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1.  A Phase 2 Study of Epothilone B Analog BMS-247550 (NSC 710428) in Patients With Relapsed Aggressive Non-Hodgkin Lymphomas 
Cancer  2013;119(9):1683-1689.
The management of relapsed aggressive lymphomas remains problematic. Ixabepilone (BMS-247550, epothilone B analog), a potent inhibitor of tubulin disassembly, has promising preclinical and early-phase clinical activity in drug-resistant malignancies.
This multicenter phase 2 clinical trial tested the activity and safety of ixabepilone in relapsed/refractory aggressive lymphoma patients with either chemosensitive (at least a partial response [PR] to most recent chemotherapy) or chemoresistant (less than PR to most recent chemotherapy) disease at 20 mg/m2 given intravenously weekly on days 1, 8, and 15 of a 28-day cycle.
Fifty-one enrolled patients with a median age of 66 years received at least 1 dose of ixabepilone. Diffuse large B-cell lymphoma (n = 25; 49%), mantle cell lymphoma (n = 16; 31%), and transformed follicular lymphoma (n = 5; 10%) were the most frequent histologies. Patients were heavily pretreated, with more than one-quarter having received 4 or more prior therapies. The overall response rate was 27% (14 of 51 patients) with 12% (6 patients) experiencing complete responses and 16% (8 patients) with PRs. All responses were in patients with chemosensitive disease. The median time to response was 2 cycles with a median duration of response of 9.7 months.
Ixabepilone was well-tolerated, with neutropenia, peripheral sensory neuropathy, fatigue, and nausea as the major toxicities. Ixabepilone has modest single-agent activity in patients with recurrent chemosensitive aggressive lymphomas.
PMCID: PMC4332882  PMID: 23310949
non-Hodgkin lymphoma; aggressive; refractory; relapsed; ixabepilone
2.  Cognitive Effects of Hormone Therapy in Men With Prostate Cancer 
Cancer  2008;113(5):1097-1106.
Men who receive androgen-deprivation therapy (ADT) for prostate cancer experience several side effects from this treatment. A few recent studies have examined the cognitive implications of ADT and how they impact a patient’s treatment decision-making, occupational pursuits, and quality of life. For this report, the authors explored possible mechanisms for this association, reviewed research in animal studies and aging men, and examined the growing literature focused on the relation between ADT and cognitive functioning in patients with prostate cancer.
A systematic literature search was conducted using the PubMed and Information Sciences Institute Web of Knowledge-Web of Science databases to identify relevant studies that investigated the relation between ADT in men with prostate cancer and its cognitive effects.
Testosterone and its derivatives may have an impact on cognition through several mechanisms in the brain, as supported by studies of animals and in aging men. Studies that researched the impact of ADT on cognition in patients with prostate cancer patients were designed relatively well but suffered from small sample sizes. Between 47% and 69% of men on ADT declined in at least 1 cognitive area, most commonly in visuospatial abilities and executive functioning. Some studies reported contradictory results with increased functioning in verbal memory.
There is a strong argument that androgen-ablation therapy is linked to subtle but significant cognitive declines in men with prostate cancer. The authors believe that clinicians should become aware of this correlation as the use of ADT increases and should inform and monitor patients for this possible side effect of treatment.
PMCID: PMC4333639  PMID: 18666210
altered cognitive function; androgen ablation; dihydrotestosterone; estradiol; prostate cancer; quality of life; testosterone
3.  Defining the Course and Prognosis of Adults With Acute Lymphocytic Leukemia in First Salvage After Induction Failure or Short First Remission Duration 
Cancer  2010;116(24):5568-5574.
Results from salvage therapy in adult patients with acute lymphocytic leukemia (ALL) are wide-ranging and depend on several disease and patient characteristics. The objectives of this study were to define the prognosis for adult patients with ALL after first salvage through multivariate analyses of patient and disease characteristics.
Adults with ALL who had primary resistance to frontline therapy or who had a disease recurrence after a first complete response (CR) duration <1 year were analyzed. Multivariate analyses for subsequent CR and survival were conducted.
Seventy-five of 245 patients (31%) achieved CR. The median CR duration was 5 months, the median survival was 4.7 months. In multivariate analysis, independent poor prognostic factors for not achieving CR were age >55 years, bone marrow blasts ≥20%, and platelet count <75 × 109/L Variables that were associated independently with shorter survival were age >55 years, bone marrow blasts ≥20%, platelet count <75 × 109/L, albumin level <3 g/L, and lactic dehydrogenase level ≥1000 IU/L. Patients who had ≥3 of the 5 adverse factors (45%) had a median survival of 2 to 3 months and CR rates of 8% to 15%. Achieving CR was associated independently with improved survival in a landmark multivariate analysis (P<.0001; hazard ratio, 0.40; 95% confidence interval, 0.03–0.72).
The current analyses identified a subset of adults patients ALL in first salvage for whom standard therapies were associated with an extremely poor outcome. The results also confirmed the importance of achieving CR to attain improved survival.
PMCID: PMC4332768  PMID: 20737576
acute lymphocytic leukemia; salvage therapy; prognosis; survival; complete response
4.  Small Renal Masses Progressing to Metastases under Active Surveillance: A Systematic Review and Pooled Analysis 
Cancer  2011;118(4):997-1006.
We conducted a systematic review and pooled analysis of small renal masses under active surveillance to identify progression risk and characteristics associated with metastases.
Materials and Methods
A MEDLINE search was performed to identify all clinical series reporting surveillance of localized renal masses. For studies reporting individual level data, clinical and radiographic characteristics of tumors without progression were compared to those progressing to metastases.
18 series (880 patients, 936 masses) met screening criteria from which 18 patients progressing to metastasis were identified (mean 40.2 months). Six studies (259 patients, 284 masses) provided individual level data for pooled analysis. With a mean follow up of 33.5±22.6 months, mean initial tumor diameter was 2.3±1.3 cm and mean linear growth rate was 0.31±0.38 cm/year. 65 masses (23%) exhibited zero net growth under surveillance; of which none progressed to metastasis. Pooled analysis revealed increased age (75.1±9.1 vs. 66.6±12.3 years, p=0.03), initial tumor diameter (4.1±2.1 vs. 2.3±1.3 cm, p<0.0001), initial estimated tumor volume (66.3±100.0 vs. 15.1±60.3 cm3, p<0.0001), linear growth rate (0.8±0.65 vs. 0.3±0.4 cm/yr, p=0.0001), and volumetric growth rate (27.1±24.9 vs. 6.2±27.5 cm3/yr, p<0.0001) in the progression cohort.
A substantial proportion of small renal masses remain radiographically static following an initial period of active surveillance. Progression to metastases occurs in a small percentage of patients and is generally a late event. These results indicate that in patients with competing health risks, radiographic surveillance may be an acceptable initial approach with delayed intervention reserved for those exhibiting significant linear or volumetric growth.
PMCID: PMC4329724  PMID: 21766302
5.  Primary Angiosarcomas of the Breast 
Cancer  2007;110(1):173-178.
The purpose of the study was to describe the clinicopathologic characteristics and clinical outcomes of patients with primary breast angiosarcoma.
The institutional database was searched to identify breast angiosarcoma patients seen between 1965 and 2002. Survival outcomes were estimated by the Kaplan-Meier method. The log-rank test was used to compare groups. Cox proportional hazards models were used for multivariate analysis.
In all, 69 patients were identified. Median follow-up was 40 months (range, 0–413 months). Median age was 46. Median tumor size at diagnosis was 5.5 cm. Thirteen (18.8%) patients received prior radiation for invasive breast carcinoma. Most patients underwent total mastectomy with (41%) or without (45%) axillary dissection. Regional metastasis to axillary lymph nodes was rare. There were 38 recurrences and 27 deaths. The 5-year overall (OS) and recurrence-free survival (RFS) rates were 61% (95% confidence interval [CI], 49%–76%) and 44% (95% CI, 33%–58%) with estimated medians of 100 and 37 months, respectively. In Cox proportional hazards models, OS and RFS were significantly associated only with T size and not with patient age, prior radiation, or chemotherapy administration. Of 29 patients treated with chemotherapy at recurrence, there were 4 complete and 10 partial responses (48%) with an anthracycline-ifosfamide or gemcitabine-taxane combination.
Breast angiosarcoma is frequently advanced at diagnosis and has a tendency for local-regional recurrence. A significant number of responses to chemotherapy was observed in the metastatic setting. These data suggest that a multidisciplinary therapeutic approach should be employed in high-risk patients with large primary tumors.
PMCID: PMC4329779  PMID: 17541936
breast cancer; angiosarcoma; therapy
6.  Placement of Radiopaque Clips for Tumor Localization in Patients Undergoing Neoadjuvant Chemotherapy and Breast Conservation Therapy 
Cancer  2007;110(11):2420-2427.
The objective of this study was to determine whether patients with breast cancer who received breast-conservation therapy after neoadjuvant chemotherapy had improved outcomes if radiopaque clips were placed to mark the primary tumor.
The authors retrospectively reviewed the records of 410 patients with nonmetastatic breast cancer who received doxorubicin-based neoadjuvant chemotherapy and breast-conservation therapy from January 1990 to September 2005. Thirty-seven of those patients were omitted because of the inability to verify radiopaque clip placement in the primary tumor.
Of the 373 patients who were analyzed, 145 patients had radiopaque clips placed to mark the primary tumor before or during neoadjuvant chemotherapy, and 228 patients did not. The distribution of clinical T classification, nuclear grade, estrogen receptor status, final margin status, and extent of residual primary disease was similar between the 2 groups. After a median follow-up of 49 months (range, 20–177 months), 21 patients developed a local recurrence in the treated breast. The 5-year rate of local control was 98.6% in patients who had radiopaque clips placed versus 91.7% in patients who did not have tumor marker clips placed (P = .02; log-rank test). On multivariate analysis, the omission of tumor bed clips was associated with a hazard ratio of 3.69 for increased local recurrence compared with patients who did have radiopaque clip placement (P = .083; 95% confidence interval, 0.84–16.16).
The placement of radiopaque clips in patients who were receiving neoadjuvant chemotherapy and breast-conservation therapy was associated with better local control independent of stage and other clinicopathologic findings. The authors concluded that the placement of tumor-marker clips should be an integral part of the multidisciplinary approach in appropriate patients.
PMCID: PMC4329780  PMID: 17941034
breast cancer; neoadjuvant chemotherapy; breast-conservation therapy; locoregional recurrence; radiopaque clip
7.  Population-Based Analysis of Occult Primary Breast Cancer With Axillary Lymph Node Metastasis 
Cancer  2010;116(17):4000-4006.
Single-institution data suggest that treatment with radiation and axillary lymph node dissection (ALND) may be an appropriate alternative to mastectomy for T0N+ breast cancer. Population-based multi-institutional data supporting this approach are lacking.
The cause-specific survival (CSS) and overall survival (OS) of women with T0N+M0 ductal, lobular, or mixed breast cancer in the Surveillance, Epidemiology, and End Results database from 1983 to 2006 were analyzed. Groups were defined as: 1) no ALND, mastectomy, or RT (observation); 2) ALND only; 3) mastectomy plus ALND with or without postmastectomy radiation (Mast); and 4) breast-conserving therapy (BCT) with ALND and radiation (BCT).
In total, 750 of 770,030 patients with breast cancer had T0N+ M0 disease (incidence, 0.10%), and 596 of those patients underwent ALND (79.5%). Patients who underwent Mast or BCT (n = 470) had a 10-year OS rate of 64.9% compared with 58.5% for patients who underwent ALND only (n = 126; P = .02) and 47.5% for patients who underwent observation only (n = 94; P = .04). The 10-year CSS rate was 75.7% for patients who underwent BCT versus 73.9% for patients who underwent Mast (P = .55). In multivariate analysis of CSS for patients who underwent Mast or BCT, the following factors were correlated with an unfavorable outcome: positive estrogen receptor status (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.24–0.96; P = .04), ≥10 positive lymph nodes (HR, 5.7; 95%CI, 2.4–13.4; P ≤ .01), and <10 resected lymph nodes (HR, 42.9; 95%CI, 1.2–7.1; P = .02). Mast did not improve CSS compared with BCT (HR, 1.09; 95%CI, 0.57–2.1; P = .79).
Definitive locoregional treatment with either Mast or BCT improved the outcome of patients with T0N+breast cancer, and no difference in survival was observed between the treatments.
PMCID: PMC4329781  PMID: 20564117
occult breast cancer; axillary lymph node metastasis; breast-conserving therapy; mastectomy; Surveillance; Epidemiology; End Results
8.  Sex disparities in diagnosis of bladder cancer after initial presentation with hematuria: a nationwide claims-based investigation 
Cancer  2013;120(4):555-561.
Women have disproportionately higher mortality rates relative to incidence for bladder cancer. Multiple etiologies have been proposed, including delayed diagnosis and treatment. Guidelines recommend rule-out of malignancy in men and women presenting with hematuria. We aimed to determine the difference in timing from presentation with hematuria to diagnosis of bladder cancer in women versus men.
This is a retrospective population-based study examining the timing from presentation with hematuria to diagnosis of bladder cancer, based on data from the MarketScan databases, which include enrollees of more than 100 health insurances plans of approximately 40 large US employers from 2004 through 2010. All study patients presented with hematuria and were subsequently diagnosed with bladder cancer. The primary outcome measure was number of days between initial presentation with hematuria and diagnosis of bladder cancer by gender.
5416 men and 2233 women met inclusion criteria. Mean days from initial hematuria claim to bladder cancer claim was significantly longer in women (85.4 vs. 73.6 days, p<0.001), and the proportion of women with >6 month delays in bladder cancer diagnosis significantly higher (17.3% vs. 14.1%, p<0.001). Women were more likely to be diagnosed with urinary tract infection (OR 2.32 [95% CI 2.07–2.59]) and less likely to undergo abdominal or pelvic imaging (OR 0.80 [95% CI 0.71–0.89]).
Both men and women experience significant delays between presentation with hematuria and diagnosis of bladder cancer, with longer delays for women. This may be partly responsible for the gender-based discrepancy in outcomes associated with bladder cancer.
PMCID: PMC3916781  PMID: 24496869
Urinary Bladder Neoplasms; Hematuria; Diagnosis; Insurance Claim Review; Standards
9.  Autophagy and Enhanced Chemosensitivity in Experimental Pancreatic Cancers Induced by Noninvasive Radiofrequency Field Treatment 
Cancer  2013;120(4):480-491.
Patients with pancreatic adenocarcinoma (PDAC) have limited therapeutic options and poor response to the standard gemcitabine (GCB)-based chemotherapy. We investigated the feasibility of non-invasive short-wave RF electric fields to improve cytotoxic effect of GCB on PDAC cells and determined its mechanism of action.
Cytotoxicity of RF alone and in combination with GCB was studied in vitro on normal pancreatic HPDE cells and different PDAC cell lines by flow cytometry, and in vivo on ectopic and orthotopic human PDAC xenograft models in mice. Mechanism of RF activity was studied by western blot and immunohistochemistry analysis. Toxicity was determined by histopathology.
Exposure of different PDAC cells to 13.56 MHz radiowaves resulted in substantial cytotoxic effect, which was accompanied by induction of autophagy, but not apoptosis. These effects of RF were absent in normal cells. Excessive numbers of autophagosomes in cancer cells persisted 24-48 h after RF exposure and then declined. Addition of a subtoxic dose of GCB to RF treatment inhibited the recovery of cancer cells from the RF-induced autophagy and enhanced cytotoxic effect of the latter on cancer cells. Treatment of PDAC cancer in situ in mice with combination of non-invasive RF and GCB had superior antitumor effect than RF or GCB alone, yet had no evidence of systemic toxicity.
Non-invasive RF treatment induced autophagy, not apoptosis in cancer cells and showed a potential as an enhancer of chemotherapy for treating pancreatic cancer without toxicity to normal cells.
PMCID: PMC3916783  PMID: 24496866
10.  Cardiovascular disease in survivors of hematopoietic cell transplantation 
Cancer  2013;120(4):469-479.
Hematopoietic cell transplantation (HCT) is increasingly offered as a curative option for many patients with hematologic malignancies. Improvements in HCT strategies and supportive care have resulted in a growing number of long-term survivors. However, these survivors are at increased risk of developing long-term debilitating chronic health conditions, including premature cardiovascular disease. These complications are more common than in the general population, and there are well-described associations between therapeutic exposures, traditional cardiovascular risk factors and subsequent cardiovascular disease risk. We present here an overview of the current state of knowledge regarding pathogenesis and risk factors for some of the more commonly occurring cardiovascular complications following HCT, highlighting existing surveillance recommendations and future directions for research to minimize cardiovascular morbidity in these survivors.
PMCID: PMC3946330  PMID: 24166350
Hematopoietic cell transplantation; cardiovascular disease; late effects; cancer survivors; screening
11.  Ganglioside GD2 as a Therapeutic Target for Antibody-Mediated Therapy in Osteosarcoma 
Cancer  2013;120(4):548-554.
Survival outcomes for patients with osteosarcoma have remained stagnant over the past three decades. Targeting of ganglioside GD2, a glycosphingolipid on the cell surface of some tumors, with immunotherapy has resulted in improved outcomes for patients with neuroblastoma. The expression pattern of GD2 was examined in osteosarcoma.
Immunohistochemistry was performed on osteosarcoma samples from patients at the time of initial biopsy, definitive surgery, and recurrence. The intensity and location of staining were scored. Cell-based ELISA was performed on osteosarcoma cell lines to quantitate the level of GD2 expression.
Forty-four osteosarcoma samples were evaluated by immunohistochemistry, including 8 samples from the initial biopsy, 28 samples from the definitive surgery, and 8 samples from the time of recurrence. GD2 was expressed on all 44 osteosarcoma samples. Osteosarcoma tissue obtained at the time of recurrence showed higher intensity of staining compared to samples obtained at initial biopsy and definitive surgery (p=0.016). The majority of osteosarcoma cell lines expressed GD2 at higher levels than the neuroblastoma cell line BE(2)-C.
Ganglioside GD2 is highly expressed on osteosarcomas. Clinical trials are needed to assess the efficacy of targeting GD2 in patients with osteosarcoma.
PMCID: PMC3946333  PMID: 24166473
osteosarcoma; ganglioside GD2; immunotherapy; antibody
12.  Costs and Outcomes Evaluation of Patient Navigation Following Abnormal Cancer Screening: Evidence from the Patient Navigation Research Program 
Cancer  2013;120(4):570-578.
Navigators can facilitate timely access to cancer services but there are little data on their economic impact.
We conduct a cost-consequence analysis of navigation vs. usual care among 10,521 individuals with abnormal breast, cervix, colorectal or prostate cancer screening results who enrolled in the Patient Navigation Research Program study from January 1 2006 to March 31 2010. Navigation costs included diagnostic evaluation, patient and staff time, materials, and overhead. Consequences or outcomes were time to diagnostic resolution and probability of resolution. Differences in costs and outcomes were evaluated using multi-level, mixed-effects regression adjusting for age, race/ethnicity, language, marital status, insurance, cancer, and site clustering.
Most individuals were minority (70.7%) and un- or publically-insured (72.7%). Diagnostic resolution was higher for navigation vs. usual care at 180 (56.2% vs. 53.8%, p=0.008) and 270 days: 70.0% vs. 68.2%, p<0.001). While there were no differences in average days to resolution (110 vs. 109 days, p=.63), the probability of ever having diagnostic resolution was higher for navigation vs. usual care (84.5% vs. 79.6%, p <0.001). The added cost of navigation vs. usual care was $275 per patient (95% CI $260 – $290, p <0.001). There was no significant difference in stage distribution among the 12.4% of navigated vs. 11% of usual care patients diagnosed with cancer.
Navigation adds costs and modestly increases the probability of diagnostic resolution among patients with abnormal screening tests. Navigation is only likely to be cost-effective if improved resolution translates into earlier cancer stage at diagnosis.
PMCID: PMC3946403  PMID: 24166217
cancer; navigation; cost; outcomes; abnormal cancer screening
13.  Low 25(OH) Vitamin D3 Levels Are Associated with Adverse Outcome in Newly-Diagnosed Intensively-Treated Adult Acute Myeloid Leukemia Patients 
Cancer  2013;120(4):521-529.
Several studies suggest that low 25(OH) vitamin D3 levels may be prognostic in some malignancies, but no studies have evaluated their impact on treatment outcome in acute myeloid leukemia (AML).
VD levels were evaluated in 97 consecutive newly diagnosed, intensively-treated AML patients. MicroRNA-expression profiles and single nucleotide polymorphisms (SNPs) in the 25(OH) vitamin D3 pathway genes were evaluated and correlated with 25(OH) vitamin D3 levels and treatment outcome.
Thirty-four (35%) patients had normal 25(OH) vitamin D3 levels (32–100 ng/ml), 34 (35%) insufficient (20–31.9 ng/ml) and 29 (30%) deficient levels (<20 ng/ml). Insufficient/deficient 25(OH) vitamin D3 levels were associated with worse relapse-free survival (RFS) compared to normal vitamin D3 levels. In multivariate analyses, deficient 25(OH) vitamin D3, smoking, European LeukemiaNet Genetic Groups and white blood cell count retained their statistical significance for RFS. A number of microRNAs and SNPs were found to be associated with 25(OH) vitamin D3 level, although none remained significant after multiple test corrections; one 25(OH) vitamin D3 receptor SNP, rs10783219, was associated with lower complete remission rate (p=0.0442), shorter RFS (p=0.0058) and overall survival (p=0.0011).
It remains to be determined what role microRNA and SNP profiles play in contributing to low 25(OH) vitamin D3 level and/or outcome and whether supplementation will improve AML outcome.
PMCID: PMC3948325  PMID: 24166051
14.  EWS-FLI-1 regulates the neuronal repressor gene REST, which controls Ewing sarcoma growth and vascular morphology 
Cancer  2014;120(4):579-588.
RE1-silencing transcription factor (REST), a neuronal repressor gene, regulates neuronal stem cell differentiation. Ewing sarcoma may originate from neural crest cells. We investigated whether REST plays a role in the growth of this tumor.
REST expression was determined by Western blot and Reverse transcription-PCR in 3 human Ewing sarcoma cell lines and 7 patient tumor samples. The role of REST in tumor growth and tumor vascular morphology was determined using a Ewing sarcoma xenograft model. Immunofluorescent staining, Hypoxyprobe and TUNEL assays were performed to investigate the impact of REST on pericyte marker expression, hypoxia, and apoptosis in vivo.
High levels of REST were expressed in all 3 human Ewing sarcoma cell lines and in 6 of the 7 patient tumor samples. Over-expression of EWS-FLI-1 in human mesenchymal stem cells and human neural progenitor cells increased REST expression. Inhibition of EWS-FLI-1 using small interfering (si) RNA decreased REST expression in human Ewing sarcoma cells. Inhibition of REST did not affect EWS-FLI-1, but significantly suppressed tumor growth in vivo, reduced the tumor vessel pericyte markers α-SMA and desmin, increased hypoxia and apoptosis in tumor tissues and decreased the expression of DLL4 and Hes1.
Inhibition of REST suppressed tumor growth, inhibited pericyte marker expression, and increased tumor hypoxia and apoptosis. As tumor vessel function has been linked to tumor growth and metastases, REST may be a new therapeutic target for Ewing sarcoma.
PMCID: PMC3969734  PMID: 24415532
EWS-FLI-1; REST; Ewing sarcoma; tumor growth; tumor vasculature
15.  “Meaningful Use” Provides a Meaningful Opportunity 
Cancer  2013;120(4):464-468.
PMCID: PMC4054930  PMID: 24496865
16.  Current Event-Free Survival After Sequential Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia 
Cancer  2010;117(2):327-335.
Imatinib is an effective tyrosine kinase inhibitor (TKI) for patients with chronic myeloid leukemia (CML) in chronic phase (CP). Although some patients may fail on therapy with imatinib, effective salvage therapy is available with second-generation TKIs. Current measurement of efficacy for each therapy is judged by its individual impact on overall survival and event-free survival (EFS).
In total, 586 patients with CML in CP who received imatinib were included in this analysis in 2 cohorts: imatinib as front-line therapy (n =281) or after failure on interferon-α (IFN-α) (n =305). By accounting for successful salvage treatment (ie, regain of complete cytogenetic response), the current EFS (CEFS) rate was calculated to obtain a more accurate impression of the outcome of patients with CML who received treatment with sequential TKIs.
For patients who received imatinib after failing on IFN-α, the 7-year EFS rate was 61%, whereas the CEFS rate was 69%. The 7-year EFS rate for patients who received imatinib as initial therapy was 81% compared with a 7-year CEFS rate of 88%.
CEFS provided a more accurate representation of the outcome of patients with CML in CP. These patients may frequently be treated successfully with subsequent TKIs after experiencing failure on the first TKI.
PMCID: PMC4327987  PMID: 20845478
event-free survival; chronic myeloid leukemia; tyrosine kinase inhibitor; current event-free survival; interferon-α; failure
17.  Mutational Analysis and Clinical Correlation of Metastatic Colorectal Cancer 
Cancer  2014;120(10):1482-1490.
Early identification of mutations may guide patients with metastatic colorectal cancer toward targeted therapies that may be life prolonging. The authors assessed tumor genotype correlations with clinical characteristics to determine whether mutational profiling can account for clinical similarities, differences, and outcomes.
Under Institutional Review Board approval, 222 patients with metastatic colon adenocarcinoma (n = 158) and rectal adenocarcinoma (n = 64) who underwent clinical tumor genotyping were reviewed. Multiplexed tumor genotyping screened for >150 mutations across 15 commonly mutated cancer genes. The chi-square test was used to assess genotype frequency by tumor site and additional clinical characteristics. Cox multivariate analysis was used to assess the impact of genotype on overall survival.
Broad-based tumor genotyping revealed clinical and anatomic differences that could be linked to gene mutations. NRAS mutations were associated with rectal cancer versus colon cancer (12.5% vs 0.6%; P < .001) and with age ≥56 years (7% vs 0.9%; P = .02). Conversely, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations were associated with colon cancer (13% vs 3%; P = .024) and older age (15.8% vs 4.6%; P = .006). TP53 mutations were associated with rectal cancer (30% vs 18%; P = .048), younger age (14% vs 28.7%; P = .007), and men (26.4% vs 14%; P = .03). Lung metastases were associated with PIK3CA mutations (23% vs 8.7%; P = .004). Only mutations in BRAF were independently associated with decreased overall survival (hazard ratio, 2.4; 95% confidence interval, 1.09–5.27; P = .029).
The current study suggests that underlying molecular profiles can differ between colon and rectal cancers. Further investigation is warranted to assess whether the differences identified are important in determining the optimal treatment course for these patients.
PMCID: PMC4327902  PMID: 24500602
colorectal cancer; mutation; clinicopathologic; NRAS; BRAF
18.  The Effect of Care Setting in the Delivery of High-Value Colon Cancer Care 
Cancer  2014;120(20):3237-3244.
The effect of care setting on value of colon cancer care is unknown.
A Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort study of 6544 patients aged ≥66 years with stage IV colon cancer (based on the American Joint Committee on Cancer staging system) who were diagnosed between 1996 and 2005 was performed. All patients were followed through December 31, 2007. Using outpatient and carrier claims, patients were assigned to a treating hospital based on the hospital affiliation of the primary oncologist. Hospitals were classified academic or nonacademic using the SEER-Medicare National Cancer Institute Hospital File.
Of the 6544 patients, 1605 (25%) received care from providers affiliated with academic medical centers. The unadjusted median cancer-specific survival was 16.0 months at academic medical centers versus 13.9 months at nonacademic medical centers (P<.001). After adjustment, treatment at academic hospitals remained significantly associated with a reduced risk of death from cancer (hazard ratio, 0.87; 95% confidence interval [95% CI], 0.82–0.93 [P<.001]). Adjusted mean 12-month Medicare spending was $8571 higher at academic medical centers (95% CI, $2340–$14,802; P =.007). The adjusted median cost was $1559 higher at academic medical centers; this difference was not found to be statistically significant (95% CI, −$5239 to $2122; P =.41). A small percentage of patients who received very expensive care skewed the difference in mean cost; the only statistically significant difference in adjusted costs in quantile regressions was at the 99.9th percentile of costs (P<.001).
Among Medicare beneficiaries with stage IV colon cancer, treatment by a provider affiliated with an academic medical center was associated with a 2 month improvement in overall survival. Except for patients in the 99.9th percentile of the cost distribution, costs at academic medical centers were not found to be significantly different from those at nonacademic medical centers.
PMCID: PMC4325980  PMID: 24954628
colon cancer; academic medical centers; cost analysis; health policy; survival analysis; incremental cost-effectiveness ratio
Cancer  2013;119(15):2789-2795.
Posterior reversible encephalopathy syndrome (PRES) comprises clinical and radiologic findings with rapid onset and potentially dire consequences. Patients experience hypertension, seizures, headache, visual disturbance, and/or altered mentation. Magnetic resonance imaging shows edematous changes in brain (especially parietal and occipital lobes). We report PRES associated with anti-GD2 monoclonal antibody (MoAb) immunotherapy which is now standard for high-risk neuroblastoma but has not previously been implicated in PRES.
Successive clinical trials using the anti-GD2 MoAb 3F8 for neuroblastoma patients involved multiple cycles of standard-dose 3F8 (SD-3F8) (20 mg/m2/day, x5 days/cycle) or two cycles of high-dose 3F8 (HD-3F8) (80 mg/m2/day, x5 days/cycle) followed by cycles of SD-3F8.
PRES was diagnosed in 5/215 (2.3%) patients, including 3/160 (1.9%) patients receiving SD-3F8 and 2/55 (3.6%) patients receiving HD-3F8 (p=0.6). All five patients had a rapid return to clinical-radiologic baseline. PRES occurred in 3/26 (11.5%) patients whose prior treatment included external-beam radiotherapy to the brain (2/6 patients status-post total body irradiation plus 1/20 patients status-post craniospinal irradiation) compared to 2/189 (1.1%) patients without prior brain irradiation (p=0.01). Hypertension, which is strongly linked to PRES, reached grade 3 toxicity in 12/215 (5.6%) patients, including the five patients with PRES and seven patients without PRES.
Patients receiving anti-GD2 MoAb immunotherapy should be closely monitored for, and undergo urgent treatment or evaluation of, symptoms (e.g., hypertension or headaches) that might herald PRES. Prior brain irradiation may be a predisposing factor for PRES with this immunotherapy.
PMCID: PMC4326066  PMID: 23633099
immunotherapy; neuroblastoma; PRES; monoclonal antibodies; hypertension
20.  Long-Term Prognostic Impact of the Use of Erythropoietic-Stimulating Agents in Patients With Chronic Myeloid Leukemia in Chronic Phase Treated With Imatinib 
Cancer  2010;117(5):982-991.
Anemia is a frequent side effect of imatinib in patients with chronic myeloid leukemia (CML). Erythropoietic-stimulating agents have been used for treatment of imatinib-induced anemia. There are no data on long-term safety of erythropoietic-stimulating agents in CML patients.
The records of chronic phase CML patients who received treatment with imatinib were reviewed for use of erythropoietic-stimulating agents and occurrence of thrombotic events. Data on cytogenetic response and survival were analyzed by use of erythropoietic-stimulating agent.
A total of 608 patients were included, and 217 patients received erythropoietic-stimulating agents. There were 30 thrombotic episodes. Patients who received erythropoietic-stimulating agents had a higher rate of thrombosis (8.5% vs 2.6%, P = .0025). There was no difference in cytogenetic response rate and survival by use of erythropoietic-stimulating agent. Development of grade 3–4 anemia occurred in 62 (10%) patients and was associated with significantly worse response and survival in patients in late chronic phase. By multivariate analysis, use of erythropoietic-stimulating agents was not a risk factor for event-free survival.
In our cohort of chronic phase CML patients, use of erythropoietic-stimulating agents did not impact survival or cytogenetic response rate, but was associated with a higher thrombosis rate. Severe anemia is associated with worse survival and response.
PMCID: PMC4324729  PMID: 20960502
chronic myeloid leukemia; imatinib; anemia; erythropoiesis-stimulating agents; tyrosine kinase inhibitors
21.  Prognostic Impact of Deletions of Derivative Chromosome 9 in Patients With Chronic Myelogenous Leukemia Treated With Nilotinib or Dasatinib 
Cancer  2011;117(22):5085-5093.
Deletions of derivative chromosome 9 are a poor prognostic factor in patients with chronic myeloid leukemia (CML) treated with hydroxyurea, interferon, or stem cell transplantation. Imatinib may overcome the adverse prognostic impact of deletions of derivative chromosome 9.
A study was undertaken to investigate the prognostic impact of deletions of derivative chromosome 9 in 353 patients with CML receiving the second generation tyrosine kinase inhibitors (TKIs) nilotinib (n = 161) or dasatinib (n = 192).
Deletion of derivative chromosome 9 status was determined in 245 (69%). Twenty-eight (11%) patients, 22 in chronic phase, 4 in accelerated phase, and 2 in blast phase, carried deletions of derivative chromosome 9, including 17 receiving nilotinib and 11 receiving dasatinib (P = .47). Overall survival (OS) at 24 months was similar between patients with or without deletions of derivative chromosome 9 (70% vs 71%, P = .76). For patients in chronic phase, no significant differences in overall major cytogenetic response (77% vs 82%, P = .57) or complete cytogenetic response (77% vs 81%, P = .71) rates were observed between patients with or without deletions of derivative chromosome 9. At 24 months, patients with CML in chronic phase without deletions of derivative chromosome 9 had improved event-free survival (EFS) (88% vs 66%, P = .07) and OS (96% vs 82%; P = .08) compared with those carrying deletions of derivative chromosome 9. However, multivariate analysis established second-line versus frontline second generation TKI therapy as the only adverse prognostic factor for EFS and increased bone marrow blast burden and older age as independent adverse prognostic factors for OS.
Deletions of derivative chromosome 9 do not appear to be an in dependent risk factor for survival among patients with CML in chronic phase receiving second generation TKIs.
PMCID: PMC4324753  PMID: 21523765
BCR-ABL1; nilotinib; dasatinib; deletion; derivative chromosome 9
22.  Temporal Trends in Population-Based Death Rates Associated With Chronic Liver Disease and Liver Cancer in the United States Over the Last 30 Years 
Cancer  2014;120(19):3058-3065.
The health and economic burden from liver disease in the United States is substantial and rising. The objective of this study was to characterize temporal trends in mortality from chronic liver disease and liver cancer and the incidence of associated risk factors using population-based data over the past 30 years.
Population-based mortality data were obtained from the National Vital Statistics System, and population estimates were derived from the national census for US adults (aged >45 years). Crude death rates (CDRs), age-adjusted death rates (ADRs), and average annual percentage change (AAPC) statistics were calculated.
In total, 690,414 deaths (1.1%) were attributable to chronic liver disease, whereas 331,393 deaths (0.5%) were attributable to liver cancer between 1981 and 2010. The incidence of liver cancer was estimated at 7.1 cases per 100,000 population. Mortality rates from chronic liver disease and liver cancer increased substantially over the past 3 decades, with ADRs of 23.7 and 16.6 per 100,000 population in 2010, respectively. The AAPC from 2006 to 2010 demonstrated an increased ADR for chronic liver disease (AAPC, 1.5%; 95% confidence interval, 0.3%–2.8%) and liver cancer (AAPC, 2.6%; 95% confidence interval, 2.4%–2.7%).
A comprehensive approach that involves primary and secondary prevention, increased access to treatment, and more funding for liver-related research is needed to address the high death rates associated with chronic liver disease and liver cancer in the United States.
PMCID: PMC4316688  PMID: 24917245
liver cancer; chronic liver disease; epidemiology; mortality
23.  FLT3 Inhibitors in the Treatment of Acute Myeloid Leukemia 
Cancer  2011;117(15):3293-3304.
Despite recent modest improvements in the chemotherapy regimens used to treat acute myeloid leukemia (AML), many patients diagnosed with AML ultimately die of the disease. Commonly occurring genetic alterations have been identified that strongly affect the prognosis for patients with AML. These alterations represent possible targets for investigational therapies that could act to specifically halt the aberrant growth of AML cells while limiting damage to normal cells. One such gene is the Fms-like tyrosine kinase 3 (FLT3) gene, which is mutated in approximately 30% of adult patients with AML and has a significant impact on prognosis. In particular, internal tandem duplications in FLT3 confer a poor prognosis to this large subgroup of patients with AML. Agents that target FLT3 are in development for the treatment of patients who have AML and offer a potential paradigm change in the current standard treatment of AML. For this report, the authors reviewed the prognostic significance of genetic alterations observed in AML with a focus on the therapeutic implications of targeting FLT3. The introduction of such agents may be the next major step toward the era of personalized therapy in AML.
PMCID: PMC4316826  PMID: 21319142
acute myeloid leukemia; cytogenetics; FLT3 protein; molecular abnormalities
24.  Statin Use and Fatal Prostate Cancer: A Matched Case-Control Study 
Cancer  2011;118(16):4046-4052.
Statins are one of the most commonly prescribed medications in medical practice and prostate cancer is the most common male malignancy. While there has been no consistent evidence that statins affect cancer incidence, including prostate cancer, several reports suggest they may decrease the rate of advanced prostate cancer. However, no study has examined statin use and prostate cancer mortality specifically. We report here a population-based case-control investigation that examines this association.
We conducted a matched case-control study. Cases were residents of New Jersey ages 55 – 79 who died from prostate cancer between 1997–2000. We individually matched population-based controls by five-year age-group and race. Medication data were obtained identically for cases and controls from blinded medical chart review. We used conditional logistic regression to adjust for confounders.
We identified 718 cases and obtained cooperation from 77% of their spouses (N=553). After review of medical records, 387 were eligible and 380 were matched to a control. The unadjusted odds ratio was 0.49 (95% CI, 0.34–0.70) which decreased to 0.37 (p<0.0001) after adjustment for education, waist size, BMI, comorbidities, and anti-hypertensive medication. There was little difference between lipophilic and hydrophilic statins but more risk reduction was noted for hi-potency statins (73%, p<0.0001) as compared to low-potency statins (31%, p=0.32).
Statin use is associated with substantial protection against prostate cancer death, adding to the epidemiologic evidence for an inhibitory effect on prostate cancer.
PMCID: PMC4314096  PMID: 22180145
prostate cancer neoplasms; statins; mortality; cholesterol
25.  Imatinib Front-Line Therapy Is Safe and Effective in Patients With Chronic Myelogenous Leukemia With Pre-Existing Liver and/or Renal Dysfunction 
Cancer  2010;116(13):3152-3159.
Imatinib 400 mg daily is the standard treatment for patients with chronic myelogenous leukemia (CML). The safety and efficacy of imatinib in CML patients with pre-existing liver and/or renal dysfunction has not been analyzed.
The authors analyzed the outcome of 259 patients with early chronic phase CML treated with imatinib (starting dose 400 mg in 50, 800 mg in 209). Pre-existing liver and/or renal dysfunction was seen in 38 (15%) and 11 (4%) patients, respectively.
Dose reductions were required in 91 (43%) of 210 patients with normal organ function, compared with 8 (73%) of 11 (P =.065) with renal dysfunction, and 19 (50%) of 38 (P =.271) with liver dysfunction. Grade 3-4 hematologic toxicities including anemia (29%, 10%, and 7% of patients with renal dysfunction, liver dysfunction, and normal organ function, respectively), neutropenia (57%, 30%, and 30%), and thrombocytopenia (43%, 30%, and 26%) were more frequent in patients with pre-existing renal dysfunction treated with high-dose imatinib. Grade 3-4 nonhematologic toxicities were observed at similar frequencies. Complete cytogenetic response rates, event-free survival, and overall survival were similar in all groups.
Although patients with pre-existing liver and/or renal dysfunction might have a higher rate of hematologic toxicity and require more frequent dose reductions, most patients can be adequately managed, resulting in response rates and survival similar to those without pre-existing organ dysfunction.
PMCID: PMC4314210  PMID: 20564631
imatinib; chronic myelogenous leukemia; liver and/or renal dysfunction; dose reduction; survival

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