Hot off the presses! Jan 11 Cancer

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Latest Articles Include:

• CancerScope
  - Cancer 116(1):1-2 (2010)
  
• New AJCC Cancer Staging Manual reflects changes in cancer knowledge
  - Cancer 116(1):2-3 (2010)
  
• New in the seventh edition
  - Cancer 116(1):3 (2010)
  
• Where does the combination of sorafenib and interferon in renal cell carcinoma stand?
  Flaherty KT - Cancer 116(1):4-7 (2009)
  Sorafenib can be combined safely with interferon, but the results of a recent randomized, phase 2 trial cast doubt on the value of further evaluating this combination. The renal cell carcinoma field continues to wrestle with the value of combining targeted therapies with cytokines.
• Protein phosphatase 2A subunit gene haplotypes and proliferative breast disease modify breast cancer risk
  Dupont WD Breyer JP Bradley KM Schuyler PA Plummer WD Sanders ME Page DL Smith JR - Cancer 116(1):8-19 (2009)
  BACKGROUND: Protein phosphatase 2A (PP2A) is a major cellular phosphatase and plays key regulatory roles in growth, differentiation, and apoptosis. Women who are diagnosed with benign proliferative breast disease are at increased risk for the subsequent development of breast cancer. METHODS: The authors evaluated genetic variation of PP2A holoenzyme subunits for their potential contribution to breast cancer risk. A nested case-control investigation was performed on a cohort of women who had a history of benign breast disease. The women were followed for an average of 18 years, and DNA prepared from the original archival benign breast biopsy (1954-1995) was available for 450 women who were diagnosed with breast cancer on follow-up and for 890 of 900 women in a control group who were matched on race, age, and year of entry biopsy. RESULTS: Single allele-based and haplotype-based tests of association were conducted with assessment of significance by permutation testing. Significant risk and protective haplotypes of the PP2A structural/regulatory subunit A isoform (PPP2R1A) were identified and had odds ratios of 1.63 (95% confidence interval [CI], 1.3-2.1) and 0.55 (95% CI, 0.41-0.76), respectively. These odds ratios remained significant after the analysis was adjusted for multiple comparisons. Women who had both the PPP2R1A risk haplotype and a history of proliferative breast disease had an odds ratio of 2.44 (95% CI, 1.7-3.5) for the subsequent development of breast cancer. The effects of haplotypes for 2 PP2A regulatory subunit genes, PP2 regulatory subunit B isoform (PPP2R2A) and PP2A regulatory subunit B isoform (PPP2R5E) on breast cancer risk were nominally significant but did not remain significant after the analysis was adjusted for multiple comparisons. CONCLUSIONS: The current findings supported the previously hypothesized role of PP2A as a tumor suppressor gene in breast cancer. Cancer 2010. © 2010 American Cancer Society.
• Treatment patterns of aging Americans with differentiated thyroid cancer
  Park HS Roman SA Sosa JA - Cancer 116(1):20-30 (2009)
  BACKGROUND: The incidence of differentiated thyroid cancer (DTC) increases with age. Total thyroidectomy, often followed by radioactive iodine (RAI), is recommended for patients who have tumors that measure 1 cm in greatest dimension. In the current study, the authors assessed the use of thyroidectomy and RAI among elderly patients with DTC and the effects on survival. METHODS: Adults aged 45 years with DTC 1 cm in the Surveillance, Epidemiology, and End Results database from 1988 to 2003 were included. Bivariate and multivariate analyses were used to measure associations between demographic, clinical, and pathologic characteristics and the likelihood of receiving treatment according to current practice guidelines. RESULTS: Of 8899 patients who were identified, 26% were ages 65 years to 79 years, and 5% were aged 80 years. Compared with younger patients, patients aged 65 years were more likely to have larger tumors, stage IV disease, extrathyroid extension, and nonpapillary histology. Elderly patients were less likely to undergo total thyroidectomy (74% vs 80%; P < .001) or to receive RAI (47% vs 54%; P < .001). These trends were most pronounced among those aged 80 years. Among the patients who did not undergo surgery, elderly patients did not report higher rates of contraindications to surgery. In multivariate analysis, the groups ages 65 years to 79 years and aged 80 years were associated with lower rates of total thyroidectomy (odds ratio, 0.77 and 0.43, respectively; P < .001) and RAI (odds ratio, 0.85 [P < .01] and 0.39 [P < .001], respectively). Among elderly patients, predictors of worse survival included no surgery (hazard ratio, 5.51; P < .001) and no RAI (hazard ratio, 1.36; P < .001! ). CONCLUSIONS: Elderly patients with DTC received less aggressive surgical and RAI treatment than younger patients despite having more advanced disease and the improved survival associated with these treatments among elderly patients. Long-term outcomes should be measured to determine the impact of this apparent discrepancy in care. Cancer 2010. © 2010 American Cancer Society.
• Procalcitonin levels predict clinical course and progression-free survival in patients with medullary thyroid cancer
  Walter MA Meier C Radimerski T Iten F Kränzlin M Müller-Brand J de Groot JW Kema IP Links TP Müller B - Cancer 116(1):31-40 (2009)
  BACKGROUND: Procalcitonin has been well established as an important marker of sepsis and systemic infection. The authors evaluated the diagnostic and predictive value of calcitonin and its prohormone procalcitonin in medullary thyroid cancer. METHODS: The authors systematically explored the ability of calcitonin and procalcitonin to identify medullary thyroid cancer and predict the endpoints local recurrence and distant metastases, as well as the progression-free survival. Patients with C-cell hyperplasia; patients after thyroidectomy for differentiated thyroid cancer, goiter, or Graves disease; and healthy subjects served as controls. The study was performed in accordance with the Reporting Recommendations for Tumor Marker Prognostic Studies of the National Cancer Institute. RESULTS: Sixty-nine medullary thyroid cancer patients and 96 controls were included (median observed interval: 10.9 years [range, 1.4-47.5 years]; 981.8 patient-years). The 1-year, 5-year, 10-year, and 20-year recurrence rates were 9%, 34%, 45%, and 56%, respectively. Calcitonin had a higher diagnostic accuracy for detecting medullary thyroid cancer than procalcitonin (area under the curve [AUC], 0.94; 95% confidence interval [95% CI], 0.90-0.99 vs AUC, 0.89; 95% CI, 0.83-0.95 [P = .038]). The procalcitonin:calcitonin ratio predicted disease progression (AUC, 0.63; 95% CI, 0.51-0.75 [P = .036]) and progression-free survival (hazards ratio, 1.49; 95% CI, 1.09-2.04 [P = .013]). CONCLUSIONS: The results of the current study indicate a superior diagnostic accuracy of calcitonin and an independent predictive value of the procalcitonin:calcitonin ratio. These findings may lead to improved diagnostic and therapeutic strategies for medullary thyroid cancer patients. Cancer 2010. © 2010 American Cancer Society.
• Reduced microRNA-218 expression is associated with high nuclear factor kappa B activation in gastric cancer
  Gao C Zhang Z Liu W Xiao S Gu W Lu H - Cancer 116(1):41-49 (2009)
  BACKGROUND: Poor expression of microRNAs (miRs) reportedly plays an important role in gastric carcinogenesis. Large-scale microarray assays have indicated that there is significant down-regulation of miR-218 in gastric cancer. miR-218 also was decreased specifically in human papillomavirus-positive cell lines, cervical lesions, and cervical cancer tissues and in bronchial airway epithelium in smokers. However, its role in carcinogenesis remains unclear, especially in Helicobacter pylori (H. pylori)-associated gastric cancer. METHODS: miR-218 levels were evaluated in 20 noncardia gastric cancer tissues, in 10 H. pylori-infected and 8 uninfected normal gastric biopsies, and in the human gastric epithelial cancer cell line AGS using TaqMan quantitative real-time polymerase chain reaction analysis. Pre-miR-218 and anti-miR-218 inhibitors were used to examine the effects of miR-218 expression on cell proliferation and apoptosis. A luciferase reporter assay was used to examine the potential target genes and related pathways. RESULTS: miR-218 expression was reduced significantly in gastric cancer tissues, in H. pylori-infected gastric mucosa, and in H. pylori-infected AGS cells. Overexpression of miR-218 inhibited cell proliferation and increased apoptosis in vitro. Epidermal growth factor receptor-coamplified and overexpressed protein (ECOP), which regulates nuclear factor kappa B (NF-B) transcriptional activity and is associated with apoptotic response, was a direct target of miR-218. Overexpression of miR-218 also inhibited NF-B transcriptional activation and transcription of cyclooxygenase -2, a proliferative gene regulated by NF-B. CONCLUSIONS: H. pylori infection resulted in a decrease in miR-218 expression. The down-regulation of miR-218 has the potential to increase carcinogenesis by losing control of its targets, and it may be correlated with the high transcriptional activity of NF-B that results from H. pylori infection. Cancer 2010. © 2010 American Cancer Society.
• Racial differences in treatment and outcomes among patients with early stage bladder cancer
  Hollenbeck BK Dunn RL Ye Z Hollingsworth JM Lee CT Birkmeyer JD - Cancer 116(1):50-56 (2009)
  BACKGROUND: Black patients are at greater of risk of death from bladder cancer than white patients. Potential explanations for this disparity include a more aggressive phenotype and delays in diagnosis resulting in higher stage disease. Alternatively, black patients may receive a lower quality of care, which may explain this difference. METHODS: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data for the years from 1992 through 2002, the authors identified patients with early stage bladder cancer. Multivariate models were fitted to measure relations between race and mortality, adjusting for differences in patients and treatment intensity. Next, shared-frailty proportional hazards models were fitted to evaluate whether the disparity was explained by differences in the quality of care provided. RESULTS: Compared with white patients (n = 14,271), black patients (n = 342) were more likely to undergo restaging resection (12% vs 6.5%; P < .01) and urine cytologic evaluation (36.8% vs 29.7%; P < .01), yet they received fewer endoscopic evaluations (4 vs 5; P < .01). The use of aggressive therapies (cystectomy, systemic chemotherapy, radiation) was found to be similar among black patients and white patients (12% vs 10.2%, respectively; P = .31). Although black patients had a greater risk of death compared with white patients (hazards ratio [HR], 1.23; 95% confidence interval [95% CI], 1.07-1.42), this risk was attenuated only modestly after adjusting for differences in treatment intensity and provider effects (HR, 1.22; 95% CI, 1.06-1.42). CONCLUSIONS: Although differences in initial treatment were evident, they did not appear to be systematic and had unclear clinical significance. Whereas black patients are at greater risk of death, this disparity did not appear to be caused by differences in the intensity or quality of care provided. Cancer 2010. © 2010 American Cancer Society.
• Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon alfa in patients with advanced renal cell carcinoma : Clinical and biomarker analysis
  Jonasch E Corn P Pagliaro LC Warneke CL Johnson MM Tamboli P Ng C Aparicio A Ashe RG Wright JJ Tannir NM - Cancer 116(1):57-65 (2009)
  BACKGROUND: The objective of this study was to independently evaluate the objective response rate of sorafenib and sorafenib plus low-dose interferon-alfa 2b (IFN) as frontline therapy in patients with metastatic renal cell carcinoma (mRCC). METHODS: Untreated patients with clear cell mRCC were randomized to receive sorafenib 400 mg orally twice daily or sorafenib 400 mg orally twice daily plus subcutaneous IFN 0.5 million U (MU) twice daily. Primary endpoints included the objective response rate (ORR) and safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the predictive value of tumor tissue biomarkers. RESULTS: Eighty patients were enrolled. The median follow-up was 19.7 months (range, 0-34.2 months). The ORR was 30% (95% confidence interval [CI], 16.6%-46.5%) in the sorafenib arm and 25% (95% CI, 12.7%-41.2%) in the combination arm. The median PFS was 7.39 months in the sorafenib-alone arm (95% CI, 5.52-9.20 months) and 7.56 months in the sorafenib plus IFN arm (95% CI, 5.19-11.07 months). The median OS was 27.04 months in the combination arm (95% CI, from 22.31 to not attained) and was not reached in the sorafenib arm. Toxicities were comparable in both arms. In a multivariate model, increased phosphorylated protein kinase B (pAKT) levels were associated with poorer PFS (hazard ratio, 1.04; 95% CI, 1.00-1.08; P = .0411) and OS (hazard ratio, 1.15; 95% CI, 1.02-1.29; P = .0173). CONCLUSIONS: The addition of low-dose IFN to sorafenib resulted in efficacy outcomes that were comparable to those achieved with sorafenib monotherapy. The current results indicated that pAKT levels may predict for clinical outcome, but further mechanistic study is required. Cancer 2010. © 2010 American Cancer Society.
• Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-Cell translocation gene 3 in prostate cancer
  Majid S Dar AA Shahryari V Hirata H Ahmad A Saini S Tanaka Y Dahiya AV Dahiya R - Cancer 116(1):66-76 (2009)
  BACKGROUND: B-cell translocation gene 3 (BTG3/ANA/APRO4) is a candidate tumor suppressor gene in some malignancies. We report here that B-cell translocation gene 3 (BTG3) is transcriptionally down-regulated in prostate cancer and the mechanism of inactivation is through promoter hypermethylation. METHODS: Prostate cancer and normal cell lines were treated with different doses of genistein and 5-aza-2-deoxycytidine (5Aza-C). BTG3 messenger ribonucleic acid (mRNA) expression was determined by quantitative real-time polymerase chain reaction in tissues and cell lines. Bisulfate-modified polymerase chain reaction, cloning and sequencing were used to examine promoter methylation in tumor samples and cell lines. Enzyme activity/inhibition assays were done to check the effect of genistein and 5Aza-C on DNA methyltransferases. ChIP assay was performed to analyze chromatin modifications caused by genistein treatment. RESULTS: BTG3 mRNA expression was down-regulated in cancer tissues and cells. Genistein and 5Aza-C induced BTG3 mRNA expression in all PC cell lines. Complete methylation of BTG3 promoter in tumor samples and cancer cell lines was observed. Genistein and 5Aza-C treatment significantly decreased promoter methylation, reactivating BTG3 expression. Genistein and 5Aza-C increased levels of acetylated histones 3, 4, histone 3 dimethylated at lysine 4, histone 3 trimethylated at lysine 4, and RNA polymerase II, decreased DNA methyl transferase and methyl-binding domain protein 2 activity, and increased histone acetyl transferase (HAT) activity. CONCLUSIONS: This is the first report to show that BTG3 is silenced in prostate cancer and can be reactivated by genistein-induced promoter demethylation and active histone modification. Genistein showed similar effects to that of 5Aza-C, which is currently undergoing phase 2 clinical trials as a treatment for prostate cancer. Because genistein is a natural, nontoxic, and dietary isoflavone, these results indicate that genistein is a novel, advantageous therapeutic agent for treating prostate cancer. Cancer 2010. © 2010 American Cancer Society.
• Prognostic value of quantitative p63 immunostaining in adenoid cystic carcinoma of salivary gland assessed by computerized image analysis
  Ramer N Wu H Sabo E Ramer Y Emanuel P Orta L Burstein DE - Cancer 116(1):77-83 (2009)
  BACKGROUND: In a long-term retrospective immunohistochemical study of adenoid cystic carcinoma (ACC) of salivary gland, we investigated the relation of p63 immunodetection to prognosis. Although it is generally agreed that the solid pattern is the most aggressive pattern of growth, ACCs with predominantly cribriform or tubular patterns have an unpredictable clinical course, with a relatively favorable 5-year survival but a low 20-year survival. METHODS: Formalin-fixed paraffin sections from 35 cases of ACC showing a predominantly better differentiated histopathology, ie, cribriform or tubular patterns of growth, were immunostained for p63. Automated image analysis was used to quantify p63 positivity, using a modification of a previously developed algorithm. RESULTS: Patients alive for more than 10 years had a lower extent of p63 expression than those who died of disease. Kaplan-Meier analysis revealed that separation of patients with morbidity and mortality from those alive with no evidence of disease, could be achieved at a cutoff of 35% p63 positivity (P = .0031, log-rank test). Multivariate analysis using the Cox proportional hazard model revealed p63 and tumor stage to be independent predictors of survival (P = .012 and P = .0003, respectively). CONCLUSIONS: To our knowledge, the present study is the first to report prognostic significance of p63 in salivary gland ACC and the first report of a robust and well-studied immunohistochemical stain performable on routinely fixed and processed tissue with prognostic utility. Cancer 2010. © 2010 American Cancer Society.
• Extent of disease burden determined with magnetic resonance imaging of the bone marrow is predictive of survival outcome in patients with multiple myeloma
  Ailawadhi S Abdelhalim AN Derby L Mashtare TL Miller KC Wilding GE Alberico RA Gottlieb R Klippenstein DL Lee K Chanan-Khan AA - Cancer 116(1):84-92 (2009)
  BACKGROUND: Multiple myeloma (MM) remains an incurable cancer. Treatment often is initiated at the time patients experience a progressive increase in tumor burden. The authors of this report investigated magnetic resonance imaging of the bone marrow (BM-MRI) as a novel approach to quantify disease burden and validated a staging system by correlating BM-MRI with common clinical and laboratory parameters. METHODS: The extent of bone marrow involvement was evaluated by BM-MRI. Clinical and laboratory parameters were assessed in patients with active MM, and correlations between variables were assessed statistically. Bone marrow involvement by BM-MRI was defined as stage A (0%), stage B (<10%), stage C (10%-50%), and stage D (>50%). RESULTS: In total, 170 consecutive patients were evaluated (77 women and 93 men), including 144 patients who had active MM. The median age was 61 years (age range, 35-83 years). Advance stage disease (stage >I) based on Durie-Salmon (DS) staging or International Staging System (ISS) criteria was observed in 122 patients (84%) and 77 patients (53%), respectively. Lytic bone disease was noted in 120 patients (83%). There was a significant association between BM-MRI involvement and DS stage (P = .0006), ISS stage (P = .0001), the presence of lytic bone disease (P < .0001) and mean -2 microglobulin levels (P < .0001). Among the patients with previously untreated MM, there was a significant association between BM-MRI stage and overall survival (OS) (univariate P = .013; multivariate P = .045). Plasmacytosis on bone marrow biopsy at diagnosis was not predictive of OS (P = .91). CONCLUSIONS: BM-MRI is a novel approach for quantifying disease burden in patients with MM. The current investigation in a large cohort of nontransplantion MM patients demonstrated that the extent of bone marrow involvement determined by BM-MRI correlates accurately with other conventional parameters of disease burden and can independently predict survival in patients with MM at the time of initial diagnosis. Cancer 2010. © 2010 American Cancer Society.
• Acute pulmonary failure during remission induction chemotherapy in adults with acute myeloid leukemia or high-risk myelodysplastic syndrome
  Al Ameri A Koller C Kantarjian H Ravandi F Verstovsek S Borthakur G Pierce S Mattiuzzi G - Cancer 116(1):93-97 (2009)
  BACKGROUND: Acute pulmonary failure during remission induction therapy is a serious complication in patients with acute myeloid leukemia (AML). To the authors' knowledge, the course and prognosis of such patients is not well known. METHODS: A total of 1541 patients referred for remission induction chemotherapy of AML or high-risk myelodysplastic syndrome were retrospectively reviewed. RESULTS: A total of 120 (8%) patients developed acute pulmonary failure within 2 weeks of the initiation of chemotherapy; 87 of these patients (73%) died during remission induction, whereas 17 (14%) achieved a complete response. The median survival among the 120 patients with early acute pulmonary failure was 3 weeks. Predictive factors for the development of early acute pulmonary failure by multivariate analysis were: male sex (P = .00038), acute promyelocytic leukemia (P = .00003), poor performance status (P = .001), lung infiltrates at diagnosis (P = .000001), and increased creatinine (P = .000005). Patients who had 0 to 1, 2, 3, or 4 to 5 adverse factors were found to have estimated predictive incidences of acute pulmonary failure of 3%, 13%, 23%, and 34%, respectively. CONCLUSIONS: Preventive approaches at the start of induction therapy in patients at high risk of pulmonary failure may improve the outcome of these patients. Cancer 2010. © 2010 American Cancer Society.
• Combination of cladribine plus topotecan for recurrent or refractory pediatric acute myeloid leukemia
  Inaba H Stewart CF Crews KR Yang S Pounds S Pui CH Rubnitz JE Razzouk BI Ribeiro RC - Cancer 116(1):98-105 (2009)
  BACKGROUND: The prognosis after recurrence of pediatric acute myeloid leukemia (AML) is poor, and effective salvage regimens are urgently needed. METHODS: In phase 1 and pilot studies, the authors evaluated the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a 5-day course of cladribine followed by topotecan in pediatric patients with recurrent/refractory AML. The cladribine dose was escalated as follows: 9.1, 13.6, 16.3, and 19.5 mg/m2 per day (8.9 mg/m2 per day in the pilot study). Outcome was analyzed according to the absence (Stratum 1) versus presence (Stratum 2) of previous allogeneic hematopoietic stem cell transplantation. Twenty-six patients (20 in Stratum 1 and 6 in Stratum 2) were treated. RESULTS: The MTD was not reached in Stratum 1, but a DLT occurred at the lowest cladribine dosage (9.1 mg/m2 per day) in Stratum 2. Febrile neutropenia was common in both strata. Nine (34.6%) of 26 patients experienced a complete response, and 7 (30.4%) achieved a partial response; 5 (19.2%) were long-term survivors at the time of last follow-up. Clinical outcome was not associated with cladribine or topotecan systemic exposure. CONCLUSIONS: The combination was well tolerated in Sratum 1, and the response rate was encouraging. This regimen offers a postrecurrence treatment alternative for patients, especially those who have received anthracycline-containing chemotherapy. Cancer 2010. © 2010 American Cancer Society.
• Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma : Results from a Multicenter Study
  Kahl BS Bartlett NL Leonard JP Chen L Ganjoo K Williams ME Czuczman MS Robinson KS Joyce R van der Jagt RH Cheson BD - Cancer 116(1):106-114 (2009)
  BACKGROUND: Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single-agent bendamustine in patients with rituximab-refractory, indolent B-cell lymphoma. METHODS: Eligible patients (N = 100, ages 31-84 years) received bendamustine at a dose of 120 mg/m2 by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0-6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression-free survival (PFS). RESULTS: An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%). CONCLUSIONS: Single-agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab-refractory indolent B-cell lymphoma. Cancer 2010. © 2010 American Cancer Society.
• Hepatitis B virus reactivation and role of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection who are receiving chemoimmunotherapy
  Koo YX Tan DS Tan IB Tao M Chow WC Lim ST - Cancer 116(1):115-121 (2009)
  BACKGROUND: Individuals who had past hepatitis B virus (HBV) infection appeared to clear their serum hepatitis B surface antigen (HBsAg) while producing antibody to the hepatitis B core antigen (HBcAb), which is detectable in their serum. Currently, it is uncertain whether patients with past HBV infection require routine antiviral prophylaxis during chemotherapy, although some cancer agencies recommend its routine use. The objective of the current study was to determine the prevalence of past HBV infection in patients with lymphoma and its relevance in terms of HBV-related complications. METHODS: The authors reviewed 430 patients with lymphoma from May 2006 to May 2008. RESULTS: Among the 430 patients, 233 had both the HBsAg and HBcAb tests performed, whereas 197 had only the HBsAg test performed. Among those with both tests performed, 34.3% (80 of 233) were HBcAb positive only. Of these 80 patients, 58 had a concomitant HBV DNA level test, which was positive in 3 (5.2%). Of the 67 patients with past and 26 with chronic HBV infection who received chemotherapy, HBV reactivation occurred in 1.5% and 42.3% of patients, respectively (P<.0001). Prophylactic lamivudine was administered in 7 (10.4%) patients with past HBV infection and in 18 (69.2%) with chronic HBV infection. CONCLUSIONS: The low rate of HBV reactivation reported in our study coupled with the high prevalence of past HBV infection in an endemic area suggests that routine usage of antiviral prophylaxis may not be required for all patients with past HBV infection. Close surveillance remains a reasonable and viable option for the majority of patients. Cancer 2010. © 2010 American Cancer Society.
• Modeling excess lung cancer risk among screened arm participants in the Mayo Lung Project
  Goldwasser DL Kimmel M - Cancer 116(1):122-131 (2009)
  BACKGROUND: The Mayo Lung Project (MLP) was a randomized clinical trial designed to test whether periodic screening by chest x-ray reduced lung cancer (LC) mortality in men who were high-risk smokers. Among MLP participants, there were more deaths from LC in the screening arm both at the trial's end and after long-term follow-up. Overdiagnosis was cited widely as an explanation for the MLP results, whereas a role for excess LC risk attributable to undergoing numerous chest x-ray screenings largely was unexamined. The authors of this report examined the consistency of the MLP data with a modified 2-stage clonal expansion (TSCE) model of excess LC risk. METHODS: By using a simulation model calibrated to the initial MLP data, the authors examined the expected statistical variance of LC incidence and mortality between the screening and control arms. A Bayesian estimation framework using a modified version of the TSCE model to evaluate the role of excess LC risk attributable to chest x-ray screening was derived and applied to the MLP data. RESULTS: Simulation experiments indicated that the overall difference in LC deaths and incidence between the study arm and the control arm was unlikely (P = .0424 and P = .0104, respectively) assuming no excess risk of LC. The authors estimated that the 10-year excess LC risk for a man aged 60 years who smoked and who received 10 chest x-ray screenings was 0.574% (P = .0021). CONCLUSIONS: The excess LC risk observed among screening arm participants was found to be statistically significant with respect to the TSCE model framework in part because of the incorporation of key risk correlates of age and screen frequency into the estimation framework. Cancer 2010. Published 2010 American Cancer Society
• Multicenter phase 2 study of belotecan, a new camptothecin analog, and cisplatin for chemotherapy-naive patients with extensive-disease small cell lung cancer
  Lee DH Kim SW Suh C Lee JS Ahn JS Ahn MJ Park K Na II Lee JC Ryoo BY Yang SH - Cancer 116(1):132-136 (2009)
  BACKGROUND: The objective of this study was to investigate the efficacy of belotecan, a new camptothecin analog, combined with cisplatin for the treatment of chemotherapy-naive patients with extensive-disease small cell lung cancer (ED SCLC). METHODS: Treatment consisted of belotecan 0.5 mg/m2 daily on Days 1 through 4 and cisplatin 60 mg/m2 on Day 1 of a 3-week cycle for up to 6 cycles unless there was disease progression, unacceptable toxicity, or patient refusal. Response assessment was done every 2 cycles using the Response Evaluation Criteria in Solid Tumors, and toxicity assessment was done every cycle using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: Between September 2006 and March 2008, 30 patients participated in the study. Among them, 21 patients achieved a partial response, and the response rate was 70% (95% confidence interval [CI], 50.6%-85.3%); and, after a median follow-up of 20.2 months, the median progression-free survival was 6.9 months (95% CI, 6.3-7.5 months), and the overall survival was 19.2 months (95% CI, 13.3-25.2 months). Grade 3 and 4 adverse events included neutropenia in 23 patients, thrombocytopenia in 8 patients, febrile neutropenia in 9 patients, nausea in 3 patients, and pneumonia in 3 patients. There was 1 treatment-related death from pneumonia. However, nonhematologic toxicity generally was mild and manageable. CONCLUSIONS: The belotecan and cisplatin combination that was studied demonstrated promising response rates and survival outcomes with a manageable toxicity profile for chemotherapy-naive patients who had ED SCLC. The authors concluded that the combination warrants further randomized trials. Cancer 2010. © 2010 American Cancer Society.
• Prognostic value of symptom burden for overall survival in patients receiving chemotherapy for advanced nonsmall cell lung cancer
  Wang XS Shi Q Lu C Basch EM Johnson VE Mendoza TR Mobley GM Cleeland CS - Cancer 116(1):137-145 (2009)
  BACKGROUND: Patient-reported outcomes have shown independent prognostic value for patients with nonsmall cell lung cancer (NSCLC). However, translating patient-reported outcomes into useful prognostic information for individual patients has been problematic. METHODS: A total of 94 patients with advanced NSCLC and an Eastern Cooperative Oncology Group performance status (PS) of 0 to 2 who qualified for chemotherapy rated symptom severity using the M. D. Anderson Symptom Inventory before and after their first chemotherapy cycle. Prognostic values of baseline symptoms and changes in symptom severity were examined by Cox proportional hazards models. RESULTS: In multivariate analysis, controlled for demographic and other factors, baseline coughing rated 4 independently predicted significantly higher risk for shorter survival (hazards ratio [HR], 8.69; P < .0001). Patients with coughing 4 and a PS of 2 were more likely to have shorter survival (HR, 20.6; P < .0001) than patients with coughing <4 and a PS of 0 to 1. A 1-point or greater increase in severity of fatigue (P < .05), shortness of breath, or poor appetite (P < .01) from baseline to the end of the first chemotherapy cycle was also found to be independently associated with higher risk for poor survival. CONCLUSIONS: An increased risk for shorter survival was indicated by moderate to severe coughing at baseline or by increased fatigue or shortness of breath during the first chemotherapy cycle in patients with advanced NSCLC. Although cross-validation is needed, these data suggest that an individual patient's symptom severity scores, quickly obtainable in the clinic, might contribute clinically useful information for treatment planning for that patient. Cancer 2010. © 2010 American Cancer Society.
• Results of a multicenter, randomized, double-blind phase 2/3 study of lenalidomide in the treatment of pretreated relapsed or refractory metastatic malignant melanoma
  Eisen T Trefzer U Hamilton A Hersey P Millward M Knight RD Jungnelius JU Glaspy J - Cancer 116(1):146-154 (2009)
  BACKGROUND: The results of an international, multicenter, randomized, double-blind, controlled study assessing the efficacy and safety of lenalidomide treatment in patients with refractory stage IV metastatic malignant melanoma are reported. METHODS: The study compared treatment with lenalidomide (25 mg/d on Days 1-21 of a 28-day cycle) to placebo in 306 patients with metastatic malignant melanoma. Treatment was continued until progression of disease or unacceptable toxicity. RESULTS: There were no significant differences between lenalidomide and placebo in overall survival (median 5.9 months vs 7.4 months, respectively; P = .32), time to progression (median 3.0 months vs 2.1 months; P = .19), or Response Evaluation Criteria in Solid Tumors tumor response (5.3% vs 5.8%; P = .82). None of the patients given placebo discontinued treatment because of treatment-related adverse events, compared with 4.6% of those treated with lenalidomide. Treatment-related myelosuppression was observed in 2.0% of patients treated with placebo and 7.3% of patients treated with lenalidomide. CONCLUSIONS: This study showed that treatment with lenalidomide (25 mg/d) has a manageable safety profile in patients with previously treated metastatic malignant melanoma but no benefit in tumor response, time to progression, or overall survival in these patients. Future trials for treatment of metastatic malignant melanoma with lenalidomide should focus on its use in combination therapies. Cancer 2010. © 2010 American Cancer Society.
• A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma
  Hersh EM O'Day SJ Ribas A Samlowski WE Gordon MS Shechter DE Clawson AA Gonzalez R - Cancer 116(1):155-163 (2009)
  BACKGROUND: nab-Paclitaxel (ABI-007, Abraxane), a 130-nM, albumin-bound (nab) particle form of Cremophor-free paclitaxel, is approved for metastatic breast cancer. In the current study, the efficacy and safety of nab-paclitaxel were evaluated in previously treated and chemotherapy-naive patients with metastatic melanoma (MM). METHODS: Patients with histologically or cytologically confirmed, measurable MM were enrolled. nab-Paclitaxel was administered intravenously weekly for 3 of 4 weeks at a dose of 100 mg/m2 (in previously treated patients) or 150 mg/m2 (in chemotherapy-naive patients). RESULTS: Thirty-seven patients were treated in each cohort. The response rate was 2.7% in the previously treated cohort and 21.6% in the chemotherapy-naive cohort; the response plus stable disease rate was 37.8% and 48.6% in the previously treated and chemotherapy-naive cohorts, respectively. The median progression-free survival (PFS) was 3.5 months and 4.5 months, and the median survival was 12.1 months and 9.6 months, respectively. The probability of being alive and free of disease progression at 6 months was 27% for the previously treated cohort and 34% for the chemotherapy-naive cohort; the probability of surviving 1 year was 49% and 41%, respectively, for the previously treated and chemotherapy-naive cohorts. Approximately 78% of the previously treated patients and 49% of the chemotherapy-naive patients were treated without dose reduction. Eight (22%) chemotherapy-naive patients discontinued therapy because of toxicities. Drug-related toxicities included grade 3 to 4 (graded acc! ording to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neuropathy, alopecia, neutropenia, and fatigue. CONCLUSIONS: nab-Paclitaxel was found to be well tolerated and demonstrated activity in both previously treated and chemotherapy-naive patients with MM. The response rate, PFS, and survival compared favorably with current standard dacarbazine therapy and combination therapies for melanoma. nab-Paclitaxel therapy of MM should be investigated further in controlled clinical trials. Cancer 2010. © 2010 American Cancer Society.
• Flavonoids activated caspases for apoptosis in human glioblastoma T98G and U87MG cells but not in human normal astrocytes
  Das A Banik NL Ray SK - Cancer 116(1):164-176 (2009)
  BACKGROUND: Human glioblastoma is a deadly brain cancer that continues to defy all current therapeutic strategies. The authors induced apoptosis in human glioblastoma T98G and U87MG cells after treatment with apigenin, (-)-epigallocatechin, (-)-epigallocatechin-3-gallate (EGCG), and genistein, which did not induce apoptosis in human normal astrocytes. METHODS: Induction of apoptosis was examined using Wright staining and ApopTag assay. Production of reactive oxygen species (ROS) and increase in intracellular free Ca2+ were measured by fluorescent probes. Analysis of mRNA and Western blotting indicated increases in expression and activities of the stress kinases and cysteine proteases for apoptosis. JC-1 showed changes in mitochondrial membrane potential (m), and use of specific inhibitors confirmed activation of kinases and proteases in apoptosis. RESULTS: Treatment of glioblastoma cells with apigenin, (-)-epigallocatechin, EGCG, or genistein triggered ROS production that induced apoptosis with phosphorylation of p38 mitogen-activated protein kinase (MAPK) and activation of the redox-sensitive c-Jun N-terminal kinase 1 pathway. Pretreatment of cells with ascorbic acid attenuated ROS production and p38 MAPK phosphorylation. Increases in intracellular free Ca2+ and activation of caspase-4 indicated involvement of endoplasmic reticulum stress in apoptosis. Other events in apoptosis included overexpression of Bax, loss of m, mitochondrial release of cytochrome c and Smac into the cytosol, down-regulation of baculoviral inhibitor-of-apoptosis repeat-containing proteins, and activation of calpain, caspase-9, and caspase-3. (-)-Epigallocatechin and EGCG also induced caspase-8 activity. Apigenin, (-)-epigallocatechin, EGCG, and genistein did not induce apoptosis in human normal astrocytes. CONCLUSIONS: Results strongly suggest that flavonoids are potential therapeutic agents for induction of apoptosis in human glioblastoma cells. Cancer 2010. © 2010 American Cancer Society.
• The symptom interval in children and adolescents with soft tissue sarcomas
  Ferrari A Miceli R Casanova M Meazza C Favini F Luksch R Catania S Fiore M Morosi C Mariani L - Cancer 116(1):177-183 (2009)
  BACKGROUND: In a series of 575 patients 21 years of age with soft tissue sarcomas (STSs), the authors investigated the association patterns between symptom interval (ie, the period between the onset of the first symptoms or signs of the disease and its definitive diagnosis) and patient/tumor characteristics or disease outcome (in terms of survival). METHODS: The analysis was based on multivariate models (linear for associations with patient/tumor characteristics and Cox's for survival). RESULTS: The symptom interval ranged between 1 week and 60 months (median, 2 months) and tended to be longer the older the patient (ie, the interval was longer in adolescents than in children) and the larger the tumor's size, and for tumors located at the extremities and for nonrhabdomyosarcoma STSs (as opposed to rhabdomyosarcomas). A longer symptom interval unfavorably influenced survival (P = .002), which was also significantly affected by the patient's age and the size and surgical stage of the tumor. A different pattern of association between symptom interval and survival emerged for different types of STS histology. CONCLUSIONS: Our study points to an independent prognostic effect of symptom interval that cannot be explained by its associations with other factors, such as patient's age or the site, size, stage, and histology of the tumor. Future studies should focus more on the possible causes of symptom interval in pediatric STS populations to enable corrective measures to be implemented to reduce the diagnostic delay. Cancer 2010. © 2010 American Cancer Society.
• Rare incidence of congestive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate
  Trent JC Patel SS Zhang J Araujo DM Plana JC Lenihan DJ Fan D Patel SR Benjamin RS Khakoo AY - Cancer 116(1):184-192 (2009)
  BACKGROUND: The authors sought to determine the incidence and severity of cardiovascular toxicity caused by imatinib mesylate in gastrointestinal stromal tumor (GIST) and other sarcoma patients, and to explore cardiotoxicity caused by imatinib mesylate using cell culture and in vitro models. METHODS: To determine the incidence and significance of serious cardiac adverse events in GIST and other sarcoma patients receiving imatinib mesylate, the authors performed a retrospective analysis of 219 consecutive patients treated with imatinib mesylate. In vitro studies of imatinib mesylate on cultured cardiomyocytes and biochemical studies of cardiac lysates from mice treated with imatinib mesylate were performed to define the potential cardiotoxic effects of imatinib mesylate. RESULTS: Grade 3 or 4 potentially cardiotoxic adverse events (mostly edema or effusions) occurred in 8.2% of patients, were manageable with medical therapy, and infrequently required dose reduction or discontinuation of imatinib mesylate. Arrhythmias, acute coronary syndromes, or heart failure were uncommon, occurring in <1% of treated patients. However, administration of imatinib in a mouse model system resulted in inhibition of activation of protein kinases that are known to be important in the cardiac stress response. CONCLUSIONS: The authors concluded that imatinib is an uncommon cause of cardiotoxicity, and that the cardiovascular adverse events that occur are manageable when recognized and treated. Nevertheless, our preclinical findings suggest that imatinib remains a potential cardiotoxin. Furthermore, the cardiac consequences of long-term imatinib therapy remain unknown. We therefore recommend treatment of risk factors for cardiovascular disease in imatinib-treated patients in accord with the American Heart Association guidelines for the prevention and treatment of heart failure. Cancer 2010. © 2010 American Cancer Society.
• Disparities in medical care among commercially insured patients with newly diagnosed breast cancer : Opportunities for intervention
  Short LJ Fisher MD Wahl PM Kelly MB Lawless GD White S Rodriguez NA Willey VJ Brawley OW - Cancer 116(1):193-202 (2009)
  BACKGROUND: African-American women have increased breast cancer mortality compared with white women. Diagnostic and treatment gaps may contribute to this disparity. METHODS: In this retrospective, longitudinal cohort study, Southern US health plan claims data and linked medical charts were used to identify racial disparities in the diagnoses, treatment, and mortality of commercially insured women with newly diagnosed breast cancer. White women (n = 476) and African-American women (n = 99) with newly diagnosed breast cancer were identified by breast cancer claims codes (International Classification of Diseases, Ninth Revision, Clinical Modification codes 174, 233.0, 238.3, and 239.3) between January 2000 and December 2004. Race, diagnoses (breast cancer stage, estrogen/progesterone receptor [ER/PR]-positive status), treatment (breast-conserving surgery, antiestrogen therapy, and chemotherapy interruption or reduction), and all-cause mortality were assessed from medical charts. Multivariate regression analyses were adjusted for age, geography, and socioeconomic status to test the association of race with diagnoses/treatment. RESULTS: White women were older (P < .001) and had higher rates of diagnosis at stage 0/I (55.2% vs 38.4%; P < .05) than African-American women. More white women had positive ER/PR status (75% vs 56% African-American; P = .001) and received antiestrogen therapy if they were positive (37.2% vs 27.3% African-American; P < .001). White women received slightly more breast-conserving surgery and chemotherapy dose modification than African-American women (P value nonsignificant). African-American women had a higher mortality rate (8.1%) than white women (3.6%; P = .06). In adjusted analyses, African-American women were diagnosed at later stages (odds ratio, 1.71; P = .02), and white women received more antiestrogen therapy (odds ratio, 2.1; P = .03). CONCLUSIONS: Disparities in medical care among patients with newly diagnosed breast cancer were evident between African-American women and white women despite health plan insurance coverage. Interventions that address the gaps identified are needed. Cancer 2010. © 2010 American Cancer Society.
• Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma
  McWilliams RR Petersen GM Rabe KG Holtegaard LM Lynch PJ Bishop MD Highsmith WE - Cancer 116(1):203-209 (2009)
  BACKGROUND: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are common in white persons and are associated with pancreatic disease. The purpose of this case-control study was to determine whether CFTR mutations confer a higher risk of pancreatic cancer. METHODS: In a case-control study, the authors compared the rates of 39 common cystic fibrosis-associated CFTR mutations between 949 white patients with pancreatic adenocarcinoma and 13,340 white controls from a clinical laboratory database for prenatal testing for CFTR mutations. The main outcome measure was the CFTR mutation frequency in patients and controls. RESULTS: Overall, 50 (5.3%) of 949 patients with pancreatic cancer carried a common CFTR mutation versus 510 (3.8%) of 13,340 controls (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.04-1.89; P = .027). Among patients who were younger when their disease was diagnosed (<60 years), the carrier frequency was higher than in controls (OR, 1.82; 95% CI, 1.14-2.94; P = .011). In patient-only analyses, the presence of a mutation was associated with younger age (median 62 vs 67 years; P = .034). In subgroups, the difference was seen only among ever-smokers (60 vs 65 years, P = .028). Subsequent sequencing analysis of the CFTR gene detected 8 (16%) compound heterozygotes among the 50 patients initially detected to have 1 mutation. CONCLUSIONS: Carrying a disease-associated mutation in CFTR is associated with a modest increase in risk for pancreatic cancer. Those affected appear to be diagnosed at a younger age, especially among smokers. Clinical evidence of antecedent pancreatitis was uncommon among both carriers and noncarriers of CFTR mutations. Cancer 2010. © 2010 American Cancer Society.
• Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients
  Sonis S Treister N Chawla S Demetri G Haluska F - Cancer 116(1):210-215 (2009)
  BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors may have efficacy as an intervention for advanced malignancies. Oral ulceration (OU), reported as mucositis, has been a dose-limiting toxicity for this new class of agents. An analysis of the appearance, course, and toxicity associations of mTOR inhibitor-associated stomatitis (mIAS) demonstrated that the condition is distinct from conventional mucositis (CM) and more closely resembles aphthous stomatitis. METHODS: Safety data from 78 solid tumor patients enrolled in 2 Phase 1, multicenter trials of the mTOR inhibitor deforolimus (AP23573, MK-8669) were evaluated. Adverse events (AEs) based on National Cancer Institute Common Toxicity Criteria for National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) criteria were coded, consolidated, and stratified according to the presence or absence and duration of concordant OU. The relation between OU and other AEs was analyzed. RESULTS: Treatment-emergent AEs were reported in 91% of 78 study participants. OUs were reported in 66%, appeared within 5 days of deforolimus administration, and were discrete, ovoid, superficial, well demarcated, and surrounded by an erythematous halo. Their clinical appearance and distribution were similar to that of aphthous stomatitis but inconsistent with CM. Patients with OU were more likely to have nonspecific rashes and acneiform dermatitis but not gastrointestinal AEs. CONCLUSIONS: OU associated with mTOR inhibitor therapy differed from CM. Lesions more closely resembled those of aphthous stomatitis. The lack of other gastrointestinal involvement but the presence of a higher incidence of concomitant cutaneous AEs provided additional evidence to suggest a distinction between mIAS and CM. Treatment strategies for aphthous stomatitis may be a rational approach for the prevention and control of mIAS. Cancer 2010. © 2010 American Cancer Society.
• Inflammatory myofibroblastic tumors in childhood : A report from the Italian Cooperative Group studies
  Alaggio R Cecchetto G Bisogno G Gambini C Calabrò ML Inserra A Boldrini R Salvo GL G d'Amore ES Dall'igna P - Cancer 116(1):216-226 (2009)
  BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are myofibroblastic lesions with unpredictable biologic behavior that occur at a young age. For this report, the authors investigated clinicopathologic features in a series of pediatric IMTs. The objective of the study was to identify morphologic or immunohistochemical prognostic markers and the possible pathogenic role of human herpes virus 8 (HHV-8). METHODS: Twenty-six patients were observed over a period of 18 years. Clinical/histologic data were reviewed, and immunohistochemical/molecular studies were performed. RESULTS: Patients ages 8-216 months (median age, 60 months) presented with tumors of the lung-bronchus (8 patients), abdomen (17 patients), and thoracic wall (1 patient). Twenty-one patients underwent complete excision, and microscopic or macroscopic residual disease was present in 5 of those patients. Chemotherapy was received by 5 patients. After a median follow-up of 6.6 years, 24 patients were in complete remission, and 2 patients had died of disease. Local recurrences were observed in 6 patients (including 4 recurrences that occurred after a complete excision). Cytologic atypia, low inflammatory infiltrate, and a rich myxoid pattern were detected in patients who had recurrent disease or a poor prognosis. Anaplastic lymphoma kinase (ALK) was positive in 7 patients (including 2 patients with recurrent disease). No correlation between clusterin expression and prognosis was demonstrated. HHV-8 was identified in 1 pulmonary IMT. CONCLUSIONS: IMTs are locally aggressive lesions. In this series, the local recurrence rate was 23%, and the 5-year and 10-year event-free survival rates were 87.4% and 72.8%, respectively. The results indicated that the treatment of choice is a complete, nonmutilating excision; chemotherapy may be given to patients who have microscopic or macroscopic residual disease, although the results are controversial; cytologic atypia and positive ALK status are more frequent in aggressive tumors, whereas metastatic tumors are negative for ALK; and HHV8 is not involved in the pathogenesis of IMT. Cancer 2010. © 2010 American Cancer Society.
• Effect of allopurinol versus urate oxidase on methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia
  Crews KR Zhou Y Pauley JL Howard SC Jeha S Relling MV Pui CH - Cancer 116(1):227-232 (2009)
  BACKGROUND: Allopurinol and urate oxidase are both effective in preventing or treating hyperuricemia during remission induction therapy for lymphoid malignancies, but to the authors' knowledge, their effects on concomitant anticancer drug therapy have not been compared. METHODS: The authors compared plasma methotrexate pharmacokinetics in pediatric patients with newly diagnosed acute lymphoblastic leukemia who received concomitant allopurinol (n = 20) versus those treated with nonrecombinant or recombinant urate oxidase (n = 96) during high-dose methotrexate administration before conventional remission induction therapy. RESULTS: The minimum plasma concentration of uric acid was significantly (P < .0001) lower after urate oxidase treatment than the concentration after allopurinol treatment. Methotrexate clearance was significantly higher (median, 117.1 mL/minute/m2 vs 91.1 mL/minute/m2; P = .019) in patients who received urate oxidase. A higher proportion of patients in the allopurinol group had elevated methotrexate plasma concentrations (36% vs 7%; P = .003) and experienced mucositis (45% vs 16%; P = .003) after methotrexate treatment compared with the urate oxidase group. CONCLUSIONS: The lower rate of methotrexate clearance in patients who received allopurinol likely reflected a less potent hypouricemic effect of allopurinol, leading to precipitation of uric acid in renal tubules. Hence, during remission induction therapy for lymphoid malignancies, the authors concluded that renally excreted drugs should be monitored closely, especially in patients who are receiving allopurinol. Cancer 2010. © 2010 American Cancer Society.
• Aggressive fibromatosis in children and adolescents : The Italian experience
  Meazza C Bisogno G Gronchi A Fiore M Cecchetto G Alaggio R Milano GM Casanova M Carli M Ferrari A - Cancer 116(1):233-240 (2009)
  BACKGROUND: Aggressive fibromatosis (AF) is a rare tumor of intermediate malignancy that has a strong potential for local invasiveness and recurrence. To date, there are no general recommendations for the clinical management of pediatric AF. METHODS: The authors retrospectively analyzed 94 patients aged 21 years, including 23 patients who underwent complete surgery (Group I), 42 patients who underwent incomplete surgery with microscopic residual tumor (Group II), and 29 patients who underwent either biopsy or macroscopically incomplete surgery (Group III). RESULTS: The 5-year event-free survival (EFS) and overall survival rates were 44% and 99%, respectively. Local recurrences developed in 22% of patients in Group I, in 76% of patients in Group II, and in 76% of patients in Group III. Two of 7 patients with abdominal disease died of tumor progression, whereas none of the patients with extra-abdominal AF died of their disease. Systemic treatment was given to 15 patients as first-line treatment and to 34 patients at time the time they developed recurrent disease: The response rate was 47% in the former patients and 50% in the latter patients. Objective responses were observed in 11 of 19 patients who received combined methotrexate plus vinblastine/vinorelbine, in 7 of 15 patients who received alkylating-agent chemotherapy, and in 4 of 11 patients who received other therapies (tamoxifen, sulindac, interferon alfa). CONCLUSIONS: The current analysis suggested that the clinical course of AF in children may resemble that of AF in adults. Local recurrences did not affect the chance of responding to systemic therapy or the survival rate. The completeness of initial resection was the main factor that influenced EFS, whereas disease control after marginal resection was much the same as that achieved after intralesional surgery/biopsy. Good responses to systemic treatments, and particularly to low-dose chemotherapy, were observed as reported previously in adults. Cancer 2010. © 2010 American Cancer Society.
• Toxicity report of a phase 1/2 dose-escalation study in patients with inoperable, locally advanced nonsmall cell lung cancer with helical tomotherapy and concurrent chemotherapy
  Bral S Duchateau M Versmessen H Verdries D Engels B Ridder MD Tournel K Collen C Everaert H Schallier D De Greve J Storme G - Cancer 116(1):241-250 (2009)
  BACKGROUND: The objective of the current study was to evaluate the feasibility and toxicity of radiation dose escalation with concurrent chemotherapy using helical tomotherapy (HT) in patients with inoperable, locally advanced, stage III nonsmall cell lung cancer (LANSCLC) (grading determined according to the American Joint Committee on Cancer 6th edition grading system). METHODS: This phase 1/2 study was designed to determine the maximum tolerated dose (MTD) of radiotherapy in patients with LANSCLC administered concurrently with docetaxel and cisplatin. Radiotherapy was delivered using HT. A dose per fraction escalation was applied starting at 2 grays (Gy), with an increase of 6% per dose cohort (DC). The Radiation Therapy Oncology Group acute radiation morbidity score was used to monitor pulmonary, esophageal, and cardiac toxicity. RESULTS: Dose escalation was performed in 34 patients over 5 DCs to a dose per fraction of 2.48 Gy. No differences were observed in acute toxicity between the different DCs. However, a significant increase in late lung toxicity in DC IV, which received a fraction size of 2.36 Gy, necessitated a halt in further dose escalation with the MTD defined as 2.24 Gy per fraction. The overall incidence of acute grade 3 esophageal and pulmonary toxicity was 24% and 3%, respectively (grading determined according to the Radiation Therapy Oncology Group-European Organisation for Research and Treatment of Cancer toxicity scoring system). The overall incidence of late lung toxicity was 21%, but the incidence was an acceptable 13% in DCs I, II, and III. The local response rate was 61% on computed tomography images. CONCLUSIONS: The use of HT to 67.2 Gy with concurrent cisplatin/docetaxel was feasible and resulted in acceptable toxicity. A full phase 2 study has been initiated to establish the true local response rate at the MTD of 2.24 Gy per fraction. Cancer 2010. © 2010 American Cancer Society.
• An animal model for chemotherapy-associated steatohepatitis and its prevention by the oral administration of fatty acid bile acid conjugate
  Keizman D Maimon N Ish-Shalom M Buchbut D Inbar M Klein B Bernheim J Goldiner I Leikin-Frenkel A Konikoff F - Cancer 116(1):251-255 (2009)
  BACKGROUND: Preoperative chemotherapy for hepatic resection of colorectal liver metastases is associated with the development of chemotherapy-associated steatohepatitis (CASH). This increases the risk of perioperative morbidity and mortality. To the authors' knowledge, an animal model for CASH has not been described previously. It has been established that fatty acid bile acid conjugates (FABACs) prevent the formation of diet-induced fatty liver. The current study was designed to establish an animal model of CASH and to use that model to study the effect of FABACs on its occurrence. METHODS: C57BL/6 mice were given different doses of oxaliplatin and irinotecan. Oxaliplatin administered once weekly at a dose of 6 mg/kg for a total dose of 24 mg/kg was tolerated best and was associated most consistently with CASH. Thus, that dose was chosen as the induction model for CASH. Subsequently, mice were divided into a control group (no treatment), an oxaliplatin group, and a CASH-prevention group, which received oxaliplatin and C20-FABAC at a dose of 150 mg/kg daily. The animals were killed after 28 days. RESULTS: Liver fat content was significantly lower (P < .0001) in the control group (51.63 mg/g) and the prevention group (62.13 mg/g) compared with the oxaliplatin group (95.35 mg/g). This difference was mainly because of the accumulation of liver triglycerides in the oxaliplatin group. CONCLUSIONS: The current results indicated that C57BL/6 mice receiving weekly oxaliplatin can be used as a model for CASH. Oral FABAC therapy reduced the development of CASH in animals that received oxaliplatin. To the authors' knowledge, this report is the first description of a model and a potential preventive treatment for CASH. Cancer 2010. © 2010 American Cancer Society.
• Racial disparities for uterine corpus tumors : Changes in clinical characteristics and treatment over time
  Grant WB - Cancer 116(1):256 (2009)
  
• Reply to Racial disparities for uterine corpus tumors : Changes in clinical characteristics and treatment over time
  Wright JD - Cancer 116(1):256-257 (2009)
  
• The atypical Spitz tumor of uncertain biologic potential : A series of 67 patients from a single institution
  Urso C - Cancer 116(1):258 (2009)
  
• Reply to The atypical Spitz tumor of uncertain biologic potential : A series of 67 patients from a single institution
  Ludgate MW Fullen DR Lowe L Johnson T - Cancer 116(1):258-259 (2009)
  
• Preoperative assessment enables the early detection and successful treatment of lymphedema
  Hayes S Cornish B Newman B - Cancer 116(1):260 (2009)