| Targeting the urokinase plasminogen activator receptor with a monoclonal antibody impairs the growth of human colorectal cancer in the liver
May 29, 2009 at 12:33 pm
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| | Urokinase plasminogen activator receptor (uPAR) expression has been shown to correlate with poor prognosis in colorectal cancer (CRC). The authors hypothesized that targeting uPAR, a receptor involved in cell proliferation, migration, invasion, adhesion, and angiogenesis, would impair the growth of CRC in the liver, the most common site of metastasis.Human CRC cell lines were examined for uPAR expression by Western blot analysis. The in vitro effects of the uPAR monoclonal antibody (MoAb) (ATN-658) were tested in proliferation and migration assays. For in vivo studies, human HCT116 CRC cells were injected directly into the livers of mice in 2 separate studies, the first to determine the effect of therapy with ATN-658 on small-volume disease (therapy begun on Day 4), and a second study to determine the effect of therapy on established disease (therapy begun on Day 12). Mice were randomized to receive either nonspecific immunoglobulin G MoAb (control) or ATN-658, and were sacrificed 1 month after tumor implantation.uPAR was expressed by all CRC cell lines studied. In vitro, ATN-658 had minimal effect on CRC proliferation in monolayers, but significantly decreased CRC cell migration. In vivo, ATN-658 lead to significant reductions in tumor growth versus control when initiated either 4 or 12 days after tumor implantation (-65% vs control [P [le] .05] and -85% vs control [P [le] .05]). ATN-658 significantly inhibited in vivo tumor cell proliferation in both studies.uPAR MoAb therapy impaired CRC tumor growth in the liver in both small-volume and large-volume disease models. Cancer 2009. © 2009 American Cancer Society. |
| Promoter methylation of glutathione S-transferase [pi]1 and multidrug resistance gene 1 in bronchioloalveolar carcinoma and its correlation with DNA methyltransferase 1 expression
May 29, 2009 at 12:33 pm
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| | The presence of glutathione S-transferase (GST) [pi]1 (GSTP1) or multidrug resistance gene 1 (MDR1) promoter methylation in lung cancer was studied for the first time to the authors' knowledge; and, to date, the clinical significance of methylation is not clear. The objective of the current study was to determine the promoter methylation status of GSTP1 and MDR1, which encode GST-[pi] and P-glycoprotein (Pgp), respectively, in patients with bronchioloalveolar carcinoma (BAC) and to investigate whether methyltransferase 1 (DNMT1)-mediated GSTP1 or MDR1 methylation are responsible for disease progression and prognosis in patients with BAC.Protein expression levels of DNTM1, GST-[pi], and Pgp were determined by immunohistochemistry in samples from 36 patients with BAC. Promoter methylation status of the GSTP1 and MDR1 genes was determined by using methylation-specific polymerase chain reaction analysis.The results demonstrated a significant correlation between the methylation of the GSTP1 or MDR1 promoters and negative expression of their respective proteins in BAC (P < .05). A significant correlation also was demonstrated between GSTP1 methylation and recurrence-free and overall survival of patients with BAC. DNMT1 protein expression levels were correlated with GSTP1 promoter methylation and patient prognosis (P < .05). However, no correlation was observed between DNMT1 expression and MDR1 methylation.GSTP1 promoter methylation mediated by DNMT1 may promote BAC progression and could serve as a poor prognostic indicator for patients with this disease. DNMT1 protein expression also may be considered as a prognostic indicator. Methylation of the MDR1 promoter may be mediated through pathways other than DNMT1 in BAC and does not appear to be associated with disease progression or patient prognosis. Cancer 2009. © 2009 American Cancer Society. |
| Associations of physician supplies with breast cancer stage at diagnosis and survival in Ontario, 1988 to 2006
May 29, 2009 at 12:33 pm
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| | The authors examined whether the supply of primary care physicians had protective effects on breast cancer stage and survival in Ontario and whether supply losses during the 1990s were associated with diminished protection.Random samples of the Ontario Cancer Registry, respectively, provided 879 women and 951 women who were diagnosed with breast cancer between 1988 and 1990 (followed until 1996) and 1998 and 2000 (followed until 2006), respectively. Active physician supply data (1991 and 2001) joined to each woman's census division of residence was taken from the Scott's Medical Database.Protective thresholds were observed among the earlier cohort for supplies of general practitioners (7 per 10,000 population) and supplies of obstetricians/gynecologists (6 per 100,000 population) at or above which women with breast cancer were significantly more likely to have been diagnosed with localized disease and to have survived for [ge]5 years. These protective effects seemed generally attenuated among the more recent cohort. The risk of living in primary care physician-undersupplied areas increased significantly between 1991 and 2001 (10%-30%), and such physician supply losses were associated with reduced cancer care protection, including less prevalent early diagnoses (odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.00-2.58) and lower 5-year survival rates (OR, 1.62; 95% CI, 1.03-2.55).Primary care physician supplies appeared to matter very much in the effective provision of cancer care in Canada. Community healthcare service endowments that include adequate physician supplies may be particularly critical to the performance of a healthcare system such as that in Canada, which provides universal accessibility to medically necessary care. Cancer 2009. © 2009 American Cancer Society. |
| The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer
May 29, 2009 at 12:33 pm
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| | Nonalcoholic steatohepatitis (NASH) is a form of liver damage that can progress to cirrhosis. NASH is associated with obesity and diabetes. The condition also may be associated with some medications, including tamoxifen. Early case reports and small series have documented NASH in patients who received tamoxifen.The records of patients registered in the St. Vincent Hospital Cancer Registry of Green Bay Wisconsin from January 1, 1992 to December 31, 2000 were reviewed.In total, 1105 patients with breast cancer were evaluated for NASH, and 24 cases of NASH were documented (2.2%). Seven patients had NASH before their diagnosis of breast cancer, and 17 patients developed NASH after their diagnosis of breast cancer. In multivariate analysis, the factors associated with NASH were tamoxifen use (odds ratio [OR], 8.2; 95% confidence interval [CI], 1.06-63.72), body mass index (BMI) (OR, 1.13; 95% CI, 1.06-1.20), and age (OR, 95% CI, 0.91-0.99). NASH improved after tamoxifen was stopped. After discontinuation of tamoxifen, transaminase levels returned to normal in 14 of 16 patients.NASH was present in 24 of 1105 patients with breast cancer (2.2%). Seven patients had NASH before they were diagnosed with breast cancer, and 17 patients developed NASH after their diagnosis. NASH was associated with the use of tamoxifen and improved when tamoxifen was stopped. Cancer 2009. © 2009 American Cancer Society. |
| Carboplatin-based primary chemotherapy for infants and young children with CNS tumors
May 29, 2009 at 12:32 pm
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| | A carboplatin-based chemotherapy regimen was used as primary postoperative therapy in infants with central nervous system (CNS) tumors to limit renal and ototoxicity and to target systemic exposure.Fifty-three patients aged <age 3 years with embryonal CNS tumor medulloblastoma (n = 20), ependymoma (EP, n = 21), choroid plexus carcinoma (CPCA, n = 5), and primitive embryonal neoplasms including atypical teratoid rhabdoid tumors (n = 7) were treated with cyclophosphamide, etoposide, and carboplatin. Radiation therapy was used only for residual disease at the end of chemotherapy or disease progression.The response rate after 2 cycles of chemotherapy was 34% (complete response, 13.8%; partial response, 20.7%). Myelosuppression was the dominant toxicity; 2 patients had toxic deaths related to thrombocytopenia with trauma. The 5-year overall survival (OS) was 49% ± 7%, and the progression-free survival (PFS) was 31% ± 7%, with a median follow-up of 11.4 years (range, 5.2-15.0 years). For medulloblastoma, the 5-year PFS was 26% ± 9%; for EP it was 33% ± 10%; for CPCA it was 80% ± 18%; and for primitive neuroectodermal and atypical teratoid rhabdoid tumors it was 0%. Localized EP patients with gross total resection who did not undergo radiotherapy had a 5-year PFS of 57% ± 17% and OS of 71% ± 16%. Two patients developed late second malignancies; 1 was associated with germline p53 mutation.The results confirm that carboplatin has similar activity to cisplatin in otherwise similar regimens. Five-year survival data are comparable to those reported in other recent studies, including high-dose chemotherapy studies. Of note is the marked activity in CPCA and gross totally resected EP. Cancer 2009. © 2009 American Cancer Society. |
| Medical interpreter knowledge of cancer and cancer clinical trials
May 29, 2009 at 12:32 pm
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| | Cancer patients with limited English proficiency may need specialized assistance to communicate with health professionals about cancer and clinical trials.Medical interpreters working in several Boston-area hospitals were invited to participate in training sessions about cancer and cancer clinical trials. We did a pre and post survey-based assessment of knowledge of basic concepts in cancer and clinical trials, and post assessment of satisfaction, among 97 interpreters in cancer training and education sessions and 79 participants in clinical trial training and education sessions.Participants had a range of prior experience with interpretation in the context of cancer and clinical trials. Training increased mean accuracy from 49% to 72% in knowledge items about cancer, and from 72% to 78% in knowledge about clinical trials. Interpreters reported several areas of concern with respect to standards of practice.Pretest surveys of medical interpreters revealed several areas of important knowledge gaps about cancer and clinical trials. Posttest assessment showed that training can be useful to improving short-term accuracy, but that more work is needed to develop curricula and testing measures to address these knowledge gaps. Cancer 2009. © 2009 American Cancer Society. |
| Measuring therapeutic alliance between oncologists and patients with advanced cancer
May 29, 2009 at 12:31 pm
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| | Patients consider their human connection with a physician an important aspect of end-of-life (EOL) care. In this study, the authors sought to develop and validate a measure of therapeutic alliance between patients with advanced cancer and their physicians and to evaluate the effects of therapeutic alliance on EOL experiences and care.The Human Connection (THC) scale was developed to measure the extent to which patients felt a sense of mutual understanding, caring, and trust with their physicians. The scale was administered to 217 patients with advanced cancer along with measures of attributes that have been related hypothetically to therapeutic alliance, including emotional acceptance of terminal illness. EOL outcomes in 90 patients who died during the study also were examined.The 16-item THC questionnaire was consistent internally (Cronbach [alpha] = .90) and valid based on its expected positive association with emotional acceptance of terminal illness (r = .31; P < .0001). THC scores were related inversely to symptom burden (r = -.19; P = .006), functional status (Karnofsky performance status; r = .22; P = .001), and mental illness (THC score: 50.69 for patients with any Diagnostic and Statistical Manual [DSM] diagnosis vs 55.22 for patients with no DSM diagnosis; P = .03). THC scores were not associated significantly with EOL discussions (P = .68). Among the patients who died, EOL intensive care unit (ICU) care was associated inversely with therapeutic alliance (THC score: 46.5 for patients who received ICU care vs 55.5 for patients without ICU care; P = .002), so that patients with higher THC scores were less likely to spend time in the ICU during the last week of life.The THC scale is a valid and reliable measure of therapeutic alliance between patients with advanced cancer and their physicians. In addition, there was no evidence to suggest that EOL discussions harm patients' therapeutic alliance. A strong therapeutic alliance was associated with emotional acceptance of a terminal illness and with decreased ICU care at the EOL among patients with advanced cancer. Cancer 2009. © 2009 American Cancer Society. |
| Does hormone treatment added to radiotherapy improve outcome in locally advanced prostate cancer?
May 29, 2009 at 12:31 pm
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| | To quantify the magnitude of benefit of the addition of hormone treatment (HT) to exclusive radiotherapy for locally advanced prostate cancer, a literature-based meta-analysis was conducted.Event-based relative risks (RR) with 95% confidence intervals (CIs) were derived through a random-effect model. Differences in primary (biochemical failure and clinical progression-free survival) and secondary outcomes (cancer-specific survival, overall survival [OS], recurrence patterns, and toxicity) were explored. Absolute differences and numbers of patients needed to treat (NNT) were calculated. A heterogeneity test, a metaregression analysis with clinical predictors of outcome, and a correlation analysis for surrogate endpoints were also performed.Seven trials (4387 patients) were gathered. Hormone suppression significantly decreased both biochemical failure (RR, 0.76; 95% CI, 0.70-0.82; P < .0001) and clinical progression-free survival (RR, 0.81; 95% CI 0.71-0.93; P = .002), with absolute differences of 10% and 7.7%, respectively, which translates into 10 and 13 NNT. cancer-specific survival (RR, 0.76; 95% CI, 0.69-0.83; P < .0001) and OS (RR, 0.86; 95% CI, 0.80-0.93; P < .0001) were also significantly improved by the addition of HT, without significant heterogeneity, with absolute differences of 5.5% and 4.9%, respectively, which translates into 18 and 20 NNT. Local and distant relapse were significantly decreased by HT, by 36% and 28%, respectively, and no significant differences in toxicity were found. Primary and secondary efficacy outcomes were significantly correlated.Hormone suppression plus radiotherapy significantly decreases recurrence and mortality of patients with localized prostate cancer, without affecting toxicity. Cancer 2009. © 2009 American Cancer Society. |
| Twenty years of controversy surrounding combined androgen blockade for advanced prostate cancer
May 29, 2009 at 12:14 pm
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| | No abstract. |
| Perineural invasion in cancer
May 29, 2009 at 11:50 am
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| | Perineural invasion (PNI) is the process of neoplastic invasion of nerves and is an under-recognized route of metastatic spread. It is emerging as an important pathologic feature of many malignancies, including those of the pancreas, colon and rectum, prostate, head and neck, biliary tract, and stomach. For many of these malignancies, PNI is a marker of poor outcome and a harbinger of decreased survival. PNI is a distinct pathologic entity that can be observed in the absence of lymphatic or vascular invasion. It can be a source of distant tumor spread well beyond the extent of any local invasion; and, for some tumors, PNI may be the sole route of metastatic spread. Despite increasing recognition of this metastatic process, there has been little progress in the understanding of molecular mechanisms behind PNI and, to date, no targeted treatment modalities aimed at this pathologic entity. The objectives of this review were to lay out a clear definition of PNI to highlight its significance in those malignancies in which it has been studied best. The authors also summarized current theories on the molecular mediators and pathogenesis of PNI and introduced current research models that are leading to advancements in the understanding of this metastatic process. Cancer 2009. © 2009 American Cancer Society. |
| Single infusion of zoledronic acid to prevent androgen deprivation therapy-induced bone loss in men with hormone-naive prostate carcinoma
May 29, 2009 at 11:50 am
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| | Androgen-deprivation therapy (ADT) decreases bone mineral density (BMD) and increases fracture risk in patients with prostate carcinoma. The authors investigated the effectiveness of a single infusion of zoledronic acid initiated subsequent to ADT on BMD with hormone-naive prostate carcinoma.Forty men received either a single infusion of zoledronic acid (4 mg intravenously on Day 1) or no infusion during ADT. BMD of the proximal femur and posteroanterior lumbar spine was measured by dual-energy x-ray absorptiometry and urinary N-telopeptide (u-NTx) at 6 and 12 months.At baseline, the overall BMDs demonstrated no significant difference in lumbar spine and hip regions. At 6months, mean (±standard error) BMD of the posteroanterior lumbar spine decreased 4.6% ± 1.0% in control patients and increased 5.1% ± 1.2% in patients receiving zoledronic acid, a significant difference (P = .0002). At 12 months, the change in BMD between the 2 groups was statistically significantly different at the lumbar region (P = .0004), indicating that zoledronate preserved BMD. For u-NTx, bone turnover was statistically significantly decreased in the zoledronate group compared with controls at 6 months (P < .0001), but returned to pretreatment levels at 12 months in the zoledronate group.Bone loss begins at 6 months with ADT. A single infusion of zoledronic acid in patients receiving ADT reduces bone mineral loss and maintains BMD at least at 12 months during ADT. Further study is needed to determine the best dosing schedule to prevent ADT-induced bone loss in men with hormone-naive prostate carcinoma. Cancer 2009. © 2009 American Cancer Society. |
| Racial/ethnic diversity in children's oncology clinical trials
May 29, 2009 at 11:49 am
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| | During the past 50 years, clinical trials have led to dramatic improvement in pediatric cancer survival. Prior studies have shown that racial/ethnic and age groups have not been enrolled proportionally. Whites, Hispanics, and adolescents are under-represented and black children are over-represented. This study identifies the current racial/ethnic/age/sex representation in pediatric (ages birth to 19 years) cancer treatment trials.The authors compared the observed proportions (O) of US children enrolled in Children's Oncology Group (COG) clinical trials from 2000 through 2003 with expected proportions (E), based on Surveillance, Epidemiology, and End Results (SEER) data. The enrollees were subgrouped by race/ethnicity, age, sex, and cancer type (solid or lymphohematopoietic). Chi-square tests and 95% confidence intervals were used for O versus E comparisons.Although representation was fairly proportional for each racial/ethnic group, significantly under-represented solid tumor subgroups were whites (males particularly), adolescents ages 10 to 19 years, and Hispanics aged <10 years. For lymphohematopoietic cancers, significantly under-represented subgroups were blacks, Hispanics, adolescents ages 10 to 19 years, blacks aged <10 years, Hispanics aged <5 years, white and black males, and black and Hispanic females. The most significantly under-represented groups were adolescents ages 15 to 19 years for both solid (9.1% O vs 34.3% E) and lymphohematopoietic (11.0% O vs 30.2% E) cancers and Hispanic females with lymphohematopoietic cancers (11.9% O vs 20.5% E). COG enrolled 26.8% of expected cancer cases.Although racial/ethnic groups are proportionally represented in COG trials, some specific subgroups including the youngest black and Hispanic children, Hispanic females, and particularly white adolescents ages 15 to 19 years may be under-represented and may benefit from targeted attention. Cancer 2009. © 2009 American Cancer Society. |
| Glioblastoma in the elderly
May 29, 2009 at 11:49 am
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| | Glioblastoma (GBM) is the most common malignant primary brain tumor, and approximately 50% of cases occur in patients aged [ge]65 years. However, to the authors' knowledge, there is no accepted standard treatment for elderly GBM patients, and specific prognostic factors in the elderly GBM population have not been systematically studied to date.The Memorial Sloan-Kettering Cancer Center institutional database was used to identify patients with histologically confirmed GBM who were aged [ge]65 years at the time of diagnosis.Three hundred ninety-four GBM patients with a median age of 71.9 years (59% of whom were men) were included. Approximately 18% of patients underwent biopsy, whereas 82% underwent tumor resection; 81% received radiotherapy (RT), and 43% received adjuvant chemotherapy. The median overall survival was 8.6 months; at the time of last follow-up, 90% of patients had died, and the median follow-up of the 39 surviving patients was 12 months. In a multivariate analysis, younger age, better Karnofsky performance status (KPS), single tumor, and surgical resection were found to be independent predictors of survival. Comparing 103 patients who received adjuvant chemotherapy with 48 who were only followed after RT, there was a 55% decrease in the risk of death (hazards ratio, 0.45; 95% confidence interval, 0.30-0.66 [P < .0001]) after adjusting for age, KPS, extent of surgical resection, and number of lesions.Similar to studies in younger GBM patients, advancing age, KPS, and extent of tumor resection were found to be independent prognostic factors in the current study. Although survival is inferior in older GBM patients, age alone should not disqualify patients from aggressive therapy with surgical resection, RT, and chemotherapy. Cancer 2009. © 2009 American Cancer Society. |
| Synergistic effect of rapamycin and cisplatin in endometrial cancer cells
May 29, 2009 at 11:49 am
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| | Mammalian target of rapamycin (mTOR) inhibitors modulate signaling pathways involved in cell cycle progression, and phase 2 trials for endometrial cancer are currently being conducted. Because rapamycin is known to enhance the cytotoxicity of chemotherapeutic drugs, the authors' goal was to examine the effects of rapamycin and cisplatin in endometrial cancer cell lines.By using Ishikawa and ECC-1 cells, cell proliferation was assessed after exposure to rapamycin, cisplatin, or both in combination. The combination index (CI) was calculated using the method of Chou and Talalay. Apoptosis was evaluated by flow cytometry. Immunoblot analysis was performed to assess expression of S6 kinase 1 and the DNA mismatch repair proteins, MSH2 and MSH6. mTOR small interfering (siRNA) was transfected into the cell lines, and proliferation and apoptosis were assessed after exposure to cisplatin.Cisplatin inhibited growth in a dose-dependent manner in both cell lines (median inhibition concentration of 8-13 [mu]M). Simultaneous exposure of cisplatin in combination with rapamycin resulted in a significant synergistic antiproliferative effect (CI < 1). Rapamycin increased cisplatin-induced apoptosis and stimulated expression of MSH2 and MSH6 in the cisplatin-treated cell lines. Cell growth was significantly decreased in cells transfected with mTOR siRNA and treated with cisplatin compared with either alone (CI < 1). Transfection of mTOR siRNA did not induce apoptosis, but combined treatment with cisplatin increased apoptosis over that of cisplatin alone.The results of the current study provide evidence of a synergistic relation between rapamycin and cisplatin in both inhibition of cell growth and induction of apoptosis. This suggests that rapamycin and cisplatin may be a rational combination of a targeted therapy for endometrial cancer. Cancer 2009. © 2009 American Cancer Society. | | | 
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