Hot off the presses! Jun 11 Cancer

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Latest Articles Include:

• Collaboration is key to treating uncommon cancers : Scientists and patients champion research in these rare diseases
  - Cancer (Philad ) 116(12):2847-2849 (2010)
  
• Deadly cancers need attention, too
  - Cancer (Philad ) 116(12):2848 (2010)
  
• Study finds that digital mammography delivers less radiation
  - Cancer (Philad ) 116(12):2849 (2010)
  
• CA 125 and the detection of recurrent ovarian cancer : A reasonably accurate biomarker for a difficult disease
  - Cancer (Philad ) 116(12):2850-2853 (2010)
  Rising cancer antigen 125 (CA125) levels have been used to detect recurrence of ovarian cancer. A recent study questions the value of this practice, but the clinical trial has significant limitations and discounts the value of early detection to permit treatment of recurrence with novel and conventional agents.
• CA 125: Value or addiction?
  - Cancer (Philad ) 116(12):2854-2855 (2010)
  The author challenges a recent study indicating that there is no apparent benefit in routinely measuring cancer antigen 125 (CA 125) in the follow-up of women with ovarian cancer.
• Trastuzumab-based neoadjuvant therapy in patients with HER2-positive breast cancer
  - Cancer (Philad ) 116(12):2856-2867 (2010)
  Overexpression, or gene amplification, of the human epidermal growth factor receptor 2 (HER2) is evident in 20% to 25% of breast cancers. The biologic agent trastuzumab is an HER2-targeted monoclonal antibody that inhibits the proliferation of tumor cells and induces tumor cell death through multiple mechanisms of action. Currently, trastuzumab is approved for use in the adjuvant and metastatic settings. Trials combining trastuzumab with neoadjuvant chemotherapy suggest that patients with HER2-positive breast cancer also may benefit from preoperative trastuzumab. For this article, the author reviewed efficacy and safety data from key studies of patients who received neoadjuvant trastuzumab-based therapy. Studies were identified from literature searches of publication and congress databases. The results of 3 large phase 3 trials (the M. D. Anderson Cancer Center neoadjuvant trastuzumab trial, the Neoadjuvant Herceptin [NOAH] trial, and the German Breast Group/Gynecologi! c Oncology Study Group GeparQuattro trial) demonstrated that, compared with chemotherapy alone, neoadjuvant trastuzumab plus chemotherapy significantly increased pathologic complete response rates to as high as 65%. Improvements in disease-free, overall, and event-free survival also were reported in the NOAH trial. In addition to demonstrated efficacy, a low incidence of cardiac dysfunction suggests that neoadjuvant trastuzumab is both effective and well tolerated. Similar results have been reported in a range of phase 2 studies using different trastuzumab-based regimens. These encouraging data led the National Comprehensive Cancer Network to recommend treating patients who have operable, locally advanced, HER2-positive breast cancer with neoadjuvant paclitaxel plus trastuzumab followed by 5-fluorouracil, epirubicin, and cyclophosphamide plus trastuzumab. Cancer 2010. © 2010 American Cancer Society.
• Dose-dense temozolomide regimens : Antitumor activity, toxicity, and immunomodulatory effects
  - Cancer (Philad ) 116(12):2868-2877 (2010)
  Temozolomide is an oral alkylating agent with established antitumor activity in patients with primary brain tumors and melanoma. The originally approved temozolomide dosing regimen is 150 to 200 mg/m2 per day (Days 1 to 5 every 28-day cycle [5 of 28 days]). However, extended dosing regimens (eg, 7 of 14 days, 21 of 28 days, 6 of 8 weeks, or continuously daily) allow for administration of a higher cumulative dose per cycle and have been shown to deplete O6-methylguanine-DNA methyltransferase, which may enhance cytotoxic activity. This article reviews efficacy and safety data from studies that investigated dose-dense temozolomide regimens in patients with recurrent glioma and advanced metastatic melanoma. The clinical benefits of these dose-dense regimens compared with the standard 5 of 28-day regimen have yet to be established. Although the toxicity profile of dose-dense temozolomide is generally similar to that of the standard 5 of 28-day regimen, it is associated with! an increased incidence and severity of lymphocytopenia. The clinical management of temozolomide-associated lymphodepletion and the potential risks and benefits of extended dosing with temozolomide are discussed. Preclinical and clinical evidence suggests that temozolomide-associated lymphodepletion may enhance the host immune response to tumor-associated antigens and/or immunotherapy and may overcome tumor-mediated immunosuppression. Further studies exploring the clinical implications of lymphodepletion are warranted. Cancer 2010. © 2010 American Cancer Society.
• Histologic changes associated with false-negative sentinel lymph nodes after preoperative chemotherapy in patients with confirmed lymph node-positive breast cancer before treatment
  - Cancer (Philad ) 116(12):2878-2883 (2010)
  BACKGROUND: A wide range of false-negative rates has been reported for sentinel lymph node (SLN) biopsy after preoperative chemotherapy. The purpose of this study was to determine whether histologic findings in negative SLNs after preoperative chemotherapy are helpful in assessing the accuracy of SLN biopsy in patients with confirmed lymph node-positive disease before treatment. METHODS: Eighty-six patients with confirmed lymph node-positive disease at presentation underwent successful SLN biopsy and axillary dissection after preoperative chemotherapy at a single institution between 1994 and 2007. Available hematoxylin and eosin-stained sections from patients with negative SLNs were reviewed, and associations between histologic findings in the negative SLNs and SLN status (true negative vs false negative) were evaluated. RESULTS: Forty-seven (55%) patients had at least 1 positive SLN, and 39 (45%) patients had negative SLNs. The false-negative rate was 22%, and the negative predictive value was 67%. The negative SLNs from 17 of 34 patients with available slides had focal areas of fibrosis, some with associated foamy parenchymal histiocytes, fat necrosis, or calcification. These histologic findings occurred in 15 (65%) of 23 patients with true-negative SLNs and in only 2 (18%) of 11 patients with false-negative SLNs (P = .03, Fisher exact test, 2-tailed). The lack of these histologic changes had a sensitivity and specificity for identifying a false-negative SLN of 82% and 65%, respectively. CONCLUSIONS: Absence of treatment effect in SLNs after chemotherapy in patients with lymph node-positive disease at initial presentation has good sensitivity but low specificity for identifying a false-negative SLN. Cancer 2010. © 2010 American Cancer Society.
• Cytologically proven axillary lymph node metastases are eradicated in patients receiving preoperative chemotherapy with concurrent trastuzumab for HER2-positive breast cancer
  - Cancer (Philad ) 116(12):2884-2889 (2010)
  BACKGROUND: The axillary pathologic complete response rate (pCR) and the effect of axillary pCR on disease-free survival (DFS) was determined in patients with HER2-positive breast cancer and biopsy-proven axillary lymph node metastases who were receiving concurrent trastuzumab and neoadjuvant chemotherapy. The use of neoadjuvant chemotherapy is reported to result in pCR in the breast and axilla in up to 25% of patients. Patients achieving a pCR have improved DFS and overall survival. To the authors' knowledge, the rate of eradication of biopsy-proven axillary lymph node metastases with trastuzumab-containing neoadjuvant chemotherapy regimens has not been previously reported. METHODS: Records were reviewed of 109 consecutive patients with HER2-positive breast cancer and axillary metastases confirmed by ultrasound-guided fine-needle aspiration biopsy who received trastuzumab-containing neoadjuvant chemotherapy followed by breast surgery with complete axillary lymph node dissection. Survival was evaluated by the Kaplan-Meier method. Clinicopathologic factors and DFS were compared between patients with and without axillary pCR. RESULTS: Eighty-one patients (74%) achieved a pCR in the axilla. Axillary pCR was not associated with age, estrogen receptor status, grade, tumor size, initial N classification, or median number of lymph nodes removed. More patients with an axillary pCR also achieved a pCR in the breast (78% vs 25%; P < .001). At a median follow-up of 29.1 months, DFS was significantly greater in the axillary pCR group (P = .02). CONCLUSIONS: Trastuzumab-containing neoadjuvant chemotherapy appears to be effective in eradicating axillary lymph node metastases in the majority of patients treated. Patients who achieve an axillary pCR are reported to have improved DFS. The success of pCR with concurrent trastuzumab and chemotherapy in eradicating lymph node metastases has implications for surgical management of the axilla in these patients. Cancer 2010. © 2010 American Cancer Society.
• Prognostic factors for recurrent breast cancer patients with an isolated, limited number of lung metastases and implications for pulmonary metastasectomy
  - Cancer (Philad ) 116(12):2890-2901 (2010)
  BACKGROUND: The aim of this study was to evaluate the clinical treatment outcomes of recurrent breast cancer with a limited number of isolated lung metastases, and to evaluate the role of pulmonary metastasectomy. METHODS: The authors consecutively enrolled 140 recurrent breast cancer patients with isolated lung metastasis from 1997 to 2007 in Seoul National University Hospital and retrospectively analyzed 45 patients who had <4 metastatic lesions. RESULTS: Fifteen patients had pulmonary metastasectomy followed by systemic treatment (pulmonary metastasectomy group), and 30 received systemic treatment alone (nonpulmonary metastasectomy group). The 3-year progression-free survival (PFS) and 4-year overall survival (OS) was significantly longer in the pulmonary metastasectomy group than in the nonpulmonary metastasectomy group (3-year PFS, 55.0% vs 4.5%, P < .001; 4-year OS, 82.1% vs 31.6%, P = .001). In multivariate analysis, a disease-free interval (DFI) of <24 months (hazard ratio [HR], 4.53; 95% CI, 1.72-11.90), no pulmonary metastasectomy (HR, 9.52; 95% CI, 3.34-27.18) and biologic subtypes such as human epithelial growth factor receptor-2 positive (HR, 3.00; 95% CI, 1.04-8.64) and triple negative (HR, 3.92; 95% CI, 1.32-11.59) were independent prognostic factors for shorter PFS. CONCLUSIONS: The authors' results demonstrated that DFI and biologic subtypes of tumor are firm, independent, prognostic factors for survival, and pulmonary metastasectomy can be a reasonable treatment option in this population. Further prospective studies are warranted to evaluate the role of pulmonary metastasectomy. Cancer 2010. © 2010 American Cancer Society.
• The 5-HT2B receptor plays a key regulatory role in both neuroendocrine tumor cell proliferation and the modulation of the fibroblast component of the neoplastic microenvironment
  - Cancer (Philad ) 116(12):2902-2912 (2010)
  BACKGROUND: Fibrosis is a cardinal feature of small intestinal neuroendocrine tumors (SI-NETs) both in local peritumoral tissue and systemic sites (cardiac). 5-HT, a commonly secreted NET amine, is a known inducer of fibrosis, although the mechanistic basis for it and growth factors regulating fibrosis and proliferation in the tumor microenvironment are unclear. We hypothesized that targeting 5-HT2B receptors on tumor cells would inhibit SI-NET 5-HT release and, thereby, fibroblast activation in the tumor microenvironment. METHODS: We studied the 5-HT2B receptor antagonist PRX-08066 in NET cell lines (KRJ-I, H720) and in the coculture system (KRJ-I cells: fibroblastic HEK293 cells) using real time polymerase chain reaction, ELISA, Ki67 immunostaining, and flow cytometry-based caspase 3 assays to assess antiproliferative and profibrotic signaling pathways. RESULTS: In the 5-HT2B expressing SI-NET cell line, KRJ-I, PRX-08066 inhibited proliferation (IC50 4.6x10-9M) and 5-HT secretion (6.9 × 10-9M) and decreased ERK1/2 phosphorylation and profibrotic growth factor synthesis and secretion (transforming growth factor beta 1 [TGF1], connective tissue growth factor [CTGF] and fibroblast growth factor [FGF2]). In the KRJ-I:HEK293 coculture system, PRX-08066 significantly decreased 5-HT release (>60%), Ki67 (transcript and immunostaining: 20%-80%), TGF1, CTGF, and FGF2 transcription (20%-50%) in the KRJ-I cell line. 5-HT itself stimulated HEK293 proliferation (25%) and synthesis of TGF1, CTGF and FGF2. PRX-08066 inhibition of KRJ-I function reversed these effects in the coculture system. CONCLUSIONS: Targeting the 5-HT2B receptor may be an effective antiproliferative and antifibrotic strategy for SI-NETs because it inhibits tumor microenvironment fibroblasts as well as NET cells. Fibrosis and proliferation appear to be biologically interfaced neuroendocrine neoplasia domains. Cancer 2010. © 2010 American Cancer Society.
• Serum sE-selectin levels and carcinoembryonic antigen mRNA-expressing cells in peripheral blood as prognostic factors in colorectal cancer patients
  Ferroni P Roselli M Spila A D'Alessandro R Portarena I Mariotti S Palmirotta R Buonomo O Petrella G Guadagni F - Cancer (Philad ) 116(12):2913-2921 (2010)
  BACKGROUND: This study analyzed the possible prognostic value of presurgical serum soluble (s)E-selectin levels and/or carcinoembryonic antigen (CEA) mRNA positivity in predicting the disease-free survival of colorectal cancer (CRC) patients. METHODS: CEA mRNA (obtained from blood-borne cells by reverse transcriptase-polymerase chain reaction [RT-PCR]), tumor necrosis factor- (TNF-), and sE-selectin levels were analyzed in blood samples obtained from 78 patients with primary (n = 62) or recurrent (n = 16) CRC, 40 patients with benign colorectal (CR) diseases, and 78 controls. RESULTS: CEA mRNA positivity by RT-PCR was significantly associated with advanced stage (P < .05). Median baseline sE-selectin levels were higher in patients with CRC (43 ng/mL) compared with controls (36 ng/mL) or patients with benign CR diseases (31 ng/mL, P < .001). These were significantly associated with CEA mRNA positivity by RT-PCR (P < .05). Multivariate analysis by forward stepping showed that elevated TNF- (P = .001) and CEA mRNA positivity by RT-PCR (P = .0001) were independent predictors of elevated baseline sE-selectin levels. Positive presurgical sE-selectin levels were associated with an increased recurrence rate compared with patients with low levels of this molecule (P < .001). Positivity for both CEA mRNA and sE-selectin had a negative prognostic impact, with a 5-year recurrence-free survival rate of 51% compared with 95% of patients with negative parameters (P < .05). CONCLUSIONS: Detection of presurgical serum sE-selectin levels and CEA mRNA-positive blood-borne cells in CRC patients might provide useful prognostic information in terms of recurrence-free survival, either alone or in combination, and may help in the choice of more aggressive treatment and/or more strict follow-up procedures in high-risk patients. Cancer 2010. © 2010 American Cancer Society.
• Association of local capacity for endoscopy with individual use of colorectal cancer screening and stage at diagnosis
  - Cancer (Philad ) 116(12):2922-2931 (2010)
  BACKGROUND: Limited capacity for endoscopy in areas in which African Americans and Hispanics live may be a reason for persistent disparities in colorectal cancer (CRC) screening and stage at diagnosis. METHODS: The authors linked data from the National Health Interview Survey on the use of CRC screening and data from Surveillance, Epidemiology, and End Results-Medicare on CRC stage with measures of county capacity for colonoscopy and sigmoidoscopy (endoscopy) derived from Medicare claims. RESULTS: Hispanics lived in counties with less capacity for endoscopy than African Americans or whites (for National Health Interview Survey, an average of 1224, 1569, and 1628 procedures per 100,000 individuals aged 50 years, respectively). Individual use of CRC screening increased modestly as county capacity increased. For example, as the number of endoscopies per 100,000 residents increased by 750, the odds of being screened increased by 4%. Disparities in screening were mitigated or diminished by adjustment for area endoscopy capacity, racial/ethnic composition, and socioeconomic status. Similarly, among individuals with CRC, those who lived in counties with less endoscopy capacity were marginally less likely to be diagnosed at an early stage. Adjustment for area characteristics diminished disparities in stage for Hispanics compared with whites but not African Americans. CONCLUSIONS: Increasing the use of CRC screening may require interventions to improve capacity for endoscopy in some areas. The characteristics of the area where an individual resides may in part mediate disparities in CRC screening use for both African Americans and Hispanics, and disparities in cancer stage for Hispanics. Cancer 2010. © 2010 American Cancer Society.
• Adjuvant therapy and survival after resection of pancreatic adenocarcinoma : A population-based analysis
  Mayo SC Austin DF Sheppard BC Mori M Shipley DK Billingsley KG - Cancer (Philad ) 116(12):2932-2940 (2010)
  BACKGROUND: The use of adjuvant chemoradiation for pancreatic adenocarcinoma (PAC) is accepted in North America, but there is a paucity of data to support this practice. The relation between adjuvant therapy and survival was assessed in a population-based cohort of patients with PAC. METHODS: A review was conducted of all cases of resected PAC from 1996 to 2003 using data from the state cancer registry augmented with data from primary medical record review. Use of adjuvant therapy was ascertained from registry data. Survival was assessed using the Kaplan-Meier method, and a Cox proportional hazards model was developed for multivariate analysis. RESULTS: A total of 298 patients from 27 hospitals met criteria for inclusion. There were 228 patients (76.5%) who were resected with curative intent, with a median overall survival of 12 months. The 6-month, 1-year, and 5-year survival rates were 80.2%, 58.4%, and 6.7%, respectively. Of the 228 patients resected, 122 (53.5%) received adjuvant treatment and had a median survival of 13.0 months versus 11.0 months for those with no adjuvant treatment (P = .16). After adjustment for surrogates of performance status, significant predictors of overall survival included no weight loss, T1/T2 pathologic stage, a microscopically complete resection (R0), and receipt of adjuvant therapy. CONCLUSIONS: An R0 resection and adjuvant therapy were found to be independently associated with an increase in overall survival in patients with resected PAC. These data underscore the importance of adjuvant therapy in resected PAC and the need for ongoing clinical trials to refine the efficacy and timing of adjuvant therapy in this disease. Cancer 2010. © 2010 American Cancer Society.
• Cost-effectiveness of treatment and endoscopic surveillance of precancerous lesions to prevent gastric cancer
  - Cancer (Philad ) 116(12):2941-2953 (2010)
  BACKGROUND: Although surveillance for Barrett esophagus and other gastrointestinal precancerous conditions is recommended, no analogous guidelines exist for gastric lesions. The objective of this study was to estimate the clinical benefits and cost-effectiveness of treatment and endoscopic surveillance to prevent gastric cancer. METHODS: The authors developed a state-transition decision model for a cohort of US men with a recent incidental diagnosis of gastric precancerous lesions (dysplasia, intestinal metaplasia, or atrophy). Strategies included 1) no surveillance or treatment and 2) referral for surveillance and treatment, and varied by surveillance frequency (none, every 10 years, every 5 years, or every year) and treatment modality for dysplastic and cancerous lesions (surgery or endoscopic mucosal resection [EMR]). The term post-treatment surveillance was restricted to surveillance of individuals after treatment. Data were based on published literature and databases. Outcomes included lifetime gastric cancer risk, quality-adjusted life expectancy, lifetime costs, and incremental cost-effectiveness ratios. RESULTS: For a cohort of men with dysplasia aged 50 years, the lifetime gastric cancer risk was 5.9%. EMR with annual surveillance reduced the lifetime cancer risk by 90% and cost $39,800 per quality-adjusted life year (QALY). Addition of post-treatment surveillance every 10 years provided little incremental benefit (5%) but cost >$1 million per QALY. Results were most sensitive to surgical risks and the proportion of lesions completely removed with EMR. For intestinal metaplasia, surveillance every 10 years reduced lifetime cancer risk by 61% and cost $544,500 per QALY. CONCLUSIONS: EMR with surveillance every 1 to 5 years for gastric dysplasia was promising for secondary cancer prevention and had a cost-effectiveness ratio that would be considered attractive in the United States. Endoscopic surveillance of less advanced lesions did not appear to be cost-effective, except possibly for immigrants from high-risk countries. Cancer 2010. © 2010 American Cancer Society.
• High-risk patients with hematuria are not evaluated according to guideline recommendations
  - Cancer (Philad ) 116(12):2954-2959 (2010)
  BACKGROUND: To determine whether high-risk patients with hematuria receive evaluation according to guideline recommendations. METHODS: We recently performed a screening study for bladder cancer using a urine-based tumor marker in 1502 subjects at high risk based on aged 50 years, 10-year smoking history, and/or a 15-year or more environmental exposure. We evaluated use of urinalysis (UA) within 3 years preceding the screening study. Chart review was performed to determine if this subset with microhematuria received any additional evaluation. RESULTS: Of 1502 study participants, routine urinalysis was performed in 73.2% and 164 (14.9%) subjects had documented hematuria (>3 red blood cells / high-power field) before inclusion. Of these, 42.1% had no further evaluation. Additional testing included repeat urinalysis (36%), urine culture (15.2%), cytology (10.4%), imaging (22.6% overall: 15.9% computed tomography, 4.3% intravenous pyelography; 2.4% magnetic resonance imaging), and cystoscopy (12.8%). Three subjects with microscopic hematuria (2%) were subsequently found to have bladder cancer during the screening study but were not referred for evaluation based on their hematuria. The source of hematuria was unknown in 65%, infection in 22%, benign prostatic enlargement in 10%, and renal stone disease in 4%, but these results are based on incomplete evaluation since only 12.8% underwent cystoscopy. CONCLUSIONS: Subjects at high risk for bladder cancer based on 10 years of smoking or environmental exposure with microscopic hematuria are rarely evaluated thoroughly and only 12.8% were referred for urologic evaluation. Further studies are needed to evaluate both the utilization and effectiveness of guidelines for hematuria. Cancer 2010. © 2010 American Cancer Society.
• Extensive inguinal lymphadenectomy improves overall 5-year survival in penile cancer patients : Results from the Surveillance, Epidemiology, and End Results program
  - Cancer (Philad ) 116(12):2960-2966 (2010)
  BACKGROUND: European Urological Association guidelines recommend potentially curative inguinal lymphadenectomy for certain cases of penile cancer such as grade 3 and pT2-4 lesions, among others. Anecdotally, the authors have noticed that few patients undergo inguinal lymphadenectomy. Therefore, they assessed the frequency of inguinal lymphadenectomy and the impact of dissection extent on survival using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The authors queried 17 SEER registries from 1988 through 2005 for grade 3 and pT2-4 penile cancer patients without distant metastases. Univariate and multivariate analyses examined predictors of inguinal lymphadenectomy. Kaplan-Meier and Cox regression analyses assessed overall 5-year survival across patient- and disease-related characteristics for patients receiving inguinal lymphadenectomy involving <8 or 8 lymph nodes, the latter a surrogate for extent of dissection based on other malignancies. RESULTS: Of 593 patients enrolled, only 26.5% received inguinal lymphadenectomy. In addition to grade 3 (P = .031) and pT2-4 disease (P = .004), age <65 years (P < .001) and marital status (P = .002) were significantly associated with receiving lymph node dissection. Increased overall 5-year survival (hazard ratio, 0.54; 95% confidence interval, 0.36-0.79) was observed in patients of all ages who received lymphadenectomy involving 8 lymph nodes. CONCLUSIONS: A significant number of penile cancer patients at risk for metastases have not received potentially curative inguinal lymphadenectomy. Patients receiving inguinal lymphadenectomy involving 8 lymph nodes experienced improved overall 5-year survival. Guidelines should not only be given more emphasis, but possibly be updated to reflect the benefit of extensive lymph node dissection in high-risk penile cancer patients. Cancer 2010. © 2010 American Cancer Society.
• Chronic kidney disease after nephroureterectomy for upper tract urothelial carcinoma and implications for the administration of perioperative chemotherapy
  - Cancer (Philad ) 116(12):2967-2973 (2010)
  BACKGROUND: The prevalence of chronic kidney disease (CKD) in patients with upper tract urothelial carcinoma (UTUC) is poorly defined, both before and after nephrouretectomy. Although multimodal treatment paradigms for UTUC are under-developed, this has important implications on patients' ability to receive cisplatin-based combination chemotherapy (CBCC). METHODS: Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula in 336 patients with UTUC, who were treated at the Cleveland Clinic by nephroureterectomy since 1992. An eGFR cutoff of 60 mL/min/1.73 m2 was used to determine the presence of CKD and eligibility for CBCC. RESULTS: Median age was 72 years and median preoperative eGFR was 59 mL/min/1.73m2. Before nephroureterectomy, only 48% of patients were eligible to receive CBCC and this decreased to 22% postoperatively (P < .001). In the 144 patients with pT2-pT4 and/or pN1-pN3 disease who are suitable to receive CBCC, these proportions were 40% and 24%, respectively (P = .009). Although 50 patients overall received some form of perioperative chemotherapy, only 3 and 11 patients received neoadjuvant and adjuvant CBCC, respectively. CONCLUSIONS: CKD is prevalent in the UTUC population and a minority of patients has an optimal eGFR to receive neoadjuvant CBCC. Nephrouretectomy may eliminate CBCC as a therapeutic option in 49% of high-risk patients if it is deferred to the adjuvant setting. Multimodal treatment strategies for UTUC should focus on neoadjuvant chemotherapy, as few patients are eligible for adjuvant CBCC because of the substantial decline in eGFR caused by nephroureterectomy. Cancer 2010. © 2010 American Cancer Society.
• Genetic alterations in the RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways in the follicular variant of papillary thyroid carcinoma
  - Cancer (Philad ) 116(12):2974-2983 (2010)
  BACKGROUND: The follicular variant of papillary thyroid carcinoma (FVPTC) is the second most common histotype among papillary thyroid cancers (PTCs). Although the prognosis of FVPTC is similar to the conventional phenotype, differential diagnostic difficulties may not be uncommon with other follicular thyroid neoplasms, and little is known about their genetic alterations. Defining these alterations may lead to the identification of diagnostic and biologic markers. METHODS: In this study, the authors evaluated genetic alterations and downstream-activated signals of the Ras/Raf-mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene (Akt) (PI3K/Akt) signaling pathways in 30 FVPTC tissue specimens. Tumors and matched normal thyroid samples were tested for RAS, for the v-raf murine sarcoma viral oncogene (BRAF) substitution of valine (V) for glutamate (E) at codon 600 (the V600E mutation), for phosphatase and tensin homolog (PTEN), for catalytic PI3k p110 subunit alpha (PIK3CA), for AKT, and for the presence of rearranged during transfection (ret) proto-oncogene/PTC (RET-PTC) and paired box-8 (PAX8)/peroxisome proliferator-activated receptor (PPAR) fusion protein (PAX8-PPAR) rearrangements by direct sequencing and reverse transcriptase-polymerases chain reaction analyses, respectively. Western blot analysis was used to assess the effects of these gene abnormalities on the activation of ! the 2 pathways. RESULTS: Genetic alterations were identified in 70% of FVPTCs. Activation of the MAPK and PI3K pathways was observed in 74% and 22% of tumors, respectively. The alterations that were identified in the genes of the 2 pathways were mutually exclusive. Chromosomal RET-PTC and PAX8-PPAR rearrangements were observed in 20% and 17% of tumors, respectively. It was noteworthy that some FVPTCs with RET-PTC had the coactivation of both pathways. CONCLUSIONS: RET-PTC and PAX8-PPAR rearrangements and mutations of the neuroblastoma RAS viral oncogene homolog N-RAS at codon 61 were the most common genetic alterations in FVPTCs. Activation of the MAPK pathway was a frequent event in FVPTCs, and the PI3K signaling pathway could be coactivated in RET-PTC tumors. These findings may have important therapeutic implication in patients with FVPTC. Cancer 2010. © 2010 American Cancer Society.
• A single nucleotide polymorphism in the alcohol dehydrogenase 7 gene (alanine to glycine substitution at amino acid 92) is associated with the risk of squamous cell carcinoma of the head and neck
  Wei S Liu Z Zhao H Niu J Wang LE El-Naggar AK Sturgis EM Wei Q - Cancer (Philad ) 116(12):2984-2992 (2010)
  BACKGROUND: The authors conducted a hospital-based study of 1110 patients with squamous cell carcinoma of the head and neck (SCCHN) and a control group of 1129 patients to replicate the associations reported by a recent, large European study between 2 potentially functional single nucleotide polymorphisms (SNPs) of the alcohol dehydrogenase (ADH) genes, a substitution in ADH1B at amino acid 48 from arginine to histidine (R48H) (reference SNP number [rs]1229984; guanine to adenine [GA]) and a substitution in ADH7 at amino acid 92 from alanine to glycine (A92G) (rs1573496; cytosine to guanine [CG]), and the risk of squamous cell carcinoma of the head and neck (SCCHN). METHODS: Multivariate logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). False-positive report probabilities (FPRPs) also were calculated for significant findings. RESULTS: The ADH7 A92G GG and combined CG + GG genotypes were associated with a decreased risk of SCCHN (GG: adjusted OR, 0.32; 95% CI, 0.13-0.82; CG + GG: adjusted OR, 0.74; 95% CI, 0.59-0.94; FPRP, .098) compared with the CC genotype. This association was also evident in subgroups of older patients (aged >57 years), men, former smokers, patients with oral cancer, and patients with N) lymph node status (P < .05 for all); however, such associations were not observed for the ADH1B R48H SNP. CONCLUSIONS: The current results support the ADH7 A92G SNP as a marker for the risk of SCCHN in non-Hispanic white populations. Cancer 2010. © 2010 American Cancer Society.
• Smoking, alcohol use, obesity, and overall survival from non-Hodgkin lymphoma : A population-based study
  - Cancer (Philad ) 116(12):2993-3000 (2010)
  BACKGROUND: Smoking, alcohol use, and obesity appear to increase the risk of developing non-Hodgkin lymphoma (NHL), but to the authors' knowledge, few studies to date have assessed their impact on NHL prognosis. METHODS: The association between prediagnosis cigarette smoking, alcohol use, and body mass index (BMI) and overall survival was evaluated in 1286 patients enrolled through population-based registries in the United States from 1998 through 2000. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox regression, adjusting for clinical and demographic factors. RESULTS: Through 2007, 442 patients had died (34%), and the median follow-up for surviving patients was 7.7 years. Compared with never smokers, former (HR, 1.59; 95% CI, 1.12-2.26) and current (HR, 1.50; 95% CI, 0.97-2.29) smokers had poorer survival, and poorer survival was found to be positively associated with smoking duration, number of cigarettes smoked per day, pack-years of smoking, and shorter time since quitting (all P <0.01). Alcohol use was associated with poorer survival (P = 0.03); compared with nonusers. Those drinking >43.1 g/week (median intake among drinkers) had poorer survival (HR, 1.55; 95% CI, 1.06-2.27), whereas those drinkers consuming less than this amount demonstrated no survival disadvantage (HR, 1.13; 95% CI, 0.75-1.71). Greater BMI was associated with poorer survival (P = 0.046), but the survival disadvantage was only noted among obese individuals (HR, 1.32 for BMI 30 vs BMI 20-24.9; 95% CI, 1.02-1.70). These results held for lymphoma-specific survival and! were broadly similar for diffuse large B-cell lymphoma and follicular lymphoma. CONCLUSIONS: NHL patients who smoked, consumed alcohol, or were obese before diagnosis were found to have a poorer overall and lymphoma-specific survival. Cancer 2010. © 2010 American Cancer Society.
• Gemtuzumab ozogamicin as first-line treatment in patients aged 70 years or older with acute myeloid leukemia
  - Cancer (Philad ) 116(12):3001-3005 (2010)
  BACKGROUND: Elderly patients with acute myeloid leukemia (AML) are generally unable to withstand the rigors of intensive induction chemotherapy and its attendant complications. Gemtuzumab ozogamicin (GO) is an immunoconjugate that had demonstrated activity in recurrent AML. METHODS: The objective of the current study was to determine the prognostic factors for achievement of complete remission (CR) in newly diagnosed elderly AML patients treated with GO as initial induction therapy. A retrospective study was performed of efficacy and toxicity associated with GO therapy, and factors potentially predictive of response were assessed in 49 previously untreated AML patients. RESULTS: CR was achieved in 14% of all treated patients. Among the patients with an intermediate-risk karyotype, the CR rate was 30%, compared with none with an unfavorable karyotype. The median duration of overall survival was 3.7 months (95% confidence interval [95% CI], 1.4-6.9 months), and the median recurrence-free survival in patients who achieved CR was 11.8 months (95% CI, 5.0-ind months). CONCLUSIONS: These data suggest that GO should be considered as a first-line treatment option in older patients with AML with intermediate-risk cytogenetics who cannot tolerate high-dose induction chemotherapy. Cancer 2010. © 2010 American Cancer Society.
• Selecting an optimal staging system for hepatocellular carcinoma : Comparison of 5 currently used prognostic models
  - Cancer (Philad ) 116(12):3006-3014 (2010)
  BACKGROUND: Selecting an appropriate staging system is crucial to predict the outcome of patients with hepatocellular carcinoma (HCC). The optimal prognostic model for HCC is under intense debate. This study investigated the prognostic ability of the 5 currently used staging systems, Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Japan Integrated Scoring (JIS) system, tumor-node-metastasis (TNM), and Tokyo score, for HCC. METHODS: Between 2002 and 2008, 1713 prospectively enrolled HCC patients were compared for their long-term survival by using the Akaike information criterion (AIC) according to the staging or scoring methods of these 5 models. RESULTS: The mean and median follow-up duration was 18 and 14 months, respectively. Among all patients, the CLIP staging system had the lowest AIC value in comparison with other systems in the Cox proportional hazards model, followed by the Tokyo score, JIS score, BCLC staging system, and TNM staging system. Patients undergoing curative treatment had a significantly better survival in comparison with patients undergoing noncurative treatment (P < .001). When the predictive accuracy of the staging systems was analyzed according to treatment strategy, the CLIP staging system had the lowest AIC value and remained the best prognostic model in patients undergoing curative (801 patients) and noncurative (912 patients) treatment. CONCLUSIONS: The CLIP staging system is the best long-term prognostic model for HCC in a cohort of patient with early to advanced stage of HCC. Its predictive accuracy is independent of the treatment strategy. Selecting an optimal staging system is helpful in improving the design of future clinical trials. Cancer 2010. © 2010 American Cancer Society.
• Distinctive expression of the polycomb group proteins Bmi1 polycomb ring finger oncogene and enhancer of zeste homolog 2 in nonsmall cell lung cancers and their clinical and clinicopathologic significance
  - Cancer (Philad ) 116(12):3015-3024 (2010)
  BACKGROUND: The polycomb group genes Bmi1 polycomb ring finger oncogene (Bmi1) and enhancer of zeste homolog 2 (EZH2) function as transcriptional repressors involved in gene silencing and in the malignant transformation and biologic aggressiveness of several human carcinomas. In the current study, the authors evaluated Bmi1 and EZH2 protein expression in specimens of human nonsmall cell lung cancer (NSCLC). METHODS: The authors conducted an immunohistochemical assessment of 157 surgically resected NSCLCs to evaluate the correlation between Bmi1 and EZH2 expression and various features, including clinical, clinicopathologic, and biologic characteristics. RESULTS: Normal bronchial epithelia revealed abundant expression of Bmi1 and sporadic expression of EZH2. Patients who had high EZH2 expression in tumor cells had a poorer prognosis than patients who had low EZH2 expression in tumor cells all pathologic stages of NSCLC (P = .001) and in pathologic stage I NSCLC (P = .006). Multivariate analysis revealed that high EZH2 expression was a independent, unfavorable prognostic factor in patients with pathologic stage I disease (P = .048). High EZH2 expression was correlated significantly with nonadenocarcinoma histology (P = .001), moderate and poor differentiation (P = .001), advanced pathologic tumor classification (P = .02), and high Ki-67 and cyclin E labeling indices (P < .001). Bmi1 expression, in contrast, was not a significant prognostic factor and was not correlated with any clinicopathologic factors other than early pathologic tumor classification. CONCLUSIONS: Bmi1 and EZH2 had characteristic and distinctive expression in NSCLCs. High EZH2 expression was correlated with tumor aggressiveness and may provide a novel prognostic marker for NSCLCs. Cancer 2010. © 2010 American Cancer Society.
• Comparison of gefitinib versus erlotinib in patients with nonsmall cell lung cancer who failed previous chemotherapy
  - Cancer (Philad ) 116(12):3025-3033 (2010)
  BACKGROUND: Gefitinib and erlotinib are commonly used for salvage therapy in patients with nonsmall cell lung cancer (NSCLC) who have progressed on prior therapies. Although both agents have similar structure and have demonstrated efficacy in NSCLC, gefitinib and erlotinib have not been directly compared in terms of efficacy and other clinical outcomes in patients with NSCLC who have failed prior chemotherapy. This prompted us to analyze the clinical outcomes between gefitinib-treated and erlotinib-treated patients with metastatic or recurrent NSCLC. METHODS: A total of 467 patients with metastatic or recurrent NSCLC who had progressed on prior therapies and received gefitinib or erlotinib therapy between January 2006 and December 2008 were retrospectively reviewed. By using a matched-pair case-control study design, 171 pairs of gefitinib-treated and erlotinib-treated patients were matched according to sex, Eastern Cooperative Oncology Group (ECOG) performance status, histologic type, and smoking history. RESULTS: The median age of all patients was 58 years (range, 20-85 years), and the median ECOG performance status was 1 (range, 0-3). Of 342 patients, 294 (86%) received an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor as second-line or third-line therapy, whereas the remaining 14% had received >2 prior chemotherapy regimens before starting EGFR TK inhibitor therapy. The confirmed overall response rate was 35.1%, and the disease control rate was 64%. With 13.2 months of follow-up, the median overall survival (OS) for the total 342 patients was 12.4 months (95% confidence interval [95% CI], 10.66-14.14 months), and the median progression-free survival (PFS) was 3.2 months (95% CI, 2.65-3.75 months). The overall response rates and disease control rates in the gefitinib-treated and erlotinib-treated groups were 38% versus 32.2% (P = .273) and 63.2% versus 64.9%, respectively (P = .677). There was no statistically significant difference noted with regard to OS (m! edian, 12.6 vs 12.1 months; P = 0.99) and PFS (median, 4.6 vs 2.7 months; P = .06) between the gefitinib-treated and erlotinib-treated groups. CONCLUSIONS: This retrospective analysis shows that gefitinib and erlotinib appear to have similar antitumor activity in terms of response rate and OS in pretreated patients with metastatic or recurrent NSCLC. Further prospective studies are warranted to elucidate any potential differences in toxicity and in dose intensity between gefitinib- and erlotinib-treated patients. Cancer 2010. © 2010 American Cancer Society.
• Physical performance limitations among adult survivors of childhood brain tumors
  - Cancer (Philad ) 116(12):3034-3044 (2010)
  BACKGROUND: Young adult survivors of childhood brain tumors (BTs) may have late effects that compromise physical performance and everyday task participation. The objective of this study was to evaluate muscle strength, fitness, physical performance, and task participation among adult survivors of childhood BTs. METHODS: In-home evaluations and interviews were conducted for 156 participants (54% men). Results on measures of muscle strength, fitness, physical performance, and participation were compared between BT survivors and members of a population-based comparison group by using chi-square statistics and 2-sample t tests. Associations between late effects and physical performance and between physical performance and participation were evaluated in regression models. RESULTS: The median age of BT survivors was 22 years (range, 18-58 years) at the time of the current evaluation, and they had survived for a median of 14.7 years (range, 6.5-45.9 years) postdiagnosis. Survivors had lower estimates of grip strength (women, 24.7 ± 9.2 kg vs 31.5 ± 5.8 kg; men, 39.0 ± 12.2 kg vs 53.0 ± 10.1 kg), knee extension strength (women, 246.6 ± 95.5 Newtons [N] vs 331.5 ± 5.8 N; men, 304.7 ± 116.4 N vs 466.6 ± 92.1 N), and peak oxygen uptake (women, 25.1 ± 8.8 mL/kg per minute vs 31.3 ± 5.1 mL/kg per minute; men, 24.6 ± 9.5 mL/kg per minute vs 33.2 ± 3.4 mL/kg per minute) than members of the population-based comparison group. Physical performance was lower among survivors and was associated with not living independently (odds ratio [OR], 5.0; 95% confidence interval [CI], 2.0-12.2) and not attending college (OR, 2.3; 95% CI 1.2-4.4). CONCLUSIONS: Muscle strength and fitness values among BT survivors were similar to those among individuals aged 60 years and were associated with physical performance limitations. Physical performance limitations were associated with poor outcomes in home and school environments. The current data indicated an opportunity for interventions targeted at improving long-term physical function in this survivor population. Cancer 2010. © 2010 American Cancer Society.
• Childhood cancer in relation to parental race and ethnicity : A 5-state pooled analysis
  - Cancer (Philad ) 116(12):3045-3053 (2010)
  BACKGROUND: Children of different racial/ethnic backgrounds have varying risks of cancer. However, to the authors' knowledge, few studies to date have examined cancer occurrence in children of mixed ancestry. METHODS: This population-based case-control study examined cancer among children aged <15 years using linked cancer and birth registry data from 5 US states from 1978 through 2004. Data were available for 13,249 cancer cases and 36,996 controls selected from birth records. Parental race/ethnicity was determined from birth records. Logistic regression analysis was used to examine the association of cancer with different racial/ethnic groups. RESULTS: Compared with whites, blacks had a 28% decreased risk of cancer (odds ratio [OR], 0.72; 95% confidence interval [95% CI], 0.65-0.80), whereas both Asians and Hispanics had an approximate 15% decrease. Children of mixed white/black ancestry also were found to be at decreased risk (OR, 0.71; 95% CI, 0.56-0.90), but estimates for mixed white/Asian and white/Hispanic children did not differ from those of whites. Compared with whites: 1) black and mixed white/black children had decreased ORs for acute lymphoblastic leukemia (OR, 0.39 [95% CI, 0.31-0.49] and OR, 0.58 [95% CI, 0.37-0.91], respectively); 2) Asian and mixed white/Asian children had decreased ORs for brain tumors (OR, 0.51 [95% CI, 0.39-0.68] and OR, 0.79 [95% CI, 0.54-1.16], respectively); and 3) Hispanic and mixed white/Hispanic children had decreased ORs for neuroblastoma (OR, 0.51 [95% CI, 0.42-0.61] and OR, 0.67 [95% CI, 0.50-0.90], respectively). CONCLUSIONS: Children of mixed ancestry tend to have disease risks that are more similar to those of racial/ethnic minority children than the white majority group. This tendency may help formulate etiologic studies designed to study possible genetic and environmental differences more directly. Cancer 2010. © 2010 American Cancer Society.
• Differential impact of high-dose cyclophosphamide, topotecan, and vincristine in clinical subsets of patients with chemoresistant neuroblastoma
  - Cancer (Philad ) 116(12):3054-3060 (2010)
  BACKGROUND: In what to the authors' knowledge is the first such study for a pediatric cancer, a large database was retrospectively analyzed to assess statistically the likelihood of response to a given salvage therapy in different clinical subsets of patients. METHODS: Treatment was comprised of high-dose cyclophosphamide (at a dose of 140 mg/kg), topotecan (at a dose of 8 mg/m2), and vincristine (at a dose of 0.067 mg/kg or 2 mg/m2, whichever was lower; maximum dose, 2 mg) (HD-CTV). The Fisher exact test was used for comparisons of response rates among standard subsets of patients (n = 126) with refractory or recurrent neuroblastoma (NB). RESULTS: Among children, major (ie, complete/partial) responses occurred in 11 of 58 (19%) with primary refractory NB, 4 of 14 (29%) with secondary refractory NB, 13 of 25 (52%) with a new (first) disease recurrence, and none of 13 patients with progressive disease (PD) while receiving therapy. Other children had mixed responses (MRs); when combining major responses and MRs, anti-NB activity was noted in 26 of 58 (45%) children with primary refractory NB, 10 of 14 (71%) children with secondary refractory NB, 20 of 25 (80%) children with a new (first) disease recurrence, and 1 of 13 (8%) children with PD while receiving therapy. The response rate was significantly different across the 4 groups of children for both major responses (P = .003) and combined responses (P = .001). All 10 adolescents/adults treated for primary refractory NB had no response, which was a significantly inferior result compared with the response rate of 45% noted in children with primary refractory NB (P = .008). CONCLUSIONS: Response to HD-CTV as salvage therapy is significantly less likely in adolescents/adults and in children with NB that is persistent or progressing on treatment rather than newly recurrent off treatment. These findings are broadly applicable and should be considered when designing, and interpreting the results of, phase 2 studies. Cancer 2010. © 2010 American Cancer Society.
• Characteristics of patients who refuse do-not-resuscitate orders upon admission to an acute palliative care unit in a comprehensive cancer center
  - Cancer (Philad ) 116(12):3061-3070 (2010)
  BACKGROUND: Refusal of appropriately indicated do-not-resuscitate (DNR) orders may cause harm and distress for patients, families, and the medical team. We conducted a retrospective study to determine the frequency and predictors of refusals of DNR in advanced cancer patients admitted to an acute palliative care unit. METHODS: A total of 2538 consecutive admissions were reviewed. Demographic and clinical characteristics from 200 consecutive patients with DNR orders and 100 consecutive patients who refused DNR were collected, and differences between the groups were determined by multivariate regression and recursive partitioning analysis. RESULTS: Of 2538 admissions, 2530 (99%) were appropriate for DNR discussion. Of the 2530 admissions, 2374 were unique patients, and 100 (4%) of 2374 refused DNR. Refusers had median (interquartile range, IQR) pain of 7 (4-9) versus 5 (3-8, P = .0005), nausea of 2 (0-7) versus 1 (0-4, P = .05), and dyspnea of 1 (0-5) versus 4 (0-7, P = .002) as compared with DNR nonrefusers, respectively. Patients with hematological malignancies and advance directives had a lower DNR refusal risk (odds ratio [OR], 0.38; P = .02, and OR, 0.36; P < .0001, respectively). Multivariate regression analysis revealed that patients with moderate-severe pain (OR, 3.19; P = .002) and with no advance directives (OR, 2.94; P .001) had higher DNR refusal risk. There were more inpatient deaths among DNR nonrefusers (87 of 200 vs 1 of 100, P < .0001). Median (IQR) time from discharge to death was 18 (8-35) days for those with DNR orders and 85 (25-206) days for DNR refusers (P .0001). CONCLUSIONS: DNR refusal in patients admitted to the acute palliative care unit is low, more frequent in patients with more pain and nausea and no advance directives, and associated with longer survival. This study demonstrates possible predictors of complicated DNR discussions. Cancer 2010. © 2010 American Cancer Society.
• The role of postoperative radiotherapy for the treatment of gangliogliomas
  - Cancer (Philad ) 116(12):3071 (2010)
  
• Reply to the Role of postoperative radiotherapy for the treatment of gangliogliomas
  - Cancer (Philad ) 116(12):3071-3072 (2010)
  
• Comparison of hospitalization risk and associated costs among patients receiving sargramostim, filgrastim, and pegfilgrastim for chemotherapy-induced neutropenia
  - Cancer (Philad ) 116(12):3073 (2010)
  
• Reply to Comparison of hospitalization risk and associated costs among patients receiving sargramostim, filgrastim, and pegfilgrastim for chemotherapy-induced neutropenia
  Heaney ML Toy EL Vekeman F - Cancer (Philad ) 116(12):3073-3074 (2010)