Line-field confocal optical coherence tomography for actinic keratosis and squamous cell carcinoma: a descriptive study.

BACKGROUND: Early and accurate diagnosis of cutaneous squamous cell carcinomas (SCCs) and actinic keratoses (AK) is fundamental to reduce their associated morbidity and to select the correct treatment. Line-field confocal optical coherence tomography (LC-OCT) is a new imaging device that can characterize healthy skin and basal cell carcinoma, but no large studies on keratinocyte cell tumours have yet been published. AIM: To identify and describe LC-OCT criteria associated with SCC and AK, and to compare LC-OCT findings in these tumours. METHODS: A retrospective observational multicentre study was conducted. Lesions were imaged with the LC-OCT device before surgery and examined histologically. LC-OCT criteria for AK/SCC were identified and their presence was evaluated in all study lesions. Univariate and multivariate analyses were performed to compare AK and SCCs, and to investigate differences between in situ and invasive tumours. RESULTS: In total, 158 patients with 50 AK and 108 SCCs (62 in situ and 46 invasive) were included. Cytological and architectural alterations were found in most lesions, and differences were found between AK and SCCs. Although the visualization of the dermoepidermal junction (DEJ) was often hampered by hyperkeratosis and acanthosis, an outlined DEJ without broad strands was observed in almost all AK and almost all in situ SCCs, but in only three invasive SCCs (P < 0.001) when the DEJ was detectable. CONCLUSION: Our results suggest that LC-OCT can help clinicians in the identification of AK and SCC and their differentiation, providing a real-time and noninvasive examination. Further studies are needed to confirm our data.

Line-field confocal optical coherence tomography of basal cell carcinoma: a descriptive study.

BACKGROUND: Early diagnosis and subtype classification of basal cell carcinoma (BCC) are crucial to reduce morbidity and optimize treatment. Good accuracy in differentiating BCC from clinical imitators has been achieved with existing diagnostic strategies but lower performance in discriminating BCC subtypes. Line-field confocal optical coherence tomography (LC-OCT) is a new technology able to combine the technical advantages of reflectance confocal microscopy and OCT. OBJECTIVES: To identify and describe LC-OCT criteria associated with BCC and explore their association with BCC subtypes. METHODS: Basal cell carcinoma were imaged with a handheld LC-OCT device before surgical excision. LC-OCT images were retrospectively evaluated by three observers for presence/absence of criteria for BCC. Multivariate logistic regression models were used to find independent predictors of BCC subtypes. RESULTS: Eighty-nine histopathologically proven BCCs were included, of which 66 (74.2%) were pure subtypes [superficial BCC (sBCC): 19/66 (28.8%); nodular BCC (nBCC): 31/66 (47.0%); infiltrative BCC (iBCC): 16/66 (24.2%)]. Lobules, blood vessels and small bright cells within epidermis/lobules were the most frequent criteria for BCC. LC-OCT criteria independently associated with sBCC were presence of hemispheric lobules, absence of lobule separation from the epidermis, absence of stretching of the stroma; with nBCC were presence of macrolobules, absence of lobule connection to the epidermis; and with iBCC were presence of branched lobules. CONCLUSIONS: This was the first study describing the characteristics of BCC under LC-OCT examination. We proposed morphologic criteria, which could be potentially useful for diagnosis and subtype classification of BCC, as well as for its therapeutic management. Future studies are needed to assess these hypotheses.

Two cases of BRAF-mutated, bulbar conjunctival melanoma, and review of the published literature.

We describe two patients with BRAF-mutated melanoma of the epithelioid cell type arising from primary acquired melanosis with severe atypia of the right bulbar conjunctiva. Patient 1 was a 71-year-old Japanese man. After adjuvant cryotherapy and enucleation of the right eyeball, therapy with vemurafenib was administered for a distant metastasis to a lumbar vertebra, accompanied by erythema multiforme and two keratinous tumours. The patient died due to metastases to the liver and multiple vertebrae, despite therapy with nivolumab and combination therapy with dabrafenib plus trametinib. Patient 2 was a 72-year-old Japanese man. After adjuvant cryotherapy, periodic mitomycin C eye drops, and excision of the superficial portion of the right parotid gland and the dissection of cervical lymph nodes, he was treated with adjuvant combination therapy with dabrafenib plus trametinib. Dermatologists should be familiar with BRAF-mutated conjunctival melanoma, which is usually located on the bulbar conjunctiva and associated with more frequent distant metastasis.

In vivo characterization of healthy human skin with a novel, non-invasive imaging technique: line-field confocal optical coherence tomography.

BACKGROUND: Line-field confocal optical coherence tomography (LC-OCT) is a non-invasive optical technique recently developed for skin examination in vivo. It provides real-time, high-resolution vertical images with an isotropic resolution of ~1 µm and a penetration depth of ~500 µm. OBJECTIVES: Study goals were to qualitatively/quantitatively characterize healthy skin at different body sites using LC-OCT. METHODS: The skin of young healthy volunteers was imaged with a handheld LC-OCT imaging device. Seven body sites (back of the hand, forehead, cheek, nose, chest, forearm and back) were investigated. An independent qualitative [cutaneous structures' description; visibility of keratinocytes' nuclei and dermal-epidermal junction (DEJ)] and quantitative [stratum corneum (SC)/epidermal thicknesses; height of dermal papillae] assessment of the LC-OCT images was performed. RESULTS: A total of 88 LC-OCT images were collected from 29 participants (20 females; nine males; mean age 25.9 years). Keratinocytes' nuclei and DEJ were visible in the totality of images. The different layers of the epidermis and the remaining cutaneous structures/findings were visualized. Body sites-related variability was detected for SC/epidermal thicknesses and height of dermal papillae. Inter-observer agreement was excellent (SC thickness), good-to-excellent (epidermal thickness) and moderate-to-good (papillae). CONCLUSIONS: Line-field confocal-OCT provides non-invasive, real-time imaging of the skin in vivo with deep penetration and high resolution, enabling the visualization of single cells. The histology-like vertical view provides an easy way to recognize/measure different cutaneous structures/findings. LC-OCT appears as a promising technique for the examination of physiological/pathological skin.

Cerebrospinal fluid orexin-A levels in systemic lupus erythematosus patients presenting with excessive daytime sleepiness.

Objective Involvement of the hypothalamus is rare in patients with systemic lupus erythematosus (SLE). In this study, we measured cerebrospinal fluid (CSF) orexin-A levels in SLE patients with hypothalamic lesions to investigate whether the orexin system plays a role in SLE patients with hypothalamic lesions who present with excessive daytime sleepiness (EDS). Methods Orexin-A levels were measured in CSF from four patients with SLE who presented with hypothalamic lesions detected by MRI. Three patients underwent repeated CSF testing. All patients met the updated American College of Rheumatology revised criteria for SLE. Results Tests for serum anti-aquaporin-4 antibodies, CSF myelin basic protein and CSF oligoclonal bands were negative in all patients. All patients presented with EDS. Low to intermediate CSF orexin-A levels (92-180 pg/ml) were observed in three patients in the acute stage, two of whom (patients 1 and 2) underwent repeated testing and showed increased CSF orexin-A levels, reduced abnormal hypothalamic lesion intensities detected by MRI and EDS dissipation at follow-up. In contrast, CSF orexin-A levels were normal in one patient (patient 4) while in the acute stage and at follow-up, despite improvements in EDS and MRI findings. Patient 4 showed markedly increased CSF interleukin-6 levels (1130 pg/ml) and a slightly involved hypothalamus than the other patients. Conclusions Our findings suggest that the orexinergic system has a role in EDS in SLE patients with hypothalamic lesions. Furthermore, cytokine-mediated tissue damage might cause EDS without orexinergic involvement.

A new algorithm for the discrimination of actinic keratosis from normal skin and squamous cell carcinoma based on in vivo analysis of optical properties by high-definition optical coherence tomography.

BACKGROUND: High-definition optical coherence tomography (HD-OCT) features of actinic keratosis (AK) may aid in its diagnosis and therapeutic strategy. A diagnostic algorithm permitting discrimination of AK from squamous cell carcinoma (SCC) and normal skin has been proposed. However, diagnostic accuracy strongly depends on the experience of physicians. In two recent studies, it was demonstrated that HD-OCT permits to quantify in vivo optical properties such as light attenuation in intrinsic ageing skin, in melanocytic lesions and in basal cell carcinoma. This approach seems to permit a semiautomated classification of lesions easier to handle by non-experts. OBJECTIVES: The aim of this paper was to quantify in vivo optical properties of facial located AK/SCC lesions, such as light attenuation, by HD-OCT. Additional objectives were to determine the best critical value of these optical properties for discrimination of AK from SCC and from normal sun exposed skin and to subdifferentiate AKs. METHODS: The technique of semi-log plot has been implemented on HD-OCT signals. This permitted the in vivo measurement of OCT signals coming from the skin entrance up to the superficial reticular dermis. Moreover, relative attenuation factor (µraf ) at different skin layers (1-3) could be determined. RESULTS: Optical properties with high diagnostic accuracy (DA) and high negative predictive values (NPV) could be defined permitting the differentiation between normal skin, non-Bowenoid AK without follicular involvement, non-Bowenoid AK with follicular involvement, Bowenoid AK, hypertrophic and lichenoid form of AK and squamous cell carcinoma. CONCLUSION: HD-OCT seems to enable the combination of in vivo morphological analysis of cellular and 3D microarchitectural structures with in vivo analysis of optical properties of tissue scatterers in AK/SCC lesions and normal sun-exposed skin. In vivoHD-OCT analysis of optical properties permits AK discrimination from SCC and AK subdifferentiation with higher accuracy than in vivoHD-OCT analysis of morphology alone.

Dedifferentiated endometrioid adenocarcinoma of the uterus: a case report.

BACKGROUND: Dedifferentiated endometrioid adenocarcinoma (DEAC) of the uterus was first described by Silva et al. in 2006. The tumor has high-grade endometrial carcinoma component which abruptly emerged from low-grade areas. DEAC showed more aggressive phenotype than FIGO grade 3 endometrioid adenocarcinoma. However, there have been a few studies evaluating effectiveness of adjuvant therapy for the patients with DEC. CASE REPORT: A 41-year-old case with Stage IVB DEAC that clinically showed resistance to several regimens of chemotherapy is reported. The uterine corpus tumor with size of 120 x 100 mm, and the metastases were found in lung, liver, and pelvic lymph nodes. She underwent supra-vaginal hysterectomy, left salpingo-oophorectomy, and partial resection of ileum. Pathologically, the tumor had both well differentiated and undifferentiated carcinoma components, and it was diagnosed as DEAC. After primary surgery, the patient received four regimens of adjuvant chemotherapy, however all regimens were judged as progressive disease. Subsequently, the patient died of disease seven months after surgery. CONCLUSION: The present case of DEAC had an exceedingly poor prognosis, as was suggested in the several previous reports. The review of adjuvant therapeutic modalities revealed that there has been no effective therapy in the response-evaluable patients with DEAC. Further investigations for new strategy to treat the cases with DEAC are needed.

High-temperature-required protein A2 as a predictive marker for response to chemotherapy and prognosis in patients with high-grade serous ovarian cancers.

BACKGROUND: High-temperature-required protein A2 (HtrA2), a protein relating with apoptosis in a caspases-dependent and non-dependent manner, has been reported to be associated with chemosensitivity in several human cancers. METHODS: Tissue microarrays made from 142 patients with high-grade serous ovarian adenocarcinoma were evaluated to assess whether HtrA2 expression was related with several clinical parameters. RESULTS: Negative HtrA2 expression was observed in 36 cases (25%) of the patients, and related with significantly lower response rates of primary chemotherapy than those with positive HtrA2 expression (56% vs 83%, P<0.01). In addition, negative HtrA2 expression was identified as an independent worse prognostic factor for progression-free survival and overall survival by multivariate analyses. Furthermore, HtrA2 downregulation modulated sensitivity to platinum in serous ovarian cancer cells in vitro. CONCLUSIONS: HtrA2 expression was a predictor for sensitivity to chemotherapy, and could be a candidate of molecular target in the treatment of high-grade serous ovarian cancers.

Interlayer structure and self-healing in suspensions of brush-stabilized nanoplatelets with smectic order.

We have investigated the rheology of an uncured epoxy fluid containing high aspect ratio (length/thickness ≈ 160) α-zirconium phosphate (ZrP) nanoplatelets with smectic order. The nanoplatelets were exfoliated into monocrystalline sheets with uniform thickness using a monoamine-terminated oligomer. The oligomers were densely grafted to the plate surfaces and behave as a molecular brush. Suspensions containing ∼ 2 vol.% ZrP and above show liquid crystalline order with scattering peaks characteristic of a smectic (layered) mesophase. At much higher loading, ∼ 4 vol.% ZrP, there is a sharp transition in visual appearance, steady shear rheology, and linear and non-linear viscoelasticity that is attributed to the reversible interdigitation of oligomer chains between closely spaced layers. The oligomers are proposed to serve as inter-lamellar bridges that store elastic stresses for intermediate rates of deformation, but are able to relax on longer time scales. Under steady shearing conditions, the smectic suspensions with "overlapped" microstructure show a discontinuous flow curve characteristic of shear banding that is attributed to the dynamic pull-out of oligomer chains from the overlap region. At high shear rates, the limiting viscosity of the concentrated suspensions is on the same order of magnitude as the unfilled suspending fluid. When the rate of deformation is reduced below a critical time scale, the original network strength, and corresponding microstructure, is recovered through a passive self-healing process. The unique combination of concentration-dependent yield stress, low post-yield viscosity, and self-healing is potentially useful for various applications in the liquid state, and desirable for scalable processing of nanocomposite materials for structural applications.

Evaluation of cutoff scores for the Parkinson's disease sleep scale-2.

BACKGROUND: The Parkinson's Disease Sleep Scale (PDSS)-2 is a recently developed tool for evaluating disease-related nocturnal disturbances in patients with Parkinson's disease (PD). However, its cutoff score has not been clinically assessed. We determined the optimal cutoff score of the Japanese version of the PDSS-2. METHODS: Patients with PD (n = 146) and controls (n = 100) completed the PDSS-2 and the Pittsburgh Sleep Quality Index (PSQI). Poor sleepers were defined as having global PSQI scores >5. Optimal cutoff scores for determining poor sleepers were assessed using the receiver operating characteristic curve. RESULTS: A PDSS-2 total score ≥ 14 exhibited 82.0% sensitivity and 70.6% specificity, whereas a PDSS-2 total score ≥ 15 provided 72.1% sensitivity and 72.9% specificity in distinguishing poor sleepers (PSQI score >5) from good sleepers (PSQI ≤ 5). Nocturnal disturbances were more frequently observed in patients with PD than in controls (PDSS-2 total score ≥ 14 or ≥ 15; 51.4% vs 20%; 45.9% vs 19%). Nocturnal disturbances were associated with higher Hoehn and Yahr stages and Unified Parkinson's Disease Rating Scale motor scores, impaired quality of life, daytime sleepiness, and depressive symptoms. CONCLUSION: We suggest that PDSS-2 total scores ≥ 15 are useful for detecting poor sleepers among patients with PD.

High-definition optical coherence tomography algorithm for the discrimination of actinic keratosis from normal skin and from squamous cell carcinoma.

BACKGROUND: Preliminary studies described morphological features of actinic keratosis (AK) and squamous cell carcinoma (SCC) imaged by High-Definition Optical Coherence Tomography (HD-OCT) and suggested that this technique may aid in their diagnosis. However, systematic studies evaluating the accuracy of HD-OCT for the diagnosis of AK and SCC are lacking so far. OBJECTIVE: In this study, we sought to design an algorithm for AK classification that could (i) distinguish SCC from AK and normal skin, (ii) differentiate AK from normal skin and (iii) discriminate AKs with adnexal involvement from those without. METHODS: A total of 53 histopathologically confirmed lesions (37 AKs and 16 SCC) were imaged by HD-OCT. Fifty-three HD-OCT images of normal skin of healthy volunteers, with matched age, skin type and anatomic site, were taken as reference. By comparing these 106 en face and cross-sectional HD-OCT images, particular features were selected based on their potential to discriminate AK from normal skin and from SCC, and to assess adnexal involvement in AK. This study represents a training set not a testing set. Severe (>300 µm) hyperkeratotic AKs were not included in this study. RESULTS: Particular features with high Phi coefficient could be identified. The absence of an outlined dermo-epidermal junction (DEJ) on cross-sectional images allowed discriminating SCC from AK and normal skin (Phi coefficient = 0.84). AK could be discriminated from normal skin in both imaging modes by the presence of alternating hyperkeratosis/parakeratosis in cross-sectional mode and/or variability in shape, size and reflectivity of cells (atypical honeycomb pattern) in en face mode. Adnexal involvement of AK could be assessed by the disappearance of the typical cocarde image of adnexal epithelium in en face mode. CONCLUSION: This study provides select 3-D HD-OCT features having a potential to discriminate SCC from AK and normal skin. Based on these particular features with high Phi coefficient, a diagnostic algorithm is designed which will be used later in validation studies to determine HD-OCT accuracy in AK/SCC classification.

High-definition optical coherence tomography algorithm for discrimination of basal cell carcinoma from clinical BCC imitators and differentiation between common subtypes.

BACKGROUND: Preliminary studies have described morphological features of basal cell carcinoma (BCC) imaged by high-definition optical coherence tomography (HD-OCT) and suggested that this technique may aid in its diagnosis and management. However, systematic studies evaluating the accuracy of HD-OCT for the diagnosis of BCC are lacking. OBJECTIVE: The aim of this study was to identify three-dimensional (3-D) HD-OCT features able i) to distinguish BCC from clinical BCC imitators and ii) to discriminate between the most common BCC subtypes. Based on these particular features, a diagnostic algorithm will be suggested. METHOD: A total of 50 histopathologically confirmed BCCs (18 superficial, 19 nodular, 13 infiltrative) were imaged by HD-OCT at the centre of the lesion prior to standard surgical excision and subsequent histopathological analysis. Fifty images of clinical BCC imitators were also retrieved as a 'pitfalls' group. RESULTS: The simultaneous presence of grey/dark subepidermal (hemi-spherical) or intradermal lobulated structure(s) presenting a typical cockade feature in both HD-OCT modes was a significant feature for BCC diagnosis. Features discriminating between BCC subtypes were location of the roof of BCC lobules, vascular pattern of the papillary plexus and stretching effect on the stroma. Clinical BCC imitators such as actinic keratosis, compound and intradermal naevi, amelanotic melanoma, sebaceous hyperplasia and small haemangioma could be differentiated from BCC by means of HD-OCT. CONCLUSION: This study provides a thorough description of 3-D HD-OCT features that can permit discrimination of BCC from clinical BCC imitators and differentiation of BCC subtypes. Based on these features, a diagnostic algorithm is proposed which requires additional validation, but enhances current understanding of the morphological correlates of HD-OCT images in skin.

X-chromosome-linked inhibitor of apoptosis as a key factor for chemoresistance in clear cell carcinoma of the ovary.

BACKGROUND: X-chromosome-linked inhibitor of apoptosis (XIAP) is one of the anti-apoptotic proteins leading to chemoresistance in several cancers. The aim of this study is to evaluate the impact of XIAP expression upon ovarian clear cell carcinoma (CCC) that has a platinum-resistant phenotype. METHODS: Tissue microarrays made from 90 CCC patients were analysed for immunohistochemical expression levels of XIAP, c-Met, p-Akt and Bcl-XL. In addition, CCC cell lines were evaluated whether XIAP silencing could modulate sensitivity to platinum agent in vitro. RESULTS: High XIAP expression was observed in 30 (33%) of 90 CCC cases, and was associated with c-Met (<0.01) and Bcl-XL (<0.01) expression. Cases with high XIAP expression had lower response rate to primary platinum-based chemotherapy (10% vs 65%, P=0.02). In stages II-IV tumours, high XIAP expression was related with worse progression-free survival (PFS, P=0.02). Furthermore, high XIAP expression was identified as an independent worse prognostic factor for PFS and overall survival. Finally, downregulation of XIAP using XIAP-specific small interfering RNA increased sensitivity to cisplatin in human cancer cells derived from CCC. CONCLUSIONS: X-chromosome-linked inhibitor of apoptosis expression was correlated with chemoresistance of primary chemotherapy, and identified as a prognostic marker for CCC. X-chromosome-linked inhibitor of apoptosis could be a candidate for new therapeutic target in CCC.

Prognostic significance of epithelial-mesenchymal transition-related markers in extrahepatic cholangiocarcinoma: comprehensive immunohistochemical study using a tissue microarray.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is characterised by the loss of cell-to-cell adhesion and gaining of mesenchymal phenotypes. Epithelial-mesenchymal transition is proposed to occur in various developmental processes and cancer progression. 'Cadherin switch', a process in which cells shift to express different isoforms of the cadherin transmembrane protein and usually refers to a switch from the expression of E-cadherin to N-cadherin, is one aspect of EMT and can have a profound effect on tumour invasion/metastasis. The aim of this study was to investigate the clinicopathological significance of EMT-related proteins and cadherin switch in extrahepatic cholangiocarcinoma (EHCC). METHODS: We investigated the association between altered expression of 12 EMT-related proteins and clinical outcomes in patients with EHCC (n=117) using immunohistochemistry on tissue microarrays. RESULTS: Univariate and multivariate analyses revealed that, in addition to N classification (P=0.0420), the expression of E-cadherin (P=0.0208), N-cadherin (P=0.0038) and S100A4 (P=0.0157) was each an independent and a significant prognostic factor. We also demonstrated that cadherin switch was independently associated with poor prognosis (P=0.0143) in patients with EHCC. CONCLUSIONS: These results may provide novel information for selection of patients with EHCC who require adjuvant therapy and strict surveillance.

Ovarian yolk sac tumor associated with pregnancy: a case report and review of the literature.

BACKGROUND: Ovarian yolk sac tumor (YST) that is diagnosed during pregnancy is extremely rare. CLINICAL CASE: A 22-year-old pregnant woman diagnosed with Stage IIIc YST at 17 weeks of gestation is presented. A 20-cm multilocular cystic tumor containing solid components with massive ascites was detected. Subsequently she underwent left salpingo-oophorectomy and cytoreductive surgery for peritoneal dissemination at 18 weeks of gestation, and the tumors were diagnosed as YST. After vaginal termination at 20 weeks of gestation, she received five cycles of combination therapy with bleomycin, etoposide, and cisplatin. There was no evidence of recurrence at 85 months after primary treatment. CONCLUSION: Considering the rarity, treatment strategy for advanced-staged YST should be further investigated in international collaborative studies.

Surgery for endometrial cancers with suspected cervical involvement: is radical hysterectomy needed (a GOTIC study)?

BACKGROUND: Radical hysterectomy is recommended for endometrial adenocarcinoma patients with suspected gross cervical involvement. However, the efficacy of operative procedure has not been confirmed. METHODS: The patients with endometrial adenocarcinoma who had suspected gross cervical involvement and underwent hysterectomy between 1995 and 2009 at seven institutions were retrospectively analysed (Gynecologic Oncology Trial and Investigation Consortium of North Kanto: GOTIC-005). Primary endpoint was overall survival, and secondary endpoints were progression-free survival and adverse effects. RESULTS: A total of 300 patients who underwent primary surgery were identified: 74 cases with radical hysterectomy (RH), 112 patients with modified radical hysterectomy (mRH), and 114 cases with simple hysterectomy (SH). Median age was 47 years, and median duration of follow-up was 47 months. There were no significant differences of age, performance status, body mass index, stage distribution, and adjuvant therapy among three groups. Multi-regression analysis revealed that age, grade, peritoneal cytology status, and lymph node involvement were identified as prognostic factors for OS; however, type of hysterectomy was not selected as independent prognostic factor for local recurrence-free survival, PFS, and OS. Additionally, patients treated with RH had longer operative time, higher rates of blood transfusion and severe urinary tract dysfunction. CONCLUSION: Type of hysterectomy was not identified as a prognostic factor in endometrial cancer patients with suspected gross cervical involvement. Perioperative and late adverse events were more frequent in patients treated with RH. The present study could not find any survival benefit from RH for endometrial cancer patients with suspected gross cervical involvement. Surgical treatment in these patients should be further evaluated in prospective clinical studies.