Criteria for melanocytic lesions in LC-OCT.

BACKGROUND: Line-field confocal optical coherence tomography (LC-OCT) is an emerging diagnostic tool with imaging depth reaching ~400 µm and a novel three-dimensional (3D) cube providing cellular resolution. As far as we are aware, there are only a limited number of papers that have reported diagnostic criteria for melanocytic lesions using this technique, and none of them have been multicentric. OBJECTIVES: Our aim was to establish the diagnostic criteria for melanocytic lesions using LC-OCT and identify the most significant architectural and cytologic features associated with malignancy. METHODS: A retrospective evaluation of 80 consecutive melanocytic lesions from a prospective multicentric data set spanning three European centres was conducted. We excluded facial, acral and mucosal lesions from the study. Dermoscopic and LC-OCT images were evaluated by a consensus of four observers. Multivariate logistic regression with backward elimination was employed. RESULTS: The main melanoma diagnostic criteria include detecting >10 pagetoid cells in 3D acquisition, irregular 3D epidermal architecture, disrupted dermoepidermal junction (DEJ) and clefting. Significant risk factors were irregular 3D epidermal architecture, >10 pagetoid cells, dendritic cells at DEJ without underlying inflammation. Novel malignancy criteria in vertical view were DEJ disruption and clefting around atypical melanocyte nests. Exclusive melanoma features were epidermal nests, epidermal consumption, dense dermal nests with atypia. Protective features in the absence of any malignancy indicators were DEJ ring pattern, cobblestone, elongated rete ridges (vertical), well-defined DEJ and wave pattern (vertical). CONCLUSIONS: A series of diagnostic criteria for the identification of melanocytic lesions with LC-OCT have been established. Validation of these criteria in clinical practice through future studies is essential to further establish their utility.

Advanced cutaneous squamous cell carcinoma of the head in two renal transplanted patients treated with cemiplimab.

It is well known that organ transplant recipients are prone to develop non-melanoma skin cancers, particularly cutaneous squamous cell carcinoma (cSCC). This is explained by the long-term use of immunosuppressants and thus the decrease of the immunosurveillance that protects from developing malignant tumours. Solid organ transplant recipients (SOTRs) are 65-250 times more likely to develop cSCC compared to the general population (Am J Transplant 2017; 17: 2509). Moreover, in these patients cSCCs follow a more aggressive course. Close follow-up and regular skin check-ups by a dermatologist are, therefore, crucial in the management of these patients. When detected early, cSCC can be easily and effectively treated by a simple excision. However, when advanced, outcomes are poor. Immune checkpoints inhibitors (ICIs) have been recently added to our arsenal and represent a breakthrough, having proved to be effective in achieving long-term responses. We, hereby, present two cases of difficult-to-treat cSCCs in renal transplanted patients.

Clinicopathological features, MCPyV status and outcomes of Merkel cell carcinoma in solid-organ transplant recipients: a retrospective, multicentre cohort study.

BACKGROUND: The proportion of Merkel cell carcinomas (MCCs) in solid-organ transplant recipients (SOTR) harbouring Merkel cell polyomavirus (MCPyV) is unknown, as are factors affecting their outcomes. OBJECTIVE: To describe clinicopathological features of MCC in SOTR, investigate the tumoral MCPyV-status and identify factors associated with tumour outcomes. METHODS: Retrospective, international, cohort-study. MCPyV-status was investigated by immunohistochemistry and polymerase chain reaction. RESULTS: A total of 30 SOTR and 44 consecutive immunocompetent patients with MCC were enrolled. SOTR were younger at diagnosis (69 vs. 78 years, P < 0.001). Thirty-three percent of SOTR MCCs were MCPyV-positive vs. 91% of immunocompetent MCCs (P = 0.001). Solid-organ transplantation was associated with an increased cumulative incidence of progression (SHR: 3.35 [1.57-7.14], P = 0.002), MCC-specific mortality (SHR: 2.55 [1.07-6.06], P = 0.034) and overall mortality (HR: 3.26 [1.54-6.9], P = 0.002). MCPyV-positivity and switching to an mTOR inhibitor (mTORi) after MCC diagnosis were associated with an increased incidence of progression (SHR: 4.3 [1.5-13], P = 0.008 and SHR: 3.6 [1.1-12], P = 0.032 respectively) in SOTR. LIMITATIONS: Retrospective design and heterogeneity of SOTR cohort. CONCLUSIONS: MCPyV appears to play a less prominent role in the aetiopathogenesis of MCC in SOTR. SOTR have a worse prognosis than their immunocompetent counterparts and switching to an mTORi after the diagnosis of MCC does not improve progression.

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.

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.

The impact of the extension of the post-natal in the adherence to breastfeeding Cohort study. / Impacto de la extensión del postnatal en la adherencia a la lactancia materna. Estudio de Cohorte.

INTRODUCTION: In Chile, Law 20,545 came into force in 2011, extending the maternity leave from 12 to 21 weeks. The National Breastfeeding Survey (ENALMA, in Spanish), applied after the exten ded maternity leave, reported a 12% increase in adherence to exclusive breastfeeding (EBF) at the sixth month. However, 63% of the women surveyed were unemployed, therefore, the main causes of cessation of breastfeeding (BF) were not related to maternal rest time. OBJECTIVES: To calculate the impact of changes in the EBF adherence in patients who attend to well-child visits in the period before and after the entry into force of the extended maternity leave. MATERIALS AND METHODS: Data were collected from electronic medical records of the San Joaquin Health Center between 2009 and 2013, which were recruited according to specified inclusion and exclusion criteria (n = 938 patients). Subsequently, they were divided into two groups according to the presence or absence of the ex tended maternity leave and with follow-up at three, six and 12 months. Using frequency tables, the characterization of the groups was carried out at the beginning of the observation period. To evaluate group homogeneity, study variables were compared between groups using Chi-square and Wicolxon Mann-Whitney tests. The prevalence of EBF maintenance was compared by pr-test between the groups with follow-up at three, six and 12 months. Using survival analysis and Cox regression, the impact of the extended maternity leave effect between both groups in the first 12 months was cal culated. RESULTS: At the beginning of the observation periods, no differences were observed between the groups in the studied variables. When comparing groups, without and with extended maternity leave, there were no significant differences in EBF adherence at three months: 327 (66%) versus 302 (68%), p = 0.492, respectively. However, in the groups in follow-up at six and 12 months, there was an increase in EBF adherence from 164 (33%) to 187 (42%), p = 0.004 and from 51 (10%) to 72 (16), p = 0.007, respectively. Analyzing the impact of the maternity leave extension on the adherence to breastfeeding, determined by risk ratio, this extension may positively influence on the adherence to EBF over time, with a HR < 1 (HR: 0.852, p=0.04 CI 95%: 0.728-0.996). CONCLUSION: Increased ma ternal resting time may influence as a protective factor for adherence to EBF.

Hadamard circular masks: high focal depth with high throughput.

We present a class of binary masks that encode, in polar coordinates, the values of a Hadamard matrix of order N. For order N ≥ 2, the binary masks increase the Strehl ratio vs. focus error by the factor N, with the highest possible light throughput. Since a Strehl ratio with high tolerance to defocus does not guarantee a modulation transfer function (MTF) with low sensitivity to focus errors, then, we show that for N = 16 the binary mask reduces also the impact of focus error on the MTF. Equivalently, the discrete binary mask has Fisher information with low variations to defocus.

Imidazole-containing phthalazine derivatives inhibit Fe-SOD performance in Leishmania species and are active in vitro against visceral and mucosal leishmaniasis.

The in vitro leishmanicidal activity of a series of imidazole-containing phthalazine derivatives 1-4 was tested on Leishmania infantum, Leishmania braziliensis and Leishmania donovani parasites, and their cytotoxicity on J774·2 macrophage cells was also measured. All compounds tested showed selectivity indexes higher than that of the reference drug glucantime for the three Leishmania species, and the less bulky monoalkylamino substituted derivatives 2 and 4 were clearly more effective than their bisalkylamino substituted counterparts 1 and 3. Both infection rate measures and ultrastructural alterations studies confirmed that 2 and 4 were highly leishmanicidal and induced extensive parasite cell damage. Modifications to the excretion products of parasites treated with 2 and 4 were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds 2 and 4 were potent inhibitors of iron superoxide dismutase enzyme (Fe-SOD) in the three species considered, whereas their impact on human CuZn-SOD was low. Molecular modelling suggests that 2 and 4 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the antioxidant features of the enzyme.

[Breastfeeding as a protective factor against overweight and obesity among pre-school children]. / Lactancia materna como factor protector de sobrepeso y obesidad en preescolares.

INTRODUCTION: The rates of overweight and obesity among children have significantly increased in Chile. OBJECTIVE: To assess the benefits of breastfeeding in preventing malnutrition by excessive intake of foods in Chilean pre-school children. METHODS: A case-control study was conducted in 2011 on pediatric patients treated in a private Chilean healthcare center (San Joaquin Medical Center, Catholic University). Gender, age, weight, height, nutritional diagnosis, type of feeding during the first 6 months of life, socioeconomic status, parental education and obesity, television viewing, and kindergarten attendance were analyzed. RESULTS: A total of 209 patients were included in the study, 53.1% of whom were male, and 60.3% were predominantly breastfed for the first 6 months of life. More than half (51.7%) were eutrophic, 29.7% were overweight, and 18.6% obese. The patients were between the ages of 2 and 3 years 11 months. The crude Odds Ratio of breast-feeding versus formula during the first 6 months of life in patients with normal weight versus overweight children was 0.442 (95% CI 0.204-0.961). CONCLUSIONS: It was found that predominantly breastfeeding during the first 6 months of life acted as a protective factor against malnutrition by excessive intake of foods in Chilean pre-school children treated in this private medical center.

Country-report pattern corrections of new cases allow accurate 2-week predictions of COVID-19 evolution with the Gompertz model.

Accurate short-term predictions of COVID-19 cases with empirical models allow Health Officials to prepare for hospital contingencies in a two-three week window given the delay between case reporting and the admission of patients in a hospital. We investigate the ability of Gompertz-type empiric models to provide accurate prediction up to two and three weeks to give a large window of preparation in case of a surge in virus transmission. We investigate the stability of the prediction and its accuracy using bi-weekly predictions during the last trimester of 2020 and 2021. Using data from 2020, we show that understanding and correcting for the daily reporting structure of cases in the different countries is key to accomplish accurate predictions. Furthermore, we found that filtering out predictions that are highly unstable to changes in the parameters of the model, which are roughly 20%, reduces strongly the number of predictions that are way-off. The method is then tested for robustness with data from 2021. We found that, for this data, only 1-2% of the one-week predictions were off by more than 50%. This increased to 3% for two-week predictions, and only for three-week predictions it reached 10%.

[Executive functions in patients with obstructive sleep apnea: exploring the prefrontal model]. / Funciones ejecutivas en pacientes con apnea obstructiva del sueño: explorando el modelo prefrontal.

INTRODUCTION: According to the prefrontal model, individuals with obstructive sleep apnea (OSA) manifest behaviours mimicking dysexecutive syndrome as a result of blood gas abnormalities and sleep fragmentation. OBJECTIVE: To compare executive functions in OSA patients with normative values and explore their relationship with blood gas abnormalities and sleep fragmentation. PATIENTS AND METHODS: Patients were recruited from the wider community and from a tertiary care hospital. The score obtained in the neuropsychological assessment was compared with Student's t-test for a sample. A multiple linear regression analysis was subsequently estimated, using polysomnographic parameters of hypercapnia, hypoxemia and sleep fragmentation as the predictor variables, and the executive function score as the variable to be predicted. RESULTS: Although the neuropsychological assessment performance of 26% of this sample was classified as executive impairment, indicators of sleep fragmentation and gas abnormalities failed to predict the performance of executive functions. CONCLUSION: A proportion of the patients with OSA presented performance similar to a dysexecutive syndrome; however, the factors underlying and fostering this type of cognitive manifestation remain unclear. Early treatment for this public health problem could be the best tool available for improving quality of life and preventing health risks.

TITLE: Funciones ejecutivas en pacientes con apnea obstructiva del sueño: explorando el modelo prefrontal.Introducción. El modelo prefrontal propone que los individuos con apnea obstructiva del sueño (AOS) manifiestan conductas similares a un síndrome disejecutivo como resultado de las alteraciones de gases en la sangre y la fragmentación del sueño. Objetivo. Comparar las funciones ejecutivas en pacientes con AOS con valores normativos y explorar su relación con las alteraciones de gases en la sangre y la fragmentación del sueño. Pacientes y métodos. Se reclutó a pacientes de la comunidad general y de un hospital de tercer nivel. La puntuación obtenida en la evaluación neuropsicológica se contrastó con la t de Student para una muestra. Posteriormente, se estimó un análisis de regresión lineal múltiple mediante parámetros polisomnográficos de hipercapnia, hipoxemia y fragmentación del sueño como variables predictoras, y la puntuación de funciones ejecutivas como variable que se debe predecir. Resultados. Pese a que el desempeño en la evaluación neuropsicológica del 26% de esta muestra se clasificó como alteración ejecutiva, los indicadores de fragmentación del sueño y alteraciones de gases no predijeron el desempeño ejecutivo. Conclusión. Una fracción de los pacientes con AOS mostró un desempeño similar a un síndrome disejecutivo; no obstante, permanecen indefinidos los factores que subyacen y favorecen este tipo de manifestaciones cognitivas. La atención temprana de este problema de salud pública podría ser la mejor herramienta disponible en aras de mejorar la calidad de vida y prevenir riesgos a la salud.

Expression profiling of breast tumors based on human epidermal growth factor receptor 2 status defines migration-related genes.

OBJECTIVE: Breast cancer is a heterogeneous neoplasm. Distinct subtypes of breast cancer have been defined, suggesting the existence of molecular differences contributing to their clinical outcomes. However, the molecular differences between human epidermal growth factor receptor 2 (HER2)-positive and HER2-negative breast cancer tumors remain unclear. The aim of this study was to identify a gene expression profile for breast tumors based on their HER2 status. METHODS: The HER2 status was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 54 breast tumor samples. Using Affymetrix microarray data from these breast tumors, we established the expression profiling of breast cancer based on HER2 IHC and FISH results. To validate microarray experiment data, real-time quantitative reverse transcription-PCR was performed. RESULTS: We found significant differences between the HER2-positive and HER2-negative breast tumor samples, which included overexpression of HER2, other genes located on 17q12 and genes functionally related to migration. CONCLUSION: Our study shows the potential of integrated genomic profiling to shed light on the molecular knowledge of HER2-positive breast tumors.

Cemiplimab for advanced cutaneous squamous cell carcinoma in kidney transplant recipients.

Background: Kidney transplant recipients (KTR) are at increased risk of cancer due to chronic immunosuppression. Non-melanoma skin cancer has an excess risk of approximately 250 times higher than the general population. Moreover, in solid organ transplant recipients (SOTR) these cancers have a more aggressive behavior, with an increased risk of metastasis and death. Cemiplimab, a human monoclonal IgG4 antibody against programmed cell death (PD-1) has shown considerable clinical activity in metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) in patients for whom no widely accepted standard of care exists. Cemiplimab has therefore been approved since 2018 for the treatment of advanced cSCC. However, data regarding the use of cemiplimab in SOTR and particularly in KTR are scarce and based on published case reports and small case series. In this study, we report on the real-life outcome of cemiplimab use in a Belgian cohort of seven KTR suffering from advanced cSCC. Objective: To report on the overall response rate (ORR) and safety of cemiplimab in KTR in Belgium. Results: Seven patients suffering from advanced cSCC, treated with cemiplimab, between 2018 and 2022, in Belgium were identified. Three patients were on corticosteroid monotherapy, one patient on tacrolimus monotherapy and three patients were on at least 2 immunosuppressants at start of cemiplimab. The ORR was 42.8%, stable disease was seen in 14.3% and progressive disease was found in 42.8% of the patients, respectively. The median administered number of cycles was 12, interquartile range (IQR) 25-75 [3.5 - 13.5]. All patients were treated with surgery before administration of cemiplimab, 71.4% received additional radiotherapy and only 1 patient was treated with chemotherapy prior to receiving cemiplimab. Biopsy-proven acute renal allograft rejection was observed in one patient, who eventually lost his graft function but showed a complete tumor response to treatment. Low grade skin toxicity was seen in one patient of the cohort. Conclusion: The present case series shows that the use of cemiplimab in KTR with advanced cSCC who failed to respond to previous surgery, chemo - and/or radiotherapy treatment is associated with an ORR of 42.8% with minimal risk of graft rejection (14.3%) and good tolerance.

[Role of the stress protein p8 in tumor progression and development of metastasis]. / Rôle de la protéine de stress p8 dans la progression tumorale et le développement des métastases.

In spite of the great advances made on the knowledge of cancer etiology and the significant breakthroughs in terms of treatment, complete remission is obtained in only around half of cancer patients. In fact, therapies that appear successful for some cancers are totally unfruitful for others, and some cancer types still remain incurables. In order to develop new therapies suitable to these tenacious cancers, we need to renew our view on cancer and to revise some old paradigms and "false friends" that can hide unexpected new therapeutic targets. A good example of these paradigms is the role of the cell stress response in tumor progression. Indeed, a number of studies has been devoted to the pivotal tumor suppressor function of some players of this response, of which the p53 protein is the best example. Nevertheless, during tumor progression and metastasis, the cancer cell faces many stresses imposed by tumor microenvironment and its survival will be conditioned by an efficient cell stress response. This review is consecrated to the role played by a pivotal actor of the cell stress response, the p8 protein, during carcinogenesis. We will recapitulate the data available on its different cell functions and the assets p8 confer to the cancer cell in terms of growth, drugs resistance and metastasis formations.

Motiva.DM2 project. A pilot behavioral intervention on diet and exercise for individuals with type 2 diabetes mellitus.

AIM: The purpose of this study was to assess the efficacy of an educational intervention based on the Behavior Change Wheel (BCW) framework for individuals with type 2 diabetes mellitus (DM2) on dietary and exercise behavior in a Spanish region. METHODS: A two-arm pilot research was developed. The intervention consisted of a 6-month period with guidelines and 4 in-person interventions. The outcome was changes in behaviors, motivation, competence, autonomy, social support to implement the recommendations, HbA1c, and body composition. RESULTS: n = 111 patients were recruited. Individuals in the intervention experienced a significative improvement on adherence to dietary recommendations (+1.23; p = 0.026), exercise (+0.86; p = 0.001), and a decrease in HbA1c levels (-0.6%; p = 0.002) and BMI (-0.73; p < 0.001). CONCLUSION: The intervention for DM2 individuals, based on the BCW framework, developed, and implemented by primary care nurses has been effective in improving the adherence to healthy eating, exercise, HbA1c levels, and body composition.