Johan Westerga

PURPOSE: This study aims to develop a robust gene expression classifier that can predict disease relapse in patients with early-stage colorectal cancer (CRC). PATIENTS AND METHODS: Fresh frozen tumor tissue from 188 patients with stage I to IV CRC undergoing surgery was analyzed using Agilent 44K oligonucleotide arrays. Median follow-up time was 65.1 months, and the majority of patients (83.6%) did not receive adjuvant chemotherapy. A nearest mean classifier was developed using a cross-validation procedure to score all genes for their association with 5-year distant metastasis-free survival. RESULTS: An optimal set of 18 genes was identified and used to construct a prognostic classifier (ColoPrint). The signature was validated on an independent set of 206 samples from patients with stage I, II, and III CRC. The signature classified 60% of patients as low risk and 40% as high risk. Five-year relapse-free survival rates were 87.6% (95% CI, 81.5% to 93.7%) and 67.2% (95% CI, 55.4% to 79.0%) for low- and high-risk patients, respectively, with a hazard ratio (HR) of 2.5 (95% CI, 1.33 to 4.73; P = .005). In multivariate analysis, the signature remained one of the most significant prognostic factors, with an HR of 2.69 (95% CI, 1.41 to 5.14; P = .003). In patients with stage II CRC, the signature had an HR of 3.34 (P = .017) and was superior to American Society of Clinical Oncology criteria in assessing the risk of cancer recurrence without prescreening for microsatellite instability (MSI). CONCLUSION: ColoPrint significantly improves the prognostic accuracy of pathologic factors and MSI in patients with stage II and III CRC and facilitates the identification of patients with stage II disease who may be safely managed without chemotherapy.

Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investigated how radiotherapy changes the relative abundance and phenotypes of brain-resident MG and peripherally recruited monocyte-derived macrophages (MDMs) in glioblastoma. We identified radiation-specific, stage-dependent MG and MDM gene expression signatures in murine gliomas and confirmed altered expression of several genes and proteins in recurrent human glioblastoma. We found that targeting these TAM populations using a colony-stimulating factor-1 receptor (CSF-1R) inhibitor combined with radiotherapy substantially enhanced survival in preclinical models. Our findings reveal the dynamics and plasticity of distinct macrophage populations in the irradiated tumor microenvironment, which has translational relevance for enhancing the efficacy of standard-of-care treatment in gliomas.

Postural development has not attracted much attention in investigations of neuro-ontogeny. In the rat, motor behaviours have been studied repeatedly but the development of postural control has been largely neglected. In the present study we have taken inventory of behavioural aspects of postural development. Postures and postural skills of 10 pups were 3-dimensionally recorded on video tape from the 2nd to the 20th day. The development of posture may be subdivided into three periods. During the first period, lasting until the 4th or 5th day, neonates were unable to lift their trunk from the floor, and the only indication for postural activity being head lifting. From then until the 12th-13th day, pups were able to walk, though staggering, and in addition they groomed and reared with forelimb support. From then, in a rapid development lasting until day 16, the adult type of fluent locomotion developed as well as grooming and rearing without support. In addition, complex motor acts developed. These results are discussed in the perspective of the structural and functional development of postural systems.

OBJECTIVE: Nodular regenerative hyperplasia (NRH) and sinusoidal dilatation have been described in relation to thiopurine use in patients with inflammatory bowel disease (IBD). However, there is a dearth of data on the prevalence of these histological abnormalities in general. The aim of our study was to describe the prevalence of these histological liver changes in a thiopurine-naïve IBD cohort. MATERIAL AND METHODS: Liver biopsy specimens were obtained from patients who were treated in a referral center and who underwent gastrointestinal surgery for IBD. Patients were excluded if thiopurines were ever used. The liver specimens were pathohistologically assessed with special attention to NRH. RESULTS: A total of 83, properly stained, liver specimens (Crohn's disease 61%) were evaluated. NRH was observed in 6% compared to sinusoidal dilatation of varying degree in 34% of specimens. An older age at biopsy was correlated with NRH (p=0.015). Fibrosis and steatosis of varying degrees were detected in 31% and 36% of liver biopsies, respectively. No cases of liver cirrhosis were observed. CONCLUSIONS: Pathohistological hepatic abnormalities are common in non-thiopurine using IBD patients. The association between thiopurine use, NRH and sinusoidal dilatation may be weaker than as reported in recent literature, as there is relatively high background prevalence in selected series.