Top advances of the year: Precision oncology

The advent of precision medicine has changed the landscape of oncologic biomarkers, drug discovery, drug development, and, more importantly, outcomes for patients with cancer. Precision oncology entails the genomic profiling of tumors to detect actionable aberrations. The advances in clinical next-generation sequencing from both tumor tissue and liquid biopsy and availability of targeted therapies has rapidly entered mainstream clinical practice. In this review, recent major developments in precision oncology that have affected outcomes for patients with cancer are discussed. Rapid clinical development was seen of targeted agents across various mutational profiles such as KRASG12C (which was considered “undruggable” for almost 4 decades), Exon 20 insertions, and RET mutations. Approaches to precision chemotherapy delivery by the introduction of antibody drug conjugates in the armamentarium against lung cancer has been appreciated.     

Young drivers who continue to drive while sleepy: What are the associated sleep‐ and driving‐related factors?

Crashes due to sleepiness account for a substantial proportion of road crash incidents. The purpose of the current study was to examine several sleep‐related factors and driving‐related factors for their association with self‐reports of continuing to drive while sleepy. In total 257 young drivers aged 18–25 years completed an online survey that assessed factors such as sleep quality, sleep duration and consistency, excessive daytime sleepiness, experiences with sleepiness and their driving‐related behaviours. The results demonstrate that being older, having a perceived ability to overcome sleepiness, committing more highway code violations and having experienced a sleep‐related close call were positively associated with an increased likelihood of continuing to drive while sleepy. The obtained results highlight the acceptance of risky driving behaviours among some younger drivers. Younger drivers’ risky driving behaviour is certainly a road safety concern given the impairment associated with sleepiness and their over‐representation in road crash incidents.     

新型驱动基因融合阳性非小细胞肺癌脑转移的研究进展北大核心

肺癌是我国最常见且死亡率最高的恶性肿瘤之一,随着表皮生长因子受体(EGFR)、间变性淋巴瘤激酶(ALK)及活性氧1(ROS1)等驱动基因及其相应分子靶向药物的出现,晚期非小细胞肺癌的治疗和预后发生了革命性变化。此外,一些少见新型驱动基因融合,包括神经调节蛋白1(NRG1)、神经营养酪氨酸受体激酶(NTRK)和转染重排因子(RET),正逐渐发展成为全身性治疗选择。然而,这些罕见新型融合驱动基因在NSCLC脑转移中的作用机制,以及优化控制和预防脑转移的意义人们所知甚少。因此,本文就近几年罕见驱动基因融合在NSCLC脑转移中的研究进行综述。     

Intraductal carcinoma of the prostate in the absence of high-grade invasive carcinoma represents a molecularly distinct type of in situ carcinoma enriched with oncogenic driver mutations

Intraductal carcinoma of the prostate (IDC-P) most often appears associated with high-grade invasive prostate carcinoma (PCa), where it is believed to represent retrograde spread. However, IDC-P rarely occurs as an isolated finding at radical prostatectomy or with concurrent low-grade (Grade Group 1) invasive carcinoma. We hypothesized that isolated IDC-P (iIDC-P) in these unusual cases may represent a distinct in situ lesion and molecularly profiled 15 cases. iIDC-P was characterized by copy number alteration (CNA) profiling and targeted next generation sequencing in cases with sufficient tissue (n = 7). Immunohistochemistry for PTEN and ERG was performed on the total cohort (n = 15), where areas of iIDC-P and associated invasive disease were evaluated separately (n = 9). By copy number profiling, iIDC-P alterations were similar to those previously described in high-grade invasive PCa (PTEN, RB1, and CHD1 loss; MYC gain). However, in four cases, targeted sequencing revealed a striking number of activating oncogenic driver mutations in MAPK and PI3K pathway genes, which are extraordinarily rare in conventional PCa. In addition, pathogenic mutations in DNA repair genes were found in two cases of iIDC-P (BRCA2, CHEK2, CDK12) and other known PCa-associated mutations (FOXA1, SPOP) in two cases. Overall, ERG was expressed in 7% (1/15) of the iIDC-P lesions and PTEN was lost in 53% (8/15). Discordance for ERG or PTEN status between IDC-P and the low-grade PCa was observed in five of nine cases, with intact PTEN in the invasive tumor and PTEN loss in IDC-P in four. Despite a CNA profile similar to conventional PCa, iIDC-P is enriched with potentially targetable oncogenic driver mutations in MAPK/PI3K genes. Based on PTEN and ERG status, iIDC-P is not likely a precursor to the associated low-grade invasive PCa, but represents a molecularly unique in situ tumor of unclear clinical significance. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Socioeconomic drivers of vaccine uptake: An analysis of the data of a geographically defined cluster randomized cholera vaccine trial in Bangladesh

BackgroundEvaluations of oral cholera vaccines (OCVs) have demonstrated their effectiveness in diverse settings. However, low vaccine uptake in some settings reduces the opportunity for prevention. This paper identifies the socioeconomic factors associated with vaccine uptake in a mass vaccination program.MethodsThis was a three-arm (vaccine, vaccine plus behavioral change, and non-intervention) cluster randomized trial conducted in Dhaka, Bangladesh. Socio-demographic and vaccination data were collected from 268,896 participants. A geographical information system (GIS) was used to design and implement the vaccination program. A logistic regression model was used to assess the association between vaccine uptake and socioeconomic characteristics.ResultsThe GIS supported the implementation of the vaccination program by identifying ideal locations of vaccination centres for equitable population access, defining catchment areas of daily activities, and providing daily coverage maps during the campaign. Among 188,206 individuals in the intervention arms, 123,686 (66%) received two complete doses, and 64,520 (34%) received one or no doses of the OCV. The vaccine uptake rate was higher in females than males (aOR: 1.80; 95% CI = 1.75–1.84) and in younger (<15 years) than older participants (aOR: 2.19; 95% CI = 2.13–3.26). Individuals living in their own house or having a higher monthly family expenditure were more likely to receive the OCV (aOR: 1.60; 95% CI = 1.50–1.70 and aOR: 1.14; 95% CI = 1.10–1.18 respectively). Individuals using treated water for drinking or using own tap as the source of water were more likely to receive the OCV (aOR: 1.23; 95% CI = 1.17–1.29 and aOR: 1.14; 95% CI = 1.02–1.25 respectively) than their counterpart. Vaccine uptake was also significantly higher in participants residing farther away from health facilities (aOR: 95% 1.80; CI = 1.36–2.37).ConclusionThe GIS was useful in designing field activities, facilitating vaccine delivery and identifying socioeconomic drivers of vaccine uptake in the urban area of Bangladesh. Addressing these socioeconomic drivers may help improve OCV uptake, thereby effectiveness of the OCV in a community.     

Structural approaches for prevention of sexually transmitted HIV in general populations: definitions and an operational approach

Introduction

Although biomedical HIV prevention efforts have seen a number of recent promising developments, behavioural interventions have often been described as failing. However, clear lessons have been identified from past efforts, including the need to address influential social, economic and legal structures; to tailor efforts to local contexts; and to address multiple influencing factors in combination. Despite these insights, there remains a pervasive strategy to try to achieve sexual behaviour change through single, decontextualized, interventions or sets of activities. With current calls for structural approaches to HIV as part of combination HIV prevention, though, there is a unique opportunity to define a structural approach to HIV prevention as one which moves beyond these past limitations and better incorporates our knowledge of the social world and the lessons from past efforts.

Discussion

A range of interlinked concepts require delineation and definition within the broad concept of a structural approach to HIV. This includes distinguishing between “structural factors,” which can be seen as any number of elements (other than knowledge) which influence risk and vulnerability, and “structural drivers,” which should be reserved for situations where an empirically established relationship to a target group is known. Operationalizing structural approaches similarly can take different paths, either working to alter structural drivers or alternatively working to build individual and community resilience to infection. A “structural diagnostic approach” is further defined as the process one undertakes to develop structural intervention strategies tailored to target groups.

Conclusions

For three decades, the HIV prevention community has struggled to reduce the spread of HIV through sexual risk behaviours with limited success, but equally with limited engagement with the lessons that have been learned about the social realities shaping patterns of sexual practices. Future HIV prevention efforts must address the multiple factors influencing risk and vulnerability, and they must do so in ways tailored to particular settings. Clarity on the concepts, terminology and approaches that can allow structural HIV prevention efforts to achieve this is therefore essential to improve the (social) science of HIV prevention.     

Declines in violence and police arrest among female sex workers in Karnataka state,south India,following a comprehensive HIV prevention programme

Introduction

Female sex workers (FSWs) frequently experience violence, harassment and arrest by the police or their clients, but there is little evidence as to the impact that such factors may have on HIV risk or whether community interventions could mitigate this impact.

Methods

As part of the evaluation of the Avahan programme in Karnataka, serial integrated behavioural and biological assessment (IBBA) surveys (four districts) (2005 to 2011) and anonymous polling booth surveys (PBS) (16 districts) (2007 to 2011) were conducted with random samples of FSWs. Logistic regression analysis was used to assess 1) changes in reported violence and arrests over time and 2) associations between violence by non-partners and police arrest and HIV/STI risk and prevalence. Mediation analysis was used to identify mediating factors.

Results

5,792 FSWs participated in the IBBAs and 15,813 participated in the PBS. Over time, there were significant reductions in the percentages of FSWs reporting being raped in the past year (PBS) (30.0% in 2007, 10.0% in 2011, p<0.001), being arrested in the past year [adjusted odds ratio (AOR) 0.57 (0.35, 0.93), p=0.025] and being beaten in the past six months by a non-partner (clients, police, pimps, strangers, rowdies) [AOR 0.69 (0.49, 0.95), p=0.024)] (IBBA). The proportion drinking alcohol (during the past week) also fell significantly (32.5% in 2005, 24.9% in 2008, 16.8% in 2011; p<0.001). Violence by non-partners (being raped in the past year and/or beaten in the past six months) and being arrested in the past year were both strongly associated with HIV infection [AOR 1.59 (1.18, 2.15), p=0.002; AOR 1.91 (1.17, 3.12), p=0.01, respectively]. They were also associated with drinking alcohol (during the past week) [AOR 1.98 (1.54, 2.53), p<0.001; AOR 2.79 (1.93, 4.04), p<0.001, respectively], reduced condom self-efficacy with clients [AOR 0.36 (0.27, 0.47), p<0.001; AOR 0.62 (0.39, 0.98), p=0.039, respectively], symptomatic STI (during the past year) [AOR 2.62 (2.07, 3.30), p<0.001; AOR 2.17 (1.51, 3.13), p<0.001, respectively], gonorrhoea infection [AOR 2.79 (1.51, 5.15), p=0.001; AOR 2.69 (0.96, 7.56), p=0.060, respectively] and syphilis infection [AOR 1.86 (1.04, 3.31), p=0.036; AOR 3.35 (1.78, 6.28), p<0.001, respectively], but not with exposure to peer education, community mobilization or HIV testing uptake. Mediation analysis suggests that alcohol use and STIs may partially mediate the association between violence or arrests and HIV prevalence.

Discussion

Violence by non-partners and arrest are both strongly associated with HIV infection among FSWs. Large-scale, comprehensive HIV prevention programming can reduce violence, arrests and HIV/STI infection among FSWs.