Molecular alterations in basal cell carcinoma subtypes

A number of genes have been implicated in the pathogenesis of BCC in addition to the Hedgehog pathway, which is known to drive the initiation of this tumour. We performed in-depth analysis of 13 BCC-related genes (CSMD1, CSMD2, DPH3 promoter, PTCH1, SMO, GLI1, NOTCH1, NOTCH2, TP53, ITIH2, DPP10, STEAP4, TERT promoter) in 57 BCC lesions (26 superficial and 31 nodular) from 55 patients and their corresponding blood samples. PTCH1 and TP53 mutations were found in 71.9% and 45.6% of BCCs, respectively. A high mutation rate was also detected in CSMD1 (63.2%), NOTCH1 (43.8%) and DPP10 (35.1%), and frequent non-coding mutations were identified in TERT (57.9%) and DPH3 promoter (49.1%). CSMD1 mutations significantly co-occurred with TP53 changes (p = 0.002). A significant association was observed between the superficial type of BCC and PTCH1 (p = 0.018) and NOTCH1 (p = 0.020) mutations. In addition, PTCH1 mutations were significantly associated with intermittent sun exposure (p = 0.046) and the occurrence of single lesions (p = 0.021), while NOTCH1 mutations were more frequent in BCCs located on the trunk compared to the head/neck and extremities (p = 0.001). In conclusion, we provide further insights into the molecular alterations underlying the tumorigenic mechanism of superficial and nodular BCCs with a view towards novel rationale-based therapeutic strategies.

“Sandwich technique” enables preservation of hearing and antivertiginous effect in cholesteatomatous labyrinthine fistula

Purpose The aim of the study was to assess hearing, surgical and clinical results of the treatment in patients with cholesteatomatous labyrinthine fistula (LF) focusing on the different techniques and materials used in the management. Methods Study group included 465 patients. Cases with LFs discovered or confirmed during surgical procedure were thoroughly analyzed. Results LFs were noted in 11.4% of all cases. Thirty-eight patients, with all follow-up data available, were included into the further analysis. Most LFs were located in the lateral semicircular canal (87%). LFs were assessed as small in 2 cases, as medium in 24 patients while 12 were described as large. Based on Dornhoffer and Milewski classification, 50% of LFs were classified as IIa, 24% as IIb, 6 LFs were very deep (type III), while 4—superficial (type I). The size and type of LF did not influence postsurgical complaints (p = 0.1070, p = 0.3187, respectively). Vertigo was less frequent in LFs treated by “sandwich technique”, especially those with opened endosteum. In 30 (79%) patients, hearing improved or did not change after surgery. Hearing outcomes were significantly better in the ears operated by means of CWU technique (p = 0.0339), in LFs with intact membranous labyrinth (p = 0.0139) and when “sandwich technique” was performed (p = 0.0159). Postsurgical bone conduction thresholds levels were significantly better in LFs covered by “sandwich method” (p = 0.0440). Conclusion “Sandwich technique” (temporal fascia–bone pate–temporal fascia) enables preservation of hearing as well as antivertiginous effect in patients with cholesteatomatous labyrinthine fistula.

Molecular Alterations in Basal Cell Carcinoma Subtypes

A number of genes have been implicated in the pathogenesis of BCC in addition to the Hedgehog pathway, which is known to drive the initiation of this tumour.We performed in-depth analysis of 13 BCC-related genes (CSMD1, CSMD2, DPH3 promoter, PTCH1, SMO, GLI1, NOTCH1, NOTCH2, TP53, ITIH2, DPP10, STEAP4, TERT promoter) in 57 BCC lesions (26 superficial and 31 nodular) from 55 patients and their corresponding blood samples. PTCH1 and TP53 mutations were found in 71.9% and 45.6% of BCCs, respectively. A high mutation rate was also detected in CSMD1 (63.2%), NOTCH1 (43.8%) and DPP10 (35.1%), and frequent non-coding mutations were identified in TERT (57.9%) and DPH3 promoter (49.1%). CSMD1 mutations significantly co-occurred with TP53 changes (p=0.002). A significant association was observed between the superficial type of BCC and PTCH1 (p=0.017) and NOTCH1 (p=0.018) mutations. In addition, PTCH1 mutations were significantly associated with intermittent sun exposure (p=0.046) and the occurrence of single lesions (p=0.021), while NOTCH1 mutations were more frequent in BCCs located on the trunk compared to the head/neck and extremities (p=0.001).In conclusion, we provide further insights into the molecular alterations underlying the tumorigenic mechanism of superficial and nodular BCCs with a view towards novel rationale-based therapeutic strategies.

Recent Advancement in Atypical Lipomatous Tumor Research

After Evans and colleagues identified the lipomatous tumor with a well-differentiated liposarcoma in a subcutaneous location or within a muscle layer, namely, atypical lipomatous tumor (ALT), this malignancy has been investigated to clarify the characteristics of clinical behavior and genomic changes. As one of the important issues for clinicians, it is a hot topic of how to distinguish ALT from benign lipoma in the clinical aspect. Recent studies revealed novel findings to clarify the risk factor for the diagnosis of ALT and molecular targets for the treatment of ALT. Clinical characteristics of superficial-type ALT well reflect the subcutaneous location of the tumor and are slightly different compared to deep-type ALT, such as tumor size. In addition, there has been a recent discovery of novel findings in ALT-related genes, namely, HMG2A (high mobility group protein 2a), YEATS4 (YEATS domain containing 4), and CPM (Carboxypeptidase M). Recent updates on treatment for advanced ALT are well developed including immunotherapy and conducting clinical trials. Finally, this review introduces one of the hot topics of ALT research focused on epigenetic changes: their attention in recent updates on clinical characteristics and the novel discovery of related genes, treatment, and epigenetic modifications in atypical lipomatous tumors.

A Retrospective Study of Superficial Type Atypical Lipomatous Tumor

Atypical lipomatous tumor (ALT) has been defined as a well-differentiated liposarcoma exhibiting a higher frequency of a local recurrence after surgical resection. ALT is mainly classified into deep type and superficial type. Compared with deep type ALT, superficial type ALT is rarely observed. One of the most important issues is that little has been known about superficial type ALT and it is not easy to predict the presence of superficial type ALT before surgical resection. To clarify the clinical manifestations of superficial type ALT, we examined 15 cases with superficial type ALT and 118 cases with benign lipoma, and analyzed their differences in clinical characteristics and the findings of MRI test. In clinical characteristics, the tumor size of superficial type ALT was significantly greater than that of benign lipoma, and superficial type ALT showed a significantly higher frequency of the tumor size of more than 4 cm. Superficial type ALT exhibited poor tumor mobility and hardness with elastic soft. In addition, a significantly higher frequency of tumor location of superficial type ALT was observed in extremities. Among tumor sites at the trunk, buttocks, and shoulder were high frequent location in superficial type ALT. In an MRI examination, superficial type ALT exhibited a significantly higher frequency of the septal structures compared with benign lipoma. The combinations of clinical characteristics, including physical examinations, MRI, and histological examinations, are helpful for the diagnosis of superficial type ALT.

Safety and Efficacy of Imiquimod in the Treatment of Infantile Hemangioma; a Systematic Review and Meta-Analysis

Objective: To study the safety and efficacy of imiquimod in the treatment of infantile hemangioma (IH). Method: Systematic search was conducted in nine electronic databases for selecting relevant articles reporting the safety and efficacy of imiquimod as a therapeutic agent for treatment of IH. Meta-analysis was used to pool the results. Results: Of total 180 records screened, we included 9 studies for this systematic review and meta-analysis. About one-fifth of the patients (20.9%) have showed clinical resolution with 95% confidence interval (CI) of 11.8% to 34.1%. Regarding IH type, superficial type showed the highest rates of both clinical resolution and excellent response rates with 31.2% (95% CI= 16.6% to 50.8%) and 26.5% (95% CI= 11.6% to 49.6%), respectively. A relatively high prevalence of any side effects with 63.1% (95% CI= 47.6% to 76.3%) has been reported. The highest reported side effect was crustation (44.1%; 95% CI= 27.8% to 61.8%). Conclusion: Imiquimod is effective in the treatment of superficial IH and it is associated with local side effects.

Visualizing prolonged hyperperfusion in post-stroke epilepsy using postictal subtraction SPECT

Diagnosis of post-stroke epilepsy is often challenging because of a low incidence of epileptiform abnormalities on electroencephalography (EEG). Hence, this study evaluated whether postictal subtraction single-photon emission computed tomography (SPECT) could visualize epileptic activity and act as a diagnostic modality in post-stroke epilepsy. Fifty post-stroke epilepsy patients, who had undergone Tc-99m-ECD SPECT twice (postictal and interictal), were enrolled. The postictal hyperperfusion area was identified by subtraction (postictal–interictal) SPECT and classified into two distribution types: superficial or deep-seated. Laterality and distribution of postictal hyperperfusion on subtraction SPECT were compared with stroke lesions, seizure symptoms, and epileptiform EEG findings. Forty-three of the 50 patients (86%) had hyperperfusion on subtraction SPECT and 26 (52%) had epileptiform EEG findings. Subtraction SPECT showed prolonged postictal hyperperfusion despite the relatively long interval between seizure end and postictal SPECT (median: 19.1 h, range: 2.2–112.5 h). The laterality of the hyperperfusion area had a high concordance rate with the laterality of stroke lesions (97.7%), seizure symptoms (91.9%), and epileptiform EEG findings (100%). Scalp EEG identified epileptiform activity more frequently in superficial type of SPECT, but less frequently in deep-seated type (both, P = 0.03). Postictal SPECT can be complementary to scalp EEG in endorsing the diagnosis and location of post-stroke epilepsy.

Epidemiology of Melanoma in the Czech Republic in East Bohemia in the Period 2002–2017 and the Effect of the Annual Sunshine Exposure

Aim: The evaluation of the trend in the occurrence of melanoma nodulare, melanoma superficiale, lentigo maligna and melanoma in situ in the period of 2002–2017 in East Bohemia region in the Czech Republic. We examine if the annual numbers of hours of sunshine could affect the number of patients with melanoma. Method: In the peridod of 2002–2017, altogether 2230 patients with new diagnosis of melanoma were examined. We studied 1) If there is some trend in the occurrence of lentigo maligna and melanoma in situ, melanoma superficiale, and melanoma nodulare and if there is a difference in the age of patients with this diagnosis (adjusted calculation of specific kind of melanomas and adjusted calculation of age). 2) If the annual numbers of hours of sunshine affect the trend in the occurrence of melanoma and if the annual numbers of hours of sunshine affect the body site of melanoma. Results and conclusion: Our study confirmed that the number of patients with lentigo maligna and melanoma in situ had increased in East Bohemia region in the period of 2002–2017. The number of melanomas of nodular and superficial type does not increase. The total number of melanomas in this period does not increase either. No difference of the age of patients with melanoma nodulare, superficiale, lentigo maligna and melanoma in situ was confirmed. We confirmed no relation of the annual numbers of hours of sunshine to the number of melanoma and to the body site of melanoma.

Feasibility and Clinical Significance of In Vivo Cholesterol Crystal Detection Using Optical Coherence Tomography

Objective: Cholesterol crystals (CCs) are frequently found at the site of acute myocardial infarctions (AMIs), but the role of CCs in the onset of AMI remains unclear due to the lack of validated in vivo imaging tools. The aim of this study was to validate the ability of optical coherence tomography (OCT) to detect CCs and to compare the prevalence and distribution of CCs in patients with AMIs and stable angina pectoris. Approach and Results: CC assessment using OCT were compared with histopathology results in 45 coronary samples. We investigated 152 consecutive patients with AMIs and 41 patients with single vessel-diseased stable angina pectoris. Based on the presence of plaque ruptures (PR), AMI patients were divided into 2 groups: those with PR (n=112) and those without PR (n=40). CCs invading fibrous caps were defined as superficial-type CCs. A multivariable logistic regression analysis was performed to determine PR predictors. The sensitivity and specificity of OCT for detecting CCs were 68% and 92%, respectively. The prevalence of plaques with CCs was higher in the AMI with PR group (AMI with PR 81%, AMI without PR 48%, stable angina pectoris 39%, P <0.01). A multivariable logistic model showed that superficial-type CCs and thin-cap fibroatheromas were positive predictors for PR. Conclusions: OCT has a high specificity and modest sensitivity for the detection of CCs. The combination of CCs invading fibrous cap and thin-cap fibroatheromas detected by OCT may better identify rupture-prone plaques.

P3387Cholesterol crystals in superficial plaque layer detected by optical coherence tomography as a new morphological feature for plaque rupture

Background While plaque rupture (PR) is the leading cause of acute myocardial infarction (AMI), other etiologies are also involved in the onset of AMI. Cholesterol crystals (CCs) are usually present abundantly in atherosclerotic plaques, especially in the culprit site of AMI. However, the relationship between in vivo CCs and PR is unclear. Optical coherence tomography (OCT) is a high-resolution imaging technique that allows for the in vivo identification of various plaque characteristics including PR and CCs. Purpose The aim of this study was to investigate prevalence and distribution of CCs between patients with AMI with PR, AMI without PR, and SAP. Method This study consisted of 146 patients with coronary artery disease (AMI with PR; n=64, AMI without PR; n=41, and SAP; n=41) who underwent OCT prior to percutaneous coronary intervention. Plaque characteristics in OCT images were assessed according to the consensus document. We classified the distribution of CCs as follows; superficial type CCs were defined by any of the CCs invading the fibrous cap and remaining CCs as deep type CCs. Result There was no statistical difference in clinical characteristics among the three groups. The % diameter stenosis was significantly smaller in the SAP group than others (AMI with PR 91±12% vs. AMI without PR 86±13% vs. SAP 65±9%, p<0.001). The prevalence of CCs was significantly higher in the AMI with PR group than others (AMI with PR 78% vs. AMI without PR 41% vs. SAP 39%, p<0.001). The prevalence of superficial type CCs was significantly different among the groups (AMI with PR 72% vs. AMI without PR 24% vs. SAP 7%, p<0.001). Multivariable logistic analysis demonstrated that lipid plaque (OR 84.5, 95% CI [6.30–11332.33], p<0.001) and superficial type CC (OR 9.5, 95% CI [2.61–34.89], p<0.001) were independent predictors of PR. Conclusion Plaque with CCs invading the fibrous cap is frequently associated with PR in patients with AMI, suggesting. In vivo CC detection is a new morphological feature for plaque rupture. Acknowledgement/Funding This study was supported by a grant from JSPS KAKENHI (17K09557).