.042) increase in mortality in patients with nodal stage N2 compared to patients with nodal stage N0, and independent predictor of overall survival with 5.132 fold (P=0.006), 5.263 fold (P=0.027) and 4.056 fold (P=0.009) increase in the mortality in patients with nodal stage N3a (before 2008), N3b (before 2008) and N2 (overall study population) when compared to patients with N0 stage, respectively. CONCLUSION: Our findings emphasize the likelihood of postoperative adjuvant CRT to have a survival benefit in patients with resectable gastric carcinoma.

The association of apoptotic protein expressions sensitive to apoptosis gene, p73 and p53 with the prognosis of cervical carcinoma.

OBJECTIVE: To evaluate the expressions of several apoptotic pathway proteins in relation to clinical parameters and survival in patients with cervical carcinoma. METHODS: A total of 20 patients with clinically advanced staged carcinoma of cervix (International Federation of Gynecology and Obstetrics [FIGO] stage IIB-IVA) aged from 40 to 75 years were included in this study. The expression profile of anti-apoptotic protein (sensitive to apoptosis gene [SAG]), mitochondrial apoptotic proteins (B-cell lymphoma-extra-large [Bcl-xL] and Bcl-2 homologous antagonist/killer [Bak]), and tumor suppressor proteins (p73 and p53) were examined by real-time polymerase chain reaction experiments along with their relation to clinical parameters and survival analyses during follow-up for 5 to 8 years. RESULTS: No significant difference was found in the expressions of SAG, Bcl-xL, Bak, p73 and p53 proteins with respect to stage and grade of tumor. A significant positive correlation was noted between SAG and Bcl-xL genes (r=0.752, P<0.001) and between SAG and Bak genes (r=0.589, P=0.006). Among genes determined to be significantly associated with overall survival in the univariate analysis (P=0.026 for SAG, P=0.002 for Bcl-xL, and P=0.027 for p53), only p53 was identified as the significant predictor in the multivariate analysis (hazard ratio: 8.53, 95% confidence interval: 1.34-54.2, P=0.023). CONCLUSION: In conclusion, our findings demonstrated a reverse correlation of SAG, Bcl-xL, and p53 expressions with overall survival of patients. No association of apoptotic pathway proteins with clinicopathological characteristics of cervical carcinoma patients was noted. Low SAG, Bcl-xL, and p53 expression levels revealed to be useful as prognostic predictors in patients with cervical carcinoma.

Prognostic role of sensitive-to-apoptosis gene expression in rectal cancer.

AIM: To investigate the association between prognosis of rectal cancer treated with chemoradiotherapy (CRT) and expression of sensitive-to-apoptosis (SAG), B-cell lymphoma-extra large (Bcl-X(L)) and Bcl-2 homologous antagonist/killer (Bak). METHODS: Real-time quantitative polymerase chain reaction was used to determine the expression of proteins of interest, namely SAG, Bcl-X(L), Bak and ß-actin, in rectal carcinoma patients who had a follow-up period of 3 years after CRT. Biopsy specimens were excised from the rectal tumor preceding CRT. RESULTS: SAG, Bcl-X(L) and Bak proteins showed significant correlations with each other. In multivariate analysis, patients with high vs low SAG expression showed a statistically significant difference in 2-year survival rates: 56% vs 73%, respectively (P = 0.056). On the other hand, there were no significant correlations between the expression levels of all three genes and metastatic rates or tumor responses to CRT. Mean overall survival in the patients with elevated SAG expression was 27.1 mo ± 3.9 mo [95% confidence interval (CI): 19.3-34.9], and in patients with reduced expression, it was 32.1 mo ± 2.5 mo (95% CI: 27.3-36.9). The corresponding values for Bcl-X(L) were 28.0 mo ± 4.1 mo (95% CI: 19.9-36.1) and 31.7 mo ± 2.9 mo (95% CI: 26.0-37.5), and those for Bak were 29.8 mo ± 3.7 mo (95% CI: 22.5-37.2) and 30.6 mo ± 2.4 mo (95% CI: 25.5-35.0), respectively. CONCLUSION: Two-year survival rates significantly correlated with low SAG expression, and SAG may be a candidate gene for good prognosis, independent of therapeutic response of different individuals.

Expression of TRF2 and its prognostic relevance in advanced stage cervical cancer patients

BACKGROUND: Telomeres are protective caps consisted of specific tandem repeats (5'-TTAGGG-3'). Shortening of telomeres at each cell division is known as "mitotic clock" of the cells, which renders telomeres as important regulators of lifespan. TRF2 is one of the critical members of shelterin complex, which is a protein complex responsible from the preservation of cap structure, and loss or mutation of TRF2 results in DNA damage, senescence or apoptosis. Since cancer is frequently associated with aberrant cell cycle progression, defective DNA repair or apoptosis pathways, TRF2 could be one likely candidate for cancer therapy. Here we investigated the prognostic role of TRF2 levels in cervical cancer patients. Fold-induction rates were evaluated with respect to median values after real-time PCR analysis. Overall survival, distant disease-free and local recurrence-free survival rates were calculated using Kaplan-Meier long rank test. RESULTS: Both five year overall- and disease-free survival rates were longer in patients with higher TRF2 expression compared to lower expression, but results were not statistically significant (69.2% vs 28.9%, respectively). Mean local recurrence-free survivals (LRF) were very close ( 58.6, CI: 44.3-72.9 vs 54.5, CI: 32.1-76.9 months) for high and low expressions, respectively. Cumulative proportion of LRF at the end of five year period was 76.9% for high and 57.1% for low TRF2 expression (P = 0.75). Statistically significant difference was found between survival ratios and Bcl-xL and p53 gene expressions, but not with TRF2. A respectable correlation between TRF2 expression and apoptosis along with distant metastasis was noted (P = 0.045 and 0.036, respectively). Additionally, high TRF2 expression levels had a positive impact in five year survival rate of stage IIIB-IVA patients (P = 0.04). CONCLUSIONS: Our results support the role of TRF2 in apoptosis and imply a positive relation with distant metastases and survival in advanced stage patients. The remarkable difference in survival periods of patients with different TRF2 expressions suggest that TRF2 may be a candidate factor to estimate survival for cervical cancer, a preliminary observation which should further be verified with a larger cohort.