Clinical characteristics and management of orbital apex syndrome: a 10-year multicentre experience.

BACKGROUND: Orbital apex syndrome (OAS) is a condition characterised by lesions within the orbital apex, leading to various ophthalmologic symptoms. This study aimed to analyse the clinical characteristics and treatment strategies of OAS with respect to aetiology. METHODS: This retrospective analysis utilised data from 5 medical institutions between 2013 and 2022. Patients who were diagnosed with OAS were initially enrolled, but patients who failed to follow up at least 1 month were excluded. The prevalence of initial ophthalmologic symptoms and visual improvement after treatment was compared according to aetiology. Factors related to visual improvement were analysed. RESULTS: Among 73 enrolled patients, the leading aetiology was tumours, followed by fungal infections and inflammation. Visual impairment and proptosis were prevalent in tumour-related OAS cases. Inflammation-related OAS exhibited a higher likelihood of painful eye movements and ophthalmoplegia. Ptosis was most frequently observed in fungal infection-related OAS. Notably, fungal infections emerged as the sole significant factor negatively impacting vision progression. In inflammation-related OAS, the time interval between symptom onset and the administration of steroids was longer in patients without visual improvement, even though there was no statistically significant difference. CONCLUSIONS: Tumours were the predominant cause of OAS. Visual impairment was a common manifestation in tumour-related OAS, while fungal infections were strongly associated with a poor visual prognosis. The timely administration of steroids might be helpful for improving vision in patients with inflammation-related OAS. However, further studies are needed to enhance understanding and management of OAS.

Epigenetic liquid biopsies for minimal residual disease, what's around the corner?

Liquid biopsy assays for minimal residual disease (MRD) are used to monitor and inform oncological treatment and predict the risk of relapse in cancer patients. To-date, most MRD assay development has focused on targeting somatic mutations. However, epigenetic changes are more frequent and universal than genetic alterations in cancer and circulating tumor DNA (ctDNA) retains much of these changes. Here, we review the epigenetic signals that can be used to detect MRD, including DNA methylation alterations and fragmentation patterns that differentiate ctDNA from noncancerous circulating cell-free DNA (ccfDNA). We then summarize the current state of MRD monitoring; highlight the advantages of epigenetics over genetics-based approaches; and discuss the emerging paradigm of assaying both genetic and epigenetic targets to monitor treatment response, detect disease recurrence, and inform adjuvant therapy.

Oncomicrobial Community Profiling Identifies Clinicomolecular and Prognostic Subtypes of Colorectal Cancer.

BACKGROUND & AIMS: Dysbiosis of gut microbiota is linked to the development of colorectal cancer (CRC). However, microbiota-based stratification of CRC tissue and how this relates to clinicomolecular characteristics and prognosis remains to be clarified. METHODS: Tumor and normal mucosa from 423 patients with stage I to IV CRC were profiled by bacterial 16S rRNA gene sequencing. Tumors were characterized for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), APC, BRAF, KRAS, PIK3CA, FBXW7, SMAD4, and TP53 mutations, subsets for chromosome instability (CIN), mutation signatures, and consensus molecular subtypes (CMS). Microbial clusters were validated in an independent cohort of 293 stage II/III tumors. RESULTS: Tumors reproducibly stratified into 3 oncomicrobial community subtypes (OCSs) with distinguishing features: OCS1 (Fusobacterium/oral pathogens, proteolytic, 21%), right-sided, high-grade, MSI-high, CIMP-positive, CMS1, BRAF V600E, and FBXW7 mutated; OCS2 (Firmicutes/Bacteroidetes, saccharolytic, 44%), and OCS3 (Escherichia/Pseudescherichia/Shigella, fatty acid ß-oxidation, 35%) both left-sided and exhibiting CIN. OCS1 was associated with MSI-related mutation signatures (SBS15, SBS20, ID2, and ID7) and OCS2 and OCS3 with SBS18 related to damage by reactive oxygen species. Among stage II/III patients, OCS1 and OCS3 both had poorer overall survival compared with OCS2 for microsatellite stable tumors (multivariate hazard ratio [HR], 1.85; 95% confidence interval [CI], 1.15-2.99; P = .012; and HR, 1.52; 95% CI 1.01-2.29; P = .044, respectively) and left-sided tumors (multivariate HR, 2.66; 95% CI, 1.45-4.86; P = .002; and HR, 1.76; 95% CI, 1.03-3.02; P = .039, respectively). CONCLUSIONS: OCS classification stratified CRCs into 3 distinct subgroups with different clinicomolecular features and outcomes. Our findings provide a framework for a microbiota-based stratification of CRC to refine prognostication and to inform the development of microbiota-targeted interventions.

Use of hydrochlorothiazide and risk of nonmelanoma skin cancer in Koreans: a retrospective cohort study using administrative healthcare data.

BACKGROUND: The incidence of skin cancer is increasing because of the ageing population and ultraviolet exposure, and previous studies have revealed that long-term use of hydrochlorothiazide (HCTZ), an antihypertensive agent, has been associated with an increased risk of nonmelanoma skin cancer (NMSC). However, the association of NMSC and HCTZ within East Asian populations is unclear. AIM: To investigate the risk of NMSC in Korean subjects using HCTZ. METHODS: A retrospective cohort study was conducted using the administrative healthcare data. The study enrolled 62 243 patients exposed to HCTZ with a cumulative dose of ≥ 2500 mg and 62 243 unexposed subjects matched 1 : 1 with the patients for age, sex and income level. RESULTS: There was a significant difference in the cumulative incidence of NMSC between the two groups (log-rank P < 0.01). Cox regression analysis was conducted after adjusting for potential confounders, and showed the risk for NMSC in the group exposed to HCTZ was significantly higher than that of the unexposed group (hazard ratio = 1.48; 95% CI 1.03-2.13). In the subgroup analysis, the oldest age group (≥ 70 years) showed increased cumulative incidence of NMSC with statistical significance compared with the unexposed control group (log-rank P < 0.01). CONCLUSIONS: In this study, we revealed that the cumulative use of HCTZ (≥ 2500 mg) could increase the risk of NMSC in Koreans, especially the older age group. Thus, HCTZ could be a risk factor for NMSC in East Asian as well as white populations.

Non-melanoma skin cancer as a clinical marker for internal malignancies: a nationwide population-based cohort study.

INTRODUCTION: Non-melanoma skin cancers (NMSCs) are the most common cancers in the world, but the risk of internal malignancy in patients with NMSC has not been well investigated. OBJECTIVES: We aimed to assess the risk of internal malignancy in patients with NMSC compared with controls without NMSC in Korean population. METHODS: This nationwide cohort study, compared 27 259 NMSC patients with 54 518 matched controls without NMSC, 40 years or older using the data from Korea Health Insurance Review and Assessment Service from 2007 to 2016. The first 2 years were washout period, and we followed the patients for 8 years to observe the development of any internal malignancies after a diagnosis of NMSC. The Cox proportional hazard model was used to determine the hazard ratios (HRs) for developing internal malignancies. RESULTS: The overall risk of internal malignancies at all sites was 2727.7 and 1392.4 per 100 000 person-years for the patients with NMSC and controls, respectively. The risk was significantly higher in the patients with NMSC (HR 1.866, 95% confidence interval [CI] 1.768-1.970). Bone cancer showed the highest risk (HR 12.745, 95% CI 6.288-25.834), followed by nasal cavity and larynx (HR 10.279, 95% CI 6.178-7.103), oral cavity and pharynx (HR 10.211, 95% CI 7.375-14.137), anus and anal canal (HR 8.147, 95% CI 3.893-17.051) and cervical (HR 5.900, 95% CI 3.694-9.423) cancers with risks greater than fivefold higher in NMSC patients compared with the controls. The risks of cancers of the thorax, oesophagus, breast, lung, stomach, thyroid gland and non-Hodgkin's lymphoma were also statistically higher in the patients with NMSC. In contrast, the risks of cancers of the colon and rectum were found to be significantly decreased in the patients with NMSC (HR 0.765, 95% CI 0.657-0.890). CONCLUSION: Patients with NMSC require careful screening and follow-up for internal malignancy.

DNA Methylation Cancer Biomarkers: Translation to the Clinic.

Carcinogenesis is accompanied by widespread DNA methylation changes within the cell. These changes are characterized by a globally hypomethylated genome with focal hypermethylation of numerous 5'-cytosine-phosphate-guanine-3' (CpG) islands, often spanning gene promoters and first exons. Many of these epigenetic changes occur early in tumorigenesis and are highly pervasive across a tumor type. This allows DNA methylation cancer biomarkers to be suitable for early detection and also to have utility across a range of areas relevant to cancer detection and treatment. Such tests are also simple in construction, as only one or a few loci need to be targeted for good test coverage. These properties make cancer-associated DNA methylation changes very attractive for development of cancer biomarker tests with substantive clinical utility. Across the patient journey from initial detection, to treatment and then monitoring, there are several points where DNA methylation assays can inform clinical practice. Assays on surgically removed tumor tissue are useful to determine indicators of treatment resistance, prognostication of outcome, or to molecularly characterize, classify, and determine the tissue of origin of a tumor. Cancer-associated DNA methylation changes can also be detected with accuracy in the cell-free DNA present in blood, stool, urine, and other biosamples. Such tests hold great promise for the development of simple, economical, and highly specific cancer detection tests suitable for population-wide screening, with several successfully translated examples already. The ability of circulating tumor DNA liquid biopsy assays to monitor cancer in situ also allows for the ability to monitor response to therapy, to detect minimal residual disease and as an early biomarker for cancer recurrence. This review will summarize existing DNA methylation cancer biomarkers used in clinical practice across the application domains above, discuss what makes a suitable DNA methylation cancer biomarker, and identify barriers to translation. We discuss technical factors such as the analytical performance and product-market fit, factors that contribute to successful downstream investment, including geography, and how this impacts intellectual property, regulatory hurdles, and the future of the marketplace and healthcare system.

A natural infection by the red sea bream iridovirus-type Megalocytivirus in the golden mandarin fish Siniperca scherzeri.

An outbreak of a Megalocytivirus infection was found in the golden mandarin fish Siniperca scherzeri during September and October 2016, in Korea. Phylogeny and genetic diversity based on the major capsid protein (MCP) and adenosine triphosphatase (ATPase) genes showed a new strain. Designated as GMIV, this strain derived from the golden mandarin fish was suggested to belong to the red sea bream iridovirus (RSIV)-subgroup I. Additionally, this train clustered with the ehime-1 strain from red sea bream Pagrus major in Japan and was distinguished from circulating isolates (RSIV-type subgroup II and turbot reddish body iridovirus [TRBIV] type) in Korea. The infection level, evaluated by qPCR, ranged from 8.18 × 102 to 7.95 × 106  copies/mg of tissue individually, suggesting that the infected fish were in the disease-transmitting stage. The diseased fish showed degenerative changes associated with cytomegaly in the spleen as general sign of Megalocytivirus infection. The results confirm that the RSIV-type Megalocytivirus might have crossed the environmental and species barriers to cause widespread infection in freshwater fish.

A multicentre, open, investigator-initiated phase IV clinical trial to evaluate the efficacy and safety of ingenol mebutate gel, 0·015% on the face and scalp, and 0·05% on the trunk and extremities, in Korean patients with actinic keratosis (PERFECT).

BACKGROUND: Ingenol mebutate gel is a novel, field-directed topical treatment for actinic keratosis (AK). Most pivotal studies have targeted Western populations. No clinical study has been conducted to investigate its efficacy and safety in Asian populations. OBJECTIVES: To evaluate the efficacy and safety of ingenol mebutate gel for treating AK of face/scalp and trunk/extremities in a large Asian (Korean) population. PATIENTS AND METHODS: In this multicentre, open-label, interventional, parallel-group, prospective phase IV study (PERFECT, trial registration no.: NCT02716714), the eligible patients were allocated into either the face/scalp or the trunk/extremities group, according to their selected treatment area location. After application of ingenol mebutate gel, the participants were followed up for 6 months. The primary efficacy endpoint was complete clearance (CC) of AK lesions in the selected treatment area at day 57. Quality of life was evaluated using Skindex-29. Safety endpoints included local skin responses, scar, pigmentation, pain and adverse events. RESULTS: In total, 78·1% [95% confidence interval (CI) 66·86-86·92%] of subjects had CC at day 57, with 76·6% (95% CI 64·31-86·25%) in the face/scalp group and 88·9% (95% CI 51·75-99·72%) in the trunk/extremities group. Among them, CC was sustained in 88·9% (48 of 54, 95% CI 77·37-95·81%) at month 6. The local skin responses significantly increased 1 day after the treatment compared with baseline, and decreased afterwards. Among the total subjects, 7·8% (6 of 77) had hyperpigmentation on the application area. Scars were not reported. CONCLUSIONS: Ingenol mebutate is effective for the treatment of AK in Asians, with tolerable safety profiles.

Blood-based protein biomarker panel for the detection of colorectal cancer.

BACKGROUND: The majority of colorectal cancer (CRC) cases are preventable by early detection and removal of precancerous polyps. Even though CRC is the second most common internal cancer in Australia, only 30 per cent of the population considered to have risk factors participate in stool-based test screening programs. Evidence indicates a robust, blood-based, diagnostic assay would increase screening compliance. A number of potential diagnostic blood-based protein biomarkers for CRC have been reported, but all lack sensitivity or specificity for use as a stand-alone diagnostic. The aim of this study was to identify and validate a panel of protein-based biomarkers in independent cohorts that could be translated to a reliable, non-invasive blood-based screening test. PRINCIPAL FINDINGS: In two independent cohorts (n = 145 and n = 197), we evaluated seven single biomarkers in serum of CRC patients and age/gender matched controls that showed a significant difference between controls and CRC, but individually lack the sensitivity for diagnostic application. Using logistic regression strategies, we identified a panel of three biomarkers that discriminated between controls and CRC with 73% sensitivity at 95% specificity, when applied to either of the two cohorts. This panel comprised of Insulin like growth factor binding protein 2 (IGFBP2), Dickkopf-3 (DKK3), and Pyruvate kinase M2(PKM2). CONCLUSIONS: Due to the heterogeneous nature of CRC, a single biomarker is unlikely to have sufficient sensitivity or specificity for use as a stand-alone diagnostic screening test and a panel of markers may be more effective. We have identified a 3 biomarker panel that has higher sensitivity and specificity for early stage (Stage I and -II) disease than the faecal occult blood test, raising the possibility for its use as a non-invasive blood diagnostic or screening test.

Hepatoprotective and neuroprotective tocopherol analogues isolated from the peels of Citrus unshiu Marcovich.

Three tocopherol analogues methoxytocopherol (1), α-tocopherol (2) and γ-tocopherol (3) were isolated from the peels of Citrus unshiu Marcovich. The protective effects of the isolated compounds against tert-butyl hydroperoxide-induced hepatotoxicity in human liver-derived HepG2 cells and glutamate-induced oxidative stress in HT22-immortalised hippocampal cells were evaluated. Compounds 1-3 were significantly protective in HepG2 cells with EC50 values of 21.22 ± 2.01, 25.21 ± 2.11 and 25.25 ± 1.21 µM, respectively, and in HT22 cells, compounds 1-3 had EC50 values of 20.62 ± 1.36, 6.44 ± 1.65 and 9.52 ± 1.54 µM, respectively.

Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway.

Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus and the culprit behind the human disease Kaposi sarcoma (KS), an AIDS-defining malignancy. KSHV encodes a viral G-protein-coupled receptor (vGPCR) critical for the initiation and progression of KS. In this study, we identified that YAP/TAZ, two homologous oncoproteins inhibited by the Hippo tumor suppressor pathway, are activated in KSHV-infected cells in vitro, KS-like mouse tumors and clinical human KS specimens. The KSHV-encoded vGPCR acts through Gq/11 and G12/13 to inhibit the Hippo pathway kinases Lats1/2, promoting the activation of YAP/TAZ. Furthermore, depletion of YAP/TAZ blocks vGPCR-induced cell proliferation and tumorigenesis in a xenograft mouse model. The vGPCR-transformed cells are sensitive to pharmacologic inhibition of YAP. Our study establishes a pivotal role of the Hippo pathway in mediating the oncogenic activity of KSHV and development of KS, and also suggests a potential of using YAP inhibitors for KS intervention.

Claudin-1 Expression Is Elevated in Colorectal Cancer Precursor Lesions Harboring the BRAF V600E Mutation.

BACKGROUND: Sessile serrated adenomas/polyps (SSA/P) are now recognised precursors of colorectal cancer (CRC) including cancers harbouring somatic BRAF (V600E) mutations. While the morphological diagnostic criteria of SSA/P have been established, distinguishing between small/early SSA/P and microvesicular hyperplastic polyps (MVHP) is challenging and may not be possible in routine practice. METHODS: Gene expression profiling of MVHP (n=5, all BRAF V600E wild-type) and SSA/P (n=5, all BRAF V600E mutant) samples was performed. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical analysis was performed to verify the expression of claudin 1 (CLDN1) in MVHP and SSA/P. RESULTS: Gene expression profiling studies conducted between MVHP and SSA/P identified CLDN1 as the most statistically significant differentially expressed gene (p<0.05). Validation with qRT-PCR confirmed an up-regulation of CLDN1 in BRAF V600E mutant polyps regardless of polyp type (p<0.0005). Immunohistochemical analysis of CLDN1 expression in BRAF V600E mutant SSA/Ps (n=53) and MVHPs (n=111) and BRAF wild-type MVHPs (n=58), demonstrated a strong correlation between CLDN1 expression and the BRAF V600E mutation in both SSA/P and MVHP samples when compared to wild-type polyps (p<0.0001). CONCLUSION: This study demonstrates an up regulation of CLDN1 protein in serrated colorectal polyps including MVHP harbouring the BRAF V600E mutation. Our results demonstrated an apparent heterogeneity on the molecular level within the MVHP group and suggest that MVHP with somatic BRAF V600E mutation and up-regulated expression of CLDN1 are closely related to SSA/P and may in fact represent a continuous spectrum of the same neoplastic process within the serrated pathway of colorectal carcinogenesis.

Colorectal cancer biomarkers: to be or not to be? Cautionary tales from a road well travelled.

Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide and places a major economic burden on the global health care system. The time frame for development from premalignant to malignant disease typically spans 10-15 years, and this latent period provides an ideal opportunity for early detection and intervention to improve patient outcomes. Currently, early diagnosis of CRC is hampered by a lack of suitable non-invasive biomarkers that are clinically or economically acceptable for population-based screening. New blood-based protein biomarkers for early detection of CRC are therefore urgently required. The success of clinical biomarker discovery and validation studies is critically dependent on understanding and adjusting for potential experimental, analytical, and biological factors that can interfere with the robust interpretation of results. In this review we outline some important considerations for research groups undertaking biomarker research with exemplars from our studies. Implementation of experimental strategies to minimise the potential effects of these problems will facilitate the identification of panels of biomarkers with the sensitivity and specificity required for the development of successful tests for the early detection and surveillance of CRC.

Multidetector CT imaging features of solid pseudopapillary tumours of the pancreas in male patients: distinctive imaging features with female patients.

OBJECTIVE: To describe multidetector CT imaging features of solid pseudopapillary tumours (SPTs) in male patients and to compare these imaging features with those found in female patients. METHODS: The institutional review board approved this retrospective study. We included the CT images of 72 patients (M:F = 12:60; mean age, 35.0 years) diagnosed with SPT by histology. CT images were reviewed on the following: location of the tumour, maximal diameter, shape, margin and the fraction of the tumour composition. Statistical differences in CT imaging features were analysed. RESULTS: Male patients with SPTs were significantly older than female patients (42.4 years vs 33.4 years, p = 0.0408) and the mean size of the SPTs in male patients was larger (6.3 cm vs 4.6 cm, p = 0.0413) than that of SPTs in female patients. Lobulated shape of the SPTs was most frequent in male patients, whereas oval shape was most frequent in female patients (p = 0.0133). SPTs in male patients tended to have a solid component (p = 0.0434). Progressive enhancement in the solid portion of the tumour was seen in 9 (81.8%) of 11 SPTs in male patients and in 30 (79.0%) of 38 SPTs in female patients on multiphasic CT. CONCLUSION: The imaging features of SPTs in male patients usually appeared as a somewhat large-sized solid mass with a lobulated margin and progressive enhancement. These imaging features may help to differentiate SPTs from other pancreatic tumours for their proper management. ADVANCES IN KNOWLEDGE: SPTs in male patients appear as somewhat large-sized solid masses with lobulated margins, and this form occurs more frequently in older male patients than in female patients.

An epidemiological study of androgenic alopecia in 3114 Korean patients.

BACKGROUND: Androgenetic alopecia (AGA) is the most common type of hair loss, and is characterized by the transformation of terminal scalp hair into vellus hair. The epidemiology of AGA is not fully understood. A strong genetic basis has long been identified, although little is known of its nongenetic causes. AIM: To evaluate the association of AGA with a number of environmental factors, including smoking, drinking and sleeping habit. METHODS: In total, 3114 Korean individuals with AGA who attended any one of 17 dermatology clinics in 6 cities in South Korea between March 2011 and February 2012 were enrolled in the study. Epidemiologic a data were collected using a standard questionnaire. RESULTS: No association was seen between eating or sleeping habits and severity of hair loss. However, drinking and smoking were associated with the severity of AGA in male patients. We also found that patients of both genders with a family history had more advanced types of hair loss, and the age of onset of AGA in male patients with a family history was earlier than that in male patients without a family history. CONCLUSIONS: Although the evidence for an environmental influence on AGA remains very weak, we did find an association between hair loss severity and certain environmental factors, such as smoking and drinking. Family history with more severe hair loss and an earlier age of onset.

Performance of serum lipocalin 2 as a diagnostic marker for colorectal cancer.

BACKGROUND: Lipocalin 2 has been implicated in colorectal tumorigenesis but its usefulness as a diagnostic marker for the disease has previously never been determined. METHODS: We have used ELISA immunoassay to measure the level of serum lipocalin 2 in a cohort consisting of colorectal cancer patients (n=196) and age/gender matched controls (n=99). RESULTS: The median concentration of lipocalin 2 was found to be significantly higher (p< 0.0001) in the patient group (105.9 ng/mL, range 10.8-444.7 ng/mL) when compared to the control subjects (86.4 ng/mL, range 17.1-190.0 ng/mL). Additionally, no significant difference was observed between disease stage (Dukes' or T stage) in the patient cohort. Receiver operating characteristic analysis was performed to determine its performance as a diagnostic marker. The area under the curve was found to be 0.641 (95% confidence interval 0.576-0.706). Furthermore, the sensitivity of lipocalin 2 was found to be 24% at 90% specificity. CONCLUSIONS: Our study indicates that lipocalin 2 is not a suitable serum biomarker for the diagnosis of CRC.