The Src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells

BACKGROUND: With the emergence of Src inhibitors in clinical trials, improved knowledge of the molecular responses of cancer cells to these agents is warranted. This will facilitate the development of tests to identify patients who may benefit from these agents, allow drug activity to be monitored and rationalize the combination of these agents with other treatment modalities. METHODS: This study evaluated the molecular and functional effects of Src inhibitor AZD0530 in human lung cancer cells, by Western blotting and reverse transcription-polymerase chain reaction, and by assays for cell viability, migration, and invasion. RESULTS: Src was activated in four of five cell lines tested and the level corresponded with the invasive potential and the histologic subtype. Clinically relevant, submicromolar concentrations of AZD0530 blocked Src and focal adhesion kinase, resulting in significant inhibition of cell migration and Matrigel invasion. Reactivation of STAT3 and up-regulation of JAK indicated a potential mechanism of resistance. AZD0530 gave a potent and sustained blockage of AKT and enhanced the sensitivity to irradiation. CONCLUSIONS: The results indicated that AZD0530, aside from being a potent inhibitor of tumor cell invasion which could translate to inhibition of disease progression in the clinic, may also lower resistance of lung cancer cells to pro-apoptotic signals.

Accelerated partial breast irradiation with interstitial brachytherapy as second conservative treatment for ipsilateral breast tumour recurrence: multicentric study of the GEC-ESTRO Breast Cancer Working Group

PURPOSE To analyse the clinical outcome after salvage lumpectomy and multi-catheter brachytherapy (MCB) for ipsilateral breast tumour recurrence (IBTR). MATERIAL AND METHODS Between 09/00 and 09/10, 217 patients presenting an IBTR underwent lumpectomy and MCB (low, pulsed, or high-dose rate). Survival rates without second local recurrence (2nd LR), distant metastasis (DM), and overall survival (OS) were analysed as well as late effects and cosmetic results. Univariate and multivariate analyses (MVA) based on IBTR data were performed to find prognostic factors for 2nd LR, DM, and OS. RESULTS Median follow-up after the IBTR was 3.9 years [range: 1.1-10.3]. Five and 10-year actuarial 2nd LR rates were 5.6% [range: 1.5-9.5] and 7.2% [range: 2.1-12.1], respectively. Five and 10-year actuarial DM rates were 9.6% [range: 5.7-15.2] and 19.1% [range: 7.8-28.3], respectively. Five and 10-year actuarial OS rates were 88.7% [range: 83.1-94.8] and 76.4% [range: 66.9-87.3], respectively. In MVA, histological grade was prognostic factor for 2nd LR (p=0.008) and OS (p=0.02); while tumour size was prognostic factor for DM (p=0.03). G3-4 complication rate was 11%. Excellent/good cosmetic result was achieved in 85%. CONCLUSION This study suggests that in case of IBTR, lumpectomy plus MCB is feasible and effective in preventing 2nd LR with an OS rate at least equivalent to those achieved with salvage mastectomy.

A reliable risk score for stage IV esophagogastric cancer

BACKGROUND The role of surgery for patients with metastatic esophagogastric adenocarcinoma (EGC) is not defined. The purpose of this study was to define selection criteria for patients who may benefit from resection following systemic chemotherapy. METHODS From 1987 to 2007, 160 patients presenting with synchronous metastatic EGC (cT3/4 cNany cM0/1 finally pM1) were treated with chemotherapy followed by resection of the primary tumor and metastases. Clinical and histopathological data, site and number of metastases were analyzed. A prognostic score was established and validated in a second cohort from another academic center (n = 32). RESULTS The median survival (MS) in cohort 1 was 13.6 months. Significant prognostic factors were grading (p = 0.046), ypT- (p = 0.001), ypN- (p = 0.011) and R-category (p = 0.015), lymphangiosis (p = 0.021), clinical (p = 0.004) and histopathological response (p = 0.006), but not localization or number of metastases. The addition of grading (G1/2:0 points; G3/4:1 points), clinical response (responder: 0; nonresponder: 1) and R-category (complete:0; R1:1; R2:2) defines two groups of patients with significantly different survival (p = 0.001) [low risk group (Score 0/1), n = 22: MS 35.3 months, 3-year-survival 47.6%); high risk group (Score 2/3/4) n = 126: MS 12.0 months, 3-year-survival 14.2%]. The score showed a strong trend in the validation cohort (p = 0.063) [low risk group (MS not reached, 3-year-survival 57.1%); high risk group (MS 19.9 months, 3-year-survival 6.7%)]. CONCLUSION We observed long-term survival after resection of metastatic EGC. A simple clinical score may help to identify a subgroup of patients with a high chance of benefit from resection. However, the accurate estimation of achieving a complete resection, which is an integral element of the score, remains challenging.

Relative survival is an adequate estimate of cancer-specific survival: baseline mortality-adjusted 10-year survival of 771 rectal cancer patients.

BACKGROUND The objective of the present investigation is to assess the baseline mortality-adjusted 10-year survival of rectal cancer patients. METHODS Ten-year survival was analyzed in 771 consecutive American Joint Committee on Cancer (AJCC) stage I-IV rectal cancer patients undergoing open resection between 1991 and 2008 using risk-adjusted Cox proportional hazard regression models adjusting for population-based baseline mortality. RESULTS The median follow-up of patients alive was 8.8 years. The 10-year relative, overall, and cancer-specific survival were 66.5% [95% confidence interval (CI) 61.3-72.1], 48.7% (95% CI 44.9-52.8), and 66.4% (95% CI 62.5-70.5), respectively. In the entire patient sample (stage I-IV) 47.3% and in patients with stage I-III 33.6 % of all deaths were related to rectal cancer during the 10-year period. For patients with AJCC stage I rectal cancer, the 10-year overall survival was 96% and did not significantly differ from an average population after matching for gender, age, and calendar year (p = 0.151). For the more advanced tumor stages, however, survival was significantly impaired (p < 0.001). CONCLUSIONS Retrospective investigations of survival after rectal cancer resection should adjust for baseline mortality because a large fraction of deaths is not cancer related. Stage I rectal cancer patients, compared to patients with more advanced disease stages, have a relative survival close to 100% and can thus be considered cured. Using this relative-survival approach, the real public health burden caused by rectal cancer can reliably be analyzed and reported.

Predictors of satisfaction with treatment decision, decision-making preferences, and main treatment goals in patients with advanced cancer

Purpose This study investigated satisfaction with treatment decision (SWTD), decision-making preferences (DMP), and main treatment goals, as well as evaluated factors that predict SWTD, in patients receiving palliative cancer treatment at a Swiss oncology network. Patients and methods Patients receiving a new line of palliative treatment completed a questionnaire 4–6 weeks after the treatment decision. Patient questionnaires were used to collect data on sociodemographics, SWTD (primary outcome measure), main treatment goal, DMP, health locus of control (HLoC), and several quality of life (QoL) domains. Predictors of SWTD (6 = worst; 30 = best) were evaluated by uni- and multivariate regression models. Results Of 480 participating patients in eight hospitals and two private practices, 445 completed all questions regarding the primary outcome measure. Forty-five percent of patients preferred shared, while 44 % preferred doctor-directed, decision-making. Median duration of consultation was 30 (range: 10–200) minutes. Overall, 73 % of patients reported high SWTD (≥24 points). In the univariate analyses, global and physical QoL, performance status, treatment goal, HLoC, prognosis, and duration of consultation were significant predictors of SWTD. In the multivariate analysis, the only significant predictor of SWTD was duration of consultation (p = 0.01). Most patients indicated hope for improvement (46 %), followed by hope for longer life (26 %) and better quality of life (23 %), as their main treatment goal. Conclusion Our results indicate that high SWTD can be achieved in most patients with a 30-min consultation. Determining the patient’s main treatment goal and DMP adds important information that should be considered before discussing a new line of palliative treatment.

Bcl-2 predicts response to neoadjuvant chemotherapy and is overexpressed in lymph node metastases of urothelial cancer of the bladder

PURPOSE To assess whether Bcl-2, an inhibitor of the apoptotic cascade, can predict response to neoadjuvant chemotherapy in patients with urothelial cancer of the bladder (UCB). METHODS Bcl-2 expression was analyzed in 2 different tissue microarrays (TMAs). One TMA was constructed of primary tumors and their corresponding lymph node (LN) metastases from 152 patients with chemotherapy-naive UCB treated by cystectomy and pelvic lymphadenectomy (chemotherapy-naive TMA cohort). The other TMA was constructed of tumor samples obtained from 55 patients with UCB before neoadjuvant chemotherapy (transurethral resection of the bladder cancer) and after cystectomy with pelvic lymphadenectomy (residual primary tumor [ypT+], n = 38); residual LN metastases [ypN+], n = 24) (prechemotherapy/postchemotherapy TMA cohort). Bcl-2 overexpression was defined as 10% or more cancer cells showing cytoplasmic immunoreactivity. RESULTS In both TMA cohorts, Bcl-2 overexpression was significantly (P<0.05) more frequent in LN metastases than in primary tumors (chemotherapy-naive TMA group: 18/148 [12%] in primary tumors vs. 39/143 [27%] in metastases; postchemotherapy TMA: ypT+7/35 [20%] vs. ypN+11/19 [58%]). In the neoadjuvant setting, patients with Bcl-2 overexpression in transurethral resection of the bladder cancer specimens showed significantly (P = 0.04) higher ypT stages and less regression in their cystectomy specimens than did the control group, and only one-eighth (13%) had complete tumor regression (ypT0 ypN0). In survival analyses, only histopathological parameters added significant prognostic information. CONCLUSIONS Bcl-2 overexpression in chemotherapy-naive primary bladder cancer is related to poor chemotherapy response and might help to select likely nonresponders.

Doppler Ultrasound Flow Evaluation of the Uterine Arteries Significantly Correlates with Tumor Size in Cervical Cancer Patients.

PURPOSE The aim of this present study was to evaluate the sonographic correlation between Doppler flow characteristics of the uterine arteries and tumor size in patients with cervical cancer, in order to establish a new potential marker to monitor treatment response. METHODS This was a retrospective cohort study of 25 patients who underwent a sonographic evaluation of Doppler flow characteristics of the uterine arteries before surgery or radiochemotherapy for early and locally advanced/advanced cervical cancer, respectively, was analyzed. The primary outcome was the correlation between Doppler flow characteristics of the uterine arteries and tumor size in patients with cervical cancer. RESULTS Median age was 49 (range 26-85) years, and mean tumor size was 40.8 ± 17 mm. A significant positive correlation was found between tumor diameter and the uterine artery end-diastolic velocity (r = 0.47, p < 0.05) as well as the peak systolic velocity (r = 0.41, p < 0.05). No correlation was found between tumor size and the pulsatility index or resistance index. CONCLUSIONS In cervical cancer, uterine artery velocity parameters are associated with tumor size. This finding could become particularly useful in the follow-up of locally advanced cervical cancer patients undergoing radiochemotherapy or in corroborating the selection of women with more possibility of a high response rate during neoadjuvant chemotherapy before surgery.