High-Resolution Anoscopy Surveillance After Anal Squamous Cell Carcinoma: High-Grade Squamous Intraepithelial Lesion Detection and Treatment May Influence Local Recurrence

BACKGROUND: Local recurrence is a significant risk after anal squamous cell carcinoma. OBJECTIVES: This study aimed to examine the occurrence of high-grade squamous intraepithelial lesions and local recurrence after anal cancer at surveillance with high-resolution anoscopy. DESIGN: This is a retrospective observational study. SETTING: This study was conducted at an anogenital neoplasia referral center. PATIENTS: There were 76 anal/perianal cancers from 1998 to 2018. Sixty-three patients were eligible and 3 were excluded, for a total of 60 patients; 35 of 60 (58%) patients were male. INTERVENTION: High-resolution anoscopy after chemoradiation or excision only for anal squamous cell carcinoma was performed. MAIN OUTCOME MEASURES: The primary outcomes measured were local recurrence and high-grade squamous intraepithelial lesion detection rates. RESULTS: Sixty patients, 27% HIV positive, underwent surveillance over a median 42 (range 7-240) months of follow-up. Seven had had a prior local recurrence at study entry so were analyzed separately. Thirty of 53 underwent chemoradiation (57%) and 23 of 53 underwent excision alone (43%); 33 had perianal cancer and 20 had anal cancer. Ten of 30 of the chemoradiation group had had stage 1 (33%) disease in comparison with 22 of 23 of the excision only group (96%, p < 0.001). OUTCOMES: High-grade squamous intraepithelial lesions were detected in 4 of 30 (13%) patients after chemoradiation and in 17 of 23 (74%) patients after excision only (p < 0.001). Twenty of 21 (95%) high-grade lesions were treated with ablation. Six of 7 (86%) patients with prior local recurrence had high-grade squamous intraepithelial lesions over a median of 21 months follow-up. One local recurrence (T1N0M0) occurred during surveillance after primary chemoradiation (0.56/1000 person-months), none occurred after excision only, and 2 of 7 with prior local recurrence developed further local recurrence (6.86/1000 person-months). All 3 local recurrences occurred after treatment of high-grade squamous intraepithelial lesions. There were no metastases, abdominoperineal excisions, or deaths from anal squamous cell carcinoma. LIMITATIONS: Retrospective data were used for this study. CONCLUSIONS: High-grade squamous intraepithelial lesions after anal squamous cell carcinoma are more common after excision only than after chemoradiation. Local recurrence is low in this high-resolution anoscopy surveillance group in which high-grade squamous intraepithelial disease was ablated. Excision of small perianal cancers appears safe; however, a subset of patients is at excess risk

Fibroadenoma in vulval ectopic breast tissue in a patient with PTEN Hamartoma Tumour Syndrome

PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline variants in PTEN predispose to benign and malignant growths of numerous organs, including of the breast. In the following report, we describe the first documented case of a fibroadenoma developing in ectopic breast tissue of the vulva in a patient with a germline pathogenic variant in PTEN. This highlights the risk of hyperplasia developing in any breast tissue, including rare ectopic sites, particularly in patients with underlying germline variants in cancer susceptibility genes

Efficiency in Multi-objective Games

In a multi-objective game, each agent individually evaluates each overall action-profile on multiple objectives. I generalize the price of anarchy to multi-objective games and provide a polynomial-time algorithm to assess it. This work asserts that policies on tobacco promote a higher economic efficiency

Measuring the nature and duration of symptoms of cervical cancer in young women: Developing an interview-based approach

Background: Some young women experience delays in diagnosis of cervical cancer, but little research about ways of studying these delays has been published. A major challenge is that gynaecological symptoms are common in young women, but cervical cancer is rare. This study describes the development and testing of a measure for studying delays in diagnosis in young women with cervical cancer. Methods: Prospective development of an interview measure and testing of its ability to reliably and systematically collect relevant data in two large hospitals in London, UK using 27 women aged 18–40 diagnosed with cervical cancer in the previous two years. We developed a semi-structured interview schedule and data extraction form to systematically collect data on symptoms (including nature and duration) and risk factors for delayed diagnosis from young women with cervical cancer. We piloted the measure among young women with cervical cancer (audiorecording it with their permission), refining it iteratively. To complete the measure, we developed a database for managing the data and a manual for using the schedule. Two researchers extracted data from the recorded interviews to assess inter-rater reliability. Results: The final interview schedule yielded quantitative data on the nature and duration of symptoms and risk factors for delayed diagnosis. Inter-rater reliability was high. In the pilot, 12 of the 27 women were diagnosed via symptomatic presentation. Median time from the symptom triggering presentation to presentation was one month (interquartile range 0–4 months). Median time from presentation to diagnosis was three months (interquartile range 1–8.5 months). Conclusions: We have developed a reliable tool for measuring the nature and duration of symptoms in young women with cervical cancer. Pilot data suggest that a substantial proportion of women experience delay between first presentation and diagnosis

Circulating HPV DNA as a Biomarker for Pre-Invasive and Early Invasive Cervical Cancer: A Feasibility Study

BACKGROUND: High-risk HPV infection is responsible for >99% of cervix cancers (CC). In persistent infections that lead to cancer, the tumour breaches the basement membrane, releasing HPV-DNA into the bloodstream (cHPV-DNA). A next-generation sequencing assay (NGS) for detection of plasma HPV circulating DNA (cHPV-DNA) has demonstrated high sensitivity and specificity in patients with locally advanced cervix cancers. We hypothesised that cHPV-DNA is detectable in early invasive cervical cancers but not in pre-invasive lesions (CIN). METHODS: Blood samples were collected from patients with CIN (n = 52) and FIGO stage 1A-1B CC (n = 12) prior to treatment and at follow-up. DNA extraction from plasma, followed by NGS, was used for the detection of cHPV-DNA. RESULTS: None of the patients with pre-invasive lesions were positive for CHPV-DNA. In invasive tumours, plasma from one patient (10%) reached the threshold of positivity for cHPV-DNA in plasma. CONCLUSION: Low detection of cHPV-DNA in early CC may be explained by small tumour size, poorer access to lymphatics and circulation, and therefore little shedding of cHPV-DNA in plasma at detectable levels. The detection rate of cHPV-DNA in patients with early invasive cervix cancer using even the most sensitive of currently available technologies lacks adequate sensitivity for clinical utility

The impact of induction and/or concurrent chemoradiotherapy on acute and late patient-reported symptoms in oropharyngeal cancer:Application of a mixed-model analysis of a prospective observational cohort registry

BACKGROUND The goal of this study was to comprehensively investigate the association of chemotherapy with trajectories of acute symptom development and late symptom recovery in patients with oropharyngeal cancer (OPC) by comparing symptom burden between induction chemotherapy followed by concurrent chemoradiotherapy (ICRT), concurrent chemo-radiotherapy (CRT), or radiotherapy (RT) alone.METHODS Among a registry of 717 patients with OPC, the 28-item patient-reported MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN) symptoms were collected prospectively at baseline, weekly during RT, and 1.5, 3 to 6, 12, and 18 to 24 months after RT. The effect of the treatment regimen (ICRT, CRT, and RT alone) was examined with mixed-model analyses for the acute and late period. In the CRT cohort, the chemotherapy agent relationship with symptoms was investigated.RESULTS Chemoradiation (ICRT/CRT) compared with RT alone resulted in significantly higher acute symptom scores in the majority of MDASI-HN symptoms (ie, 21 out of 28). No late symptom differences between treatment with or without chemotherapy were observed that were not attributable to ICRT. Nausea was lower for CRT with carboplatin than for CRT with cisplatin; cetuximab was associated with particularly higher scores for acute and late skin, mucositis, and 6 other symptoms. The addition of ICRT compared with CRT or RT alone was associated with a significant increase in numbness and shortness of breath.CONCLUSION The addition of chemotherapy to definitive RT for OPC patients was associated with significantly worse acute symptom outcomes compared with RT alone, which seems to attenuate in the late posttreatment period. Moreover, induction chemotherapy was specifically associated with worse numbness and shortness of breath during and after treatment.LAY SUMMARYChemotherapy is frequently used in addition to radiotherapy cancer treatment, yet the (added) effect on treatment-induced over time is not comprehensively investigatedThis study shows that chemotherapy adds to the symptom severity reported by patients, especially during treatment</p

Plasma cell-free DNA methylation analysis for ovarian cancer detection: Analysis of samples from a case-control study and an ovarian cancer screening tria

Analysis of cell-free DNA methylation (cfDNAme), alone or combined with CA125, could help to detect ovarian cancers earlier and may reduce mortality. We assessed cfDNAme in regions of ZNF154, C2CD4D and WNT6 via targeted bisulfite sequencing in diagnostic and early detection (preceding diagnosis) settings. Diagnostic samples were obtained via prospective blood collection in cell-free DNA tubes in a convenience series of patients with a pelvic mass. Early detection samples were matched case-control samples derived from the UK Familial Ovarian Cancer Screening Study (UKFOCSS). In the diagnostic set (ncases  = 27, ncontrols  = 41), the specificity of cfDNAme was 97.6% (95% CI: 87.1%-99.9%). High-risk cancers were detected with a sensitivity of 80% (56.3%-94.3%). Combination of cfDNAme and CA125 resulted in a sensitivity of 94.4% (72.7%-99.9%) for high-risk cancers. Despite technical issues in the early detection set (ncases  = 29, ncontrols  = 29), the specificity of cfDNAme was 100% (88.1%-100.0%). We detected 27.3% (6.0%-61.0%) of high-risk cases with relatively lower genomic DNA (gDNA) contamination. The sensitivity rose to 33.3% (7.5%-70.1%) in samples taken <1 year before diagnosis. We detected ovarian cancer in several patients up to 1 year before diagnosis despite technical limitations associated with archival samples (UKFOCSS). Combined cfDNAme and CA125 assessment may improve ovarian cancer screening in high-risk populations, but future large-scale prospective studies will be required to validate current findings

Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine