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Uncontrolled chemotherapy-induced nausea and vomiting (CINV) can reduce patients’ quality of life and may result in premature discontinuation of chemotherapy. Although nausea and vomiting are commonly grouped together, research has shown that antiemetics are clinically effective against chemotherapy-induced vomiting (CIV) but less so against chemotherapy-induced nausea (CIN). Nausea remains a problem for up to 68% of patients who are prescribed guideline-consistent antiemetics. Despite the high prevalence of CIN, relatively little is known regarding its etiology independent of CIV. In this review paper, we summarize a metagenomics approach to the study and treatment of CIN with the goal of encouraging future research. Metagenomics focuses on genetic risk factors, encompassing both human (i.e., host) and gut microbial genetic variation. Little work to date has focused on metagenomics as a putative biological mechanism of CIN. Metagenomics has the potential to be a powerful tool in advancing scientific understanding of CIN by identifying new biological pathways and intervention targets. Investigation of metagenomics in the context of well-established demographic, clinical, and patient-reported risk factors may help to identify patients at risk and facilitate prevention and management of CIN.

Restrictions to hospital visiting were mandated during the COVID-19 pandemic, with variability in the degree of restriction imposed. At times, paediatric intensive care units (ICU) restricted visiting to one parent/carer. Views of parents/carers and ICU staff about changes in the visiting policy are not well understood.Service evaluation involving questionnaire survey incorporating rating scales and free-text comments.Inner-city specialist children's hospital.Parents/carers of children on ICU between December 2020-March 2021 and staff who were working on ICU during May-June 2021.Parents and staff on ICU were invited to complete a questionnaire focusing on their experience of being or working on ICU. Quantitative data were analysed descriptively and free-text comments were thematically analysed. Completed questionnaires were received from 81/103 (79%) parents/carers and 217/550 (39%) staff. The majority of parents (n = 60;77%) and staff (n = 191;89%) understood the need for the one-parent visiting policy but acknowledged it was a source of considerable stress. More staff than parents agreed it was appropriate other relatives/friends visiting was not permitted (Z = 3.715;p .001). There was no association between parents' satisfaction with their child's care and views about the visiting policy. However, staff were more likely to report an impact on their ability to deliver family centred care if they disagreed with the policy.The COVID-19 visiting policy had a clear impact on parents and staff. In the event of any future threat to open-access visiting to children in hospital, the potentially damaging effect on children, parents, and staff must be considered.Visiting policies need to take account of parents being partners in their child's care, rather than purely visitors to the unit where their child is being cared for. Visiting for two carers should always be facilitated, including during a crisis such as a pandemic.

Endocrine therapy (ET) is recommended as first-line therapy for the majority of patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative advanced breast cancer (ABC); however, the efficacy of ET in patients with visceral metastases (VM) versus patients whose disease is limited to non-visceral metastases (non-VM) is debated. Meta-analyses including available data from randomised controlled trials of first- and second-line endocrine monotherapies for patients with HR+ ABC were performed to address this question. In one and two-stage meta-analyses, progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and duration of clinical benefit (DoCB) outcomes were analysed. In the first-line meta-analysis (seven trials; n = 1988) tamoxifen and fulvestrant significantly improved PFS, OS and CBR for patients with non-VM versus those whose disease included VM. The most substantial hazard ratios were observed for fulvestrant 500 mg; 0.56 (95% confidence interval [CI] 0.45−0.70) and 0.55 (95% CI 0.42−0.72) for PFS and OS, respectively. In the second-line meta-analysis (seven trials; n = 2324), all ET combined was more effective (in terms of PFS, OS and DoCB) for non-VM versus VM. In both meta-analyses, patients with non-liver VM had better clinical outcomes than patients with liver VM for all types of ET. Patients whose disease included non-VM sites had better clinical outcomes with endocrine monotherapy compared with patients whose disease included VM. These findings may facilitate better informed treatment decision-making.

High-grade pneumonitis is a severe and potentially life-threatening adverse event associated with concurrent chemoradiation (cCRT) in patients with non-small cell lung cancer (NSCLC). The aim of this study was to summarize and quantify the incidence of severe (grade 3-5) cCRT-induced pneumonitis in unresectable stage III NSCLC patients.A systematic literature review and meta-analysis were performed in accordance with PRISMA guidelines. Published literature was searched for randomized controlled trials (RCTs), observational studies, and non-randomized trials from 2014 to April 2020. The primary outcome of interest was incidence of grade 3-5 pneumonitis.Included were 17 studies for the review and 11 for the meta-analysis (1,788 participants); all studies examined radiation-related pneumonitis (RP). The pooled incidence of cCRT-induced grade 3-5 RP in unresectable stage III NSCLC patients was estimated to be 3.62% [95% confidence interval (CI): 1.65-6.21] in RCTs, 5.98% [95% CI: 2.26-12.91] in observational studies, and 7.85% [95% CI: 4.08-13.10] in observational studies using platinum-based doublet chemotherapies.These results suggest the incidence of severe and fatal RP in patients with unresectable stage III NSCLC treated with cCRT ranges from 3.62% to 7.85%, with incidence varying by study design and chemotherapy regimen. Estimates of RP incidence were higher in the real-world setting compared to RCTs. These results can be used to contextualize the baseline risk of cCRT-induced pneumonitis in unresectable stage III NSCLC to better understand the adverse event of pneumonitis associated with novel immunotherapy treatments indicated for concomitant use with this modality.

BackgroundThe tracheobronchial and oral microbiome may be associated with lung cancer, potentially acting as predictive biomarkers. Therefore, we studied the lung and oral bacteriome and virome in non-small cell lung cancer (NSCLC) patients compared to melanoma controls to discover distinguishable features.MethodsIn this pilot case-control study, we recruited ten patients with resectable NSCLC (cases) and ten age-matched melanoma patients (controls) who both underwent tumor resection. Preoperative oral gargles were collected from both groups, who then underwent transbronchoscopic tracheal lavage after intubation. Lung tumor and adjacent non-neoplastic lung were sterilely collected after resection. Microbial DNA from all specimens underwent 16S rRNA gene sequencing. Lavage and gargle specimens underwent whole-genome shotgun sequencing. Microbiome metrics were calculated to compare both cohorts. T-tests and Wilcoxon rank sum tests were used to test for significant differences in alpha diversity between cohorts. PERMANOVA was used to compare beta diversity. ResultsNo clear differences were found in the microbial community structure of case and control gargles, but beta diversity of case and control lavages significantly differed. Two species, Granulicatella adiacens and Neisseria subflava, appeared in higher abundance in case versus control lavages. Case lavages also maintained higher relative abundances of oral commensals compared to controls. ConclusionsLung lavages demonstrated oral microbiota enrichment in cases compared to controls, suggesting microaspiration and resultant inflammation. The oral commensals Granulicatella adiacens and Neisseria subflava were more abundant in the tracheobronchial lavages of lung cancer versus melanoma patients, implicating these microorganisms as potential lung cancer biomarkers, warranting further validation studies.

BackgroundRecent studies show that human gut microbial composition can determine whether a patient is a responder or non-responder to immunotherapy but have not identified a common microbial signal shared by responding patients. The functional relationship between immunity, intestinal microbiota, and NSCLC response to immune checkpoint inhibitor/inhibition (ICI) in an American cohort remains unexplored.MethodsRNAlater-preserved fecal samples were collected from 65 pre-treatment (baseline) and post-treatment stage III/IV NSCLC patients undergoing ICI therapy, categorized as responders or non-responders according to RECIST criteria. Pooled and individual responder and non-responder microbiota were transplanted into a gnotobiotic mouse model of lung cancer and treated with ICIs. 16S rDNA and RNA sequencing was performed on patient fecal samples, 16S rDNA sequencing on mouse fecal samples, and flow cytometric analysis on mouse tumor tissue.ResultsResponder patients have both a different microbial community structure than non-responders (P= 0.004) and a different bacterial transcriptome (PC2 = 0.03) at baseline. Taxa significantly enriched in responders include amplicon sequence variants (ASVs) belonging to the generaRuminococcus,Akkermansia, andFaecalibacterium. Pooled and individual responder microbiota transplantation into gnotobiotic mice decreased tumor growth compared to non-responder colonized mice following ICI (P= 0.023,P= 0.019,P= 0.008, respectively). Responder tumors showed an increased anti-tumor cellular phenotype following ICI treatment. Responder mice are enriched with ASVs belonging to the generaBacteroides,Blautia,Akkermansia, andFaecalibacterium. Overlapping taxa mapping between human and mouse cohorts correlated with tumor size and weight revealed a network highlighting responder-associated ASVs belonging to the generaColidextribacter,Frisingicoccus,Marvinbryantia, andBlautiawhich have not yet been reported.ConclusionsThe role of isolate-specific function and bacterial gene expression in gut microbial-driven responsiveness to ICI has been underappreciated. This work supports further investigation using isolate-driven models to characterize the mechanisms underlying this phenomenon.

Background: It remains clinically important to identify ER positive breast cancers likely to respond to tamoxifen (TAM) and so we aimed to select a group of biomarkers able to predict response. We also assessed whether data from different sample types [tumor microarrays (TMAs) and core biopsies] or tumor sites could be combined for biomarker studies. Methods: A total of 123 endocrine treatment naïve patients with known ER and HER2 status treated with TAM had paraffin-embedded tumor tissue available either as TMAs (n=102) or core biopsies (n=21). TMA cores were collected from three different tumor sites, two central and one peripheral. Ten biomarkers were evaluated by immunohistochemistry, for % positivity and/or H-Score, comprising: ER, HER2, Ki67, phosphorylated forms of ER (Ser118), IGF1R, PRAS40, Akt & MAPK (ERK1/2), and PTEN & androgen receptor expression (AR). Each tumor was analysed for Akt1 E17K somatic mutation using BEAMing technology. Patient outcome was assessed by clinical benefit (CB) rate & survival analyses [time to progression (TTP) and time to death (TTD)]. Results: There was no significant difference in % positivity or H-Score between central & peripheral tumor sites for all biomarkers examined. After False Discovery Rate (FDR) correction differences (P

Fecal specimen collection in the clinical setting is often unfeasible for large population studies, especially because cancer patients on immunotherapy often experience constipation. A method for constructing and using an at-home stool collection kit designed for epidemiological studies in cancer patients is presented. Participation and compliance rates of the collection kit among late-stage cancer patients from an ongoing, longitudinal study are also discussed. The kit includes three different media on which samples are introduced. Using one stool sample, patients collect specimens by smearing stool onto a fecal occult blood test (FOBT) card, containing three slides for collection. Additional specimens from the same stool sample are added to one tube containing 8 mL of RNAlater preservative and one tube containing 8 mL of 95% ethanol. Stool specimens are stored at room temperature and returned to researchers within 3 days of collection. The purpose of this kit is to yield stool specimens on a variety of media that can be preserved for extended periods of time at room temperature and are compatible with multi-omics approaches for specimen analysis. According to leading microbiome researchers and published literature, each collection method is considered optimal for use in large epidemiological studies. Moreover, the kit is comprised of various components that make stool collection easy, so as not to burden the patient and hence maximize overall compliance. Use of this kit in a study of late-stage lung cancer patients had a participation rate of 83% and baseline compliance rate of 58%. Electronic supplementary material The online version of this article (10.1007/s00248-019-01346-2) contains supplementary material, which is available to authorized users.

There is a prevailing belief that ET for HR+ advanced BC is not as effective in patients with visceral metastases (VM) compared to non-visceral metastases (nVM), particularly with later lines of ET. Recently fulvestrant 500mg (Ful 500), has been reported to have greater efficacy in nVM compared to i) VM treated by Ful 500 but also compared to ii) nVM treated by Ful 250 (2nd line) and iii) nVM treated by aromatase inhibitor (AI), anastrozole (1st Line) – implying both site and agent related efficacy. Absence of significant overall survival (OS) difference in PALOMA 3 (2nd line) has increased the debate regarding when to add CDK 4/6is to ET, especially given the OS advantage for Ful 500 monotherapy in the 1st & 2nd line settings. Patients & Methods: Anonymised, individual patient level data was obtained from randomised controlled trials (RCTs) involving AI & SERD used as mono-theraphy in 2nd or 3rd Line setting in known HR+ BC. All the trials were Phase 3 double-blind, placebo RCTs. All were rigorously assessed for clinical benefit (CB), progression free survival (PFS), duration of CB (DoCB) and OS. Details of the studies, types of ET and patient numbers are shown in the Table. Results: Outcome data is presented for each study and then summarised under AI, SERD (Ful 250 or 500) and 'all Ets combined'. Odds ratios (Ors) & hazard ratios (HRs) for VM versus nVM by endocrine agents are shown in the Table. AgentStudyTotal Pats.HR+ Pats.CBRPFSOSDoCBAI(n)(n)OR (95%Cis)HR (95%Cis)HR (95%Cis)HR (95%Cis)Exe00202301831.181.441.271.50Exe00211931681.151.951.832.12AnaEFECT3403360.941.521.201.10AnaSOFEA2492491.291.181.051.41subtotal7636871.11 (0.84-1.48)1.47*** (1.22-1.79)1.21* (1.01-1.45)1.43** (1.10-1.86)SERDFul 25000202191601.791.701.401.23Ful 25000212041771.281.811.322.06Ful 250EFECT3513450.791.401.311.03Ful 250SOFEA2312310.701.171.242.22Ful 250CONFIRM1521521.131.071.510.84Subtotal9268341.05 (0.75-1.45)1.39*** (1.16-1.67)1.34*** (1.14-1.57)1.36 (0.93-1.98)SERDFul 500CONFIRM1441442.24 (1.12-4.48)1.30 (0.90-1.87)1.33 (1.14-1.57)0.97 (0.55-1.66)All ETsTotal183316651.13 (0.92-1.39)1.42*** (1.26-1.59)1.28*** (1.14-1.44)1.35** (1.09-1.66) [Pats=Patients; (n)=number; CBR-Clinical Benefit Rate; p-values p Median PFS (months) for nVM for AI, SERD250, SERD500 & ‘all Ets combined’ were 5.4, 5.5, 11.0 & 5.5 respectively: for VM they were 2.9, 3.5, 5.5 & 3.2 respectively. Median OS (months) for nVM for AI, SERD250, SERD500 & ‘all Ets combined’ was 24.2, 26.0, 35.4 & 25.4 respectively: for VM the figures were 22.8, 20.8, 26.4 & 22.0 respectively.Conclusions:1) In the 2nd line HR+ setting AI & Ful 250 both significantly increased PFS & OS in nVM versus VM. Longer PFS appears due to longer duration of control (DoCB) than increasing the number of patients responding (CBR). 2) Median OS for nVM ranged from 24 – 35 months versus 20.8-26.4 months for VM: for the majority of patients the 2nd line ET setting is not ‘immediately life threating’ and ET is therefore an option to consider. 3) These data on site of disease (nVM vs VM) contribute to the selection of which patients should receive endocrine mono- and which endocrine combination therapy (ie plus mTORi or CDK4/6i) in the second line setting. Citation Format: Robertson JFR, Di Leo A, Johnston S, Chia S, Bliss J, Bradbury I, Campbell C. Meta-analyses of visceral versus non-visceral metastases treated by AI & SERD agents as 2nd line endocrine therapy (ET) for HR+ breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-13.

Background In our recent study, most non-small-lung cancer (NSCLC) tumor specimens harbored viral DNA but it was absent in non-neoplastic lung. However, their targets and roles in the tumor cells remain poorly understood. We analyzed gene expression microarrays to identify genes and pathways differentially altered between virus-infected and uninfected NSCLC tumors. Methods Gene expression microarrays of 30 primary and 9 metastatic NSCLC patients were preprocessed through a series of quality control analyses. Linear Models for Microarray Analysis and Gene Set Enrichment Analysis were used to assess differential expression. Results Various genes and gene sets had significantly altered expressions between virus-infected and uninfected NSCLC tumors. Notably, 22 genes on the viral carcinogenesis pathway were significantly overexpressed in virus-infected primary tumors, along with three oncogenic gene sets. A total of 12 genes, as well as seven oncogenic and 133 immunologic gene sets, were differentially altered in squamous cell carcinomas, depending on the virus. In adenocarcinoma, 14 differentially expressed genes (DEGs) were identified, but no oncogenic and immunogenic gene sets were significantly altered. In bronchioloalveolar carcinoma, several genes were highly overexpressed in virus-infected specimens, but not statistically significant. Only five of 69 DEGs (7.2%) from metastatic tumor analysis overlapped with 1527 DEGs from the primary tumor analysis, indicating differences in host cellular targets and the viral impact between primary and metastatic NSCLC. Conclusions The differentially expressed genes and gene sets were distinctive among infected viral types, histological subtypes, and metastatic disease status of NSCLC. These results support the hypothesis that tumor viruses play a role in NSCLC by regulating host genes in tumor cells during NSCLC differentiation and progression. Electronic supplementary material The online version of this article (10.1186/s12885-018-4748-0) contains supplementary material, which is available to authorized users.

Because patients' preoperative nutritional status influences the outcomes, we have used a preoperative nutrition program for surgical patients for a 2-year period and compared the results with those from a cohort treated in the previous 2 years.We retrospectively reviewed curative thoracic neoplasm resections from July 15, 2016, to July 15, 2018, in patients who had received a preoperative nutritional-enhanced recovery after surgery (N-ERAS) protocol. The protocol consisted of 5 days of an oral immunonutrition drink 3 times daily, daily receipt of probiotics, and a carbohydrate-loading drink the night before surgery. The historical control cohort (standard group) included those patients who had undergone surgery by the same surgeon during the previous 24 months. We excluded patients who had undergone esophageal, diagnostic, benign, emergency, or palliative procedures. Nonparametric and parametric statistical tests were used to analyze the data.The data from 462 patients were analyzed: 229 N-ERAS patients and 233 standard patients. No significant demographic or caseload differences were found between the 2 groups. The major significant outcome differences included fewer postoperative complications (30 [13.1%] in the N-ERAS group vs 60 [25.8%] in the standard group; P .001) and shorter hospital stays (3.8 ± 1.9 days for the N-ERAS group vs 4.4 ± 2.6 days for the standard group; P = .001). Use of the N-ERAS protocol resulted in a 16% reduction ($2198; P .001) in the mean direct hospital costs/patient. Consequently, for the N-ERAS cohort, the hospital was likely saved $503,342 during the 2-year period for the 229 patients just by using the N-ERAS protocol.Thoracic surgeons should consider using the nontoxic, patient-compliant N-ERAS protocol for their patients, with an expectation of improved clinical results at lower hospital costs-an important consideration when exploring methods to decrease costs because hospitals are increasingly being paid by a negotiated prospective bundled payment reimbursement model.

e20532 Background: Recent clinical trials have shown positive results for therapies combining concurrent chemoradiation therapy (cCRT) and checkpoint immunotherapy in unresectable non-small cell lung cancer (NSCLC). cCRT is associated with an increased risk of pneumonitis, a severe and life-threatening inflammation of the lungs. To further inform clinical decision-making and support the evaluation of new therapies combining immunotherapies with cCRT, it is important to understand the baseline risk of pneumonitis associated with cCRT alone. The objective of this study was to quantify the incidence of cCRT-induced grade 3−5 pneumonitis (immune-mediated and radiation pneumonitis) in unresectable stage III NSCLC patients. Methods: A systematic literature review and meta-analysis were performed in accordance with PRISMA guidelines. MEDLINE, Embase, and the Cochrane Central Register were searched from 2014 to April 24, 2020. Chemotherapies of interest were cisplatin, pemetrexed, etoposide, carboplatin, and paclitaxel. Randomized controlled trials (RCTs), observational studies, and non-randomized trials were included. Bayesian meta-analysis using a binomial model random effects model was conducted with SAS 9.4. Results: Among 1,889 records identified from the search, 17 studies (6 RCTs, 8 observational studies, 3 single-arm trials) met inclusion criteria. Eleven studies were included in the meta-analysis (5 RCTs, 6 observational studies; 1,788 patients). All studies specified radiation-related pneumonitis (RP), although this is clinically indistinguishable from immune-mediated pneumonitis. Patient populations were comparable across studies; the most common chemotherapies were paclitaxel + carboplatin (n = 6) and pemetrexed + cisplatin (n = 5), and radiation doses ranged from 60–74 Gy. There was variation across studies in intervention, outcome reporting, and follow-up (median range: 12–73 months), but this variation was considered acceptable based on sensitivity analyses. The estimated pooled incidence of grade 3−5 RP in cCRT-treated unresectable stage III NSCLC patients was 3.62% [95% confidence interval (CI): 1.65−6.21] in RCTs and 5.98% [95% CI: 2.26−12.91] in observational studies. The pooled incidence of fatal (grade 5) RP was 0.37% [95% CI: 0−2.78] in RCTs and 1.73% [95% CI: 0.53−4.33] in observational studies. Conclusions: This study estimates that 3.62–5.98% of patients with unresectable stage III NSCLC develop grade 3−5 RP when treated with cCRT, with incidence varying by study design. Estimates of RP incidence were higher in the real-world setting compared to RCTs. These results can be used to contextualize the baseline risk of cCRT-induced pneumonitis in unresectable stage III NSCLC to better understand the adverse event of pneumonitis associated with novel immunotherapy treatments indicated for concomitant use with this modality.

Data on cutaneous human papillomavirus (HPV) seroprevalence are primarily derived from skin cancer case–control studies. Few studies have reported the seroprevalence of cutaneous HPV among healthy men. This study investigated the seroprevalence of cutaneous HPV types and associated risk factors among men residing in Brazil, Mexico and the USA. Six hundred men were randomly selected from the HPV Infection in Men study. Archived serum specimens were tested for antibodies against 14 cutaneous HPV genotypes, β-HPV types (5/8/12/14/17/22/23/24/38/48), α-HPV 27, γ-HPV 4, µ-HPV1 and ν-HPV 41 using a glutathione S-transferase L1-based multiplex serology assay. Risk factor data were collected by a questionnaire. Binomial proportions were used to estimate seroprevalence, and logistic regression to examine factors associated with seropositivity. Overall, 65.4 % of men were seropositive to ≥1 of the 14 cutaneous HPV types, and 39.0 % were positive for ≥1 β-HPV types. Seroprevalence was 8.9, 30.9, 28.6 and 9.4 % for α-HPV 27, γ-HPV 4, µ-HPV 1 and ν-HPV 41, respectively. In multivariate analyses, seropositivity for any cutaneous HPV type was associated with higher education [adjusted odds ratio (AOR) 1.75; 95 % confidence interval (CI) 1.08–2.83], and seropositivity of any β-HPV type was significantly associated with increasing age (AOR 1.72; 95 % CI 1.12–2.63, for men aged 31–44 years vs men aged 18–30 years). Other factors associated with various type-specific cutaneous HPV seropositivity included country, circumcision and lifetime number of male sexual partners. These data indicate that exposure to cutaneous HPV is common. Future studies are needed to assess the role of cutaneous HPV in diseases.

Background: Although ∼20% of human cancers are caused by microorganisms, only suspicion exists for a microbial cause of lung cancer. Potential infectious agents were investigated in non-small cell lung cancer (NSCLC) and non-neoplastic lung. Methods: Seventy NSCLC tumours (33 squamous cell carcinomas, 17 adenocarcinomas, 10 adenocarcinomas with lepidic spread, and 10 oligometastases) and 10 non-neoplastic lung specimens were evaluated for molecular evidence of microorganisms. Tissues were subjected to the Lawrence Livermore Microbial Detection Array, an oncovirus panel of the International Agency for Research on Cancer, and human papillomavirus (HPV) genotyping. Associations were examined between microbial prevalence, clinical characteristics, and p16 and EGFR expression. Results: Retroviral DNA was observed in 85% squamous cell carcinomas, 47% adenocarcinomas, and 10% adenocarcinomas with lepidic spread. Human papillomavirus DNA was found in 69% of squamous cell carcinomas with 30% containing high-risk HPV types. No significant viral DNA was detected in non-neoplastic lung. Patients with tumours containing viral DNA experienced improved long-term survival compared with patients with viral DNA-negative tumours. Conclusions: Most squamous cell carcinomas and adenocarcinomas contained retroviral DNA and one-third of squamous cell carcinomas contained high-risk HPV DNA. Viral DNA was absent in non-neoplastic lung. Trial results encourage further study of the viral contribution to lung carcinogenesis.

The role of antibody-mediated immunity in preventing newly acquired oral human papillomavirus (HPV) is not well understood. Among 1618 men participating in the HPV Infection in Men (HIM) Study, we evaluated oral rinses for HPV DNA and baseline sera for HPV-6, -11, -16, and -18 L1 antibodies. Thirty percent of men (486) were seropositive for ≥1 HPV type, and 25 men developed incident oral HPV infection (HPV-6 was detected in 7, HPV-11 in 0, HPV-16 in 17, and HPV-18 in 1). Cox models revealed that men with circulating antibodies to HPV-6, -11, -16, or -18 were not less likely to acquire type-specific oral HPV than men without antibodies (hazard ratio for the risk of acquiring HPV-6, -11, -16, or -18, 1.63; 95% confidence interval, .56–4.76).

Background Fulvestrant 500 mg has demonstrated improved efficacy vs fulvestrant 250 mg (time to progression [TTP]/progression free survival [PFS] and overall survival) in the treatment of postmenopausal women with advanced breast cancer (ABC). Few clinical trials have demonstrated a significant increase in clinical benefit rate (CBR) for one endocrine therapy (ET) over another for the treatment of ABC. This implies that TTP/PFS improvements have been achieved principally by prolonging time to developing acquired resistance. However, it would be beneficial to know whether CBR is also improved, indicating that more patients experience tumor remission. We performed a meta-analysis to determine if there was a difference in CBR between fulvestrant 500 mg and its comparators in randomized clinical trials (RCTs). Methods Five RCTs evaluating fulvestrant 500 mg were included: CONFIRM, China CONFIRM, FINDER1 and FINDER2 (vs fulvestrant 250 mg) as second-line ET and FIRST (vs anastrozole) as first-line ET. CBR was calculated as the proportion of patients experiencing a best objective response of stable disease for ≥24 weeks, complete response or partial response. Peto method was used to calculate odds ratios (ORs), 95% confidence intervals (CIs) and p values. Separate fixed effect (FE) models were constructed for first- and second-line data combined, and for second-line only data. For each model Tarone's test for heterogeneity assessed the assumption of constant trial effect. Results Unadjusted ORs for CBR from CONFIRM, FINDER1 and FINDER2, adjusted OR for China CONFIRM (as reported in the trial publications), and combined FE models are shown (Table).The OR (95% CI) of the FE model for all trials indicated that CBR was higher with fulvestrant 500 mg than with comparator treatments (OR: 1.34 [1.12-1.61]; FE p=0.001; Tarone's test p=0.91). When assessing second-line ET only, the OR was similar to the overall combined analysis. ORs (95% CI) of CBR from individual trials and meta-analysis. nOR of CBR for fulvestrant 500 mg vs comparator (95% CI)First-lineFIRST2051.30 (0.72–2.38)Second-lineCONFIRM7361.28 (0.95–1.71)China CONFIRM2211.37 (1.04–1.80)FINDER1921.20 (0.53–2.74)FINDER2931.96 (0.84–4.54)Fixed effects modelFirst- and second-line combined13471.34 (1.12–1.61) FE p=0.001; Tarone's test p=0.91Second-line only11421.35 (1.11–1.63) FE p=0.002; Tarone's test p=0.81CBR, clinical benefit rate; CI, confidence interval; FE, fixed effects model; OR, odds ratio. Adjusted odds ratio and CI (as reported in the trial publications) are presented for China CONFIRM; unadjusted odds ratios and CIs are used for all other trials. FINDER1 and FINDER2 included fulvestrant 500 mg, 250 mg plus loading dose, and 250 mg treatment arms. Data shown for fulvestrant 500 mg versus 250 mg. Conclusions These data suggest that fulvestrant 500 mg is associated with a significant improvement in CBR of approximately 34% compared with comparator ETs (i.e. more tumors are placed into remission). This finding is consistent in both second- and first-line ET settings. We await the results of the Phase 3 FALCON first-line ET RCT to see if it supports this finding of increased CBR with fulvestrant 500 mg. Citation Format: Robertson JFR, Zefei J, Di Leo A, Ohno S, Pritchard KI, Ellis M, Bradbury I, Campbell C. A meta-analysis of clinical benefit rates for fulvestrant 500 mg versus alternative therapies for treatment of postmenopausal, estrogen receptor-positive advanced breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-01.

Early HPV infection in males is difficult to detect clinically and pathologically. This study assessed histopathology in diagnosing male genital HPV. External genital lesions (n = 352) were biopsied, diagnosed by a dermatopathologist, and HPV genotyped. A subset (n = 167) was diagnosed independently by a second dermatopathologist and also re-evaluated in detail, tabulating the presence of a set of histopathologic characteristics related to HPV infection. Cases that received discrepant diagnoses or HPV-related diagnoses were evaluated by a third dermatopathologist (n = 163). Across dermatopathologists, three-way concordance was fair (k = 0.30). Pairwise concordance for condyloma was fair to good (k = 0.30-0.67) and poor to moderate for penile intraepithelial neoplasia (k = -0.05 to 0.42). Diagnoses were 44-47% sensitive and 65-72% specific for HPV 6/11-containing lesions, and 20-37% sensitive and 98-99% specific for HPV 16/18. Presence of HPV 6/11 was 75-79% sensitive and 35% specific for predicting pathologic diagnosis of condyloma. For diagnosis of penile intraepithelial neoplasia, HPV 16/18 was 95-96% specific but only 40-64% sensitive. Rounded papillomatosis, hypergranulosis, and dilated vessels were significantly (P

Background: There remains a perception among many clinicians that visceral metastases (VMs) from hormone receptor positive (HR) breast cancer (BC) respond less well to endocrine therapy (ET) than non-VMs and so should receive chemotherapy as first line treatment. Patients & Methods: Four phase 3 randomised controlled trials (RCTs) of first line ET, all with tamoxifen (TAM) as their control arm) have been reviewed – Exemestane (Exe), fulvestrant 250mg (F250) and two with anastrozole (Ana); the latter, were study 27 in the Rest of the World (ROW) & study 30 in North America (NA). All reported objective response (OR), clinical benefit (CB), time to progression (TTP) / progression free survival (PFS): all have been published (1-5). Only HR positive tumors were included in this review. Data have been analysed both for Tam control arms alone and also for the four different endocrine agents combined. Results: CB & OR for TAM alone in each study individually and then combined are shown in the Table. The OR and CB rates were similar for non-VMs versus VMs in all studies except study 30 (NA) where CB rates were 59% for non-VM and 33% for VM (Test for heterogeneity of CB rates was p=0.047). For the four studies combined, the CB rates for non-VM versus VMs were 64% and 57% respectively (p=0.06) while the OR rates were 34% versus 30% respectively (p= 0.28). When all endocrine agents were combined the OR rate between non-VMs and VMs was significantly different (p = 0.038) as was the CB rate (p = 0.0015). Rates of CB and OR in study 30 (NA) again appear different between non-VMs and VMs (data not shown). The Median Duration of CB on Tam appear similar between non-VMs versus VMs, both for each study individually and when combined (see Table); when combined the Medians were 420 versus 418 days respectively with a Hazard Ratio (HR)=0.952 (0.748-1.211) (p=0.69). When all endocrine therapies for the combined four studies were assessed the HR for DoCB between non-VMs and VMs was 0.922 (0.779-1.093) (p=0.35). For the TTP the HR of non-VMs versus VMs on Tam alone was 0.851 (0.715-1.011) (p=0.07) and for all endocrine therapies the HR was 0.821 (0.727-0.926) (p=0.001). Conclusions: HR+VMs which achieve clinical benefit on ET remain controlled for as long as non-VMs as shown by the DoCB results for both Tam and all endocrine therapies combined. There was no significant difference in OR rates between VMs and non-VMs with Tamoxifen. There was when all endocrine agents were combined and the difference appears to be primarily due to one study (30 – NA). There is no confirmed explanation for these differences. TTP differences appear to be due primarily to the difference in initial CB rates in study 30 (see Table). HR+ VMs have hormone sensitivity similar to non-visceral mets – they respond as well and for as long as non-VMs. In the absence of visceral crisis (ie immediately life-threatening disease) ET would appear to be the treatment of choice for VMs in the same way as it is for non-VMs. Clinical Outcome by VM and Non VM (Tamoxifen only patients) N (%)StudiesExeAna (EUR)Ana (NA)F250Combined N = 168N = 144N = 162N = 209N=683Without VM (55%)N = 88N = 71N = 82N = 135N=376CB (%)66 (75)42 (59)47 (59)87 (64)242 (64)OR (%)41 (47)26 (37)15 (19)45 (33)127 (34)TTP (Median in days)287254305234277DoCB (Median in days)343360445451420With VM (45%)N = 80N = 73N = 80N = 74N=307CB (%)64 (80)38 (52)27 (33)46 (62)175 (57)OR (%)36 (45)21 (29)13 (16)21 (28)91 (30)TTP (Median in days)340230152281238DoCB (Median in days)376505411339418 Citation Format: John FR Robertson, Robert Paridaens, Jan Bogaerts, Yuri Rukazenkov, Christine Campbell, Ian Bradbury. Visceral metastases from hormone receptor positive breast cancer are as sensitive to endocrine therapy as non-visceral metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-02.

Aim: To select tumor biomarkers, included in the AKT pathway, able to predict response to tamoxifen (TAM) in patients with estrogen receptor (ER) positive breast cancer. Patients & Methods: 157 endocrine treatment naïve patients with known ER and HER2 status were treated with TAM: tumour tissue was available either as tissue microarrays (TMA) (n=107) or core biopsies (n=50). After removal of duplicates, ER(-) BCs, & patients without full outcome data 103 patients were available. Ten biomarkers were evaluated by immunohistochemical staining (% positivity and/or H-Score): ER, HER2, Ki67, & phosphorylated forms of MAPK, AKT, ER (Ser118), PRAS40, and IGF1R, as well as pTEN & also androgen receptor (AR) expression. TMA cores were collected from three tumor sites, two central and one peripheral. Tumors were also analysed for AKT1 E17K somatic mutation using BEAMing technology. Patient outcome was assessed by clinical benefit (CB) rate & survival analyses (Time To Progression (TTP) and Time To Death (TTD)). Biomarkers were selected by regression trees to be included in multivariate models for clinical outcomes. False Discovery Rate(FDR) was applied to univariate results. Combinations of pAKT & pPRAS40, Ki67 & ER and ER/AR ratio-were also analysed. Results: Type of Biopsy (Core versus TMA): Generally % positivity was lower in TMAs than cores, for HER2, pER118, pIGF1R and cytoplasmic pAKT and pPRAS40. pAKT, pMAPK and Ki67 were largely unaffected by biopsy type. After FDR testing, significant differences remained for pER118 (p=0.002), pIGF1R (p Biopsy Location (TMAs): There was no significant difference in % positivity between central & peripheral tumor sites for all biomarkers examined. After FDR correction modest differences were seen for HER2 & pER118 (both p=0.044) only between the two central samples. IHC endpoints versus clinical outcome: Univariate analyses identified only lower levels of pTEN and higher levels of Ki67 (% positivity) as predictive of poor outcome (TTP & TTD) following TAM treatment. In the luminal A (ER+/HER2-) subgroup only Ki67 was predictive of poor outcome (p=0.012). The predictive power of Ki67 for TTP was not improved by combination with pTEN or ER. An inverse ER H-Score association with TTP was confined to the 'luminal A' cohort. AR was not predictive. 71 patients had AR/ER ratio: 61 had ratio Only 2 /146 ( Conclusions: Biomarker staining cannot be assumed to be the same in TMAs & core biopsies: such data should be combined with caution. Importantly however, there was no evidence of difference in Ki67 between TMA & core samples. There is no evidence to suggest that biomarker staining (including Ki67) at different tumor sites shouldn't be combined, or that ranking of scores differs across such sites. The findings confirmed previous reports that Ki67 & reduced level of PI3K /AKT pathway regulator pTEN can predict resistance to TAM in ER+ BCs. The AKT mutation rate was low. Citation Format: Campbell C, Mathew J, Ellis I, Finlay P, Green A, Bradbury I, Borgquist S, Elebro K, Politz O, Haegebarth A, Gee JM, Robertson JF. Markers of PI3K/Akt, ER & AR pathways and Ki67 expression in relation to tamoxifen outcome in ER+ breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-03-02.

Human papillomaviruses (HPVs) cause cancer at multiple anatomic sites in men and women, including cervical, oropharyngeal, anal, vulvar and vaginal cancers in women and oropharyngeal, anal and penile cancers in men. In this EUROGIN 2014 roadmap, differences in HPV-related cancer and infection burden by gender and anatomic site are reviewed. The proportion of cancers attributable to HPV varies by anatomic site, with nearly 100% of cervical, 88% of anal and

Purpose: Oropharyngeal cancer (OPC) incidence continues to increase dramatically in the US. Accumulating evidence suggests that oral microbiota (communities of microorganisms that reside in the oral cavity) may influence cancer treatment-related toxicities. We sought to examine the composition and diversity of oral microbiota in OPC patients prior to treatment, and identify associations between oral microbiota and subsequent development of oral mucositis (inflammation of mucous membranes) and candidiasis (fungal infection with Candida yeast). Methods: 60 newly diagnosed, treatment naïve, OPC patients were recruited from Moffitt Cancer Center (2015-2017). Patients provided mouthwash-based oral gargles before starting chemoradiation or radiation. DNA was isolated using the QIAGEN DNeasy PowerSoil kit, and the V1-V3 region of the bacterial 16S rRNA gene was sequenced. An operational taxonomic unit table was generated and Ribosomal Database Project Classifier used to assign taxonomy. The development of oral mucositis (no/mild vs. severe) and candidiasis (no vs. yes) during treatment was abstracted from medical records. Comparisons of bacterial relative abundance (Mann Whitney U), alpha diversity (Chao1, Shannon, and Simpson), and beta diversity (Bray-Curtis) were performed in R and its extension (Phyloseq). Results: Of 60 OPC patients, 65% were stage IV, 48% tonsillar and 42% base of tongue, and 40% never smokers. Pre-treatment levels of genus Klebsiella and class Gammaproteobacteria were significantly greater in the oral cavity of patients who had no/mild mucositis vs. those who developed severe mucositis (p Conclusions: Microbiome profiling may hold promise as a prognostic biomarker of treatment-related toxicities. Several potentially predictive taxa were identified to be differentially abundant in OPC patients who subsequently developed oral mucositis or candidiasis. Future analyses will evaluate the role of oral microbial resilience (the rate of recovery after disturbance) using oral specimens collected 3 mo. after treatment. Translational research focused on understanding how oral microbiota influence local immune and inflammatory responses may aid in the development of microbiota-based interventions to minimize adverse events. Citation Format: Christine M. Pierce, Stephanie Hogue, Shirlene Paul, Bo-Young Hong, Wildson Vieira da Silva, Maria F. Gomez, Anna R. Giuliano, Jimmy J. Caudell, George M. Weinstock. Mucositis, candidiasis, and associations with the oral microbiome in treatment naive patients with oropharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3326.

Summary Background Oral human papillomavirus (HPV) infection causes a subset of oropharyngeal cancers. These cancers disproportionately affect men, are increasing in incidence, and have no proven prevention methods. We aimed to establish the natural history of oral HPV infection in men. Methods To estimate incidence and clearance of HPV infections, men residing in Brazil, Mexico, and the USA who were HIV negative and reported no history of anogenital cancer were recruited into the HPV Infection in Men (HIM) cohort study. A subset of the cohort who provided two or more oral rinse-and-gargle samples with valid HPV results and who completed a minimum of 2 weeks of follow-up were included in this analysis. Oral rinse-and-gargle samples and questionnaire data were obtained every 6 months for up to 4 years. Samples were analysed for the presence of oncogenic and non-oncogenic HPV infections by the linear array method. Findings 1626 men aged 18–73 years and with a median follow-up of 12·7 months (IQR 12·1–14·7) were included in the analysis. During the first 12 months of follow-up, 4·4% (95% CI 3·5–5·6; n=115 incident infections) of men acquired an incident oral HPV infection, 1·7% (1·2–2·5; n=53 incident infections) an oral oncogenic HPV infection, and 0·6% (0·3–1·1; n=18 incident infections) an oral HPV 16 infection. Acquisition of oral oncogenic HPV was significantly associated with smoking and not being married or cohabiting, but was similar across countries, age groups, and reported sexual behaviours. Median duration of infection was 6·9 months (95 % CI 6·2–9·3; n=45 cleared infections) for any HPV, 6·3 months (6·0–9·9; n=18 cleared infections) for oncogenic HPV, and 7·3 months (6·0–not estimable; n=5 cleared infections) for HPV 16. Eight of the 18 incident oral HPV 16 infections persisted for two or more study visits. Interpretation Newly acquired oral oncogenic HPV infections in healthy men were rare and most were cleared within 1 year. Additional studies into the natural history of HPV are needed to inform development of infection-related prevention efforts. Funding US National Cancer Institute, Merck Sharp & Dohme.

Reply to: Comment on ‘Molecular evidence of viral DNA in non-small cell lung cancer and non-neoplastic lung’

Background Cutaneous human papillomaviruses (HPVs) increase the risk of non-melanoma skin cancer in sun-exposed skin. We examined the role of beta-HPV in the development of male external genital lesions (EGLs), a sun-unexposed site. Methods In this nested case-control study (67 men with pathologically-confirmed EGLs and 134 controls), exfoliated cells collected from the surface of lesions and normal genital skin 0, 6, and 12 months preceding EGL development were tested for beta-HPV DNA using a type-specific multiplex genotyping assay. Beta-HPV prevalence was estimated and conditional logistic regression was used to evaluate the association with condyloma, the most common EGL. Results While beta-HPV prevalence among controls remained stable, the prevalence among cases was lowest on the surface of lesion. Detecting beta-HPV on the normal genital skin was not associated with the presence or development of condyloma. Conclusions Cutaneous beta-HPV does not appear to be contributing to pathogenesis in male genital skin.

Our goal was to describe prevalence of β-HPVs at three anatomic sites among 717 men from Brazil, Mexico and US enrolled in the HPV Infection in Men (HIM) Study. β-HPVs were genotyped using Luminex technology. Overall, 77.7%, 54.3% and 29.3% men were positive for any β-HPV at the genitals, anal canal, and oral cavity, respectively. Men from US and Brazil were significantly less likely to have β-HPV at the anal canal than men from Mexico. Older men were more likely to have β-HPV at the anal canal compared to younger men. Prevalence of β-HPV at the oral cavity was significantly associated with country of origin and age. Current smokers were significantly less likely to have β-HPV in the oral cavity than men who never smoked. Lack of associations between β-HPV and sexual behaviors may suggest other routes of contact such as autoinoculation which need to be explored further.

OBJECTIVE: To provide a comprehensive analysis of the descriptive epidemiology of invasive cervical cancer in Latin America and the Caribbean by analyzing quality data from the area's cancer registries, including data that were excluded from the International Agency for Research on Cancer (IARC) publication, Cancer Incidence in Five Continents, Vol. IX (CI5-IX). METHODS: This was a descriptive epidemiologic study that involved 20 cancer registries, 9 of which were included by IARC in CI5-IX, and 11 of which were not. Data on invasive cervical cancers diagnosed from 1998-2002 were obtained from IARC. A cervical cancerspecific quality assessment was performed on all registries whether or not they were included in CI5-IX. Data from 14 registries met quality criteria and were analyzed. Incidence rates were calculated and compared across registries. RESULTS: A substantial variation in incidence rates existed among the registries; agestandardized rates ranged from 14.6-44.0 per 100 000 women per year. Mean cervical cancer incidence rates were 10.4% higher for registries included in CI5-IX than for those excluded; however, this difference was not significant (P = 0.541). CONCLUSIONS: This study compared cervical cancer rates from a more diverse group of Latin American and Caribbean countries than that of the CI5-IX. The heterogeneity found among registries highlights the importance of examining data from as many registries as possible when characterizing risk across a geographic area. Data from developing countries can be used to better understand cancer distribution and enable Region-specific recommendations on cancer control and prevention once data quality has been establishedOBJETIVO: Efectuar un análisis integral de las características epidemiológicas descriptivas del cáncer de cervicouterino invasor en América Latina y el Caribe mediante el análisis de datos de calidad de los registros de cáncer de la región, incluso datos que fueron excluidos de la publicación del Centro Internacional de Investigaciones sobre el Cáncer (CIIC), Incidencia del cáncer en cinco continentes, Vol. IX (CI5-IX). MÉTODOS: En este estudio epidemiológico descriptivo se incluyeron 20 registros sobre el cáncer, de los cuales solo nueve fueron incluidos por el CIIC en el informe CI5-IX. Los datos sobre cáncer cervicouterino invasor diagnosticado entre 1998 y 2002 se obtuvieron a partir del CIIC. Se llevó a cabo una evaluación de la calidad de todos los registros específica para el cáncer cervicouterino, con independencia de que estuvieran incluidos en el informe CI5-IX o no. Los datos de 14 registros satisficieron los criterios de calidad y se analizaron. Se calcularon las tasas de incidencia y se compararon estas entre los registros. RESULTADOS: Entre los registros se comprobó una variación sustancial en las tasas de incidencia; las tasas normalizadas según la edad variaron entre 14,6 y 44,0 por 100 000 mujeres por año. Las tasas de incidencia medias de cáncer cervicouterino fueron 10,4% mayores en los registros incluidos en el CI5-IX que en aquellos excluidos; sin embargo, esta diferencia no fue significativa (P = 0,541). CONCLUSIONES: En este estudio se compararon las tasas de cáncer cervicouterino de un grupo más diverso de países de América Latina y el Caribe que el comprendido en el informe CI5-IX. La heterogeneidad encontrada entre los registros destaca la importancia de examinar los datos de tantos registros como sea posible cuando se caracteriza el riesgo en una zona geográfica. Los datos de los países en desarrollo pueden usarse para conocer más a fondo la distribución del cáncer y permiten formular recomendaciones específicas para la región sobre el control y la prevención del cáncer, una vez que se ha comprobado la calidad de los datos.

Mounting evidence suggests that a prominent T cell response in the colorectal cancer (CRC) tumor microenvironment is a valuable prognostic indicator, independent of stage at diagnosis. However, the strength and quality of host immune responses are highly variable across patients, and the factors that influence this variability are not well understood. The unique microbial communities present in the CRC tumor microenvironment may contribute to the modulation of local host immune responses, but prior investigations have been limited and focused on candidate microbes. Here, we investigated the association between the CRC tumor bacterial microbiome and the quantity and clonality of the T cell infiltrate. This investigation included 51 CRC from the Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based case-control study in northern Israel. Genomic DNA was extracted from fresh frozen tumors using microbiome-optimized techniques and sequenced using a PCR amplicon-mediated workflow on the Illumina MiSeq. Sequences from the V1-V3 hypervariable regions of the bacterial 16S rRNA gene region were clustered into operational taxonomic units (OTUs), a proxy for species, and taxonomic identification was determined using the Ribosomal Database Project. In addition, T cell repertoires were measured using the DNA-based immunoSEQ assay (Adaptive Biotechnologies), and T cell fraction (i.e. proportion of rearranged T cells relative to all nucleated cells) and clonality (i.e. T cell receptor diversity) were calculated. Bacterial sequencing was successful in 48 (94%) of samples, with a total of 868 OTUs identified. Klebsiella and Escherichia/Shigella were the most prevalent genera, detected in approximately 90% of tumors, followed by Propionibacterium, Pelomonas, and Veillonella, with each detected in approximately 50% of tumors. Fusobacterium, a genus of oral anaerobic bacteria believed to accelerate tumor progression and enable immune evasion in CRC, was detected in 20% of tumors. When present, Bacteroides and Fusobacterium were the most abundant, comprising 10-15% of all bacteria within each tumor, on average. ImmunoSEQ analysis identified a mean productive T cell fraction of 0.08 (SD: 0.16) and a mean productive clonality of 0.14 (SD: 0.06). Analysis of molecular variance (AMOVA) of the Theta YC measure of dissimilarity showed a statistically significant difference in bacterial community structure (i.e. composition and relative abundance) between samples in the highest versus lower three quartiles of T cell fraction (P=0.03) and clonality (P=0.01). These preliminary findings suggest a potential relationship between microbial community structure and the quantity and diversity of the CRC T cell infiltrate. Additional analyses are underway to better understand this association as well as the independent contributions of the microbiome to CRC prognosis. Citation Format: Christine M. Pierce, Bo-young Hong, Hannah J. Hoehn, Maria F. Gomez, Marilena Melas, Kevin McDonnell, Youngchul Kim, Erica Sodergren, George Weinstock, Hedy S. Rennert, Thomas Giordano, Joel Greenson, Gad Rennert, Stephen B. Gruber, Stephanie L. Schmit. Microbes in the tumor microenvironment: Bacterial influences on host immunity in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4746.

Aims Linaclotide is an orally administered 14-amino acid peptide being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation. We determined the stability of linaclotide in the intestine, measured the oral bioavailability, and investigated whether the pharmacodynamic effects elicited in rodent models of gastrointestinal function are mechanistically linked to the activation of intestinal guanylate cyclase C (GC-C). Main methods Linaclotide binding to intestinal mucosal membranes was assessed in competitive binding assays. Stability and oral bioavailability of linaclotide were measured in small intestinal fluid and serum, respectively, and models of gastrointestinal function were conducted using wild type (wt) and GC-C null mice. Key findings Linaclotide inhibited in vitro [ 125 I]-STa binding to intestinal mucosal membranes from wt mice in a concentration-dependent manner. In contrast, [ 125 I]-STa binding to these membranes from GC-C null mice was significantly decreased. After incubation in vitro in jejunal fluid for 30 min, linaclotide was completely degraded. Pharmacokinetic analysis showed very low oral bioavailability (0.10%). In intestinal secretion and transit models, linaclotide exhibited significant pharmacological effects in wt, but not in GC-C null mice: induction of increased fluid secretion into surgically ligated jejunal loops was accompanied by the secretion of elevated levels of cyclic guanosine-3′,5′-monophosphate and accelerated gastrointestinal transit. Significance Linaclotide is a potent and selective GC-C agonist that elicits pharmacological effects locally in the gastrointestinal tract. This pharmacological profile suggests that orally administered linaclotide may be capable of improving the abdominal symptoms and bowel habits of patients suffering from IBS-C and chronic constipation.

Summary Objectives Secretory leukocyte protease inhibitor (SLPI) is an innate-immunity protein displaying antimicrobial and anti-inflammatory properties that is found in high concentrations in saliva. The role of extracellular salivary SLPI in head and neck squamous cell carcinoma (HNSCC) remains unclear. Thus, we aimed to evaluate the association between SLPI and HNSCC risk in the Cancer Prevention Study II Nutrition Cohort. Materials and methods Among 53,180 men and women with no history of cancer who provided an oral rinse between 2001 and 2002, 60 were subsequently diagnosed with incident HNSCC between specimen collection and June 2009. In this nested case-control study, archived oral supernatants were evaluated using the Human SLPI Quantikine ELISA Kit for all 60 cases and 180 controls individually matched on gender, race, date of birth, and date of oral rinse collection. Conditional logistic regression was used to estimate HNSCC risk. Results Overall, pre-diagnostic salivary SLPI was associated with a non-statistically significant higher risk of HNSCC (OR = 1.6, 95% CI = 0.9–3.0). Among never smokers, high SLPI was associated with a non-statistically significant lower risk (OR = 0.5, 95% CI = 0.1–1.9), whereas among ever smokers, high SLPI was associated with a statistically significant higher risk (OR = 2.1, 95% CI = 1.0–4.3) of HNSCC, compared to low SLPI. Conclusion While results from this study suggest that higher concentrations of salivary SLPI might increase the risk of HNSCC among ever smokers, more research is needed to verify these findings and define the mechanisms by which SLPI and smoking influence the etiology of HNSCC.

Persistent infection with oral HPV16 is believed to drive the development of most oropharyngeal cancers. However, patterns of oral HPV16 persistence remain understudied, particularly among HIV-negative individuals. Oral HPV16 persistence was evaluated among 1,626 participants of the HPV Infection in Men (HIM) Study. Twenty-three oral HPV16-positive men who provided an oral gargle sample on ≥2 study visits were included in the analysis. Archived oral samples from all follow-up visits were tested for HPV16 using Linear Array and INNO-LiPA detection methods. Persistence was evaluated using consecutive HPV16-positive visits held approximately 6 months apart and using the Kaplan–Meier method. Oral HPV16-positive men were aged 18 to 64 years [median, 36 years; interquartile range (IQR), 25–42] and were followed for a median of 44.4 months (IQR, 29.9–49.5). Of 13 incident infections, 4 (30.8%) persisted ≥12 months, 1 (10.0%) persisted ≥24 months, and none persisted ≥36 months [median infection duration, 7.3 months; 95% confidence interval (CI), 6.4–NA)]. Of 10 prevalent infections, 9 (90.0%) persisted ≥12 months, 8 (80.0%) persisted ≥24 months, 4 (57.1%) persisted ≥36 months, and 2 (40.0%) persisted ≥48 months (median infection duration, NA). Twelve-month persistence of incident infections increased significantly with age (Ptrend = 0.028). Prevalent oral HPV16 infections in men persisted longer than newly acquired infections, and persistence appeared to increase with age. These findings may explain the high prevalence of oral HPV observed at older ages. Understanding oral HPV16 persistence will aid in the identification of men at high-risk of developing HPV-related oropharyngeal cancer. Cancer Prev Res; 8(3); 190–6. ©2015 AACR.

Violence in healthcare is a global problem and nurses are subjected to workplace violence (WPV) more than any healthcare professional. The International Council of Nurses (ICN) reports that nurses are three more likely to experience workplace violence than any other group. The Emergency department (ED) is one of the most frequent locations where this occurs. There is evidence that this problem is severely underestimated due to the under-reporting of WPV events and as such negative consequences ofWPV impact patient outcomes. Additional evidence suggests that the percentage of individuals reporting such events is low. The purpose of this study was to explore nurses' experiences ofWPV, whether events ofWPV were being reported and if not what were the barriers that contributed to the events not being reported. This mixed method study utilized a 19 item checklist ofWPV behaviors which was adapted from a 2007 Emergency Nurses Association (ENA) study (ENA Workplace Violence Toolkit, 201 0). A total of 54 nurses from a local ED were surveyed. The Theory of Planned Behavior was used to guide this project. Results of the study suggested that while a majority of nurses experienced WPV, there was a dramatic culture of under-reporting. A majority of participants indicated reporting would not result in changes and therefore not worth reporting. This study suggests evidence ofWPV as a flourishing problem and that documenting the extent ofWPV events continues to be problematic due to underreporting. Future research needs to further explore barriers to reporting WPV and develop policies and protocols to increase reporting of WPV and ultimately mitigate WPV.

Background Human papillomavirus (HPV) causes two types of external genital lesions (EGLs) in men: genital warts (condyloma) and penile intraepithelial neoplasia (PeIN). Objective The purpose of this study was to describe genital HPV progression to a histopathologically confirmed HPV-related EGL. Design, setting, and participants A prospective analysis nested within the HPV Infection in Men (HIM) study was conducted among 3033 men. At each visit, visually distinct EGLs were biopsied; the biopsy specimens were subjected to pathologic evaluation and categorized by pathologic diagnoses. Genital swabs and biopsies were used to identify HPV types using the Linear Array genotyping method for swabs and INNO-LiPA for biopsy specimens. Outcome measurements and statistical analysis EGL incidence was determined among 1788 HPV-positive men, and cumulative incidence rates at 6, 12, and 24 mo were estimated. The proportion of HPV infections that progressed to EGL was also calculated, along with median time to EGL development. Results and limitations Among 1788 HPV-positive men, 92 developed an incident EGL during follow-up (9 PeIN and 86 condyloma). During the first 12 mo of follow-up, 16% of men with a genital HPV 6 infection developed an HPV 6-positive condyloma, and 22% of genital HPV 11 infections progressed to an HPV 11-positive condyloma. During the first 12 mo of follow-up, 0.5% of men with a genital HPV 16 infection developed an HPV 16-positive PeIN. Although we expected PeIN to be a rare event, the sample size for PeIN ( n =10) limited the types of analyses that could be performed. Conclusions Most EGLs develop following infection with HPV 6, 11, or 16, all of which could be prevented with the 4-valent HPV vaccine. Patient summary In this study, we looked at genital human papillomavirus (HPV) infections that can cause lesions in men. The HPV that we detected within the lesions could be prevented by a vaccine.

PURPOSE: Despite advances in cancer treatment, patients with advanced head and neck cancer (HNC) have a median overall survival of METHODS: Fresh frozen tumor tissues from 30 newly diagnosed, treatment-naïve patients who received chemoradiation at Moffitt Cancer Center for squamous cell HNC were evaluated. Genomic DNA was extracted from 25mg of tissue. The V1-V3 hypervariable region of the bacterial 16S rRNA gene and fungal internal transcribed spacer (ITS) 1 region were sequenced using a PCR amplicon-mediated workflow on the Illumina MiSeq. 16S sequences were clustered into operational taxonomic units and taxonomic identification was determined using the RDP database and ITS sequences were classified using an in house reference database. Patients' charts were reviewed to ascertain clinical response 3, 6 and 12 months after treatment cessation. Response was dichotomized as complete (no evidence of disease) and incomplete (partial response, stable disease, and progressive disease). RESULTS: At the time of tumor collection, patients ranged in age from 20-79 years, and were predominantly men (83%) and current smokers (40%). The most common anatomic site was the oral cavity (70%) followed by the larynx (20%) and oropharynx (10%), and most were diagnosed at stage 4 (87%). Three, 6 and 12 months after treatment cessation, 4 (14%), 9 (36%), and 10 (40%) patients had an incomplete response to therapy, respectively. Bacterial sequencing was successful in 29 (97%) samples and fungal in 15 (50%). Clustering analyses of bacterial abundance profiles suggested that 4 types of communities existed, each dominated by Fusobacterium, Prevotella, Streptococcus, or Treponema. HNC patients with incomplete clinical responses (3, 6, or 12 months after treatment) were more likely to have treatment-naïve tumors dominated by Fusobacterium (cluster 1; 56%) than any other genus, whereas patients with complete clinical responses were more likely to have treatment-naïve tumors dominated by Prevotella (cluster 2; 40%) than any other genus. None of the patients with incomplete responses were dominated by Streptococcus (cluster 3) or Treponema (cluster 4). Fungal ITS profiling revealed that the tumor microbiome was largely dominated by the fungi Malassezia. CONCLUSIONS: The current study demonstrates that intratumoral bacterial profiles dominated by Prevotella may serve as a biomarker of improved prognosis, while profiles dominated by Fusobacterium may indicate a poor prognosis following chemoradiation in HNC patients. Citation Format: Christine M. Pierce Campbell, Bo-Young Hong, Maria F. Gomez, Blake M. Hanson, Erica Sodergren, Sybil T. Sha, Jeffery S. Russell, George M. Weinstock. Microbial profiling of the head and neck tumor microenvironment as a biomarker of clinical response to chemoradiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2252. doi:10.1158/1538-7445.AM2017-2252

Background The genital skin of males hosts a diversity of HPV genotypes and uncharacterized HPV genotypes. Previously we demonstrated that a specific viral genotype was not identified in 14% of all genital specimens (i.e., HPV unclassified specimens) using the Roche Linear Array method. Our goal was to identify and assess the prevalence of individual HPV types among genital HPV unclassified specimens collected in the HIM Study population, at enrollment, and examine associations with socio-demographic and behavioral characteristics. Methods Genital skin specimens of men that were considered unclassified (HPV PCR positive, no genotype specified) at enrollment were typed by sequencing amplified PGMY09/11 products or cloning of PGMY/GP+ nested amplicons followed by sequencing. PGMY/GP+ negative specimens were further analyzed using FAP primers. HPV type classification was conducted through comparisons with sequences in the GenBank database. Results Readable nucleotide sequences were generated for the majority of previously unclassified specimens (66%), including both characterized (77%) and yet uncharacterized (23%) HPV types. Of the characterized HPV types, most (73%) were Beta [β]-HPVs, primarily from β-1 and β-2 species, followed by Alpha [α]-HPVs (20%). Smokers (current and former) were significantly more likely to have an α-HPV infection, compared with any other genus; no other factors were associated with specific HPV genera or specific β-HPV species. Conclusions Male genital skin harbor a large number of β-HPV types. Knowledge concerning the prevalence of the diverse HPV types in the men genital is important to better understand the transmission of these viruses. Electronic supplementary material The online version of this article (doi:10.1186/s12879-014-0677-y) contains supplementary material, which is available to authorized users.

Human papillomavirus (HPV) is known to cause external genital lesions (EGLs) in men, including condylomata acuminata, commonly referred to as condyloma or genital warts, as well as penile intraepithelial neoplasia (PeIN), which is believed to be a precursor to penile cancer [1]. While HPV-related condyloma is considered a benign lesion, the substantial economic and psychosocial burden of this clinical manifestation of infection cannot be overlooked. The incidence of penile cancer is increasing globally, with incidence rates in Brazil among the highest worldwide [2] and no routine screening tests available for penile cancer or the precursor PeIN lesions. Studies of HPV-related EGLs have primarily been limited to condyloma and low-risk HPV genotypes 6 and 11, owing to the rarity of PeIN and the lack of long-term, prospective cohorts of men. Studies to determine the role of other high- or low-risk types in the etiology of these EGLs are similarly limited. A quadrivalent vaccine, offering protection against HPV genotypes 6 and 11 and high-risk HPV genotypes 16 and 18, has been demonstrated as efficacious in men [3] but has not yet been approved for the prevention of penile cancer. This vaccine is also approved only for use in young men (ages 9–26 years); it is recommended by the Centers for Disease Control and Prevention for males ages 11–22 years and for high-risk males aged up to 26 years, but no HPV vaccine prevention options are currently available for men at older ages. Further studies of the causative HPV genotypes of benign and precancerous lesions and the ages at which these lesions occur are necessary to inform development of prevention and screening strategies. Using the established HPV Infection in Men (HIM) study cohort, a multinational study of men across the life span from the United States, Brazil, and Mexico, we sought to determine the incidence of pathologically confirmed EGLs, by lesion type, among men in different age groups and to evaluate the HPV types that were associated with EGL development.

Human papillomaviruses (HPVs) cause cancer at multiple anatomic sites in men and women, including cervical, oropharyngeal, anal, vulvar, and vaginal cancers in women and oropharyngeal, anal, and penile cancers in men. In this EUROGIN 2014 roadmap, differences in HPV-related cancer and infection burden by gender and anatomic site are reviewed. The proportion of cancers attributable to HPV varies by anatomic site, with nearly 100% of cervical, 88% of anal, and less than 50% of lower genital tract and oropharyngeal cancers attributable to HPV, depending on world region and prevalence of tobacco use. Often mirroring cancer incidence rates, HPV prevalence and infection natural history varies by gender and anatomic site of infection. Oral HPV infection is rare and significantly differs by gender; yet HPV-related cancer incidence at this site is several-fold higher than at either the anal canal or penile epithelium. HPV seroprevalence is significantly higher among women compared to men, likely explaining the differences in age-specific HPV prevalence and incidence patterns observed by gender. Correspondingly, among heterosexual partners, HPV transmission appears higher from women to men. More research is needed to characterize HPV natural history at each anatomic site where HPV causes cancer in men and women, information that is critical to inform the basic science of HPV natural history and the development of future infection and cancer prevention efforts.

Background Cutaneous human papillomaviruses (HPVs) may be associated with cutaneous epithelial lesions and non-melanoma skin cancers. No study has systematically evaluated the presence of genus beta [β]-HPV in male genital skin or external genital lesions (EGLs) Objectives To examine cutaneous β-HPV types detected on the surface of EGLs in men and describe their presence prior to EGL development. Study design A retrospective case series was conducted among 69 men with pathologically confirmed EGLs (n = 72) who participated in the HPV Infection in Men Study. Archived exfoliated cells collected from the surface of each EGL and normal genital skin specimens 6–12 months preceding EGL development were tested for β-HPV DNA using a type-specific multiplex genotyping assay. Results β-HPV DNA was detected on 61.1% of all EGLs, with types 38 (16.7%), 5 (15.3%), and 12 (12.5%) most commonly identified. HPV prevalence differed across pathological diagnoses, with the largest number of β-HPV types detected on condylomas. Most β-HPV types were detected on normal genital skin prior to EGL development, though the prevalence was lower on EGLs compared to preceding normal genital skin. Conclusions EGLs and the normal genital skin of men harbor a large number of β-HPV types; however, it appears that β-HPVs are unrelated to EGL development in men. Despite evidence to support a causal role in skin carcinogenesis at UVR-exposed sites, cutaneous HPV appears unlikely to cause disease at the UVR-unexposed genitals.

Secretory leukocyte protease inhibitor (SLPI) is an innate immunity-associated protein known to inhibit HIV transmission, and is thought to inhibit a variety of infectious agents, including human papillomaviruses (HPVs). We aimed to optimize an established ELISA-based SLPI quantification assay for use with oral gargle specimens collected using mouthwash, and to assess preliminary associations with age, smoking status, and alcohol intake.Oral gargle supernatants from 50 individuals were used to optimize the Human SLPI Quantikine ELISA Kit. Sample suitability was assessed and quality control analyses were conducted.Salivary SLPI was successfully recovered from oral gargles with low intra-assay and high inter-individual variability. Initial measurements showed that salivary SLPI varied considerably across individuals, and that SLPI was inversely associated with age.This optimized assay can be used to examine the role of SLPI in the acquisition of oral HPV and other infections.

The HPV infection in men (HIM) study examines the natural history of genital HPV infection in men. Genotyping methods used in this study identify 37 α-HPV types; however, the viral type could not be identified in approximately 22% of male genital specimens that were HPV PCR positive. Our aim was to genotype HPV-unclassified specimens by sequencing PGMY09/11, GP5+/6+ or FAP59/64 PCR products. Using this approach we were able to detect 86 unique HPV types among 508 of 931 specimens analyzed. We report for the first time the presence of a broad range of α-, β- and γ-HPV at the male genitals.

(See the editorial commentary by Hariri and Warner on pages 367–9.) Human papillomavirus (HPV) infection is the most common sexually transmitted infection (STI) worldwide [1]. Approximately 50% of men [2, 3] and 40% of women [4] in the United States are infected with HPV at any given time. HPV transmission occurs via skin-to-skin contact, usually during sexual intercourse, and is often transmitted unknowingly, because most infections are asymptomatic. HPV infection can lead to benign disease, including anogenital warts [5], or to malignant cancers of the cervix, vagina, vulva, anal canal, penis, and oropharynx [6]. At present, prophylactic vaccination is the only proven and available method of primary HPV prevention; however, the vaccine is only routinely available for those younger than 26 years, and vaccine dissemination rates in the United States remain low [7, 8]. Therefore, effective methods are still needed to prevent HPV infection and reduce HPV transmission among men and women. Male condoms offer substantial protection against acquisition of many STIs [9], including human immunodeficiency virus infection, gonorrhea, chlamydial infection, herpes simplex virus type 2 infection, and syphilis. However, data on the efficacy of condoms in preventing HPV acquisition are limited. Consistent condom use has been associated with a decreased likelihood of HPV acquisition among young women [10]; however, data among men are sparse [9, 11]. Some cross-sectional studies have demonstrated protective associations between condom use and prevalence of genital HPV infection [12–15]. Only 2 prospective studies of condom efficacy have been conducted in men, and the studies were restricted by small sample sizes and short follow-up times; however, their results suggest that condom use may reduce the risk of acquiring genital HPV infections [16] and may promote the regression of HPV-related lesions [17]. To our knowledge, no study has had sufficient power to examine the efficacy of condom use in reducing HPV acquisition and decreasing HPV infection duration in men or the ability to detect differences in condom efficacy across sexual behavior risk groups or sex partner types. Using data from a large cohort of sexually active men, we assess whether consistent condom use reduces the risk of acquiring new genital HPV infections or decreases the duration of HPV infections. The association between condom use and genital HPV infection was further evaluated according to sexual risk behaviors and partnerships.

Over the past several decades, invasive cervical cancer (ICC) incidence in the United States has declined dramatically. Much of this decline has been attributed to widespread use of cytology screening followed by treatment of precancerous lesions. Despite available technologies to prevent ICC and screening programs targeting high-risk women, certain populations in the United States experience disproportionately high rates of ICC (e.g., racial/ethnic minorities and rural women). Limited access to and use of screening/follow-up services underlie this disparity. The licensure of the human papillomavirus (HPV) vaccine in 2006 introduced an additional method of ICC prevention. Unfortunately, dissemination of the vaccine to age-eligible females has been lower than expected (32% have received all 3 recommended doses). Decreasing the burden of HPV infection and HPV-related diseases in the United States will require greater dissemination of the HPV vaccine to adolescents and young adults, along with successful implementation of revised ICC screening guidelines that incorporate HPV and cytology cotesting. While a future without ICC is possible, we will need a comprehensive national health care program and innovative approaches to reduce ICC burden and disparities. Cancer Epidemiol Biomarkers Prev; 21(9); 1402–8. ©2012 AACR.