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

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

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

Sex-linked mating strategies diverge with a manipulation of genital salience

Trivers (Sexual selection and the descent of man, Aldine-Atherton, Chicago, pp 136–179, 1972) proposed that evolutionary factors should favor divergent mating strategies for males versus females. Such differences may be less pronounced among human beings than other animals and social norms and sex roles are also pertinent influences. The present experiment (N = 133 college undergraduates, 74 female) sought to bypass some of these other influences. Participants were randomly assigned to a condition designed to increase attention to the genital region (a downward pointing arrow) or not (an upward pointing arrow). They then reported on their interest in short-term (e.g., a one-night stand) and long-term (e.g., a potential marital partner) mating opportunities. A theory-consistent three-way interaction occurred such that the genital salience manipulation primed a shorter-term reproductive strategy among men and a longer-term reproductive strategy among women. The results provide unique support for evolution-linked ideas about sex differences in the form of a role for bodily attention

Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration

PURPOSE: Transplantation of human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells offers the potential for benefit in macular degeneration. Previous trials have reported improved visual acuity (VA), but lacked detailed analysis of retinal structure and function in the treated area. DESIGN: Phase 1/2 open-label dose-escalation trial to evaluate safety and potential efficacy (clinicaltrials.gov identifier, NCT01469832). PARTICIPANTS: Twelve participants with advanced Stargardt disease (STGD1), the most common cause of macular degeneration in children and young adults. METHODS: Subretinal transplantation of up to 200 000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks. MAIN OUTCOME MEASURES: The primary end points were the safety and tolerability of hESC-derived RPE cell administration. We also investigated evidence of the survival of transplanted cells and measured retinal structure and function using microperimetry and spectral-domain OCT. RESULTS: Focal areas of subretinal hyperpigmentation developed in all participants in a dose-dependent manner in the recipient retina and persisted after withdrawal of systemic immunosuppression. We found no evidence of uncontrolled proliferation or inflammatory responses. Borderline improvements in best-corrected VA in 4 participants either were unsustained or were matched by a similar improvement in the untreated contralateral eye. Microperimetry demonstrated no evidence of benefit at 12 months in the 12 participants. In one instance at the highest dose, localized retinal thinning and reduced sensitivity in the area of hyperpigmentation suggested the potential for harm. Participant-reported quality of life using the 25-item National Eye Institute Visual Function Questionnaire indicated no significant change. CONCLUSIONS: Subretinal hyperpigmentation is consistent with the survival of viable transplanted hESC-derived RPE cells, but may reflect released pigment in their absence. The findings demonstrate the value of detailed analysis of spatial correlation of retinal structure and function in determining with appropriate sensitivity the impact of cell transplantation and suggest that intervention in early stage of disease should be approached with caution. Given the slow rate of progressive degeneration at this advanced stage of disease, any protection against further deterioration may be evident only after a more extended period of observation

The avoiding late diagnosis of ovarian cancer (ALDO) project; A pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2

Background: Our study aimed to establish â € real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). Methods: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. Results: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-Adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of-£102,496/QALY. Conclusion: OC surveillance for women deferring RRSO in a â € real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery