Relevance of shrinkage versus fragmented response patterns in rectal cancer.

AIMS: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome. METHODS AND RESULTS: The study included a test (n = 197) and a validation cohort (n = 218) of post-CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three-step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II-IV, 78% versus 35%; P < 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19-3.50, P = 0.008) and disease-free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23-5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS. CONCLUSIONS: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response.

Survival differences with immediate versus delayed chemotherapy for asymptomatic incurable metastatic colorectal cancer.

BACKGROUND: For patients with asymptomatic, incurable, metastatic colorectal cancer, palliative, systemic treatment can be started immediately, or can be delayed until disease-related symptoms occur. How the potential survival benefit of starting palliative, systemic treatment immediately after diagnosis weighs up against the potential side effects is currently under debate, and was investigated in this review. OBJECTIVES: To assess the effects of immediate versus delayed chemotherapy, with or without targeted therapy, on overall survival, toxicity, quality of life, progression-free survival, and compliance with chemotherapy for individuals with asymptomatic, metastatic, incurable colorectal cancer. SEARCH METHODS: We searched CENTRAL; 2018, Issue 8, MEDLINE Ovid, Embase Ovid, PsycINFO, the World Health Organization International Clinical Trials Registry Platform, and Clinicaltrials.gov, from inception to 23 August 2018. We did not apply limitations based on language or date of publication. We searched the reference lists of all included studies to identify trials that may not have been identified from the electronic searches. SELECTION CRITERIA: Randomised controlled trials evaluating immediate versus delayed chemotherapy in persons with asymptomatic, metastatic, incurable colorectal cancer. DATA COLLECTION AND ANALYSIS: We applied standard methodological procedures, according to the recommendations of Cochrane and Cochrane Colorectal Cancer. Two review authors independently reviewed the studies identified by literature searches, selected relevant trials, extracted data, and assessed risk of bias of the included studies. We used the Cochrane tool to assess risk of bias, Review Manager 5 software for meta-analysis, GRADE methods to evaluate the quality of the evidence, and GRADEpro GDT software to develop a 'Summary of findings' table. MAIN RESULTS: We included three randomised controlled trials (351 participants) investigating immediate versus delayed chemotherapy in people diagnosed with asymptomatic, metastatic, incurable colorectal cancer. Giving immediate versus delayed chemotherapy may make little or no difference to overall survival (hazard ratio (HR) 1.17, 95% confidence interval (CI) 0.93 to 1.46; 3 studies, 351 persons; low-quality evidence). For toxicity, giving immediate versus delayed chemotherapy may make little or no difference to the risk of grade 3 or 4 nausea and vomiting (risk ratio (RR) 0.84, 95% CI 0.31 to 2.25; 2 studies, 140 persons; very low-quality evidence), stomatitis (RR 1.10, 95% CI 0.47 to 2.55; 2 studies, 140 persons; very low-quality evidence), or diarrhoea (RR 0.69, 95% CI 0.34 to 1.40; 2 studies, 140 persons, very low-quality evidence). We are uncertain whether delayed chemotherapy made a difference to quality of life (very low-quality evidence), progression-free survival (low-quality evidence), or compliance with chemotherapy (low-quality evidence), as we had insufficient data to pool for these outcomes. AUTHORS' CONCLUSIONS: Based on a limited number of trials, very sparse data, and uncertainty of the evidence, this review was unable to establish whether there was a difference in overall survival or other clinically relevant outcomes, between immediate or delayed chemotherapy in persons with metastatic, incurable, colorectal cancer. The results should be interpreted with caution.

Age determines the prognostic role of the cancer stem cell marker aldehyde dehydrogenase-1 in breast cancer.

BACKGROUND: The purpose of this study was to compare the expression and the prognostic effect of the breast cancer stem cell marker aldehyde dehydrogenase-1 (ALDH1) in young and elderly breast cancer patients. METHODS: The study population (N = 574) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Median follow-up was 17.9 years (range: 0.1 to 23.5). Tissue microarray slides were immunohistochemically stained for ALDH1 expression and quantified by two independent observers who were blinded to clinical outcome. Assessment of the prognostic effect of ALDH1 expression was stratified according to age and systemic treatment. RESULTS: Complete lack of expression of ALDH1 was found in 40% of tumors. With increasing age more tumors showed complete absence of ALDH1 expression (P < .001). In patients aged > 65 years, ALDH1 status was not associated with any clinical outcome. Conversely, in patients aged < 65 years, ALDH1 positivity was an independent risk factor of worse outcome for relapse free period (hazard ratio = 1.71 (95% CI, 1.09 to 2.68); P = .021) and relative survival (relative excess risks of death = 2.36 (95% CI, 1.22 to 3.68); P = .016). Ten-year relative survival risk was 57% in ALDH1-positive patients compared to 83% in ALDH1-negative patients. CONCLUSION: ALDH1 expression and its prognostic effect are age-dependent. Our results support the hypothesis that breast cancer biology is different in elderly patients compared to their younger counterparts and emphasizes the importance of taking into consideration age-specific interactions in breast cancer research.

Biomarker expression in rectal cancer tissue before and after neoadjuvant therapy.

PURPOSE: Intraoperative identification of rectal cancer (RC) can be challenging, especially because of fibrosis after treatment with preoperative chemo- and radiotherapy (CRT). Tumor-targeted fluorescence imaging can enhance the contrast between tumor and normal tissue during surgery. Promising targets for RC imaging are carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM) and the tyrosine-kinase receptor Met (c-Met). The effect of CRT on their expression determines their applicability for imaging. Therefore, we investigated whether CRT modifies expression patterns in tumors, lymph node (LN) metastases and adjacent normal rectal tissues. PATIENTS AND METHODS: Preoperative biopsies, primary tumor specimens and metastatic LNs were collected from 38 RC patients who did not receive CRT (cohort 1) and 34 patients who did (cohort 2). CEA, EpCAM and c-Met expression was determined using immunohistochemical staining and was semiquantified by a total immunostaining score (TIS), consisting of the percentage and intensity of stained tumor cells (0-12). RESULTS: In both cohorts CEA, EpCAM and c-Met were significantly highly expressed in >60% of tumor tissues compared with adjacent normal epithelium (T/N ratio, P<0.01). EpCAM showed the most homogenous expression in tumors, whereas CEA showed the highest T/N ratio. Most importantly, CEA and EpCAM expression did not significantly change in normal or neoplastic RC tissue after CRT, whereas levels of c-Met changed (P=0.02). Tissues of eight patients with a pathological complete response after CRT showed expression of all biomarkers with TIS close to normal epithelium. CONCLUSION: Histological evaluation shows that CEA, EpCAM and c-Met are suitable targets for RC imaging, because all three are significantly enhanced in cancer tissue from primary tumors or LN metastases compared with normal adjacent tissue. Furthermore, the expression of CEA and EpCAM is not significantly changed after CRT. These data underscore the applicability of c-Met and especially, CEA and EpCAM as targets for image-guided RC surgery, both before and after CRT.

A dual-labeled cRGD-based PET/optical tracer for pre-operative staging and intraoperative treatment of colorectal cancer.

cRGD peptides target integrins associated with angiogenesis (e.g., αvß3) and cancer, and have been used as binding ligands for both positron emission tomography (PET) and near-infrared fluorescence (NIRF) optical imaging. This study introduces the hybrid tracer cRGD-ZW800-1-Forte-[89Zr]Zr-DFO, which is based on a novel zwitterionic fluorophore structure that reduces non-specific background uptake during molecular imaging of tumors. An in vitro binding assay was used to validate tracer performance. 10 nmol ZW800F-cRGD-Zr-DFO was injected in mice (n=7) bearing orthotopic human colorectal tumors (HT29-luc2) for tumor detection with NIRF imaging. Subsequently, ZW800F-cRGD-Zr-DFO was loaded with 89Zr and 10 nmol cRGD-ZW800-1-Forte-[89Zr]Zr-DFO (3 MBq) was injected in mice (n=8) for PET/CT imaging. Imaging and biodistribution was performed at 4 and 24 h. NIRF imaging was performed up to 168 h after administration. Sufficient fluorescent signals were measured in the tumors of mice injected with ZW800F-cRGD-Zr-DFO (emission peak ~800 nm) compared to the background. The signal remained stable for up to 7 days. The fluorescence signal of cRGD-ZW800-1-Forte-[89Zr]Zr-DFO remained intact after labeling with 89Zr. PET/CT permitted clear visualization of the colorectal tumors at 4 and 24 h. Biodistribution at 4 h showed the highest uptake of the tracer in kidneys and sufficient uptake in the tumor, remaining stable for up to 24 h. A single molecular imaging agent, ZW800F-cRGD-[89Zr]Zr-DFO, permits serial PET and NIRF imaging of colorectal tumors, with the latter permitting image-guided treatment intraoperatively. Due to its unique zwitterionic structure, the tracer is rapidly renally cleared and fluorescent background signals are low.

Prognostic Impact of Urokinase Plasminogen Activator Receptor Expression in Pancreatic Cancer: Malignant Versus Stromal Cells.

The urokinase plasminogen activator receptor (uPAR) has been proposed as a potential prognostic factor for various malignancies. The aim of this study is to assess the prognostic value of uPAR expression in neoplastic and stromal cells of patients with pancreatic adenocarcinoma. Urokinase plasminogen activator receptor expression was determined by immunohistochemistry in 122 pancreatic ductal adenocarcinomas. Kaplan-Meier and Cox regression analyses were used to determine the association with survival. Respectively 66%, 82% and 62% of patients with pancreatic cancer expressed uPAR in neoplastic cells, stromal, and in both combined. Multivariate analysis showed a significant inverse association between uPAR expression in both neoplastic and stromal cells and overall survival. The prognostic impact of uPAR in stromal cells is substantial, but not as pronounced as that of uPAR expression in neoplastic cells. This study suggests a role for uPAR as a biomarker to single out higher risk subgroups of patients with pancreatic cancer.

Optimal surgery for advanced gastric cancer.

Locoregional control remains a major problem after surgery, although a curative resection is still the only treatment to offer a cure for patients with gastric cancer. Despite the results of major randomized trials, the extent of nodal dissection continues to be debated. If there is a survival benefit to be gained by extended lymphadenectomy, added operative mortality should be eliminated. A pancreas and spleen-preserving D2 lymphadenectomy provides superior staging information and may provide a survival benefit while avoiding its excess morbidity. Splenectomy during gastric resection for tumors not adjacent to or invading the spleen increases morbidity and mortality without improving survival. Therefore, splenectomy should not be performed unless there is direct tumor extension. The Maruyama Index and nomograms that predict disease-specific survival may help to discriminate between patients with a high risk of relapse and select those patients who will be most likely to benefit from tailored multimodality treatment. There is growing evidence that gastric cancer surgery should be performed in high-volume centers with experienced specialists to reduce morbidity and operative mortality and to achieve better survival results.