Almost all cervical cancers are caused by human papillomaviruses (HPVs). In most cases, HPV DNA is integrated into the human genome. We found that tumor-specific, HPV-human DNA junctions are detectable in serum cell-free DNA of a fraction of cervical cancer patients at the time of initial treatment and/or at 6 months following treatment. Retrospective analysis revealed these junctions were more frequently detectable in women in whom the cancer later recurred. We also found that cervical cancers caused by HPV types outside of phylogenetic clade α9 had a higher recurrence frequency than those caused by α9 types in both our study and The Cancer Genome Atlas cervical cancer database, despite the higher prevalence ofα9 types, including HPV16, in cervical cancer. Thus, HPV-human DNA junction detection in serum cell-free DNA and HPV type determination in tumor tissue may help predict recurrence risk. Screening serum cell-free DNA for junctions may also offer an unambiguous non-invasive means to monitor absence of recurrence following treatment.

ABSTRACT Immune responses correlated with clearance of human papillomavirus type 16 (HPV16) were sought in PVX2 immunotherapy-treated CIN ≤1 patients. PVX2 comprises intramuscular vaccinations with HPV16 E7-targeted pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine (3 mg, weeks 0 and 4) and HPV16 L2E7E6 fusion protein (TA-CIN; 100 µg week 8). Administering PVX2 to 12 women with HPV16+ CIN ≤1 elicited both antibody and CD8+ T-cell responses, including changes in TCR diversity, clonal expansion, and emergence of public clonotypes. HPV16 was not detected in 5/11 evaluable participants at month 6. Post-vaccination E6, E7, and L2-specific antibody titers were higher, but none correlated with clearance. Neither TCR clonal diversity/expansion nor public clonotypes were associated with HPV16 clearance. While the fractions of expanded/new clonotypes were not associated with HPV16 clearance, a higher proportion of vaccine antigen-specific reads was evident post-vaccination in those clearing HPV16. High baseline serum MCP-1 associated with HPV16 persistence, and MIP-1β trended higher post-vaccination in those clearing HPV16. IMPORTANCE HPV16 is a necessary cause of over half of all cervical cancers, and in even higher fractions of other anogenital and oropharyngeal cancers. Treatments for HPV16 infection and associated pre-cancerous lesions are needed given the disease burden and limitations of current treatments. Women with persistent HPV infections endure anxiety and stress due to frequent colposcopies, inconvenience, healthcare costs from active surveillance, and potential to transmit the virus to other sexual partners. Since a majority of patients can spontaneously clear their infections, administration of an immunotherapy may promote the elimination of otherwise persistent infections where disease can progress.

Supplementary Table S4 shows respiratory rate of study participants at each visit, including immediately pre- and 30 minutes post-vaccination

The World Health Organization (WHO) has clearly published the necessary metrics for elimination of cervical cancer as a public health problem, which includes adequate treatment of both cervical cancer and its precursors for at least 90 % of affected individuals. To improve cervical cancer outcomes, universal access to the best surgical procedures, radiation therapy including brachytherapy, and systemic therapy as well as palliative care and end-of-life care is paramount. Although implementation at the state and regional levels can be impactful, providing uniform high-quality treatment throughout the United States is needed to achieve the WHO goal. This manuscript defines broadly acceptable minimum standards of care which need to be funded with closed loopholes for access and payment to achieve eradication of cervical cancer as a public health problem.

Supplementary Table S5 shows the baseline blood counts and chemistry of study participants

Supplementary Table S2 shows Systolic blood pressure of study participants at each visit, including immediately pre- and 30 minutes post-vaccination

PURPOSE:The Anal Cancer/High-grade squamous intraepithelial lesions Outcomes Research (ANCHOR) trial demonstrated that treating precancerous anal HSIL reduces the incidence of anal cancer by 57% in people with HIV. It remains unclear how HSIL treatment or monitoring without treatment affects patient-reported health-related quality of life (HRQoL). We evaluated differences in HRQoL for individuals who were randomly assigned to active monitoring (AM) or treatment for anal HSIL. METHODS:Using an index designed and validated for use in ANCHOR, HRQoL was assessed before random assignment (T1), 2-7 days (+3 days) after random assignment/treatment (T2), and 28 days (±7 days) after random assignment/treatment (T3). RESULTS:ANCHOR participants living with HIV (N = 124; mean [standard deviation, SD] age, 52.6 years [10.3]; n = 101 [81.5%] men; n = 65 [52.4%] White; n = 95 [76.6%] non-Hispanic; treatment n = 70 [56.4%]; and AM n = 54 [43.6%]) were included. Treatment arm participants had significant mean worsening from T1-T2 in physical symptoms (mean [SD] difference, 0.31 [0.51]; P = .0001) and impact on psychological functioning (mean [SD] difference, 0.25 [0.64]; P = .022) that significantly improved to T1 levels from T2-T3 (ie, mean [SD] difference, -0.25 [0.52]; P = .003; and mean [SD] difference, -0.07 [0.23]; P = .039, respectively). AM arm participants experienced significant mean improvement in impact on psychological functioning from T1-T3 (mean [SD], difference, -0.20 [0.50]; P = .017). After adjusting for T1, treatment arm participants had a larger mean improvement than AM arm participants in physical symptoms from T2-T3 (mean [SD] difference, -0.25 [0.52]; P = .024); no between-arm differences were observed for impact on physical or psychological functioning. CONCLUSION:Treatment arm participants experienced significant worsening in physical symptoms and impact on psychological functioning from T1-T2 but returned to prerandomization levels by T3, indicating that any immediate anal HSIL treatment-related impacts to HRQoL are temporary. Further research is needed to determine long-term impacts of anal HSIL treatment on HRQoL.

BackgroundCervical cancer disparities persist among minoritized women due to infrequent screening and poor follow-up. Structural and psychosocial barriers to following up with colposcopy are problematic for minoritized women. Evidence-based interventions using patient navigation and tailored telephone counseling, including the Tailored Communication for Cervical Cancer Risk (TC3), have modestly improved colposcopy attendance. However, the efficacious TC3 intervention is human resource-intense and could have greater reach if adapted for mobile health, which increases convenience and access to health information. ObjectiveThis study aimed to describe feedback from clinic staff members involved in colposcopy processes and patients referred for colposcopy regarding adaptions to the TC3 phone-based intervention to text messaging, which addresses barriers among those referred for colposcopy after abnormal screening results. MethodsSemistructured depth qualitative interviews were conducted over Zoom [Zoom Communications, Inc] or telephone with a purposive sample of 22 clinic staff members (including clinicians and support staff members) and 34 patients referred for colposcopy from 3 academic obstetrics and gynecology (OB-GYN) clinics that serve predominantly low-income, minoritized patients in different urban locations in New Jersey and Pennsylvania. Participants were asked about colposcopy attendance barriers and perspectives on a proposed text message intervention to provide tailored education and support in the time between abnormal cervical screening and colposcopy. The analytic team discussed interviews, wrote summaries, and consensus-coded transcripts, analyzing output for emergent findings and crystallizing themes. ResultsClinic staff members and patients had mixed feelings about a text-only intervention. They overwhelmingly perceived a need to provide patients with appointment reminders and information about abnormal cervical screening results and colposcopy purpose and procedure. Both groups also thought messages emphasizing that human papillomavirus is common and cervical cancer can be prevented with follow-up could enhance attendance. However, some had concerns about the privacy of text messages and text fatigue. Both groups thought that talking to clinic staff members was needed in certain instances; they proposed connecting patients experiencing complex psychosocial or structural barriers to staff members for additional information, psychological support, and help with scheduling around work and finding childcare and transportation solutions. They also identified inadequate scheduling and reminder systems as barriers. From this feedback, we revised our text message content and intervention design, adding a health coaching component to support patients with complex barriers and concerns. ConclusionsClinic staff members and patient perspectives are critical for designing appropriate and relevant interventions. These groups conveyed that text message-only interventions may be useful for patients with lesser barriers who may benefit from reminders, basic educational information, and scheduling support. However, multimodal interventions may be necessary for patients with complex barriers to colposcopy attendance, which we intend to evaluate in a subsequent trial.

Cervical cancer remains a significant source of morbidity and mortality worldwide, both in high-income countries such as the United States and in low- and middle-income countries. Access to high quality radiation therapy (RT) is critical for improving outcomes yet remains a challenge even in high resource settings. The World Health Organization (WHO) announced the "Global strategy to accelerate the elimination of cervical cancer as a public health problem," adopted by the World Health Assembly in 2020, which sets the laudatory goals of 90 % vaccination for HPV by the age of 15, 70 % screening rates by the ages of 35 and 45, and 90 % of those with cancer effectively treated by 2030. Access to high-quality RT for those with cancer is an integral part of this strategy, yet significant barriers remain to achieving this goal, including the geographic distribution of clinical technology, physician expertise, and socioeconomic disparities which often co-vary with the incidence of this disease. This article was developed by the Society of Gynecologic Oncology (SGO) taskforce on the elimination of cervical cancer in conjunction with the American Society of Radiation Oncology (ASTRO) and the American Brachytherapy Society (ABS), serving as a companion piece to the Minimum Quality Standards for Cervical Cancer in the United States position statement, and will identity the indications for radiotherapy, propose minimum and advanced standards for radiation quality, and discuss barriers and solutions to achieve comprehensive access.

BACKGROUND:Although immunotherapy has emerged as a therapeutic strategy for many cancers, there are limited studies establishing the safety and efficacy in people living with HIV (PLWH) and cancer.METHODS:PLWH and solid tumors or Kaposi sarcoma (KS) receiving antiretroviral therapy and a suppressed HIV viral load received nivolumab at 3 mg/kg every 2 weeks, in two dose deescalation cohorts stratified by CD4 count (stratum 1: CD4 count > 200/µL and stratum 2: CD4 count 100-199/µL). An expansion cohort of 24 participants with a CD4 count > 200/µL was then enrolled.RESULTS:A total of 36 PLWH received nivolumab, including 15 with KS and 21 with a variety of other solid tumors. None of the first 12 participants had dose-limiting toxicity in both CD4 strata, and five patients (14%) overall had grade 3 or higher immune related adverse events. Objective partial response occurred in nine PLWH and cancer (25%), including in six of 15 with KS (40%; 95% CI, 16.3-64.7). The median duration of response was 9.0 months overall and 12.5 months in KS. Responses were observed regardless of PDL1 expression. There were no significant changes in CD4 count or HIV viral load.CONCLUSIONS:Nivolumab has a safety profile in PLWH similar to HIV-negative subjects with cancer, and also efficacy in KS. Plasma HIV remained suppressed and CD4 counts remained stable during treatment and antiretroviral therapy, indicating no adverse impact on immune function.TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02408861.

Due to limited effective therapeutics for uterine leiomyosarcoma (uLMS), the impact of the gamma secretase inhibitor (GSI) MK-0752 with common chemotherapeutics was explored in uLMS. MTT assays were performed on two human uLMS cell lines, SK-UT-1B and SK-LMS-1, using MK-0752, docetaxel, doxorubicin, and gemcitabine, individually and in combination, to determine cell viability after treatment. Synergistic combinations were used in transwell invasion assays, cell cycle flow cytometry, proliferation assays, and RNA sequencing. In SK-UT-1B, MK-0752 was synergistic with doxorubicin and gemcitabine plus docetaxel. In SK-LMS-1, MK-0752 was synergistic with all individual agents and with the combination of gemcitabine plus docetaxel. MK-0752, gemcitabine, and docetaxel decreased invasion in SK-UT-1B 2.1-fold* and in SK-LMS-1 1.7-fold*. In SK-LMS-1, invasion decreased 1.2-fold* after treatment with MK-0752 and docetaxel and 2.2-fold* after treatment with MK-0752 and doxorubicin. Cell cycle analysis demonstrated increases in the apoptotic sub-G1 population with MK-0752 alone in SK-UT-1B (1.4-fold*) and SK-LMS-1 (2.7-fold**), along with increases with all combinations in both cell lines. The combination treatments had limited effects on proliferation, while MK-0752 alone decreased proliferation in SK-LMS-1 (0.63-fold**). Both MK-0752 alone and in combination altered gene expression and KEGG pathways. In conclusion, the combinations of MK-0752 with either doxorubicin, docetaxel, or gemcitabine plus docetaxel are potential novel therapeutic approaches for uLMS. (* p < 0.05, ** p < 0.01).

This Research Letter summarizes all updates to the 2019 Guidelines through September 2023, including: endorsement of the 2021 Opportunistic Infections guidelines for HIV+ or immunosuppressed patients; clarification of use of human papillomavirus testing alone for patients undergoing observation for cervical intraepithelial neoplasia 2; revision of unsatisfactory cytology management; clarification that 2012 guidelines should be followed for patients aged 25 years and older screened with cytology only; management of patients for whom colposcopy was recommended but not completed; clarification that after treatment for cervical intraepithelial neoplasia 2+, 3 negative human papillomavirus tests or cotests at 6, 18, and 30 months are recommended before the patient can return to a 3-year testing interval; and clarification of postcolposcopy management of minimally abnormal results.

HPV infections are associated with a fraction of vulvar cancers. Through hybridization capture and DNA sequencing, HPV DNA was detected in five of thirteen vulvar cancers. HPV16 DNA was integrated into human DNA in three of the five. The insertions were in introns of human NCKAP1, C5orf67, and LRP1B. Integrations in NCKAP1 and C5orf67 were flanked by short direct repeats in the human DNA, consistent with HPV DNA insertions at sites of abortive, staggered, endonucleolytic incisions. The insertion in C5orf67 was present as a 36 kbp, human-HPV-hetero-catemeric DNA as either an extrachromosomal circle or a tandem repeat within the human genome. The human circularization/repeat junction was defined at single nucleotide resolution. The integrated viral DNA segments all retained an intact upstream regulatory region and the adjacent viral E6 and E7 oncogenes. RNA sequencing revealed that the only HPV genes consistently transcribed from the integrated viral DNAs were E7 and E6*I. The other two HPV DNA+ tumors had coinfections, but no evidence for integration. HPV-positive and HPV-negative vulvar cancers exhibited contrasting human, global gene expression patterns partially overlapping with previously observed differences between HPV-positive and HPV-negative cervical and oropharyngeal cancers. A substantial fraction of the differentially expressed genes involved immune system function. Thus, transcription and HPV DNA integration in vulvar cancers resemble those in other HPV-positive cancers. This study emphasizes the power of hybridization capture coupled with DNA and RNA sequencing to identify a broad spectrum of HPV types, determine human genome integration status of viral DNAs, and elucidate their structures.

Background Detection and treatment of anal histologic high-grade squamous intraepithelial lesions (hHSIL) prevents anal cancer. However, anal hHSIL incidence among women with human immunodeficiency virus (HIV, WHIV) remains unknown. Performance of anal high-risk human papillomavirus ([hr]HPV), anal cytology (anal-cyt), and both for hHSIL detection longitudinally over 2 years also remains undetermined.Methods We determined 2-year incidence and cumulative risk estimates (2-y-CR) of anal hHSIL among WHIV using prevalence and incidence (per 100 person-years [py]) observations stratified by baseline hrHPV and/or anal-cyt results.Results In total, 229 WHIV with complete baseline data were included in the analysis; 114 women without prevalent anal hHSIL were followed with 2 annual evaluations. Median age was 51, 63% were Black, and 23% were Hispanic. Anal hrHPV or abnormal anal-cyt was associated with an increased risk of incident anal hHSIL at 2 years (18.9/100py [95% confidence interval {CI} 11.4-31.3] and 13.4/100py [95% CI 8.0-22.7], respectively) compared with no detection of anal HPV or negative cytology (2.8/100py [95% CI 1.1-7.4] and 4.2 [95% CI, 1.8-10.2]) The presence of anal hrHPV with abnormal cytology was associated with 2-y-CR of anal hHSIL of 65.6% (95% CI 55.4%-75%); negative hrHPV with negative cytology was associated with 2-y-CR of anal hHSIL of 9.2% (95% CI 7.0-16.0).Conclusions Detection of anal hrHPV or abnormal anal cytology are comparable predictors for 2-y-CR of anal hHSIL. The absence of anal hrHPV combined with negative cytology was predictive of a lower (but measurable) risk of developing anal hHSIL. These findings provide important data to inform anal cancer screening guidelines for WHIV. Women with human immunodeficiency virus (HIV) have a high incidence of anal high-grade squamous intraepithelial lesions (HSIL). Detection of anal human papillomavirus (HPV) and/or abnormal anal cytology predict high rates of prevalent, incident and 2-year cumulative anal HSIL. Graphical Abstract https://tidbitapp.io/tidbits/two-year-incidence-and-cumulative-risk-and-predictors-of-anal-high-grade-squamous-intraepithelial-lesions-anal-precancer-among-women-with-hiv-84f972c8-a553-41d2-b8ba-4ba3b7a031fe/update