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Aims: Patients with metastatic colorectal carcinoma (mCRC) carrying activating mutations of the KRAS gene do not benefit from treatment with anti-EGF receptor monoclonal antibodies. Therefore, KRAS mutation testing of mCRC patients is mandatory in the clinical setting to aid in the choice of appropriate therapy. Materials & methods: We developed a cost-effective approach for the determination of KRAS mutations in codons 12 and 13 in clinical practice based on a sensitive PCR/sequencing technique and the commercially available real-time PCR-based Therascreen® kit (DxS Ltd). Results & conclusion: The PCR/sequencing test was able to detect 10% mutant DNA in a background of wild-type DNA. By using this assay, we determined the mutational status of KRAS in 527 out of 540 (97.6%) formalin-fixed paraffin-embedded tissues from mCRC patients. PCR/sequencing was not conclusive in 13 cases, in which low-intensity peaks suggestive of potential mutations were identified. The DxS assay, which showed a sensitivity of 1%, identified mutations in 11 out of 13 inconclusive cases. Interestingly, five of these 11 cases showed high levels of DNA fragmentation. No significant difference was found in the ability of PCR/sequencing and DxS to identify KRAS mutations within 160 cases with more than 30% tumor cells. However, in 24 samples with less than 30% tumor cells, DxS showed an higher sensitivity. In conclusion, our findings suggest that PCR/sequencing can be used for mutational analysis of the majority of tumor samples that have more than 30% tumor cell content, whereas more sensitive and expensive tests should be reserved for inconclusive cases and for samples with a low amount of tumor cells.

Purpose The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken. Patients and Methods Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series. Results The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis. Conclusion The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

to assess the results of bladder preservation in infiltrating bladder cancer. The potential for neoadjuvant chemotherapy followed by extensive TUR and radiotherapy was investigated in 40 patients with T2-T4a G2-G3 bladder carcinoma.from 1983 to 1995, 40 patients were submitted to bladder-sparing treatment consisting of neoadjuvant chemotherapy, extensive, TUR and radiotherapy. Most patients had T3G3 cancer. Cystectomy was not performed due to patient" choice in 29 cases (72.5%), for severe pulmonary or cardiovascular disease in disease in 9 patients (22.5) and age over 80 in 2 (5%) patients. A deep TUR-biopsy was performed before and after chemotherapy and an extensive TUR was repeated at the end of radiotherapy. In the first 30 patients chemotherapy consisted of 2-4 cycles of 70 mg/m2 cisplatin on fay 1, and 40 mg/m2 methotrexate on days 8 and 15. In the last 10 patients chemotherapy consisted of 3 cycles of CMV (100 mg/m2 cisplatin on day 2, 30 mg/m2 of vinblastine on days 1 and 8). Total dose of radiotherapy was 60-65 Gy. Recurrent superficial tumors were treated transurethrally. Radical cystectomy, when feasible, was considered for persistent or recurrent invasive disease.after chemotherapy, a clinical objective response was obtained in 27 patients (67.5%), 19 (47.5%) of whom showed a complete response. Thirteen (32.5%) patients showed no response and 5 (12.5%) progressed during chemotherapy. After extensive TUR of any residual mass and radiotherapy, a complete response was achieved in 6 patients who initially showed a partial response and in other 2 patients and stable disease after chemotherapy. Altogether, 27 patients (67.5%) presented had local recurrences, 3 patients underwent cystectomy. Fourteen patients (35%) are alive and 13 NED (65 months mean survival). Five patients died of unrelated disease. Twenty-one patients (52.5%) died of distant metastases (mean survival 28 months). Four patients presented distant metastases after vesical infiltrating recurrence and 4 patients had distant metastases in the absence of loco-regional recurrence. Twenty-two patients (55%) maintained an intact bladder. Patients with complete response to chemotherapy showed a low risk for developing recurrent infiltrating tumors and metastases.A complete tumor was maintained at 5 years in over 50% of the patients conservatively treated. Bladder salvage is feasible in selected patients.

Follicular carcinoma, in association with other prognostic factors, identifies a class of "high-risk" patients in which a more aggressive treatment is indicated. In fact, in patients operated on for follicular carcinoma bone metastases, also many years after primary surgery, are reported. A case of skull metastases in a young women occurred 3 years after a near total lobectomy for follicular thyroid carcinoma is described. After six years the patient underwent total thyroidectomy, resection of skull metastases, radiometabolic therapy with I131 180 m Ci; now she is disease free at three years of follow-up. The biology of metastases in thyroid follicular carcinoma, risk factors and diagnostic and therapeutic controversies are analyzed. Good prognostic factors are considered age < 45 years, good degree of differentiation of primary tumor, small size of bone metastases and early appearance after primary diagnosis. The conclusions is drawn that bone metastases are the worst prognostic factors. In case of single lesion, surgical treatment allows good results. Follicular carcinoma, in association with other prognostic factors, identifies a class of 'high risk' patients in which a more aggressive treatment is indicated. In fact, in patients operated on for follicular carcinoma bone metastases, also many years after primary surgery, are reported. A case of skull metastases in a young women occurred 3 years after a near total lobectomy for follicular thyroid carcinoma is described. After six years the patient underwent total thyroidectomy, resection of skull metastases, radiometabolic therapy with I131 180 m Ci; now she is disease free at three years of follow-up. The biology of metastases in thyroid follicular carcinoma, risk factors and diagnostic and therapeutic controversies are analyzed. Good prognostic factors are considered age < 45 years, good degree of differentiation of primary tumor, small size of bone metastases and early appearance after primary diagnosis. The conclusions is drawn that bone metastases are the worst prognostic factors. In case of single lesion, surgical treatment allows good results.