Increased risk of colorectal adenomas in Italian subjects carrying the p53 PIN3 A2-Pro72 haplotype.

BACKGROUND: Few reports have investigated the association of two p53 polymorphisms (Arg72Pro and PIN3-A2) with colorectal cancer (CRC) risk, and no previous study has analyzed their role as susceptibility alleles for colorectal adenoma. AIM: To explore the impact of the p53 PIN3-Arg72Pro haplotype on colorectal adenoma formation and progression to cancer. METHODS: One hundred and eighty-four colorectal tumor patients (124 with adenomas and 60 with adenocarcinoma) and 188 controls (42 subjects with a clean colon, 54 hospital controls and 92 blood donors) from the Italian population were tested for PIN3-Arg72Pro haplotype status. RESULTS: A significantly increased risk of colorectal adenomas was observed in patients carrying the PIN3 A2-Pro72 haplotype (OR = 2.02, 95% CI: 1.17-3.48; p = 0.01), while those carrying the PIN3 A1-Pro72 haplotype had a significantly increased risk of developing CRC (OR = 3.33; 95% CI: 1.40-7.89; p = 0.006). Comparisons of cases with the clean colon control group provided stronger evidence of the associations. A family history of CRC did not affect the risk estimates. No association was observed between the pathologic features of adenomas, the Arg72Pro and PIN3 polymorphisms, and the PIN3-Arg72Pro haplotype. CONCLUSIONS: Our finding that two different p53 haplotypes are associated with colorectal adenoma and cancer, respectively, suggests that each of these haplotypes may independently impact on p53 function(s) within different genetic pathways of colorectal carcinogenesis.

Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer.

BACKGROUND: Irinotecan and raltitrexed are active agents in advanced colorectal cancer (ACC) and preclinical data suggest a remarkable synergistic activity. Phase I studies demonstrated that single-agent full dose of both drugs can be administered with moderate toxicity. The aim of this phase II trial was to assess the activity and tolerability of the combination in untreated ACC. PATIENTS AND METHODS: Forty-eight patients entered the trial and received irinotecan 350 mg/m2 d.1 and raltitrexed 3 mg/m2 d.2, every three weeks. After recruitment of the first 16 patients, grade III-IV toxicity was observed in 6 patients (38%). Therefore, an amendment reduced by 15% the dose of both drugs (irinotecan 300 mg/m2, raltitrexed 2.6 mg/m2). RESULTS: A total of 290 cycles were administered (range 1-18, median number 6). According to intention-to-treat analysis, the overall response rate was 27% (95% confidence interval 16%-42%), including 3 complete responses and 10 partial responses. The median duration of response was 10 months, while median progression-free survival and overall survival were 5 and 14 months, respectively. In the first 16 patients, the main toxicities were grade III-IV diarrhea in 25% and grade III-IV neutropenia in 13%. In the subsequent 32 patients, they were grade III-IV diarrhea in 34% and grade III neutropenia in 6%. Two toxic deaths occurred. CONCLUSION: The combination irinotecan-raltitrexed is an active regimen, but the significant incidence of side-effects requires accurate patient selection and, eventually, new schedules.

Concomitant chemo-radiotherapy in the treatment of locally advanced and/or metastatic soft tissue sarcomas: experience of the National Cancer Institute of Genoa.

Previous in vitro and in vivo studies showed a synergistic effect of concomitant doxorubicin and radiotherapy in a variety of solid tumors. From 1988 to 2000, we have investigated in a pilot study and then in a phase II study the efficacy of a concomitant doxorubicin radiotherapy treatment in patients with advanced and/or metastatic soft tissue sarcomas (STS). We enrolled and treated a group of 115 patients with advanced STS, with metastases (61%), frequently pretreated (59%), predominantly G2/G3 (84%). Doxorubicin was administered by continuous infusion at a dose of 12 mg/m(2)/day over 5 consecutive days concomitantly with radiotherapy; treatment was given on ambulatory basis at 2-week intervals with support of granulocytes colony stimulating factors (GCSF). In the whole group of 115 patients a clinical objective response (ORs) rate of 67% was obtained, with 11% complete and 56% partial responses. No patient progressed while on therapy, except one who progressed in non-irradiated metastatic tumor. Treatment (median 3 cycles) was well tolerated with no WHO grade 3 toxicity (apart from alopecia) and no acute or chronic cardiotoxicity. Thirty-nine responder patients underwent surgery (24 primary tumors, 10 relapses, 5 relapses plus isolated lung metastases). The median survival time(s) was 29 months in the whole series and over 50 months in responder patients. A multivariate analysis showed a positive association between survival and sex (HR=1.8; CI 95%, 1.0-3.4), performance status (HR=2.1; CI 95%, 1.1-4.0), ORs (HR=7.9; CI 95%, 3.5-18.1) and surgery (HR=8.8; CI 95%, 2.1-35.9). Low toxicity, high OR rate and positive survival time trend make the concomitant chemo-radiotherapy an efficacious approach for advanced STS.

Empirical first-line treatment with tigecycline for febrile episodes following abdominal surgery in cancer patients.

Cancer patients with complicated infections following abdominal surgery represent one of the worst clinical scenarios that is useful for testing the efficacy of empirical antimicrobial therapy. No study so far has evaluated the performance of tigecycline (TIG) when administered as empirical first-line treatment in a homogeneous population of surgical cancer patients with a febrile episode. An observational review of the data records of 24 sequential patients receiving TIG for a febrile episode following a major abdominal procedure in a single cancer institute was performed. Large bowel surgery represented 68% of all procedures, followed by gastric surgery (16%) and urinary-gynaecologic-biliary surgery (16%). Complications following surgery were observed in 68% of febrile episodes, with peritonitis and sepsis accounting for 59% and 24% of complications, respectively. Eight patients needed repeat surgery for source control. The mean duration of TIG treatment was 8 days. Causative pathogens were detected in 16 episodes (64%), and a total of 44 microorganisms were recovered (29% Escherichia coli, 9% Enterococcus faecalis and 9% coagulase-negative staphylococci). TIG was effective in 12 episodes (48%). The success rate was 67% when infectious episodes sustained by intrinsically resistant bacteria and fungi were excluded. Treatment failure was associated with the presence of complications and with microbiologically documented infection. TIG may be useful as a first-line treatment option in cancer patients requiring antibiotic treatment following surgery when complications are not present or suspected on clinical grounds and when local microbial epidemiology shows a low incidence of primary resistant bacteria.

Prognostic value of sentinel lymph node biopsy in the pathologic staging of colorectal cancer patients.

BACKGROUND AND OBJECTIVES: Over the last decade, lymphatic mapping and sentinel lymph node (sN) biopsy have greatly increased the possibility of identifying nodal metastasis in clinically node-negative patients with melanoma and breast cancer, thus improving the accuracy of pathologic staging. Recently, sN biopsy has been applied also in colorectal cancer. This prospective study aimed to assess its feasibility and accuracy in predicting regional lymph nodes metastases in colorectal cancer patients as well as the impact on treatment decision-making. MATERIALS AND METHODS: Lymphatic mapping was accomplished by means of blue dye, which was intraoperatively injected into the subserosa overlying the tumor site in 26 patients undergoing colorectal cancer surgery. Following bowel resection, the operative specimen was inspected to identify each blue-stained node, the sN, which was sent separately to the pathologist. One half of each sN was examined by multiple 200 microm sections, while the second half was examined by standard bi-valving technique with hematoxylin-eosin (H and E) staining; all the other regional non-sentinel nodes were routinely examined by standard bi-valving technique and H and E staining. RESULTS: At least one sN was detected in 24 of 26 patients (92.3%); two patients with rectal cancer had no sN identified. Overall, 70 sN were retrieved into the operative specimens, with a mean of 2.9 sNs/patient, and 19 sNs were tumor-positive. An agreement between sN and regional lymph-node status was observed in 20 of 24 patients (83.4%). The sN was histologically negative in two of nine patients with positive regional nodes (sensitivity = 77.8%; false-negative rate of 22.2%); in two of seven patients with tumor-positive sN (28.6%), the sN was the exclusive site of regional nodal metastasis. The negative predictive value was 88.2% (15 of 17 patients), and the overall accuracy was 91.7% (22 of 24 patients). As regards the contribution to the detection of nodal metastasis according to the pathologic technique, standard H and E bi-valving technique detected 16 of 19 tumor-positive sNs (84.2%) while, by means of serial sectioning, metastases were detected in the remaining 3 of 19 sNs (15.8%). CONCLUSIONS: The sN biopsy proved feasible, with a rather short learning curve. The focused analysis of the sN by means of serial sectioning improved the detection rate of nodal metastasis compared to standard bi-valving examination, so that a more accurate nodal staging should be expected; finally, an elective localization of metastasis within the sN was observed in almost one third of regional node-positive patients.