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EBioMedicine Jun 2020To date, no studies have successfully shown that a highly specific, blood-based tumour marker to detect clinically relevant HPV-induced disease could be used for...
BACKGROUND
To date, no studies have successfully shown that a highly specific, blood-based tumour marker to detect clinically relevant HPV-induced disease could be used for screening, monitoring therapy response or early detection of recurrence. This study aims to assess the clinical performance of a newly developed HPV16-L1 DRH1 epitope-specific serological assay.
METHODS
In a multi-centre study sera of 1486 patients (301 Head and Neck Squamous Cell Carcinoma (HNSCC) patients, 12 HIV+ anal cancer patients, 80 HIV-positive patients, 29 Gardasil-9-vaccinees, 1064 healthy controls) were tested for human HPV16-L1 DRH1 antibodies. Analytical specificity was determined using WHO reference-sera for HPV16/18 and 29 pre- and post-immune sera of Gardasil-9-vaccinees. Tumour-tissue was immunochemically stained for HPV-L1-capsidprotein-expression.
FINDINGS
The DRH1-competitive-serological-assay showed a sensitivity of 95% (95% CI, 772-999%) for HPV16-driven HNSCC, and 90% (95% CI, 555-997%) for HPV16-induced anal cancer in HIV-positives. Overall diagnostic specificity was 9946% for men and 9929% for women ≥ 30 years. After vaccination, antibody level increased from average 364 ng/ml to 37,500 ng/ml. During post-therapy-monitoring, HNSCC patients showing an antibody decrease in the range of 30-100% lived disease free over a period of up to 26 months. The increase of antibodies from 2750 to 12,000 ng/ml mirrored recurrent disease. We can also show that the L1-capsidprotein is expressed in HPV16-DNA positive tumour-tissue.
INTERPRETATION
HPV16-L1 DRH1 epitope-specific antibodies are linked to HPV16-induced malignant disease. As post-treatment biomarker, the assay allows independent post-therapy monitoring as well as early diagnosis of tumour recurrence. An AUC of 096 indicates high sensitivity and specificity for early detection of HPV16-induced disease.
FUNDING
The manufacturer provided assays free of charge.
Topics: Adult; Aged; Aged, 80 and over; Anus Neoplasms; Area Under Curve; Biomarkers, Tumor; Capsid Proteins; Carcinoma, Squamous Cell; Carrier Proteins; Case-Control Studies; Cross-Sectional Studies; Female; HIV Infections; Head and Neck Neoplasms; Human papillomavirus 16; Humans; Male; Middle Aged; Neoplasms; Oncogene Proteins, Viral; Papillomavirus Infections; Papillomavirus Vaccines; Prospective Studies; Sensitivity and Specificity
PubMed: 32535546
DOI: 10.1016/j.ebiom.2020.102804 -
AIDS (London, England) Mar 2022Our study aim was to validate the use of computer-aided narrative content analysis in the extraction of standard diagnostic categories using an archived cytology... (Review)
Review
OBJECTIVE
Our study aim was to validate the use of computer-aided narrative content analysis in the extraction of standard diagnostic categories using an archived cytology database that included individually overread reference classification.
DESIGN
A retrospective analysis of narrative anal cytology results collected on HIV-infected patients at the University of California, San Diego between January and December 2001.
METHODS
We used computer-assisted content analysis extraction methodology using Wordstat 8.0 (Provalis Research) that operated using a classification dictionary that we developed for the following diagnostic categories: NAMC, ASCUS, LSIL, HSIL. We compared its accuracy to a physician overread manually extracted method: that classified each report into the most severe diagnostic category referenced in the narrative report. Agreement between content analysis mapped diagnostic categories and the reference category was evaluated using kappa agreement.
RESULTS
During 2001, 901 patients underwent 997 anal cytological examinations as routine screening. By reference diagnostic category: 54 (5.4%) were unsatisfactory, 460 (46.1%) were NAMC, 291 (29.2%) were ASCUS, 131 (13.1%) were LSIL, and 61 (6.1%) were HSIL. Computer-aided content analysis extracted a single diagnosis from each report in 963 (96.2%) cases and two diagnoses in 38 (3.8%) cases. The Kappa agreement was 0.96 (0.019 s.e.). There were 29 cases classified ASCUS by reference category but LSIL by adjudicated content analysis. A focused review indicated that the over reader assigned reference category was in error.
CONCLUSION
Computer-aided narrative content analysis of anal cytology results yielded accurate and time-efficient classification into meaningful diagnostic categories that can be used to evaluate screening programs and modeling natural history.
Topics: Anal Canal; Anus Neoplasms; Atypical Squamous Cells of the Cervix; Carcinoma in Situ; HIV Infections; Humans; Retrospective Studies
PubMed: 34750293
DOI: 10.1097/QAD.0000000000003123 -
The Oncologist Mar 2023Anal squamous cell carcinoma (SCCA) is an uncommon malignancy with a rising incidence that has a high cure rate in its early stages. There is an unmet need for a...
BACKGROUND
Anal squamous cell carcinoma (SCCA) is an uncommon malignancy with a rising incidence that has a high cure rate in its early stages. There is an unmet need for a reliable method to monitor response to treatment and assist in surveillance. Circulating tumor DNA (ctDNA) testing has shown great promise in other solid tumors for monitoring disease progression and detecting relapse in real time. This study aimed to determine the feasibility and use of personalized and tumor-informed ctDNA testing in SCCA.
PATIENTS AND METHODS
We analyzed real-world data from 251 patients (817 plasma samples) with stages I-IV SCCA, collected between 11/5/19 and 5/31/22. The tumor genomic landscape and feasibility of ctDNA testing was examined for all patients. The prognostic value of longitudinal ctDNA testing was assessed in patients with clinical follow-up (N = 37).
RESULTS
Whole-exome sequencing analysis revealed PIK3CA as the most commonly mutated gene, and no associations between mutations and stage. Anytime ctDNA positivity and higher ctDNA levels (MTM/mL) were associated with metastatic disease (P = .004). For 37 patients with clinical follow-up, median follow-up time was 21.0 months (range: 4.1-67.3) post-diagnosis. For patients with stages I-III disease, anytime ctDNA-positivity after definitive treatment was associated with reduced DFS (HR: 28.0; P = .005).
CONCLUSIONS
Our study demonstrates the feasibility of personalized and tumor-informed ctDNA testing as an adjunctive tool in patients with SCCA as well as potential use for detection of molecular/minuteimal residual disease, and relapse during surveillance. Prospective studies are needed to better evaluate the use of ctDNA testing in this indication.
Topics: Humans; Circulating Tumor DNA; Cell-Free Nucleic Acids; Biomarkers, Tumor; Neoplasm Recurrence, Local; Carcinoma, Squamous Cell; DNA, Neoplasm; Anus Neoplasms; Mutation
PubMed: 36562592
DOI: 10.1093/oncolo/oyac249 -
Clinical Colorectal Cancer Sep 2020The standard treatment for localized squamous-cell carcinoma of the anal canal is definitive chemoradiotherapy. A meta-analysis of published studies conducted by our... (Comparative Study)
Comparative Study
BACKGROUND
The standard treatment for localized squamous-cell carcinoma of the anal canal is definitive chemoradiotherapy. A meta-analysis of published studies conducted by our group showed significantly lower rates of disease-free survival (DFS) and overall survival at 3 years among HIV-positive patients. We aimed to compare detailed treatment outcomes between the groups of HIV-positive and -negative patients.
PATIENTS AND METHODS
We performed a retrospective multicenter study of a comparative cohort of consecutive patients with histologic diagnosis of localized squamous-cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients' characteristics and outcomes were compared according to HIV status. The primary end points were time to complete response (CR) and DFS time.
RESULTS
From June 2001 to September 2018, a total of 185 patients were included; 43 (30.2%) were HIV positive and 142 (69.8%) were HIV negative. The overall CR rates were 67.4% and 91.5% for HIV-positive and -negative patients, respectively (P < .001). The median follow-up was 47.8 months and the median time to experience CR was 7.8 months (95% confidence interval [CI], 5.7-10.5) for HIV-positive versus 4.89 months (95% CI, 4.54-5.25) for HIV-negative (P < .001) patients. The median DFS times were 79.7 months (95% CI, 56.8-102.6) and 127.9 months (95% CI, 112.6-143.2) for HIV-positive and -negative patients, respectively (P = .02). There was a trend toward greater grade 3/4 toxicity in the HIV-positive group.
CONCLUSION
HIV-positive patients take longer to experience CR and present worse DFS. These findings have clinical implications because waiting longer to define CR among these patients may prevent unnecessary anorectal amputations.
Topics: Adult; Aged; Aged, 80 and over; Anal Canal; Anus Neoplasms; Argentina; Brazil; Carcinoma, Squamous Cell; Chemoradiotherapy; Disease-Free Survival; Female; Follow-Up Studies; HIV Infections; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Progression-Free Survival; Retrospective Studies; Risk Factors; Time Factors
PubMed: 32389596
DOI: 10.1016/j.clcc.2020.03.006 -
The American Journal of Gastroenterology Sep 2023Colorectal cancer (CRC) is one of the major life-threatening complications in patients with Crohn's disease (CD). Previous studies of CD-associated CRC (CD-CRC) have...
INTRODUCTION
Colorectal cancer (CRC) is one of the major life-threatening complications in patients with Crohn's disease (CD). Previous studies of CD-associated CRC (CD-CRC) have involved only small numbers of patients, and no large series have been reported from Asia. The aim of this study was to clarify the prognosis and clinicopathological features of CD-CRC compared with sporadic CRC.
METHODS
A large nationwide database was used to identify patients with CD-CRC (n = 233) and sporadic CRC (n = 129,783) over a 40-year period, from 1980 to 2020. Five-year overall survival (OS), recurrence-free survival (RFS), and clinicopathological characteristics were investigated. The prognosis of CD-CRC was further evaluated in groups divided by colon cancer and anorectal cancer (RC). Multivariable Cox regression analysis was used to adjust for confounding by unbalanced covariables.
RESULTS
Compared with sporadic cases, patients with CD-CRC were younger; more often had RC, multiple lesions, and mucinous adenocarcinoma; and had lower R0 resection rates. Five-year OS was worse for CD-CRC than for sporadic CRC (53.99% vs 71.17%, P < 0.001). Multivariable Cox regression analysis revealed that CD was associated with significantly poorer survival (hazard ratio 2.36, 95% confidence interval: 1.54-3.62, P < 0.0001). Evaluation by tumor location showed significantly worse 5-year OS and RFS of CD-RC compared with sporadic RC. Recurrence was identified in 39.57% of CD-RC cases and was mostly local.
DISCUSSION
Poor prognosis of CD-CRC is attributable primarily to RC and high local recurrence. Local control is indispensable to improving prognosis.
Topics: Humans; Anus Neoplasms; Crohn Disease; East Asian People; Prognosis; Rectal Neoplasms; Retrospective Studies; Colitis-Associated Neoplasms
PubMed: 36988310
DOI: 10.14309/ajg.0000000000002269 -
Cancer Medicine Jan 2022Anal squamous cell carcinoma (ASCC) is the main subtype of anal cancer and has great heterogeneity in prognosis. We aimed to construct a nomogram for predicting their...
BACKGROUND
Anal squamous cell carcinoma (ASCC) is the main subtype of anal cancer and has great heterogeneity in prognosis. We aimed to construct a nomogram for predicting their 1-, 3-, and 5-year overall survival (OS) rates.
METHODS
Patients with ASCC, enrolled between January 1, 2010 and December 31, 2017, were identified from the SEER database. They were divided into a training group and a validation group in a ratio of 7:3. Univariate and multivariate Cox analyses were used to identify the prognostic factors for OS. Then a prognostic nomogram was established and validated by Harrell consistency index (C-index), area under the curve (AUC) of the receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA).
RESULTS
We identified 761 patients in training group and 326 patients in validation group. Four prognostic factors including age, sex, AJCC stage, and radiotherapy were identified and integrated to construct a prognostic nomogram. The C-index and AUC values proved the model's effectiveness and calibration plots manifested its excellent discrimination. Furthermore, in comparison to the AJCC stage, the C-index, AUC, and DCA proved the nomogram to be of good predictive value. Finally, we constructed a risk stratification model for dividing patients into low-risk, medium-risk, and high-risk groups, and there were obvious differences in OS.
CONCLUSIONS
A prognostic nomogram was firstly established for predicting the survival probability of ASCC patients and helping clinicians improve their risk management.
Topics: Aged; Anus Neoplasms; Area Under Curve; Carcinoma, Squamous Cell; Female; Humans; Male; Middle Aged; Neoplasm Staging; Nomograms; Proportional Hazards Models; ROC Curve; SEER Program; Survival Rate
PubMed: 34850581
DOI: 10.1002/cam4.4458 -
United European Gastroenterology Journal Feb 2020Disease heterogeneity, according to the age at onset, has been reported in Crohn's disease (CD). (Comparative Study)
Comparative Study
BACKGROUND
Disease heterogeneity, according to the age at onset, has been reported in Crohn's disease (CD).
OBJECTIVE
This study aimed to compare natural history in CD patients diagnosed ≤17 (early onset (EO)) versus ≥60 (late onset (LO)) years old.
METHODS
EO CD and LO CD patients referred to two Italian inflammatory bowel disease (IBD) centres were included. Relevant data comprised sex, current smoking, disease location and behaviour, IBD family history, extra-intestinal manifestations and use of medical/surgical therapy during the follow-up period.
RESULTS
Among 2321 CD patients, 160 met the inclusion criteria: 92 in the EO and 68 in the LO group (mean follow-up 11.7 ± 7.7 years). Family history of IBD was more frequent in EO compared to LO CD (26% vs. 4%; < 0.0001). Ileocolonic, upper gastrointestinal and perianal involvement occurred more frequently in EO compared to LO CD (56% vs. 21%, < 0.0001; 17% vs. 3%, < 0.01; and 38% vs. 19%, < 0.01, respectively). Progression to complicated disease occurred more frequently in EO CD (40% vs. 10% < 0.005), with an increased use of corticosteroids and anti-tumour necrosis factor alpha agents within 10 years since diagnosis (81% vs. 58%, = 0.004, and 36% vs. 16%, = 0.01, respectively), while the cumulative probability of surgery did not differ between the two groups.
CONCLUSIONS
Patients with EO CD are more likely to develop a more aggressive disease with perianal involvement and a greater use of drug treatment compared to those with LO CD, without carrying an increased need for surgery.
Topics: Adolescent; Age of Onset; Aged; Aged, 80 and over; Anus Diseases; Biological Products; Child; Child, Preschool; Crohn Disease; Digestive System Surgical Procedures; Disease Progression; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Italy; Medical History Taking; Middle Aged; Retrospective Studies; Risk Factors; Severity of Illness Index; Smoking; Tumor Necrosis Factor-alpha
PubMed: 32213053
DOI: 10.1177/2050640619860661 -
MBio Aug 2021Up to 95% of all anal cancers are associated with infection by human papillomavirus (HPV); however, no established preclinical model exists for high-grade anal disease...
Up to 95% of all anal cancers are associated with infection by human papillomavirus (HPV); however, no established preclinical model exists for high-grade anal disease and cancer mediated by a natural papillomavirus infection. To establish an infection-mediated model, we infected both immunocompromised NSG and immunocompetent FVB/NJ mice with the recently discovered murine papillomavirus MmuPV1, with and without the additional cofactors of UV B radiation (UVB) and/or the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Infections were tracked via lavages and swabs for MmuPV1 DNA, and pathology was assessed at the endpoint. Tissues were analyzed for biomarkers of viral infection and papillomavirus-mediated disease, and the localization of viral infection was investigated using biomarkers to characterize the anal microanatomical zones. We show, for the first time, that MmuPV1 infection is sufficient to efficiently mediate high-grade squamous intraepithelial lesions in the anal tract of mice using the NSG immunocompromised strain and that MmuPV1, in combination with the chemical carcinogen DMBA, has carcinogenic potential. We further show that MmuPV1 is able to persist for up to 6 months in the anal tract of FVB/NJ mice irradiated with UVB and contributes to high-grade disease and cancer in an immunocompetent strain. We demonstrate that MmuPV1 preferentially localizes to the anal transition zone and that this localization is not an artifact of infection methodology. This study presents a valuable new preclinical model for studying papillomavirus-mediated anal disease driven by a natural infection.
Topics: Anal Canal; Animals; Anthracenes; Anus Neoplasms; Disease Models, Animal; Female; Male; Mice; Mice, Inbred NOD; Mice, SCID; Papillomaviridae; Papillomavirus Infections; Piperidines; Squamous Intraepithelial Lesions; Ultraviolet Rays
PubMed: 34281391
DOI: 10.1128/mBio.01611-21 -
Experimental and Molecular Pathology Apr 2022Low-grade anal dysplasia is a disease that can progress to high-grade anal dysplasia and eventually anal cancer if left untreated. Research has shown that low-grade anal...
Low-grade anal dysplasia is a disease that can progress to high-grade anal dysplasia and eventually anal cancer if left untreated. Research has shown that low-grade anal dysplasia is marked by significant autophagic dysfunction. We hypothesized that systemic induction of autophagy, via phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibition, would be effective in preventing anal cancer development in human papillomavirus (HPV) mice (K14E6/E7) with established low-grade anal dysplasia. Mice began treatment at 15 weeks of age, when 75% of mice spontaneously develop low-grade anal dysplasia, and were divided into the following groups: no treatment, systemic LY3023414 (4.5 mg/kg, dual PI3K/mTOR inhibitor) alone, topical 7,12 dimethylbenz[a]anthracene (DMBA) alone, or systemic LY3023414 and topical DMBA. Groups were compared for final histology, PI3K activity, mTOR activity, autophagic induction (light chain 3B (LC3β)), autophagic function (p62 protein), and tumor-free survival. Untreated mice or mice treated with LY3023414 alone did not progress to cancer. There was a statistically significant decrease in the number of mice that developed histologic evidence of cancer when comparing mice that received systemic LY3203414 with topical DMBA versus those that received topical DMBA alone (p = 0.0003). PI3K and mTOR activity decreased in groups treated with systemic LY3023414 and topical DMBA as compared with those treated with topical DMBA alone (p = 0.0005 and p = 0.0271, respectively). LC3β and p62 expression was not statistically altered with systemic LY3023414 treatment. Mice developed less overt tumors and had increased tumor-free survival when treated with systemic LY3023414 in the presence of topical DMBA compared to topical DMBA alone (p = 0.0016 and p < 0.001, respectively). Systemic LY3023414 treatment is effective in anal cancer prevention in the setting of established low-grade anal dysplasia in an HPV-associated mouse model of anal cancer.
Topics: Animals; Anus Neoplasms; Mammals; Mice; Papillomaviridae; Papillomavirus Infections; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; TOR Serine-Threonine Kinases
PubMed: 35183509
DOI: 10.1016/j.yexmp.2022.104752 -
CA: a Cancer Journal For Clinicians Mar 2022Although rare, the rate of squamous cell carcinoma of the anus (SCCA) is rising globally. Most patients present with nonmetastatic disease and are curable with...
Although rare, the rate of squamous cell carcinoma of the anus (SCCA) is rising globally. Most patients present with nonmetastatic disease and are curable with appropriate treatment, which has evolved significantly over the last several decades. Before the 1970s, SCCA was managed with radical surgery, resulting in a permanent colostomy. Researchers found that preoperative treatment with chemotherapy and concurrent radiation could achieve a pathologic complete response. After this observation, definitive therapy shifted from radical surgery to sphincter-preserving chemoradiation. Investigations into the necessity of chemotherapy and the optimal regimen found that chemotherapy with mitomycin-C and 5-fluorouracil is required for cure. Further studies evaluating the addition of induction or maintenance chemotherapy, monoclonal antibody therapy, or higher radiation doses have demonstrated no significant benefit to disease control. Advanced radiation delivery with intensity-modulated radiotherapy techniques is now considered the standard of care because of its prospectively determined, favorable acute toxicity profile compared with 3-dimensional conformal radiation. It is important to note that chemoradiation treatment response may be slow (up to 26 weeks) and should be assessed through serial clinical examinations. Today, surgical management of SCCA is reserved only for the lowest risk, early stage tumors or for recurrent/persistent disease. Current studies are evaluating radiation dose de-escalation in early stage disease and radiation dose escalation and the addition of immune checkpoint inhibitors in locally advanced cancers. In reviewing how and why modern-day treatment of SCCA was established, the objective of this report is to reenforce adherence to current treatment paradigms to assure the best possible outcomes for patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Carcinoma, Squamous Cell; Chemoradiotherapy; Fluorouracil; Humans; Radiotherapy, Intensity-Modulated
PubMed: 34847242
DOI: 10.3322/caac.21712