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Global methylation analysis of gene promoters is promising for detection of high-grade squamous intraepithelial lesions or worse (HSIL+) in high-risk human papillomavirus (hrHPV)-positive women. However, diagnostic performance of methylation data at individual CpG-sites is limited. We explored methylation for predicting HSIL+ in self- and clinician-collected samples from Papua New Guinea.Methylation of EPB41L3 (1–6 CpG-sites), hTERT (1–10 CpG-sites) and FAM19A4 (1–5 CpG-sites) was assessed through pyrosequencing from 44 HPV+ samples (4 cancers, 19 HSIL, 4 low-grade squamous intraepithelial lesions (LSIL), 17 normal). New primers were designed for FAM19A4 directed to the first exon region not explored previously.In clinician-collected samples, methylation at CpG-sites 4 and 5 of EPB41L3 were the best HSIL predictors (AUC >0.83) and CpG-site 4 for cancer (0.925). Combination of EPB41L3 sites 2/4 plus FAM19A4 site 1 were the best HSIL+ markers [100% sensitivity, 63.2% specificity].Methylation at CpG-site 5 of FAM19A4 was the best HSIL predictor (0.67) in self-collected samples, and CpG-sites 1 and 3 of FAM19A4 for cancer (0.77). Combined, FAM19A4 site 1 plus HPV 16/18 detection yielded sensitivity of 82.6% and specificity of 61.9%.In conclusion, methylation at individual CpG-sites of EPB41L3 and FAM19A4 outperformed global analysis and improved HSIL+ detection, warranting further investigation.

Abstract Objective Primary care practitioners are crucial to engaging people in Australia's national cervical screening program. From July 2022, practitioners have been able to offer all screen‐eligible people the choice to collect their own self‐collected sample; an option introduced to increase equity. This study explored how practitioners are intending to incorporate universal access to self‐collection into their clinical care. Methods Semi‐structed interviews with 27 general practitioners, nurses, and practice managers from 10 practices in Victoria, Australia conducted between May and August 2022. Interviews were deductively coded, informed by the Consolidated Framework for Implementation Research. The Diffusion of Innovations theory was used to categorise intention to provide self‐collection. Results Participants were supportive of universal access to self‐collection, citing benefits for screen‐eligible people and that it overcame the limited adaptability of the previous policy. Most participants' practices (n = 7, 70%) had implemented or had plans to offer the option for self‐collection to all. Participants deliberating whether to provide universal access to self‐collection held concerns about the correct performance of the self‐test and the perceived loss of opportunity to perform a pelvic examination. Limited time to change practice‐level processes and competing demands within consultations were anticipated as implementation barriers. Conclusions The extent to which self‐collection can promote equity within the program will be limited without wide‐spread adoption by practitioners. Communication and education that addresses concerns of practitioners, along with targeted implementation support, will be critical to ensuring that self‐collection can increase participation and Australia's progression towards elimination of cervical cancer.

Program ROSE (removing obstacles to cervical screening) is a primary HPV-based cervical screening program that incorporates self-sampling and digital technology, ensuring that women are linked to care. It was developed based on the principles of design thinking in the context of Malaysia. The program illustrates the importance of collaborative partnerships and addressing the multi-faceted barriers from policy changes, and infrastructure readiness to the implementation of a radically new cervical screening program in communities. The paradigm shift in cervical cancer requires a monumental and concerted effort in educating both the healthcare providers and the general public. In this short review, we highlight how Pilot Project ROSE incorporated evidence-based tools that rapidly scaled up to Program ROSE. These ideas and solutions can be adapted and adopted by other countries. Notwithstanding the impact of COVID-19, it is incumbent on countries to pave the road towards the elimination of cervical cancer with pre-existing footpaths.

Australia's cervical screening program transitioned from cytology to HPV-testing with genotyping for HPV16/18 in Dec’2017. We investigated whether program data could be used to monitor HPV vaccination program impact (commenced in 2007) on HPV16/18 prevalence and compared estimates with pre-vaccination benchmark prevalence. Pre-vaccination samples (2005–2008) (n = 1933; WHINURS), from 25 to 64-year-old women had been previously analysed with Linear Array (LA). Post-vaccination samples (2013-2014) (n = 2989; Compass pilot), from 25 to 64-year-old women, were analysed by cobas 4800 (cobas), and by LA for historical comparability. Age standardised pre-vaccination HPV16/18 prevalence was 4.85% (95%CI:3.81–5.89) by LA; post-vaccination estimates were 1.67% (95%CI:1.21–2.13%) by LA, 1.49% (95%CI:1.05–1.93%) by cobas, and 1.63% (95%CI:1.17–2.08%) for cobas and LA testing of non-16/18 cobas positives (cobas/LA). Age-standardised pre-vaccination oncogenic HPV prevalence was 15.70% (95%CI:13.79–17.60%) by LA; post-vaccination estimates were 9.06% (95%CI:8.02–10.09%) by LA, 8.47% (95%CI:7.47–9.47%) by cobas and cobas/LA. Standardised rate ratios between post-vs. pre-vaccination rates were significantly different for HPV16/18, non-16/18 HPV and oncogenic HPV: 0.34 (95%CI:0.23–0.50), 0.68 (95%CI:0.55–0.84) and 0.58 (95%CI:0.48–0.69), respectively. Additional strategies (LA for all cobas positives; combined cobas and LA results on all samples) had similar results. If a single method is applied consistently, it will provide important data on relative changes in HPV prevalence following vaccination.

Background Safety of rechallenge of immune checkpoint inhibitor (ICI) after grade ≥2 immune-related adverse events (irAEs) leading to ICI discontinuation remains unclear.Methods All adverse drug reactions involving at least one ICI reported up to December 31, 2019 were extracted from the French pharmacovigilance database. Patients were included if they experienced at least one grade ≥2 irAE resulting in ICI discontinuation, with subsequent ICI rechallenge. The primary outcome was the recurrence of at least one grade ≥2 irAE in these patients after ICI rechallenge.Results We included 180 patients: 61.1% were men (median age of 66 years), 43.9% had melanoma and 78.9% were receiving anti-programmed cell death 1. First ICI discontinuation was related to 191 irAEs. After ICI rechallenge, 38.9% of the patients experienced at least one grade ≥2 irAE. Among them, 70.0% experienced the same irAE, 25.7% a distinct irAE, and 4.3% both the same and a distinct irAE. Lower recurrence rates of irAEs were associated with rechallenge with the same ICI treatment (p=0.02) or first endocrine irAEs (p=0.003). Gastrointestinal irAEs were more likely to recur (p=0.007). The median duration from ICI discontinuation to rechallenge and the severity of the initial irAE did not predict recurrent irAEs after ICI rechallenge (p=0.53 and p=0.40, respectively).Conclusions In this study, 61.1% of the patients who discontinued ICI treatment for grade ≥2 irAEs experienced no recurrent grade ≥2 irAEs after ICI rechallenge. Although ICI rechallenge appears to be safe under close monitoring, it should always be discussed balancing usefulness of rechallenge, patient comorbidities and risk of recurrence of first irAE(s). Due to inherent bias associated with pharmacovigilance studies, further prospective studies are needed to assess risk factors that may influence patient outcomes after ICI rechallenge.

Ifosfamide is used in the treatment of sarcomas and other tumors. It sometimes provokes encephalopathy, which is a serious complication even if it is usually reversible within 48-72 h after drug cessation. Ifosfamide is required to be activated by hepatic cytochrome P450 (CYP), especially the 3A4 subtype, leading to 4-hydroxy-ifosfamide. Ifosfamide is also converted by CYP3A4 to inactive but neurotoxic metabolites. Aprepitant is a neurokinin-1 receptor antagonist that is a potent antiemetic used in combination with 5-HT3 antagonists and corticosteroids. Aprepitant has an inhibitory effect, as well as a possible inductive effect, on CYP3A4. Since ifosfamide and aprepitant are both substrates of CYP3A4, a pharmacokinetic interaction could result in secondary effects such as the potentialization of neurological side effects. In this report, we describe 2 cases of fatal encephalopathy in patients who have received both ifosfamide and aprepitant, and we discuss the mechanisms that could be involved. Our observations draw attention to the fact that aprepitant must be avoided, or at least used with caution, in patients who are receiving ifosfamide due to the risk of severe neurological side effects.