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Phase II Trial of Doxycycline with Radiotherapy for Rectal Cancer

ABSTRACT: Interventions: Doxycycline is a broad-spectrum antibiotic, which prevents the binding of amino-acyltRNA to the messenger RNA-30S ribosomal subunit, preventing polyribosome formation. It is approved in New Zealand for the treatment of chronic prostatitis, sinusitis, syphilis, pelvic inflammatory disease, malaria, recurrent aphthous ulceration, and acne vulgaris. Doxycycline primarily exerts it’s antimicrobial action by bacteriostasis. It also has antinflammatory effects. Doxycycline will be administered as two 100mg tablets orally each morning, starting two days prior to the first dose of short-course radiotherapy (SCRT), until one day prior to surgery for rectal cancer. Surgery will be performed within three weeks of starting radiotherapy treatment. The duration of doxycycline will be between 12 and 23 days, and will be determined by each participant s individual treatment schedule. Adherence will be assessed through a combination of a patient diary, and count of the number of tablets remaining in the drug container on the patients admission for rectal cancer surgery. Primary outcome(s): Difference in the mean immunohistochemistry (IHC) H-scores for CD133 in resected tumours between the doxycycline and control groups.[Based on rectal cancers surgically resected within 3 weeks of radiotherapy.] Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Type of endpoint: Safety/efficacy

DISEASE(S): Cancer-bowel-back Passage (rectum) Or Large Bowel (colon),Rectal Cancer

PROVIDER: 2471032 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Background: MicroRNAs (miRNAs) are small, non-coding, RNA molecules which regulate numerous cellular processes. Specific miRNA may be abnormally down-regulated or up-regulated in colorectal cancer and have been found associated with prognosis or response to treatments. However, no study has ever addressed their predictive role in rectal cancer. Therefore, we used microarray technology and RT-PCR to profile miRNA expression patterns in patients (pts) with rectal cancer, with the aim to identify a specific M-bM-^@M-^\signatureM-bM-^@M-^] associated with pathological complete response after neoadjuvant chemo-radiotherapy. Methods: 38 pts with locally advanced rectal cancer (cT3-4/N+) were treated with capecitabine-oxaliplatin and pelvic conformal radiotherapy (45 cGy) followed by surgery (after 6-8 weeks). Pathologic response was scored according to the tumor regression grade (TRG) scale. MiRNA expression profile was analysed by microarray on fresh frozen biopsies obtained before treatment start and confirmed by RT-PCR. The correlation between miRNA expression profile and the TRG coded as TRG1 (pathologic Complete Response-pCR) versus TRG >1 (no pCR) was assessed by statistical analysis methods specifically designed for this study. Findings: 14 miRNAs were selected by arrays analysis as differentially expressed in TRG1 pts and 13 were confirmed by RT-PCR. In particular, 11 miRNAs (miR-1183, miR-483-5p, miR-622, miR-125a-3p, miR-1224-5p, miR-188-5p, miR-1471, miR-671-5p, miR-1909*, miR-630 and miR-765) were significantly up-regulated in TRG1 pts, while 2 miRNAs were under -expressed (miR-1274b and miR-720). miR-622 and miR-630 showed 100% sensitivity and specificity in selecting TRG1 cases and were significantly correlated with EGFR (M-OM-^G2=11M-bM-^@M-"793; p= 0M-bM-^@M-"001) and TS expression (M-OM-^G2=10M-bM-^@M-"589; p= 0M-bM-^@M-"001). Interpretation: A set of 13 miRNAs is strongly associated with pathologic complete response and may represent a specific marker of response to chemo-radiotherapy in locally advanced rectal cancer. Experiments were performed on purified RNA from preoperatory biopsies of 38 patients with histological diagnosis of rectal adenocarcinoma invading through the intestinal wall and/or with pelvic lymph node involvement as evaluated by endorectal ultrasonography (uT3-T4 and/or uN+). Patients were treated with neoadjuvant chemo-radiotherapy (capecitabine + oxaliplatin in combination with 45 Gy of pelvic conformal radiotherapy). Patients have been divided in the following two groups: group A those who had obtained a pathologic complete response M-bM-^@M-^S TRG 1, including the patient without detectable disease who refused surgery, group B any pathologic response other than complete.

Project description:Title: Transcriptome analysis of human endometrial tissues from healthy post-menoupausal women reflecting the endometrial response to 3-weeks treatment with tibolone, E2 and E2+MPA. In an observational, open, non-randomized, controlled study uterine tissues were collected in order to generate endometrial gene expression profiles. healthy postmenopausal women were enrolled into the following treatment groups: Control-group; Tibolone-group, 2,5 mg of tibolone (administered orally) every day, starting 21 days prior to surgery; Estradiol-group, 2 mg of estradiol (administered orally) every day, starting 21 days prior to surgery; Estradiol+progestagen-group, 2 mg of estradiol (administered orally) and 5 mg of MPA (Medroxy Progesteroneacetate, administered orally) every day, starting 21 days prior to surgery. Pure (100%) endometrium was isolated from the snap-frozen uterine tissues and used for RNA isolation. RNA was labbeled and hybridized to whole genome Affymetrix U133plus2 GeneChips containing 54,614 probe sets, representing approximately 47,000 transcripts. Relative to the control group, 940 genes are regulated in the endometrium of E2 treated patients, whereas only 198 genes are significantly regulated in endometria from tibolone or E2+MPA treated patients. Furthermore, only 9% of E2 regulated genes are also regulated by tibolone (85 out of 940), only 5% are also regulated by E2+MPA treatment and the overlap between tibolone and E2+MPA treatment is about 10%. This indicated that tibolone-treatment results in a weak endometrial profile similarity to E2 treatment and no profile similarity to E2+MPA treatment. A more detailed analysis showed that down stream processes, such as regulation of the cell cycle, angiogenesis and cell proliferation are almost not affected by tibolone treatment but, in contrast, are significantly affected by E2. For example, upon staining with Ki67, a marker for mitotic activity, significantly increased stromal as well as glandular cell proliferation was observed in the endometria from the E2-only treated group, while tibolone treatment resulted only in a slight increase in stromal cell proliferation (and no increase in glandular cell proliferation). These results indicate that in contrast to long-term tibolone use, short-term (21-days) use results in some estrogenic stimulation of the endometrium, which is clearly far less and rather different from what is observed during E2 treatment. References:; Klaassens et al., 2006; Hanifi-Moghaddam et al., 2007; Verheul et al., 2007 Experiment Overall Design: This study was designed as a controlled clinical trial. Patients who visited our clinics to undergo vaginal hysterectomy for treatment of prolapse, were eligible to participate in this study. The trial was performed in the period before the scheduled surgery. After informed consent, the patients were sequentially assigned to one of the following treatment groups: Experiment Overall Design: - Control-group (no hormonal treatment); Experiment Overall Design: - Tibolone-group (2.5 mg tibolone (Livial, N.V. Organon, Oss, The Netherlands) administered orally every day, starting 21 days prior to surgery); Experiment Overall Design: - E2 group (2 mg of estradiol administered orally every day, starting 21 days prior to surgery); Experiment Overall Design: - E2+MPA-group (2 mg estradiol + 5 mg MPA administered orally every day, starting 21 days prior to surgery). Experiment Overall Design: Pure endometrium was isolated and used for profiling. 31 samples, 3 of which were duplicates, were analyzed.

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Phase II Trial of Doxycycline with Radiotherapy for Rectal Cancer

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