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Background: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Testing for plasma tumor tissue modified viral (TTMV)-HPV DNA has emerged as a biomarker strategy for post-treatment surveillance to identify recurrent disease. We aimed to understand the prognostic and predictive potential of TTMV-HPV DNA when monitoring patients who had developed recurrent or metastatic (R/M) HPV+OPSCC., Methods: This retrospective observational cohort study included 80 patients from 4 academic centers with R/M HPV+OPSCC if they had ≥ 1 plasma TTMV-HPV DNA test obtained at any point during their R/M disease course. Physician-reported clinical data and treatment history were captured in a centralized database, along with investigator-assessed response to therapy and survival. Descriptive statistics and non-parametric tests of association were employed along with survival analyses (Kaplan-Meier method)., Results: Sixteen (20 %) patients had ≥ 5 test results over time. Consecutive TTMV-HPV DNA tests were performed a median of 73 days apart. Median TTMV-HPV DNA scores were higher with an increasing per-patient number of metastatic sites (<2 vs. 2+; p < 0.01). Score changes over time were influenced by R/M treatment modality and became undetectable in 67 % (12/18) of patients who achieved a complete response to R/M therapy. Patients with detectable scores at last follow-up had significantly worse survival compared with those who were undetectable (log-rank test, p < 0.01)., Conclusions: TTMV-HPV DNA appears useful as a prognostic tool for monitoring response to therapy in the R/M setting. In the future, TTMV-HPV DNA could be explored as an exploratory clinical trial endpoint in the metastatic setting., Competing Interests: Declaration of competing interest CDF and JJ are employees or contractors for Naveris, Inc. with stock holdings. GH and MRP receive research support from, and have consulted for Naveris in the past, unrelated to the work presented here. ER receives in-kind support from Naveris only. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Mohs micrographic surgery is the gold standard for treating many types of skin cancer, particularly skin cancers of high-risk areas such as the face, genitalia, and digits, due to its tissue-sparing technique and low recurrence rates. The use of Mohs micrographic surgery for human papilloma virus-associated cutaneous malignancies has yet to be explored in a systematic review. The authors sought to assess outcomes including recurrence rates of Mohs micrographic surgery for human papilloma virus-associated cutaneous malignancies. PubMed was searched for the use of Mohs micrographic surgery in types of human papilloma virus-associated cutaneous malignancies. After application of exclusion and inclusion criteria, 33 articles were included. 700 cases from 33 studies were included. Overall recurrence rate following Mohs micrographic surgery was 39/478 (8.2%) at a mean follow-up time of 51.5 months. Recurrence rate for nail unit/digit squamous cell carcinoma was 10/103 (9.7%) at mean follow-up of 47.6 months. Recurrence rate for penile squamous cell carcinoma was 15/181 (8.3%) at mean follow-up of 45.9 months. Recurrence rate for Bowen's disease in extragenital areas was 11/189 (5.9%) at mean follow-up of 59.7 months. Patients overall reported satisfactory functional and cosmetic results. Mohs micrographic surgery demonstrates low recurrence rates and excellent functional and cosmetic outcomes in the treatment of human papilloma virus-associated cutaneous malignancies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study aimed to report the clinical outcomes and risk factors for survival of patients with low-risk early-stage human papillomavirus-associated (HPVA) endocervical adenocarcinoma (EAC) treated with surgery alone. This retrospective study obtained the clinicopathological data of patients with early-stage HPVA EAC who underwent surgery between 2012 and 2018. The Silva pattern of invasion was determined by reviewing pathology slides. Locoregional recurrence-free survival (RFS), RFS, and overall survival were calculated, and the risk factors for survival were analyzed. One hundred seventeen patients with a median follow-up of 5.2 years (0.5-9.7 yr) were included. The most common histologic type was usual (94/117, 80.3%). The Silva pattern was A in 79 patients (67.5%), B in 30 (25.6%), and C in 8 (6.8%). The 5-year locoregional RFS, RFS, and overall survival rates were 92.4%, 87.8%, and 97.2%, respectively. The presence of intermediate-risk factors and Silva pattern C were significantly associated with worse survival. Based on these findings, patients were categorized into 2 groups: Group 1 (Silva pattern A or Silva pattern B without intermediate-risk factors) and Group 2 (Silva pattern B with intermediate-risk factors or Silva pattern C ). Group 2 showed significantly worse outcomes than Group 1, including the 5-year locoregional RFS (98.6% vs 68.0%), RFS (96.4% vs 54.6%), and overall survival (100.0% vs 86.5%). In conclusion, surgery alone for early-stage HPVA EAC resulted in favorable outcomes. Consideration of the Silva pattern, in addition to well-known risk factors, could help in precise risk group stratification of low-risk, early-stage HPVA EAC., Competing Interests: H.S.K.’s work is supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT; 2023R1A2C2006223). The remaining authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

Background: First aim was to compare ddPCR assays of ctHPVDNA with p16 IHC and qualitative HPV PCR. Second aim was to carry out longitudinal blood sampling to test for association of ctHPVDNA with histological confirmed recurrence. Third aim was to perform a multidimensional assessment which included: (1) clinical features; (2) ctHPVDNA; (3) MRI-based tumor size measurements of primary tumor (PT) and cervical lymph node metastases (CLNM)., Methods: Plasma samples were collected before treatment and during follow-up, and ddPCR assay comprising E6 of HPV16 and HPV 33 and HPV 35 was used., Results: Present study was conducted at diagnosis in 117 patients and revealed a ctHPVDNA sensitivity of 100% (95% CI 95.5-100) and a specificity of 94.4 (95% CI 81.3-99.3), positive predictive value (PPV) of 94.4 (95% CI 81.3-99.3), and negative predictive value (NPP) of 100% (95% CI 89.7-100). During follow-up ctHPVDNA had a sensitivity of 100% (95% CI 72.1-100)% and specificity of 98.4% (95% CI 91.7-100)%, PPV% of 90.9% (95% CI 62.3-98.4) and NPV% of 100% (95% CI 94.3-100) for ability to detect recurrence. Correlation between both the CLNM volume and the sum of PT and CLNM volume was observed., Conclusions: ctHPVDNA was superior to p16 in identification of HPV-OPSCC at diagnosis. Introduction of ctHPVDNA, beyond diagnostic setting, represents a great opportunity to improve follow-up protocol of OPSCC patients., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Denmark, alongside other Scandinavian countries, the United States, Canada, and the United Kingdom, has high prevalence of human papillomavirus (HPV). Our oropharyngeal squamous cell carcinoma (OPSCC) database includes all diagnosed cases in Eastern Denmark during a period of more than two decades. We investigated the incidence, survival, and recurrence of patients with OPSCC with combined p16- and HPV testing covering a consecutive 21-year period. Age-adjusted incidence rate (AAIR) per 100,000, survival models, and Cox proportional-hazards model were employed. Two thousand eight hundred thirty-four patients were included (57.5% HPV positive (HPV+)/p16 positive (p16+), 33.7% HPV negative (HPV-)/p16 negative (p16-), 4% HPV+/p16-, and 4.8% HPV-/p16+). The AAIR for all patients increased from 1.8 to 5.1 per 100,000 from 2000 to 2020 linked to an increasing AAIR of HPV+/p16+ OPSCCs from 0.9 to 3.5 per 100,000 from 2000 to 2020. The AAIR for the HPV-/p16- OPSCCs decreased from 1.6 to 1.4 from 2017 to 2020. HPV+/p16+ OPSCCs had a higher 5-year overall survival (OS) of 79.2% compared to the other subgroups (HPV+/p16- OS: 50.4%; HPV-/p16+ OS: 49.4%; HPV-/p16- OS: 35.1%). The AAIR of the total OPSCC group increased from year 2000 to 2020, driven by a rise in the HPV+/p16+ group. A decreasing incidence rate was observed for the HPV-/p16- OPSCCs from 2017 to 2020. The OS for HPV+/p16+ OPSCCs was significantly higher compared to all other HPV/p16 subgroups. Therefore, we recommend testing for combined HPV and p16 status in patients with OPSCC when selecting patients for clinical trials, especially in case of de-escalating/escalating., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background and Aims: Antiviral therapy (AVT) is required in patients with newly diagnosed hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), if HBV DNA is detectable. We compared the risk of recurrence according to HBV replication activity at the curative treatment of HBV-related HCC., Methods: Patients with HBV-related HCC who underwent surgical resection or radiofrequency ablation between 2013 and 2018 were enrolled in this retrospective cohort study. Patients were categorized into two groups according to HBV replication activity at the curative treatment of HBV-related HCC (group 1: patients who met the AVT indication for HBV-related HCC due to detectable HBV DNA but did not meet the AVT indication if without HCC; group 2: patients who met the AVT indication, regardless of HCC)., Results: In the entire cohort (n = 911), HCC recurred in 303 (33.3%) patients during a median follow-up of 4.7 years. After multivariate adjustment, group 2 showed a statistically similar risk of HCC recurrence (adjusted hazard ratio [aHR] = 1.18, P = 0.332) compared to that of group 1. In addition, group 2 showed statistically similar risks of early (< 2 years; aHR = 1.31) and late (≥ 2 years; aHR = 0.83) recurrence than that of group 1 (all P>0.05). Propensity score matching and inverse probability of treatment weighting analysis also yielded similar risks of HCC recurrence between the two groups (all P>0.05, log-rank tests)., Conclusions: The risk of HCC recurrence in patients who received curative treatment for newly diagnosed HBV-related HCC was similar regardless of HBV replication activity, if AVT was properly initiated., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) have proven benefit from anti-programmed cell death 1 (anti-PD-1) monotherapy. Here, we retrospectively analyze the association of plasma Epstein-Barr virus (EBV) DNA load and tumor viral lytic genome with clinical outcome from 2 registered phase I trials., Methods: Patients with RM-NPC from Checkmate 077 (nivolumab phase I trial in China) and Camrelizumab phase I trial between March 2016 and January 2018 were enrolled. Baseline EBV DNA titers were tested in 68 patients and EBV assessment was performed in 60 patients who had at least 3 post-baseline timepoints of EBV data and at least 1 post-baseline timepoint of radiographic assessment. We defined "EBV response" as 3 consecutive timepoints of load below 50% of baseline, and "EBV progression" as 3 consecutive timepoints of load above 150% of baseline. Whole-exome sequencing was performed in 60 patients with available tumor samples., Results: We found that the baseline EBV DNA load was positively correlated with tumor size (spearman p < 0.001). Both partial response (PR) and stable disease (SD) patients had significantly lower EBV load than progression disease (PD) patients. EBV assessment was highly consistent with radiographic evaluation. Patients with EBV response had significantly improved overall survival (OS) than patients with EBV progression (log-rank p = 0.004, HR = 0.351 [95% CI: 0.171-0.720], median 22.5 vs. 11.9 months). The median time to initial EBV response and progression were 25 and 36 days prior to initial radiographic response and progression, respectively. Patients with high levels of EBV lytic genomes at baseline, including BKRF2, BKRF3 and BKRF4, had better progression-free survival (PFS) and OS., Conclusion: In summary, early clearance of plasma EBV DNA load and high levels of lytic EBV genes were associated with better clinical outcome in patients with RM-NPC receiving anti-PD-1 monotherapy., (© 2024. The Author(s).)

Purpose: Human papillomavirus (HPV) is the cause of the majority of cervical cancer cases and has been showed to be released as cell-free tumor DNA (ctHPV DNA) into the circulation. Here, we analyze if ctHPV DNA could be used as a prognostic biomarker and/or to detect relapse earlier than traditional methods in locally advanced cervical cancer (LACC)., Experimental Design: A total of 74 patients with LACC were included; 66of 74 were positive for 13 high-risk HPV types on a bead-based assay of tumor biopsy samples. HPV-type-specific droplet digital PCR assays were developed. Longitudinal plasma samples were then analyzed for the biopsy-verified HPV type for each patient. In total, 418 plasma samples were analyzed. Patients were followed for a median of 37 months. Results were correlated to tumor and clinical characteristics., Results: Of the pretreatment plasma samples, 92.4% were positive for ctHPV DNA. Persistent ctHPV DNA in end-of-treatment, early follow-up (1-2 months after end-of-treatment), or tumor evaluation (3-4 months after end-of-treatment) plasma was correlated with worse progression-free survival (P < 0.001) compared with if ctHPV DNA was not found. The positive predictive value of ctHPV status at early follow-up for predicting disease progression was 87.5%, and the negative predictive value was 89.3%. ctHPV DNA was found in plasma before relapse was diagnosed using radiology in all patients (n = 10) who experienced relapse after complete clinical response to treatment with a median 315 days lead time., Conclusions: ctHPV DNA in follow-up plasma is a promising prognostic biomarker in patients with LACC, useful for analysis of response to therapy and for early detection of relapse., (©2024 American Association for Cancer Research.)

Objectives: About 17% of patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC), which is mainly comprised of oropharyngeal SCC (OPSCC), will experience disease recurrence, which is often considered incurable when manifested at a metastatic and/or recurrent stage. We conducted a critical qualitative systematic review. Our objectives were to provide an overview of the molecular landscape of recurrent/metastatic HPV-positive HNSCC as well as novel molecular biomarkers., Design: A literature review was conducted to identify studies reporting on the molecular characteristics of recurrent/metastatic HPV-positive HNSCC, novel molecular biomarkers and treatment options. The reviews of abstracts, full articles, and revision of the included studies, followed by data extraction and quality assessment were performed by three independent assessors. All primary literature, such as retrospective, prospective, and clinical trials as well as basic research studies were considered, and the final search was conducted at the end of February 2023. The level of evidence was rated using the guidelines published by the Oxford Centre for Evidence-based Medicine and quality was assessed using the Newcastle-Ottawa Scale criteria., Results and Conclusions: The literature search resulted in the identification of 1991 articles. A total of 181 full articles were screened, and 66 articles were included in this analysis. Several studies reported that recurrent/metastatic HPV-positive HNSCC had higher rates of TP53 mutation and were genomically similar to HPV-negative HNSCC. The detection of circulating tumour tissue-modified HPV DNA (ctHPVDNA) as a specific biomarker has shown promising results for monitoring treatment response and recurrence in the subset of HPV-positive HNSCC. In addition, evidence for targeted therapy in recurrent/metastatic HPV-positive HNSCC has emerged, including agents that inhibit overexpressed EGFR. Studies of combination immunotherapy are also underway. Our review outlines the latest evidence on the distinct molecular profiles of recurrent/metastatic HPV-positive HNSCC as well as the clinical potential of ctHPVDNA testing in routine practice. More controlled and longitudinal studies are needed to identify additional molecular targets and to assess the performance and benefits of novel molecular biomarkers in clinical practice., (© 2024 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Purpose: Available data on hepatocellular carcinoma (HCC) recurrence after direct-acting antivirals (DAAs) treatment for hepatitis C virus (HCV) are conflicting. No randomized trials were done. This study aims to compare the 1-year HCC recurrence rates in patients who received DAAs after tumor ablation versus those who postponed HCV treatment for 1 year., Methods: Included patients were randomized after complete HCC ablation into two groups: a postponed DAAs group for whom DAAs initiation was postponed for 12 months and a DAAs group who were given sofosbuvir/velpatasvir. Patients were followed for 1 year., Results: Eighty-four HCV patients with a mean age of 56.35 ± 8.12 years were included; 78.57% of them were males. The number of lesions per patient ranged from 1 to 3 lesions, and the size of the largest lesion ranged from 1.5 to 5 cm. There were no statistically significant differences between both groups regarding baseline characteristics. In the DAAs group (43 patients), 11 patients had HCC recurrence, while 25 patients in the postponed DAAs group (41 patients) had HCC recurrence. Using Kaplan-Meier analysis, the 1-year recurrence-free survival (RFS) was significantly higher in the DAAs group (72.2% vs. 38%, P = 0.001). On multivariate analysis, both higher albumin levels (HR 0.147, 95% CI 0.066-0.329) and receiving DAAs (HR 0.358, 95% CI 0.176-0.730) 1 year after ablation were associated with significantly lower recurrence., Conclusion: Direct-acting antiviral usage after complete hepatocellular carcinoma ablation significantly decreases the 1-year HCC recurrence rates, but the risk of recurrence is still not eliminated. The study registration number on clinicaltrials.gov : NCT04653818 (initial release on 28/11/2020)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The primary aim of this study was to assess the association between human papilloma virus (HPV) and p53 expression and local recurrence (LR), disease specific survival (DSS), and overall survival (OS) in patients with vulvar squamous cell carcinoma (VSCC). Secondary, the accuracy of p16 immunohistochemistry for HPV status was assessed. The tumor tissue of 255 patients, surgically treated for primary unifocal VSCC between 2000 and 2010, was analyzed. HPV-PCR and P16 and p53 immunohistochemical stainings were performed. All histologic slides were independently reviewed by two expert gyneco-pathologists. Time to first LR, DSS, and OS for the variables p16, p53, and HPV-PCR were compared using univariable and multivariable Cox-regression analyses. In 211/255 (83.5%) patients, HPV-PCR was negative. The local recurrence rate was significantly lower in patients positive with HPV-PCR (10-year LR rate 24.6%) versus negative tumors (47.5%), p = 0.004. After multivariable analyses, this difference remained significant (HR 0.23 (95% CI 0.08-0.62) p = 0.004). There was no difference in LR rate correlated to the p53 expression. DSS and OS did not significantly differ after multivariable analyses for all different subgroups. Sensitivity and specificity of p16 staining for presence of HPV detected by HPV-PCR were 86.4% and 93.8%, respectively. In conclusion, patients with HPV-negative VSCCs have significantly more LR compared to patients with HPV-positive VSCCs, and p16 immunohistochemistry is a reliable surrogate marker for HPV status. No relevant subgroup for LR or survival based on HPV/p53 status could be identified. We advise to perform an HPV-PCR or p16 IHC staining in all patients with VSCC., (© 2023. The Author(s).)

Background: Highly active hepatitis B virus (HBV) is known to be associated with poor outcomes in patients with hepatocellular carcinoma (HCC). This study aims to investigate the relationship between HBV status and HCC recurrence after liver transplantation., Methods: The study retrospectively analyzed HCC patients undergoing liver transplantation in two centres between January 2015 and December 2020. The authors reviewed post-transplant HBV status and its association with outcomes., Results: The prognosis of recipients with hepatitis B surface antigen (HBsAg) reappearance ( n =58) was poorer than those with HBsAg persistent negative ( n =351) and positive ( n =53). In HBsAg persistent positive group, recipients with HBV DNA reappearance or greater than 10-fold increase above baseline had worse outcomes than those without ( P <0.01). HBV reactivation was defined as (a) HBsAg reappearance or (b) HBV DNA reappearance or greater than 10-fold increase above baseline. After propensity score matching, the 5-year overall survival rate and recurrence-free survival rate after liver transplantation in recipients with HBV reactivation were significantly lower than those without (32.0% vs. 62.3%; P <0.01, and 16.4% vs. 63.1%; P <0.01, respectively). Moreover, HBV reactivation was significantly related to post-transplant HCC recurrence, especially lung metastasis. Cox regression analysis revealed that beyond Milan criteria, microvascular invasion and HBsAg-positive graft were independent risk factors for post-transplant HBV reactivation, and a novel nomogram was established accordingly with a good predictive efficacy (area under the time-dependent receiver operating characteristic curve=0.78, C-index =0.73)., Conclusions: Recipients with HBV reactivation had worse outcomes and higher tumour recurrence rates than those without. The nomogram could be used to evaluate the risk of post-transplant HBV reactivation effectively., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the most common HPV-associated cancer in the United States, with a rapid increase in incidence over the last two decades. The burden of HPV+ HNSCC is likely to continue to rise, and given the long latency between infection and the development of HPV+ HNSCC, it is estimated that the effect of the HPV vaccine will not be reflected in HNSCC prevalence until 2060. Efforts have begun to decrease morbidity of standard therapies for this disease, and its improved characterization is being leveraged to identify and target molecular vulnerabilities. Companion biomarkers for new therapies will identify responsive tumors. A more basic understanding of two mechanisms of HPV carcinogenesis in the head and neck has identified subtypes of HPV+ HNSCC that correlate with different carcinogenic programs and that identify tumors with good or poor prognosis. Current development of biomarkers that reliably identify these two subtypes, as well as biomarkers that can detect recurrent disease at an earlier time, will have immediate clinical application.

Purpose: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Consensus guidelines recommend clinical exams and imaging in decreasing frequency as part of posttreatment surveillance for recurrence. Plasma tumor tissue modified viral (TTMV)-HPV DNA testing has emerged as a biomarker which can inform disease status during surveillance., Experimental Design: This retrospective observational cohort study involved 543 patients who completed curative-intent therapy for HPV-associated OPSCC between February 2020 and January 2022 at eight U.S. cancer care institutions. We determined the negative predictive value (NPV) of TTMV-HPV DNA for recurrence when matched to physician-reported clinical outcome data (median follow-up time: 27.9 months; range: 4.5-154)., Results: The cohort included mostly men with a median age of 61 who had locoregionally advanced disease. HPV status was determined by p16 positivity in 87% of patients, with a positive HPV PCR/ISH among 55%; while pretreatment TTMV-HPV DNA status was unknown for most (79%) patients. Patients had a mean of 2.6 tests and almost half had three or more TTMV-HPV DNA results during surveillance. The per-test and per-patient sensitivity of the assay was 92.5% [95% confidence interval (CI): 87.5-97.5] and 87.3% (95% CI: 79.1-95.5), respectively. The NPV for the assay was 99.4% (95% CI: 98.9-99.8) and 98.4% (95% CI: 97.3-99.5), respectively., Conclusions: TTMV-HPV DNA surveillance testing yields few false negative results and few missed recurrences. These data could inform decisions on when to pursue reimaging following first disease restaging and could inform future surveillance practice. Additional study of how pretreatment TTMV-HPV DNA status impacts sensitivity for recurrence is needed., (©2023 The Authors; Published by the American Association for Cancer Research.)

Patients with hemato-oncologic diseases are particularly vulnerable to severe infections. Adult patients with blood cancers infected with SARS-CoV-2 had poorer treatment outcomes and higher mortality than patients with COVID-19 without burden. However, in pediatric patients with hemato-oncologic diseases the course of COVID-19 is milder than in adults in the same group of patients. In this report, we describe the case of our patient with acute lymphoblastic leukemia infected with SARS-CoV-2 and treated with remdesivir. We also review the existing literature of pediatric patients who have been diagnosed with both hemato-oncologic diseases and COVID-19., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To analyze the oncologic outcomes and risk factors for recurrence in patients who underwent surgery for oropharyngeal squamous cell carcinoma (OPSCC), and in whom adjuvant therapy was not recommended or was declined., Methods: Retrospective cohort study of patients with OPSCC who were treated with transoral surgery only at a tertiary care academic medical center from April 2010 to March 2019., Results: Seventy-four patients met inclusion criteria. In 16, adjuvant therapy was recommended but declined. There were 8 recurrences, of which 6 had been given recommendations for adjuvant therapy. Of the 8 recurrences, 2 died, 2 are alive with disease, and 4 were successfully salvaged. Five patients died of unrelated causes. Lymphovascular invasion (LVI, P  = .016) had a significant impact on recurrence, while other pathologic features of the primary tumor such as size, location, human papillomavirus (HPV) status, and margin status did not. Margins were classified as "positive" in 4 patients, "close" in 54, and "negative" in 16. There were 3 local recurrences (4.1%), each of whom had declined adjuvant therapy. Lymph node features such as N-stage ( P  = .0004), number of positive nodes ( P  = .0005), and presence of extra-nodal extension (ENE, P  = .0042) had a statistically significant impact on relapse. Smoking history and surgical approach showed no significant impact on recurrence., Conclusion: Patients who undergo surgery for HPV-positive OPSCC with negative margins, no PNI, no LVI, and ≤1 positive lymph node without ENE have low risk for recurrence. These patients can likely be safely treated with surgery alone. Patients with these risk factors who decline adjuvant therapy are at risk for recurrence, and should be monitored.

In head and neck cancer, early detection of recurrence after treatment is important. The contemporary development of therapeutic agents have improved the prognosis after recurrence; however, no biomarker has been established for evaluating therapeutic effects or detecting recurrence. Recently, circulating tumor DNA (ctDNA), which comprises DNA derived from tumor cells and exists in the form of cell-free DNA in the blood, has attracted attention as a minimally invasive and repeatable biomarker for detecting cancer. We validated the usefulness of ctDNA of human papilloma virus (HPV)-derived sequences as a biomarker in HPV-related p16-positive oropharyngeal cancer by assessing 25 patients with p16-positive oropharyngeal cancer. Blood samples were collected from each patient at multiple time points during the treatment, and the plasma was preserved. The ctDNA was extracted from the plasma and analyzed using digital polymerase chain reaction. HPV-derived ctDNA was detected in 14 (56%) of the 25 patients. In all the patients, the samples were found to be ctDNA-negative after initial treatment. Cancer recurrence was observed in 2 of the 14 patients; HPV-derived ctDNA was detected at the time of recurrence. Our results indicate that HPV-derived ctDNA can be a prospective biomarker for predicting the recurrence of p16-positive oropharyngeal cancer., (© 2022. The Author(s).)

Objective: To analyze the patterns, risk factors, and salvage outcomes for locoregional recurrences (LRR) after treatment with transoral robotic surgery (TORS) for HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC)., Study Design: Retrospective analysis of HPV+ OPSCC patients completing primary TORS, neck dissection, and NCCN-guideline-compliant adjuvant therapy at a single institution from 2007 to 2017., Methods: Features associated with LRR, detailed patterns of LRR, and outcomes of salvage therapy were analyzed. Disease-free survival (DFS) and overall survival (OS) were calculated for subgroups of patients receiving distinct adjuvant treatments., Results: Of 541 patients who completed guideline-indicated therapy, the estimated 5-year LRR rate was 4.5%. There were no identifiable clinical or pathologic features associated with LRR. Compared to patients not receiving adjuvant therapy, those who received indicated adjuvant radiation alone had a lower risk of LRR (HR 0.28, 95% CI [0.09-0.83], P = .023), but there was no difference in DFS (P = .21) and OS (P = .86) between adjuvant therapy groups. The 5-year OS for patients who developed LRR was 67.1% vs. 93.9% for those without LRR (P < .001). Patients who initially received adjuvant chemoradiation and those suffering local, in-field, and/or retropharyngeal node recurrences had decreased disease control after salvage therapy., Conclusion: LRR rates are low for HPV+ OPSCCs completing TORS and guideline-compliant adjuvant therapy. Patients without indication for adjuvant therapy more often suffer LRR, but these recurrences are generally controllable by salvage therapy. Improved understanding of the patterns of recurrence most amenable to salvage therapy may guide treatment decisions, counseling, and adjuvant therapy de-escalation trials., Level of Evidence: 3 Laryngoscope, 131:E2865-E2873, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Almost all cervical cancers are caused by human papillomavirus (HPV) and patients with advanced stage are at high risk for relapse. Circulating HPV DNA (HPV ctDNA) may serve as a residual tumor marker at the end of chemoradiation or to predict relapse during the follow-up period., Experimental Design: We analyzed serum samples from 94 HPV16- or HPV18-related CCs from the BioRAIDs prospective cohort. Samples were collected before and after treatment and during an 18-month follow-up period. Using digital droplet PCR (ddPCR), we assessed the relevance of circulating HPV E7 gene as a marker for residual disease compared to HPV integration site and PIK3CA mutations. Finally, the prognostic impact of circulating HPV E7 gene was assessed with its prediction value of relapse., Results: HPV E7 gene was the most sensitive tumor marker, superior to both HPV integration sites and PIK3CA mutations in serum. Circulating HPV DNA (HPV ctDNA) was detected in 63% (59/94) of patients, before treatment. HPV ctDNA detection in serum sample was associated with high FIGO stage ( P = 0.02) and para-aortic lymph node involvement ( P = 0.01). The level of HPV ctDNA was positively correlated with HPV copy number in the tumor ( R = 0.39, P < 0.001). Complete clearance of HPV ctDNA by the end of treatment was significantly associated with a longer PFS ( P < 0.0001). Patients with persistent HPV ctDNA in serum relapsed with a median time of 10 months (range, 2-15) from HPV ctDNA detection., Conclusions: HPV ctDNA detection is a useful marker to predict relapse in cervical cancer. See related commentary by Wentzensen and Clarke, p. 5733 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Low-level viremia generally refers to detectable HBV DNA levels lower than 2000 IU/mL. Studies show that low-level viremia is a risk factor for hepatocellular carcinoma. The aim of this study was to explore the characteristics of low-level viremia patients with hepatitis B-related hepatocellular carcinoma and identify prognostic factors after curative hepatectomy., Methods: Data from chronic hepatitis B patients with hepatocellular carcinoma receiving curative hepatectomy for the first time in the first hospital of China Medical University were studied. Patients were divided into two groups based on preoperative HBV DNA levels: group 1 (low-level viremia group, HBV DNA < 2000 IU/mL) and group 2 (HBV DNA ≥ 2000 IU/mL)., Results: Of the 212 patients, 104 patients were in group 1 and 108 patients were in group 2. There was a lower proportion of patients with HBsAg levels > 250 IU/mL (the upper limit of detection in our laboratory) in group 1 than in group 2 (71.2% vs. 86.1%, P < 0.01). The percentage of patients with a tumor diameter < 5 cm was 67.3% in group 1 and 37.0% in group 2 (P < 0.000). The percentage of tumor recurrence was 40.4% (42) in group 1 and 54.6% (59) in group 2 (P < 0.05). Median recurrence-free survival was 30.1 months in group 1 and 17.6 months in group 2 (P < 0.01). Multivariate analysis showed that a tumor diameter ≥ 5 cm (hazard ratio [HR] = 1.819, 95% confidence interval [CI] 1.193-2.775, P = 0.005), intrahepatic metastasis (HR = 1.916, 95% CI 1.077-3.407, P = 0.027), and an HBV DNA level ≥ 100 IU/mL (the lower limit of detection in our laboratory, HR = 2.943, 95% CI 1.916-4.520, P < 0.000) were independent prognostic factors associated with an increased risk of hepatocellular carcinoma recurrence., Conclusion: Preoperative low-level viremia was related with a long tumor recurrence interval and complete virologic response after curative hepatectomy was associated with a lower risk of hepatocellular carcinoma recurrence., (© 2021. The Author(s).)

High-risk human papillomavirus (HR-HPV) infection is a major risk factor of head and neck cancers (HNCs). Despite the rising prevalence of HPV-driven HNC (HPV-HNC), biomarkers for detection, prognostication, and disease monitoring are lacking. To evaluate the capacity of salivary HR-HPV DNA as a biomarker of HPV-HNC, the salivary HR-HPV statuses of 491 and 10 patients with primary and recurrent HNC, respectively, were determined at diagnosis, using quantitative real-time PCR and MassARRAY. Tumor cyclin-dependent kinase inhibitor 2A (p16) expression was determined by IHC analysis. Patients with oropharyngeal cancer (OPC) (n = 215) were followed up for ≤5 years. Survival characteristics were evaluated in terms of event-free and cause-specific survival. Of the primary-HNC cohort, 43.2% were positive for salivary HR-HPV DNA, with most having OPC. Salivary HR-HPV DNA was detected in 81.4% of tumor p16-positive OPC patients at diagnosis. Prognosis in salivary HR-HPV-positive OPC patients was favorable compared with that in salivary HR-HPV-negative patients (event-free survival, hazard ratio = 0.42 [95% CI, 0.21-0.81, P = 0.010]; cause-specific survival, hazard ratio = 0.39 [95% CI, 0.18-0.86, P = 0.019]). In the recurrent-HNC cohort, salivary HR-HPV DNA was detected in 83.3% of those who previously had tumor p16-positive HNC. These findings indicate that this liquid biopsy-based, noninvasive biomarker can play an essential role in the detection and management of HPV-HNC., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-based intralesional oncolytic immunotherapy approved for the treatment of unresectable melanoma. The present, ongoing study aimed to estimate the treatment effect of neoadjuvant T-VEC on recurrence-free survival (RFS) of patients with advanced resectable melanoma. An open-label, phase 2 trial (NCT02211131) was conducted in 150 patients with resectable stage IIIB-IVM1a melanoma who were randomized to receive T-VEC followed by surgery (arm 1, n = 76) or surgery alone (arm 2, n = 74). The primary endpoint was a 2-year RFS in the intention-to-treat population. Secondary and exploratory endpoints included overall survival (OS), pathological complete response (pCR), safety and biomarker analyses. The 2-year RFS was 29.5% in arm 1 and 16.5% in arm 2 (overall hazard ratio (HR) = 0.75, 80% confidence interval (CI) = 0.58-0.96). The 2-year OS was 88.9% for arm 1 and 77.4% for arm 2 (overall HR = 0.49, 80% CI = 0.30-0.79). The RFS and OS differences between arms persisted at 3 years. In arm 1, 17.1% achieved a pCR. Increased CD8 + density correlated with clinical outcomes in an exploratory analysis. Arm 1 adverse events were consistent with previous reports for T-VEC. The present study met its primary endpoint and estimated a 25% reduction in the risk of disease recurrence for neoadjuvant T-VEC plus surgery versus upfront surgery for patients with resectable stage IIIB-IVM1a melanoma., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: This study assessed the correlation between Epstein-Barr virus (EBV) biomarkers and the eighth American Joint Committee on Cancer staging system and the prognostic values of IgG antibodies against replication and transcription activator (Rta-IgG), IgA antibodies against Epstein-Barr nuclear antigen 1, and BamH1 Z transactivator (Zta-IgA) in locoregionally advanced nasopharyngeal carcinoma (NPC) patients., Materials and Methods: Serum EBV antibody levels were measured by enzyme-linked immunosorbent assay in 435 newly diagnosed stage III-IVA NPC patients administered intensity-modulated radiation therapy±chemotherapy. The primary endpoint was progression-free survival (PFS)., Results: Rta-IgG and Zta-IgA levels were positively correlated with the N category and clinical stage. Patients with high Rta-IgG levels (> 29.07 U/mL) showed a significantly inferior prognosis as indicated by PFS (77% vs. 89.8%, p=0.004), distant metastasis-free survival (DMFS) (88.3% vs. 95.8%, p=0.021), and local recurrence-free survival (LRFS) (91.2% vs. 98.3%, p=0.009). High Rta-IgG levels were also significantly associated with inferior PFS and LRFS in multivariable analyses. In the low-level EBV DNA group (≤ 1,500 copies/mL), patients with high Rta-IgG levels had significantly inferior PFS and DMFS (both p < 0.05). However, in the high-level EBV DNA group, Rta-IgG levels were not significantly associated with PFS, DMFS, and LRFS. In the advanced T category (T3-4) subgroup, high Rta-IgG levels were also significantly associated with inferior PFS, DMFS, and LRFS (both p < 0.05)., Conclusion: Rta-IgG and Zta-IgA levels were strongly correlated with the TNM classification. Rta-IgG level was a negative prognostic factor in locoregionally advanced NPC patients, especially those with advanced T category or low EBV DNA level.

Hepatitis B virus-related hepatocellular carcinoma recurrence after liver transplantation (LT) is notoriously difficult to manage and fatal. As a therapeutic option, adoptive cell therapy with HBV-specific TCR-redirected T cells could be employed to target and control relapses in these patients. However, indispensable immunosuppressive medications post-transplantation can significantly hinder the optimum efficacy of such therapy in the clinic. Here we report a new class of Armored TCR T cells which are able to attack recurrent cancer cells in liver transplanted recipients, while temporarily evading immunosuppressant drugs. We believe this strategy could open up new opportunities for treating pathologies under immunosuppressant treatment.

Kaposi sarcoma (KS) is an AIDS-defining angio-proliferative malignancy highly prevalent in Sub-Saharan Africa. The main objective of this study was to determine the factors associated with recurrence of HIV-associated KS. We recruited a cohort of individuals on antiretroviral therapy who were in remission for HIV-associated KS after undergoing cytotoxic cancer chemotherapy. Collected variables included sociodemographic and clinical parameters, cytokines and chemokines, HIV viral loads, and CD4 counts. Compared to individuals who had KS recurrence, IL-5 was significantly higher at time of follow-up in individuals who had sustained remission (22.7pg/ml vs. 2.4pg/ml; p = 0.02); IL-6 was significantly higher at baseline and time of follow-up in individuals who had sustained remission, (18.4pg/ml vs. 0pg/ml; p = 0.01) and (18.0pg/ml vs. 0.18pg/ml; p = 0.03) respectively; IP-10 was significantly lower at baseline and at time of follow-up in individuals who had sustained remission, (534pg/ml vs. 920pg/ml; p = 0.04) and (446pg/ml vs.1098pg/ml; p = 0.01) respectively; while HIV viral load was significantly lower at baseline and at time of follow-up in individuals who had sustained remission, (0copies/ml vs. 113copies/ml; p = 0.004) and (0copies/ml vs. 152copies/ml; p = 0.025) respectively. Plasma levels of IL-5, IL-6, and IP-10 are associated with recurrence of HIV-associated KS, while persistently detectable HIV viral loads increase the risk of KS recurrence., Competing Interests: The authors have declared that no competing interests exist.

To assess the impact of HCV eradication on the outcomes of cirrhotic patients treated curatively for incidental hepatocellular carcinoma (HCC) detected during surveillance program. Data were collected on 1,323 French patients with compensated biopsy-proven HCV cirrhosis recruited in 35 centers (ANRS CO12 CirVir cohort). Sustained virologic responses (SVR) and the occurrence of HCC were recorded prospectively. During a median follow-up of 68.3 months, 218 patients developed HCC, 126 of whom underwent a curative procedure as first-line therapy (ablation = 95, resection = 31). The HCC BCLC stage was 0/A in 97.5% of patients; 74 (58.7%) never achieved SVR. During a median follow-up of 26.0 months after HCC treatment, 59 (46.8%) experienced HCC recurrence. SVR was not associated with a recurrence, whether considering final SVR status [HR = 0.77; 95% confidence interval (95% CI), 0.43-1.39; P = 0.39] or its time to achievement (prior to/after HCC occurrence; global P = 0.28). During the same timeframe, 46 patients with HCC (36.5%) died (liver failure: 41.9%, HCC progression: 37.2%, extrahepatic causes: 20.9%). Under multivariate analysis, SVR was associated with improved survival [HR = 0.21; 95% CI, 0.08-0.52; P = 0.001]. Survival benefit was explained by a lower incidence of liver decompensation and higher rates of sequential HCC re-treatment. Direct antiviral intake was not associated with a higher risk of HCC recurrence, but with improved survival (HR = 0.23; 95% CI, 0.06-0.83; P = 0.024). HCV eradication in primary or secondary prevention optimizes HCC management through preservation of liver function and improves survival, whatever the regimen. PREVENTION RELEVANCE: Liver failure is a competing risk of death in patients with HCC eligible for curative procedures. HCV eradication does not decrease risk of HCC recurrence in the first two years, but enables sequential curative HCC treatments through preservation of liver function. Direct-acting antiviral agent intake is not associated with HCC recurrence and improves survival., (©2021 American Association for Cancer Research.)

Serum hepatitis B virus (HBV) mutations can predict hepatocellular carcinoma (HCC) occurrence. We aimed to clarify if HBV evolves synchronously in the sera, adjacent liver and tumors and predict HCC prognosis equally. A total of 203 HBV-positive HCC patients with radical hepatectomy in Shanghai, China, during 2011-15 were enrolled in this prospective study. Quasispecies complexity (QC) in HBV core promoter region was assessed using clone-based sequencing. We performed RNA sequencing on tumors and paired adjacent tissues of another 15 HCC patients and analyzed it with three public data sets containing 127 samples. HBV QC was positively correlated to APOBEC3s' expression level (r = 0.28, P < 0.001), higher in the adjacent tissues than in the tumors (P = 6.50e-3), and higher in early tumors than in advanced tumors (P = 0.039). The evolutionary distance between the sera-derived HBV strains and the tumor-derived ones was significantly longer than that between the sera-derived ones and the adjacent tissue-derived ones (P < 0.001). Multivariate Cox regression analyses indicated that high HBV QC in the sera predicted an unfavorable overall survival (P = 0.002) and recurrence-free survival (RFS; P = 0.004) in HCC, whereas, in the tumors, it predicted a favorable RFS (P < 0.001). APOBECs-related HBV mutations, including G1764A, were more frequent in the sera than in the adjacent tissues. High-frequent A1762T/G1764A in the sera predicted an unfavorable RFS (P < 0.001), whereas, in the tumors, it predicted a favorable RFS (P = 0.035). In conclusion, HBV evolves more advanced in the sera than in the tumors. HBV QC and A1762T/G1764A in the sera and tumors have contrary prognostic effects in HCC., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Nasopharyngeal carcinoma (NPC) results from the aberrant and uncontrolled growth of the nasopharyngeal epithelium. It is highly associated with the Epstein-Barr virus, especially in regions where it is endemic. In the last decade, significant advances in genetic sequencing techniques have allowed the discovery of many new abnormal molecular processes that undoubtedly contribute to the establishment, growth and spread of this deadly disease. In this review, we consider NPC as EBV induced. We summarise the recent discoveries and how they add to our understanding of the pathophysiology of NPC in the context of genomics first in primary and then in recurrent disease. Overall, we find key early events lead to p16 inactivation and cyclin D1 expression, allowing latent viral infection. Host and viral factors work together to affect a variety of molecular pathways, the most fundamental being activation of NF-κB. Nonetheless, much still yearns to be discovered, especially in recurrent NPC.

The Epstein-Barr Virus (EBV) is a gamma-herpesvirus involved with a variety of human cancers, notably the endemic Burkitt lymphoma and nasopharyngeal carcinoma. In 2004, EBV was described as one the first known human oncoviruses to encode viral microRNAs (miRNAs), and these molecules were found to interact with viral and host targets. EBV miRNAs modulate biological processes that are critical for carcinogenesis, contributing to cell transformation and tumor progression of EBV-associated cancers. Herein we review and discuss EBV miRNAs as modulators of viral biology and carcinogenesis, as well as their usefulness as putative markers to monitor the onset, progression, and recurrence of cancers associated with the EBV infection., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: This study was performed to investigate whether long-term monitoring of dynamic changes in plasma Epstein-Barr virus (EBV) DNA could improve prognosis prediction of nasopharyngeal carcinoma (NPC)., Materials and Methods: About 1077 nonmetastatic NPC patients were recruited to retrospectively analyze the prognostic value of plasma EBV DNA load pretreatment and 3, 12, 24, and 36 months posttreatment. We also examined the prognostic value of dynamic changes in plasma EBV DNA at various time points., Results: Patients with plasma EBV DNA load above optimal pre- and posttreatment cut-offs had significantly worse five-year progression-free survival, distant metastasis-free survival, locoregional relapse-free survival, and overall survival (OS) at all-time points, excluding only OS at 36 months posttreatment due to limited mortalities. Patients with persistently undetectable plasma EBV DNA at the first four time points had the best prognosis, followed by those with positive detection pretreatment and consistently negative detection posttreatment, those with negative detection pretreatment and positive detection at one time point posttreatment, and those with positive detection pretreatment and at one time point posttreatment, whereas patients with positive detection at ≥2 time points posttreatment had the worst prognosis. Cox proportional hazard models identified the dynamic change pattern as an independent prognostic factor, and receiver operating characteristic curve analysis demonstrated that the dynamic change at four time point was more valuable than any single time point for predicting disease progression, distant metastasis, locoregional relapse, and mortality., Conclusions: Dynamic changes in plasma EBV DNA pre- and posttreatment could predict the long-term survival outcome and provide accurate risk stratification in NPC., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background and Aims: Studies have suggested that tenofovir disoproxil fumarate (TDF) treatment is associated with a significantly lower risk of hepatocellular carcinoma (HCC) occurrence when compared with entecavir (ETV) therapy in patients with chronic hepatitis B. We aimed to compare HCC recurrence and survival of patients treated with TDF or ETV after surgical resection for hepatitis B virus (HBV)-related HCC., Approach and Results: This historical cohort study included 1,695 consecutive patients treated with ETV (n = 813) or TDF (n = 882) after curative-intent hepatectomy for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A in Korea between 2010 and 2018. HCC recurrence and overall survival of patients were compared between ETV and TDF groups by propensity score-matched and multivariable-adjusted Cox regression analyses from the date of hepatectomy for HCC. The mean age of the study patients was 54.8 years, and 1,294 patients (76.3%) were male. During the median follow-up duration of 37.6 months with continued ETV or TDF therapy, 561 (33.1%) patients developed HCC recurrence, 144 (8.4%) died, and 22 (1.3%) received liver transplant. Compared with ETV, TDF therapy was associated with significantly higher recurrence-free (P = 0.02) and overall survival (P = 0.03) rates by propensity score-matched analysis. By multivariable-adjusted analysis, the TDF group was associated with significantly lower rates of HCC recurrence (hazard ratio [HR], 0.82; 95% confidence interval, 0.68-0.98; P = 0.03), and death or transplantation (HR, 0.62; 95% confidence interval, 0.44-0.88; P = 0.01). TDF therapy was an independent protective factor for both early (<2 years; HR, 0.79; P = 0.03) and late (≥2 years; HR, 0.68; P = 0.03) postoperative HCC recurrence., Conclusions: Among patients who underwent curative hepatectomy for HBV-related HCC, TDF therapy was associated with a significantly lower risk of HCC recurrence and better overall patient survival compared with ETV therapy., (© 2020 by the American Association for the Study of Liver Diseases.)

Patients with HPV-driven (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) have a significantly improved overall survival compared to patients with HPV-negative (HPV-) OPSCC. Nevertheless, 13%-25% of patients with HPV+OPSCC develop local/distant recurrence (LDR) and have a course of disease similar to HPV-OPSCC. We hypothesize that HPV+OPSCCs of patients with LDR have a mutation frequency and pattern similar to HPV-OPSCCs, which is associated with severe outcome. We performed targeted next-generation sequencing using a customized gene panel and compared data from 56 matched HPV+and HPV-OPSCC of patients with/without LDR regarding protein-altering variants. Despite improved overall survival of patients with HPV+OPSCC, those who develop LDR show a strongly reduced survival rate that is similar or even worse compared to HPV-OPSCC patients. Overall, the number of mutations was similar in OPSCC of patients with and without LDR. In total and with respect to TP53, HPV-OPSCC had significantly more protein-altering mutations than HPV+OPSCC. The number of mutations was similar in HPV-OPSCC of patients with and without LDR with the exception of FAT1, which was mutated more frequently in patients without LDR. In HPV+OPSCC, HRAS, PIK3R1, STK11 and TP63 were more frequently mutated in patients with LDR compared to patients without. HPV+OPSCC of patients with LDR have a similar mutation pattern as HPV-OPSCC, except TP53, which was mutated to a significantly lower extent. In conclusion, HPV-and HPV+OPSCC with LDR have similar mutation counts in the analyzed genes. We suspect that the number of mutations is not causal for disease progression, rather specific mutations could be important., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68 Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.

Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a rare peripheral T-cell lymphoma that predominantly occurs in Asian and South American populations. The treatment of ENKL has been a challenge for a long time. This study was conducted to compare the clinical efficacy and safety of cisplatin, dexamethasone, gemcitabine, and pegaspargase (DDGP) and methotrexate, dexamethasone, ifosfamide, L-asparaginase, and etoposide (SMILE) regimens for relapsed/refractory ENKL and explore the prognostic factors. From October 2014 to July 2019, 54 patients with relapsed/refractory ENKL who received DDGP or SMILE chemotherapy were retrospectively assessed in this study. Thirty-one patients received DDGP chemotherapy and 23 patients received SMILE chemotherapy. A higher complete response rate was observed in patients treated with DDGP regimen (61.3% vs. 30.4%, P = 0.025). The DDGP group (95% confidence interval (CI) of 5-year progression-free survival (PFS): 24.6-66.2%; 95% CI of 5-year overall survival (OS): 8.5-91.7%) was also significantly associated with longer 5-year PFS and 5-year OS (P = 0.008 for 5-year PFS, P = 0.023 for 5-year OS). More serious leucopenia (P = 0.021), neutropenia (P = 0.041), and allergy (P = 0.040) were observed in the SMILE group. Post-treatment Epstein-Barr virus (EBV)-DNA status (P = 0.001 for PFS, P = 0.018 for OS) was identified as a significant prognostic factor for PFS and OS in multivariate analysis. The present research suggested that compared with SMILE chemotherapy, DDGP chemotherapy can significantly improve the response and survival of relapsed/refractory ENKL with better tolerance. Post-treatment EBV-DNA status was identified as a significant prognostic factor for PFS and OS in relapsed/refractory ENKL., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Head and neck squamous cell carcinoma (HNSCC) is the one of the most frequently found cancers in the world. The aim of the study was to find the genes responsible and enriched pathways associated with HNSCC using bioinformatics and survival analysis methods. A total of 646 patients with HNSCC based on clinical information were considered for the study. HNSCC samples were grouped according to the parameters (RFS, DFS, PFS, or OS). The probe ID of these 11 genes was retrieved by Affymetrix using the NetAffx Query algorithm. The protein-protein interaction (PPI) network and Kaplan-Meier curve were used to find associations among the genes' expression data. We found that among these 11 genes, nine genes, CCNA1, MMP3, FLRT3, GJB6, ZFR2, PITX2, SYCP2, MEI1, and UGT8 were significant (p < .05). A survival plot was drawn between the p value and gene expression. This study helped us find the nine significant genes which play vital roles in HNSCC along with their key pathways and their interaction with other genes in the PPI network. Finally, we found the biomarker index for relapse time and risk factors for HNSCC in cancer patients., (© 2020 Wiley Periodicals LLC.)

Objective: To investigate the postoperative recurrence of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after liver resection in patients with and without the achievement of sustained virologic response (SVR) through the administration of direct-acting antivirals (DAA)., Methods: Among 28 patients with HCC detected after DAA-SVR (DAA group) and 197 patients with HCC who did not receive treatment for HCV infection or who did not achieve an SVR (control group) between January 2000 and July 2019, we performed propensity score matching (PSM) to avoid confounding differences between the two groups., Results: After PSM, 28 patients in each group were selected for analysis. The DAA-SVR patients showed improved liver function at operation and at recurrence in comparison to the control group. The disease-free survival rate at 3 years after surgery was 69% in the DAA group and 35% in the control group, respectively (P = .021). In the DAA group, all three patients with recurrence met the Milan criteria and could be managed by curative treatments and none died of liver failure during the follow-up period., Conclusions: SVR status suppresses postoperative recurrence of HCV-related HCC detected after DAA-SVR. Improved liver function may contribute to the successful treatment and prevention of liver failure., (© 2020 Wiley Periodicals LLC.)

Introduction: The objective of this study is to evaluate locoregional and distant failure for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) using American Joint Committee on Cancer eighth edition (AJCC 8) staging., Materials and Methods: Retrospective cohort study of 457 patients with HPV + OPSCC, treated with platinum-based chemoradiation from 2002 to 2018, followed for a median of 4.3 years. Time to locoregional failure (TTLRF) and distant failure (TTDF) were estimated by Kaplan-Meier method. Log-rank, recursive partitioning analysis (RPA), and multivariable Cox proportional hazards were used to evaluate associated factors and stratify risk., Results: Rates of five-year locoregional control (LRC) and distant control (DC) were 92% (95% CI, 90-95%) and 89% (95% CI, 85-92%), respectively. Smoking, T4, N3, and stage III were associated with significantly worse TTLRF. RPA identified three distinct locoregional failure groups: cT1-3 and <19 pack-years vs. cT1-3 with ≥19 pack-years vs. cT4 (five-year LRC: 97% vs. 90% vs. 82%, P < .0001). The only factor associated with significantly worse TTDF was smoking status, while stage was not correlated. RPA identified two prognostic groups: former or never smokers vs. current smokers (five-year DC: 92% vs. 77%, P = .0003)., Discussion: In the largest evaluation of HPV + OPSCC after platinum-based chemoradiation using AJCC 8, risk for locoregional recurrence was stratified by smoking, T category, N category, and overall stage. Risk of distant recurrence was only stratified by smoking status and not related to stage. This has implications for surveillance and clinical trial design., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Aims: Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to implement salvage therapies appropriately. This study examined the feasibility of virus-host chimera DNA (vh-DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting., Approach and Results: HBV integration in 50 patients with HBV-related HCC was determined by the Hybridization capture-based next-generation sequencing (NGS) platform. For individual HCC, the vh-DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV-related HCC. Tumor-specific ddPCR was developed to measure the corresponding vh-DNA copy number in baseline plasma from each patient immediately before surgery. vh-DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh-DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh-DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh-DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh-DNA, whereas 18.2% were from de novo HCC., Conclusions: vh-DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV-related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection., (© 2020 by the American Association for the Study of Liver Diseases.)

Objective: This study investigated survival among patients with oropharyngeal squamous cell carcinoma (OPSCC) after recurrence, persistence, and second primary malignancies (SPMs)., Study Design: Retrospective cohort study., Setting: Patients were treated at a tertiary cancer center., Subjects and Methods: Patients with OPSCC who had completed treatment between 2001 and 2017 were included. Survival estimates of 4 groups of patients were calculated: (1) patients who were disease free after initial treatment, (2) patients who had persistent disease, (3) those with recurrent disease, and (4) patients with SPMs. Cox proportional hazard models and parametric survival analyses (using Weibull distributions) were used to obtain hazard ratios (HRs) and time ratios (TRs)., Results: The cohort included 364 patients. The crude overall SPM prevalence was 8.2%. Mean overall survival (OS) time in years for patients who remained disease free after treatment was 4.02 years. Among patients who experienced recurrence, the recurrence-free survival (RFS) was 2.58 years while their mean (SD) OS was 3.67 (2.7) years. Participants who experienced persistence had a mean (SD) OS of 1.67 (1.68) years. Patients with observed SPMs had a mean (SD) OS of 6.39 (4.06) years since their primary cancer but shortened survivals of 1.75 (2.34) years since the secondary diagnosis. Differences were present even after accounting for human papillomavirus (HPV) and smoking status., Conclusions: Our findings stress the importance of active surveillance as per current National Comprehensive Cancer Network guidelines, irrespective of the HPV status or smoking status. Prospective studies with a larger number of SPM cases and longer follow-up are needed to validate survival trends even beyond 5 years.

In the current study, a 58-year-old male patient presented with recurrent glioblastoma multiforme (GBM). The patient underwent surgical resection, 4 months earlier, followed by radiotherapy and chemotherapy. During the second surgical intervention, tumour tissue and whole blood were sampled and analysed for human cytomegalovirus (HCMV) DNA, immediate early (IE) mRNA and pp65 mRNA. HCMV DNA was detected only in the recurrent tumour tissue but not in the whole blood. Neither IE mRNA nor pp65 mRNA was expressed. Our result suggests HCMV latency in the brain tumour with detectable level of viral DNA. More data are needed to understand the HCMV infection chronology in the brain tumours but our data could be important for further studies of HCMV antigens on the tumour surface and anti-GBM therapy.

Objective: The aim of study was to evaluate the association of endocervical gland involvement (EGI) on histological samples with high risk (HR) human papillomavirus (HPV) infection and with the persistence/recurrence rate of cervical intraepithelial neoplasia (CIN) after treatment., Methods: A total of 1301 subjects who had conization procedures after cervical punch biopsies (533 persistent CIN1, 768 CIN2+ including 20 microinvasive cervical cancer) were enrolled in the study. HPV genotypes were identified using the INNO-LiPA HPV genotyping assay on cervical scraping. Logistic regression and Cox regression analyses were used to evaluate the association of EGI on the persistence/recurrence rate of CIN after treatment., Results: The rate of EGI on final histology was 46.3% (602/1301). HPV 16 was the only HR-HPV significantly associated with increasing rates of EGI (231/602 as compared to 211/699, p = 0.002). EGI was also associated with an excess of multiple HR-HPV infections (237/602 as compared with 225/699, p = 0.006). After correction for confounders, the odds ratio of EGI among women infected by HPV 16 was 1.41 (95% CI = 1.12-178). CIN2+ lesions were diagnosed in 40.5% (283/699) of EGI negative subjects and 86.7% (522/602, p < 0.001 compared to negative subjects) of EGI positive subjects.After a median of 25 months of follow-up (IQR = 15-47) of 1090 treated women, the persistence of HPV 16 during follow-up was 38.1% (93/217, p = 0.03 compared to EGI negative) among EGI positive and 32% (58/181) among controls. After corrections for potential confounders, the odds ratio of CIN2+ persistence and or recurrence was higher among EGI positive (OR = 2.35, 95% CI = 1.16-4.77) than negative controls., Conclusion: EGI on histological samples is associated with increased rates of HPV 16, multiple high risk-HPV infections and CIN2+ lesions. EGI positive subjects also had an increased CIN recurrence/persistence after treatment compared to controls., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Conization aims to remove pre-neoplastic lesions of the uterine cervix. Several techniques for conization have been compared, but evidence regarding the most effective therapeutic option is scant. Here, we aimed to compare the recurrence rate following laser conization and loop electrosurgical excision procedure (LEEP) in patients with high-grade cervical dysplasia (HSIL/CIN2+)., Methods: This is a retrospective multi-institutional study. Medical records of consecutive patients with HSIL/CIN2+ undergoing conization between 2010 and 2014 were retrieved. A propensity-score matching (PSM) was applied in order to reduce allocation bias. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models., Results: Overall, 2966 patients had conization over the study period, including 567 (20%) and 2399 (80%) patients having laser conization and LEEP, respectively. Looking at predictors of recurrence, diagnosis of CIN3 (HR:3.80 (95%CI:2.01,7.21); p < 0.001) and HPV persistence (HR:1.81 (95%CI:1.11,2.96); p < 0.001) correlated with an increased risk of recurrence. After applying a PSM we selected 500 patients undergoing laser conization and 1000 undergoing LEEP. Patients undergoing LEEP were at higher risk of having positive surgical margins in comparison to patients undergoing laser conization (11.2% vs. 4.2%). The risk of having persistence of HPV was similar between the two groups (15.0% vs. 11.6%;p = 0.256). Five-year recurrence rate was 8.1% and 4% after LEEP and laser conization, respectively (p = 0.023). HPV persistence was the only factor associated with [5-]year recurrence after both laser conization (p = 0.003) and LEEP (p = 0.001)., Conclusions: HPV persistence is the only factor associated with an increased risk of recurrence after either laser conization or LEEP. Owing to the lack of data regarding obstetrical outcomes, we are not able to assess the best therapeutic option for women with cervical dysplasia., (Copyright © 2020. Published by Elsevier Inc.)

Objective: There is great need for better risk stratification in vulvar squamous cell carcinoma (VSCC). Our aim was to define the prognostic significance of stratifying VSCC based on p16 and p53 immunohistochemistry (IHC) as surrogate markers for HPV and TP53 mutations., Methods: A large retrospective cohort of surgically treated women with primary VSCC was used. VSCC were classified into three subtypes: HPV-positive (HPVpos), HPV-negative/p53 mutant (HPVneg/p53mut), and HPV-negative/p53 wildtype (HPVneg/p53wt). Overall survival (OS), relative survival (RS), and recurrence-free period (RFP) were depicted using the Kaplan-Meier method and survival curves for relative survival; associations were studied using univariable and multivariable Cox proportional hazard models., Results: Of the 413 VSCCs, 75 (18%) were HPVpos, 63 (15%) HPVneg/p53wt, and 275 (66%) HPVneg/p53mut VSCC. Patients with HPVneg/p53mut VSCC had worse OS and RS (HR 3.43, 95%CI 1.80-6.53, and relative excess risk (RER) of 4.02; 95%CI 1.48-10.90, respectively, and worse RFP (HR 3.76, 95%CI 2.02-7.00). HPVpos VSCC patients showed most favorable outcomes. In univariate analysis, the molecular subtype of VSCC was a prognostic marker for OS, RS and RFP (p = 0.003, p = 0.009, p < 0.001, respectively) and remained prognostic for RFP even after adjusting for known risk factors (p = 0.0002)., Conclusions: Stratification of VSCC by p16- and p53-IHC has potential to be used routinely in diagnostic pathology. It results in the identification of three clinically distinct subtypes and may be used to guide treatment and follow-up, and in stratifying patients in future clinical trials., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Inflammation plays an important role in the progression and prognosis of hepatocellular carcinoma (HCC). Our aim is to explore the prognostic value of preoperative and postoperative peripheral lymphocyte differences and to develop a dynamic prognosis nomogram in hepatitis B virus-related HCC patients., Methods: Important indicators related to overall survival (OS) are screened out by Cox proportional hazard models. The receiver operating characteristic curves, decision curve analysis curves, net reclassification improvement, and integrated discrimination improvement were used to evaluate the performance of the model., Results: Lymphocyte (L) difference was an independent risk factor. It was further verified that the performance of the nomogram was significantly improved after the L difference was incorporated into the nomogram. The nomogram generated had the area under curves of 0.779, 0.775, and 0.793 at 3, 5, and 7 years after surgery, respectively. Our nomogram models showed significantly better performance in predicting the HCC prognosis compared to other models. And online webserver and scoring system table was built based on the proposed nomogram for convenient clinical use., Conclusions: It is newly found that L difference is an effective predictor of OS, and the nomogram based on this indicator can accurately predict the prognosis of HCC patients., (© 2020 Wiley Periodicals LLC.)

Acquisition of recurrent/metastatic potential by a tumor cell defines a critical step in malignant progression. However, understanding of metastatic progression at the molecular level is scarce for cervical carcinomas (CES). In this study, we performed genomic, transcriptomic, and viral profiling of five pairs of primary (CES-P) and matched recurrent/metastatic tumors (CES-R/M) with high risk human papillomavirus. Whole exome sequencing revealed mutation features of CES-R/M including elevated mutation burdens and prevalent copy number alterations compared to their matched CES-P. A relative deficit of APOBEC-related mutation signatures accompanying the transcriptional downregulation of APOBEC3A was observed for CES-R/M. Mutations in genes encoding epigenetic regulators were commonly observed as CES-R/M-specific alterations. Immunoprofiling and gene set analysis revealed CES-Ps were enriched with transcripts representing activated anticancer immunity such as interferon-gamma pathway, while CES-R/M exhibited upregulation of genes involved in epithelial-mesenchymal transition and angiogenesis. Viral capture sequencing revealed that integration sites remained enriched in viral E1 protein domain during malignant progression. Moreover, we found transcriptional upregulation of POSTN and downregulation of APOBEC3A were associated with unfavorable clinical outcomes in CES. Comprehensive genomic and transcriptomic profiling of a rare cohort including CES-R/M identified metastases-specific features to advance the molecular understanding into CES metastatic progression with potential clinical implications., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: There is a shortage of radiation therapy service centers in low- to middle-income countries. TARGIT-intraoperative radiation therapy (IORT) may offer a viable alternative to improve radiation treatment efficiency and alleviate hospital patient loads. The Breast Care Unit in Johannesburg became the first facility in Africa to offer TARGIT-IORT, and the purpose of this study was to present a retrospective review of patients receiving IORT at this center between November 2017 and May 2020., Patients and Methods: Patient selection criteria were based mainly on the latest American Society of Radiation Oncology guidelines. Selection criteria included early-stage breast carcinoma (luminal A) and luminal B with negative upfront sentinel lymph node biopsy that negated external-beam radiation therapy (EBRT). Patient characteristics, reasons for choosing IORT, histology, and use of oncoplastic surgery that resulted in complications were recorded., Results: One hundred seven patients successfully received IORT/TARGIT-IORT. Mean age was 60.8 years (standard deviation, 9.3 years). A total of 73.8% of patients presented with luminal A, 15.0% with luminal B, and 5.6% with triple-negative cancer. One patient who presented with locally advanced breast cancer (T4N2) opted for IORT as a boost in addition to planned EBRT. Eighty-seven patients underwent wide local excision (WLE) with mastopexy, and 12 underwent WLE with parenchymal. Primary reasons for selecting IORT/TARGIT-IORT were distance from the hospital (43.9%), choice (40.2%), and age (10.3%)., Conclusion: This retrospective study of IORT/TARGIT-IORT performed in Africa confirms its viability, with low complication rates and no detrimental effects with breast conservation, resulting in positive acceptance and the potential to reduce Oncology Center patient loads. Limitations of the study include the fact that only short-term data on local recurrence were available. Health and socioeconomic value models must still be addressed in the African setting.

Severe coronavirus disease 2019 (COVID-19) causes a hyperactivation of immune cells, resulting in lung inflammation. Recent studies showed that COVID-19 induces the production of factors previously implicated in the reawakening of dormant breast cancer cells such as neutrophil extracellular traps (NETs). The presence of NETs and of a pro-inflammatory microenvironment may therefore promote breast cancer reactivation, increasing the risk of pulmonary metastasis. Further studies will be required to confirm the link between COVID-19 and cancer recurrence. However, an increased awareness on the potential risks for breast cancer patients with COVID-19 may lead to improved treatment strategies to prevent metastatic relapse.