Predictive Factors of Late-onset Rectal Mucosal Changes After Radiotherapy of Prostate Cancer.

BACKGROUND/AIM: The Vienna Rectoscopy Score (VRS; from 0, absence of rectal mucosal changes, to 5) assessed 1 year after radiotherapy is a surrogate end-point of late rectal toxicity. The aim of this study was to investigate the association between treatment-related factors and 1-year VRS. PATIENTS AND METHODS: We performed a retrospective analysis of prospectively collected data. Patients with prostate adenocarcinoma treated with definitive or postoperative radiotherapy (RT) underwent endoscopy 1 year after RT. Relationships between VRS of 2 or more and treatment parameters were investigated by univariate and multivariate logistic analyses. RESULTS: One hundred and ninety-five patients (mean age=69 years; range=43-81 years) were considered eligible for the study. At univariate analysis, patients treated with hypofractionation plus radiosurgery boost (p<0.001) and an equivalent dose in 2 Gy per fraction (EQD2) (α/ß=3) ≥75 Gy (p<0.001) was associated with a significantly higher incidence of VRS ≥2 after 1 year of follow-up. At multivariate analysis, radiosurgery boost was an independent risk factor for developing rectal mucosal lesions (VRS ≥2), yielding an odds ratio (OR) of 4.14 (95% confidence interval (CI)=1.2-13.8), while pelvic surgery was inversely associated with VRS ≥2 (OR=0.39; 95% CI=0.17-0.94). CONCLUSION: Hypofractionation followed by radiosurgery boost significantly increased the risk of developing late-onset rectal mucosal changes. Therefore, special care and preventative treatment strategies are needed when using radiosurgery boost after hypofractionated RT.

Early radiation-induced mucosal changes evaluated by proctoscopy: predictive role of dosimetric parameters.

BACKGROUND AND PURPOSE: Late rectal complications are assessed according to different scoring systems. Endoscopy can provide a more sensitive estimation of early radiation damage. The aim of this paper is to investigate the correlation between dosimetric parameters and rectal mucosal changes after radiotherapy (RT). MATERIALS AND METHODS: Patients with prostate adenocarcinoma treated with curative or adjuvant RT underwent endoscopy 1 year after RT. Receiver operating characteristics (ROC) analysis was performed to analyze the predictive capability of the dosimetric variables in determining mucosal changes classified by Vienna Rectoscopy Score (VRS). RESULTS: The best dosimetric predictors of grade ≥2 telangiectasia were rectal (r) V(60 Gy) (p=0.014), rV(70 Gy) (p=0.017) and rD(mean) (p=0.018). Similar results were obtained for grade ≥2 VRS. The set of rV(60 Gy)<34.4%, rV(70 Gy)<16.7% and rD(mean)<57.5 Gy was associated with a decreased risk of grade ≥2 telangiectasia and VRS. CONCLUSIONS: rV(60 Gy), rV(70 Gy) and rD(mean) were the strongest predictors of rectal mucosal alterations. In-depth analysis is required to correlate each mucosal alteration with late rectal toxicity in order to suggest early proctoscopy as surrogate end-point for rectal late toxicity in studies aimed at reducing this important complication.

Early proctoscopy is a surrogate endpoint of late rectal toxicity in prostate cancer treated with radiotherapy.

PURPOSE: To predict the grade and incidence of late clinical rectal toxicity through short-term (1 year) mucosal alterations. METHODS AND MATERIALS: Patients with prostate adenocarcinoma treated with curative or adjuvant radiotherapy underwent proctoscopy a year after the course of radiotherapy. Mucosal changes were classified by the Vienna Rectoscopy Score (VRS). Late toxicity data were analyzed according to the Kaplan-Meier method. Comparison between prognosis groups was performed by log-rank analysis. RESULTS: After a median follow-up time of 45 months (range, 18-99), the 3-year incidence of grade ≥ 2 rectal late toxicity according to the criteria of the European Organization for Research and Treatment of Cancer and the Radiation Therapy Oncology Group was 24%, with all patients (24/24; 100%) experiencing rectal bleeding. The occurrence of grade ≥ 2 clinical rectal late toxicity was higher in patients with grade ≥ 2 (32% vs. 15 %, p = 0.02) or grade ≥ 3 VRS telangiectasia (47% vs. 17%, p ≤ 0.01) and an overall VRS score of ≥ 2 (31% vs. 16 %, p = 0.04) or ≥ 3 (48% vs. 17%, p = 0.01) at the 1-year proctoscopy. CONCLUSIONS: Early proctoscopy (1 year) predicts late rectal bleeding and therefore can be used as a surrogate endpoint for late rectal toxicity in studies aimed at reducing this frequent complication.

Neoadjuvant accelerated concomitant boost radiotherapy and multidrug chemotherapy in locally advanced rectal cancer: a dose-escalation study.

OBJECTIVES: To determine the maximal and safely dose of preoperative radiotherapy and concurrently intensified chemotherapy regimen (raltitrexed plus oxaliplatin) in locally advanced rectal cancer patients. METHODS: Patients with cT3-T4 and/or cN≥1 or locally recurrent rectal cancer were sequentially assigned to 4 treatment schedules of chemoradiation: standard radiotherapy (50.4 Gy/5.5 wk) plus raltitrexed (cohort A), accelerated radiotherapy (55 Gy/5 wk) plus raltitrexed (cohort B), standard radiotherapy plus raltitrexed and oxaliplatin (cohort C), accelerated radiotherapy plus raltitrexed and oxaliplatin (cohort D). Patients were treated in cohorts of 6 to 12 per group. The maximal tolerated dose was exceeded if more than one-third of patients in a given cohort experienced dose-limiting toxicity (DLT). DLT was defined as any grade ≥3 toxicity according to the Radiation Therapy Oncology Group criteria. RESULTS: Forty-six consecutive patients were enrolled. In cohort A, 6 patients received the planned treatment with no DLT. In cohort B, 1 of 8 patients experienced a DLT. In cohort C, a DLT occurred in 2 of 6 patients and therefore, a cohort expansion was required. Three of 16 patients treated at this dose level experienced a DLT. In addition, cohort D was expanded and DLT was found in 4 of 16 patients. Therefore, the maximal tolerated dose was not exceeded at any treatment level. CONCLUSIONS: An intensified regimen of chemoradiotherapy delivering raltitrexed and oxaliplatin concurrently with concomitant boost radiotherapy (55 Gy/5 wk) can be safely administered in patients with locally advanced rectal cancer. On the basis of these results, this intensified regimen could be tested in a phase II study.

Infliximab therapy downregulation of basic fibroblast growth factor/syndecan 1 link: a possible molecular pathway of mucosal healing in ulcerative colitis.

BACKGROUND: It is known that syndecan 1 in inflammatory bowel diseases is able to migrate from epithelial basolateral site to the stromal area and apical surface of epithelium with a consequent activation and modulation of basic fibroblast growth factor (bFGF), and this process sustains mucosal healing of ulcers. On the other hand, tumour necrosis factor (TNF) α mucosal levels are directly related to the entity of the damage in these disorders. Aim of the study A 'post-hoc' retrospective study was performed to estimate mucosal TNF α in rectal biopsies of subjects with ulcerative colitis (UC) before and after effective infliximab therapy and its relationship with syndecan 1, bFGF and endoscopic mucosal healing. MATERIAL AND METHODS: Paraffin-embedded rectal samples from 12 patients with UC responders to infliximab were analysed for TNF α, syndecan 1 and bFGF before and 6 months after therapy using a real-time reverse transcriptase polymersase chain reaction. Additionally, syndecan 1 location was evaluated by immunohistochemistry. Samples from 12 subjects with irritable bowel symptoms without endoscopic/histological abnormalities represented the control group. Mucosal healing induced by the treatment was defined by an endoscopic Mayo subscore changing from 2-3 to 0. ANOVA plus Student-Newman-Keuls was used for statistical analysis. RESULTS: The authors found that in the active disease, an increase in TNF α (p<0.001) is accompanied by raised levels of both syndecan 1 (p<0.005) and bFGF (p<0.005) compared with the control group. Infliximab-induced TNF α decrease to levels similar to controls is associated with both endoscopic mucosal healing and adhesion molecule/growth factor significant reduction. Additionally, syndecan 1 location, which is predominant in the stromal cells and apical epithelium in the active disorder, is quite exclusively located at the basolateral epithelial area in both healed mucosa and controls. CONCLUSIONS: Balanced interaction among TNF α inhibition by infliximab, syndecan 1 migration, bFGF repair modulation and final adhesion molecule reversal to its normal location might represent a suitable molecular pathway of endoscopic mucosal healing in UC.

A new regimen of bowel preparation for PillCam colon capsule endoscopy: a pilot study.

BACKGROUND: Colon capsule endoscopy (CCE) represents a new diagnostic, endoscopic technology for colonic exploration. Current protocols of preparation led to discordant rates of adequate cleansing level or CCE excretion. AIM: To evaluate the effect of a new regimen of bowel preparation for CCE on colon cleansing levels and on rate of capsule excretion. STUDY: 60 patients were prospectively enrolled. The new regimen of preparation consisted of a split regimen of PEG administration and of a 45 mL dose of sodium phosphate (NaP). Four senna tablets and a low-residue diet were also included. CCE excretion rate, colon cleansing, and accuracy were assessed. RESULTS: Forty-six patients were included in the final analysis, 13 patients (22%) being excluded because of preparation protocol deviations and one due to CCE technical failure (2%). At CCE, bowel preparation was rated as good in 78% of patients, fair in 20% and poor in 2%. CCE excretion rate occurred in 83% of patients. CCE sensitivity and specificity for significant findings was 100% and 95%, respectively. CONCLUSIONS: The combination of a split-dose of PEG solution with a low dose of NaP boosters resulted in high rates of adequate cleansing level and CCE excretion.

Capecitabine based postoperative accelerated chemoradiation of pancreatic carcinoma. A dose-escalation study.

UNLABELLED: The objective of this study was to evaluate the safety of escalating up to 55 Gy within five weeks, the dose of external beam radiotherapy to the previous tumor site concurrently with a fixed daily dose of capecitabine, in patients with resected pancreatic cancer. MATERIAL AND METHODS: Patients with resected pancreatic carcinoma were eligible for this study. Capecitabine was administered at a daily dose of 1600 mg/m (2). Regional lymph nodes received a total radiation dose of 45 Gy with 1.8 Gy per fractions. The starting radiation dose to the tumor bed was 50.0 Gy (2.0 Gy/fraction, 25 fractions). Escalation was achieved up to a total dose of 55.0 Gy by increasing the fraction size by 0.2 Gy (2.2 Gy/fraction), while keeping the duration of radiotherapy to five weeks (25 fractions). A concomitant boost technique was used. Dose limiting toxicity (DLT) was defined as any grade>3 hematologic toxicity, grade>2 liver, renal, neurologic, gastrointestinal, or skin toxicity, by RTOG criteria, or any toxicity producing prolonged (> 10 days) radiotherapy interruption. RESULTS AND DISCUSSION: Twelve patients entered the study (median age: 64 years). In the first cohort (six patients), no patient experienced DLT. Similarly in the second cohort, no DLT occurred. All 12 patients completed the planned regimen of therapy. Nine patients experienced grade 1-2 nausea and/or vomiting. Grade 2 hematological toxicity occurred in four patients. The results of our study indicate that a total radiation dose up to 55.0 Gy/5 weeks can be safely administered to the tumor bed, concurrently with capecitabine (1600 mg/m (2)) in patients with resected pancreatic carcinoma.

Polyethylene glycol plus simethicone in small-bowel preparation for capsule endoscopy.

BACKGROUND: Small-bowel contents can hamper the quality of video-capsule endoscopy (VCE). No standardized protocol has been proposed and overnight fasting remains the proposed preparation for VCE. AIMS: The aim was to evaluate the effects of 2 regimens of bowel preparation on small intestine cleansing, diagnostic yield and capsule transit times. METHODS: This is a prospective, randomized, blinded, and controlled study. Sixty patients referred for VCE were randomized into 2 groups. Group A ingested 2l of a polyethylene glycol and simethicone solution 16h before VCE. Group B were instructed to consume a fibre-free diet and allowed to consume clear liquids the day before VCE. The small-bowel cleansing was graded as "complete" if the entire wall was assessable, "incomplete" if more than 50% of the wall was visible, and "insufficient" if less than 50% of the wall was visible. RESULTS: In group A, a "complete", "incomplete" and "insufficient" small-bowel cleansing was achieved in 42%, 39% and 19% of cases respectively. In group B, a "complete", "incomplete" and "insufficient" small-bowel cleansing was achieved in 43%, 33% and 24% of cases respectively. No significant differences were observed between the two groups, regarding small-bowel cleansing level (p=0.65). No differences were also observed in the diagnostic yield (48.2%, 13.8% and 38% vs 65.5%, 6.9% and 27.6% of positive, suspicious and no findings respectively, in groups A and B [p=0.39]) and small-bowel transit times (mean 288min and 299 min in groups A and B respectively [p=0.70]). CONCLUSIONS: The results of the present study do not support the use of 2l of a polyethylene glycol and simethicone solution before VCE.

A systematic review of resectability and survival after concurrent chemoradiation in primarily unresectable pancreatic cancer.

PURPOSE: The objective of this study was to determine the effect on resection rate and survival of neoadjuvant chemoradiotherapy for primarily unresectable locally advanced pancreatic carcinoma. METHODS: A systematic review of recently published literature was performed. Resection rates and survival data were derived from reports published from 2000 onwards. Only recent studies, based on radiotherapy with standard dose and fractionation, have been analyzed. RESULTS: Thirteen studies with a total of 510 patients met selection criteria. A resection rate of 8.3-64.2% was reported (median, 26.5%). Of the operated patients, 57.1-100% (median, 87.5%) had R0 tumor resection. Most papers reported occasional pathological complete responses (CR, 3.0-8.8%). When outcome in all patients was considered, median survival ranged from 9 to 23 (median, 13.3) months, comparing favorably with literature data based on concurrent chemoradiation alone (range, 8.6-13 months). Surprisingly, in patients with unresectable tumor at presentation, median survival after surgery ranged from 16.4 to 32.3 (median, 23.6) months. CONCLUSIONS: The finding of a high proportion of R0 resection among all resections performed confirms the activity of neoadjuvant radiochemotherapy and should not be neglected. Based on these data, patients with unresectable pancreatic cancer without disease progression after chemoradiotherapy should be considered for radical surgery.

Differential immunohistochemical expression of syndecan-1 and tumor necrosis factor alpha in colonic mucosa of patients with Crohn's disease.

Tumor necrosis factor alpha (TNFalpha) in intestinal mucosa plays a key role in the inflammation characterizing Crohn's disease (CD). Moreover, adhesion molecule syndecan-1 mediates the maintenance of mucosal integrity and supports tissue repair. Therefore, our aim in this study was to correlate simultaneous expression of TNFalpha and syndecan-1 in patients affected by CD. Biopsies from 10 patients with CD of large bowel and 10 subjects with irritable bowel syndrome (controls) were studied by immunohistochemical detection of both TNFalpha and syndecan-1 on successive serial sections. Overall labeling index (OLI) was indicated by the percentage of positive stromal (i.e., nonepithelial) cells/1000 counted in randomized fields, whereas selected labeling index (SLI) was represented by the simultaneous evaluation of both molecules in a same single selected field of each specimen. TNFalpha and syndecan-1 OLI were significantly higher in CD compared with controls, while SLI showed an inverse relationship between the molecules in CD which was not observed in controls. Epithelial syndecan-1 cytoplasmatic staining of superficial epithelium was associated with loss of basolateral staining in the crypts and high stromal TNFalpha in CD. In conclusion, TNFalpha and syndecan-1 expression is increased in the intestinal mucosa of patients with CD. However, the expression of the two molecules is inversely related when a single field is considered, these data supporting the possibility of a downregulation exerted by TNFalpha.