The risk of hepatocellular carcinoma (HCC) increases with increasing level of hepatitis B virus (HBV) in serum (viral load). However, it is unclear whether genetic characteristics of HBV, including HBV genotype and specific genetic mutations, contribute to the risk of HCC. We examined the HCC risk associated with HBV genotypes and common variants in the precore and basal core promoter (BCP) regions.
From January 5, 1991, to December 21, 1992, baseline blood samples were collected from 2762 Taiwanese men and women who were seropositive for HBV surface antigen but had not been diagnosed with HCC; the samples were tested for HBV viral load by real-time polymerase chain reaction and genotyped by melting curve analysis. Participants who had a baseline serum HBV DNA level greater than 104 copies/mL (n = 1526) were tested for the precore G1896A and BCP A1762T/G1764A mutants by direct sequencing. Incident cases of HCC were ascertained through follow-up examinations and computerized linkage to the National Cancer Registry and death certification profiles. A Cox proportional hazards model was used to estimate the risk of HCC associated with HBV genotype and precore and BCP mutants after adjustment for other risk factors. All statistical tests were two-sided.
A total of 153 HCC cases occurred during 33 847 person-years of follow-up. The HCC incidence rates per 100 000 person-years for participants infected with HBV genotype B or C were 305.6 (95% confidence interval [CI] = 236.9 to 388.1) and 785.8 (95% CI = 626.8 to 972.9), respectively. Among participants with a baseline HBV DNA level of at least 104 copies/mL, HCC incidence per 100 000 person-years was higher for those with the precore G1896 (wild-type) variant than for those with the G1896A variant (955.5 [95% CI = 749.0 to 1201.4] vs 269.4 [95% CI = 172.6 to 400.9]) and for those with the BCP A1762T/G1764A double mutant than for those with BCP A1762/G1764 (wild-type) variant (1149.2 [95% CI = 872.6 to 1485.6] vs 358.7 [95% CI = 255.1 to 490.4]). The multivariable-adjusted hazard ratio of developing HCC was 1.76 (95% CI = 1.19 to 2.61) for genotype C vs genotype B, 0.34 (95% CI = 0.21 to 0.57) for precore G1896A vs wild type, and 1.73 (95% CI = 1.13 to 2.67) for BCP A1762T/G1764A vs wild type. Risk was highest among participants infected with genotype C HBV and wild type for the precore 1896 variant and mutant for the BCP 1762/1764 variant (adjusted hazard ratio = 2.99, 95% CI = 1.57 to 5.70, P < .001).
HBV genotype C and specific alleles of BCP and precore were associated with risk of HCC. These associations were independent of serum HBV DNA level.
The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up.
From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided.
During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001).
Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.
Cancer-related fatigue is an important clinical problem. It is common, distressing, and often difficult to treat. There is a role for drug treatment of cancer-related fatigue, but no consensus has been reached on which drugs are useful. This systematic review and meta-analysis aims to review the available evidence and make recommendations for practice and research.
We searched the Cochrane register of controlled trials (through the second quarter 2007), Medline (January 1, 1966, through August 1, 2007), and EMBASE (January 1, 1980, through August 1, 2007) by use of a predetermined list of search terms. Cochrane Collaboration meta-analysis review methodology was used for this study. The change in fatigue score on the instrument used in each study and other outcomes of interest (adverse events and withdrawal rates) were compared between treatment and control arms by use of the standardized mean difference (SMD) with 95% confidence intervals (CIs). All statistical tests were two-sided.
We identified 27 eligible trials of drug treatments for cancer-related fatigue (with a total of 6746 participants). The overall effect size for all drug classes was small. A meta-analysis of two studies (n = 264 patients) indicated that methylphenidate (a psychostimulant) was superior to placebo (standardized mean difference [SMD] in change in fatigue score = –0.30, 95% confidence interval [CI] = –0.54 to –0.05; P = .02) for treating cancer-related fatigue. A meta-analysis of 10 studies (n = 2226 patients) evaluating erythropoietin in anemic cancer patients who were undergoing chemotherapy indicated that erythropoietin was superior to placebo (SMD = –0.30, 95% CI = –0.46 to –0.29; P = .008). Among anemic patients (four studies with n = 964 patients), improvement in fatigue was associated with darbepoetin treatment compared with placebo treatment (SMD = –0.13, 95% CI = –0.27 to 0.00; P = .05). Progestational steroids and paroxetine were no better than placebo in the treatment of cancer-related fatigue.
There is some evidence that treatment of cancer-related fatigue with methylphenidate appears to be effective. More robust evidence indicates that treatment with hematopoietic agents appears to relieve cancer-related fatigue caused by chemotherapy-induced anemia. Further confirmatory trials are required for both observations.
The potent antiresorptive drug zoledronic acid (Zol) enhances the antitumor effects of chemotherapy agents in vitro. We investigated the effects of clinically achievable doses of doxorubicin (Dox) and Zol, given alone, in sequence, and in combination, on the growth of established breast tumors in vivo.
Female MF1 nude mice were inoculated subcutaneously with 5 x 105 human breast cancer MDA-MB-436 cells that stably expressed green fluorescent protein (ie, MDA-G8 cells). Beginning on day 7 after tumor cell injection, the mice were injected weekly for 6 weeks with saline, Dox (2 mg/kg body weight via intravenous injection), Zol (100 µg/kg body weight via intraperitoneal injection), Dox plus Zol, Zol followed 24 hours later by Dox, or Dox followed 24 hours later by Zol (n = 8–9 mice per group). The effects of treatment on tumor growth were determined by measuring tumor volume; on tumor cell apoptosis and proliferation by immunohistochemistry using antibodies for caspase-3 and Ki-67, respectively; and on bone by microcomputed tomography and bone histomorphometry. All P values are two-sided.
Treatment with Dox or Zol alone or Zol followed 24 hours later by Dox did not statistically significantly decrease final tumor volume compared with saline. Mice treated with Dox plus Zol had statistically significantly smaller final tumor volumes than those treated with Dox alone (mean = 122 mm3 vs 328 mm3, difference = 206 mm3, 95% confidence interval [CI] = 78 to 335 mm3, P < .001), with Zol alone (122 mm3 vs 447 mm3, difference = 325 mm3, 95% CI = 197 to 454 mm3, P < .001), or with Zol followed 24 hours later by Dox (122 mm3 vs 418 mm3, difference = 296 mm3, 95% CI = 168 to 426 mm3, P < .001). Treatment with Dox followed 24 hours later by Zol almost completely abolished tumor growth. Tumors from mice that were treated with Dox followed by Zol had more caspase-3–positive cells than tumors from mice treated with saline (mean number of caspase-3–positive cells per square millimeter: 605.0 vs 82.19, difference = 522.8, 95% CI = 488.2 to 557.4, P < .001), with Zol alone (605.0 vs 98.44, difference = 506.6, 95% CI = 472.0 to 541.2, P < .001), or with Zol followed by Dox (605.0 vs 103.1, difference = 501.9, 95% CI = 467.3 to 536.5, P < .001). The treatment-induced increase in the number of caspase-3–positive cells was mirrored by a decrease in the number of tumor cells positive for the proliferation marker Ki-67. No evidence of bone disease was detected in any of the treatment groups following microcomputed tomography and histological analysis of bone.
Sequential treatment with Dox followed by Zol elicited substantial antitumor effects in subcutaneous breast tumors in vivo, in the absence of bone disease.