Apocrine carcinoma with marked sebocyte-like cytological features: A report of two cases.

Apocrine carcinoma cases with sebaceous differentiation have not been reported and can be misdiagnosed as sebaceous carcinoma. We present two cases of apocrine carcinoma with marked sebocyte-like cytological features. Tumors were observed in the left axilla of a 68-year-old man (Case 1) and the right axilla of a 72-year-old man (Case 2). Both patients presented with multiple lymph node metastases. Histopathology revealed densely distributed solid nests of tumor cells containing foamy cytoplasm and enlarged round nuclei with prominent nucleoli. The tumor cells diffusely expressed adipophilin, PRAME (cytoplasmic pattern), androgen receptor, BerEP4, and GCDFP15 but did not express p63 in both cases. PIK3CA E726K and H1047R mutations were detected in Cases 1 and 2, respectively. Tumor location in the axilla, the presence of eosinophilic granular cytoplasm, prominent nucleoli, and PIK3CA mutations, immunoreactivity for BerEP4 and GCDFP15, and lack of p63 immunoexpression findings matched apocrine carcinoma characteristics, but not sebaceous carcinoma. Thus, apocrine carcinoma can demonstrate intracytoplasmic lipid accumulation and rarely exhibit sebocyte-like cytological features. Apocrine carcinoma should be distinguished from sebaceous carcinoma due to the former's higher metastatic potential and lack of association with Muir-Torre syndrome.

Evaluation of prognostic prediction ability of the novel Japanese risk factor scoring system in a Japanese cohort of resectable cutaneous squamous cell carcinoma: A retrospective cross-sectional study.

Japanese patients with very high-risk cutaneous squamous cell carcinomas (cSCCs), based on the National Comprehensive Cancer Network guidelines, have been reported to display a higher cumulative incidence of relapse and disease-specific death (DSD) than those with high-risk cSCC. Therefore, prognosis prediction is crucial for Japanese patients with very high-risk cSCCs. Herein, we aimed to evaluate the prognostic prediction ability of our novel Japanese Risk Factor Scoring Systems (JARF scoring) in a Japanese cohort of cSSC patients. Data of 424 Japanese patients with resectable very high-risk cSCCs were analysed. We compared the prognostic ability of the following three staging systems: Brigham and Women's Hospital (BWH) tumour staging, number of NCCN very high-risk factors, and JARF scoring, including recurrent tumour, high-risk histological features, deep tumour invasion and lymphatic or vascular involvement as risk factors. The prognostic ability of these staging systems was evaluated according to the cumulative incidence of local recurrence (LR), regional lymph node metastasis (RLNM), DSD, and overall survival (OS). When BWH staging was used, high T stage led to significantly poor outcomes only in the cumulative incidence of RLNM (p = 0.01). The presence of very high-risk NCCN factors led to significantly poor outcomes in terms of RLNM (p = 0.03) and OS (p = 0.02). Meanwhile, a high number of risk factors in the JARF scoring system clearly led to poor outcomes in terms of LR (p = 0.01), RLNM (p < 0.01), DSD (p = 0.03), and OS (p < 0.01). The JARF scoring system may accurately predict the risk of recurrence and death in very high-risk cSCC patients in Japan.

Diseases and comorbidities associated with early-onset scoliosis: a retrospective multicenter analysis.

PURPOSE: To determine the frequencies of various diseases associated with all types of early-onset scoliosis, both idiopathic and nonidiopathic. METHODS: Retrospective collection of patients within a 21-year interval. Children under 10 years old presenting with scoliosis were included. Medical records were used to collect: identifier, date of birth, sex, diagnosis, follow-up, curve pattern, comorbidities, initial and final cobb angle. Different patient variables were tabulated with associated comorbidities for comparison. RESULTS: The cohort contained 469 patients, with 227(48.4%) males and 242(51.6%) females. Total comorbidities equaled 1051, where 190 were unique. Only 124(26.4%) patients had an isolated diagnosis of early-onset scoliosis, 79(16.8%) had a single comorbidity, and 266(56.7%) had multiple comorbidities. "Global developmental delay" was most commonly observed, 198(42.2%) times. The central nervous system was involved more often than other organ systems, seen in 394(54.4%) instances. Males had more comorbidities than females. Idiopathic patients had the least number of comorbidities, while neuromuscular patients had the most. Idiopathic types had more musculoskeletal conditions, while congenital types had more cardiovascular diseases. Curve sides did not affect distributions. Cases which progressed had more comorbidities, especially in the respiratory, digestive, and cardiovascular systems. Diseases that could affect either extremity or side, were more likely to be bilateral. CONCLUSIONS: Early-onset scoliosis patients may present with complex comorbidities in multiple organ systems. The most commonly observed disease entities were: global developmental delay, developmental dysplasia of the hip, and epilepsy. Clinicians should be aware of the common associations, in order to screen for and begin appropriate investigations, referrals, and treatments in affected cases. LEVEL OF EVIDENCE: Level III.

Deriving a Novel Score for the Stratification of Risk Progression in Early-onset Scoliosis: A Multicenter Initiative.

STUDY DESIGN: This was a retrospective multicenter study. OBJECTIVE: To develop a novel progression risk stratification scoring system for early-onset scoliosis. SUMMARY OF BACKGROUND DATA: There is a lack of investigations into variables affecting the risk of curve progression in early-onset scoliosis, which prevents stratification. A novel risk score system is needed to help in progression risk estimation. METHODS: A retrospective analysis was done at three centers, from 1995 to 2020. Scoliosis cases before the age of 10 years, were included. Medical identifier, date of birth, sex, primary diagnosis, curve type, date/modality of treatment, date of follow-up appointments, and Cobb angles, were collected. Five ranks were selected for stratification. Categories with the same ranks were discarded. Point scores started at 0, for the lowest risk, and ended at 4, for highest risk. Iterations of variable combinations were conducted and clinical relevance was determined by evaluating sensitivity, specificity, positive predictive value, and negative predictive value based on score ranges for low and high risk of progression. RESULTS: A total of 476 (230 males, 246 females) early-onset scoliosis patients were collected. The average age at diagnosis was 4.8 years (SD±2.8 yr). The average follow-up duration was 9.3 years (SD±6.9 yr, range: 5 mo-38 yr). Appointments totaled 2911, giving 2182 observations for the analysis. Patient observations numbered: 800 (36.7%) ending in progression, 1265 (58.0%) for nonprogression, 117 (5.4%) for inadequate follow-up, and 368 (16.9%) for rapid progression. The risk scoring system contained four categories: etiology, age, curve magnitude, and curve type. Categorized point combinations totaled 755, giving 1975 iterations. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated to be 85.8%, 96.5%, 89.7%, and 95.1%, respectively. CONCLUSION: A novel progression risk score for early-onset scoliosis was derived. The system can reliably differentiate between low and high-risk cases in clinical settings. Further validation in other regions may be important for verifying clinical relevance. LEVEL OF EVIDENCE: Level 3.

Knapperer Resektionsrand bei Plattenepithelkarzinomen mit hohem oder sehr hohem Risiko: eine retrospektive multizentrische Studie mit 1000 Patienten.

HINTERGRUND UND ZIELE: Bei kutanen Plattenepithelkarzinomen (PEK) ist die Einhaltung der in Leitlinien empfohlenen festen Resektionsränder oft schwierig und knappere Ränder sind wünschenswert. Ziel dieser Studie war die Bewertung des Auftretens von Rezidiven und krankheitsspezifischen Todesfällen bei knapperen Resektionsrändern für PEK mit hohem oder sehr hohem Risiko. PATIENTEN/METHODEN: PEK-Patienten mit hohem oder sehr hohem Risiko, bei denen eine Tumorexzision durchgeführt wurde, wurden retrospektiv untersucht. Die Patienten wurden in eine Gruppe mit Standardrand gemäß Leitlinienempfehlung (standard margin group, SMG) und eine Gruppe mit knapperen Rändern (narrower-margin group, NMG) eingeteilt. Gemeinsame primäre Endpunkte waren lokales Rezidiv, PEK-Rezidiv und PEK-bedingter Tod. Die Wahrscheinlichkeit eines PEK-bedingten Tods und konkurrierender Mortalitätsrisiken wurde mittels kumulativer Inzidenzfunktion (CIF) beschrieben. Unterschiede bei der CIF zwischen den Gruppen wurden mit dem Test nach Gray verglichen. ERGEBNISSE: Insgesamt wurden 1.000 Patienten mit PEK (hohes Risiko, 570; sehr hohes Risiko, 430) eingeschlossen. In der Kohorte mit hohem Risiko gab es keine signifikanten Unterschiede bei der unvollständigen Exzisionsrate (IER) zwischen SMG und NMG (2,6 % vs. 3,0 %, P > 0,99). In der Kohorte mit sehr hohem Risiko war die IER in der SMG jedoch signifikant geringer als in der NMG (8.9 % vs. 16.2 %, P = 0,03). Keine signifikanten Unterschiede zwischen SMG und NMG wurden für Lokalrezidiv (hohes Risiko, P = 0.56; sehr hohes Risiko, P = 0,70), PEK-Rezidiv (hohes Risiko, P = 0,30; sehr hohes Risiko, P = 0,47) und PEK-bedingtem Tod (hohes Risiko, P = 0,23; sehr hohes Risiko, P = 0,83) beobachtet. SCHLUSSFOLGERUNGEN: Die Größe des Resektionsrands hat einen begrenzten Einfluss auf Randkontrolle, Rezidive und krankheitsspezifischen Tod bei PEK mit hohem Risiko.

Narrower clinical margin in high or very high-risk squamous cell carcinoma: a retrospective, multicenter study of 1,000 patients.

BACKGROUND AND OBJECTIVES: In cutaneous squamous cell carcinoma (cSCC), adherence to guideline-recommended fixed surgical margins is often difficult, and narrower margins are preferable. This study aimed to evaluate relapse and disease-specific death with narrower margins for high or very high-risk cSCC. PATIENTS/METHODS: We retrospectively investigated high or very high-risk cSCC patients who underwent tumor excision. Patients were divided into guideline-recommended standard margin group (SMG) and narrower-margin group (NMG). Co-primary outcomes were local relapse, SCC relapse, and SCC death. Cumulative incidence function (CIF) was used to describe SCC death probability and competing risk mortality. Gray's test was used to compare differences in CIF between the groups. RESULTS: In total, 1,000 patients with cSCC (high-risk, 570; very high-risk, 430) were included. In the high-risk cohort, there were no significant differences in incomplete excision rate (IER) between SMG and NMG (2.6 % vs. 3.0 %, P > 0.99). However, in the very high-risk cohort, IER in SMG was significantly lower than in NMG (8.9 % vs. 16.2 %, P = 0.03). No significant differences were observed between SMG and NMG for local relapse (high-risk, P = 0.56; very high-risk, P = 0.70), SCC relapse (high-risk, P = 0.30; very high-risk, P = 0.47), and SCC death (high-risk, P = 0.23; very high-risk, P = 0.83). CONCLUSIONS: Surgical margin size has limited impact on margin control, relapse, and disease-specific death in high-risk cSCC.

Concordance in judgment of clinical borders of basal cell carcinomas in Japanese patients: A preliminary study of JCOG2005 (J-BASE-MARGIN).

Basal cell carcinoma is the most common type of skin cancer, and surgical excision with clear margins is the standard of care. Surgical margins are determined based on risk factors (high or low risk) for recurrence according to the National Comprehensive Cancer Network and Japanese basal cell carcinoma guidelines. The clarity of the clinical tumor border (well-defined or poorly defined) is considered a risk factor, and significant discrepancies in the judgment of clinical tumor borders among dermato-oncologists may occur. Therefore, we analyzed the dermato-oncologists' concordance in judging the clinical tumor border of basal cell carcinoma. Forty-seven dermato-oncologists (experts: 37; young trainees: 10) participated in this study. The datasets of clinical and dermoscopic photographs of 79 Japanese cases of head and neck basal cell carcinoma were used to determine the concordance in the judgment of clinical tumor border. The probability of the border that was selected more often was used to calculate the rater agreement rate for each dataset. Correct judgment was defined as a more frequently selected border, and the concordance rate of clarity of clinical tumor border for each dermato-oncologist was calculated based on the definition of the correct judgment. A median concordance rate of 85% or higher for all dermato-oncologists was predefined as an acceptable rate for clinical use. Of the 79 datasets, rater agreement rates were 80-100%, 60-79%, and 51-59% for 55, 19, and five datasets, respectively. The median concordance rate for all dermato-oncologists was 86% (interquartile range: 82-89%). There was no significant difference in the concordance rate between the experts and the trainees (median, 87% vs. 85.5%; p = 0.58). The concordance rates of dermato-oncologists for all datasets were relatively high and acceptable for clinical use.

The incidence and prevalence of early-onset scoliosis: a regional multicenter epidemiological study.

BACKGROUND CONTEXT: Despite the many advances in understanding and treating early-onset scoliosis, the incidence and prevalence of this disease in the population remains unknown. Such knowledge is important for guiding clinical practice, directing research and raising awareness. PURPOSE: To identify the incidence and prevalence of early-onset scoliosis, including all categories, within the population. STUDY DESIGN: A regional multicenter retrospective cohort study PATIENT SAMPLE: All patients diagnosed with early-onset scoliosis in the region, who were followed-up between January 2000 and December 2020. OUTCOME MEASURES: Frequency distributions for early-onset scoliosis subtypes, demographics, curve patterns and progression statuses. METHODS: Relevant population data, for children under 10 years old, was extracted from the official government census for the years 2000 to 2020. Identification of cases was carried out by pediatricians at mandatory government funded regular child wellness check-up visits. Outpatient records were reviewed for all included patients, with extraction of the following: Medical identifier, date of birth, date of initial visit, sex, primary diagnosis, length of follow-up, curve pattern, initial cobb angle, and final cobb angle. Incidence and prevalence values were calculated using population figures and case numbers. Kaplan-Meier survival analysis and Log-rank testing was performed on curve progression data. RESULTS: The regional population of children, under the age of 10 years, included a total of 2,295,929 children, 1,170,149 (51.0%) males and 1,125,780 (49.0%) females, between the years 2000 and 2020. Early-onset scoliosis cases followed within the same timeframe, totaled 469 patients, 227 (48.4%) males and 242 (51.6%) females. The annual incidence of early-onset scoliosis was found to be 0.019% (95% CI: 0.015%-0.023%), and the prevalence was 0.077% (95% CI: 0.059%-0.096%). The most common age at first presentation was 6 years old. More females (51.6%) than males (48.4%) were observed, and more left-sided curves (54.2%) than right-sided curves (45.8%) were encountered, with the majority being single thoracic curves (38.2%). Scoliosis curves did not progress in 44.3% of cases, while they progressed in 38% of them. Follow-up was inadequate to determine progression status in 17.7% of cases. Neuromuscular etiologies were the most common, at 40.1%, of which 83.5% had cerebral palsy. CONCLUSIONS: Based on the regional population included in this study, the annual incidence of early-onset scoliosis in children under 10 years old was calculated to be 0.019%, while the prevalence of early-onset scoliosis in children under 10 years old was found to be 0.077%.

Polyherbal Formulation Enhancing Cerebral Slow Waves in Sleeping Rats.

Polyherbal medicines are composed of multiple herbs and have traditionally been used in East Asian countries for the remedy of physiological symptoms. Although the effects of polyherbal formulations have been investigated at the molecular and behavioral levels, less is known about whether and how medicinal herbs affect the central nervous system in terms of neurophysiology. We introduced a novel blended herbal formulation that consisted of 35% linden, 21% mulberry, 20% lavandin, 20% butterfly pea, and 4% tulsi. After intraperitoneal administration of this formulation or saline, we simultaneously recorded epidural electrocorticograms (ECoGs) from the olfactory bulb (OB), primary somatosensory cortex (S1), and primary motor cortex (M1), along with electromyograms (EMGs) and electrocardiograms (ECGs), of rats exploring an open field arena. Using the EMGs and OB ECoGs, we segmented the behavioral states of rats into active awake, quiet awake, and sleeping states. Compared to saline, herbal medicine significantly shortened the total sleep time. Moreover, we converted the ECoG signal into a frequency domain using a fast Fourier transform (FFT) and calculated the powers at various ECoG oscillation frequencies. In the sleeping state, a slow component (0.5-3 Hz) of S1 ECoGs was significantly enhanced following the administration of the formulation, which suggests a region- and frequency-specific modulation of extracellular field oscillations by the polyherbal medicine.

Prediction of the invasive level of basal cell carcinomas in the facial area: Analysis of 718 Japanese cases.

BACKGROUND: Basal cell carcinoma (BCC) is the most common skin cancer. While Mohs micrographic surgery is commonly accepted for BCC treatment, surgical excision with free margins is widely considered the best treatment modality for BCCs in Japan. However, little is known about the predictors of the invasion levels of BCCs. OBJECTIVE: To investigate the optimization of deep surgical margins by identifying factors significantly influencing the invasion levels of facial BCCs. METHODS: The tumor invasion level was defined as the deepest part of a tumor. Tumor thickness was measured from the top of the granular layer to the deepest extension of the tumor or from the ulcer base overlying the deepest point of invasion in ulcerated lesions. Factors independently associated with tumor thickness and invasion level were identified by multivariate analysis. Six variables were tested: age, sex, anatomical region (nose, orbit, others), histologic pattern (aggressive, non-aggressive), presence of pigmentation, and diameter. RESULTS: We included 718 cases of facial BCCs involving 705 Japanese patients. The most frequent anatomical region and histologic pattern were the nose and nodular pattern, respectively. Only tumor diameter showed a correlation with tumor thickness (ß = 0.377, P < 0.001). Tumor diameter (AOR = 71.189, 95 % CI: 11.420-430.931, P = 0.01) and the following anatomical regions showed correlations with the invasion level: nose/others: AOR=2.769, 95 % CI: 1.235-6.493, P = 0.01; orbit/others: AOR=6.369, 95 % CI: 2.728-15.429, P < 0.001; orbit/nose: AOR=2.300, 95 % CI: 1.056-4.984, P = 0.04. CONCLUSIONS: This study serves as a guide for optimizing deep surgical margins and planning surgery for facial BCCs considering independently associated factors.

Vitiligo expansion and extent correlate with durable response in anti-programmed death 1 antibody treatment for advanced melanoma: A multi-institutional retrospective study.

Vitiligo is an autoimmune disorder resulting from the destruction of melanocytes. Several reports indicate the association between vitiligo and treatment response in advanced melanoma during immunotherapy. It has not been investigated, however, if an increase of vitiligo while on treatment with anti-programmed death 1 (PD-1) antibodies is associated with more durable responses. The aim of this study is to evaluate the correlation between the vitiligo dynamics and clinical efficacy of anti-PD-1 antibodies. This study included advanced melanoma patients who were treated with nivolumab or pembrolizumab and developed vitiligo thereafter. Correlation between vitiligo expansion (defined as an increase of lesion size at two separate time points at least 4 weeks apart) as well as vitiligo extent (body surface area [BSA] affected) and clinical efficacy based on response rate, progression-free survival and overall survival was assessed. We retrospectively reviewed 29 patients. The median time from the initiation of anti-PD-1 antibody to vitiligo onset was 4.3 months in patients who showed a response and 5.5 months in patients who showed no response (P = 0.31). Twelve patients showed vitiligo expansion, and in nine of these patients, vitiligo increased to grade 2 (covering ≥ 10% BSA). Vitiligo expansion and grade 2 vitiligo showed no improvement in treatment response (P = 0.59 and 0.25) but were associated with prolonged progression-free survival (P = 0.019 and 0.04). Grade 2 vitiligo also showed a trend for prolonged overall survival (P = 0.07). Trend of expansion and larger vitiligo extent may be predictive factors of prolonged survival during anti-PD-1 antibody in melanoma patients.

Confirmatory trial of non-amputative digit preservation surgery for subungual melanoma: Japan Clinical Oncology Group study (JCOG1602, J-NAIL study protocol).

BACKGROUND: Amputation is the standard of care even for early-stage subungual melanomas (SUMs), known as nail apparatus melanoma, because the nail bed and nail matrix are close to the distal phalanx. However, a recent study demonstrated that not all patients with SUMs had histologic invasion of the underlying distal phalanx. As most SUMs occur in the thumb or big toe, amputation of either the thumb or big toe substantially interferes with activities of daily living, including poor cosmesis, loss of function, and phantom pain. Non-amputative digit preservation surgery can thus be applied in such cases without compromising patient prognosis. METHODS: We are conducting a multi-institutional single-arm trial to confirm the safety and efficacy of non-amputative digit preservation surgery. We will compare our results with those reported in the Japanese Melanoma Study, in which patients underwent amputation for SUMs as a traditional standard of care. Patients aged between 20 and 80 years with stage I, II, or III without evidence of tumor invasion to the underlying distal phalanx on preoperative radiograph are included in the study. The primary endpoint is major relapse-free survival (major RFS), which does not include local recurrence as an event; secondary endpoints include overall survival, digit-preservation survival, relapse-free survival, local relapse-free survival, partial relapse-free survival, and incidence of adverse events. A total of 85 patients from 21 Japanese institutions will be recruited within 5.5 years, and the follow-up period will last at least 5 years. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in August 2017, and patient enrollment began in November 2017. Ethical approval was obtained from each institution's Institutional Review Board prior to patient enrollment. DISCUSSION: This is the first prospective trial to confirm the safety and efficacy of non-amputative digit preservation surgery for SUM without distant metastasis or bony invasion. The results of this trial could provide evidence to support this less-invasive surgery as a new standard of care to preserve adequately functioning digits. TRIAL REGISTRATION: Registry number: UMIN000029997 . Date of Registration: 16/Nov/2017. Date of First Participant Enrollment: 12/Dec/2017.