Hair Repigmentation During Immunotherapy Treatment With an Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Agent for Lung Cancer.

Importance: New targeted therapies for cancer have been released in recent years, opening new horizons in the treatment of patients with cancer. However, their related adverse events (AE) are not fully characterized. Hair repigmentation (HR) is a nondescribed effect secondary to anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1 ) therapy for treatment of lung cancer (LC), in opposition to the vitiligo reactions that develop during melanoma treatment. Objective: To describe a new adverse event occurring during anti-PD-1/anti-PD-L1 therapy for LC. Design, Setting, and Participants: A case series from a descriptive observation of 14 patients with HR after anti-PD-1/anti-PD-L1 treatment, recruited between September and December, 2016, who were followed up to detect whether they developed cutaneous AE at the time HR was detected. The patients had all been treated in the dermatology department at Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Main Outcomes and Measures: Clinical observation of HR during anti-PD-1/anti-PD-L1 therapy for LC, proved by comparing old pictures provided by the patients and recent pictures taken during the follow-up. Results: Fourteen patients (13 men and 1 woman; mean age, 64.9 years) receiving anti-PD-1 or anti-PD-L1 therapy for non-small-cell lung cancer (NSCLC) presented hair repigmentation during follow-up. This hair repigmentation consisted in a diffuse darkening of the hair in 13 of 14 patients, or in black patches between white hairs in 1. Thirteen of 14 patients presented a good clinical response to the treatment, with at least stable disease, and only 1 had to stop the therapy after only 4 cycles of treatment owing to a life-threatening progression of the disease. Conclusions and Relevance: We present to our knowledge the first report of hair repigmentation owing to anti-PD-1/anti-PD-L1 therapy for lung cancer in a series of 14 patients. Hair repigmentation may be a good response marker in patients receiving anti-PD1/anti-PD-L1 therapy for LC.

Intravascular (blood vessel) histiocytosis with haemophagocytosis.

AIMS: Many types of intravascular lymphohistiocytic proliferation have been described recently; this was previously an unnoticed or misinterpreted phenomenon. Intralymphatic lymphohistiocytic aggregates are relatively common, and include benign, malignant and indeterminate conditions. In contrast, all non-endothelial proliferations in the lumina of blood vessels have been interpreted so far as malignant. Herein, we present three cases of histiocytic proliferations in the lumen of blood vessels associated with intracytoplasmic granulocyte debris (haemophagocytosis), a previously undescribed entity. METHODS AND RESULTS: We identified three patients from two institutions with similar cutaneous lesions, both clinically and microscopically. Information regarding clinical history, histological features and immunoprofiles were obtained. The three cases presented intravascular histiocytosis with haemophagocytosis involving blood vessels of the dermis, a process that may be representative of a new entity. The patients were two women and one man who presented a symmetrical reticulated erythema with a tendency to involve the skin of the breasts. The lesions were indolent, did not ulcerate and followed a benign course. CONCLUSION: This seemingly novel condition is characterized by the presence of histiocytic cells inside blood vessels, where they have not been described previously as an entity. The most reasonable explanation for this process is an origin from the non-classical subset of monocytes that 'patrol' the inner face of blood vessels acting as macrophages. The existence of this entity should be kept in mind to avoid overdiagnosis of malignancy.

A cellular model reflecting the phenotypic heterogeneity of mutant HRAS driven squamous cell carcinoma.

Squamous cell carcinomas have a range of histopathological manifestations. The parameters that determine this clinically observed heterogeneity are not fully understood. Here, we report the generation of a cell culture model that reflects part of this heterogeneity. We have used the catalytic subunit of human telomerase hTERT and large T to immortalize primary UV-unexposed keratinocytes. Then, mutant HRAS G12V has been introduced to transform these immortal keratinocytes. When injected into immunosuppressed mice, transformed cells grew as xenografts with distinct histopathological characteristics. We observed three major tissue architectures: solid, sarcomatoid and cystic growth types, which were primarily composed of pleomorphic and basaloid cells but in some cases displayed focal apocrine differentiation. We demonstrate that the cells generated represent different stages of skin cancerogenesis and as such can be used to identify novel tumor-promoting alterations such as the overexpression of the PADI2 oncogene in solid-type SCC. Importantly, the cultured cells maintain the characteristics from the xenograft they were derived from while being amenable to manipulation and analysis. The availability of cell lines representing different clinical manifestations opens a new tool to study the stochastic and deterministic factors that cause case-to-case heterogeneity despite departing from the same set of oncogenes and the same genetic background.

Neoinnervation and neovascularization of acellular pericardial-derived scaffolds in myocardial infarcts.

Engineered bioimplants for cardiac repair require functional vascularization and innervation for proper integration with the surrounding myocardium. The aim of this work was to study nerve sprouting and neovascularization in an acellular pericardial-derived scaffold used as a myocardial bioimplant. To this end, 17 swine were submitted to a myocardial infarction followed by implantation of a decellularized human pericardial-derived scaffold. After 30 days, animals were sacrificed and hearts were analyzed with hematoxylin/eosin and Masson's and Gallego's modified trichrome staining. Immunohistochemistry was carried out to detect nerve fibers within the cardiac bioimplant by using ßIII tubulin and S100 labeling. Isolectin B4, smooth muscle actin, CD31, von Willebrand factor, cardiac troponin I, and elastin antibodies were used to study scaffold vascularization. Transmission electron microscopy was performed to confirm the presence of vascular and nervous ultrastructures. Left ventricular ejection fraction (LVEF), cardiac output (CO), stroke volume, end-diastolic volume, end-systolic volume, end-diastolic wall mass, and infarct size were assessed by using magnetic resonance imaging (MRI). Newly formed nerve fibers composed of several amyelinated axons as the afferent nerve endings of the heart were identified by immunohistochemistry. Additionally, neovessel formation occurred spontaneously as small and large isolectin B4-positive blood vessels within the scaffold. In summary, this study demonstrates for the first time the neoformation of vessels and nerves in cell-free cardiac scaffolds applied over infarcted tissue. Moreover, MRI analysis showed a significant improvement in LVEF (P = 0.03) and CO (P = 0.01) and a 43 % decrease in infarct size (P = 0.007).

Childhood granulomatous periorificial dermatitis with a good response to oral metronidazole.

Childhood granulomatous periorificial dermatitis (CGPD) is a condition included in the spectrum of rosacea and perioral dermatitis that affects prepubescent children. It is characterized by papular eruptions located around the mouth, nose, and eyes that histopathologically show a granulomatous pattern. We report a 9-year-old girl with CGPD who required treatment with an oral antibiotic. Oral metronidazole was administered because of its known efficacy in adult rosacea and its safety in children. The patient responded well to this therapy, showing resolution of the lesions.

Carcinoma epidermoide infiltrante de clítoris en paciente de 30 años, no ligado a infección por virus del papiloma humano / Invasive squamous cell carcinoma of the vulva in a 30-year-old woman not associated with human papillomavirus infection

El carcinoma epidermoide invasor de vulva es excepcional antes de los 40 años. Presentamos un el caso de un carcinoma epidermoide diferenciado de clítoris en una paciente de 30 años, nulípara, que debutó con una clínica de vulvodinia de 2 años de evolución. A la exploración, se detectó una tumoración sospechosa en el clítoris, que se biopsió y correspondió a un carcinoma epidermoide invasor de vulva estadio Ia. Se practicó una cirugía conservadora (tumorectomía con márgenes de seguridad y ganglio centinela) con buena recuperación de la paciente y reinserción de ella a la vida laboral normal en un plazo inferior a los 30 días (AU)

Invasive squamous cell carcinoma of the vulva is exceptional before the age of 40 years. We present a differentiated squamous carcinoma of the clitoris in a 30-year-old nulliparous woman who presented with vulvodynia for the past 2 years. On examination, a suspicious tumor was detected in the clitoris. Biopsy revealed an invasive squamous cell carcinoma of the vulva, stage Ia. Conservative surgery (tumorectomy with safety margins and sentinel node) was performed with good patient recovery and return to normal working life before 30 days (AU)

Methionine synthase polymorphism is a risk factor for Alzheimer disease.

Alzheimer disease (AD) patients show increased plasma levels of homocysteine, whose conversion to methionine is catalyzed by methionine synthase (MS). Although altered MS activity may result from the MS A2756G polymorphism, the latter's possible associ-ation with AD remains unexplored. To assess whether the MS A2756G polymorphism holds any influence on AD risk, we have analyzed 172 AD patients and 166 controls. We have also investigated whether the MS-A or MS-G allele interacts with the APOE4 allele. Our results indicate that association with the MS-AA genotype is an APOE4 allele-independent risk factor for AD. These findings provide novel evidence implicating genetic enzymatic alterations of homocysteine metabolic pathways in the pathogenesis of AD.

Linfoma b cutáneo primario de centro folicular con epidermotropismo / Primary cutaneous follicle center cell lymphoma with epidermotropism

El linfoma cutáneo primario de células del centro folicular (LCPCF) de la clasificación EORTC es el linfoma cutáneo de células B más frecuente. Su presentación clínica es variable, pero por lo general las lesiones se localizan en la cabeza y el cuello o el tronco y tiene un curso indolente, siendo infrecuente la diseminación extracutánea. Histológicamente las lesiones se caracterizan por un infiltrado nodular o difuso formado por centrocitos y ocasionales centroblastos con abundantes células T reactivas en los estadios iniciales que casi siempre respeta la epidermis. Presentamos el caso de un varón de 67 años con una pápula localizada en región cervical, cuyo estudio histopatológico fue diagnóstico de linfoma B cutáneo primario (LCPCF de la clasificación EORTC), destacando la presencia de granulomas y un evidente epidermotropismo de linfocitos B. El estudio de extensión fue negativo y la lesión fue tratada mediante extirpación quirúrgica y radioterapia, sin recidiva hasta la fecha. El epidermotropismo de linfocitos, si bien constituye una característica histopatológica habitual en los linfomas T cutáneos, puede observarse ocasionalmente en los linfomas B cutáneos primarios; para algunos autores la demostración de la estirpe B de los linfocitos epidermotropos es muy sugestiva del diagnóstico de linfoma B cutáneo primario (AU)