Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome.

Genetic studies have shown that mutations of complement inhibitors such as membrane cofactor protein, Factors H, I, or B and C3 predispose patients to atypical hemolytic uremic syndrome (aHUS). Factor I is a circulating serine protease that inhibits complement by degrading C3b and up to now only a few mutations in the CFI gene have been characterized. In a large cohort of 202 patients with aHUS, we identified 23 patients carrying exonic mutations in CFI. Their overall clinical outcome was unfavorable, as half died or developed end-stage renal disease after their first syndrome episode. Eight patients with CFI mutations carried at least one additional known genetic risk factor for aHUS, such as a mutation in MCP, CFH, C3 or CFB; a compound heterozygous second mutation in CFI; or mutations in both the MCP and CFH genes. Five patients exhibited homozygous deletion of the Factor H-related protein 1 (CFHR-1) gene. Ten patients with aHUS had one mutation in their CFI gene (Factor I-aHUS), resulting in a quantitative or functional Factor I deficiency. Patients with a complete deletion of the CFHR-1 gene had a significantly higher risk of a bad prognosis compared with those with one Factor I mutation as their unique vulnerability feature. Our results emphasize the necessity of genetic screening for all susceptibility factors in patients with aHUS.

Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma.

PURPOSE: To compare the toxicities, tumor control, survival, and quality of life of nasopharyngeal cancer (NPC) patients treated with sequential neoadjuvant chemotherapy followed by concurrent cisplatin-radiotherapy (CRT) or CRT alone. PATIENTS AND METHODS: Previously untreated stage III to IVB NPC were randomly assigned to (1) neoadjuvant docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 3 weeks for two cycles, followed by cisplatin 40 mg/m(2)/wk concurrent with radiotherapy, or (2) CRT alone. Planned accrual was 30 patients per arm to detect 20% difference of toxicities based on 95% CIs. RESULTS: From November 2002 to November 2004, 65 eligible patients were randomly assigned to neoadjuvant chemotherapy followed by CRT (n = 34) or CRT alone (n = 31). There was a high rate of grade 3/4 neutropenia (97%) but not neutropenic fever (12%) during neoadjuvant chemotherapy. No significant differences in rates of acute toxicities were observed between the two arms during CRT. Dose intensities of concurrent cisplatin, late RT toxicities and quality of life scores were comparable in both arms. The 3-year progression-free survival for neoadjuvant versus control arm was 88.2% and 59.5% (hazard ratio = 0.49; 95% CI, 0.20 to 1.19; P = .12). The 3-year overall survival for neoadjuvant versus control arm was 94.1% and 67.7% (hazard ratio = 0.24; 95% CI, 0.078 to 0.73; P = .012). CONCLUSION: Neoadjuvant docetaxel-cisplatin followed by CRT was well tolerated with a manageable toxicity profile that allowed subsequent delivery of full-dose CRT. Preliminary results suggested a positive impact on survival. A phase III study to definitively test this neoadjuvant-concurrent strategy is warranted.

Relationship between pretreatment level of plasma Epstein-Barr virus DNA, tumor burden, and metabolic activity in advanced nasopharyngeal carcinoma.

PURPOSE: Plasma Epstein-Barr virus DNA (pEBV DNA) is an important prognostic marker in nasopharyngeal carcinoma (NPC). This study tested the hypotheses that pEBV DNA reflects tumor burden and metabolic activity by evaluating its relationship with tumor volume and 18F-fluorodeoxyglucose (18F-FDG) uptake in NPC. METHODS AND MATERIALS: Pre-treatment pEBV DNA analysis, 18F-FDG positron emission tomography-computed tomography scan (PET-CT) and magnetic resonance imaging (MRI) of the head and neck were performed in 57 patients. Net volume (cm3) of the primary tumor (T(vol)) and regional nodes (N(vol)) were quantified on MRI. 18F-FDG uptake was expressed as the maximum standardized uptake value (SUV(max)) at the primary tumor (T(suv)) and regional nodes (N(suv)). Lesions with SUV(max) > or = 2.5 were considered malignant. Relationship between SUV(max), natural logarithm (log) of pEBV DNA, and square root (sq) of MRI volumes was analyzed using the Wilcoxon test. A linear regression model was constructed to test for any interaction between variables and disease stage. RESULTS: Log-pEBV DNA showed significant correlation with sq-T(vol) (r = 0.393), sq-N(vol) (r = 0.452), total tumor volume (sq-Total(vol) = T(vol) + N(vol), r = 0.554), T(suv) (r = 0.276), N(suv) (r = 0.434), and total SUV(max) (Total(suv) = T(suv) + N(suv), r = 0.457). Likewise, sq-T(vol) was correlated to T(suv) (r = 0.426), and sq-N(vol) with N(suv) (r = 0.651). Regression analysis showed that only log-pEBV DNA was significantly associated with sq-Total(vol) (p < 0.001; parameter estimate = 8.844; 95% confidence interval = 3.986-13.703), whereas Sq-T(vol) was significantly associated with T(suv) (p = 0.002; parameter estimate = 3.923; 95% confidence interval = 1.498-6.348). CONCLUSION: This study supports the hypothesis that cell-free plasma EBV DNA is a marker of tumor burden in EBV-related NPC.

Prospective validation of serum CYFRA 21-1, beta-2-microglobulin, and ferritin levels as prognostic markers in patients with nonmetastatic nasopharyngeal carcinoma undergoing radiotherapy.

BACKGROUND: Patients with undifferentiated nasopharyngeal carcinoma (NPC) have elevated serum levels of CYFRA 21-1 (CYFRA), ferritin, and beta-2-microglobulin (beta2M) compared with healthy control individuals. The prognostic value of these markers has never been validated prospectively. METHODS: Paired serum samples from 160 patients with newly diagnosed, nonmetastatic, undifferentiated NPC were collected before radiotherapy (RT) and at 4-6 weeks after the completion of RT. Pre-RT and post-RT levels of serum CYFRA, ferritin, and beta2M were analyzed and correlated with overall survival (OS), progression-free survival (PFS), time to locoregional recurrence, (TLR) and time to distant recurrence (TDR). The results of pre-RT and post-RT plasma Epstein-Barr virus (EBV) DNA levels available from a previous study were included in a Cox regression model together with age, tumor (T) classification, and lymph node (N) classification. RESULTS: Sixty percent of patients had International Union Against Cancer Stage III-IV disease. At a median follow-up of 116 weeks (range, 37-239 weeks), 38 patients had disease progression. On multivariate analysis, pre-RT CYFRA and post-RT EBV DNA levels were independent predictors of poor OS, post-RT EBV DNA level and N classification predicted poor PFS and TDR; and only T classification predicted TLR. Patients who had pre-RT CYFRA levels > or = 1.5 U/mL were more likely to die (hazard ratio, 1.18; 95% confidence interval, 1.10-1.26) compared with patients who had pre-RT CYFRA levels < 1.5 U/mL. There were no associations between age, post-RT CYFRA levels and pre-RT or post-RT serum ferritin and beta2M levels, and the survival and recurrence rates on multivariate analysis. CONCLUSIONS: Serum CYFRA levels taken before RT predicted reduced survival in patients with nonmetastatic, undifferentiated NPC who underwent RT.

A prospective study of pre-treatment cell kinetics and clinical outcome in nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To study pre-treatment cell kinetics and their clinical correlations in nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Ninety newly diagnosed NPC patients were studied using in vivo Bromodeoxyuridine (BrdU) labeling and flow cytometric analysis. Immunohistochemical staining for BrdU and Ki 67 was also performed. RESULTS: The median S-phase duration (Ts) was 6.2 h (range 3.5-18.7 h), median flow cytometric labeling index (FCM-LI) was 7.4% (1.3-37.6%), and median potential doubling time (Tpot) was 3.6 days (0.5-19.9 days). The median histologic labeling index (H-LI) was 12.4% (1.2-43.3%), and median histologic Tpot (H-Tpot) was 2.1 days (0.5-33.3 days). FCM-LI and H-LI were both positively correlated with Ki67 whereas Tpot and H-Tpot were both negatively correlated with Ki67 and N-stage. In univariate analysis, Tpot and H-Tpot showed a trend for progression free survival. Tpot was significantly associated with local relapse free survival, but lost its significance in multivariate analysis. N-stage was the only significant prognostic factor for all radiotherapy outcomes in both univariate and multivariate analyses. CONCLUSIONS: Tpot was the only pre-treatment cell kinetic parameter for which some evidence was found for an association with survival in NPC patients. Future studies should aim to combine cell kinetic parameters together with other biological markers and clinical parameters to provide more useful prognostic information to guide individual patient's therapy.

Hepatitis B virus reactivation in breast cancer patients receiving cytotoxic chemotherapy: a prospective study.

Breast cancer is a rapidly increasing problem in many developing countries, and cytotoxic chemotherapy is now an integral part of its management. In several developing countries, the carriage of hepatitis B virus (HBV) in cancer patients may be as high as 12%, and such patients are at risk of developing fatal HBV reactivation during chemotherapy. HBV reactivation is well recognized in patients with hematological malignancies, but limited data are available on patients with other, more common, cancers, such as breast cancer. Recent data have suggested that increased viral replication, an indication of HBV reactivation, may precede clinical hepatitis. In the absence of serial HBV DNA monitoring, HBV reactivation during chemotherapy may have been underestimated. In this prospective study, breast cancer patients who were hepatitis B surface antigen (HBsAg) seropositive were followed up during chemotherapy. The main objectives were to determine the incidence of HBV reactivation in breast cancer patients undergoing conventional chemotherapy; to investigate whether "serial HBV DNA monitoring" improves the accuracy of diagnosing HBV reactivation when compared with previous schema that only measured HBV DNA at the time of clinical hepatitis ("conventional monitoring"); and to assess the clinical consequences as a result of developing the condition. The secondary objective was to identify risk factors associated with this condition. Over an 18-month period, 41 patients were studied. Ten developed HBV reactivation by conventional monitoring criteria, but with serial HBV DNA monitoring, seven additional patients were diagnosed when increased HBV DNA levels were detected before, but not concomitant with, clinical hepatitis. Thus, a total of 17 patients (41%) developed HBV reactivation. Premature termination of chemotherapy or delay in treatment schedules occurred in 71% of the patients who developed viral reactivation, as compared with 33% in those who did not develop the condition (P = 0.019). No risk factors associated with the development of HBV reactivation could be identified. Serial monitoring of HBV DNA, in addition to liver function, increases the sensitivity of diagnosing of HBV reactivation, and helps explain some cases that would otherwise be labeled as "cryptogenic hepatitis," for which concomitant HBV DNA measured at the time of hepatitis was undetectable. The present study highlights the importance of monitoring HBsAg-seropositive patients who are receiving chemotherapy for common solid tumors such as breast cancer.

Phase II study of docetaxel and epirubicin in Chinese patients with metastatic breast cancer.

The efficacy and safety of docetaxel-epirubicin chemotherapy in the treatment of metastatic breast cancer was investigated in Chinese women. Three-weekly cycles comprised epirubicin 75 mg/m2 i.v. followed 1 h later by docetaxel 75 mg/m2 i.v. After 3 cycles, responding patients received a further 3 cycles, followed by 3 cycles of docetaxel alone. Forty-six patients entered the study, of whom 37% had received prior adjuvant chemotherapy. Three patients withdrew due to toxicity and were not evaluable for response. There were five complete responses and 31 partial responses, giving an overall response rate of 83.7% (95% CI 72.7-94.8%). The median time to progression was 10.96 months (95% CI 7.76-12.86) and median survival was 24.2 months (95% CI 16.6-). The most common grade 3/4 adverse events were neutropenia (96% of patients) and neutropenia with fever (39%). Hepatotoxicity occurred in six patients, two being attributable to hepatitis B virus reactivation. No patients suffered grade 3/4 cardiac toxicity and there were no treatment-related mortalities. Quality of life aspects deteriorated after 3 cycles, but there was a trend towards improved emotional aspects after 9 cycles. We conclude that docetaxel-epirubicin chemotherapy is highly effective for recurrent metastatic/locoregional breast cancer, with myelosuppression being the main toxicity.