[Squamous cell anal carcinoma. What's next ?] / Cancer épidermoïde du canal anal métastatique en 2020.

Despite its status as a rare disease, the incidence of the squamous cell carcinoma of the anus (SCCA) is surging, especially in its metastatic form. In addition, the prognosis of initially localized diseases has not substantially changed since the 1970s with a recurrence rate of between 25-40 % after the chemoradiotherapy. The updated data from 115 patients included in the Epitopes-HPV01 and Epitopes-HPV02 trials, confirm the modified regimen of DCF (mDCF) as the treatment of choice for patients with advanced SCCA given the rate of sustained remissions and complete molecular responses observed. The carboplatin-paclitaxel regimen may be considered as an option for patients with contraindication to cisplatin or 5-FU. In chemo-refractory patients, the efficacy of anti-PD-1/PD-L1 in monotherapy is limited and only brings benefit to 10-20 % of patients, and its use cannot be generalized in the absence of an association potentiating its effectiveness. In order to better understand the immunological parameters associated with advanced SCCA, an analysis of peripheral immune responses was carried out in the Epitopes-HPV01 and 02 trials. It demonstrated the key role of CD4 Th1 specific responses of telomerase and M-MDSC as main prognostic factors for the therapeutic efficacy of DCF. Numerous combination trials are currently underway or will soon begin in localized SCCA, as well as in the first and second-line in the advanced stage. Finally, the detection of circulating tumor DNA of HPV oncoprotein E6 and E7 (HPVtc), especially by the "digital droplet PCR" technique, is highly sensitive and specific, and can be used in daily practice.

The Influence of Systemic Inflammation on Treatment Response and Survival in Anal Squamous Cell Cancer.

AIMS: The incidence of anal squamous cell cancer (SCCA) is rising. Although chemoradiotherapy (CRT) provides a chance of cure, a proportion of patients have an incomplete response or develop recurrence. This study assessed the value of inflammation-based prognostic indicators, including the modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR), in patients with SCCA treated by CRT with curative intent. MATERIAL AND METHODS: Patients with histologically confirmed SCCA were identified from pathology records. Medical records were retrospectively reviewed and clinical, pathological and treatment characteristics were abstracted. The mGPS (0 = normal C-reactive protein [CRP] and albumin, 1 = CRP >10 mg/l and 2 = CRP >10 mg/l and albumin <35 mg/l) and NLR were calculated from routine blood tests obtained prior to CRT. RESULTS: In total, 118 patients underwent CRT for SCCA between December 2007 and February 2018. Of these, 99 patients had appropriate pretreatment blood results available. Systemic inflammation as indicated by NLR >3 and mGPS >0 was present in 41% and 39% of patients, respectively. Most patients had T2 or larger tumours (n = 85, 86%) without nodal involvement (n = 64, 65%). An elevated mGPS was associated with more advanced T-stage (56% versus 35%, P = 0.036). NLR >5 was associated with nodal positivity (56% versus 31%, P = 0.047). On multivariate analysis, more advanced T-stage (odds ratio 7.49, 95% confidence interval 1.51-37.20, P = 0.014) and a raised mGPS (odds ratio 5.13, 95% confidence interval 1.25-21.14, P = 0.024) were independently related to incomplete CRT response. An elevated mGPS was prognostic of inferior survival (hazard ratio 3.09, 95% confidence interval 1.47-6.50, P = 0.003) and cancer-specific survival (hazard ratio 4.32, 95% confidence interval 1.54-12.15, P = 0.006), independent of TNM stage. CONCLUSION: Systemic inflammation, as measured by the mGPS, is associated with an incomplete CRT response and is independently prognostic of inferior survival in patients with SCCA. The mGPS may offer a simple marker of inferior outcome that could be used to identify high-risk patients.

Distribution pattern of tumor infiltrating lymphocytes and tumor microenvironment composition as prognostic indicators in anorectal malignant melanoma.

Anorectal malignant melanoma (ARMM) is a rare disease with poor prognosis. Determining ARMM prognosis precisely is difficult due to the lack of proper assessment techniques. Immunotherapy has proven effective against cutaneous malignant melanoma and may show efficacy in ARMM. Herein, we assessed the immune profile of ARMM to identify possible prognostic biomarkers. Twenty-two ARMM formalin-fixed and paraffin-embedded samples were evaluated using an nCounter® PanCancer Immune Profiling Panel. Validation was performed through immunohistochemical staining for CD3, CD8, Foxp3, CD68, CD163, and PD-L1. RNA analysis revealed significantly decreased scores for pathways involved in cell regulation and function, as well as chemokines, in recurrent patients compared to nonrecurrent patients. In cell-type profiling, the recurrent cases displayed significantly low tumor infiltrating lymphocyte (TIL) scores. Recurrence/death prediction models were defined using logistic regression and showed significantly lower scores in recurrent and deceased patients (all, P < 0.001) compared to those in nonrecurrent and surviving patients. The high total TIL and tumor-associated macrophage (TAM) groups had significantly better overall survival outcomes compared to the low total TIL and TAM groups (P = 0.007 and P = 0.035, respectively). In addition, the presence of CD3 + TILs in the invasion front was an independent favorable prognostic indicator (P = 0.003, hazard ratio = 0.21, 95% confidential interval, 0.01-0.41). Patients with inflamed or brisk-infiltration type tumors also had a significantly better overall survival than that of patients with immune-desert/excluded and absent/non-brisk type tumors (P = 0.03 and P = 0.0023, respectively). In conclusion, TILs have a strong prognostic value in ARMM, and the quantification of TILs and an analysis of the TIL phenotype and infiltration pattern during pathological diagnosis are essential to guide treatment strategies and accurate prognosis in ARMM.

Anti-Telomerase CD4+ Th1 Immunity and Monocytic-Myeloid-Derived-Suppressor Cells Are Associated with Long-Term Efficacy Achieved by Docetaxel, Cisplatin, and 5-Fluorouracil (DCF) in Advanced Anal Squamous Cell Carcinoma: Translational Study of Epitopes-HPV01 and 02 Trials.

Docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy regimen is highly effective in advanced anal squamous cell carcinoma (SCCA), as demonstrated by the Epitopes-HPV02 study results. Here, we analyzed the impact of DCF regimen and the prognostic value of adaptive immune responses and immunosuppressive cells in SCCA patients included in two prospective studies (Epitopes-HPV01 and HPV02). The presence of T-cell responses against Human papillomavirus (HPV)16-E6/E7 and anti-telomerase (hTERT)-antigens was measured by IFNᵧ-ELISpot. Here, we showed that HPV-adaptive immune responses are increased in SCCA patients. SCCA patients also displayed enhanced circulating TH1 T-cells restricted by hTERT. Exposition to DCF increased hTERT immunity but not HPV or common viruses immune responses. Notably, the correlation of hTERT immune responses with SCCA patients' clinical outcomes highlights that hTERT is a relevant antigen in this HPV-related disease. The influence of peripheral immunosuppressive cells was investigated by flow cytometry. While both regulatory T-cells and monocytic-myeloid-derived suppressive cells (M-MDSC) accumulated in the peripheral blood of SCCA patients, only high levels of M-MDSC were negatively correlated with hTERT adaptive immune responses and predicted poor prognosis. Altogether, our results reveal that hTERT is a relevant antigen in HPV-driven SCCA disease and that M-MDSC levels influence TH1-adaptive immune responses and patients' survival.

Feasibility and Outcome of Routine Use of Concurrent Chemoradiation in HIV-positive Patients With Squamous Cell Anal Cancer.

OBJECTIVES: Clinical concerns about hematologic toxicities in human immunodeficiency virus (HIV)+ patients with squamous cell anal cancer (SCAC) may lead to de-escalation of treatment intensity. The objective of this study is to evaluate clinical outcomes including toxicity following standard concurrent curative-intent chemoradiation for HIV+ and HIV- patients with SCAC. MATERIALS AND METHODS: Among 97 evaluable patients treated between 2009 and 2016 (median age 52.2 y), 43 (44.3%) were HIV+ and 54 (55.7%) HIV-. The majority of the radiation was delivered using intensity-modulated radiation therapy and chemotherapy consisting primarily (93%) of 5-fluorouracil and mitomycin C. Clinical outcomes assessed included toxicity, locoregional control (LRC), distant metastasis (DM), progression-free survival (PFS), colostomy-free survival (CFS), overall survival (OS), and cause-specific survival (CSS). RESULTS: With a median follow-up of 45 months, HIV+ patients exhibited a trend toward reduced OS compared with HIV- patients (4 y OS 61.2% vs. 78.3%; HR 2.09; 95% CI, 0.97-4.52; P=0.055) on univariable analysis, but HIV status was not significant after adjusting for additional parameters on multivariable analysis. Toxicity rates, LRC, CFS, PFS, freedom from DM, and CSS were similar between the 2 cohorts. On multivariable analysis, tumor size >5 cm impacted all clinical outcomes (trend for LRC) except CFS. Radiation treatment extension beyond 7 days was found to negatively impact LRC and CSS. Male sex was associated with worse CFS. CONCLUSIONS: Radiation therapy with concurrent 5-fluorouracil and mitomycin C chemotherapy is reasonably well-tolerated as curative treatment for HIV+ patients with SCAC, and no significant difference in outcomes was noted relative to HIV- patients.

Correlation of Cancer Development and Human Papilloma Virus Infection in Patients After Organ Transplantation.

Immunosuppressed patients are at higher risk of developing human papilloma virus (HPV) cancerous and precancerous lesions in the anogenital region Carcinogenesis after organ transplantation due to immunosuppressive therapy is the major cause of long-term negative transplantation results. This is a rationale for the improvement of transplantation programs with carcinogenesis risk stratification in patients referred for transplantation. There is a need for a study on HPV-related carcinogenesis also in terms of its risk factors in the population after organ transplantation. This study aimed to assess the morbidity of anogenital carcinoma in patients with HPV infection, including those after organ transplantation and evaluate risk factors for carcinoma occurrence in patients after organ transplantation and with HPV infection. Our analysis directly indicates the group of patients with a high risk of HPV-related oncological complications of immunosuppression in anogenital region.

Genetic Profile and Functional Proteomics of Anal Squamous Cell Carcinoma: Proposal for a Molecular Classification.

Anal squamous cell carcinoma is a rare tumor. Chemo-radiotherapy yields a 50% 3-year relapse-free survival rate in advanced anal cancer, so improved predictive markers and therapeutic options are needed. High-throughput proteomics and whole-exome sequencing were performed in 46 paraffin samples from anal squamous cell carcinoma patients. Hierarchical clustering was used to establish groups de novo Then, probabilistic graphical models were used to study the differences between groups of patients at the biological process level. A molecular classification into two groups of patients was established, one group with increased expression of proteins related to adhesion, T lymphocytes and glycolysis; and the other group with increased expression of proteins related to translation and ribosomes. The functional analysis by the probabilistic graphical model showed that these two groups presented differences in metabolism, mitochondria, translation, splicing and adhesion processes. Additionally, these groups showed different frequencies of genetic variants in some genes, such as ATM, SLFN11 and DST Finally, genetic and proteomic characteristics of these groups suggested the use of some possible targeted therapies, such as PARP inhibitors or immunotherapy.

A Unique Case of Primary Extranodal Marginal Zone Lymphoma of the Anal Canal.

Marginal zone lymphomas represent approximately 10-12% of all B-cell lymphomas. Extranodal marginal zone lymphomas (EMZL) or mucosa-associated lymphoid tissue (MALT) lymphomas are the most common subtype. Almost half of all MALT lymphomas arise in the gastrointestinal (GI) tract and, while the stomach is the most common site of GI involvement, the small and large intestines can also be involved. Rare cases of MALT lymphoma involving the rectum have been reported; however, to our knowledge, involvement of the anal canal has never been reported in the literature. Here, we describe a unique case of MALT lymphoma of the anal canal. Infectious agents have been implicated in the pathogenesis of MALT lymphomas, possibly through persistent antigenic stimulation of the area; however, in our case no such infection was documented.

Importance of anal cytology and screening for anal dysplasia in individuals living with HIV with an emphasis on women.

BACKGROUND: The incidence of squamous cell carcinoma of the anal canal has been increasing in high-risk populations. To the authors' knowledge, there is no international consensus regarding screening for squamous cell carcinoma of the anal canal, but screening is commonly comprised of a Papanicolaou (Pap) test in combination with digital anorectal examination followed by high-resolution anoscopy if necessary. The current study focused on individuals living with HIV and particularly on women living with HIV. METHODS: In this 5-year retrospective study, the authors identified 5982 Pap tests, 1848 of which had follow-up biopsy within 6 months. The rate of atypical squamous cells of undetermined significance was 42%, and approximately 38.1% of cases with this interpretation were diagnosed as high-grade squamous intraepithelial lesions on follow-up biopsy. In addition, 82 women with anal cytology had long-term follow-up (>10 years) available. RESULTS: The authors investigated a relationship between cervicovaginal human papillomavirus (HPV) results, cervical pathology, CD4 T-cell count, and CD4/8 ratio with the anal cytology interpretation. A statistical correlation was noted between the CD4 count and the CD4/8 ratio and the presence of anal dysplasia. Nearly one-half of the women without cervicovaginal HPV positivity presented with anal dysplasia. CONCLUSIONS: The results of the current study demonstrated that, among women living with HIV, screening for anal dysplasia should not be eschewed, regardless of lower genital tract pathology and/or HPV status. To the authors' knowledge, the current study is the largest reported retrospective anal cytology cohort in individuals living with HIV.

New Insights into the Role of Human Papillomavirus in Anal Cancer and Anal Wart Development.

Human papillomavirus is associated with several anogenital and oropharyngeal lesions, including warts, premalignant lesions, and cancer. There are specific groups that were identified as high-risk groups for anal squamous cell carcinoma and anal human papillomavirus infection, namely HIV-positive patients, men who have sex with men, women with genital tract neoplasia, and solid organ transplant recipients. Condylomas have classically been considered to be a benign lesion, with an exception made for the Buschke-Loewenstein tumor, but several publications have shown that a high percentage of condylomas harbor high-grade lesions. Due to the similarities between anal and cervical carcinogenesis, anal cancer screening based on anal cytology and referral to high-resolution anoscopy, in case of abnormalities, have been advocated. Testing for anal human papillomavirus is not routinely done in anal cancer screening, because of the very high prevalence in high-risk populations. The large majority of anal cancers are squamous cell carcinomas (SCC), and around 90% are attributed to human papillomavirus. Human papillomavirus positivity in anal SCC seems to have a prognostic value, with better survival in those patients with positive tumors. Prophylactic vaccination has been shown to be important for prevention of anal human papillomavirus-related lesions.

High IDO1 Expression Is Associated with Poor Outcome in Patients with Anal Cancer Treated with Definitive Chemoradiotherapy.

BACKGROUND: This study characterizes the tumor-immune microenvironment in pretreatment, localized anal squamous cell carcinoma (ASCC), including two markers that have not previously been studied in ASCC: indoleamine 2,3 dioxygenase 1 (IDO1) and human leukocyte antigen (HLA) class I. MATERIALS AND METHODS: Retrospective review identified 63 patients with ASCC receiving definitive chemoradiation between 2005 and 2016 with pretreatment tissue available. Immunohistochemistry was used to quantify cluster of differentiation 8 (CD8), programmed cell death protein 1, programmed death-ligand 1, HLA class I, and IDO1. Cox proportional hazards models evaluated associations between outcomes and immune markers, controlling for clinical characteristics. RESULTS: With a median follow-up of 35 months, 3-year overall survival was 78%. The only marker found to have a robust association with outcome was tumor IDO1. In general, the percentage of tumor cells expressing IDO1 was low (median 1%, interquartile range 0%-20%); however, patients with >50% of tumor cells expressing IDO1 had significantly worse overall survival (hazard ratio [HR] 4.7, p = .007) as well as higher local recurrence (HR 8.6, p = .0005) and distant metastasis (HR 12.7, p = .0002). Tumors with >50% IDO1 were also more likely to have the lowest quartile of CD8 infiltrate (<40 per high-power field, p = .024). CONCLUSION: ASCC has a diverse immune milieu. Although patients generally do well with standard therapy, IDO1 may serve as a prognostic indicator of poor outcome and could help identify a patient population that might benefit from IDO-targeted therapies. IMPLICATIONS FOR PRACTICE: After definitive chemoradiation, patients with locally advanced anal cancer may experience significant treatment morbidity and high risk of recurrence. The goal of the current study is to identify novel prognostic factors in the tumor-immune microenvironment that predict for poor outcomes after definitive chemoradiation. This study characterizes the tumor-immune microenvironment in pre-treatment, localized anal squamous cell carcinoma (ASCC), including two markers which have not previously been studied in ASCC: indoleamine 2,3 dioxygenase 1 (IDO1) and HLA class I. With a median follow-up of 3 years, this study demonstrated that high IDO1 expression is correlated with significantly worse 3-year overall survival (88% vs. 25%). Whereas recent studies of IDO1 inhibitors have shown mixed results, this study suggests that patients with anal cancer with high IDO1 expression have dismal prognosis and may represent a patient population primed for response to targeted IDO1 inhibition.

Human Papillomavirus-Associated Invasive Condylomas in a Man with Immunosuppressive Comorbidities.

Human papilloma virus (HPV) infections are one of the most common sexually transmitted diseases. We present the case of a 77-year-old Caucasian male with enormous genital warts of the penis, scrotum, groins and anus. Lesions were excised by electrosurgery. The histological examination revealed Condylomata gigantea as well as an invasive perianal squamous cell carcinoma. Mucosal "low-risk" HPV type 6 was detected. The patient had a history of an immunosuppressing disease. During the 4-year follow-up, multiple relapses occurred. Thus, particularly in immunosuppressed patients, early prophylactic HPV vaccination seems to be indicated for use in the prevention of HPV-associated mutilating and life-threatening disease. Vaccination should also protect from "low-risk" HPV.

Warts and all: Fingolimod and unusual HPV-associated lesions.

BACKGROUND: Fingolimod is used to reduce relapse rates in relapsing-remitting multiple sclerosis (MS). It is a sphingosine 1-phosphate (S1P) analogue having antagonistic effects on S1P receptors. Its immunosuppressive effect is due to reduced circulating lymphocyte numbers, and it may also be associated with impaired intrinsic cancer surveillance. Fingolimod side effects include increased rates and severity of viral infections particularly varicella zoster. METHODS: We present five cases of chronic and treatment refractory warts associated with fingolimod therapy. RESULTS: Each of the five cases presenting with chronic warts while receiving fingolimod therapy had prolonged periods of lymphopenia and improvements were seen following dose reduction or cessation of fingolimod. CONCLUSION: Cutaneous warts are associated with human papilloma virus (HPV) infection, suggesting an increased risk of other HPV-driven conditions such as cervical cancer following fingolimod administration. HPV viruses are responsible for approximately 90% of cervical cancers as well as a significant portion of anogenital cancers and have a high prevalence in sexually active adults. Given the reduced immune response to viral infections and potential impaired cancer surveillance in those receiving fingolimod, HPV vaccination and frequent assessment for the development of HPV-associated malignancies are recommended.

Role of Immunotherapy in the Treatment of Squamous Cell Carcinoma of the Anal Canal.

Anal cancer is a rare malignancy for which cisplatin with 5-fluorouracil is the recommended treatment for patients with metastatic disease. Because most cases of anal cancer are linked to prior infection with oncogenic strands of the human papillomavirus, immunotherapeutic approaches have been of great interest in the development of new treatments for this virally driven tumor. This article reviews the early successes of anti-PD-1 therapies and adoptive T-cell therapies for metastatic anal cancer as a potential foundation for novel combination immunotherapy trials in the future.

An Examination of HPV16 Natural Immunity in Men Who Have Sex with Men (MSM) in the HPV in Men (HIM) Study.

Background: Evidence suggests that natural antibodies developed after HPV16 infection may protect some women but not men against subsequent HPV16 reacquisition. Less is known whether antibodies developed following HPV16 infection are protective among men who have sex with men (MSM).Methods: Four hundred seventy-five MSM from the Human Papillomavirus Infection in Men (HIM) study were tested for serum antibodies to HPV16 L1 using enzyme-linked immunosorbent assays, and for anal and genital HPV16 DNA using PCR consensus primer system (PGMY 09/11). Adjusted Cox regression was used to evaluate whether baseline HPV16 seropositivity impacts subsequent genital or anal HPV16 DNA.Results: The risk of subsequent genital HPV16 [aHR = 1.05, 95% confidence interval (CI) = 0.66-1.68] and anal HPV16 infections among MSM (aHR = 2.34, 95% CI = 0.92-5.98) was similar or nonsignificantly higher in HPV16-seropositive than HPV16-seronegative MSM. The risk of genital HPV16 was also similar between HPV16-seronegative and HPV16-seropositive MSM in the highest tertile of HPV16 antibody levels and when restricting to those with new sex partners during follow-up (P > 0.20). Among the 118 MSM who were HPV16 seropositive, 90% remained HPV16 seropositive up to 4 years later. When tested together, MSM with the highest antibody titers (top tertile) had similar levels to females (mean = 130.3 vs. 134.5 EU/mL, P = 0.84).Conclusions: Despite years of HPV16 seropositivity persistence and antibody titers comparable with females, this study suggested no evidence of HPV16 natural antibodies protecting against subsequent genital or anal HPV16 infection in MSM.Impact: This could help partially explain the high incidence of genital and anal HPV16 infection and related anal cancer seen in middle-aged and older MSM. Cancer Epidemiol Biomarkers Prev; 27(4); 496-502. ©2018 AACR.

Effect of CD4 Count on Treatment Toxicity and Tumor Recurrence in Human Immunodeficiency Virus-Positive Patients With Anal Cancer.

PURPOSE: To study the effects of immunosuppression on treatment toxicity, long-term cancer recurrence risk, and survival among human immunodeficiency virus (HIV)-positive anal cancer patients. METHODS AND MATERIALS: From a nationwide retrospective cohort of veterans with anal cancer we identified 142 HIV-positive patients with stage I-III disease, diagnosed between 2000 and 2015 and treated with definitive-intent chemotherapy and radiation. We used regression models to study the impact of pretreatment CD4 counts and longitudinal posttreatment CD4 counts on outcomes including acute toxicity, long-term ostomy rates, cancer recurrence, cancer-specific survival, and overall survival. All models were adjusted for potential confounders. RESULTS: The median pretreatment CD4 count was 375 cells/mm3, which dropped to 157 cells/mm3 after treatment. Each 100-cell/mm3 decrease in pretreatment CD4 count was associated with an increased risk of acute hematologic toxicity (odds ratio 1.19, 95% confidence interval [CI] 1.01-1.42, P=.04) and hospitalization for hematologic toxicity (odds ratio 1.24, 95% CI 1.00-1.54, P=.049) but not gastrointestinal toxicity, tumor recurrence, or cancer-specific mortality (P>.05). Each 100-cells/mm3 decrease in posttreatment CD4 count increased the risk of recurrence by 54% (hazard ratio 1.54, 95% CI 1.09-2.17, P=.01) and cancer mortality by 46% at a trend level (hazard ratio 1.46, 95% CI 0.99-2.14, P=.06). Neither pre- nor posttreatment CD4 count influenced long-term ostomy rates or overall survival (all P>.05). CONCLUSIONS: Lower pretreatment CD4 counts were associated with acute hematologic toxicity, and lower posttreatment CD4 count levels were associated with an increased risk of tumor recurrence. These results suggest that immune surveillance may play an important role in long-term disease control in anal cancer.

Prevention of human papillomavirus (HPV)-related tumors in people living with human immunodeficiency virus (HIV).

INTRODUCTION: In comparison to their HIV-negative counterparts, people living with HIV (PLWH) have a higher prevalence of human papillomavirus (HPV) infection in various anatomical sites coupled with increased HPV persistence, higher risk of HPV-related tumors, and faster disease progression. Areas covered: Gender-neutral prevention strategies for HPV-related cancers in PLWH discussed: ABC approach, HPV vaccination, antiretroviral treatment (ART), anal cancer screening, and smoking cessation. Gender specific strategies: cervical cancer screening reduces the incidence and mortality of cervical cancer and circumcision might reduce the risk of HPV infections in men. Expert commentary: HPV-related cancer incidence has not declined (e.g. cervical cancer) and has even increased (e.g. anal cancer) in the ART era, demanding an effective HPV prevention strategy. HPV vaccination should be introduced into national prevention programs worldwide immediately because current prophylactic vaccines are safe, tolerable, and immunogenic in PLWH. HPV vaccine efficacy trials in PLWH are essential to determine the most appropriate immunization schedule. The population most at risk of anal cancer is HIV-positive men who have sex with men, who are not protected by herd immunity if only the female population is vaccinated. Unvaccinated PLWH need enhanced surveillance for early detection of HPV-related cancers and their precursors.

Adjuvant HPV vaccination for anal cancer prevention in HIV-positive men who have sex with men: The time is now.

IMPORTANCE: Outcomes of treating high-grade squamous intraepithelial lesions (HSIL), a precursor to anal cancer, remain uncertain. Emerging evidence shows that post HSIL treatment adjuvant quadrivalent human papillomavirus (qHPV) vaccination improves the effectiveness of treatment. However, no recommendations exist regarding the use of qHPV vaccine as an adjuvant form of therapy. Our objective was to determine whether post-treatment adjuvant vaccination should be adopted in HIV-infected MSM (individuals at highest risk for anal cancer) on the basis of cost-effectiveness determined using existing evidence or whether future research is needed. METHODS: We developed a Markov (state-transition) cohort model to assess the cost-effectiveness of post-treatment adjuvant HPV vaccination of 27years or older HIV-infected MSM. We first estimated cost-effectiveness and then performed value-of-information (VOI) analysis to determine whether future research is required by estimating the expected value of perfect information (EVPI). We also estimated expected value of partial perfect information (EVPPI) to determine what new evidences should have highest priority. RESULTS: With the incremental cost-effectiveness ratio (ICER) of $71,937/QALY, "treatment plus vaccination" was the most cost-effective HSIL management strategy using the willingness-to-pay threshold of 100,000/QALY. We found that population-level EVPI for conducting future clinical research evaluating HSIL management approaches was US$12 million (range $6-$20 million). The EVPPI associated with adjuvant qHPV vaccination efficacy estimated in terms of hazards of decreasing HSIL recurrence was $0 implying that additional data from a future study evaluating efficacy of adjuvant qHPV vaccination will not change our policy conclusion that "treatment plus vaccination" was cost-effective. Both the ICER and EVPI were sensitive to HSIL treatment compliance. CONCLUSION: Post-treatment adjuvant qHPV vaccination in HIV-infected MSM aged 27 or above is likely to be cost-effective. Use of adjuvant qHPV vaccination could be considered as a potential strategy to reduce rising anal cancer burden among these high-risk individuals.

HPV circulating tumor DNA to monitor the efficacy of anti-PD-1 therapy in metastatic squamous cell carcinoma of the anal canal: A case report.

Squamous cell carcinoma of the anal canal (SCCA) is a rare HPV-associated cancer with limited sensitivity to standard chemotherapy. In a phase 2 study, nivolumab, an anti PD-1 immune checkpoint inhibitor, demonstrated significant efficacy as single-agent therapy in metastatic SCCA patients. Nevertheless, imaging assessment by standard RECIST criteria of the efficacy of immune therapy can be difficult in some patients due to tumor immune cell infiltration, and biomarkers of treatment efficacy are needed. We have previously developed a quantitative droplet digital PCR (ddPCR) technique to detect HPV circulating tumor DNA (HPV ctDNA), with excellent sensitivity and specificity. Here, we report, for the first time, the kinetics of HPV ctDNA during therapy in a patient with metastatic SCCA, who obtained sustained partial response to single-agent nivolumab. We observed an early and very significant decrease of HPV ctDNA during therapy from the baseline level of 3713 copies/ml plasma to 564 copies/ml plasma at 4 weeks, and 156 copies/ml at 6 weeks, followed by a plateau. This observation provides proof-of-concept that HPV ctDNA can be used as a noninvasive early dynamic biomarker to monitor the efficacy of new immunotherapy agents.