Combination of a six microRNA expression profile with four clinicopathological factors for response prediction of systemic treatment in patients with advanced colorectal cancer.

BACKGROUND: First line chemotherapy is effective in 75 to 80% of patients with metastatic colorectal cancer (mCRC). We studied whether microRNA (miR) expression profiles can predict treatment outcome for first line fluoropyrimidine containing systemic therapy in patients with mCRC. METHODS: MiR expression levels were determined by next generation sequencing from snap frozen tumor samples of 88 patients with mCRC. Predictive miRs were selected with penalized logistic regression and posterior forward selection. The prediction co-efficients of the miRs were re-estimated and validated by real-time quantitative PCR in an independent cohort of 81 patients with mCRC. RESULTS: Expression levels of miR-17-5p, miR-20a-5p, miR-30a-5p, miR-92a-3p, miR-92b-3p and miR-98-5p in combination with age, tumor differentiation, adjuvant therapy and type of systemic treatment, were predictive for clinical benefit in the training cohort with an AUC of 0.78. In the validation cohort the addition of the six miR signature to the four clinicopathological factors demonstrated a significant increased AUC for predicting treatment response versus those with stable disease (SD) from 0.79 to 0.90. The increase for predicting treatment response versus progressive disease (PD) and for patients with SD versus those with PD was not significant. in the validation cohort. MiR-17-5p, miR-20a-5p and miR-92a-3p were significantly upregulated in patients with treatment response in both the training and validation cohorts. CONCLUSION: A six miR expression signature was identified that predicted treatment response to fluoropyrimidine containing first line systemic treatment in patients with mCRC when combined with four clinicopathological factors. Independent validation demonstrated added predictive value of this miR-signature for predicting treatment response versus SD. However, added predicted value for separating patients with PD could not be validated. The clinical relevance of the identified miRs for predicting treatment response has to be further explored.

Inhomogeneous localization of radioactivity in the human kidney after injection of [(111)In-DTPA]octreotide.

UNLABELLED: In peptide receptor radionuclide therapy (PRRT) using somatostatin analogs labeled with beta-emitters, the radiosensitive kidney is the dose-limiting organ, because of high uptake and retention of the radionuclides after glomerular filtration. Dosimetry calculations are mostly based on the MIRD scheme, assuming homogeneous renal radioactivity distribution. The aim of this study was to reveal the radioactivity distribution in the normal human kidney after intravenous injection of [(111)In-diethylenetriaminepentaacetic acid (DTPA)]octreotide. METHODS: Three patients received intravenous injection of [(111)In-DTPA]octreotide before nephrectomy because of renal cancer. Distribution of radioactivity in the human kidney was investigated using SPECT scanning before and ex vivo autoradiography of the kidney after surgery. RESULTS: Radioactivity was localized predominantly in the cortex of the kidney. In the cortex, radioactivity was not distributed homogeneously but formed a striped pattern, with most of the radioactivity centered in the inner cortical zone. CONCLUSION: These findings show that average dose calculations using the MIRD scheme, assuming homogeneous renal radioactivity distribution, are inadequate to estimate the radiation dose to various parts of the kidney after PRRT. Different effects due to inhomogeneity can be expected from PRRT using radionuclides emitting particles with short particle ranges, for example, Auger electron emitters, alpha-emitters, and low-energy beta-emitters.