The genomic expression test EndoPredict is a prognostic tool for identifying risk of local recurrence in postmenopausal endocrine receptor-positive, her2neu-negative breast cancer patients randomised within the prospective ABCSG 8 trial.

BACKGROUND: The aim of this study was to examine whether EndoPredict (EP), a novel genomic expression test, is effective in predicting local recurrence (LR)-free survival (LRFS) following surgery for breast cancer in postmenopausal women. In addition, we examined whether EP may help tailor local therapy in these patients. METHODS: From January 1996 to June 2004, 3714 postmenopausal patients were randomly assigned to either tamoxifen or tamoxifen followed by anastrozole within the prospective ABCSG 8 trial. Using assay scores from EP, we classified breast tumour blocks as either low or high risk for recurrence. RESULTS: Data were gathered from 1324 patients. The median follow-up was 72.3 months and the cumulative incidence of LR was 2.6% (0.4% per year). The risk of LR over a 10-year period among patients with high-risk lesions (n=683) was significantly higher (LRFS=91%) when compared with patients with low-risk lesions (n=641) (10-year LRFS=97.5%) (HR: 1.31 (1.16-1.48) P<0.005). The groups that received breast conservation surgery (BCT) and mastectomy (MX) had similar LR rates (P=0.879). Radiotherapy (RT) after BCT significantly improved LRFS in the cohorts predicted by EP to be low-risk for LR (received RT: n=436, 10-year LRFS 99.8%; did not receive RT: n=63, 10-year LRFS 83.6%, P<0.005). CONCLUSIONS: EndoPredict is an effective prognostic tool for predicting LRFS. Among postmenopausal, low-risk patients, EP does not appear to be useful for tailoring local therapy.

LGR5 rs17109924 is a predictive genetic biomarker for time to recurrence in patients with colon cancer treated with 5-fluorouracil-based adjuvant chemotherapy.

We recently found variants in cancer stem cell genes (CD44, ALCAM and LGR5) significantly associated with increased time to recurrence (TTR) in patients with stage III and high-risk stage II colon cancer treated with 5-fluorouracil (5-FU)-based chemotherapy. In this study, we validated these genetic biomarkers in a large and independent patient cohort (n=599). Patients who received 5-FU-based adjuvant chemotherapy (n=391) carrying at least one C allele in LGR5 rs17109924 had a significantly increased TTR compared with patients carrying the homozygous T/T variant (HR 0.38, 95%CI 0.19-0.79; P=0.006). In patients treated with surgery alone (n=208), no association between LGR rs17109924 and TTR was found (P=0.728). In the multivariate Cox-analysis, LGR5 rs17109924 remained statistically significant (HR 0.38, 95%CI 0.18-0.78; P=0.008) for patients who received adjuvant chemotherapy. We confirmed in a large and independent study cohort that LGR5 rs17109924 is a predictive genetic biomarker for TTR in patients with colon cancer treated with 5-FU-based adjuvant chemotherapy.

The cyclin D1 (CCND1) rs9344 G>A polymorphism predicts clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy.

Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G>A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G>A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G>A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G>A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.

Validation of C-reactive protein levels as a prognostic indicator for survival in a large cohort of pancreatic cancer patients.

BACKGROUND: Recent evidence indicates that the host inflammatory response has an important role in the tumour progression. Elevated C-reactive protein (CRP) levels have been previously associated with poor prognosis in several cancer types including small-scale studies in pancreatic cancer (PC) patients. The purpose of the present study was to validate the prognostic impact of plasma CRP levels at date of diagnosis on cancer-specific survival (CSS) in a large cohort of PC patients. METHODS: Data from 474 consecutive patients with adenocarcinoma of the pancreas, treated between 2004 and 2012 at a single centre, were evaluated retrospectively. CSS was analysed using the Kaplan-Meier method. To evaluate the prognostic significance of plasma CRP levels, univariate and multivariate Cox analyses were applied. RESULTS: High plasma CRP levels at diagnosis were significantly associated with well-established prognostic factors, including high tumour stage and tumour grade and the administration of chemotherapy (P<0.05). In univariate analysis, we observed that a high plasma CRP level was a consistent factor for poor CSS in PC patients (hazard ratio (HR)=2.21; 95% confidence interval (CI)=1.68-2.92, P<0.001). In multivariate analysis, tumour stage, grade, administration of chemotherapy, a high neutrophil-lymphocyte ratio and the highest quartile of CRP levels (HR=1.60, 95% CI=1.16-2.21; P=0.005) were identified as independent prognostic factors in PC patients. CONCLUSION: In conclusion, we confirmed a significant association of elevated CRP levels with poor clinical outcome in PC patients. Our results indicate that the plasma CRP level might represent a useful marker for patient stratification in PC management.

The current and future role of the medical oncologist in the professional care for cancer patients: a position paper by the European Society for Medical Oncology (ESMO).

The number of cancer patients in Europe is rising and significant advances in basic and applied cancer research are making the provision of optimal care more challenging. The concept of cancer as a systemic, highly heterogeneous and complex disease has increased the awareness that quality cancer care should be provided by a multidisciplinary team (MDT) of highly qualified healthcare professionals. Cancer patients also have the right to benefit from medical progress by receiving optimal treatment from adequately trained and highly skilled medical professionals. Built on the highest standards of professional training and continuing medical education, medical oncology is recognised as an independent medical specialty in many European countries. Medical oncology is a core member of the MDT and offers cancer patients a comprehensive and systemic approach to treatment and care, while ensuring evidence-based, safe and cost-effective use of cancer drugs and preserving the quality of life of cancer patients through the entire 'cancer journey'. Medical oncologists are also engaged in clinical and translational research to promote innovation and new therapies and they contribute to cancer diagnosis, prevention and research, making a difference for patients in a dynamic, stimulating professional environment. Medical oncologists play an important role in shaping the future of healthcare through innovation and are also actively involved at the political level to ensure a maximum contribution of the profession to Society and to tackle future challenges. This position paper summarises the multifarious and vital contributions of medical oncology and medical oncologists to today's and tomorrow's professional cancer care.

An internally and externally validated prognostic score for metastatic breast cancer: analysis of 2269 patients.

BACKGROUND: The prognosis of metastatic breast cancer (MBC) is extremely heterogeneous. Although patients with MBC will uniformly die to their disease, survival may range from a few months to several years. This underscores the importance of defining prognostic factors to develop risk-adopted treatment strategies. Our aim has been to use simple measures to judge a patient's prognosis when metastatic disease is diagnosed. PATIENTS AND METHODS: We retrospectively analyzed 2269 patients from four clinical cancer registries. The prognostic score was calculated from the regression coefficients found in the Cox regression analysis. Based on the score, patients were classified into high-, intermediate-, and low-risk groups. Bootstrapping and time-dependent receiver operating characteristic curves were used for internal validation. Two independent datasets were used for external validation. RESULTS: Metastatic-free interval, localization of metastases, and hormone receptor status were identified as significant prognostic factors in the multivariate analysis. The three prognostic groups showed highly significant differences regarding overall survival from the time of metastasis [intermediate compared with low risk: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.36-2.27, P < 0.001; high compared with low risk: HR 3.54, 95% CI 2.81-4.45, P < 0.001). The median overall survival in these three groups were 61, 38, and 22 months, respectively. The external validation showed congruent results. CONCLUSIONS: We developed a prognostic score, based on routine parameters easily accessible in daily clinical care. Although major progress has been made, the optimal therapeutic management of the individual patient is still unknown. Besides elaborative molecular classification of tumors, simple clinical measures such as our model may be helpful to further individualize optimal breast cancer care.

The preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer.

BACKGROUND: Inflammation has a critical role in the pathogenesis and progression of cancer. The lymphocyte to monocyte ratio (LMR) could be shown to be prognostic in haematologic neoplasia. In this study, we analysed the LMR with clinical outcome in stage II and III colon cancer patients. METHODS: Three hundred and seventy-two patients with stage II and III colon cancer were included in this retrospective study. Kaplan-Meier curves and multivariate Cox-regression analyses were calculated for time to recurrence (TTR) and overall survival (OS). RESULTS: Including all patients, the elevated preoperative LMR was significantly associated with increased TTR and OS in multivariate analysis (HR: 0.47, 95%CI: 0.29-0.76, P=0.002; HR: 0.51, 95%CI: 0.31-0.83, P=0.007; respectively). In subanalyses, the association was limited to patients with stage III (HR: 0.40, 95%CI: 0.22-0.72, P=0.002), in contrast to patients with stage II (HR: 0.40, 95%CI: 0.28-1.66, P=0.397). When the subgroup of patients with 'high-risk' LMR≤2.83 was analysed, no benefit of adjuvant 5-FU-based chemotherapy could be found (HR: 0.99; 95%CI: 0.60-1.63; P=0.953). CONCLUSION: The LMR might be an independent prognostic marker for TTR in stage III colon cancer patients. Our results further suggest that high-risk patients based on the LMR do not benefit from adjuvant chemotherapy. Independent validation of our findings is warranted.

Validation of the prognostic relevance of plasma C-reactive protein levels in soft-tissue sarcoma patients.

BACKGROUND: The concept of the involvement of systemic inflammation in cancer progression and metastases has gained attraction within the past decade. C-reactive protein (CRP), a non-specific blood-based marker of the systemic inflammatory response, has been associated with decreased survival in several cancer types. The aim of the present study was to validate the prognostic value of pre-operative plasma CRP levels on clinical outcome in a large cohort of soft-tissue sarcoma (STS) patients. METHODS: Three hundred and four STS patients, operated between 1998 and 2010, were retrospectively evaluated. CRP levels and the impact on cancer-specific survival (CSS), disease-free survival (DFS) and overall survival (OS) were assessed using Kaplan-Meier curves and univariate as well as multivariate Cox proportional models. Additionally, we developed a nomogram by supplementing the plasma CRP level to the well-established Kattan nomogram and evaluated the improvement of predictive accuracy of this novel nomogram by applying calibration and Harrell's concordance index (c-index). RESULTS: An elevated plasma CRP level was significantly associated with established prognostic factors, including age, tumour grade, size and depth (P<0.05). In multivariate analysis, increased CRP levels were significantly associated with a poor outcome for CSS (HR=2.05; 95% CI=1.13-3.74; P=0.019) and DFS (HR=1.88; 95% CI=1.07-3.34; P=0.029). The estimated c-index was 0.74 using the original Kattan nomogram and 0.77 when the plasma CRP level was added. CONCLUSION: An elevated pre-operative CRP level represents an independent prognostic factor that predicts poor prognosis and improves the predictive ability of the Kattan nomogram in STS patients. Our data suggest to further prospectively validate its potential utility for individual risk stratification and clinical management of STS patients.

A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients.

BACKGROUND: Inflammation has a critical role in the pathogenesis and progression of cancer. Recently, the derived neutrophil to lymphocyte ratio (absolute count of neutrophils divided by the absolute white cell count minus the absolute count of neutrophils; dNLR) has been shown to influence clinical outcome in various cancer entities. In this study, we analysed the dNLR with clinical outcome in stage II and III colon cancer patients. METHODS: Three-hundred and seventy-two patients with stage II and III colon cancer were included in this retrospective study. Kaplan-Meier curves and multivariate Cox proportion analyses were calculated for time to recurrence (TTR) and overall survival (OS). RESULTS: In univariate analysis, the elevated preoperative dNLR was significantly associated with decreased TTR (hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.57-3.6, P<0.001) and remained significant in multivariate analysis. Patients with dNLR >3 had a median TTR of 83 months, and patients with dNLR ≤ 3 showed a median TTR of 132 months. In OS analysis, a dNLR >2.2 was significantly associated with decreased OS in univariate (HR 1.85, 95% CI 1.11-3.08, P=0.018) and multivariate analysis. Patients with dNLR >2.2 showed a median OS of 121 months, and patients with dNLR ≤ 2.2 had a median OS of 147 months. CONCLUSION: The dNLR may be an independent prognostic marker for TTR and OS in patients with stage II and III colon cancer. Independent validation of our findings is warranted.

The predictive impact of body mass index on the efficacy of extended adjuvant endocrine treatment with anastrozole in postmenopausal patients with breast cancer: an analysis of the randomised ABCSG-6a trial.

BACKGROUND: We investigated whether body mass index (BMI) can be used as a predictive parameter indicating patients who benefit from extended aromatase inhibitor (AI) treatment. METHODS: The ABCSG-6a trial re-randomised event-free postmenopausal hormone receptor-positive patients from the ABCSG-6 trial to receive either 3 additional years of endocrine therapy using anastrozole vs nil. In this retrospective analysis, we investigated the prognostic and predictive impact of BMI on disease outcome and safety. RESULTS: In all, 634 patients (177 normal weight, 307 overweight, and 150 obese) patients were included in this analysis. Normal weight patients with additional 3 years of anastrozole halved their risk of disease recurrence (disease-free survival (DFS) HR 0.48; P=0.02) and death (HR 0.45; P=0.06) and had only a fifth of the risk of distant metastases (HR 0.22; P=0.05) compared with normal weight patients without any further treatment. In contrast, overweight+obese patients derived no benefit from additional 3 years of anastrozole (DFS HR 0.93; P=0.68; distant recurrence-free survival HR 0.91; P=0.78; and OS HR 0.9; P=0.68). The possible predictive impact of BMI on extended endocrine treatment could be strengthened by a Cox regression interaction model between BMI and treatment (P=0.07). CONCLUSION: Body mass index may be used to predict outcome benefit of extended AI treatment in patients with receptor-positive breast cancer.

The predictive value of serum soluble E-cadherin levels in breast cancer patients undergoing preoperative systemic chemotherapy.

OBJECTIVES: To date, no reliable markers are available to predict response to or to assess prognosis after preoperative systemic chemotherapy (PST) in patients with locally advanced breast cancer. Previous studies demonstrated that elevated levels of soluble E-cadherin (sE-cadherin), a product of proteolytic cleavage of cell surface E-cadherin, are associated with higher risk for metastatic disease and poor prognosis in various tumor types. We, therefore, hypothesized that serum sE-cadherin levels measured before PST may correlate with pathological response. DESIGN AND METHODS: In a retrospective analysis, sE-cadherin levels were measured in sera of 108 female patients with histologically proven breast cancer before initiation of PST by using a commercially available quantitative sandwich enzyme immunoassay technique. Patients received a median number of 4 (range 3-6) cycles of anthracyline-based chemotherapy. The median patient age was 51.5 (range 21-71) years. Tumor size was measured clinically and translated into the tumor-node-metastasis (TNM)-system before the start of chemotherapy. Histopathological response in surgically removed specimens was evaluated using a modified Sinn regression score. In univariate analyses the correlations between levels of sE-cadherin and pathological response to PST were calculated. RESULTS: The histopathological regression scores correlated significantly with tumor grading (p=0.045), clinical lymph node status before PST (p=0.031) and sE-cadherin levels (p=0.039). No correlation was seen between histopathological regression scores and hormone receptor and menopausal status as well as Her2-neu status. CONCLUSION: sE-cadherin may be a marker predicting response to PST for patients with breast cancer. Our findings warrant further evaluation of sE-cadherin in a prospective trial.

Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response. Previous findings from small-scale studies revealed conflicting results about its independent prognostic significance with regard to different clinical end points in pancreatic cancer (PC) patients. Therefore, the aim of our study was the external validation of the prognostic significance of NLR in a large cohort of PC patients. METHODS: Data from 371 consecutive PC patients, treated between 2004 and 2010 at a single centre, were evaluated retrospectively. The whole cohort was stratified into two groups according to the treatment modality. Group 1 comprised 261 patients with inoperable PC at diagnosis and group 2 comprised 110 patients with surgically resected PC. Cancer-specific survival (CSS) was assessed using the Kaplan-Meier method. To evaluate the independent prognostic significance of the NLR, the modified Glasgow prognostic score (mGPS) and the platelet-lymphocyte ratio univariate and multivariate Cox regression models were applied. RESULTS: Multivariate analysis identified increased NLR as an independent prognostic factor for inoperable PC patients (hazard ratio (HR)=2.53, confidence interval (CI)=1.64-3.91, P<0.001) and surgically resected PC patients (HR=1.61, CI=1.02-2.53, P=0.039). In inoperable PC patients, the mGPS was associated with poor CSS only in univariate analysis (HR=1.44, CI=1.04-1.98). CONCLUSION: Risk prediction for cancer-related end points using NLR does add independent prognostic information to other well-established prognostic factors in patients with PC, regardless of the undergoing therapeutic modality. Thus, the NLR should be considered for future individual risk assessment in patients with PC.

Elevated preoperative neutrophil/lymphocyte ratio is associated with poor prognosis in soft-tissue sarcoma patients.

BACKGROUND: Recent data indicate that tumour microenvironment, which is influenced by inflammatory cells, has a crucial role in cancer progression and clinical outcome of patients. In the present study, we investigated the prognostic relevance of preoperative neutrophil/lymphocyte (N/L) ratio on time to tumour recurrence (TTR) and overall survival (OS) in soft-tissue sarcoma (STS) patients who underwent curative surgical resection. METHODS: In all, 260 STS patients were included in this retrospective study. Kaplan-Meier curves and multivariate Cox proportional models were calculated for TTR and OS. RESULTS: In univariate analysis, elevated N/L ratio was significantly associated with decreased TTR (hazard ratio (HR), 2.32; 95% confidence interval (CI), 1.30-4.14; P=0.005) and remained significant in the multivariate analysis (HR, 1.98; 95%CI, 1.05-3.71; P=0.035). Patients with elevated N/L ratio showed a median TTR of 77.9 months. In contrast, patients with low N/L ratio had a median TTR of 99.1 months. Regarding OS, elevated N/L ratio was also significantly associated with decreased survival in univariate analysis (HR, 2.90; 95%CI, 1.82-4.61; P=0.001) and remained significant in multivariate analysis (HR, 1.88; 95%CI, 1.14-3.12; P=0.014). CONCLUSION: In conclusion, our findings suggest that an elevated preoperative N/L ratio predicts poor clinical outcome in STS patients and may serve as a cost-effective and broadly available independent prognostic biomarker.

Low expression of the putative tumour suppressor spinophilin is associated with higher proliferative activity and poor prognosis in patients with hepatocellular carcinoma.

BACKGROUND: Spinophilin, a multifunctional intracellular scaffold protein, is reduced in certain types of cancer and is regarded as a novel putative tumour suppressor protein. However, the role of spinophilin in hepatocellular carcinoma (HCC) has never been explored before. METHODS: In this study, we determined for the first time the expression pattern of spinophilin in human HCC by immunohistochemistry and quantitative reverse transcriptase-PCR analysis. In addition, we performed immunohistochemical analysis of p53, p14(ARF) and the proliferation marker Ki-67. Kaplan-Meier curves and multivariate Cox proportional models were used to study the impact on clinical outcome. Small interfering RNA (siRNA) was used to silence spinophilin and to explore the effects of reduced spinophilin expression on cellular growth. RESULTS: In our study, complete loss of spinophilin immunoreactivity was found in 44 of 104 HCCs (42.3%) and reduced levels were found in an additional 37 (35.6%) cases. After adjusting for other prognostic factors, multivariate Cox regression analysis identified low expression of spinophilin as an independent prognostic factor with respect to disease-free (hazard ratio (HR)=1.8; 95% confidence interval (CI)=1.04-3.40; P=0.043) and cancer-specific survival (HR=2.0; CI=1.1-3.8; P=0.025). Reduced spinophilin expression significantly correlated with higher Ki-67 index in HCC (P=0.014). Reducing spinophilin levels by siRNA induced a higher cellular growth rate and increased cyclin D2 expression in tumour cells (P<0.05). CONCLUSION: This is the first study of the expression pattern and distribution of spinophilin in HCC. According to our data, the loss of spinophilin is associated with higher proliferation and might be useful as a prognostic marker in patients with HCC.

Efficacy of tamoxifen ± aminoglutethimide in normal weight and overweight postmenopausal patients with hormone receptor-positive breast cancer: an analysis of 1509 patients of the ABCSG-06 trial.

BACKGROUND: There exists evidence that body mass index (BMI) impacts on the efficacy of aromatase inhibitors in patients with breast cancer. The relationship between BMI and the efficacy of tamoxifen is conflicting. We investigated the impact of BMI on the efficacy of single tamoxifen and tamoxifen plus an aromatase inhibitor in the well-defined prospective study population of the ABCSG-06 trial. METHODS: ABCSG-06 investigated the efficacy of tamoxifen vs tamoxifen plus aminoglutethimide in postmenopausal women with hormone receptor-positive breast cancer. Taking BMI at baseline, patients were classified as normal weight (BMI=18.5-24.9 kg m(-)(2)), overweight (BMI=25-29.9 kg m(-)(2)), and obese (30 kg m(-)(2)) according to WHO criteria. RESULTS: Overweight+obese patients had an increased risk for distant recurrences (hazard ratio (HR): 1.51; Cox P=0·018) and a worse overall survival (OS; HR: 1·49; Cox P=0·052) compared with normal weight patients. Analysing patients treated with single tamoxifen only, no difference between overweight+obese patients and normal weight patients regarding distant recurrence-free survival (HR: 1.35; Cox P=0·24) and OS (HR: 0.99; Cox P=0·97) could be observed. In contrast, in the group of patients treated with the combination of tamoxifen plus aminoglutethimide, overweight+obese patients had an increased risk for distant recurrences (1.67; Cox P=0·03) and a worse OS (1.47; Cox P=0·11) compared with normal weight patients. CONCLUSION: BMI impacts on the efficacy of aromatase inhibitor-based treatment but not single tamoxifen.

Asymptomatic deep vein thrombosis and superficial vein thrombosis in ambulatory cancer patients: impact on short-term survival.

BACKGROUND: Asymptomatic venous thrombotic events (VTEs) are possible findings in ambulatory cancer patients. Data regarding the incidence and clinical impact of asymptomatic VTEs are conflicting. We therefore conducted a study to evaluate the occurrence of asymptomatic VTEs of the lower limbs in ambulatory cancer patients to further evaluate the association of these asymptomatic VTEs on survival during a 9-month follow-up period. METHODS: In our prospective cohort, we included 150 consecutive ambulatory cancer patients who were free of any clinical symptoms for VTEs. Compression ultrasound to detect deep vein thrombosis (DVT) and superficial venous thrombosis (SVT) of the lower limbs was performed by a vascular specialist in all patients at baseline. In case of pathological findings the patients were treated with low molecular weight heparin (LMWH) because of current established guidelines. The occurrence of death was investigated during a 9-month follow-up period. RESULTS: A total of 27 (18%) patients with VTEs were detected, which included 13 patients (8.7%) with a SVT and 16 patients (10.7%) showing a DVT. Two patients had both, a SVT and a DVT as well. During the 9-month follow-up period the occurrence of a VTE at baseline was associated with a 2.4-fold increased risk for death (HR 2.4 (1.2-5.3); P=0.03). CONCLUSION: Asymptomatic VTEs of the lower limbs in ambulatory cancer patients are frequently occurring concomitant features and are associated with poor survival during a 9-month follow-up period despite anticoagulation with LMWH.

Down-regulation of KRAS-interacting miRNA-143 predicts poor prognosis but not response to EGFR-targeted agents in colorectal cancer.

BACKGROUND: MicroRNA-143 (miRNA-143) is frequently down-regulated in colorectal cancer (CRC) and may influence CRC cell proliferation, apoptosis and sensitivity to 5-fluorouracil. mRNA encoded by the KRAS oncogene has been identified as a target of miRNA-143. However, the prognostic significance of miRNA-143 expression and the ability to predict patient response to epidermal growth factor receptor (EGFR)-targeted agents have not yet been explored. METHODS: We examined 77 CRC patients who were identified by pyrosequencing to have wild-type KRAS and were subsequently treated with EGFR-targeted therapy with the monoclonal antibodies cetuximab or panitumumab. MicroRNA-143 expression was measured in CRC tissue and corresponding non-neoplastic colon tissue by RT-PCR and its expression level was correlated with clinico-pathological characteristics. Univariate and multivariate analyses were used to calculate cancer-specific survival (CSS). The progression-free survival (PFS) and objective response rates on EGFR-targeted therapy were also evaluated. RESULTS: Down-regulation of miRNA-143 was observed in 47 out of 77 (61%) tumours. Multivariate Cox regression analysis identified low levels of miRNA-143 expression as an independent prognostic factor with respect to CSS (hazard ratio=1.92, confidence interval=1.1-3.4, P=0.024). A significant difference was also observed with regard to PFS on EGFR-targeted therapy (P=0.031), but there were no significant differences with regard to the objective response rates. CONCLUSION: Our data indicate that miRNA-143 expression levels serve as an independent prognostic biomarker for CRC in KRAS wild-type patients. No role for miRNA-143 expression as a predictive biomarker for EGFR-targeted agents could be identified. Given its negative impact on CSS and PFS, miRNA-143 represents a novel prognosticator and a promising drug target for patients with CRC.

Prolactin receptor is a negative prognostic factor in patients with squamous cell carcinoma of the head and neck.

BACKGROUND: The influence of human prolactin (hPRL) on the development of breast and other types of cancer is well established. Little information, however, exists on the effects of hPRL on squamous cell carcinomas of the head and neck (SCCHNs). METHODS: In this study, we evaluated prolactin receptor (PRLR) expression in SCCHN cell lines and assessed by immunohistochemistry the expression in 89 patients with SCCHNs. The PRLR expression was correlated with clinicopathological characteristics as well as clinical outcome. The effect of hPRL treatment on tumour cell growth was evaluated in vitro. RESULTS: Immunoreactivity for PRLR was observed in 85 out of 89 (95%) tumours. Multivariate COX regression analysis confirmed high levels of PRLR expression (>25% of tumour cells) to be an independent prognostic factor with respect to overall survival (HR=3.70, 95% CI: 1.14-12.01; P=0.029) and disease-free survival (P=0.017). Growth of PRLR-positive cancer cells increased in response to hPRL treatment. CONCLUSION: Our data indicate that hPRL is an important growth factor for SCCHN. Because of PRLR expression in a vast majority of tumour specimens and its negative impact on overall survival, the receptor represents a novel prognosticator and a promising drug target for patients with SCCHNs.

In vivo confocal laser scanning microscopy in the diagnosis of melanocytic skin tumours.

Melanoma of the skin represents one of the greatest challenges in early or preventive detection. Whereas surgical excision in early stages of melanoma development is almost always curative, delayed recognition puts the patient at risk for destructive growth and death from disease once the tumour has progressed to competence for metastasis. The worldwide introduction of dermoscopy has led to improved diagnostic accuracy for melanocytic skin tumours. Whereas dermoscopy has probably reached the method's inherent potential diagnostic accuracy because of the lack of cellular level evaluation, further improvements could be expected by in vivo confocal laser scanning microscopy. In vivo confocal microscopy represents a novel imaging tool that allows the noninvasive examination of skin cancer morphology in real time at a 'quasihistopathological' resolution viewing microanatomical structures and individual cells. Numerous morphological confocal features of melanocytic skin tumours have been described and histopathological correlates of confocal structures have been previously elucidated. Recently, several studies have evaluated the diagnostic accuracy of in vivo confocal microscopy for melanocytic skin tumours, investigating approximately 50,000 tumour images. Remarkably, sensitivity superior to the diagnostic accuracy achieved with dermoscopy could be reached by this imaging modality. These studies represent a significant contribution to the body of research necessary for the evaluation and implementation of in vivo confocal microscopy in clinical practice to avoid many currently unnecessary biopsies. In vivo confocal microscopy probably augurs a sea change in the way we evaluate melanocytic skin tumours in the future and will ultimately move the art of histological diagnosis closer to the bedside.

In vivo confocal laser scanning microscopy of melanocytic skin tumours: diagnostic applicability using unselected tumour images.

BACKGROUND: In vivo confocal laser scanning microscopy (CLSM) represents a novel imaging tool that allows the noninvasive examination of skin cancer morphology in real time at a 'quasi-histopathological' resolution viewing microanatomical structures and individual cells. OBJECTIVES: To validate diagnostic confocal examination of melanocytic skin tumours using unselected tumour images. METHODS: In the present study, we used a total of 3709 unselected CLSM tumour images obtained from 20 malignant melanomas and 50 benign naevi. The entire set of images derived from each tumour was evaluated by independent observers. Classification tree analysis based on a subsample of 857 tumour images was performed to develop a diagnostic algorithm. RESULTS: Overall, sensitivity and specificity of 97.5% and 99% could be achieved by the independent observers (positive predictive value 97.5%, negative predictive value 99%). Classification tree analysis yielded a three-step algorithm based on only three morphological CLSM features, facilitating a correct classification in 92.4% of the benign naevus images and 97.6% of melanoma images. CONCLUSIONS: In vivo CLSM augurs a sea change in the way we will view skin tumour processes clinically at the bedside and merits application for use as a screening tool in skin oncology.