Trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is highly efficacious yet costly and time-intensive, and few data are available about its utilization. We examined receipt and completion of adjuvant trastuzumab by race/ethnicity and education for women with HER2-positive disease.
Using the National Comprehensive Cancer Network (NCCN) Breast Cancer Outcomes Database, we identified 1,109 women diagnosed with stage I–III, HER2-positive breast cancer during September 2005 through December 2008 who were followed for ≥1 year. We assessed the association of race/ethnicity and education with receipt of trastuzumab, and among women who initiated trastuzumab, with completion of >270 days of therapy, using multivariable logistic regression.
The cohort was 75% white, 8% black, and 9% Hispanic; 20% attained a high school degree or less. Most women (83%) received trastuzumab, with no significant differences by race/ethnicity or SES. Among women initiating trastuzumab, 73% of black women vs. 87% of white women (p=.007) and 70% of women with less than high school education vs. 90% of women with a college degree completed >270 days of therapy (p=.006). In adjusted analyses, black (vs. white) women and those without a high school degree (vs. college degree) had lower odds of completing therapy (odds ratio [OR]=.45, 95% confidence interval [CI]=.27–.74 and OR=0.27, 95% CI=.14–.51, respectively).
We observed differences in trastuzumab completion by race and educational attainment for women treated at NCCN centers. Efforts to assure appropriate utilization of trastuzumab and understand treatment barriers are needed and could lead to improved outcomes.
breast cancer; disparities; trastuzumab; race; socioeconomic status
Guidelines for breast cancer staging exist, but adherence remains
unknown. This study evaluates patterns of imaging in early-stage breast
cancer usually reserved for advanced disease.
Surveillance Epidemiology and End Results data linked to Medicare
claims from 1992–2005 were reviewed for stage I/II breast cancer
patients. Claims were searched for preoperative performance of CT, PET, and
bone scans, and brain MRIs (“advanced imaging”).
There were 67,874 stage I/II breast cancer patients; 18.8%
(n=12,740) had preoperative advanced imaging. The proportion of patients
having CTs, PET scans and brain MRIs increased from 5.7% to
12.4% (p<0.0001), 0.8% to 3.4%
(p<0.0001) and 0.2% to 1.1% (p=0.008), respectively,
from 1992–2005. Bone scans declined from 20.1% to
10.7% (p<0.0001). “Breast cancer” (174.x)
was the only diagnosis code associated with 62.1% of PET scans,
37.7% of bone scans, 24.2% of CTs, and 5.1% of brain
MRIs. ≥1 symptom or metastatic site was suggested for 19.6%
of bone scans, 13.0% of CTs, 13.0% of PET scans and
6.2% of brain MRIs. Factors associated (p<0.05) with use of
all modalities were urban setting, breast MRI and ultrasound. Breast MRI was
the strongest predictor (p<0.0001) of bone scan (OR1.63,
95%CI 1.44–1.86), Brain MRI (OR1.74, 95%CI
1.15–2.63), CT (OR2.42, 95%CI 2.12–2.76), and PET
(OR5.71, 95%CI 4.52–7.22).
Aside from bone scans, performance of advanced imaging is increasing
in early-stage Medicare breast cancer patients, with limited rationale
provided by coded diagnoses. In light of existing guidelines and increasing
scrutiny about healthcare costs, greater reinforcement of current
indications is warranted.
High-quality care must be not only appropriate but also timely. We assessed time to initiation of adjuvant chemotherapy for breast cancer as well as factors associated with delay to help identify targets for future efforts to reduce unnecessary delays.
Using data from the National Comprehensive Cancer Network (NCCN) Outcomes Database, we assessed the time from pathological diagnosis to initiation of chemotherapy (TTC) among 6622 women with stage I to stage III breast cancer diagnosed from 2003 through 2009 and treated with adjuvant chemotherapy in nine NCCN centers. Multivariable models were constructed to examine factors associated with TTC. All statistical tests were two-sided.
Mean TTC was 12.0 weeks overall and increased over the study period. A number of factors were associated with a longer TTC. The largest effects were associated with therapeutic factors, including immediate postmastectomy reconstruction (2.7 weeks; P < .001), re-excision (2.1 weeks; P < .001), and use of the 21-gene reverse-transcription polymerase chain reaction assay (2.2 weeks; P < .001). In comparison with white women, a longer TTC was observed among black (1.5 weeks; P < .001) and Hispanic (0.8 weeks; P < .001) women. For black women, the observed disparity was greater among women who transferred their care to the NCCN center after diagnosis (P
interaction = .008) and among women with Medicare vs commercial insurance (P
interaction < .001).
Most observed variation in TTC was related to use of appropriate therapeutic interventions. This suggests the importance of targeted efforts to minimize potentially preventable causes of delay, including inefficient transfers in care or prolonged appointment wait times.
Although no specific delay threshold after diagnosis of breast cancer has been demonstrated to affect outcome, delays can cause anxiety, and surgical waiting time has been suggested as a quality measure. This study was performed to determine the interval from presentation to surgery in Medicare patients with nonmetastatic invasive breast cancer who did not receive neoadjuvant chemotherapy and factors associated with a longer time to surgery.
Medicare claims linked to Surveillance, Epidemiology, and End Results data were reviewed for factors associated with delay between the first physician claim for a breast problem and first therapeutic surgery.
Between 1992 and 2005, 72,586 Medicare patients with breast cancer had a median interval (delay) between first physician visit and surgery of 29 days, increasing from 21 days in 1992 to 32 days in 2005. Women (29 days v 24 days for men; P < .001), younger patients (29 days; P < .001), blacks and Hispanics (each 37 days; P < .001), patients in the northeast (33 days; P < .001), and patients in large metropolitan areas (32 days; P < .001) had longer delays. Patients having breast conservation and mastectomies had adjusted median delays of 28 and 30 days, respectively, with simultaneous reconstruction adding 12 days. Preoperative components, including imaging modalities, biopsy type, and clinician visits, were also each associated with a specific additional delay.
Waiting times for breast cancer surgery have increased in Medicare patients, and measurable delays are associated with demographics and preoperative evaluation components. If such increases continue, periodic assessment may be required to rule out detrimental effects on outcomes.
The number of women diagnosed with ductal carcinoma in situ (DCIS) is increasing. While many eventually develop second breast cancers (SBC), little is known about the characteristics of SBC. We describe the characteristics of SBC and examine associations between the pathologic features of SBC and index DCIS cases.
We identified women in the National Comprehensive Cancer Network Outcomes Database diagnosed with DCIS from 1997–2008 and treated with lumpectomy who subsequently developed SBC (including DCIS or invasive disease occurring in the ipsilateral or contralateral breast). Fisher exact and Spearman tests were used to examine associations between the pathologic characteristics of SBC and index DCIS cases.
Among 2,636 women who received lumpectomy for DCIS, 150 (5.7%) experienced an SBC after a median of 55.5 months of follow-up. Of these 150 women, 105 (70.0%) received adjuvant radiotherapy and 50 (33.3%) received tamoxifen for their index DCIS. SBCs were ipsilateral in 54.7% of cases and invasive in 50.7% of cases. Among index DCIS cases, 60.6% were estrogen receptor (ER) positive and 54.0% were high grade, while 77.5% of SBCs were ER-positive and 48.2% were high grade. Grade (P = .003) and ER status (P = .02) were significantly associated between index DCIS and SBC; tumor size was not (P = .87).
After breast conservation for DCIS, SBC in either breast exhibits pathologic characteristics similar to the index DCIS, suggesting that women with DCIS may be at risk for developing subsequent breast cancers of a similar phenotype.
DCIS; Breast conserving therapy; Lumpectomy; Radiation; Tamoxifen; Second breast cancer; Contralateral breast cancer; Grade; Estrogen receptor
We examined differences in time to diagnosis by race/ethnicity, the relationship between time to diagnosis and stage, and the extent to which it explains differences in stage at diagnosis across racial/ethnic groups. Our analytic sample includes 21,427 non-Hispanic White (White), Hispanic, non-Hispanic Black (Black) and non-Hispanic Asian/Pacific Islander (Asian) women diagnosed with stage I to IV breast cancer between January 1, 2000 and December 31, 2007 at one of eight National Comprehensive Cancer Network centers. We measured time from initial abnormal mammogram or symptom to breast cancer diagnosis. Stage was classified using AJCC criteria. Initial sign of breast cancer modified the association between race/ethnicity and time to diagnosis. Among symptomatic women median time to diagnosis ranged from 36 days among Whites to 53.6 for Blacks. Among women with abnormal mammograms median time to diagnosis ranged from 21 days among Whites to 29 for Blacks. Blacks had the highest proportion (26%) of Stage III or IV tumors. After accounting for time to diagnosis, the observed increased risk of stage III/IV breast cancer was reduced from 40% to 28% among Hispanics and from 113% to 100% among Blacks, but estimates remained statistically significant. We were unable to fully account for the higher proportion of late-stage tumors among Blacks. Blacks and Hispanics experienced longer time to diagnosis than Whites, and Blacks were more likely to be diagnosed with late-stage tumors. Longer time to diagnosis did not fully explain differences in stage between racial/ethnicity groups.
BREAST CANCER; MINORITY HEALTH; DIAGNOSIS DELAY; DISPARITIES
We aimed to describe clinicopathological features, patterns of recurrence, and survival according to breast cancer subtype, with a focus on triple-negative tumors.
We evaluated 15,204 women presenting to NCCN centers with stage I-III breast cancer between January 2000 and December 2006. Tumors were classified as hormone receptor positive [HR+]/HER2− (ER+ and/or PR+, and HER2−), HER2+ (HER2+, any ER or PR), or triple-negative (ER−, PR−, and HER2−).
Subtype distribution was: triple-negative 17% (n=2,569), HER2+ 17% (n=2,602), HR+/HER2− 66% (n=10,033). Triple-negative subtype was more frequent in African-Americans, compared with Caucasians (adjusted odds ratio [OR] 1.98; p<0.0001). Premenopausal, but not postmenopausal, women with high body mass index had an increased likelihood of triple negative subtype (p=0.02). Women with triple-negative cancers were less likely to present on the basis of an abnormal screening mammogram (29% vs. 48%, p<0.0001), more likely to present with higher T stage, but less likely to have nodal involvement. Relative to HR+/HER2− tumors, triple-negative tumors were associated with a higher risk of brain or lung metastases, and had worse breast cancer-specific and overall survival, even after adjusting for age, stage, race, grade, and receipt of adjuvant chemotherapy (adjusted hazard ratio [HR] for overall survival 2.72, 95% CI 2.39–3.10, p<0.0001). The difference in risk of death by subtype was most dramatic within the first two years after diagnosis (HR for OS for 0 to 2 yrs 6.10 [95% CI 4.81, 7.74]).
Triple-negative tumors are associated with unique risk factors and worse outcomes compared to HR+/HER2− tumors.
Triple-negative; basal-like; breast cancer; outcomes; brain metastases; obesity; race
The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer.
Patients and Methods
Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m2 with or without paclitaxel 80 mg/m2 per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks.
We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases).
Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.
Gene expression profile (GEP) testing is a relatively new technology that offers the potential of personalized medicine to patients, yet little is known about its adoption into routine practice. One of the first commercially available GEP tests, a 21-gene profile, was developed to estimate the benefit of adjuvant chemotherapy for hormone receptor–positive breast cancer (HR-positive BC).
Patients and Methods
By using a prospective registry data set outlining the routine care provided to women diagnosed from 2006 to 2008 with HR-positive BC at 17 comprehensive and community-based cancer centers, we assessed GEP test adoption and the association between testing and chemotherapy use.
Of 7,375 women, 20.4% had GEP testing and 50.2% received chemotherapy. Over time, testing increased (14.7% in 2006 to 27.5% in 2008; P < .01) and use of chemotherapy decreased (53.9% in 2006 to 47.0% in 2008; P < .01). Characteristics independently associated with lower odds of testing included African American versus white race (odds ratio [OR], 0.70; 95% CI, 0.54 to 0.92) and high school or less versus more than high school education (OR, 0.63; 95% CI, 0.52 to 0.76). Overall, testing was associated with lower odds of chemotherapy use (OR, 0.70; 95% CI, 0.62 to 0.80). Stratified analyses demonstrated that for small, node-negative cancers, testing was associated with higher odds of chemotherapy use (OR, 11.13; 95% CI, 5.39 to 22.99), whereas for node-positive and large node-negative cancers, testing was associated with lower odds of chemotherapy use (OR, 0.11; 95% CI, 0.07 to 0.17).
There has been a progressive increase in use of this GEP test and an associated shift in the characteristics of and overall reduction in the proportion of women with HR-positive BC receiving adjuvant chemotherapy.
Streptococcus pyogenes (Group A Streptococcus or GAS) is a Gram-positive bacterial pathogen that has shown complex modes of regulation of its virulence factors to cause diverse diseases. Bacterial small RNAs are regarded as novel widespread regulators of gene expression in response to environmental signals. Recent studies have revealed that several small RNAs (sRNAs) have an important role in S. pyogenes physiology and pathogenesis by regulating gene expression at the translational level. To search for new sRNAs in S. pyogenes, we performed a genomewide analysis through computational prediction followed by experimental verification. To overcome the limitation of low accuracy in computational prediction, we employed a combination of three different computational algorithms (sRNAPredict, eQRNA and RNAz). A total of 45 candidates were chosen based on the computational analysis, and their transcription was analyzed by reverse-transcriptase PCR and Northern blot. Through this process, we discovered 7 putative novel trans-acting sRNAs. Their abundance varied between different growth phases, suggesting that their expression is influenced by environmental or internal signals. Further, to screen target mRNAs of an sRNA, we employed differential RNA sequencing analysis. This study provides a significant resource for future study of small RNAs and their roles in physiology and pathogenesis of S. pyogenes.
The relationship among young age (≤40 years), the likelihood of a delay in diagnosis, and stage was examined in breast cancer patients using a National Comprehensive Cancer Network database. Young age was not an independent predictor of a delay in diagnosis and only modestly predicted higher disease stage.
Young women with breast cancer are more likely to present with more advanced disease and are more likely to die as a result of breast cancer than their older counterparts. We sought to examine the relationship among young age (≤40 years), the likelihood of a delay in diagnosis, and stage.
We examined data from women with newly diagnosed stage I–IV breast cancer presenting to one of eight National Comprehensive Cancer Network centers in January 2000 to December 2007. Delay in diagnosis was defined as time from initial sign or symptom to breast cancer diagnosis >60 days.
Among 21,818 women with breast cancer eligible for analysis, 2,445 were aged ≤40 years at diagnosis. Young women were not more likely to have a delay in diagnosis >60 days (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.98–1.19) after adjustment for type of initial sign or symptom. Young women were only modestly more likely to present with higher stage disease after a similar adjustment (OR, 1.18; 95% CI, 1.07–1.31). Women presenting with symptomatic disease, more common in younger women, were more likely to have a delay in diagnosis (OR, 3.31; 95% CI, 3.08–3.56) and higher stage (OR, 4.31; 95% CI 4.05–4.58).
Young age is not an independent predictor of delay in diagnosis of breast cancer and only modestly is associated with higher stage disease. Presenting with symptoms of breast cancer predicts delay and higher stage at diagnosis.
Breast cancer; Young age; Delay in diagnosis; Breast cancer screening
Methadone is a widely used substitution therapy for opioid addiction. Large inter-individual variability has been observed in methadone maintenance dosages and P-glycoprotein (P-gp) was considered to be one of the major contributors. To investigate the mechanism of P-gp’s interaction with methadone, as well as the effect of genetic variants on the interaction, Flp-In™-293 cells stably transfected with various genotypes of human P-gp were established in the present study. The RNA and protein expression levels of human P-gp were confirmed by real-time quantitative RT-PCR and western blot, respectively. Utilizing rhodamine 123 efflux assay and calcein-AM uptake study, methadone was demonstrated to be an inhibitor of wild-type human P-gp via non-competitive kinetic (IC50 = 2.17±0.10 µM), while the variant-type human P-gp, P-gp with 1236T-2677T-3435T genotype and P-gp with 1236T-2677A-3435T genotype, showed less inhibition potency (IC50 = 2.97±0.09 µM and 4.43±1.10 µM, respectively) via uncompetitive kinetics. Methadone also stimulated P-gp ATPase and inhibited verapamil-stimulated P-gp ATPase activity under therapeutic concentrations. These results may provide a possible explanation for higher methadone dosage requirements in patients carrying variant-type of P-gp and revealed the possible drug-drug interactions in patients who receive concomitant drugs which are also P-gp substrates.
While a number of genome-wide association studies have identified microtubule-associated protein tau as a strong risk factor for Parkinson’s disease (PD), little is known about the mechanism through which human tau can predispose an individual to this disease. Here, we demonstrate that expression of human wild-type tau is sufficient to disrupt the survival of dopaminergic neurons in a Drosophila model. Tau triggers a synaptic pathology visualized by vesicular monoamine transporter-pHGFP that precedes both the age-dependent formation of tau-containing neurofibrillary tangle-like pathology and the progressive loss of DA neurons, thereby recapitulating the pathological hallmarks of PD. Flies overexpressing tau also exhibit progressive impairments of both motor and learning behaviors. Surprisingly, contrary to common belief that hyperphosphorylated tau could aggravate toxicity, DA neuron degeneration is alleviated by expressing the modified, hyperphosphorylated tauE14. Together, these results show that impairment of VMAT-containing synaptic vesicle, released to synapses before overt tauopathy may be the underlying mechanism of tau-associated PD and suggest that correction or prevention of this deficit may be appropriate targets for early therapeutic intervention.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1105-x) contains supplementary material, which is available to authorized users.
Parkinson’s disease; Dopamine; Tau; MAPT; Neuron degeneration; Tauopathy
Background: Diabetic nephropathy (DN) is one of the most common chronic complications of diabetes and the leading cause of end-stage renal disease. Recent research has found that oxidative stress participates in the development of diabetic nephropathy. α-lipoic acid (α-LA), a powerful antioxidant, plays an important role in renal protection against DN, but the underlying mechanism remains unknown. This study modeled the renal protective effects of α-lipoic acid in streptozotocin (STZ) induced diabetic rats and explore the underlying mechanism, which provides new theoretical bases for clinical treatment of diabetic nephropathy. Methods: The diabetic model was induced by intraperitoneal injection of STZ on Male SD and then the diabetic rats were randomly divided into two groups: untreated-diabetic group (DM group), α-LA treated-diabetic group (α-LA group), and the normal rats served as control group (NC group). After 8 weeks of STZ induction, Blood glucose (BG), Blood Urea Nitrogen (BUN), Serum Creatinine (SCr) and urinary albumin excretion rate (UAER) were examined, and morphological changes were assessed by histology. The levels of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD) were also evaluated in serum and renal cortex. Additionally, kidney mitochondrial membrane potential and mitochondrial swelling were measured for different groups. The expression of voltage-dependent anion channel (VDAC) on mitochondria were evaluated by both Western blotting and Immunohistochemistry. Results: After 8 weeks induction of STZ, significant reductions in BUN, SCr, UAER (P<0.01 or P<0.05) and histological improvement were observed in the α-LA group compared to the DM group. In the serum and renal cortex of α-LA group, the content of MDA and the activities of SOC were both significantly decreased (P<0.05). Compared to the DM group, the mitochondrial membrane potential in the α-LA group was significantly increased (P<0.05) and mitochondrial swelling was reduced. Meanwhile, the expression of VDAC on mitochondrial was significantly increased (P<0.05) in the α-LA group. Conclusion: Our findings indicate that antioxidant α-LA exerts a protective role against the development of DN, and the underlying mechanism may involve effective suppression of the generation of oxidants, protection of mitochondrial function, and up-regulating of VDAC expression.
Diabetic nephropathy; reactive oxygen species; mitochondria; voltage-dependent anion channel; α-lipoic acid
Robotic surgery has been widely adopted for radical prostatectomy. We hypothesize that this change is rapidly shifting procedures away from hospitals that do not offer robotics and consequently increasing patient travel.
A population-based observational study of all prostatectomies for cancer in NY, NJ, and PA from 2000–2009 was performed using hospital discharge data. Hospital procedure volume was defined as the number of prostatectomies performed for cancer in a given year. Straight-line travel distance to treating hospital was calculated for each case. Hospitals were contacted to determine year of acquisition of first robot.
From 2000–2009, the total number of prostatectomies performed annually increased substantially. The increase occurred almost entirely at the very high volume centers (≥106 prostatectomies/year). The number of hospitals performing prostatectomy fell 37% from 2000–2009. By 2009, the 9% (21/244) of hospitals that had very high volume performed 57% of all prostatectomies, and the 35% (86/244) of hospitals with a robot performed 85% of all prostatectomies. Median travel increased 54% from 2000–2009, p<0.001. The proportion of patients traveling ≥15 miles increased from 24% to 40%, p<0.001.
Over the past decade, the number of radical prostatectomies performed has risen substantially. These procedures have been increasingly centralized at high volume centers, leading to longer patient travel distances. Few prostatectomies are now performed at hospitals that do not offer robotic surgery. Future work should focus on the impact of these trends on cancer control, functional outcomes, access to care and cost.
The anomalous origin of the right pulmonary artery from the ascending aorta combined with coarctation of aorta is a rare congenital malformation. The method chosen for performing a prompt surgery to correct the multiple disease lesions is important. Here we report one-stage surgical strategy which involved a double-flap technique alongside an extended end-to-end arch reconstruction in a newborn baby.
Anomalous origin of the pulmonary artery; anomalous origin of the right pulmonary artery; AORPA; arch hypoplasia; double flap technique
Though patients who receive surgery from high-volume surgeons tend to have better outcomes, black patients are less likely to receive surgery from high-volume surgeons.
Among men with localized prostate cancer, we examined whether disparities in use of high-volume urologists resulted from racial differences in patients being diagnosed by high-volume urologists and/or changing to high-volume urologists for surgery.
Retrospective cohort study from Surveillance, Epidemiology, and End Results-Medicare data
26,058 black and white men in SEER-Medicare diagnosed with localized prostate cancer from 1995 to 2005 that underwent prostatectomy. Patients were linked to their diagnosing urologist and a treating urologist (who performed the surgery).
Diagnosis and receipt of prostatectomy by a high-volume urologist, and changing between diagnosing and treating urologist
After adjustment for confounders, black men were as likely as white men to be diagnosed by a high-volume urologist; however, they were significantly less likely than white men to be treated by a high-volume urologist (Odds ratio 0.76, 95% Confidence Interval [CI] 0.67, 0.87). For men diagnosed by a low-volume urologist, 46.0% changed urologists for their surgery. Black men were significantly less likely to change to a high-volume urologist (Relative Risk Ratio 0.61, 95%CI 0.47, 0.79). Racial differences appeared to reflect black and white patients being diagnosed by different urologists and having different rates of changing after being diagnosed by the same urologists.
Lower rates of changing to high-volume urologists for surgery among black men contribute to racial disparities in treatment by high-volume surgeons.
Prostate Cancer; Healthcare Disparities; High-volume; Provider Changing
The CD34+CD38- subset of AML cells is enriched for resistance to current chemotherapeutic agents and considered to contribute to disease progression and relapse in Acute Myeloid Leukaemia (AML) patients following initial treatment.
Chemosensitivity in phenotypically defined subsets from 34 primary AML samples was measured by flow cytometry following 48 hr in vitro treatment with gemtuzumab ozogamicin (GO, Mylotarg) and the farnesyltransferase inhibitor tipifarnib/zarnestra. The DNA damage response was measured using flow cytometry, immunofluorescence and immunohistochemistry.
Using a previously validated in vitro minimal residual disease model, we now show that the combination of GO (10 ng/ml) and tipifarnib (5 μM) targets the CD34+CD38- subset resulting in 65% median cell loss compared to 28% and 13% CD34+CD38- cell loss in GO-treated and tipifarnib-treated cells, respectively. Using phosphokinome profiling and immunofluorescence in the TF-1a cell line, we demonstrate that the drug combination is characterised by the activation of a DNA damage response (induction of γH2A.X and thr68 phosphorylation of chk2). Higher induction of γH2AX was found in CD34+CD38- than in CD34+CD38+ patient cells. In a model system, we show that dormancy impairs damage resolution, allowing accumulation of γH2AX foci.
The chemosensitivity of the CD34+CD38- subset, combined with enhanced damage indicators, suggest that this subset is primed to favour programmed cell death as opposed to repairing damage. This interaction between tipifarnib and GO suggests a potential role in the treatment of AML.
Tipifarnib/Zarnestra; Gemtuzumab ozogamicin/ Mylotarg; AML CD34+CD38- cells; DNA damage response
To assess whether incidental screening resulting from imaging conducted for other purposes has resulted in earlier detection or better outcomes in patients with adrenocortical carcinoma (ACC).
MATERIALS AND METHODS
We used the National Cancer Database (NCDB) to assemble a cohort diagnosed with ACC from 1985 to 2007. Trends in the distribution of grouped tumor sizes were assessed with the Cochran Armitage Chi-square test. Relative 5-year survival rates were calculated for cases diagnosed through 2002.
Median survival for the full cohort (n=4,275) was 24 months. Localized ACC accounted for 43.9% of cases. No stage migration over time was noted. No statistical trends were noted in changes of tumor size over the years in patients who underwent surgery for localized disease (p=0.32). Furthermore, no improvement in 5-year survival over the time period was observed (p>0.1).
In this cohort of ACC patients – the largest reported to date – fewer than half presented with localized disease (43.9%). No shift toward lower stage nor smaller tumor size over a 22 year period was noted, despite the advent of abdominal imaging and its resulting “incidental screening” of the adrenal gland. These data are in contrast to the well-documented stage and size migration for tumors of the kidney – a neighboring retroperitoneal organ. Furthermore, no improvement in survival was noted. As such, better risk-stratifying patients with adrenal incidentalomas, while improving treatment efficacy for those with proven ACC is an essential clinical and epidemiological task.
adrenocortical carcinoma; National Cancer Database; cancer screening; stage migration
Experiences and inflammatory mediators are fundamental in the provocation of major depressive disorders (MDDs). We investigated the roles and mechanisms of inducible nitric oxide synthase (iNOS) in stress-induced depression.
We used a depressive-like state mouse model induced by unpredictable chronic mild stress (UCMS). Depressive-like behaviors were evaluated after 4 weeks of UCMS, in the presence and absence of the iNOS inhibitor N-(3-(aminomethyl)benzyl)acetamidine (1400 W) compared with the control group. Immunohistochemistry was used to check the loss of Nissl bodies in cerebral cortex neurons. The levels of iNOS mRNA expression in the cortex and nitrites in the plasma were measured with real-time reverse transcription PCR (RT-PCR) and Griess reagent respectively.
Results showed that the 4-week UCMS significantly induced depressive-like behaviors, including decreased sucrose preference in a sucrose preference test, increased duration of immobility in a forced swim test, and decreased hole-searching time in a locomotor activity test. Meanwhile, in the locomotor activity test, UCMS had no effect on normal locomotor activities, such as resting time, active time and total travel distance. Furthermore, the levels of iNOS mRNA expression in the cortex and nitrites in the plasma of UCMS-exposed mice were significantly increased compared with that of the control group. Neurons of cerebral cortex in UCMS-exposed mice were shrunken with dark staining, together with loss of Nissl bodies. The above-mentioned stress-related depressive-like behaviors, increase of iNOS mRNA expression in the cortex and nitrites in the plasma, and neuron damage, could be abrogated remarkably by pretreating the mice with an iNOS inhibitor (1400 W). Moreover, neurons with abundant Nissl bodies were significantly increased in the 1400 W + UCMS group.
These results support the notion that stress-related NO (derived from iNOS) may contribute to depressive-like behaviors in a mouse model, potentially concurrent with neurodegenerative effects within the cerebral cortex.
Depressive behavior; inducible nitric oxide synthase; unpredictable chronic mild stress
We sought to evaluate the survival of patients who received breast surgery prior to any other breast cancer therapy following a metastatic diagnosis. Standard treatment for stage IV breast cancer is systemic therapy without resection of the primary tumor. Registry-based studies suggest that resection of the primary tumor may improve survival in stage IV cancer. We performed a retrospective analysis using data from the National Comprehensive Cancer Network (NCCN) Breast Cancer Outcomes Database. Patients were eligible if they had a metastatic breast cancer diagnosis at presentation with disease at a distant site and either received surgery prior to any systemic therapy or received systemic therapy only. Eligible patients who did not receive surgery were matched to those who received surgery based on age at diagnosis, ER, HER2, and number of meta-static sites. To determine whether estimates from the matched analysis were consistent with estimates that could be obtained without matching univariate and multivariable analyses of the unmatched sample were also conducted. There were 1,048 patients in the NCCN database diagnosed with stage IV breast cancer from 1997 to 2007. 609 meta-static breast cancer patients were identified as eligible for the study. Among the 551 patients who had data available for matching, 236 patients who did not receive surgery were matched to 54 patients who received surgery. Survival was similar between the groups with a median of 3.4 years in the nonsurgery group and 3.5 years in the surgery group. The groups were similar after adjusting for the presence of lung metastases and use of trastuzumab therapy (HR = 0.94, CI 0.83–1.08, P = 0.38). When matching for the variables associated with a survival benefit in previous studies, surgery was not shown to improve survival in the stage IV setting for this subset
Stage IV breast cancer; Surgery; Survival; Mastectomy
Prostate cancer screening rates are higher than colorectal cancer screening rates, despite the established benefit of screening in reducing colorectal cancer incidence and mortality.
We used data from the 2006 Behavioral Risk Factor Surveillance System (BRFSS) to identify correlates of colorectal cancer screening among men who have undergone prostate cancer screening.
Our sample included 41,781 men aged 50 years and older who reported undergoing prostate cancer screening in the last year. More than two-thirds (69.2%) of the men were up to date with colorectal cancer screening. On multivariable analysis, men who were younger, Hispanic, less educated, not married or partnered, employed, not a veteran, did not have a personal doctor, lacked a recent medical checkup, smoked, or were sedentary were less likely to be adherent to colorectal cancer screening.
Tailored interventions targeted towards men who have already undergone prostate cancer screening may improve rates of colorectal cancer screening in a group that may be already aware of, and interested in, the benefits of cancer risk prevention. The prostate cancer screening encounter may represent a “teachable moment” to increase colorectal cancer screening rates.
Data from the National Comprehensive Cancer Network's Breast Cancer Outcomes Database were used to characterize the use of trastuzumab beyond disease progression in National Comprehensive Cancer Network centers prior to the 2009 publication supporting it use.
The role of continued trastuzumab after progression in women with human epidermal growth factor receptor (HER)-2+ metastatic breast cancer is controversial. Controlled clinical trials that establish a benefit from continued trastuzumab have been difficult to complete.
In the National Comprehensive Cancer Center Network (NCCN) Breast Cancer Outcomes Database, we identified women treated with trastuzumab for metastatic or relapsed HER-2+ breast cancer at eight NCCN centers who subsequently progressed. Patients were eligible for this analysis if they initiated treatment at an NCCN institution between July 1997 and December 2004, received trastuzumab-containing treatment, and progressed while on therapy. We calculated the proportion of patients who received trastuzumab after progression, and in a multivariate analysis assessed the association of patient and provider characteristics with continued trastuzumab therapy.
Our final cohort consisted of 218 women who experienced disease progression while on trastuzumab-containing therapy. Of these, 168 (77%) continued trastuzumab. Of these, 36 patients (17%) received therapy as part of a clinical trial. The only factors significantly associated with continuation of trastuzumab beyond progression were the presence of bone metastases and more recent year of development of progressive disease.
Prior to the availability of any high-quality evidence supporting this practice, over three quarters of patients treated with trastuzumab for HER-2+ metastatic breast cancer at eight NCCN centers continued therapy beyond progression. Further work is needed to understand how physicians adopt new treatments when there is ambiguity surrounding their benefit.
PSA doubling time (PSADT) is commonly used as an indication for salvage androgen deprivation therapy (ADT) for PSA failure following RT. Previously, we had shown that PSADT of <12 months is an important predictor of distant metastasis following 3DCRT using the ASTRO definition of BF. We sought to determine if this approach is still valid using the Phoenix definition.
Eligible patients included 432 men with T1-3N0M0 prostate cancer who demonstrated PSA failure after completing definitive 3DCRT or IMRT from 1989–2005. Endpoints included freedom from distant metastasis (FDM), cause-specific survival (CSS) and overall survival (OS). PSADT was stratified by 0–6, 6–12, 12–18, 18–24, and >24 months. The median follow-up was 95 months (6–207 months).
The 7 year FDM, CSS, and OS rates for the entire group were 73%, 77% and 52%, respectively. 7 year FDM was 50% for PSADT <6 months vs. 83% for PSADT >6 months (p=0.0001). 7 year CSS was 61% for PSADT <6 and 85% for PSADT >6 (p=0.0001). 7 year OS was 47% for PSADT <6 and 53% for PSADT >6 (p=0.04). The proportion of men with BF receiving salvage ADT with a PSADT <6 months was 59%, 6–12 was 45%, 12–18 was 42%, 18–24 was 36%, >24 was 28%. ADT was associated with improved 7 year CSS (68% vs. 46%, p=0.015). Of the 314 men with PSADT >6 months, 124 received ADT and 190 were observed. With a median follow-up of 38 months from BF, there was no demonstrable benefit to ADT in the 7 year CSS (87% vs. 79%, respectively; p=0.758). Independent predictors of FDM were PSADT (p<0.0001), GS (p=0.011), and the use of initial ADT (p=0.005).
PSADT remains a significant predictor of clinical failure and CSS for men treated with 3DCRT or IMRT who fail according to the Phoenix definition. Immediate use of ADT in patients with PSADT <6 months is significantly associated with improved CSS, although the benefit is less apparent in patients with longer PSADT. These results further refine the role of PSADT in predicting which patients may benefit from salvage ADT and those who may be observed expectantly.
Prostate Cancer; Prostate Specific Antigen; IMRT; PSA Doubling Time; Biochemical Failure; Phoenix Definition