Kaposi sarcoma secondary to endogenous adrenocorticotropic hormone-dependent Cushing syndrome.

Kaposi sarcoma (KS) is an angioproliferative tumour that develops as a result of an infection by human herpesvirus 8, which is considered a necessary cause but not sufficient. Other factors - genetic, immunological and environmental - might play a role in the development of the disease. We report a case of KS secondary to endogenous Cushing syndrome (ECS) due to a pituitary adenoma, an association that has been reported only once. We also conducted a search through the Medline and PubMed databases for cases involving KS and ECS, finding only three additional cases that shared common clinical and prognostic features with ours. ECS might favour the development of KS due to immunosuppression. Dermatologists and other clinicians should be aware of this association, as it might be an underdiagnosed condition. It also has an important impact on the management of KS, and based on this review it relies on a good prognosis when ECS is well controlled.

Use of the flavonoid taxifolin for sperm cryopreservation from the threatened Bermeya goat breed.

Taxifolin is a plant flavonoid effective as an antioxidant. This study aimed to assess the effect of adding taxifolin to the semen extender during the cooling period before freezing on the overall post-thawing sperm variables of Bermeya goats. In the first experiment, a dose-response experiment was performed with four experimental groups: Control, 10, 50, and 100 µg/ml of taxifolin using semen from 8 Bermeya males. In the second experiment, semen from 7 Bermeya bucks was collected and extended at 20 °C using a Tris-citric acid-glucose medium supplemented with different concentrations of taxifolin and glutathione (GSH): control, 5 µM taxifolin, 1 mM GSH, and both antioxidants. In both experiments, two straws per buck were thawed in a water bath (37 °C, 30 s), pooled, and incubated at 38 °C. Motility (CASA) was assessed at 0, 2, and 5 h, and sperm physiology was assessed at 0 and 5 h by flow cytometry (viability, intact acrosome membrane, mitochondria membrane potential, capacitation, intracellular reactive oxygen species -ROS-, mitochondrial superoxide, and chromatin status). In experiment 2, an artificial insemination trial (AI) was included with 29 goats for testing the taxifolin 5-µM treatment on fertility. Data were analyzed with the R statistical environment using linear mixed-effects models. In experiment 1 and compared to the control, T10 increased progressive motility (P < 0.001) but taxifolin decreased total and progressive motility at higher concentrations (P < 0.001), both post-thawing and after the incubation. Viability decreased post-thawing in the three concentrations (P < 0.001). Cytoplasmic ROS decreased at 0 and 5 h at T10 (P = 0.049), and all doses decreased mitochondrial superoxide post-thawing (P = 0.024). In experiment 2, 5 µM taxifolin or 1 mM GSH (alone or combined) increased total and progressive motility vs. the control (P < 0.01), and taxifolin increased kinematic parameters such as VCL, ALH, and DNC (P < 0.05). Viability was not affected by taxifolin in this experiment. Both antioxidants did not significantly affect other sperm physiology parameters. The incubation significantly affected all the parameters (P < 0.004), overall decreasing sperm quality. Fertility after artificial insemination with doses supplemented with 5 µM taxifolin was 76.9% (10/13), not significantly different from the control group (69.2%, 9/13). In conclusion, taxifolin showed a lack of toxicity in the low micromolar range and could benefit goat semen cryopreservation.

Diffuse hepatocutaneous hemangiomatosis: an unusual presentation. / Hemangiomatosis hepatocutánea difusa: presentación inusual.

INTRODUCTION: Infantile hemangiomas with multi-organ involvement are rare, and presentation in the form of uncontrollable bleeding is exceptional. CLINICAL CASE: 4-day-old newborn with multiple hepatocutaneous hemangiomas and a purplish vascular lesion in the third finger of the right hand. In the third week of life, the lesion became ulcerated and caused uncontrollable bleeding. Therefore, urgent amputation was required, with a histopathological result of GLUT-1 positive infantile hemangioma, and an architecture compatible with arteriovenous malformation in the deep portion. Imaging tests revealed it was a high-flow lesion. Genetic tests (MAP2KI, RASA 1, EPHB4, GNAQ, and GNA 11) were negative. Patient progression was good, with hepatocutaneous lesions receding and eventually disappearing. DISCUSSION: No explanation has been given yet as to why the same vascular lesion may behave differently in different patients. New mutations may be accountable for this.

INTRODUCCION: Los hemangiomas infantiles con afectación multivisceral son escasos y su presentación en forma de hemorragia incontrolable es excepcional. CASO CLINICO: Recién nacido de 4 días de vida que presentaba múltiples hemangiomas hepatocutáneos y una lesión vascular púrpura-violácea, que abarcaba el tercer dedo de la mano derecha. En la tercera semana de vida, la lesión presentó ulceración y un sangrado incoercible requiriendo amputación urgente, con un resultado histopatológico de hemangioma infantil GLUT-1 positivo, con arquitectura compatible con malformación arteriovenosa en la parte profunda. Las pruebas de imagen mostraron que se trataba de una lesión de alto flujo. La genética (MAP2KI, RASA 1, EPHB4, GNAQ y GNA 11) fue negativa. La evolución del paciente fue buena, con la involución de las lesiones hepatocutáneas hasta su desaparición. COMENTARIOS: La divergencia en el comportamiento de las mismas lesiones vasculares en diferentes pacientes aún no ha encontrado explicación. Es posible que nuevas mutaciones puedan darnos una respuesta.

Efficiency of the EmERGE Pathway to provide continuity of care for Spanish people living with medically stable HIV.

OBJECTIVE: Calculate the efficiency of the EmERGE Pathway of Care for medically stable people living with HIV at the Hospital Clínic-IDIBAPS, Barcelona, Spain. METHODS: 546 study participants were followed between 1st July 2016 and 30th October 2019 across three HIV outpatient clinics, but the virtual clinic was closed during the second year. Unit costs were calculated, linked to mean use outpatient services per patient year, one-year before and after the implementation of EmERGE. Costs were combined with primary and secondary outcomes. RESULTS: Annual costs across HIV-outpatient services increased by 8%: €1073 (95%CI €999-€1157) to €1158 (95%CI €1084-€1238). Annual cost of ARVs was €7,557; total annual costs increased by 1% from €8430 (95%CI €8356-8514) to €8515 (95%CI €8441-8595). Annual cost for 433 participants managed in face-to-face (F2F) clinics decreased by 5% from €958 (95%CI 905-1018) to €904 (95%CI 863-945); participants transferred from virtual to F2F outpatient clinics (V2F) increased their annual cost by a factor of 2.2, from €115 (95%CI 94-139) to €251 (95%CI 219-290). No substantive changes were observed in primary and secondary outcomes. CONCLUSION: EmERGE Pathway is an efficient and acceptable intervention. Increases in costs were caused by internal structural changes. The cost reduction observed in F2F clinics were off-set by the transfer of participants from the virtual to the F2F clinics due to the closure of the virtual clinic during the second year of the Study. Greater efficiencies are likely to be achieved by extending the use of the Pathway to other PLHIV.

Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions.

The elucidation of molecular alterations that occur during human breast cancer progression may contribute to the development of preventative strategies. Using in situ hybridizations on a cohort of 94 biopsy lesions, quantitatively increased cyclin D mRNA expression levels were observed in only 18% of benign lesions, which confer no or slightly increased breast cancer risk, and 18% of premalignant atypical ductal hyperplasias, which confer a four to fivefold increase in breast cancer risk. The transition to carcinoma was accompanied by frequent cyclin D mRNA overexpression in 76% of low-grade ductal carcinomas in situ, 87% of higher grade comedo ductal carcinomas in situ and 83% of infiltrating ductal breast carcinomas. The data identify a molecular event that may separate benign and premalignant human breast lesions from any form of breast carcinoma.

Bilateral segmental neurofibromatosis diagnosed during pregnancy.

Bilateral segmental neurofibromatosis is a rare subtype of neurofibromatosis type 1 defined by lesions affecting a single segment of the body and crossing the midline, with no systemic involvement. We present a case diagnosed during pregnancy because of the characteristic increase in size of the lesions during this period.

[Septic emboli to the skin following angioplasty]. / Embolismos sépticos cutáneos tras angioplastia.

Invasive vascular procedures have good efficacy and safety profiles and are now widely used for the diagnosis and treatment of many cardiovascular disorders. However, they do have potential complications that can occasionally be life-threatening. We present a new case of infectious pseudoaneurysm following percutaneous transluminal coronary angioplasty and complicated by septic emboli to the skin. It is a rare condition characterized by persistent bacteremia, sepsis of unknown origin, and regional septic emboli. Histopathology of the skin lesions typically reveals gram-positive coccobacilli and septic vasculitis. The condition carries a significant morbidity and mortality, making early diagnosis essential. Both cholesterol and septic emboli should be considered in the differential diagnosis of skin lesions after invasive vascular procedures.

Efficiency of the EmERGE Pathway to provide continuity of care for Spanish people living with medically stable HIV.

OBJECTIVE: Calculate the efficiency of the EmERGE Pathway of Care for medically stable people living with HIV at the Hospital Clínic-IDIBAPS, Barcelona, Spain. METHODS: 546 study participants were followed between 1st July 2016 and 30th October 2019 across three HIV outpatient clinics, but the virtual clinic was closed during the second year. Unit costs were calculated, linked to mean use outpatient services per patient year, one-year before and after the implementation of EmERGE. Costs were combined with primary and secondary outcomes. RESULTS: Annual costs across HIV-outpatient services increased by 8%: €1073 (95%CI €999-€1157) to €1158 (95%CI €1084-€1238). Annual cost of ARVs was €7,557; total annual costs increased by 1% from €8430 (95%CI €8356-8514) to €8515 (95%CI €8441-8595). Annual cost for 433 participants managed in face-to-face (F2F) clinics decreased by 5% from €958 (95%CI 905-1018) to €904 (95%CI 863-945); participants transferred from virtual to F2F outpatient clinics (V2F) increased their annual cost by a factor of 2.2, from €115 (95%CI 94-139) to €251 (95%CI 219-290). No substantive changes were observed in primary and secondary outcomes. CONCLUSION: EmERGE Pathway is an efficient and acceptable intervention. Increases in costs were caused by internal structural changes. The cost reduction observed in F2F clinics were off-set by the transfer of participants from the virtual to the F2F clinics due to the closure of the virtual clinic during the second year of the Study. Greater efficiencies are likely to be achieved by extending the use of the Pathway to other PLHIV.

Granulomas in Dermatopathology: Principal Diagnoses - Part 1. / Granulomas en dermatopatología: principales entidades. Parte I.

This series of 2 articles on dermatopathologic diagnoses reviews conditions in which granulomas form. Part 1 clarifies concepts, discusses the presentation of different types of granulomas and giant cells, and considers a large variety of noninfectious diseases. Some granulomatous diseases have a metabolic origin, as in necrobiosis lipoidica. Others, such as granulomatous mycosis fungoides, are related to lymphomas. Still others, such as rosacea, are so common that dermatologists see them nearly daily in clinical practice.

Granulomas in Dermatopathology: Principal Diagnoses - Part 2. / Granulomas en dermatopatología: principales entidades. Parte II.

Part 2 of this series on granulomatous diseases focuses on skin biopsy findings. Whereas the first part treated noninfectious conditions (metabolic disorders and tumors, among other conditions), this part mainly deals with various types of infectious disease along with other conditions seen fairly often by clinical dermatologists.

Clinical and Histopathologic Characteristics of the Main Causes of Vascular Occusion - Part II: Coagulation Disorders, Emboli, and Other. / Dermatopatología de la oclusión intraluminal vascular: parteII (coagulopatías, émbolos y miscelánea).

Vascular occlusion has multiple, diverse clinical manifestations, some of which can have grave consequences for patients. It also has a wide variety of causes, including thrombi, which we recently addressed in partI of this review. In this second part, we look at additional causes of vascular occlusion.

Clinical and Histopathologic Characteristics of the Main Causes of Vascular Occlusion - Part I: Thrombi. / Dermatopatología de la oclusión intraluminal vascular: parte I (trombos).

Vascular occlusion has multiple, diverse clinical manifestations, some of which can have grave consequences for patients. The causes of vascular occlusion are also highly variable, ranging from thrombi triggered by the uncontrolled activation of coagulation mechanisms, on the one hand, to endothelial dysfunction or occlusion by material extrinsic to the coagulation system on the other. In a 2-part review, we look at the main causes of vascular occlusion and the key clinical and histopathologic findings. In this first part, we focus on vascular occlusion involving thrombi.

Tolerance to tumor necrosis factor in rats and the relationship to endotoxin tolerance and toxicity.

Treatment of rats with recombinant human TNF initially causes a marked decrease in food intake, a loss of body weight, and a negative nitrogen balance. These alterations normalize with continued twice daily intraperitoneal injections of the same dose. Rats tolerized to TNF in this manner are refractory to a lethal dose of TNF. Also, TNF-pretreated and -tolerized rats have prolonged survival and reversed histopathologic changes after injection of a lethal dose of endotoxin compared with control animals. The TNF-tolerant state is dependent on the dose of TNF used and the length of TNF pretreatment. TNF-induced tolerance is relatively short lived, being present 2-4 d after TNF pretreatment and dissipating by 2 wk. Rats made tolerant to endotoxin are also tolerant to a lethal dose of TNF. A bidirectional crossreacting tolerance exists between TNF and endotoxin. The mechanism of TNF tolerance is unclear, but it does not appear to be due to a humoral immune response or a perturbation of the uptake and clearance of injected TNF.

Intrauterine growth retardation associated with precocious puberty and sertoli cell hyperplasia.

The original description of patients with Russell-Silver syndrome included precocious puberty, the mechanism of which was unclear. We describe a child with a Russell-Silver syndrome-like phenotype who presented with precocious puberty that was associated with hyperplasia of the Sertoli cells. The patient was found to have an immature cryptorchid testicle; hyperplastic Sertoli cells were also aneuploid carrying trisomy 8. This chromosomal abnormality was present in Sertoli cells only and could not be detected in peripheral lymphocytes, tunica vaginalis, or other, normal, testicular tissue. Sertoli cells in culture showed excess aromatization providing an explanation for the rapid advancement of the patient's bone age. We conclude that in a patient with a Russell-Silver syndrome-like phenotype, Sertoli cell hyperplasia was associated with somatic trisomy 8, increased aromatization, and gonadotropin-independent precocious puberty.

Penetrance and clinical consequences of a gross SDHB deletion in a large family.

Mutations in the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) are inherited in an autosomal dominant manner and are associated with hereditary paraganglioma (PGL) and pheochromocytoma. The phenotype of patients with SDHB point mutations has been previously described. However, the phenotype and penetrance of gross SDHB deletions have not been well characterized as they are rarely described. The objective was to describe the phenotype and estimate the penetrance of an exon 1 large SDHB deletion in one kindred. A retrospective and prospective study of 41 relatives across five generations was carried out. The main outcome measures were genetic testing, clinical presentations, plasma catecholamines and their O-methylated metabolites. Of the 41 mutation carriers identified, 11 were diagnosed with PGL, 12 were found to be healthy carriers after evaluation, and 18 were reportedly healthy based on family history accounts. The penetrance of PGL related to the exon 1 large SDHB deletion in this family was estimated to be 35% by age 40. Variable expressivity of the phenotype associated with a large exon 1 SDHB deletion was observed, including low penetrance, diverse primary PGL tumor locations, and malignant potential.

BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) (MIM 135150) is an autosomal dominant predisposition to the development of follicular hamartomas (fibrofolliculomas), lung cysts, spontaneous pneumothorax, and kidney neoplasms. Germline mutations in BHD are associated with the susceptibility for BHDS. We previously described 51 BHDS families with BHD germline mutations. OBJECTIVE: To characterise the BHD mutation spectrum, novel mutations and new clinical features of one previously reported and 50 new families with BHDS. METHODS: Direct bidirectional DNA sequencing was used to screen for mutations in the BHD gene, and insertion and deletion mutations were confirmed by subcloning. We analysed evolutionary conservation of folliculin by comparing human against the orthologous sequences. RESULTS: The BHD mutation detection rate was 88% (51/58). Of the 23 different germline mutations identified, 13 were novel consisting of: four splice site, three deletions, two insertions, two nonsense, one deletion/insertion, and one missense mutation. We report the first germline missense mutation in BHD c.1978A>G (K508R) in a patient who presented with bilateral multifocal renal oncocytomas. This mutation occurs in a highly conserved amino acid in folliculin. 10% (5/51) of the families had individuals without histologically confirmed fibrofolliculomas. Of 44 families ascertained on the basis of skin lesions, 18 (41%) had kidney tumours. Patients with a germline BHD mutation and family history of kidney cancer had a statistically significantly increased probability of developing renal tumours compared to patients without a positive family history (p = 0.0032). Similarly, patients with a BHD germline mutation and family history of spontaneous pneumothorax had a significantly increased greater probability of having spontaneous pneumothorax than BHDS patients without a family history of spontaneous pneumothorax (p = 0.011). A comprehensive review of published reports of cases with BHD germline mutation is discussed. CONCLUSION: BHDS is characterised by a spectrum of mutations, and clinical heterogeneity both among and within families.

First-in-human phase 0 study of 111In-CHX-A"-DTPA trastuzumab for HER2 tumor imaging.

INTRODUCTION: Tumors over-expressing the human epithelial receptor 2 (HER2) or exhibiting amplification or mutation of its proto-oncogene have a poorer prognosis. Using trastuzumab and/or other HER2 targeted therapies can increase overall survival in patients with HER2(+) tumors making it critical to accurately identify patients who may benefit. We report on a Phase 0 study of the imaging agent, 111In-CHX-A"-DTPA trastuzumab, in patients with known HER2 status to evaluate its safety and biodistribution and to obtain preliminary data regarding its ability to provide an accurate, whole-body, non-invasive means to determine HER2 status. METHODS: 111In-CHX-A"-DTPA trastuzumab was radiolabeled on-site and slowly infused into 11 patients who underwent single (n=5) or multiple (n=6) ɣ-camera (n=6) and/or SPECT (n=8) imaging sessions. RESULTS: No safety issues were identified. Visual and semi-quantitative imaging data were concordant with tissue HER2 expression profiling in all but 1 patient. The biodistribution showed intense peak liver activity at the initial imaging timepoint (3.3h) and a single-phase clearance fit of the average time-activity curve (TAC) estimated t1/2=46.9h (R2=0.97; 95%CI 41.8 to 53h). This was followed by high gastrointestinal (GI) tract activity peaking by 52h. Linear regression predicted GI clearance by 201.2h (R2 =0.96; 95%CI 188.5 to 216.9h). Blood pool had lower activity with its maximum on the initial images. Non-linear regression fit projected a t1/2=34.2h (R2 =0.96; 95%CI 25.3 to 46.3h). Assuming linear whole-body clearance, linear regression projected complete elimination (x-intercept) at 256.5hr (R2=0.96; 95%CI 186.1 to 489.2h). CONCLUSION: 111In-CHX-A"-DTPA trastuzumab can be safely imaged in humans. The biodistribution allowed for visual and semiquantitative analysis with results concordant with tissue expression profiling in 10 of 11 patients. Advances in Knowledge and Implications for Patient Care Using readily available components and on-site radiolabeling 111In-CHX-A"-DTPA trastuzumab SPECT imaging may provide an economical, non-invasive means to detect HER2 over-expression.