[show abstract][hide abstract] ABSTRACT: Platinum-based chemotherapy regimens are frequently used in patients with triple-negative breast cancer (TNBC). The aim of the current study was to assess whether or not platinum-based chemotherapy is associated with an increased time to progression when compared with non-platinum-based regimens in TNBC and non-TNBC. A retrospective analysis was conducted within a cohort of patients with metastatic breast cancer who received platinum-based chemotherapy at a single institution. Data were collected for up to three lines of treatment for metastatic disease. Time to progression was determined for platinum-based chemotherapy and non-platinum-based regimens for each line of treatment. Adjusted hazard ratios (HRs), together with 95% confidence intervals (CIs) were estimated comparing the time to progression associated with the use of platinum-based chemotherapy versus non-platinum-based regimens. A total of 159 patients were included in the analysis, with 58 diagnosed with TNBC. Among the patients with TNBC, compared with non-platinum-based chemotherapy, no correlation was identified between platinum-based chemotherapy and an improved time to progression [first line: HR, 0.97 (95% CI, 0.40-2.35); second line: HR, 0.91 (95% CI, 0.42-2.01); and third line: HR, 2.83 (95% CI, 0.73-11.03)]. By contrast, patients with non-TNBC appeared to improve with non-platinum-based chemotherapy [first line: HR, 2.57 (95% CI, 1.11-5.99); second line: HR, 1.91 (95% CI, 1.00-3.63); and third line: HR, 1.08 (95% CI, 0.53-2.18)]. Although the present study was limited by the sample size and its observational nature, the results indicated that platinum-based chemotherapy does not offer a discernible or distinct advantage compared with standard regimens in patients with TNBC, and is perhaps less efficacious in patients with non-TNBC.
[show abstract][hide abstract] ABSTRACT: The aim of this study was to determine whether type 2 diabetes is associated with the incidence of prostate cancer mortality and all-cause mortality.
This study was conducted by linking four databases from the United Kingdom: the National Cancer Data Repository, the Clinical Practice Research Datalink, the Hospital Episodes Statistics database, and the Office for National Statistics database. The cohort consisted of men newly diagnosed with non-metastatic prostate cancer between 1 April 1998 and 31 December 2009, followed until 1 October 2012. Cox proportional hazard models were used to estimate adjusted hazard ratios with 95 % confidence intervals (CIs) of prostate cancer mortality and all-cause mortality comparing patients with to without type 2 diabetes. All models were adjusted for a number of potential confounders, which included excessive alcohol use, smoking, comorbidities, and prostate cancer-related variables.
The cohort consisted of 11,920 patients, which included 1,132 (9.5 %) with preexisting type 2 diabetes. During a mean follow-up of 4.7 (SD 3.0) years, there were 3,605 deaths (incidence rate: 6.4 %/year) including 1,792 from prostate cancer (incidence rate: 3.3 %/year). Type 2 diabetes was associated with a 23 % increased risk of prostate cancer mortality (HR 1.23, 95 % CI 1.04-1.46) and a 25 % increased risk in all-cause mortality (HR 1.25, 95 % CI 1.11-1.40).
The results of this large population-based study indicate that type 2 diabetes is associated with an increased risk of prostate cancer mortality and all-cause mortality, which may signal an association between hyperinsulinemia or other diabetes-associated metabolic derangements and cancer aggressivity.
Cancer Causes and Control 01/2014; · 3.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective
Clinical practice guidelines disagree on whether health care professionals should screen women for depression during pregnancy or postpartum. The objective of this systematic review was to determine whether depression screening improves depression outcomes among women during pregnancy or the postpartum period.
Searches included the CINAHL, EMBASE, ISI, MEDLINE, and PsycINFO databases through April 1, 2013; manual journal searches; reference list reviews; citation tracking of included articles; and trial registry reviews. RCTs in any language that compared depression outcomes between women during pregnancy or postpartum randomized to undergo depression screening versus women not screened were eligible.
There were 9,242 unique titles/abstracts and 15 full-text articles reviewed. Only 1 RCT of screening postpartum was included, but none during pregnancy. The eligible postpartum study evaluated screening in mothers in Hong Kong with 2-month-old babies (N = 462) and reported a standardized mean difference for symptoms of depression at 6 months postpartum of 0.34 (95% confidence interval = 0.15 to 0.52, P < 0.001). Standardized mean difference per 44 additional women treated in the intervention trial arm compared to the non-screening arm was approximately 1.8. Risk of bias was high, however, because the status of outcome measures was changed post-hoc and because the reported effect size per woman treated was 6–7 times the effect sizes reported in comparable depression care interventions.
There is currently no evidence from any well-designed and conducted RCT that screening for depression would benefit women in pregnancy or postpartum. Existing guidelines that recommend depression screening during pregnancy or postpartum should be re-considered.
[show abstract][hide abstract] ABSTRACT: An increased risk of stroke was observed in two atrial fibrillation (AF) trials of oral factor Xa inhibitors, when patients were transitioned to open label warfarin at the end of the study. The objective of this study is to determine whether initiation of warfarin is associated with an increased risk of stroke in patients with AF.
Using the UK Clinical Practice Research Datalink, a nested case-control analysis was conducted within a cohort of 70 766 patients with AF between 1993 and 2008. Stroke cases were randomly matched with up to 10 controls on age, sex, date of AF diagnosis, and time since AF diagnosis. Conditional logistic regression was used to estimate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) of stroke associated with current warfarin use classified according to time since initiation of treatment (<30 days, 31-90 days, and >90 days), when compared with non-use. A total of 5519 patients experienced a stroke during follow-up. Warfarin was associated with a 71% increased risk of stroke in the first 30 days of use (RR: 1.71, 95% CI: 1.39-2.12), while decreased risks were observed with initiation >30 days before the event (31-90 days: RR: 0.50, 95% CI: 0.34-0.75 and >90 days: RR: 0.55, 95% CI: 0.50-0.61, respectively).
Patients initiating warfarin may be at an increased risk of stroke during the first 30 days of treatment, supporting the biological plausibility of a transient hypercoagulable state at the start of the treatment, although additional studies are needed to confirm these findings.
European Heart Journal 12/2013; · 14.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: The Eph and Ephrin proteins, which constitute the largest family of receptor tyrosine kinases, are involved in normal tissue development and cancer progression. Here, we examined the expression and role of the B-type Eph receptor EphB2 in breast cancers. By immunohistochemistry using a progression tissue microarray of human clinical samples, we found EphB2 to be expressed in benign tissues, but strongly increased in cancers particularly in invasive and metastatic carcinomas. Subsequently, we found evidence that EphB2, whose expression varies in established cell breast lines, possesses multiple functions. First, the use of a DOX-inducible system to restore EphB2 function to low expressers resulted in decreased tumor growth in vitro and in vivo, while its siRNA-mediated silencing in high expressers increased growth. This function involves the onset of apoptotic death paralleled by caspases 3 and 9 activation. Second, EphB2 was also found to induce autophagy, as assessed by immunofluorescence and/or immunoblotting examination of the LC3, ATG5 and ATG12 markers. Third, EphB2 also has a pro-invasive function in breast cancer cells that involves the regulation of MMP2 and MMP9 metalloproteases and can be blocked by treatment with respective neutralizing antibodies. Furthermore, EphB2-induced invasion is kinase-dependent and is impeded in cells expressing a kinase-dead mutant EphB2. In summary, we identified a mechanism involving a triple role for EphB2 in breast cancer progression, whereby it regulates apoptosis, autophagy, and invasion.
Experimental Cell Research 11/2013; · 3.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine whether the use of statins after prostate cancer diagnosis is associated with a decreased risk of cancer-related mortality and all-cause mortality and to assess whether this association is modified by prediagnostic use of statins.
A cohort of 11,772 men newly diagnosed with nonmetastatic prostate cancer between April 1, 1998, and December 31, 2009, followed until October 1, 2012, was identified using a large population-based electronic database from the United Kingdom. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% CIs of mortality outcomes associated with postdiagnostic use of statins, lagged by 1 year to account for latency considerations and to minimize reverse causality, and considering effect modification by prediagnostic use of statins.
During a mean follow-up time of 4.4 years (standard deviation, 2.9 years), 3,499 deaths occurred, including 1,791 from prostate cancer. Postdiagnostic use of statins was associated with a decreased risk of prostate cancer mortality (HR, 0.76; 95% CI, 0.66 to 0.88) and all-cause mortality (HR, 0.86; 95% CI, 0.78 to 0.95). These decreased risks of prostate cancer mortality and all-cause mortality were more pronounced in patients who also used statins before diagnosis (HR, 0.55; 95% CI, 0.41 to 0.74; and HR, 0.66; 95% CI, 0.53 to 0.81, respectively), with weaker effects in patients who initiated the treatment only after diagnosis (HR, 0.82; 95% CI, 0.71 to 0.96; and HR, 0.91; 95% CI, 0.82 to 1.01, respectively).
Overall, the use of statins after diagnosis was associated with a decreased risk in prostate cancer mortality. However, this effect was stronger in patients who also used statins before diagnosis.
Journal of Clinical Oncology 11/2013; · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Experimental studies have suggested that metformin may decrease the incidence of colorectal cancer in patients with type 2 diabetes. However, previous observational studies have reported contradictory results, which are likely due to important methodological limitations. Thus, the objective of this study was to assess whether the use of metformin is associated with the incidence of colorectal cancer in patients with type 2 diabetes. Methods: A cohort study of patients newly-treated with non-insulin anti-diabetic agents was assembled using the United Kingdom Clinical Practice Research Datalink. A nested case-control analysis was conducted, where all incident cases of colorectal cancer occurring during follow-up were identified and randomly matched with up to 10 controls. Conditional logistic regression was used to estimate adjusted rate ratios (RRs) of colorectal cancer associated with ever use, and cumulative duration of use of metformin. All models accounted for latency and were adjusted for relevant potential confounding factors. Results: Overall, ever use of metformin was not associated with the incidence of colorectal cancer (RR: 0.93; 95% CI: 0.73-1.18). Similarly, no dose-response relationship was observed in terms of cumulative duration of use. Conclusion: The use of metformin was not associated with the incidence of colorectal cancer in patients with type 2 diabetes. Impact: The results of this study do not support the launch of metformin randomized controlled trials for the chemoprevention of colorectal cancer.
Cancer Epidemiology Biomarkers & Prevention 08/2013; · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: The use of androgen deprivation therapy (ADT) in the treatment of advanced prostate cancer has been shown to delay the clinical progression of the disease. However, the testosterone suppression associated with this therapy may lead to a hypogonadal condition that can have detrimental effects on renal function, thus raising the hypothesis that ADT-induced hypogonadism could potentially lead to acute kidney injury (AKI).
To determine whether the use of ADT is associated with an increased risk of AKI in patients newly diagnosed with prostate cancer.
A nested case-control analysis using medical information extracted from the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database.
Men newly diagnosed with nonmetastatic prostate cancer between January 1, 1997, and December 31, 2008, were selected and followed up until December 31, 2009. Cases were patients with incident AKI during follow-up who were randomly matched with up to 20 controls on age, calendar year of prostate cancer diagnosis, and duration of follow-up.
Conditional logistic regression was used to estimate odds ratios (ORs) with 95% CIs of AKI associated with the use of ADT. ADT was categorized into 1 of 6 mutually exclusive groups: gonadotropin-releasing hormone agonists, oral antiandrogens, combined androgen blockade, bilateral orchiectomy, estrogens, and combination of the above. RESULTS A total of 10,250 patients met the study inclusion criteria. During a mean follow-up of 4.1 (SD, 2.9) years, 232 incident cases of AKI were identified (rate, 5.5/1000 person-years). Overall, current use of any ADT was associated with an increased risk of AKI when compared with never use (OR, 2.48 [95% CI, 1.61-3.82]), generating a rate difference of 4.43/1000 persons per year (95% CI, 1.54-7.33). This association was mainly driven by a combined androgen blockade consisting of gonadotropin-releasing hormone agonists with oral antiandrogens (OR, 4.50 [95% CI, 2.61-7.78]), estrogens (OR, 4.00 [95% CI, 1.06-15.03]), other combination therapies (OR, 4.04 [95% CI, 1.88-8.69]), and gonadotropin-releasing hormone agonists (OR, 1.93 [95% CI, 1.20-3.10]).
In a cohort of patients with newly diagnosed nonmetastatic prostate cancer, the use of ADT was significantly associated with an increased risk of AKI. These findings require replication in other well-designed studies as well as further investigation of their clinical importance.
JAMA The Journal of the American Medical Association 07/2013; 310(3):289-96. · 29.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Panitumumab is a fully human monoclonal antibody that targets the epidermal growth factor receptor. Results from the primary analysis of a phase 3, randomized, controlled study showed a statistically significant improvement in progression-free survival for patients receiving panitumumab; however, overall survival was confounded by best supportive care (BSC) patients that crossed over to panitumumab therapy after disease progression. Three post hoc analyses are presented that approximate the panitumumab overall survival treatment effect in both the all-randomized and wild-type (WT) KRAS populations by using the BSC patients with mutant (MT) KRAS as the comparator group to discount the effect of crossover from BSC to panitumumab. The primary post hoc analysis showed a median overall survival of 6.4 months for all KRAS-evaluable patients randomized to panitumumab versus 4.4 months for patients with MT KRAS tumors randomized to BSC, yielding an adjusted hazard ratio (95 % CI) of 0.764 (0.598-0.977). Similar results were observed for the two secondary post hoc analyses. These analyses suggest a positive treatment effect of panitumumab in both the overall and WT KRAS patient populations consistent with an improvement in overall survival relative to BSC.
[show abstract][hide abstract] ABSTRACT: PURPOSE: Androgens are known to play an important protective role on colorectal carcinogenesis, and thus the objective of this study was to determine whether androgen deprivation therapy (ADT) is associated with an increased risk of incident colorectal cancer in patients with prostate cancer. METHODS: We conducted a population-based cohort study within the UK General Practice Research Database population which included all patients newly diagnosed with prostate cancer between 1 January 1988 and 31 December 2008, followed until 31 December 2009. Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) of incident primary colorectal cancer associated with the use of ADT. Secondary analyses considered cumulative duration of use and specific ADTs. RESULTS: The cohort included a total of 21,503 patients, of whom 184 were diagnosed with colorectal cancer during a mean (SD) follow-up 4.0 (3.0) years (rate 2.4/1,000 person-years). Overall, use of ADT was not associated with an increased risk of colorectal cancer (HR 0.99, 95 % CI 0.73-1.35). Similarly, no association was observed in terms of duration use, although this secondary analysis may have been limited by statistical power. With respect to specific ADTs, bilateral orchiectomy was the only therapy associated with an increased risk of colorectal cancer (HR 2.50, 95 % CI 1.13-5.52). CONCLUSION: Overall, the use of ADT is not associated with an increased risk of incident colorectal cancer. The increased risk observed with bilateral orchiectomy may possibly be due to the prolonged androgen suppression of this therapy.
Cancer Causes and Control 04/2013; · 3.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with atrial fibrillation (AF) often receive, in addition to warfarin, antithrombotic drugs to manage other comorbid conditions. To date, few population-based studies have quantified the bleeding risk associated with the concurrent use of these therapies. The United Kingdom General Practice Research Database was used to identify a cohort of 70,760 patients newly-diagnosed with AF between 1993 and 2008. A nested case-control analysis was conducted within that cohort, and conditional logistic regression was used to estimate adjusted rate ratios (RRs) of bleeding associated with current use of warfarin, aspirin, and clopidogrel in single therapy, as well as in dual and triple therapy, as compared with non-use of any therapy. A total of 10,850 patients experienced a bleeding event during follow-up. In single therapy, warfarin was associated with the highest increased risk (RR: 2.08, 95% confidence interval [CI]: 1.95-2.23), followed by clopidogrel (RR: 1.57, 95% CI: 1.37-1.81) and aspirin (RR: 1.25, 95% CI: 1.17-1.34). In dual therapy, combinations containing warfarin were associated with a higher increased risk (warfarin-aspirin: RR: 2.87, 95% CI: 2.58-3.19, and warfarin-clopidogrel: RR: 2.74, 95% CI: 2.14-3.51), than those not containing warfarin (aspirin-clopidogrel: RR: 1.68, 95% CI: 1.44-1.97). Triple therapy of warfarin-aspirin-clopidogrel was associated with the highest increased risk (RR: 3.75, 95% CI: 2.71-5.19). This large population-based study suggests that while all antithrombotic therapies are associated with an elevated risk of bleeding, the risks increase in an additive fashion with dual and triple therapy, particularly in combinations containing warfarin.
Thrombosis and Haemostasis 01/2013; 109(3). · 6.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess whether a double therapy combination consisting of diuretics, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers with addition of non-steroidal anti-inflammatory drugs (NSAIDs) and the triple therapy combination of two of the aforementioned antihypertensive drugs to which NSAIDs are added are associated with an increased risk of acute kidney injury.
Retrospective cohort study using nested case-control analysis.
General practices contributing data to the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database.
A cohort of 487 372 users of antihypertensive drugs.
Rate ratios with 95% confidence intervals of acute kidney injury associated with current use of double and triple therapy combinations of antihypertensive drugs with NSAIDs.
During a mean follow-up of 5.9 (SD 3.4) years, 2215 cases of acute kidney injury were identified (incidence rate 7/10 000 person years). Overall, current use of a double therapy combination containing either diuretics or angiotensin converting enzyme inhibitors or angiotensin receptor blockers with NSAIDs was not associated with an increased rate of acute kidney injury. In contrast, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio 1.31, 95% confidence interval 1.12 to 1.53). In secondary analyses, the highest risk was observed in the first 30 days of use (rate ratio 1.82, 1.35 to 2.46).
A triple therapy combination consisting of diuretics with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and NSAIDs was associated with an increased risk of acute kidney injury. The risk was greatest at the start of treatment. Although antihypertensive drugs have cardiovascular benefits, vigilance may be warranted when they are used concurrently with NSAIDs.