Unsettling the Peace? The Role of Illicit Economies in Peace Processes
The long-term legacies of civil war economies-often characterized by widespread illicit economic activities and the proliferation of criminal and quasi-criminal networks-pose significant challenges to achieving sustainable postwar settlements. This essay surveys predominant strategies to address war economies in peace processes for countries emerging from war. I identify three prevailing approaches-criminalization, co-option, and neglect-and discuss trade-offs associated with each. While there is no clear consensus on which approach is most likely to succeed and most countries will require a balanced combination of all three, it is increasingly clear that peace agreements that fail to sufficiently incorporate the perspectives of communities dependent on illicit economies and to account for how illicit economies shape national and subnational political settlements are more likely to produce unstable postwar regimes in the medium to long-run. I conclude with some reflections on future research agendas and potential policy implications that merit further exploration.
Critical policy frontiers: The drugs-development-peacebuilding trilemma
Recent years have seen the emergence of a policy consensus around the need for fundamental reforms of global drug policies. This is reflected in the call for 'development-oriented drug policies' that align and integrate drug policies with development and peacebuilding objectives, as captured in the Sustainable Development Goals (SDGs). These calls have been important in acknowledging the damage caused by the war on drugs and in drawing attention to how drugs are inextricably linked to wider development and peacebuilding challenges. Yet there is surprisingly limited academic research that looks critically at the drugs-development-peace nexus and which asks whether the goals of a 'drug-free world', 'sustainable development' and 'the promotion of peace' are commensurate with one another, can be pursued simultaneously, or are indeed achievable. This articles studies these policy fields and policy-making processes from the geographical margins of the state - frontiers and borderland regions - because they offer a privileged vantage point for studying the contested nature of policymaking in relation to the drugs-development-peace nexus. We set out a historical political economy framework to critically assess the assumptions underlying the integrationist agenda, as well as the evidence base to support it. By developing the notion of a policy trilemma we are critical of the dominant policy narrative that 'all good things come together', showing instead the fundamental tensions and trade-offs between these policy fields. In exploring the interactions between these policy fields, we aim to advance discussion and debate on how to engage with the tensions and trade-offs that this integrationist agenda reveals, but which have to date been largely ignored.
Drugs, conflict and development [Editorial]
Improved survival for BRCA2-associated serous ovarian cancer compared with both BRCA-negative and BRCA1-associated serous ovarian cancer
BACKGROUND: Multiple observational studies have suggested that breast cancer gene (BRCA)-associated ovarian cancers have improved survival compared with BRCA-negative ovarian cancers. However, most of those studies combined BRCA1 and BRCA2 patients or evaluated only BRCA1 patients. The objective of the current study was to examine whether BRCA1-associated and BRCA2-associated ovarian cancers were associated with different outcomes. METHODS: This was a single-institution, retrospective analysis of patients who had a new diagnosis of histologically confirmed stage III or IV serous ovarian, fallopian tube, or primary peritoneal cancer between January 1, 1996 and February 1, 2011 and who underwent BRCA mutation testing on 1 of 2 institutional review board-approved follow-up studies. Patients who had been tested for BRCA mutations beyond 24 months of diagnosis were excluded from analysis to minimize selection bias from including patients who were referred for genetic testing because of long survival. RESULTS: Data from 190 patients (143 BRCA-negative patients, 30 BRCA1-positive patients, and 17 BRCA2-positive patients) were analyzed. During the study period, 73 deaths were observed (60 BRCA-negative patients, 10 BRCA1-positive patients, 3 BRCA2-positive patients). The median follow-up for the remaining 117 survivors was 2.5 years. At 3 years, 69.4%, 90.7%, and 100% of BRCA-negative patients, BRCA1-positive patients, and BRCA2-positive patients were alive, respectively. On univariate analysis, age, BRCA2 mutations, debulking status, and type of first-line therapy (intravenous or intraperitoneal) were significant predictors of overall survival. On multivariate analysis, BRCA2 mutations (hazard ratio, 0.20; 95% confidence interval, 0.06-0.65; P = .007), but not BRCA1 mutations (hazard ratio, 0.70; 95% confidence interval, 0.36-1.38; P = .31), predicted for improved overall survival compared with BRCA-negative patients. When carriers of BRCA2 mutations were directly compared with carriers of BRCA1 mutations, BRCA2 mutations appeared to confer improved overall survival (hazard ratio, 0.29; 95% confidence interval, 0.08-1.05; P = .060), although this finding did not reach significance. CONCLUSIONS: The current data suggests that BRCA2 mutations confer an overall survival advantage compared with either being BRCA-negative or having a BRCA1 mutation in high-grade serous ovarian cancer. This finding may have important implications for clinical trial design.
Outcomes of primary surgical cytoreduction in patients with BRCA-associated high-grade serous ovarian carcinoma
OBJECTIVE: BRCA-associated and sporadic ovarian cancers have different pathologic and clinical features. Our goal was to determine if BRCA mutation status is an independent predictor of residual tumor volume following primary surgical cytoreduction. METHODS: We conducted a retrospective analysis of patients with FIGO stage IIIC-IV high-grade serous ovarian cancer classified for the presence or absence of germline BRCA mutations. The primary outcome was tumor-debulking status categorized as complete gross resection (0mm), optimal but visible disease (1-10 mm), or suboptimal debulking (>10 mm) following primary surgical cytoreduction. Overall survival by residual tumor size and BRCA status was also assessed as a secondary endpoint. RESULTS: Data from 367 patients (69 BRCA mutated, 298 BRCA wild-type) were analyzed. Rate of optimal tumor debulking (0-10 mm) in BRCA wild-type and BRCA-mutated patients were 70.1% and 84.1%, respectively (P=0.02). On univariate analysis, increasing age (10-year OR, 1.33; 95% CI, 1.07-1.65; P=0.01) and wild-type BRCA status (OR, 0.47; 95% CI, 0.23-0.94, P=0.03) were both significantly associated with suboptimal surgical outcome. On multivariate analysis, BRCA mutation status was no longer associated with residual tumor volume (OR, 0.63; 95% CI, 0.31-1.29; P=0.21) while age remained a borderline significant predictor (10-year OR, 1.25; 95% CI, 1.01-1.56; P=0.05). Both smaller residual tumor volume and mutant BRCA status were significantly associated with improved overall survival. CONCLUSION: BRCA mutation status is not associated with the rate of optimal tumor debulking at primary surgery after accounting for differences in patient age. Improved survival of BRCA carriers is unlikely the result of better surgical outcomes but instead intrinsic tumor biology.
Germline BRCA mutation does not prevent response to taxane-based therapy for the treatment of castration-resistant prostate cancer
OBJECTIVE:â€¢ To investigate the relationship between BRCA mutation status and response to taxane-based chemotherapy, since BRCA mutation carriers with prostate cancer appear to have worse survival than non-carriers and docetaxel improves survival in patients with castration-resistant prostate cancer. PATIENTS AND METHODS/METHODS:â€¢ We determined BRCA mutation prevalence in 158 Ashkenazi Jewish (AJ) men with castration-resistant prostate cancer. Clinical data were collected as part of an institutional prostate cancer research database and through additional medical record review. â€¢ Clinical records and DNA samples were linked through a unique identifier, anonymizing the samples before genetic testing for the AJ BRCA1/2 founder mutations. â€¢ Response to taxane-based therapy was defined by the prostate-specific antigen nadir within 12 weeks of therapy. RESULTS:â€¢ In all, 88 men received taxane-based treatment, seven of whom were BRCA carriers (three BRCA1, four BRCA2; 8%). Initial response to taxane was available for all seven BRCA carriers and for 69 non-carriers. â€¢ Overall, 71% (54/76) of patients responded to treatment, with no significant difference between carriers (57%) and non-carriers (72%) (absolute difference 15%; 95% confidence interval -23% to 53%; P= 0.4). â€¢ Among patients with an initial response, the median change in prostate-specific antigen was similar for BRCA carriers (-63%, interquartile range -71% to -57%) and non-carriers (-60%, interquartile range -78% to -35%) (P= 0.6). â€¢ At last follow-up, all seven BRCA carriers and 49 non-carriers had died from prostate cancer. One BRCA2 carrier treated with docetaxel plus platinum survived 37 months. CONCLUSION/CONCLUSIONS:â€¢ In this small, hypothesis-generating study approximately half of BRCA carriers had a prostate-specific antigen response to taxane-based chemotherapy, suggesting that it is an active therapy in these individuals.
Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2
INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.
Susceptibility loci associated with prostate cancer progression and mortality
PURPOSE: Prostate cancer is a heterogeneous disease with a variable natural history that is not accurately predicted by currently used prognostic tools. EXPERIMENTAL DESIGN: We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and prostate-specific antigen. We investigated associations between 29 single nucleotide polymorphisms (SNP) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Subsequently, we did an independent analysis using a high-resolution panel of 13 SNPs. RESULTS: On univariate analysis, two SNPs were associated (P<0.05) with biochemical recurrence, three SNPs were associated with clinical metastases, and one SNP was associated with prostate cancer-specific mortality. Applying a Bonferroni correction (P<0.0017), one association with biochemical recurrence (P=0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer-specific mortality in KLK3 (P<0.0005 by both univariate and multivariable analysis). CONCLUSIONS: We identified associations between prostate cancer susceptibility SNPs and clinical end points. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region were strongly associated with prostate cancer-specific survival, and rs10486567 in the 7JAZF1 gene were associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models
Germline BRCA mutations denote a clinicopathologic subset of prostate cancer
PURPOSE: Increased prostate cancer risk has been reported for BRCA mutation carriers, but BRCA-associated clinicopathologic features have not been clearly defined. EXPERIMENTAL DESIGN: We determined BRCA mutation prevalence in 832 Ashkenazi Jewish men diagnosed with localized prostate cancer between 1988 and 2007 and 454 Ashkenazi Jewish controls and compared clinical outcome measures among 26 BRCA mutation carriers and 806 noncarriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason score, and logistic regression models were used to determine associations between carrier status, prostate cancer risk, and Gleason score. Hazard ratios (HR) for clinical end points were estimated using Cox proportional hazards models. RESULTS: BRCA2 mutations were associated with a 3-fold risk of prostate cancer [odds ratio, 3.18; 95% confidence interval (95% CI), 1.52-6.66; P = 0.002] and presented with more poorly differentiated (Gleason score > or =7) tumors (85% versus 57%; P = 0.0002) compared with non-BRCA-associated prostate cancer. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, prostate-specific antigen, Gleason score, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence [HR (95% CI), 2.41 (1.23-4.75) and 4.32 (1.31-13.62), respectively] and prostate cancer-specific death [HR (95% CI), 5.48 (2.03-14.79) and 5.16 (1.09-24.53), respectively] than noncarriers. CONCLUSIONS: BRCA2 mutation carriers had an increased risk of prostate cancer and a higher histologic grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have implications for tailoring clinical management of this subset of hereditary prostate cancer
Perioperative complications of blood brain barrier disruption under general anesthesia: a retrospective review
Blood brain barrier disruption enhances drug delivery in primary central nervous system lymphoma. In this study, we report adverse events that were encountered intraoperatively and in the postoperative period in these patients. A retrospective analysis of 17 patients documenting demographic data, preprocedure medical history, intraoperative, and postoperative anesthetic complications was conducted between January 2002 and December 2004. Seventeen patients underwent 210 treatments under general anesthesia with a mean of 12.4+/-7.2 treatments per patient. Focal seizures occurred in 13% of patients. Generalized motor seizures occurred in 4 treatment sessions in 2 different patients. The incidence of seizures was significantly higher when the internal carotid artery was used for injection, as opposed to the vertebral artery (20.8% and 6.02%, respectively, P=0.0034). Tachycardia associated with ST segment depression occurred 9 times (4.3%) in 3 patients. One patient had significant ST segment elevation (more than 1.5 mm). Transient cerebral vasospasm after methotrexate injection occurred in 9% of patients. Postoperative nausea and vomiting were observed in 11.9% of patients. After emergence, lethargy and obtundation occurred in 7.6% of the cases. The incidence of postoperative headache and reversible motor deficits was 6% and 3.8%, respectively. Our review highlights the problems that were encountered during blood brain barrier disruption under anesthesia and in the postoperative period. Further prospective studies are required for comprehensive evaluation of intraprocedure and postprocedure complications that will allow development of an optimal anesthetic plan and will improve patient outcome by preventing potential complications.