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Specific human papillomavirus genotypes are associated with most ano‐genital carcinomas and a large subset of oro‐pharyngeal carcinomas. Human papillomavirus DNA is thus a tumour marker that can be detected in the blood of patients for clinical monitoring. However, data concerning circulating human papillomavirus DNA in cervical cancer patients has provided little clinical value, due to insufficient sensitivity of the assays used for the detection of small sized tumours. Here we took advantage of the sensitive droplet digital PCR method to identify circulating human papillomavirus DNA in patients with human papillomavirus‐associated carcinomas. A series of 70 serum specimens, taken at the time of diagnosis, between 2002 and 2013, were retrospectively analyzed in patients with human papillomavirus‐16 or human papillomavirus‐18‐associated carcinomas, composed of 47 cases from the uterine cervix, 15 from the anal canal and 8 from the oro‐pharynx. As negative controls, 18 serum samples from women with human papillomavirus‐16‐associated high‐grade cervical intraepithelial neoplasia were also analyzed. Serum samples were stored at −80°C (27 cases) or at −20°C (43 cases). DNA was isolated from 200 µl of serum or plasma and droplet digital PCR was performed using human papillomavirus‐16 E7 and human papillomavirus‐18 E7 specific primers. Circulating human papillomavirus DNA was detected in 61/70 (87%) serum samples from patients with carcinoma and in no serum from patients with cervical intraepithelial neoplasia. The positivity rate increased to 93% when using only serum stored at −80°C. Importantly, the two patients with microinvasive carcinomas in this series were positive. Quantitative evaluation showed that circulating viral DNA levels in cervical cancer patients were related to the clinical stage and tumour size, ranging from 55 ± 85 copies/ml (stage I) to 1774 ± 3676 copies/ml (stage IV). Circulating human papillomavirus DNA is present in patients with human papillomavirus‐associated invasive cancers even at sub‐clinical stages and its level is related to tumour dynamics. Droplet digital PCR is a promising method for circulating human papillomavirus DNA detection and quantification. No positivity was found in patients with human papillomavirus‐associated high grade cervical intraepithelial neoplasia.

Background Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients. Methods Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy. Discussion Although the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA. Trial registration NCT03519295 .

Abstract Background This study described the clinical characteristics, outcomes, and prognosis of Crohn’s disease (CD) patients with anal cancer in a tertiary referral center. Methods The electronic medical records of 35 adult CD patients, including CD of the pouch, with anal carcinoma evaluated at Mayo Clinic Rochester, Florida, or Arizona between January 1989 and August 2022 were retrospectively reviewed. Results Before cancer diagnosis, patients with pouch-related carcinoma had a shorter median duration of inflammatory bowel disease than those with anal carcinoma (10 vs 26 years). Twenty-six patients (74%) had perianal diseases or rectovaginal fistula, and 35% had a history of human papillomavirus infection. Twenty-one patients (60%) were diagnosed with cancer by anal examination under anesthesia (EUA). More than half of adenocarcinomas were mucinous. Sixteen patients (47%) were American Joint Committee on Cancer (AJCC) Tumor Nodes Metastasis (TNM) stage 3, and 83% were treated by surgery. At last follow-up, 57% of patients were alive without cancer. The 1-, 3- and 5-year overall survival rates were 93.8% (95% confidence interval [CI], 85.7%-100%), 71.5% (95% CI, 56.4%-90.7%), and 67.7% (95% CI, 51.2%-87.7%), respectively. Advanced AJCC TNM stage (hazard ratio, 3.20 per stage; 95% CI, 1.05-9.72; P = .040) was significantly associated with increased risk of death, whereas the period of cancer diagnosis in 2011-2022 (HR, relative to 1989-2000, 0.16; 95% CI, 0.04-0.72; P = .017) was significantly related to decreased risk of death. Conclusions Anal and pouch-related carcinomas were rare complications of CD, and long-standing perianal diseases were an important risk factor. Anal EUA improved the diagnostic yield. Newer cancer treatment strategies and surgery were associated with excellent survival outcome. Lay Summary This study described the uncommon Crohn’s disease (CD) complications of squamous cell carcinoma and adenocarcinoma of the anus and was characterized pouch-related carcinoma in patients with CD of the ileal pouch-anal anastomosis (IPAA). The 5-year overall survival rate was 68%.

The purpose of the present trial was to determine the feasibility of the daily topical application of the piperidine nitroxide, MTS-01, combined with chemoradiotherapy in the treatment of patients with anal carcinoma. The secondary study endpoints were the description of the effects of this agent on skin toxicity and rectal-associated lymphoid tissue. The participants received radiotherapy concurrent with mitomycin-C and 5-fluorouracil for carcinoma of the anal canal. MTS-01 was applied to the bilateral inguinal area and the gluteal cleft. Dermatologic and non-dermatologic toxicity was graded throughout the treatment period. Circulating lymphocytes were serially collected for phenotyping. Rectal mucosal snag biopsies were collected at baseline and at 1 year of follow-up. A total of 5 patients received topical MTS-01. Adverse events attributed to MTS-01 included asymptomatic grade 1 hypoglycemia and grade 1-2 diarrhea. Dermatitis within untreated, radiated skin was not more severe than dermatitis in MTS-01-treated, unirradiated skin. Circulating CD4+ lymphocyte suppression was noted at >1 year following treatment in human immunodeficiency virus-negative participants. CD4+ lymphocytes remained suppressed in the irradiated rectal mucosa at 1 year, whereas the CD8+ lymphocyte numbers recovered or increased. On the whole, the present study demonstrates that the MTS-01 topical application was tolerable with minimal toxicity. Chemoradiation for anal cancer led to prolonged CD4+ lymphocytopenia in the circulation and gut mucosa.

This study aimed to investigate sex differences in anal squamous cell carcinomas (ASCC), with a particular focus on the prognostic significance of the American Joint Committee on Cancer (AJCC) 9th edition staging system for oncological outcome. A retrospective analysis was conducted in 188 patients with histologically confirmed ASCC who underwent definitive (chemo)radiotherapy between 2004 and 2020. Patient- and tumor-related data were collected. Tumor stage groups were classified according to the AJCC 9th edition. Overall survival (OS), disease-free survival (DFS), freedom from recurrence (FFR), and colostomy-free survival (CFS) were analyzed using the Kaplan-Meier method for univariate testing and Cox regression models for multivariate analysis. Differences between sexes were assessed. The cohort included 134 females and 54 males, with a median follow-up of 83 months. Females exhibited significantly better OS (p = 0.01), DFS (p = 0.01), and CFS (p = 0.03). For male patients, there was a clear trend towards better OS (p = 0.08), DFS (p = 0.10), and FFR (p = 0.09) in earlier tumors as well as significantly better CFS (p = 0.04). In contrast, in the female subgroup, there were no significant differences in OS (p = 0.64), DFS (p = 0.52), and CFS (p = 0.25) with respect to tumor stage. In multivariate analysis, male sex, older age, and advanced tumor stages were significant risk factors for poorer OS, DFS, and CFS. This study highlights significant sex differences in ASCC prognoses, with females showing better survival outcomes. The prognostic value of the AJCC 9th edition staging system differs between sexes; thus, we support the inclusion of sex as a prognostic factor in staging systems.

Background Using dose-painted intensity-modulated radiation therapy, specific dose volume constraints or implantation of tissue expanders prior to radiotherapy are validated options for reducing radiation dose on the bowel and therefore minimizing acute gastrointestinal toxicity during chemoradiation for anorectal malignancies. We describe the rare case of a female patient with a locally advanced anal carcinoma where a large myomatous uterus served as a natural spacer to protect the bowel during radiation therapy. Case presentation Initially the patient presented with anal pain, proctoscopy followed by an excisional biopsy confirmed the diagnosis of a squamous cell carcinoma of the anus. Imaging examination showed a locally advanced tumor and in addition a large uterus with typical leiomyomas up to 11.5 cm in diameter. The patient underwent chemoradiation; because of the large leiomyomas there was almost no dose burden for the small intestine and therefore practically no gastrointestinal toxicity. Conclusion As we know, this report describes the situation that a large myomatous uterus served as a natural spacer during radiation therapy in a way that is unique to date.

Atopic dermatitis (AD) affects up to 25% of children and 10% of adults in Western countries. When severe or recurrent infections and exceedingly elevated serum IgE levels occur in AD patients, an inborn error of immunity (IEI) may be suspected. The International Union of Immunological Societies classification lists variants in different genes responsible for so-called Hyper-IgE syndromes. Diagnosing an underlying IEI may influence treatment strategies. Clinical and diagnostic workup of family members are presented including a detailed immunological description and histology of the carcinoma. Functional testing of the novel variant in underlying 'CARD11-associated atopy with dominant interference of NF-kB signaling' (CADINS) was performed. We report on an 18-year-old patient with a long-standing history of infections, accompanied by hypogammaglobulinemia, intermittent agranulocytosis, atopy, eosinophilia and colitis. The working diagnosis of common variable immunodeficiency was revised when a novel heterozygous variant [c.223C>T; p.(Arg75Trp)] was identified. Functional studies confirmed this variant to have a dominant negative (DN) effect, as previously described in patients with CADINS. Five other family members were affected by severe atopy associated with the above variant, but not hypogammaglobulinemia. Malignancies occurred in two generations: an HPV-positive squamous cell carcinoma and a cutaneous T-cell lymphoma. So far, one patient is under treatment with dupilumab, which has shown marked benefit in controlling severe eczema. The phenotypic spectrum associated with heterozygous DN mutations is broad. Partial T-cell deficiency, diminished IFN-γ cytokine and increased IL-4 production, were identified as disease-causing mechanisms. Malignant disease associated with germline DN variants has only been reported sporadically. HPV vaccination in teenage years, and cytology screening analogous with routine cervical swabs may be recommended. Treatment with dupilumab, a monoclonal antibody blocking interleukin-4- and interleukin-13 signaling, may be of benefit in controlling severe and extended AD for some patients as reported for STAT3 loss-of-function.

Background The squamous cell carcinoma of the anus (SCCA) is a rare disease, but its incidence is markedly increasing. About 15% of patients are diagnosed at metastatic stage, and more than 20% with a localized disease treated by chemoradiotherapy (CRT) will recur. In advanced SCCA, cisplatin and 5-fluorouracil (CF) combination is the standard option but complete response is a rare event and the prognosis remains poor with most disease progression occurring within the first 12 months. We have previously published the potential role of the addition of docetaxel (D). Among 8 consecutive patients with advanced recurrent SCCA after CRT, the DCF regimen induced a complete response in 4 patients, including 3 pathological complete responses. Then, the Epitopes-HPV02 study was designed to confirm the interest of DCF regimen in SCCA patients. Methods This multicentre phase II trial assesses the DCF regimen in advanced SCCA patients. Main eligibility criteria are: histologically proven SCCA, unresectable locally advanced recurrent or metastatic disease, Eastern Cooperative Oncology Group-performance status (ECOG-PS) <2, and being eligible for DCF. Patients receive either 6 cycles of standard DCF or 8 cycles of modified DCF depending on age (> vs. ≤ 75 years-old) and ECOG-PS (0 vs. 1). The trial was set up based on a Simon’s optimal two-stage design for phase II trials, allowing an early futility interim analysis. The primary endpoint is the observed progression-free survival (PFS) rate at 12 months from the first DCF cycle. A PFS rate below 10% is considered uninteresting, while a PFS rate above 25% is expected. With a unilateral alpha error of 5% and a statistical power of 90%, 66 evaluable patients should be included. Main secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and the correlation of biomarkers with treatment efficacy. Discussion Since the recommended CF regimen is based in a small retrospective analysis and generates a low rate of complete responses, the Epitopes-HPV02 study will establish a new standard in case of a positive result. Associated biomarker studies will contribute to understand the underlying mechanism of resistance and the role of immunity in SCCA. Trial registration NCT02402842 , EudraCT: 2014–001789-81.

Pivotal studies with curative chemoradiation (CRT) in anal cancer did not include HIV-positive (HIV+) patients. HIV status impact remains unknown in this scenario. In this retrospective matched cohort study, electronic medical records were reviewed at Sao Paulo State Cancer Institute between 2010 and 2021 patients with anal cancer T1-4 N0-1 M0 by AJCCVIII were selected. For each HIV+ patient, one or two HIV-negative (HIV-) cases were matched by age, stage (T, N) and ECOG. The primary endpoint was OS, estimated using Kaplan-Meir and compared with the log-rank test. 122 patients were selected, 45 being HIV+. The median follow-up was 37 months. Most patients, = 119 (98%), received concomitant CRT and had ECOG 0/1 ( = 116, 95%). Stage III corresponded to 69% of the patients ( = 85). Positive nodes were detected in 76 patients (62%). No difference was observed in complete clinical response (cCR) post-CRT (68% in HIV+ versus 63% in HIV-; = 0.6). Median recurrence-free survival (RFS) was not reached; 3-year RFS rates were 60.7% in HIV+ versus 63.1% in HIV- [hazard ratio (HR) 1.20, 95% CI 0.66-2.17, = 0.538]. Median OS was not reached; 3-year OS was 66.4% HIV+ versus 72.2% in HIV- (HR 1.23, 95% CI 0.61-2.47, = 0.546). HIV+ pts presented significantly more hospital admissions due to toxicity, 30% ( = 12/40) versus 13% ( = 10/74) ( = 0.049). No difference between groups was found for colostomy ( = 0.69) and salvage surgery ( = 1). Anal carcinoma HIV+ patients treated with CRT presented similar cCR, RFS and OS compared with HIV- patients. Optimal therapy should be attempted in the HIV+ population; however, close clinical monitoring due to higher hospital admission is required.