Citations

PurposeOn initial publication of GI Intergroup Radiation Therapy Oncology Group (RTOG) 98-11 [A Phase III Randomized Study of 5-Fluorouracil (5-FU), Mitomycin, and Radiotherapy Versus 5-Fluorouracil, Cisplatin and Radiotherapy in Carcinoma of the Anal Canal], concurrent chemoradiation (CCR) with fluorouracil (FU) plus mitomycin (MMC) decreased colostomy failure (CF) when compared with induction plus concurrent FU plus cisplatin (CDDP), but did not significantly impact disease-free survival (DFS) or overall survival (OS) for anal canal carcinoma. The intent of the updated analysis was to determine the long-term impact of treatment on survival (DFS, OS, colostomy-free survival [CFS]), CF, and relapse (locoregional failure [LRF], distant metastasis) in this patient group.Patients and MethodsStratification factors included sex, clinical node status, and primary size. DFS and OS were estimated univariately by the Kaplan-Meier method, and treatment arms were compared by log-rank test. Time to relapse and CF were estimated by the cumulative incidence method and treatment arms were compared by using Gray's test. Multivariate analyses used Cox proportional hazard models to test for treatment differences after adjusting for stratification factors.ResultsOf 682 patients accrued, 649 were analyzable for outcomes. DFS and OS were statistically better for RT + FU/MMC versus RT + FU/CDDP (5-year DFS, 67.8% v 57.8%; P = .006; 5-year OS, 78.3% v 70.7%; P = .026). There was a trend toward statistical significance for CFS (P = .05), LRF (P = .087), and CF (P = .074). Multivariate analysis was statistically significant for treatment and clinical node status for both DFS and OS, for tumor diameter for DFS, and for sex for OS.ConclusionCCR with FU/MMC has a statistically significant, clinically meaningful impact on DFS and OS versus induction plus concurrent FU/CDDP, and it has borderline significance for CFS, CF, and LRF. Therefore, RT + FU/MMC remains the preferred standard of care.

Abstract A major contributor to cancer mortality is recurrence and subsequent metastatic transformation following therapeutic intervention. Therefore, in order to develop new treatment modalities and improve the efficacy of current ones, it is important to understand the molecular mechanisms that promote resistance to therapy in cancer cells. One pathway contributing to therapy resistance is autophagy, a self-digestive process that can eliminate unnecessary or damaged organelles to protect cancer cells from death. We have found that the VEGF-C/NRP-2 axis is involved in the activation of autophagy, which helps cancer cell survival following treatment. Inhibition of mTOR complex 1 activity by this axis is the underlying mechanism for the activation of autophagy. Furthermore, we identified two VEGF-C/NRP-2-regulated genes, LAMP-2 and WDFY-1, that have previously been suggested to participate in autophagy and vesicular trafficking. Upregulation of WDFY-1 following VEGF-C or NRP-2 depletion contributes to cytotoxic drug-mediated cell death. Together, these data suggest a link between the VEGF-C/NRP-2 axis and cancer cell survival despite the presence of chemotherapy-induced stress. Effective targeting of this pathway may lead to the development of new cancer therapies. Cancer Res; 73(1); 160–71. ©2012 AACR.

Objectively measured severe physical inactivity (SPI) has been reported as the strongest independent predictor of mortality in patients with chronic obstructive pulmonary disease (COPD). Activity monitoring is not feasible in routine clinical practice; therefore, we set out to determine the utility of simple clinical measures for predicting SPI in patients with COPD. A total of 165 patients with COPD wore an activity monitor for 5 days to define the presence or absence of SPI. Logistic models were generated including the modified Medical Research Council (MMRC) dyspnea grade, spirometry and the age–dyspnea–airflow obstruction (ADO) index. Physical Activity Scale for the Elderly (PASE) and Stanford Brief Activity Scale (SBAS) were also tested for validity and reliability in a subgroup of 67 patients. The MMRC dyspnea grade, PASE score, ADO index and SBAS score were associated with SPI, but general self-efficacy and spirometry were not. An MMRC dyspnea grade ≥3 was the best independent predictor of SPI (AUC: 0.74; PPV: 0.83; NPV: 0.68) followed closely by a PASE score of <111. The combination of MMRC dyspnea grade and PASE score provided the most robust model (AUC: 0.83; Positive Predictive Value (PPV): 0.95; Negative Predictive Value (NPV): 0.63). The results were confirmed using 5000 bootstrapped models from the cohort of 165 patients. MMRC dyspnea grade ≥3 may be the best triage tool for SPI in patients with COPD. The combination of the MMRC and PASE score provided the most robust prediction. Our results may have significant practical applicability for clinicians caring for patients with COPD.

Breast tumor development is regulated in part by cues from the local microenvironment, including interactions with neighboring nontumor cells as well as the ECM. Studies using homogeneous populations of breast cancer cell lines cultured in 3D ECM have shown that increased ECM stiffness stimulates tumor cell invasion. However, at early stages of breast cancer development, malignant cells are surrounded by normal epithelial cells, which have been shown to exert a tumor-suppressive effect on cocultured cancer cells. Here we explored how the biophysical characteristics of the host microenvironment affect the proliferative and invasive tumor phenotype of the earliest stages of tumor development, by using a 3D microfabrication-based approach to engineer ducts composed of normal mammary epithelial cells that contained a single tumor cell. We found that the phenotype of the tumor cell was dictated by its position in the duct: proliferation and invasion were enhanced at the ends and blocked when the tumor cell was located elsewhere within the tissue. Regions of invasion correlated with high endogenous mechanical stress, as shown by finite element modeling and bead displacement experiments, and modulating the contractility of the host epithelium controlled the subsequent invasion of tumor cells. Combining microcomputed tomographic analysis with finite element modeling suggested that predicted regions of high mechanical stress correspond to regions of tumor formation in vivo. This work suggests that the mechanical tone of nontumorigenic host epithelium directs the phenotype of tumor cells and provides additional insight into the instructive role of the mechanical tumor microenvironment.

BACKGROUND:The American Academy of Pediatrics (AAP) introduced revised return-to-care recommendations for mildly ill children in 2009 that were added to national standards in 2011. Child care directors' practices in a state without clear emphasis on return-to-care guidelines are unknown. We investigated director return-to-care practices just before the release of recently revised AAP guidelines.METHODS:A telephone survey with 5 vignettes of mild illness (cold symptoms, conjunctivitis, vomiting/diarrhea, fever, and ringworm) was administered to randomly sampled directors in metropolitan Milwaukee, Wisconsin. Directors were asked about return-to-care criteria for each illness. Questions for return-to-care criteria were open-ended; multiple responses were allowed. Answers were compared with AAP return-to-care recommendations.RESULTS:A total of 305 directors participated. Based on director responses to vignettes, the percentage of correct responses regarding return-to-child care management compared with AAP return-to-care recommendations was low: fever (0%); conjunctivitis (0%); diarrhea (1.6%); cold symptoms (12%); ringworm (21%); and vomiting (80%). Two illnesses (conjunctivitis and cold symptoms) would require the child to have an urgent medical evaluation or treatment not recommended by the AAP, as follows: Conjunctivitis—antibiotics for 24 hours (62%), physician visit (49%), any antibiotic treatment (6%), and symptom resolution (4%); and Cold Symptoms—physician visit (45.6%), antibiotics (10%), and symptom resolution (25%).CONCLUSIONS:Directors’ self-reported return-to-child care practices differed substantially before the release of revised AAP return-to-care recommendations. Active adoption of AAP return-to-child care guidelines would decrease the need for unnecessary urgent medical evaluation and treatment as well as unnecessary exclusion of a child from child care.