PIK3R1, HRAS and AR Gene Alterations Associated with Sclerosing Polycystic Adenoma of the Parotid Gland.

Sclerosing polycystic adenoma (SPA) is a rare neoplasm occurring in the salivary glands, mainly the parotid gland. Although it was originally thought to represent a non-neoplastic process, recent genetic data have proven its monoclonality, supporting its neoplastic origin. We report a case of a 73-year-old woman who presented with left neck swelling and pain. A 3 cm hypoechoic, heterogeneous, solid mass was identified on neck ultrasonography within the left parotid gland. Fine needle aspiration revealed benign acinar cells and lymphocytes. Left partial superficial parotidectomy was performed and a diagnosis of SPA was made. Targeted next-generation sequencing (NGS) revealed three clinically significant alterations in the PIK3R1, HRAS, and AR genes. Alterations in the PIK3R1 gene have been previously reported in cases of SPA; however, this study is the first to report two novel clinically significant genomic alterations in the HRAS and AR genes. AR protein expression by immunohistochemistry was strongly and diffusely positive in the neoplastic epithelial cells compared to the adjacent normal salivary gland tissue, which was dead negative for AR. This molecular profile will enhance our understanding of the molecular pathways underlying the development of this tumor. Although this entity was initially thought to be a reactive process, evidence from our case and similar cases strongly support the notion that it is neoplastic due to the presence of specific genetic alterations linked to it.

Multicenter, double-blind, placebo-controlled trial of seviprotimut-L polyvalent melanoma vaccine in patients with post-resection melanoma at high risk of recurrence.

BACKGROUND: Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here. METHODS: Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients. RESULTS: For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)). CONCLUSIONS: Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas. TRIAL REGISTRATION NUMBER: NCT01546571.

Parathyroid hemangioma.

BACKGROUND: Hemangiomas are benign neoplasms of capillary proliferation that arise from a developmental anomaly where angioblastic mesenchyme fails to form canals. Most hemangiomas arise in the head and neck region, either superficially in the skin or deeper within endocrine organs such as the parotid gland. Parathyroid hemangiomas, however, are extremely rare, with only five cases previously reported in the literature. CASE PRESENTATION: Herein, we present a case of a 68-year-old man with a hemangioma almost completely replacing the right upper parathyroid gland, grossly measuring 1.3 × 1.3 × 1.2 cm and weighing 700 mg, associated with primary hyperparathyroidism. CONCLUSIONS: Parathyroid gland enlargement due to vascular neoplasms such as hemangiomas can mimic, both clinically and radiographically, hyperplasias and/or adenomas. Surgeons need to be aware of the presence of this entity and should consider it in the differential diagnosis of hyperparathyroidism or parathyroid gland enlargement.

[Levels of 25 hydroxy vitamin D of serum and broncho-alveolar lavage in patients with pulmonary tuberculosis]. / Concentraciones de 25 hidroxi vitamina D séricas y en lavado bronco-alveolar en pacientes con tuberculosis pulmonar.

BACKGROUND: Alteration of vitamin D is a risk factor for tuberculosis (TB). AIM: To evaluate the pulmonary and serum levels of 25-hydroxy vitamin D (25OHD) in patients with and without pulmonary TB. METHODS: Two-stage study: the first part was retrospective cross-sectional and the second prospective. Those > 18 years of age who underwent fiberoptic bronchoscopy for suspected pulmonary TB and in whom the infection was confirmed were included. Patients with another type of infection without TB and non-infectious diseases were taken as controls for the first stage and infectious controls without TB in the prospective phase. The measurement of 25OHD was performed by ELFA (enzyme-linked fluorescence assay). The Kruskal-Wallis test was used to evaluate association, considering a value of p < 0.05 to be significant. The data were processed with the SPSS version 23 program. RESULTS: The total sample was 77 patients (35 in the first stage and 42 in the second). The characteristics between the groups were homogeneous. Serum (second phase) and broncho-alveolar lavage (first and second phase) levels of 25OHD were lower in TB patients compared to controls and were independent of serum calcium level (serum: 22.4 ng/mL vs 33 ng/mL, p = 0.006 and broncho-alveolar lavage: 9.7 ng/mL vs 12.2 ng/mL; p = 0.012). CONCLUSIONS: There was a significant difference between the levels of 25OHD in both serum and broncho-alveolar lavage in patients with pulmonary TB in relation to their controls.

Concentraciones de 25 hidroxi vitamina D séricas y en lavado bronco-alveolar en pacientes con tuberculosis pulmonar / Levels of 25 hydroxy vitamin D of serum and broncho-alveolar lavage in patients with pulmonary tuberculosis

INTRODUCCIÓN: La alteración de la vitamina D es un factor de riesgo para enfermar de tuberculosis (TBC). OBJETIVO: Evaluar la concentración pulmonar y sérica del compuesto 25-hidroxi-vitamina D (25OHD) en pacientes con y sin TBC pulmonar. METODOLOGÍA: Estudio de dos etapas: la primera parte fue de corte transversal, retrospectiva, y la segunda prospectiva. Se incluyeron > 18 años a los que se les realizó fibrobroncoscopia por sospecha de TBC pulmonar y en quienes se confirmó la infección. Se tomaron como controles a pacientes con otro tipo de infección no TBC, y enfermedades no infecciosas para la primera etapa y controles infecciosos sin TBC en la fase prospectiva. La medición de 25OHD se realizó mediante ELFA (ensayo de fluorescencia ligado a enzima). Se empleó la prueba de Kruskal-Wallis para evaluar asociación considerando significativo un valor de p < 0,05. Los datos se procesaron con el programa SPSS versión 23. RESULTADOS: La muestra total fue de 77 pacientes (35 en la primera etapa y 42 en la segunda). Las características entre los grupos fueron homogéneas. Las concentraciones en suero (segunda fase) como en el lavado bronco-alveolar (primera y segunda fase) de 25OHD fueron más bajas en pacientes con TBC comparado con los controles e independientes de la concentración de calcio sérico (suero: 22,4 ng/mL vs 33 ng/mL, p = 0,006 y lavado bronco-alveolar: 9,7 ng/mL vs 12,2 ng/mL; p = 0,012). CONCLUSIONES: Hubo una diferencia significativa entre las concentraciones de 25OHD, tanto en suero como en lavado bronco-alveolar, en pacientes con TBC pulmonar con relación a sus controles.

BACKGROUND: Alteration of vitamin D is a risk factor for tuberculosis (TB). AIM: To evaluate the pulmonary and serum levels of 25-hydroxy vitamin D (25OHD) in patients with and without pulmonary TB. METHODS: Two-stage study: the first part was retrospective cross-sectional and the second prospective. Those > 18 years of age who underwent fiberoptic bronchoscopy for suspected pulmonary TB and in whom the infection was confirmed were included. Patients with another type of infection without TB and non-infectious diseases were taken as controls for the first stage and infectious controls without TB in the prospective phase. The measurement of 25OHD was performed by ELFA (enzyme-linked fluorescence assay). The Kruskal-Wallis test was used to evaluate association, considering a value of p < 0.05 to be significant. The data were processed with the SPSS version 23 program. RESULTS: The total sample was 77 patients (35 in the first stage and 42 in the second). The characteristics between the groups were homogeneous. Serum (second phase) and broncho-alveolar lavage (first and second phase) levels of 25OHD were lower in TB patients compared to controls and were independent of serum calcium level (serum: 22.4 ng/mL vs 33 ng/mL, p = 0.006 and broncho-alveolar lavage: 9.7 ng/mL vs 12.2 ng/mL; p = 0.012). CONCLUSIONS: There was a significant difference between the levels of 25OHD in both serum and broncho-alveolar lavage in patients with pulmonary TB in relation to their controls.

Parathyroid hemangioma

Background Hemangiomas are benign neoplasms of capillary proliferation that arise from a developmental anomaly where angioblastic mesenchyme fails to form canals. Most hemangiomas arise in the head and neck region, either superficially in the skin or deeper within endocrine organs such as the parotid gland. Parathyroid hemangiomas, however, are extremely rare, with only five cases previously reported in the literature. Case presentation Herein, we present a case of a 68-year-old man with a hemangioma almost completely replacing the right upper parathyroid gland, grossly measuring 1.3 × 1.3 × 1.2 cm and weighing 700 mg, associated with primary hyperparathyroidism. Conclusions Parathyroid gland enlargement due to vascular neoplasms such as hemangiomas can mimic, both clinically and radiographically, hyperplasias and/or adenomas. Surgeons need to be aware of the presence of this entity and should consider it in the differential diagnosis of hyperparathyroidism or parathyroid gland enlargement.

Aneurisma de arteria pulmonar: un hallazgo incidental / Pulmonary artery aneurysm: an incidental finding

Resumen Los aneurismas de la arteria pulmonar son entidades infrecuentes y su tratamiento es tema de discusión. Desde el punto de vista etiológico pueden ser congénitos o adquiridos. Los primeros, generalmente se asocian a malformaciones cardiacas que producen hipertensión pulmonar, siendo el ductus arterioso la más frecuente. Otras anomalías incluyen defectos auriculares o ventriculares. Las causas adquiridas pueden ser idiopáticas o estar asociadas a infecciones (tuberculosis, sífilis), traumatismos o colagenopatías. Presentamos el caso de una mujer de 62 años, quien consultó por un cuadro clínico en el que se destacaba su sintomatología neurológica e infecciosa, con posterior progresión a un choque séptico y en quien los hallazgos de las imágenes mostraron un aneurisma gigante de la arteria pulmonar siendo este un hallazgo incidental y sin relación a la sintomatología de la paciente.

Abstract Aneurysms of the pulmonary artery are rare entities and their treatment is a matter of discussion. From the etiological point of view, they can be congenital or acquired. Those in the first group are generally associated with cardiac malformations that generate pulmonary hypertension, with the ductus arteriosus being the most frequent. Other abnormalities include atrial or ventricular defects. The acquired causes may be idiopathic or associated with infections (tuberculosis, syphilis), trauma, or collagen disease. We present the case of a 62-year-old woman, which consulted for a clinical condition where neurological and infectious symptoms stood out, with subsequent progression to a state of septic shock, and in whom the imaging finding showed a giant pulmonary artery aneurysm. this being an incidental finding and unrelated to the patient's symptoms.

Understanding the histogenesis of a HRAS-PIK3R1 co-driven metastatic metaplastic breast carcinoma associated with squamous metaplasia of lactiferous ducts.

Metaplastic breast carcinoma (MBC) represents a heterogeneous group of aggressive primary breast cancers that can show differentiation into carcinomatous and sarcomatous elements. Due to its rapid growth, this malignancy can replace precursor lesions, which remain unknown in most cases. Herein, we describe a MBC presenting as a deceptive post-biopsy hematoma. Histopathological and immunohistochemical evaluation of the primary tumor revealed a squamous cell carcinoma arising in a background of squamous metaplasia of lactiferous ducts (SMOLD). In the absence of ductal carcinoma in situ, we consider SMOLD as a nonobligatory precursor of MBC. The tumor showed 'dedifferentiation' into spindle, mucin-producing, osteoclast-like giant cell and fibromatosis-like carcinoma. Next-generation sequencing revealed the driver mutations HRASQ61R and PIK3R1c.1738_1745+2del in addition to MYH11S638L and amplification of ERCC5 and FGF14, which were potential contributors to tumor phenotype. Tumor dedifferentiation was probably facilitated by epithelial-to-mesenchymal transition (EMT) with aberrant expression of platelet and endothelial adhesion molecule-1, leading to early metastasis via hematogenous route rather than lymphatic. The co-occurrence of phosphoinositide 3-kinase and mitogen-activated protein kinase pathway abnormalities along with EMT could mediate divergent growth in breast cancer.

Evaluación de la médula ósea en pacientes citopénicos infectados con el virus de la inmunodeficiencia humana tipo 1 en hospital colombiano del tercer nivel / Evaluation of the bone marrow in cytopenic patients infected with human immunodeficiency virus type 1 in a third level Colombian hospital

Resumen Objetivo: describir los hallazgos en el estudio de medula ósea de los pacientes con infección por virus de inmunodeficiencia humana que presentaron algún tipo de citopenia. Materiales y métodos: estudio descriptivo retrospectivo con 37 pacientes adultos con infección confirmada por el virus de inmuno deficiencia humana que presentaron algún tipo de citopenia, durante enero 2011 a diciembre de 2014 en el Hospital Universitario Hernando Moncaleano Perdomo de Neiva. Resultados: la mediana de edad fue 35 años, el 59 % fueron hombres; en el 48,6 % el tiempo de diagnóstico de la infección fue inferior a un año y el 59 % no recibían terapia antiretroviral al momento de ingreso. La mediana de recuento leucocitario de 2 400 células/mm3, neutró filos de 1 400 células/mm3 y de linfocitos CD4 de 43 células/mm3. El estudio de medula ósea fue positivo en el 27 %, encontrando infección oportunista diseminada en seis pacientes; dos con neoplasias, además de uno con hipo plasia medular y otro con anemia megaloblástica. Conclusión: el estudio de medula ósea en los pacientes con infección por virus de inmunodeficiencia humana es una herramienta útil y se debe realizar a todos los pacientes con enfermedad avanzada en el estudio de citopenia asociada o no a fiebre.

Abstract Objective: To describe the findings in the study of bone marrow of patients with human immunodeficiency virus (HIV) infection who present some type of cytopenia in a highly complex hospital in southern Colombia. Materials and methods: Retrospective descriptive study of case series. All adult pa tients with confirmed HIV infection who presented some type of cytopenia during January 2011 to December 2014 at the University Hospital Hernando Moncaleano Perdomo de Neiva, were included. A total of 37 patients com pleted the inclusion criteria. Results: the median age was 35 years, 59 % men; in 48.6 % of the individuals, the time of diagnosis by HIV was less than one year and 59 % did not receive antiretroviral therapy at the time of admission. A median was found in a leukocyte count of 2400 cells / mm3, neutrophils of 1400 cells / mm3, CD4 lymphocytes of 43 cells / mm3. The bone marrow study was positive in 27 % of the cases (10 patients), finding disseminated opportunistic infection in six patients; two neoplasms, plus a medullar hypoplasia and a case of megaloblastic anemia. Conclusion: The study of bone marrow in patients with HIV infection is a useful tool and should be performed in all patients with HIV infection with advanced disease in the study of cytopenia associated or not with fever.

Disseminated Kaposi sarcoma with epithelioid morphology in an HIV/AIDS patient: A previously unreported variant.

Kaposi sarcoma is an oligoclonal HHV-8-driven vascular proliferation that was first described by a Viennese dermatologist Dr Moritz Kaposi. The disease has been seen in different clinical-epidemiological settings with a wide morphologic spectrum. We report a 52-year-old Caucasian man with HIV/AIDS and Kaposi sarcoma who presented with dyspnea and pleural effusion. He reported numerous tender subcutaneous nodules developing over the past few months on his chest, back and abdomen. An excisional biopsy of one of the nodules was performed. Touch preps revealed malignant cells in clusters. Microscopically, the neoplasm appeared undifferentiated with an epithelioid morphology, and involved the dermis and subcutaneous fat. Despite the medical history, Kaposi sarcoma was not considered foremost in the differential diagnosis. The malignant cells were positive for vimentin and negative for S100 protein, keratin AE1/3, CK7, CK20, napsin A, TTF-1 and synaptophysin. Additional stains revealed positivity for HHV-8, CD31 and D2-40, supporting the diagnosis of Kaposi sarcoma. Kaposi sarcoma has been well described with many variants that may cause diagnostic difficulty. An epithelioid variant has not been reported and consequently, may cause misinterpretation of an otherwise well-known entity that may become life threatening if appropriate treatment is not initiated in a timely manner.

Adenoid cystic carcinoma of the breast, 20 years of experience in a single center with review of literature.

BACKGROUND: Adenoid cystic carcinoma (ACC) of the breast is a rare type of breast cancer, which presents inconsistencies in the optimal management strategy. METHODS: A retrospective review of prospectively collected data, spanning the last 20 years, was performed using the cancer registry database at our institution. RESULTS: Six patients were diagnosed with ACC of the breast, out of 5,813 total patients diagnosed with breast cancer (0.1%). Our identified patients had a median age of 66, all with the early stage cancer (Stage I/II). The average size of the breast lesion was 1.62 cm, and nodal status was negative for all cases. All patients had resection as primary therapy (partial or total mastectomy), with one patient also undergoing external beam radiation and tamoxifen hormonal therapy. Median follow-up was 85 months, with all patients being disease-free at last follow-up. CONCLUSIONS: ACC of the breast has an indolent course, despite triple negative status. Our study suggests that radiation may not be warranted and confirms the rarity of axillary node metastases, indicating that sentinel node excision may also not be necessary. Ultimately, the hope is that our findings along with the reviewed literature will aid in determining the most appropriate options for management of ACC of the breast.

Chondroid Metaplasia in a Fibroepithelial Polyp of Gingiva.

Gingival masses are commonly encountered in clinical practice and can be a result of many conditions one of them could be metaplasia. Metaplasia is defined as the replacement of the lining of an organ with the type of lining normally found at another site. We are reporting a case of a 17-year-old Mexican male who presented with a pedunculated nodule associated to maxillary anterior gingiva. The histopatological examination revealed a chondroid material covered by stratified squamous epithelium and was diagnosed as chondroid metaplasia.

Quantum dot labeling and tracking of cultured limbal epithelial cell transplants in vitro.

PURPOSE: Cultured human limbal epithelial cells (HLECs) have shown promise in the treatment of limbal stem cell deficiency but little is known about their survival, behavior, and long-term fate after transplantation. The aim of this research was to evaluate, in vitro, quantum dot (Qdot) technology as a tool for tracking transplanted HLECs. METHODS: In vitro cultured HLECs were labeled with Qdot nanocrystals. Toxicity was assessed using live-dead assays. The effect on HLEC function was assessed using colony-forming efficiency assays and expression of CK3, P63alpha, and ABCG2. Sheets of cultured HLECs labeled with Qdot nanocrystals were transplanted onto decellularized human corneoscleral rims in an organ culture model and observed to investigate the behavior of transplanted cells. RESULTS: Quantum dot labeling had no detrimental effect on HLEC viability or function in vitro. Proliferation resulted in a gradual reduction in Qdot signal but sufficient signal was present to allow tracking of cells through multiple generations. Cells labeled with Qdots could be reliably detected and observed using confocal microscopy for at least 2 weeks after transplantation in our organ culture model. In addition, it was possible to label and observe epithelial cells in intact human corneas by using the Rostock corneal module adapted for use with the Heidelberg HRA. CONCLUSIONS: This work demonstrates that Qdots combined with existing clinical equipment could be used to track HLEC for up to 2 weeks after transplantation; however, our model does not permit the assessment of cell labeling beyond 2 weeks. Further characterization in in vivo models are required.

Three bisphosphonate ligands improve the water solubility of quantum dots.

Synthesised Quantum Dots (QDs) require surface modification in order to improve their aqueous dispersion and biocompatibility. Here, we suggest bisphosphonate molecules as agents to modify the surface of QDs for improved water solubility and biocompatibility. QDs_TOPO (CdSe/ZnS-trioctylphosphine oxide) were synthesised following modification of the method of Bawendi et al. (J. Phys. Chem. B, 1997, 101, 9463-9475). QDs surface modification is performed using a ligand exchange reaction with structurally different bisphosphonates (BIPs). The BIPs used were ethylene diphosphonate (EDP), methylenediphosphonate (MDP) and imidodiphosphonate (IDP). After ligand exchange, the QDs were extensively purified using centrifugation, PD-10 desalting columns and mini dialysis filters. Transmission electron microscopy (TEM) and fluorescent spectroscopy have been used to characterise the size and optical properties of the QDs. Cell toxicity was investigated using MTT (tetrazolium salt) and glutathione assays and intracellular uptake was imaged using confocal laser scanning microscopy and assessed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). QDs_TOPO and QDs-capped with BIPs (QDs_BIPs) were successfully synthesised. TEM showed the size and morphology of the QDs to be 5-7 nm with spherical shape. The stabilised QDs_BIPs showed significantly improved dispersion in aqueous solutions compared to QDs_TOPO. The cytotoxicity studies showed very rapid cell death for cells treated by QDs_TOPO and a minor effect on cell viability when QDs_BIPs were applied to the cells. Both EDP- and MDP-modified QDs did not significantly increase the intracellular levels of glutathione. In contrast, IDP-modified QDs substantially increased the intracellular glutathione levels, indicating potential cadmium leakage and inability of IDP to adequately cap and stabilise the QDs. EDP- and MDP-modified QDs were taken up by IGROV-1 (ovarian cancer) cells as shown by fluorescence microscopy, however, the IDP-modified QD signal was not clearly visible in the cells. Cellular uptake measured by intracellular cadmium levels using ICP-MS showed significant uptake of all three BIPs QDs. The structure of BIPs appears to play a significant role in the ability of these molecules to act as capping agents. Our findings demonstrate a novel approach to produce water-dispersible QDs through ligand exchange with certain types of BIPs molecules that can find application in bioimaging.