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- Cancer 116(9):2065-2066 (2010)
- Jury still out on cell phone - Cancer connection
- Cancer 116(9):2067 (2010)
- Intra-arterial chemotherapy for head and neck cancer : Is There a Verdict?
Robbins KT Howell SB Williams JS - Cancer 116(9):2068-2070 (2010)
Although it would appear that there is no difference in outcomes for intra-arterial (IA) versus intravenous cisplatin chemoradiotherapy, one must consider the technique by which the tumors were infused. The authors used the less effective method of bilateral infusion in 58% of patients compared to <5% by us. This large difference could have affected the outcome thus leaving the value of IA cisplatin infusion in question. - A new era in anticancer peptide vaccines
Perez SA von Hofe E Kallinteris NL Gritzapis AD Peoples GE Papamichail M Baxevanis CN - Cancer 116(9):2071-2080 (2010)
The use of synthetic peptides as vaccines aimed at the induction of therapeutic CD8-positive T-cell responses against tumor cells initially experienced great enthusiasm, mostly because of advances in vaccine technology, including design, synthesis, and delivery. However, despite impressive results in animal models, the application of such vaccines in humans has met with only limited success. The therapeutic activity of vaccine-stimulated, tumor-specific, CD8-positive T cells can be hampered through the physical burden of the tumor, tolerance mechanisms, and local factors within the tumor microenvironment. Recently, accumulating evidence has suggested that combining a peptide-based therapeutic vaccination with conventional chemotherapy can uncover the full potential of the antitumor immune response, increasing the success of immunotherapy. In addition, therapeutic vaccination in the preventive setting has been extremely effective in eliciting antitumor responses in prec! linical tumor models and has demonstrated good promise clinically in patients with minimal residual disease. The rationale behind preventive vaccination is that patients with minimal tumor burden still have a fully competent immune system capable of developing robust antitumor responses. Finally, therapeutic CD8-positive T-cell peptide vaccines have been improved by coimmunization with T-helper epitopes expressed on long peptides. Cancer 2010. © 2010 American Cancer Society. - Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high-risk, premenopausal breast cancer
Ejlertsen B Mouridsen HT Jensen MB Andersen J Andersson M Kamby C Knoop AS for the Danish Breast Cancer Cooperative Group - Cancer 116(9):2081-2089 (2010)
BACKGROUND: The Danish Breast Cancer Cooperative Group (DBCG) 77B trial examined the relative efficacy of levamisole, single-agent oral cyclophosphamide, and the classic combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) against no adjuvant systemic therapy in high-risk breast cancer patients. The authors report the results from that trial after a potential follow-up of 25 years. METHODS: Between 1977 and 1983, 1146 premenopausal patients who had tumors >5 cm or positive axillary lymph nodes were assigned randomly to 1 of 4 options: no systemic therapy, levamisole 5 mg weekly for 48 weeks (the levamisole arm), oral cyclophosphamide 130 mg/m2 on Days 1 through 14 every 4 weeks for 12 cycles (the C arm), or oral cyclophosphamide 80 mg/m2 on Days 1 through 14 plus methotrexate 30 mg/m2 and fluorouracil 500 mg/m2 intravenously on Days 1 and 8 every 4 weeks for 12 cycles (the CMF arm). RESULTS: The 10-year invasive disease-free survival (IDFS) rate was 38.6% in the control arm compared with 55.5% in the C arm, 48.8% in the CMF arm, and 35.2% in the levamisole arm. Compared with the control arm, the hazard ratio for an IDFS event was 0.62 in the C arm (P = .001) and 0.70 in the CMF arm (P = .01). The hazard ratio for death was 0.70 in both the C arm (P = .02) and the CMF arm (P = .02) at 10 years, and the overall survival (OS) benefit was maintained during 25 years of follow-up. No significant differences were observed in IDFS or OS between the C arm and the CMF arm or between the levamisole arm and the control arm. CONCLUSIONS: Compared with controls, both cyclophosphamide and CMF significantly improved disease-free survival and OS, and the benefits persisted for at least 25 years in premenopausal patients who had high-risk breast cancer. Cancer 2010. © 2010 American Cancer Society. - American Society of Clinical Oncology-recommended surveillance and physician specialty among long-term breast cancer survivors
Hollowell K Olmsted CL Richardson AS Pittman HK Bellin L Tafra L Verbanac KM - Cancer 116(9):2090-2098 (2010)
BACKGROUND: It is unclear whether it is appropriate to transfer the follow-up care of breast cancer (BrCa) survivors from cancer specialists to primary care physicians (PCPs). This contemporary study compared physician specialty and documented the long-term surveillance of survivors who underwent surgery at an American academic center. METHODS: Women in this institutional review board-approved study underwent breast surgery between 1996 and 2006. Data were collected for 270 patients with stage I to III BrCa (mean follow-up, 6 years). Charts were reviewed based on American Society of Clinical Oncology (ASCO) guidelines for recommended surveillance frequency and care. RESULTS: The majority of patients (90%; n = 242) were followed by specialists with 10% (n = 28) followed by PCPs. Patients with advanced disease and a greater risk of disease recurrence more often received specialist care. Patients followed by specialists were more often seen at ASCO-recommended intervals (eg, 89% vs 69% of patients followed by a PCP at follow-up Year 6; P < .01); however, many patients were followed inconsistently. Breast disease was often not the focus of PCP visits or mentioned in clinic notes (18% patients). Women seen by specialists were more likely to have documented clinical examinations of the breast (93% vs 44% at Year 6), axilla (94% vs 52%), or annual mammograms (74% vs 48%; P = .001-.02). CONCLUSIONS: Consistent compliance with surveillance guidelines and chart documentation needs improvement among all providers; however, specialists more consistently met ASCO guidelines. If transfer of care to a PCP occurs, it should be formalized and include follow-up recommendations and defined physician responsibilities. Providers and patients should be educated regarding surveillance care and current guidelines incorporated into standard clinical practice. Cancer 2010. © 2010 American Cancer Society. - Changes in markers of ovarian reserve and endocrine function in young women with breast cancer undergoing adjuvant chemotherapy
Yu Md B Douglas N Ferin MJ Nakhuda GS Crew K Lobo RA Hershman DL - Cancer 116(9):2099-2105 (2010)
BACKGROUND: Premenopausal women undergoing chemotherapy are at risk for amenorrhea and impaired fertility. The objective of the current study was to assess levels of mullerian inhibitory substance (MIS), estradiol (E2), follicle-stimulating hormone (FSH), and menstrual status, in women undergoing chemotherapy. METHODS: A nested prospective cohort study was conducted in women aged <40 years with breast cancer (BC) who were undergoing adjuvant chemotherapy (n = 26). Serum MIS, FSH, and E2 were measured before chemotherapy (baseline) and at Weeks 6, 12, 36, and 52. Controls were 134 age-matched women with known fertility. Hormone levels were compared between the cases and controls at baseline. Differences between amenorrhea and age subgroups were tested using the nonparametric Wilcoxon 2-sample test using a 2-sided of 0.05. RESULTS: Subjects with BC and age-matched controls had similar baseline MIS levels (median, 0.94 ng/mL vs 0.86 ng/mL;, P > .05). Serum MIS decreased significantly at 6 weeks and remained suppressed for 52 weeks. E2 levels decreased, and FSH levels increased during chemotherapy; however, at 52 weeks, the levels returned to baseline. At 52 weeks, only 1 patient had MIS above the lower normal range, 15 had return of menstrual function, 11 had premenopausal levels of FSH, and 13 had follicular phase levels of E2. In women aged <35 years, 25% remained amenorrheic, whereas in women aged >35 years, 50% were amenorrheic. Amenorrheic and menstruating women were found to have similar MIS values at baseline and follow-up. CONCLUSIONS: In young women with BC, chemotherapy decreases MIS rapidly and dramatically. Rapid reductions in MIS do not appear to be predictive of subsequent menstrual function. Ovarian reserve and endocrine function may be affected differently by chemotherapy. Cancer 2010. © 2010 American Cancer Society. - Radiofrequency ablation as an adjunct to systemic chemotherapy for colorectal pulmonary metastases
Chua TC Thornbury K Saxena A Liauw W Glenn D Zhao J Morris DL - Cancer 116(9):2106-2114 (2010)
BACKGROUND: Radiofrequency ablation (RFA) is an alternative to local treatment for pulmonary metastases in patients who are nonsurgical candidates. Based on previously documented efficacy of this treatment, the authors retrospectively studied the prognostic factors for long-term survival. METHODS: One hundred patients with unresectable colorectal pulmonary metastases underwent percutaneous RFA. Clinical and treatment variables were collected and evaluated using univariate and multivariate analyses with overall survival as the primary endpoint. RESULTS: At a median follow-up period of 23 (range, 1 to 96) months from the time of RFA treatment, 49 patients have died. The median overall survival after RFA treatment was 36 months and 5-year overall survival rates of 30%. Univariate analyses demonstrated that histopathological grade (p < .001), time to RFA treatment (p = .017), response to treatment (p < .001), repeat RFA treatments (p = .001), presence of extrapulmonary metastases (p < .001), presence of mediastinal lymphadenopathy (p = .007), and adjunct systemic chemotherapy (p < .001) were associated with overall survival. Multivariate analyses demonstrated that response to RFA treatment (p < .001), repeat RFA treatment (p = .002), presence of extrapulmonary metastases (p = .008), and use of adjunct systemic chemotherapy (p = .05) were independent predictors for survival. CONCLUSIONS: Radiofrequency ablation for colorectal pulmonary metastases represents a step forward towards a nonsurgical option of combining systemic and local treatment for metastatic disease and is a safe treatment with a low risk profile. Cancer 2010. © 2010 American Cancer Society. - Cumulative evaluation of a quantitative immunochemical fecal occult blood test to determine its optimal clinical use
Rozen P Comaneshter D Levi Z Hazazi R Vilkin A Maoz E Birkenfeld S Niv Y - Cancer 116(9):2115-2125 (2010)
BACKGROUND: Quantified, human hemoglobin (Hb)-specific, immunochemical fecal occult blood test (IFOBT) measurements are now used for colorectal cancer (CRC) screening. The objective was to evaluate sensitivity and specificity for CRC and advanced adenomatous polyps (APs) by the fecal Hb threshold used to determine a positive test and the number of IFOBTs prepared per test, so as to determine the least number of colonoscopies required to detect a neoplasm. METHODS: Cumulative data were analyzed from a prospective cross-sectional double-blind study of 1682 consecutive, ambulatory, nonbleeding colonoscopy patients who volunteered for IFOBTs, most of above average risk, from 3 ambulatory-endoscopy centers. Fecal Hb was measured in 3 samples and analyzed by an automated instrument, and the highest result 50 ng Hb/mL of buffer was related to findings. RESULTS: Colonoscopy identified CRC in 20 patients and advanced APs in 129. Sensitivity for either was best when any of 3 tests had 50 ng Hb/mL of buffer; sensitivity was 61.1% (95% confidence interval [CI], 53.2-68.9), and specificity was 87.8% (95% CI, 86.2-89.4). Positive tests identified 100% of CRCs and 55% of advanced APs every 3.1 colonoscopies. Sensitivity of a single test at the commonly used 100-ng Hb/mL threshold was lower at 31.5% (95% CI, 24.1-39.0) (P<.001), but specificity was higher at 96.4% (95% CI, 95.5-97.3) (P<.001). Positive tests identified 65% of CRCs and 26.4% of advanced APs every 2.2 colonoscopies. CONCLUSIONS: The fecal Hb cutoff chosen by the screener and the number of samples collected per patient determine sensitivity and specificity for CRC/advanced AP; these factors determine the number of colonoscopies needed for positive tests and neoplasia yield. This information provides guidelines for IFOBT screening. Limitations are 1-time screening and most examinees not being at average risk for CRC. Cancer 2010. © 2010 American Cancer Society. - Quality of end-of-life care in low-income, uninsured men dying of prostate cancer
Bergman J Chi AC Litwin MS - Cancer 116(9):2126-2131 (2010)
BACKGROUND: The quality of end-of-life care was assessed in disadvantaged men prospectively enrolled in a public assistance program. That end-of-life care would be aggressive, moreso than recommended by quality-of-care guidelines, was hypothesized. METHODS: Included in the study were all 60 low-income, uninsured men in a state-funded public assistance program who had died since its inception in 2001. To measure quality of end-of-life care, information was collected regarding timing of the institution of new chemotherapeutic regimens, time from administration of last chemotherapy dose to death, the number of inpatient admissions and intensive care unit stays made in the 3 months preceding death, and the number of emergency room visits made in the 12 months before dying. Also noted were hospice use and the timing of hospice referrals. RESULTS: Eighteen men (30%) enrolled in hospice before death and the average hospice stay lasted 45 days (standard deviation, 32; range, 2-143 days; median, 41 days). Two patients (11%) were enrolled for fewer than 7 days, and none were enrolled for more than 180 days. The average time from administration of the last dose of chemotherapy to death was 104 days. Chemotherapy was never initiated within 3 months of death, and in only 2 instances (6%) was the final chemotherapeutic regimen administered within 2 weeks of dying. Use of hospital resources (emergency room visits, inpatient admissions, and intensive care unit stays) was uniformly low (mean, 1.0 ± 1.0, 0.65 ± 0.82, and 0.03 ± 0.18, respectively). CONCLUSIONS: End-of-life care in disadvantaged men dying of prostate cancer, who enroll in a comprehensive statewide assistance program, is high-quality. Cancer 2010. © 2010 American Cancer Society. - Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (Calcitriol) in combination with dexamethasone for castration-resistant prostate cancer
Chadha MK Tian L Mashtare T Payne V Silliman C Levine E Wong M Johnson C Trump DL - Cancer 116(9):2132-2139 (2010)
BACKGROUND: Preclinical data indicate that there is substantial antitumor activity and synergy between calcitriol and dexamethasone. On the basis of these data, the authors conducted a phase 2 trial of intravenous (iv) calcitriol at a dose of 74 g weekly (based on a recent phase 1 trial) and dexamethasone in patients with castration-resistant prostate cancer (CRPC). METHODS: A 2-stage Kepner-Chang design was used. Oral dexamethasone at a dose of 4 mg was given weekly on Days 1 and 2, and iv calcitriol (74 g over 1 hour) was administered weekly on Day 2 from 4 to 8 hours after the dexamethasone dose in patients with CRPC. Laboratory data were monitored weekly, and renal sonograms, computed tomography scans, and bone scans were obtained every 3 months. Disease response was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) and standard criteria for prostate-specific antigen (PSA) response. The calcitriol dose was delineated by from the authors' recent phase 1 trial. RESULTS: Of 18 evaluable patients, 15 patients were Caucasian (83%). No patients had a complete or partial response by either RECIST or PSA response criteria. Fourteen patients had progressive disease, 2 patients refused to continue treatment (after 64 days and 266 days), and 2 patients remain on the trial (for 306 days and 412 days).The median time to disease progression was 106 days (95% confidence interval, 80-182 days). Fourteen episodes of grade 3 or 4 toxicity were noted in 7 patients (hyperglycemia, hypocalemia, chest pain, dyspnea, hypercalcemia, hypophosphatemia, cardiac arrhythmia, and pain). Only 1 episode of grade 3/ 4 toxicity was related definitely to calcitriol (hypercalcemia). No treatment-related deaths were noted. CONCLUSIONS: High-dose, iv calcitriol at a dose of 74 g weekly in combination with dexamethasone was well tolerated but failed to produce a clinical or PSA response in men with CRPC. Cancer 2010. © 2010 American Cancer Society. - Increased risk of high-grade prostate cancer among infertile men
Walsh TJ Schembri M Turek PJ Chan JM Carroll PR Smith JF Eisenberg ML Van Den Eeden SK Croughan MS - Cancer 116(9):2140-2147 (2010)
BACKGROUND: It has been reported that fatherhood status may be a risk factor for prostate cancer. In the current study, the authors examined the subsequent occurrence of prostate cancer in a cohort of men evaluated for infertility to determine whether male infertility is a risk factor for prostate cancer. METHODS: A total of 22,562 men who were evaluated for infertility from 1967 to 1998 were indentified from 15 California infertility centers and linked to the California Cancer Registry. The incidence of prostate cancer was compared with the incidence in an age-matched and geography-matched sample of men from the general population. The risk of prostate cancer in men with and those without male factor infertility was modeled using a Cox proportional hazards regression model. RESULTS: A total of 168 cases of prostate cancer that developed after infertility were identified. Men evaluated for infertility but not necessarily with male factors were not found to have an increased risk of cancer compared with the general population (standardized incidence ratio [SIR], 0.9; 95% confidence interval [95% CI], 0.8-1.1). This risk was found to be highest for men with male factor infertility who developed high-grade prostate cancer (SIR, 2.0; 95% CI, 1.2-3.0). On multivariate analyses, men with male factor infertility were found to be 2.6 times more likely to be diagnosed with high-grade prostate cancer (hazard ratio, 2.6; 95% CI, 1.4-4.8). CONCLUSIONS: Men with male factor infertility were found to have an increased risk of subsequently developing high-grade prostate cancer. Male infertility may be an early and identifiable risk factor for the development of clinically significant prostate cancer. Cancer 2010. © 2010 American Cancer Society. - hsa-miR-210 is a marker of tumor hypoxia and a prognostic factor in head and neck cancer
Gee HE Camps C Buffa FM Patiar S Winter SC Betts G Homer J Corbridge R Cox G West CM Ragoussis J Harris AL - Cancer 116(9):2148-2158 (2010)
BACKGROUND: Hypoxia is an important mechanism of treatment resistance in head and neck squamous cell carcinoma (HNSCC). MicroRNAs are short noncoding RNAs that regulate multiple mRNAs and are frequently dysregulated in cancer. The authors have investigated the role of 3 microRNAs, including the hypoxia-induced hsa-miR-210, as potential markers of hypoxia or prognosis. METHODS: Three hypoxia-related microRNAs, hsa-miR-210, hsa-miR-21, and hsa-miR-10b, were measured in 46 samples from patients with HNSCC. Expression levels were correlated with clinicopathological variables and other markers of hypoxia: a published 99-gene hypoxia metagene, individual hypoxia-related genes such as TWIST1, and immunohistochemical expression of hypoxia-inducible factor 1 and its target gene carbonic anhydrase 9. We then performed survival analyses to investigate the prognostic significance of these microRNAs. RESULTS: Only the level of hsa-miR-210 was significantly correlated with other markers of hypoxia, including the 99-gene hypoxia metagene (rho = 0.67, P < .001). We found no association between hsa-miR-210, hsa-miR-21, or hsa-miR-10b and clinicopathological variables such as tumor size, differentiation, and stage. However, high levels of hsa-miR-210 were associated with locoregional disease recurrence (P = .001) and short overall survival (P = .008). hsa-miR-21 and hsa-miR-10b had no prognostic significance. CONCLUSIONS: Expression of hsa-miR-210 in head and neck cancer correlates with other approaches for assessing hypoxia and is associated with prognosis. This warrants further study as a classification marker of patients for therapies involving modulation of hypoxia. Cancer 2010. © 2010 American Cancer Society. - Intra-arterial versus intravenous chemoradiation for advanced head and neck cancer: Results of a randomized phase 3 trial
Rasch CR Hauptmann M Schornagel J Wijers O Buter J Gregor T Wiggenraad R Paul de Boer J Ackerstaff AH Kroger R Hoebers FJ Balm AJ - Cancer 116(9):2159-2165 (2010)
BACKGROUND: Chemoradiation is the preferred treatment for advanced stage IV head and neck cancer. Higher doses of chemotherapy yielded promising results in vitro and vivo, confirmed by intra-arterial (IA) cisplatin-based chemoradiation in phase 2 studies. METHODS: Two hundred and thirty-nine patients with (functionally) unresectable head and neck cancer were included, from 2000 to 2004, in a multicenter, randomized phase 3 trial, comparing IA and intravenous chemoradiation. Intravenous chemoradiation comprised 3×100 mg/m2 cisplatin infusion on Days 1, 22, 43 combined with 70 Gy in 35 daily fractions. The IA chemoradiation treatment arm comprised 4x150 mg/m2 cisplatin administered in the tumor-feeding artery on Days 1, 8, 15, 22, immediately followed by systemic rescue with sodium thiosulfate with the same radiotherapeutic regimen. RESULTS: Two patients were excluded from analysis because of nontreatment-related death immediately after randomization (n = 1) and esophageal carcinoma (n = 1). The median follow-up was 33 months 1-104 months. Ninety percent of the patients required tube feeding during treatment. Renal toxicity >grade 2 was 9% in the intravenous compared with 1% in the IA treatment arm (P .0001). There was no difference in locoregional control, disease-free survival (DFS) or overall survival (OS), between the treatment arms. At 3 years, local control, locoregional control, DFS, and OS was .76, .63, .44, .51 in the IA versus .70, .65, .47, .47 in the intravenous treatment arm, respectively. CONCLUSIONS: Cisplatin-based IA chemoradiation was not superior to intravenous chemoradiation for advanced stage IV head and neck cancer regarding locoregional control and survival. Cancer 2010. © 2010 American Cancer Society. - Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience
Singhi AD Westra WH - Cancer 116(9):2166-2173 (2010)
BACKGROUND: Human papillomavirus (HPV) is a causative agent in a subset of head and neck squamous cell carcinomas (HNSCCs). These HPV-related cancers have a clinicopathologic profile that diverges from HPV-negative HNSCCs. Accordingly, HPV testing may soon become integrated into standard pathologic assessment of HNSCCs. METHODS: Data were prospectively collected for all patients with head and neck carcinomas who had undergone HPV testing at the Johns Hopkins Hospital as part of clinical care during a 57-month period. HPV testing consisted of concurrent HPV16 in situ hybridization (ISH) and p16 immunohistochemistry (IHC). Wide spectrum HPV ISH was reserved for p16-positive cases that were HPV-16 negative. RESULTS: HPV analysis was performed on 256 head and neck carcinomas in an effort to predict clinical outcomes (56%), localize primary tumor origin (21%), establish tumor classification (9%), determine patient eligibility for vaccine trials (8%), or satisfy patient curiosity (5%). A total of 182 (71%) tumors were HPV positive. HPV positivity correlated with oropharyngeal site (82% vs 9%) and male sex (77% vs 48%). p16 positivity was present in all 176 HPV16-positive cases, and in 19 of 80 (24%) cases that were HPV-16 negative. In 6 (32%) discordant cases, p16 expression was because of the presence of another HPV type. CONCLUSIONS A feasible strategy that incorporates p16 IHC and HPV ISH is able to detect HPV in a high percentage of oropharyngeal carcinomas. HPV status is frequently requested by the oncologist to estimate clinical outcome, and used by pathologists to establish tumor classification and determine site of tumor origin. Cancer 2010. © 2010 American Cancer Society. - Cause of death in patients with lower-risk myelodysplastic syndrome
Dayyani F Conley AP Strom SS Stevenson W Cortes JE Borthakur G Faderl S O'Brien S Pierce S Kantarjian H Garcia-Manero G - Cancer 116(9):2174-2179 (2010)
BACKGROUND: The authors have recently shown that a majority of patients with myelodysplastic syndrome (MDS) classified by the International Prognostic Scoring System as lower risk die without transformation to acute myelogenous leukemia (AML). The cause of death (COD) of these patients is not well understood. Identifying the COD could help to guide early therapy decisions. METHODS: The authors retrospectively analyzed the COD in a cohort of 273 deceased patients with lower-risk MDS according to the International Prognostic Scoring System at presentation to The University of Texas M. D. Anderson Cancer Center from 1980 to 2004. MDS-related death was defined as infection, bleeding, transformation to AML, or disease progression. Remaining CODs were classified as non-MDS-related. RESULTS: Median age at presentation was 66 years (range, 19-88 years). Overall median survival was 59 weeks (range, 1-831 weeks). All French-American-British leukemia classification subgroups were represented. The percentage of International Prognostic Scoring System low and intermediate-1 groups were 21% and 79%, respectively. The most common cytogenetic abnormality (9%) was del(5q). Patients received supportive care only. The COD was identified as MDS-related in 230 of 273 (84%) patients. The most common disease-related CODs were infection (38%), transformation to AML (15%), and hemorrhage (13%). The most frequent non-disease-related COD was cardiovascular events (19 of 43 patients). CONCLUSIONS: The majority of patients with low- or intermediate-1 risk MDS will die because of causes related to their underlying disease. Although these results need to be validated in different populations, early therapeutic intervention could be considered in the management of these patients to improve survival. Cancer 2010. © 2010 American Cancer Society. - Pentostatin and rituximab therapy for previously untreated patients with B-cell chronic lymphocytic leukemia
Kay NE Wu W Kabat B Laplant B Lin TS Byrd JC Jelinek DF Grever MR Zent CS Call TG Shanafelt TD - Cancer 116(9):2180-2187 (2010)
BACKGROUND: The combination of pentostatin (P), cyclophosphamide (C), and rituximab (R) achieved an overall response (OR) rate >90%, with >40% complete responses (CRs) in patients with untreated chronic lymphocytic leukemia (CLL). METHODS: To evaluate whether the tolerability of this regimen could be enhanced without sacrificing efficacy, a phase 2 trial was conducted of P and R without C, using a higher P dose (4 mg/m2). Among the 33 patients enrolled, 82% were male, the median age was 65 years (9 patients were aged 70 years), and 64% were classified as having Rai stage III to IV disease. RESULTS: The OR rate was 76%, with 9 CRs (27%), 5 nodular partial responses, and 11 partial responses (PRs) reported. At the time of last follow-up, 29 of 33 patients were still alive at a median follow-up of 14 months (range, 1-34.8 months). Four (12%) patients experienced grade 3 or higher hematologic toxicity, and 5 (15%) experienced grade 3 or higher nonhematologic toxicity. Comparison of this trial with the previous PCR trial demonstrated that patients treated with PCR had a higher OR rate (91% vs 76%) and CR rate (41% vs 27%) compared with patients treated with PR. The median treatment-free survival for all accrued patients was notably longer in patients treated with PCR compared with PR (30 months vs 16 months). CONCLUSIONS: The findings of the current study suggest that increasing the dose of the purine nucleoside analogue does not eliminate the need for cyclophosphamide in chemoimmunotherapy for the treatment of CLL. Cancer 2010. © 2010 American Cancer Society. - Beta-2-microglobulin is an independent predictor of progression in asymptomatic multiple myeloma
Rossi D Fangazio M De Paoli L Puma A Riccomagno P Pinto V Zigrossi P Ramponi A Monga G Gaidano G - Cancer 116(9):2188-2200 (2010)
BACKGROUND: Although serum beta-2 microglobulin (B2M) represents a key variable for symptomatic multiple myeloma (MM) prognostication, its role in predicting the risk of progression of asymptomatic MM to symptomatic disease has not been explored. METHODS: This study was bases on a consecutive series of 148 patients with asymptomatic MM and explored the cumulative probability of progression to symptomatic MM as the primary endpoint. RESULTS: In univariate analysis, a serum B2M level >2.5 mg/L was associated with an increased probability of disease progression (5-year risk, 64.5%; P < .001) along with serum monoclonal component (sMC) (P < .001), urinary monoclonal component (uMC) (P < .001), and bone marrow plasma cells (BMPCs) (P < .001). In multivariate analysis, serum B2M was selected as an independent predictor of progression (hazard ratio, 3.30; P = .002). Serum B2M was combined with sMC, uMC, and BMPC to create a risk-stratification model based on 4 groups with different risk of progression: very low (5-year risk, 0%), low-intermediate (5-year risk, 19.6%), high-intermediate (5-year risk, 60.7%), and high (5-year risk, 80.7%). The model that included serum B2M along with sMC, uMC, and BMPC was able to predict disease progression better than the model that was based on sMC, uMC, and BMPC without serum B2M (C statistics, 0.760 vs 0.726). CONCLUSIONS: The current results indicated that 1) serum B2M is an independent predictor of asymptomatic MM progression, and 2) serum B2M adds prognostic information when combined with the most widely used prognosticators of asymptomatic MM progression. Cancer 2010. © 2010 American Cancer Society. - The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation
Zent CS Laplant BR Johnston PB Call TG Habermann TM Micallef IN Witzig TE - Cancer 116(9):2201-2207 (2010)
BACKGROUND: Patients with recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) often have chemotherapy-resistant disease, resulting in poor prognosis. The aim of this study was to learn if inhibition of the mammalian target of rapamycin (mTOR) would produce tumor responses. METHODS: This was a phase 2 study of oral single-agent everolimus (10 mg/day) for recurrent/refractory indolent lymphoid malignancies including CLL. RESULTS: Four of 22 patients with CLL (18%; 95% confidence interval, 5%-40%) achieved a partial remission to therapy. An unanticipated finding in this study was an increase in absolute lymphocyte count (ALC) associated with a decrease in lymphadenopathy in 8 (36%) patients. ALC increased a median of 4.8-fold (range, 1.9- to 25.1-fold), and the clinically measurable lymphadenopathy decreased a median of 75.5% (range, 38%-93%) compared with baseline measurements. CONCLUSIONS: Everolimus has modest antitumor activity against CLL and can mobilize malignant cells from nodal masses into the peripheral circulation in a subset of CLL patients. Because CLL cells in lymphatic tissue and bone marrow can be more resistant to therapy than circulating CLL cells, the ability of everolimus to mobilize CLL cells into the circulation could be used in combination therapeutic regimens. Cancer 2010. © 2010 American Cancer Society. - The cisplatin, epirubicin, 5-fluorouracil, gemcitabine (PEFG) regimen in advanced biliary tract adenocarcinoma
Cereda S Passoni P Reni M Viganò MG Aldrighetti L Nicoletti R Villa E - Cancer 116(9):2208-2214 (2010)
BACKGROUND: Biliary tract adenocarcinoma (BTA) is an uncommon tumor with a poor prognosis and no standard, systemic chemotherapy. The combined cisplatin, epirubicin, 5-fluorouracil, and gemcitabine (PEFG) regimen is an effective, upfront treatment for advanced pancreatic cancer. In this study, the authors assessed the activity and safety of this combination regimen in patients with advanced BTA. METHODS: PEFG (cisplatin 40 mg/m2 and epirubicin 40 mg/m2 on Day 1; gemcitabine 600 mg/m2 on Days 1 and 8; and 5-fluorouracil [FU] 200 mg/m2 daily as a continuous infusion) was administered to chemotherapy-naive patients who had a cytologic or histologic diagnosis of locally advanced or metastatic BTA, aged 75 years, and a performance status (PS) >60 either until they had evidence progressive disease or for a maximum of 6 months. Tumor size was assessed every 2 months during treatment. RESULTS: Between May 1999 and December 2005, 37 patients (62% metastatic) who had a median age of 62 years and a median PS of 90 received the PEFG regimen at the authors' institution. Primary tumor sites were the intrahepatic bile duct in 10 patients (27%), the extrahepatic bile duct in 8 patients (22%), the gallbladder in 12 patients (32%), and the ampulla of Vater in 7 patients (19%). A partial response was observed in 16 patients (43%), and stable disease was observed in 12 patients (32%). The median overall survival (OS) was 12.1 months, and the 1-year OS rate was 52%. The median progression-free survival (PFS) was 7.9 months, and the 6-month PFS rate was 67%. The main grade 3/4 toxicity was neutropenia in 18% of cycles followed by thrombocytopenia in 9% of cycles, nausea/vomiting in 5% of cycles, and febrile neutropenia, fatigue, anemia, and stomatitis in 2% of cycles. CONCLUSIONS: The current results demonstrated that PEFG was an active regimen with a manageable toxicity profile for patients with advanced BTA. Cancer 2010. © 2010 American Cancer Society. - Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center
Moreno MA Roberts DB Kupferman ME Demonte F El-Naggar AK Williams M Rosenthal DS Hanna EY - Cancer 116(9):2215-2223 (2010)
BACKGROUND: Sinonasal mucosal melanoma is a rare disease associated with a very poor prognosis. Because most of the series extend retrospectively several decades, we sought to determine prognostic factors and outcomes with recent treatment modalities. METHODS: A retrospective chart review of 58 patients treated for sinonasal melanoma at a tertiary cancer center between 1993 and 2004. The patients were retrospectively staged according to the sinonasal American Joint Committee on Cancer (AJCC) staging system. Demographic, clinical and pathological parameters were identified and correlated with outcomes. RESULTS: There were 35 males and 23 females with a median age of 63 years; 56 patients were treated surgically and 33 received radiation therapy. According to Ballantyne's clinical staging system, 88% of the patients presented with stage I (local) disease. Classification by the AJCC staging classified yielded 27% of the patients with T1, 33% with T2, 21% with T3, and 19% with T4. T-stage and the degree of tumor pigmentation were associated with a worse survival (P = .0096 and P = .018, respectively), while pseudopapillary architecture was associated with a higher locoregional failure (P = .0144). Postoperative radiation therapy improved locoregional control when a total dose greater than 54 Gy was used (P = .0215), but did not affect overall survival. CONCLUSIONS: Tumor stage according to sinonasal AJCC staging system is an effective outcome predictor and should be the staging system of choice. Postoperative radiation therapy improves locoregional control when a higher dose and standard fractionations are used. Histological features such as pigmentation and pseudopapillary architecture are associated with worse outcome. Cancer 2010. © 2010 American Cancer Society. - Intratumoral forkhead box P3-positive regulatory T cells predict poor survival in cyclooxygenase-2-positive uveal melanoma
Mougiakakos D Johansson CC Trocme E All-Ericsson C Economou MA Larsson O Seregard S Kiessling R - Cancer 116(9):2224-2233 (2010)
BACKGROUND: Forkhead box P3 (FOXP3)-positive regulatory T cells (Tregs) are key mediators of peripheral tolerance and suppress efficient antitumor responses. Prostaglandin E2 (PGE2) produced by inducible cyclooxygenase-2 (COX-2) can lead to Treg induction. COX-2 expression has been linked to tumorigenesis and growth in various malignancies. The objective of the current study was to investigate whether Tregs infiltrate uveal melanomas (UMs) and whether their prevalence is linked to COX-2 expression and the prediction of overall survival (OS). METHODS: One hundred patients who underwent enucleation after they were diagnosed with UM were included in the study. Immunohistochemical staining with monoclonal anti-FOXP3, anti-CD4, and anti-COX-2 antibodies was performed, and immunoreactivity was assessed. Correlations of COX-2 expression with the presence of Tregs, established clinicopathologic parameters, and OS were evaluated in univariate and multivariate analyses. RESULTS: High expression of COX-2 was predictive of shortened OS. FOXP3-positive Tregs were detectable in 24% of UMs and were restricted to malignant tissue. The extent of COX-2 expression was associated significantly with Treg prevalence (P = .004) and Treg intratumoral localization (P = .005). Intratumoral Tregs (but not the prevalence of Tregs) were independent marker for worse OS with a hazard ratio of 5.36 in patients with COX-2-positive tumors. CONCLUSIONS: The current results demonstrated that high COX-2 expression is associated with OS and Treg prevalence in UM. These findings are in line with the observations that COX-2/PGE2 induces Tregs and that Tregs may alter antitumor responses, resulting in a negative effect on the clinical disease course. Intratumoral Tregs are an independent prognostic marker for COX-2-positive UM, and these results put COX-2 inhibitors and Treg depletion into the spotlight of potential novel treatment modalities for patients with UM. Cancer 2010. © 2010 American Cancer Society. - Conditional survival estimates improve over time for patients with advanced melanoma : Results from a population-based analysis
Xing Y Chang GJ Hu CY Askew RL Ross MI Gershenwald JE Lee JE Mansfield PF Lucci A Cormier JN - Cancer 116(9):2234-2241 (2010)
BACKGROUND: Conditional survival (CS) has emerged as a clinically relevant measure of prognosis for cancer survivors. The objective of this analysis was to provide melanoma-specific CS estimates to help clinicians promote more informed patient decision making. METHODS: Patients with melanoma and at least 5 years of follow-up were identified from the Surveillance Epidemiology and End Results registry (1988-2000). By using the methods of Kaplan and Meier, stage-specific, 5-year CS estimates were independently calculated for survivors for each year after diagnosis. Stage-specific multivariate Cox regression models including baseline survivor functions were used to calculate adjusted melanoma-specific CS for different subgroups of patients further stratified by age, gender, race, marital status, anatomic tumor location, and tumor histology. RESULTS: Five-year CS estimates for patients with stage I disease remained constant at 97% annually, while for patients with stages II, III, and IV disease, 5-year CS estimates from time 0 (diagnosis) to 5 years improved from 72% to 86%, 51% to 87%, and 19% to 84%, respectively. Multivariate CS analysis revealed that differences in stages II through IV CS based on age, gender, and race decreased over time. CONCLUSIONS: Five-year melanoma-specific CS estimates improve dramatically over time for survivors with advanced stages of disease. These prognostic data are critical to patients for both treatment and nontreatment related life decisions. Cancer 2010. © 2010 American Cancer Society. - Glutathione S-transferase polymorphisms are associated with survival in anaplastic glioma patients
Kilburn L Okcu MF Wang T Cao Y Renfro-Spelman A Aldape KD Gilbert MR Bondy M - Cancer 116(9):2242-2249 (2010)
BACKGROUND: Glutathione S-transferases (GSTs) are polymorphic enzymes that are responsible for glutathione conjugation of alkylators and scavenging of free radicals created by radiation. GST polymorphisms may result in altered or absent enzyme activity and have been associated with survival in patients with cancer. The authors of this report hypothesized that patients with anaplastic glioma (AG) who have GST genotypes that encode for lower activity enzymes will have longer survival than similar patients who have higher activity genotypes. The current study was performed to investigate the role of GST enzyme polymorphisms in predicting the survival of patients with AG. METHODS: The medical records of 207 patients with AG from a single cancer center were reviewed retrospectively. Polymorphisms for the GST 1 (GSTM1), GST 1 (GSTT1), and GST 1 (GSTP1) enzymes were identified. Overall survival was compared using the Kaplan-Meier method and Cox proportional hazards analyses adjusting for age, sex, histology, and therapy. RESULTS: Among the patients with oligodendroglial tumors (n = 94), patients who had the GSTT1 null genotype had a 2.9 times increased risk of death (95% confidence interval [CI], 1.3-6.3) compared with patients who had the GSTT1 non-null genotype. Adjustment for 1p/19q status did not change the finding. In the patients who had anaplastic astrocytoma (n = 113), the patients with all GSTP1 genotypes except GSTP1 *B/*B had a 3.8 times increased risk of death (95% CI, 0.5-29.6) compared with patients who had the GSTP1 *B/*B genotype. CONCLUSIONS: In patients with anaplastic oligodendroglial tumors, the GSTT1 null genotype may be associated with poor survival, possibly because of modifications in therapy secondary to increased toxicity. This hypothesis is under investigation. In patients with anaplastic astrocytoma, the GSTP1 *B/*B genotype may confer a survival advantage. Cancer 2010. © 2010 American Cancer Society. - Radiosurgical decompression of metastatic epidural compression
Ryu S Rock J Jain R Lu M Anderson J Jin JY Rosenblum M Movsas B Kim JH - Cancer 116(9):2250-2257 (2010)
BACKGROUND: Surgical decompression of metastatic epidural compression (MEC) improved ambulatory function. Spine radiosurgery can accurately target the epidural tumor and deliver high radiation doses for tumor control. Therefore, a clinical trial was performed to quantitatively determine the degree of epidural decompression by radiosurgery of metastatic epidural compression. METHODS: Sixty-two patients with a total of 85 lesions of metastatic epidural compression were treated. Epidural compression was diagnosed by magnetic resonance imaging (MRI) scans. Main criteria of inclusion were neurological status with muscle power 4 of 5 or better. Radiosurgery was performed to the involved spine segment, including the epidural mass with median dose of 16 Gy (range 12-20 Gy) in a single session. All patients had prospective clinical follow-up, ranging from 1-48 months (median 11.5 months), and 36 patients had pretreatment and post-treatment imaging, ranging from 2-33 months (median 9.3 months). Primary endpoints were epidural tumor control and thecal sac decompression. RESULTS: The mean epidural tumor volume reduction was 65 ± 14% at 2 months after radiosurgery. The epidural tumor area at the level of the most severe spinal cord compression was 0.82 ± 0.08 cm2 before radiosurgery and 0.41 ± 0.06 cm2 after radiosurgery (P < .001). Thecal sac patency improved from 55 ± 4% to 76 ± 3% (P < .001). Overall, neurological function improved in 81%. CONCLUSIONS: This study demonstrated a radiosurgical decompression of epidural tumor. Although neurosurgical decompression and radiotherapy is the standard treatment in patients with good performance, radiosurgical decompression can be a viable noninvasive treatment option for malignant epidural compression. Cancer 2010. © 2010 American Cancer Society. - Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor)
de Camargo VP Keohan ML D'Adamo DR Antonescu CR Brennan MF Singer S Ahn LS Maki RG - Cancer 116(9):2258-2265 (2010)
BACKGROUND: In the current study, the authors examined the outcomes of patients with desmoid tumors who received systemic therapy at a single institution to provide a basis for the examination of newer agents. METHODS: Records of patients with desmoid tumors who were treated with chemotherapy at the study institution were reviewed. The activity of nonsteroidal anti-inflammatory drugs was not addressed. Patients without measurable disease and those receiving therapy could not be documented, and those receiving prophylactic therapy were excluded. RESULTS: A total of 68 patients received 157 lines of therapy. At the time of last follow-up, 9 patients had died, 7 of progressive disease. The cohort was 62% female, with a median age of 32.5 years. Approximately 32% of the patients had Gardner syndrome. The median follow-up was 63 months, and patients received a median of 2 lines of therapy. An intra-abdominal primary tumor location was the most common (44%). The greatest Response Evaluation Criteria in Solid Tumors (RECIST) response rate was observed with anthracyclines and hormonal therapy and the lowest response was noted with single-agent dacarbazine/temozolomide or tyrosine kinase inhibitors, principally imatinib. On multivariate analysis, macroscopic nodular morphology and the presence of Gardner syndrome were the only tumor factors found to be associated with a greater time to disease progression. CONCLUSIONS: Compared with other agents, antiestrogens and anthracycline-containing regimens appear to be associated with a higher radiological response rate against desmoid tumors. Systemic therapy can be successful in patients with desmoid tumors, and is a viable option in lieu of morbid or disabling surgery. Cancer 2010. © 2010 American Cancer Society. - Grading of nonrhabdomyosarcoma soft tissue sarcoma in children and adolescents : A comparison of parameters used for the Fédération Nationale des Centers de Lutte Contre le Cancer and Pediatric Oncology Group Systems
Khoury JD Coffin CM Spunt SL Anderson JR Meyer WH Parham DM - Cancer 116(9):2266-2274 (2010)
BACKGROUND: Two systems for grading soft tissue sarcoma are widely used currently: the National Cancer Institute (NCI) and the Fédération Nationale des Centers de Lutte Contre le Cancer (FNCLCC) systems. Both were developed using cohorts of predominantly adult patients. The Pediatric Oncology Group (POG) system, based on the NCI system, was adapted for grading pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). The applicability and prognostic utility of the FNCLCC system in pediatric NRSTS has not been assessed or compared with the POG system. METHODS: Tumors from 130 patients with malignant NRSTS enrolled on 3 completed multi-institutional clinical trials were assessed. Of 130 tumors, 102 (78%) were localized and 28 (22%) metastatic. Of the localized tumors, 55 of 102 (54%) were >5 cm. The estimated 5-year event-free survival (EFS) for the entire group was 47%. RESULTS: As expected, stage and tumor sizes were predictive of EFS (P < .001). Both systems were predictive of 5-year EFS (POG, P = .0095 and FNCLCC, P = .0075). Patients whose tumors received discrepant grades (POG-G3 vs FNCLCC-G2/G1) (n = 44) had an intermediate outcome between those with concordant (G3 [n = 44] or G1/G2 [n = 42]) grades on both systems (P = .0018). By multivariate analysis, the mitotic index was predictive of EFS, using a cutoff of 10 mitotic figures per 10 high-power fields (P < .001). CONCLUSIONS: In conclusion, both FNCLCC and POG systems provide an adequate prognostic measure of outcome for pediatric NRSTS; albeit, a sizeable subset of cases with apparently intermediate prognosis was graded differently by the 2 systems. The mitotic index appears to be a key parameter in grading pediatric NRSTS. Cancer 2010. © 2010 American Cancer Society. - Predictors of weight loss during radiotherapy in patients with stage I or II head and neck cancer
Nourissat A Bairati I Samson E Fortin A Gélinas M Nabid A Brochet F Têtu B Meyer F - Cancer 116(9):2275-2283 (2010)
BACKGROUND: The purpose of the study was to identify predictors of weight loss during radiotherapy (RT) in patients with stage I or II head and neck (HN) cancer. METHODS: This study was conducted as part of a phase 3 chemoprevention trial. A total of 540 patients were randomized. The patients were weighed before and after RT. Their baseline characteristics, including lifestyle habits, diet, and quality of life, were assessed as potential predictors. Predictors were identified using multiple linear regressions. The reliability of the model was assessed by bootstrap resampling. A receiver operating characteristics curve was generated to estimate the model's accuracy in predicting critical weight loss (5%). RESULTS: The mean weight loss was 2.2 kg (standard deviation, 3.4). Five factors were associated with a greater weight loss: all HN cancer sites other than the glottic larynx (P<.001), higher pre-RT body weight (P<.001), stage II disease (P = .002), dysphagia and/or odynophagia before RT (P = .001), and a lower Karnofsky performance score (P = .028). There was no association with pre-RT lifestyle habits, diet, or quality of life. The bootstrapping method confirmed the reliability of this predictive model. The area under the curve was 71.3% (95% confidence interval, 65.8-76.9), which represents an acceptable ability of the model to predict critical weight loss. CONCLUSIONS: These results could be useful to clinicians for screening patients with early stage HN cancer treated by RT who require special nutritional attention. Cancer 2010. © 2010 American Cancer Society. - Multiple endocrine syndrome type 2B in early childhood : Long-term benefit of prophylactic thyroidectomy
Waguespack SG Rich TA - Cancer 116(9):2284 (2010)
- Retraction: Tumor Necrosis Factor Enhances SN38-Mediated Apoptosis in Mesothelioma Cells: The Role of Nuclear Factor-B Pathway Activation. Patrizia Russo, Alessia Catassi, Davide Malacarne, Stefano Margaritora, Alfredo Cesario, Luigi Festi, Antonino Mulé, Luigi Ferri, Pierluigi Granone. Cancer. 2005;103: 1503-1518.
- Cancer 116(9):2285 (2010)
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