Paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the Prospective Rosacea Refractory Erythema Randomized Clinical Trial.

BACKGROUND: Patients with refractory erythema of rosacea have limited treatment options. OBJECTIVE: To evaluate the efficacy and safety of a 12-week course of paroxetine for moderate-to-severe erythema of rosacea. METHODS: In a multicenter, randomized, double-blinded, placebo-controlled trial, patients with refractory erythema of rosacea were randomly assigned (1:1) to receive paroxetine 25 mg daily or placebo for 12 weeks. RESULTS: Overall, 97 patients completed the study (paroxetine: 49; placebo: 48). The primary end point was the proportion of participants achieving Clinical Erythema Assessment success (defined as Clinical Erythema Assessment score of 0, 1, or ≥2-grade improvement from baseline) at week 12; this was significantly greater in the paroxetine group than in the placebo group (42.9% vs 20.8%, P = .02). Some secondary end points were met, such as flushing success with point reductions ≥2 (44.9% vs 25.0%, P = .04) and improvement in overall flushing (2.49 ± 3.03 vs 1.68 ± 2.27, P = .047), burning sensation (46.9% vs 18.8%, P = .003), and depression (P = .041). The most reported adverse events associated with paroxetine were dizziness, lethargy, nausea, dyspepsia, and muscle tremors. LIMITATIONS: Only a single-dosage regimen of paroxetine within a 12-week study was evaluated. CONCLUSIONS: Paroxetine is an effective and well-tolerated alternative treatment for moderate-to-severe erythema of rosacea.

Wider indications and more efficient drug delivery: A bibliometric analysis and visualization of photodynamic therapy in skin cancer.

BACKGROUND: Photodynamic therapy (PDT) has been widely accepted in keratocyte carcinoma and an increasing number of literatures concerning PDT in skin cancer is published. But a detailed examination of publication patterns of PDT in skin cancer has not yet been carried out. METHODS: Bibliographies were retrieved from Web of Science Core Collection restricted the publication date from January 1, 1985 to December 31, 2021. The search terms were photodynamic therapy and skin cancer. Visualization analysis and statistical analysis were performed by VOSviewer (Version 1.6.13), R software (Version 4.1.2) and Scimago Graphica (Version 1.0.15). RESULTS: 3248 documents were selected for analysis. The results showed that the number of annual publications related to PDT in skin cancer was gradually increased and would continue to increase in the future. The results illustrated that "melanoma", "nanoparticles", "drug-delivery", "mechanism", "delivery" and "in-vitro" are newly occurred topics. The most prolific country was the United States and the most productive institution was the University of Sao Paulo in Brazil. German researcher Szeimies RM published the most papers related to PDT in skin cancer. British Journal of Dermatology was the most popular journal in this field. CONCLUSION: The topic that PDT in skin cancer is a heated issue. Our study revealed the bibliometric result of the field, which might provide the prospects for further research. We recommend future investigations focusing on PDT in treating melanoma, innovation of photosensitizer, improvement of drug delivery and the mechanism of PDT in skin cancer.

NPAS4 Exacerbates Pyroptosis via Transcriptionally Regulating NLRP6 in the Acute Phase of Intracerebral Hemorrhage in Mice.

Intracerebral hemorrhage (ICH) is a severe cerebrovascular disease with a high disability rate and high mortality, and pyroptosis is a type of programmed cell death in the acute phase of ICH. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is a specific transcription factor highly expressed in the nervous system, yet the role of NPAS4 in ICH-induced pyroptosis is not fully understood. NLR family Pyrin-domain-containing 6 (NLRP6), a new member of the Nod-like receptor family, aggravates pyroptosis via activating cysteine protease-1 (Caspase-1) and Caspase-11. In this study, we found that NPAS4 was upregulated in human and mouse peri-hematoma brain tissues and peaked at approximately 24 h after ICH modeling. Additionally, NPAS4 knockdown improved neurologic dysfunction and brain damage induced by ICH in mice after 24 h. Meanwhile, inhibiting NPAS4 expression reduced the levels of myeloperoxidase (MPO)-positive cells and Caspase-1/TUNEL-double-positive cells and decreased cleaved Caspase-1, cleaved Caspase-11, and N-terminal GSDMD levels. Consistently, NPAS4 overexpression reversed the above alternations after ICH in the mice. Moreover, NPAS4 could interact with the Nlrp6 promoter region (-400--391 bp and -33--24 bp) and activate the transcription of Nlrp6. Altogether, our study demonstrated that NPAS4, as a transcription factor, can exacerbate pyroptosis and transcriptionally activate NLRP6 in the acute phase of intracerebral hemorrhage in mice.

Next generation sequencing targeted detection of somatic mutations in patients with mucinous adenocarcinoma of the appendix.

The aim of this study was to investigate the mutations in mucinous adenocarcinoma of the appendix (MAA). SNV was detected in 15 patients with MAA, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and reactome pathway analyses were performed. Tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), microsatellite instability (MSI) was analysis. Finally, the human leukocyte antigen (HLA) typing of the samples was detected. The results showed that TP53 (27 %) and KRAS (20 %) were the highest mutation frequency in the sample, mainly occur in p53 pathway and RTK-RAS pathway. GO analysis reveals mutated genes are closely related to the regulation of GTPase activity, regulation of small GTPase mediated signal transduction and other BP, related to the CC and MF. Analysis of KEGG pathways indicated that the top canonical pathways associated with SNV was Wnt signaling pathway. Reactome pathway analysis further revealed that the mutant genes were closely related to muscle contraction. Only one patient had moderate TMB level and one patient with high MSI. In conclusion, the most common mutated genes and the signaling pathways closely related to MAA development were detected in this study, which will contribute to the development of immunotherapy for patients with MAA.

Impact of preoperative transcatheter rectal arterial chemoembolization with concurrent chemoradiotherapy on surgery and prognosis of patients with locally advanced rectal cancer.

BACKGROUND AND OBJECTIVES: To analyze and evaluate the impact of preoperative transcatheter rectal arterial chemoembolization (TRACE) with concurrent chemoradiotherapy on surgery and prognosis of locally advanced rectal cancer (LARC). METHODS: A total of 118 patients with LARC were enrolled in this nonrandomized prospective study. They were assigned into the experimental group receiving preoperative TRACE with concurrent chemoradiotherapy (TRACE-CRT group, N = 60) and the control group receiving only neoadjuvant chemoradiotherapy (CRT group, N = 58). All patients underwent surgery after their preoperative treatments. RESULTS: All patients successfully completed the surgical operation. No significant differences were found in sphincter preservation rate and R0 resection rate between TRACE-CRT group and CRT group (p > 0.05). No significant differences were found between the two groups in terms of the perioperative indicators and postoperative complications except mean operation time (165.8 vs. 196.6 min, p < 0.001). Local recurrence occurred in 8 and 5 patients, respectively (p > 0.05). Distant metastasis occurred in 5 and 11 patients, respectively (p < 0.05). CONCLUSIONS: Adding TRACE in the preoperative standard treatment for LARC did not increase perioperative complications. In addition, it has the potential advantage of preventing distant metastasis. It is worthy of further application and promotion in clinical practice.

Relationship Between Tea Drinking Behaviour and Rosacea: A Clinical Case-control Study.

The exact mechanisms of rosacea development are unknown, but it has been suggested that tea consumption may be associated with its development. To determine the relationship between tea drinking behaviour and rosacea, this clinical case-control study recruited 2,063 participants, who completed a questionnaire about tea drinking behaviour. A 1:1 ratio propensity score matching method was used to generate 619 cases and 619 controls. High-frequency tea drinking (3 times/day: adjusted odds ratio (aOR) 2.592; 95% confidence interval (95% CI) 1.225-5.485; ≥ 4 times/day; aOR 8.86; 95% CI 3.43-22.887), non-fermented tea (aOR 2.172; 95% CI 1.562-3.022), and hot tea (aOR 2.793; 95% CI 1.796-1.344) were associated with an increased risk of rosacea. Further results showed that these tea drinking behaviours were significantly associated with an increased risk of flushing (aOR 1.41; 95% CI 1.07-1.87) and erythema (aOR 1.48; 95% CI 1.10-2.00). Tea drinking behaviour is closely related to rosacea and.

Comparison of Fractional Micro-Plasma Radiofrequency and Fractional Microneedle Radiofrequency for the Treatment of Atrophic Acne Scars: A Pilot Randomized Split-Face Clinical Study in China.

BACKGROUND AND OBJECTIVE: Both fractional micro-plasma radiofrequency (RF) and fractional microneedle RF are novel devices that can be applied for the treatment of atrophic acne scars, and they have both been proved to be effective. To compare the clinical effectiveness and adverse reactions of fractional micro-plasma RF and fractional microneedle RF for the therapy of facial atrophic acne scars in a randomized split-face study. STUDY DESIGN/MATERIALS AND METHODS: Sixty patients with facial atrophic acne scars received three applications at 2-month intervals in a randomized split-face study using fractional micro-plasma RF and fractional microneedle RF on different sides of the face. Three independent dermatologists evaluated the improvement in acne scars using the ECCA grading scale (Echelle d'Evaluation Clinique des Cicatrices d'Acné) by comparing the digital images and graded the improvement in the acne scars. Patients were asked to provide a self-evaluation of satisfaction for efficacy and safety. Adverse effects were also recorded after each treatment. RESULTS: In total sixty patients completed the entire study. A significant improvement was observed in the appearance of acne scars, and the mean ECCA scores improved significantly after both modalities. The mean decrease in ECCA scores from the baseline was significantly more pronounced in fractional micro-plasma RF as compared with fractional microneedle RF (41.33 ± 20.19 vs 32.17 ± 17.35; P < 0.05). The degree of clinical improvement was also significantly better for fractional micro-plasma RF. Pain, erythema, and swelling were observed in all patients after both treatments. The pain was more intense during micro-plasma RF treatment (P = 0.000), and the duration of pain and erythema were longer than with fractional microneedle RF (P = 0.000). Postinflammatory hyperpigmentation (PIH) was observed in one patient on the fractional micro-plasma RF side while no PIH was observed on the fractional microneedle RF side. No infections or worsening of scarring was observed with either treatment. No subject was dissatisfied with the efficacy of either device. Rolling scars tended to respond better to fractional micro-plasma RF treatment compared with fractional microneedle RF (P = 0.000). CONCLUSIONS: Both fractional micro-plasma RF and fractional microneedle RF are effective and safe methods for improving atrophic acne scars. Fractional micro-plasma RF is significantly more effective for atrophic acne scars, especially for rolling scars. However, fractional microneedle RF has fewer side effects plus shorter downtime, and patients are more comfortable after the treatment. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Efficacy of non-ablative fractional 1440-nm laser therapy for treatment of facial acne scars in patients with rosacea: a prospective, interventional study.

Acne scarring is one of the most common facial skin disorders. The appropriate treatments for acne scars in patients with rosacea have not been studied. This study was designed to evaluate the efficacy and safety of non-ablative fractional 1440-nm laser (1440-nm NAFL) therapy for treatment of atrophic acne scars in patients with rosacea. In this prospective, interventional study, 32 patients with rosacea and acne scars underwent three sessions of 1440-nm NAFL therapy. Therapy efficacy, epidermal barrier function, and side effects were evaluated. Thirty patients completed and the median acne scar scores significantly reduced from 45 (30, 50) to 15 (15, 30) after three treatments (P < 0.001). The improvement score of acne scars was 2.7 ± 0.7; 22 (73.3%) were satisfied or highly satisfied. The rosacea erythema scores changed from 2.1 ± 0.4 to 1.9 ± 0.5 (P = 0.326), and flushing, burning, and stinging were not worse. The oil content after treatments was significantly reduced (P < 0.001), while there was no significant difference in other indicators of skin barrier function. The quality-of-life score decreased from 17.5 ± 3.8 to 14.1 ± 3.0 (P < 0.001). No serious side effects were observed. The 1440-nm NAFL therapy is effective in the treatment of acne scaring in patients with rosacea with little damage to the skin barrier.

A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-A possible reference for coronavirus disease-19 treatment option.

In the past few decades, coronaviruses have risen as a global threat to public health. Currently, the outbreak of coronavirus disease-19 (COVID-19) from Wuhan caused a worldwide panic. There are no specific antiviral therapies for COVID-19. However, there are agents that were used during the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) epidemics. We could learn from SARS and MERS. Lopinavir (LPV) is an effective agent that inhibits the protease activity of coronavirus. In this review, we discuss the literature on the efficacy of LPV in vitro and in vivo, especially in patients with SARS and MERS, so that we might clarify the potential for the use of LPV in patients with COVID-19.

Multi-Factors Associated With Efficacy and Adverse Events of Fractional Erbium:YAG Laser-Assisted Delivery of Topical Betamethasone for Stable Vitiligo: A Retrospective Analysis.

BACKGROUND AND OBJECTIVES: Although topical corticosteroids are still the first-line option for vitiligo, its efficacy is still unsatisfactory for stable vitiligo. A few studies have focused on laser-assisted drug delivery (LADD) but were limited by their sample deficiency and analyses of the influencing factors. To determine the efficacy, adverse events, and their influencing factors of fractional erbium: yttrium-aluminum-garnet (Er:YAG) laser-assisted topical delivery of corticosteroids in stable vitiligo. STUDY DESIGN/MATERIALS AND METHODS: We retrospectively reviewed 1,026 lesions in 684 patients with stable vitiligo who underwent treatment with fractional Er:YAG laser-assisted delivery of topical compound betamethasone solution between January 2014 and December 2017. Multi-factors associated with different outcomes were analyzed by logistic regression in this study. RESULTS: A total of 413 of 1,026 lesions (40.3%) were effective 12 months after the first treatment. Age (<14 years old), disease duration (<1 year), lesion location (on face and neck), hairy lesions, and drug concentration were independent factors associated with effective repigmentation. A common adverse event was hyperpigmentation (14.4%), which was highly correlated with 22% density. CONCLUSIONS: Fractional Er:YAG laser-assisted delivery of topical compound betamethasone is a good option for the management of vitiligo. The treatment may be suggested in these situations: younger patients, shorter disease duration, and lesions on the face and neck with hair. The appearance of white hair in the lesion area does not affect our confidence in vitiligo treatment. Density >22% may cause hyperpigmentation, but it does not significantly contribute to the efficacy. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Mechanisms of Wheat Allergenicity in Mice: Comparison of Adjuvant-Free vs. Alum-Adjuvant Models.

Wheat protein is considered a major type of food allergen in many countries including the USA. The mechanisms of allergenicity of wheat proteins are not well understood at present. Both adjuvant-based and adjuvant-free mouse models are reported for this food allergy. However, it is unclear whether the mechanisms underlying wheat allergenicity in these two types of models are similar or different. Therefore, we compared the molecular mechanisms in a novel adjuvant-free (AF) model vs. a conventional alum-adjuvant (AA) model of wheat allergy using salt-soluble wheat protein (SSWP). In the AF model, Balb/cJ mice were sensitized with SSWP via skin exposure. In the AA model, mice were sensitized by an intraperitoneal injection of SSWP with alum. In both models, allergic reactions were elicited using an identical protocol. Robust IgE as well as mucosal mast cell protein-1 responses were elicited similarly in both models. However, an analysis of the spleen immune markers identified strikingly different molecular activation patterns in these two models. Furthermore, a number of immune markers associated with intrinsic allergenicity were also identified in both models. Since the AF model uses skin exposure without an adjuvant, the mechanisms in the AF model may more closely simulate the human wheat allergenicity mechanisms from skin exposure in occupational settings such as in the baking industry.

Formulation, characterization and clinical evaluation of propranolol hydrochloride gel for transdermal treatment of superficial infantile hemangioma.

The objective of the present study is to formulate and characterize propranolol hydrochloride (PPL · HCl) gel, and to evaluate the efficacy of this formulation in transdermal treatment for superficial infantile hemangioma (IH). The transdermal PPL · HCl gel was prepared by a direct swelling method, which chose hydroxypropyl methylcellulose (HPMC) as the matrix and used terpenes plus alcohols as permeation enhancer. Permeation studies of PPL · HCl were carried out with modified Franz diffusion cells through piglet skin. Our results pointed to that among all studied permeation enhancers, farnesol plus isopropanol was the most effective combination (Q24, 6027.4 ± 563.1 µg/cm(2), ER, 6.8), which was significantly higher than that of control gel (p < 0.05). High percutaneous penetration with related lower plasma drug level of PPL · HCl gel was confirmed by microdialysis technique in rats using the homemade PPL · HCl oral solution as a control. Clinical studies also confirmed the excellent therapeutic response and few side effects of the PPL · HCl gel. These results suggest that transdermal application of the PPL · HCl gel is an effective and safe formulation in treating superficial IH.

Clinical characteristics of the well-defined upper eyelid vascular network pattern in patients with rosacea.

BACKGROUND: Rosacea is a chronic inflammatory skin disease. The diagnosis is based on the symptoms and physical signs, which still lacks objective laboratory tests or imaging tests. OBJECTIVES: To propose and evaluate the upper eyelid network pattern in rosacea. METHODS: Participants included patients diagnosed with rosacea, other facial erythematous skin diseases, and normal controls, all of whom underwent full-face imaging utilizing the VISIA® system software. According to these images, researchers evaluated the condition of the upper eyelid vascular network, developed the grading scale and then compared the difference of distribution in the three groups. RESULTS: The occurrence rate of upper eyelid vascular network in rosacea was significantly higher than that in other facial erythematous skin diseases (84.3 vs. 32.0%, P < 0.001) and normal controls (84.3 vs. 28.0%, P < 0.001). The upper eyelid vascular network pattern was proposed (none [no clearly reticular vessels], mild [10-50% area of reticular vessels], moderate-to-severe [>50% area of reticular vessels]). Moderate-to-severe grade was defined as well-defined upper eyelid vascular network pattern, which was specific to patients with rosacea (rosacea vs. other facial erythematous skin diseases, adjusted odds ratio [aOR] = 5.814, 95% confidence interval [CI]: 3.899-8.670) (rosacea vs. heathy controls, aOR = 12.628, 95% CI: 8.334-19.112). The severity of the well-defined pattern had no significant association with age, duration, and phenotypes of rosacea (P > 0.05). CONCLUSION: The well-defined upper eyelid vascular network pattern specifically appeared in patients with rosacea, which could be a possible clue to the diagnosis of rosacea.

Negative prognostic impact of Co-mutations in TGFß and TP53 pathways in surgically resected rectal tumors following neoadjuvant chemoradiotherapy.

BACKGROUND: Preoperative neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) is a common approach for treating patients with locally advanced rectal cancer. Nevertheless, the mutational profile and its prognostic impact in surgically resected tumor specimens after nCRT remains to be clarified. METHODS: The comprehensive analysis of mutational landscape was retrospectively conducted by target regions sequencing approach that covered 150 tumor-related genes. Univariate and multivariate logistic regression and Cox regression was used to examine the association of mutation status in genes and pathways with pathological response and prognosis. Data from Memorial Sloan Kettering Cancer Center (MSK) cohort was used for comparison with our results. RESULTS: The top five commonly mutated genes in resected rectal tumor tissue samples following nCRT were TP53 (42%), APC (31%), KRAS (27%), PIK3CA (14%) and FBXW7 (11%). Mutations in the WNT pathway, which was mainly represented by APC mutation, were found to be significantly associated with tumor regression grade (TRG) 3. In our cohort, co-mutations in the receptor tyrosine kinase (RTK)/RAS and WNT pathways were found to be independently associated with reduced risk of recurrent and significantly associated with longer disease-free survival (DFS). In both our cohort and the MSK cohort, co-mutations in the TGF-ß and TP53 pathways were significantly associated with worse DFS. CONCLUSIONS: Resected rectal tumor samples from patients without complete pathological response can be appropriately used to detect mutations. Co-mutations in the TGF-ß and TP53 pathways may provide more prognostic information beyond commonly used clinical factors.

Correction: A Novel Convolutional Neural Network for the Diagnosis and Classification of Rosacea: Usability Study.

[This corrects the article DOI: 10.2196/23415.].

Low-Frequency Ultrasound Sensitive Piezo1 Channels Regulate Keloid-Related Characteristics of Fibroblasts.

Keloids are benign fibroproliferative tumors that severely diminish the quality of life due to discomfort, dysfunction, and disfigurement. Recently, ultrasound technology as a noninvasive adjuvant therapy is developed to optimize treatment protocols. However, the biophysical mechanisms have not yet been fully elucidated. Here, it is proposed that piezo-type mechanosensitive ion channel component 1 (Piezo1) plays an important role in low-frequency sonophoresis (LFS) induced mechanical transduction pathways that trigger downstream cellular signaling processes. It is demonstrated that patient-derived primary keloid fibroblasts (PKF), NIH 3T3, and HFF-1 cell migration are inhibited, and PKF apoptosis is significantly increased by LFS stimulation. And the effects of LFS is diminished by the application of GsMTx-4, the selective inhibitor of Piezo1, and the knockdown of Piezo1. More importantly, the effects of LFS can be imitated by Yoda1, an agonist of Piezo1 channels. Establishing a patient-derived xenograft keloid implantation mouse model further verified these results, as LFS significantly decreased the volume and weight of the keloids. Moreover, blocking the Piezo1 channel impaired the effectiveness of LFS treatment. These results suggest that LFS inhibits the malignant characteristics of keloids by activating the Piezo1 channel, thus providing a theoretical basis for improving the clinical treatment of keloids.

Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea.

Rosacea is a chronic inflammatory skin disorder with high incidence rate. Although genetic predisposition to rosacea is suggested by existing evidence, the genetic basis remains largely unknown. Here we present the integrated results of whole genome sequencing (WGS) in 3 large rosacea families and whole exome sequencing (WES) in 49 additional validation families. We identify single rare deleterious variants of LRRC4, SH3PXD2A and SLC26A8 in large families, respectively. The relevance of SH3PXD2A, SLC26A8 and LRR family genes in rosacea predisposition is underscored by presence of additional variants in independent families. Gene ontology analysis suggests that these genes encode proteins taking part in neural synaptic processes and cell adhesion. In vitro functional analysis shows that mutations in LRRC4, SH3PXD2A and SLC26A8 induce the production of vasoactive neuropeptides in human neural cells. In a mouse model recapitulating a recurrent Lrrc4 mutation from human patients, we find rosacea-like skin inflammation, underpinned by excessive vasoactive intestinal peptide (VIP) release by peripheral neurons. These findings strongly support familial inheritance and neurogenic inflammation in rosacea development and provide mechanistic insight into the etiopathogenesis of the condition.

Hemoporfin-mediated photodynamic therapy for the treatment of port-wine stain: A multicenter, retrospective study.

BACKGROUND: Hemoporfin-mediated photodynamic therapy (Hemoporfin-PDT) has been approved for port-wine stain (PWS) in China in 2017. This study evaluated the efficacy and safety of Hemoporfin-PDT for PWS in a real life setting and investigated factors that influence the efficacy. METHODS: A multicenter retrospective study included patients with PWS who underwent Hemoporfin-PDT in 29 hospitals across China and completed at least two months of follow-up. The efficacy was evaluated based on patien photographs. RESULTS: A total of 1679 patients were included. After the first and second sessions of Hemoporfin-PDT, 63.5 and 75.3% of patients responded, respectively. The response rate of purple-type PWS was significantly lower than that of pink-type PWS (OR: 0.71, 95% CI: 0.54-0.94, P < 0.05), and there was no significant difference between thick- and pink-type (OR: 0.72, 95% CI: 0.42-1.22, P > 0.05). The response rate of PWS on the limbs was significantly lower than that on the mid-face (OR: 0.35, 95% CI: 0.23-0.53, P < 0.0001), while no significant difference was observed between PWS on the peripheral part of the face, neck or other parts of the body and PWS on the mid-face (P > 0.05). The response rate was lower in male patients with an age > 3 years or ≤ 6 years (P < 0.05). Previous treatment history did not affect the efficacy (P > 0.05). Hemoporfin-PDT was well tolerated. CONCLUSION: Patients with PWS have a good response and good tolerance to Hemoporfin-PDT.

Identification of four immune subtypes in locally advanced rectal cancer treated with neoadjuvant chemotherapy for predicting the efficacy of subsequent immune checkpoint blockade.

Introduction: Neoadjuvant chemoradiotherapy (nCRT) is the foundation treatment for locally advanced rectal cancer (LARC). The nCRT can improve the efficacy of immunotherapy because of its in situ vaccine effect. Objective: The aim is to identify stable and reliable transcriptome signatures to predict the efficacy of immune checkpoint blockade (ICB) in patients with LARC. Methods: Immunophenotyping was established using xCell immune cell infiltration abundance and consistent clustering in GSE39582 and verified in several data sets. The effects of immunophenotyping, follicular regulatory T cells, tumor-associated fibroblasts (CAFs), and tertiary lymphoid structure (TLS) signatures on the efficacy of ICB were analyzed using IMvigor210, GSE91061, and an independent Daping Hospital (DPH) cohort. Results: There are four stable and repeatable immune subtypes in rectal cancer, among which C1 is a low immune infiltration type, C2 is a high interstitial infiltration type, C3 is a high immune infiltration type, and C4 is an ion channel type. C2 is mainly characterized by high infiltration of CAF. C3 is characterized by high infiltration of cytotoxic T lymphocytes, high expression of PD-L1 and TLS. In rectal cancer patients receiving nCRT, immunophenotyping was not significantly associated with pathological remission rate, but immunophenotyping was an independent prognostic factor of RFS. In IMvigor210 patients treated with atezolizumab, the pathological remission rates of C1, C2, C3, and C4 were 23.86%, 10.94%, 33.33%, and 23.08% respectively (χ2 = 8.981, P = 0.029), which were 11.76%, 50.00%, 42.86%, and 0.0% respectively in the GSE91061 patient treatment with nivolumab (Fisher's exact probability, P = 0.018). Both follicular regulatory T cells and CAF showed a further impact on the ICB therapeutic efficacy of C2 and C3 subtypes. Additionally, both the GSE91404 and DPH cohorts showed that nCRT treatment induced a significant increase in the expression of TNFRSF9 and the abundance of macrophages in the C3 subtype. Conclusion: Our data suggest that there are four immune types of rectal cancer, which are related to the prognosis of patients. Among them, C3 and some C2 subtypes represent the patients who may benefit from ICB after nCRT treatment.

Prognostic Value of HPV E6 and APOBEC3B in Upper Urinary Tract Urothelial Carcinoma.

Background: APOBEC mutation signature is common in upper urinary tract urothelial carcinoma (UTUC). When virus infection occurs, upregulated APOBEC plays an antiviral role by deoxycytidine deaminase activity. However, the carcinogenic roles of HPV E6 protein and APOBEC mutation signature in UTUC have not been investigated. Aims: This study explored the relationship among HPV E6, APOBEC, and clinicopathological characteristics in patients with UTUC and impacts of their expression on the prognosis. Methods: The expression of HPV E6 and APOBEC3B of 78 patients with UTUC was detected by immunohistochemistry. Correlation of HPV E6 and APOBEC3B expression levels with clinicopathological characteristics was statistically analyzed. Univariate and multivariate Cox regression analyses were used to evaluate the prognosis of HPV E6 and APOBEC3B for disease-free survival (DFS); survival analysis was performed using Kaplan-Meier methods. Results: The expression of APOBEC3B was positively correlated with the expression of HPV E6 (r = 0.383, P = 0.001). HPV E6 was significantly increased in patients with stage I (χ 2 = 4.938, P = 0.026) and low-grade urothelial carcinoma (χ 2 = 3.939, P = 0.047), as well as in patients without LVI (χ 2 = 4.064, P = 0.044). Meanwhile, APOBEC3B was highly expressed in patients with stage I (χ 2 = 4.057, P = 0.044) and low-grade urothelial carcinoma (χ 2 = 7.153, P = 0.007). Multivariate Cox regression analysis revealed the APOBEC3B expression was the independent prognostic factor for DFS, Kaplan-Meier survival analysis showed that low expression of APOBEC3B and HPV E6 was significantly associated with the poor prognosis of UTUC patients. Conclusion: HPV E6 expression is positively associated with APOBEC3B expression, and the high expression of HPV E6 and APOBEC3B is associated with favorable prognosis of patients with UTUC.