Conventional and Novel Treatment Strategies for Porokeratoses: A Narrative Review.

Porokeratoses are a heterogenous group of autoinflammatory keratinization disorders all characterized by the presence of a cornoid lamella. In addition to gene mutations affecting the mevalonate pathway, environmental factors such as UV radiation, immunosuppression, trauma, and infection are also thought to contribute to porokeratoses. To date, there are no management guidelines or levels of evidence for commonly used pharmacologic and non-pharmacologic treatment options for porokeratoses. Conventional treatment strategies encompass topical and systemic drugs (e.g., salicylic acid, topical glucocorticoids, and retinoids), phototherapy, laser, and surgical interventions. Better insights into the pathogenesis of porokeratoses have paved the way for the development of novel therapeutic approaches, such as topical statins or the use of monoclonal antibodies. This narrative review aims to summarize both conventional and novel treatment options, including their level of evidence, advantages, and disadvantages.

Device-based physical therapies in chronic pruritus: a narrative review.

Chronic pruritus is a highly prevalent disease associated with high psychosocial and economic burdens. In addition to pharmacological treatments, device-based physical therapies also offer antipruritic effects. Phototherapy, laser treatment, electrical neurostimulation technologies, acupuncture, cryotherapy, and cold atmospheric plasma are, in part, still experimental but emerging treatment options that augment our repertoire to treat patients with chronic pruritus. In this narrative review, we provided an overview of these physical modalities and their role in itch management.

Oncologic outcome with versus without target volume compartmentalization in postoperative radiotherapy for oral cavity squamous cell carcinoma.

Background and purpose: The volume treated with postoperative radiation therapy (PORT) in patients with oral cavity squamous cell carcinoma (OCSCC) is a mediator of toxicity affecting quality of life. Current guidelines only allow for very limited reduction of PORT volumes. This study investigated the safety and efficacy of de-intensified PORT for patients with OCSCC by refined compartmentalization of the treatment volume. Materials and methods: This retrospective cohort study identified 103 OCSCC patients treated surgically from 2014 to 2019 with a loco-regional risk profile qualifying for PORT according to guidelines. PORT was administered only to the at-risk compartment and according to a refined compartmentalization concept (CC). Oncological outcome of this CC cohort was compared to a historical cohort (HC) of 98 patients treated before the CC was implemented. Results: Median follow-up time was 4.5 and 4.8 years in the CC and HC cohorts, respectively. In the CC cohort, a total of 72 of 103 patients (70%) had a pathological risk profile that allowed for further compartmentalization and, hence, received a reduced treatment volume or omission of PORT altogether. Loco-regional control at 3 and 5 years was 77% and 73% in the CC cohort versus 78% and 73% in the HC (p = 0.93), progression-free survival was 72% and 64% versus75% and 68% (p = 0.58), respectively. Similarly, no statistically significant difference was seen in other outcome measures. Conclusions: De-intensified PORT limiting the treatment volume to the at-risk compartment or avoiding PORT altogether for low-risk patients with OCSCC does not seem to compromise disease control in this retrospective comparison. Based on these hypothesis-generating findings, a prospective study is being planned.

The Monocle Sign on 18 F-FDG PET Indicates Contralateral Peripheral Facial Nerve Palsy.

BACKGROUND: The aim of our study was to retrospectively analyze FDG PET/CT data in patients with facial nerve palsy (FNP) for the presence of the monocle sign. PATIENTS AND METHODS: A total of 85 patients with unilateral FNP were included into our study, thereof 73 with peripheral FNP and 12 with central FNP. FDG uptake (SUV max , SUV mean , total lesion glycolysis) was measured in both orbicularis oculi muscles (OOMs). FDG uptake of paretic and nonparetic muscles was compared in patients with FNP (Wilcoxon test and Mann-Whitney U test) and was also compared with FDG uptake in 33 patients without FNP (Mann-Whitney U test). SUV max ratios of OOM were compared. A receiver operating characteristic curve and Youden Index were used to determine the optimal cutoff SUV max ratio for the prevalence of contralateral peripheral FNP. RESULTS: The SUV max ratio of OOM was significantly higher in patients with peripheral FNP compared with patients with central FNP and those without FNP (1.70 ± 0.94 vs 1.16 ± 0.09 vs 1.18 ± 0.21, respectively; P < 0.001). The SUV max ratio of OOM yielded an area under the curve (AUC) of 0.719 (95% confidence interval, 0.630-0.809), with an optimal cutoff of 1.41, yielding a specificity of 94.4% and a sensitivity of 44.1% for identifying contralateral peripheral FNP. One hundred percent specificity is achieved using a cutoff of 1.91 (sensitivity, 29.4%). CONCLUSIONS: Asymmetrically increased FDG uptake of the OOM (the "monocle sign") indicates contralateral peripheral FNP. A nearly 2-fold higher SUV max represents a practically useful cutoff.

Molecular analysis using SalvGlandDx improves risk of malignancy estimation and diagnosis of salivary gland cytopathology: An exploratory multicenter study.

BACKGROUND: Diagnosis of salivary gland neoplasms is challenging, especially on cytological specimens acquired by fine-needle aspiration. The recently implemented standardized Milan system for reporting salivary gland cytopathology provides an estimated risk of malignancy (ROM); yet, for two of the categories, the diagnosis of the lesion remains unclear. However, a precise diagnosis is desirable for optimal patient management, including planning of surgery and imaging procedures. METHODS: Cytological specimens (n = 106) were subjected to molecular analysis using the SalvGlandDx panel. The risk of malignancy was calculated for each detected alteration based on the diagnosis of the resection specimen. By taking into account the molecular alterations, their associated ROM, the clinical and cytological features, and the current literature, the Milan category was evaluated. RESULTS: Of n = 63 technically valid cases, 76% revealed a molecular alteration. A total of 94% of these molecularly altered cases could be assigned to a different Milan category when additionally taking molecular results into account. In only 2% of the salivary gland neoplasms of uncertain malignant potential, in which a molecular alteration was detected, the classification remained salivary gland neoplasms of uncertain malignant potential. CONCLUSION: Molecular analysis of cytological specimens provides a benefit in classifying salivary gland neoplasms on fine-needle aspiration. It can improve the ROM estimation and thus help to assign cases of formerly unknown malignant potential to clearly benign or malignant categories.

High-Throughput Screening for the Prevalence of Neutralizing Antibodies against Human Adenovirus Serotype 5.

Adenoviral vectors based on the human adenovirus species C serotype 5 (HAdV-C5) are commonly used for vector-based gene therapies and vaccines. In the preclinical stages of development, their safety and efficacy are often validated in suitable animal models. However, pre-existing neutralizing antibodies may severely influence study outcomes. Here, we generated a new HAdV-C5-based reporter vector and established a high-throughput screening assay for the multivalent detection of HAdV-C5-neutralizing antibodies in serum. We screened the sera of rhesus macaques at different primate centers, and of rabbits, horses, cats, and dogs, showing that HAdV-C5-neutralizing antibodies can be found in all species, albeit at different frequencies. Our results emphasize the need to prescreen model animals in HAdV-C5-based studies.

The impact of phototherapy on itch intensity and itch-related quality of life amongst different skin diseases, skin phototypes and genders - A prospective study with 102 patients.

BACKGROUND: Phototherapy is a mainstay to treat itchy conditions. However, only little is known about differences in the antipruritic effect of phototherapy amongst different skin conditions, phototypes and genders. METHODS: In this prospective, single-center study, we analyzed the effect of phototherapy on itch intensity and itch-related quality of life amongst these subgroups after a treatment duration of 4 weeks, while on-demand treatment with topical corticosteroids, topical calcineurin inhibitors and/or antihistamines was allowed. RESULTS: Of 102 patients (age 53.0 ± 18.7, 56 females [54.9%]), 72 (78.3%) reported a significant reduction of itch intensity by Δ -2.76 on a 0-10 Numerical Rating Scale (NRS), p = <.001, 95% CI [2.2; 3.3] paralleled by a significant improvement of itch-related quality of life as measured by the German version of the ItchyQoL by Δ 7.3, p = <.001, 95% CI [4.4; 11.6]. The best improvement of itch intensity and itch-related QoL was reported by patients with pruritus on non-diseased skin (ΔNRS -3.5; Δ 9.7 Ger-ItchyQoL points), followed by patients with atopic dermatitis and psoriasis. We found no statistical differences in the response to phototherapy amongst Fitzpatrick phototypes I-VI. Women had higher itch intensities at baseline but itch-related quality of life impairment at baseline and phototherapy treatment response did not significantly differ between genders. CONCLUSION: Phototherapy appears to induce a meaningful itch reduction in various itchy skin conditions, all phototypes and both genders within 4 weeks that directly translates into improvement of itch-related quality of life.

Sinonasal mucosal melanoma treatment response assessment to immune checkpoint inhibitors using hybrid positron emission tomography imaging.

The purpose of this retrospective study was to investigate response of sinonasal mucosal melanoma (SMM) patients to treatment with immune checkpoint inhibitors (ICI), using hybrid PET imaging. Fifteen SMM patients underwent hybrid PET imaging before and three months after initiation of ICI. The disease-specific survival (DSS) was calculated. Quantitative PET parameters of the primary tumor and their association with DSS and therapy response were investigated. Nine of the fifteen (60%) patients responded to ICI therapy. Patients with therapy response depicted on hybrid PET imaging had better DSS than those without (p = 0.0058). Quantitative PET parameters of the initial PET harbored no association with DSS or therapy response. However, these findings lack of sufficient statistical power and must be interpreted with caution. The first restaging PET-imaging after ICI initiation can help stratify patients with regard to DSS.

Pruritus in cutaneous graft-versus-host disease: A systematic review.

Pruritus is a common symptom of cutaneous graft-versus-host disease (GVHD) following haematopoietic stem cell transplantation (HSCT). However, little is known about its prevalence, pathophysiology, perceptual characteristics, impact on quality of life and response to antipruritic therapies. The aim of this review was to determine the current knowledge on pruritus in cutaneous GVHD. The review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Of the 338 studies screened, 13 were included. The prevalence of pruritus in cutaneous GVHD was reported in three studies, ranging from 37.0% to 63.8%. Only four trials used pruritus assessment tools. There was little or no information on the intensity of pruritus, its qualitative perception, the location of pruritus and the impact of pruritus on quality of life. Antipruritic treatments for GVHD-associated pruritus were mentioned in five studies (38.5%), including topical ointments (steroids, tacrolimus and calcipotriene), broadband UVB, systemic antihistamines and oral ursodeoxycholic acid. In conclusion, pruritus in cutaneous GVHD appears to be common, but very little is known about the pathophysiology, impact on quality of life and effective treatment options. Basic research and controlled clinical trials are warranted to improve knowledge and management of this important issue.

Addressing Patient Safety Hazards Using Critical Incident Reporting in Hospitals: A Systematic Review.

INTRODUCTION: Critical incident reporting systems (CIRS) are in use worldwide. They are designed to improve patient care by detecting and analyzing critical and adverse patient events and by taking corrective actions to prevent reoccurrence. Critical incident reporting systems have recently been criticized for their lack of effectiveness in achieving actual patient safety improvements. However, no overview yet exists of the reported incidents' characteristics, their communication within institutions, or actions taken either to correct them or to prevent their recurrence. Our main goals were to systematically describe the reported CIRS events and to assess the actions taken and their learning effects. In this systematic review of studies based on CIRS data, we analyzed the main types of critical incidents (CIs), the severity of their consequences, their contributing factors, and any reported corrective actions. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we queried MEDLINE, Embase, CINAHL, and Scopus for publications on hospital-based CIRS. We classified the consequences of the incidents according to the National Coordinating Council for Medication Error Reporting and Prevention index, the contributing factors according to the Yorkshire Contributory Factors Framework and the Human Factors Classification Framework, and all corrective actions taken according to an action hierarchy model on intervention strengths. RESULTS: We reviewed 41 studies, which covered 479,483 CI reports from 212 hospitals in 17 countries. The most frequent type of incident was medication related (28.8%); the most frequent contributing factor was labeled "active failure" within health care provision (26.1%). Of all professions, nurses submitted the largest percentage (83.7%) of CI reports. Actions taken to prevent future CIs were described in 15 studies (36.6%). Overall, the analyzed studies varied considerably regarding methodology and focus. CONCLUSIONS: This review of studies from hospital-based CIRS provides an overview of reported CIs' contributing factors, characteristics, and consequences, as well as of the actions taken to prevent their recurrence. Because only 1 in 3 studies reported on corrective actions within the healthcare facilities, more emphasis on such actions and learnings from CIRS is required. However, incomplete or fragmented reporting and communication cycles may additionally limit the potential value of CIRS. To make a CIRS a useful tool for improving patient safety, the focus must be put on its strength of providing new qualitative insights in unknown hazards and also on the development of tools to facilitate nomenclature and management CIRS events, including corrective actions in a more standardized manner.

Risk Factors for Fear of Recurrence in Head and Neck Cancer Patients.

OBJECTIVE: Fear of recurrence (FoR) affects the quality of life of head and neck cancer survivors. Identification of factors predisposing to FoR may help to recognize and treat patients at risk. MATERIALS AND METHODS: For this exploratory study, 101 disease-free head and neck cancer survivors completed a cross-sectional survey in 2017 that included the FoR questionnaire at a random point in time during their follow-up. Additionally, the patients were asked to choose their favorite among four follow-up schedules with or without systematic imaging and varying frequency of visits. RESULTS: Elevated FoR was present in 36.6% of patients. Females and patients ≤65 years showed significantly higher FoR overall scores than males (score difference 3.40; CI 0.49-6.32; p = 0.022) and patients >65 years (score difference 4.25; CI 1.58-6.92; p = 0.002). A history of cancer recurrence or second primary malignancy increased the relative risk (RR) for elevated FoR (RR 1.7; CI 1.01-2.86; p = 0.046). Tumor stage and treatment modality were not significantly associated with elevated FoR or FoR overall score. Higher FoR overall scores were recorded in patients who favored intensive follow-up plans (mean overall FoR score 18 vs. 15; SD 7.7; p = 0.076) and systematic imaging in follow-up (17 vs. 13, SD 7.1; p = 0.034). CONCLUSION: Fear of recurrence in head and neck cancer patients is associated with female sex, younger age, and history of a past recurrence or second primary malignancy. Due to its high prevalence, it should be addressed in clinical practice and future research. LEVEL OF EVIDENCE: NA Laryngoscope, 133:1630-1637, 2023.

Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma.

Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3' untranslated region (3'UTR) regions of EVC (48% of specimens), PPP1R1A (48% of specimens), and ABCA4 (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene PTPRD was observed. Gene amplification was much less frequent, and few genes were recurrently amplified. Single nucleotide variants driver analyses from three tools confirmed TP53 and CDKN2A as recurrently mutated genes but also identified C9 as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of "TGF-beta regulation of extracellular matrix" and "cell cycle G1 to S check points." These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC.

Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) of the head and neck region is the second most prevalent skin cancer, with metastases to regional lymph nodes occurring in 2%-5% of cases. To further our understanding of the molecular events characterizing cSCC invasion and metastasis, we conducted targeted cancer progression gene expression and pathway analysis in non-metastasizing (PRI-) and metastasizing primary (PRI+) cSCC tumors of the head and neck region, cognate lymph node metastases (MET), and matched sun-exposed skin (SES). The highest differentially expressed genes in metastatic (MET and PRI+) versus non-metastatic tumors (PRI-) and SES included PLAU, PLAUR, MMP1, MMP10, MMP13, ITGA5, VEGFA, and various inflammatory cytokine genes. Pathway enrichment analyses implicated these genes in cellular pathways and functions promoting matrix remodeling, cell survival and migration, and epithelial to mesenchymal transition, which were all significantly activated in metastatic compared to non-metastatic tumors (PRI-) and SES. We validated the overexpression of urokinase plasminogen activator receptor (uPAR, encoded by PLAUR) in an extended patient cohort by demonstrating higher uPAR staining intensity in metastasizing tumors. As pathway analyses identified epidermal growth factor (EGF) as a potential upstream regulator of PLAUR, the effect of EGF on uPAR expression levels and cell motility was functionally validated in human metastatic cSCC cells. In conclusion, we propose that uPAR is an important driver of metastasis in cSCC and represents a potential therapeutic target in this disease.

Association of Multiprofessional Preoperative Assessment and Information for Patients With Head and Neck Cancer With Postoperative Outcomes.

IMPORTANCE: Multidisciplinary perioperative assessment for patients undergoing complex oncologic head and neck cancer (HNC) surgery is widely implemented. However, to our knowledge, the association of multiprofessional preoperative assessment, information, and briefing with postoperative outcomes has not been evaluated. OBJECTIVE: To compare postoperative complications, length of hospital stay (LOS), readmissions, mortality, and costs per case among patients undergoing complex oncologic HNC surgery before and after the implementation of a comprehensive preoperative multiprofessional assessment and information day (MUPAID). DESIGN, SETTING, AND PARTICIPANTS: This retrospective, single-center case-control study was conducted at a tertiary referral head and neck anticancer center/university cancer institute and compared patients with HNC who were undergoing complex oncological surgeries between January 2012 and July 2018 before (control group) and after (intervention group) implementation of the institutional MUPAID. Data analysis was conducted between 2019 and 2020. The intervention group comprised patients who participated in the MUPAID beginning in February 2015. These patients were assessed by a multiprofessional team and provided with structured and comprehensive information on the surgical procedure and its functional, social, financial, and psychological effects, as well as the postoperative care, rehabilitation, and follow-up period. Patients in the control group had also undergone complex oncologic HNC surgery and were selected through surgical procedure codes. MAIN OUTCOMES AND MEASURES: The end points were postoperative rate and severity of complications, LOS, readmissions, mortality, and costs per case. RESULTS: The study included 161 patients, 81 in the intervention (25 women [30.9%]) and 80 in the control group (18 women [22.5%]). The groups showed no relevant differences in sociodemographic, disease, and procedural characteristics. The intervention cohort presented with fewer major local and systemic complications (Clavien-Dindo score, III-V: 34.6% vs 52.5%; difference proportion, -0.179; 95% CI, -0.33 to -0.03), shorter median LOS (12 days [IQR, 10-16 days] vs 16 days [IQR, 11-20] days; effect size, 0.482; 95% CI Cohen d, 0.152-0.812) and decreased median charge per case ($50 848 [IQR, $42 510-$63 479] vs $69 602 [IQR, $45 631-$96 280]; effect size, 0.534; 95% CI Cohen d, 0.22-0.85). CONCLUSIONS AND RELEVANCE: The results of this case-control study suggest that MUPAID for patients who are undergoing complex oncologic HNC surgery is associated with shortened LOS and costs per case as well as decreased complications severity. These results are promising on a patient level in the potential to minimize individual treatment burden, as well as on an institutional and health care system level in the potential significant optimization of surgical outcomes and financial aspects.