Familial bilateral macronodular adrenal hyperplasia due to a novel ARMC 5 germline mutation: Clinical status and possible association with other neoplasms.

INTRODUCTION/OBJECTIVES: Mutations in the ARMC5 (armadillo repeat containing 5, OMIM 615549) gene, a putative tumor suppressor gene, have recently been identified as a common cause of sporadic and familial bilateral macronodular adrenal hyperplasia (BMAH). Familial BMAH is thought to be caused by two mutations, one germline and the other somatic, as suggested by the 2-hit theory. The objective is to describe a new mutation and develop its clinical characteristics and implications. METHODS, RESULTS AND CONCLUSIONS: We present an affected family with 11 members carrying a novel mutation of the ARMC5 gene (NM_001288767.1): c.2162T>C p. (Leu721Pro). Two of the carriers developed clinical Cushing's syndrome (CS), two mild autonomous cortisol secretion (MACS) and one presented with autonomous cortisol secretion (ACS). Four patients developed other tumors, three of whom died from this cause. It is not known whether these tumors could be related to the described mutation.

Difficulties of gender affirming treatment in trans women with BRCA1+ mutation: A case report.

Gender affirming treatment in transgender women is based on a combination of antiandrogens and estrogens, with the latter maintained over the long term. When prescribing these treatments, we must consider the possibility of developing estrogen-dependent breast cancer. In transgender women, a breast cancer incidence of 4.1 per 100,000 has been estimated, which would increase the risk by 46% in relation to cisgender men but decrease it by 70% in relation to cisgender women. It is known that certain gene mutations such as BRCA1 imply an increased risk of breast cancer, but at present the risk in transgender women with BRCA1 treated with estrogens is not well established. We present the case of a transgender woman with a family history of breast cancer and BRCA1 mutation and the therapeutic decisions made in a multidisciplinary team. Following this case, we review and discuss the published literature.

Bioavailability and systemic transport of oleanolic acid in humans, formulated as a functional olive oil.

Evidence of the pharmacological activity of oleanolic acid (OA) suggests its potential therapeutic application. However, its use in functional foods, dietary supplements, or nutraceuticals is hindered by limited human bioavailability studies. The BIO-OLTRAD trial is a double-blind, randomized controlled study with 22 participants that received a single dose of 30 mg OA formulated as a functional olive oil. The study revealed that the maximum serum concentration of OA ranged from 500 to 600 ng mL-1, with an AUC0-∞ value of 2862.50 ± 174.50 ng h mL-1. Furthermore, we discovered a physiological association of OA with serum albumin and triglyceride-rich lipoproteins (TRL). UV absorption spectra showed conformational changes in serum albumin due to the formation of an adduct with OA. Additionally, we demonstrated that TRL incorporate OA, reaching a maximum concentration of 140 ng mL-1 after 2-4 hours. We conjecture that both are efficient carriers to reach target tissues and to yield high bioavailability.

Telemedicine screening program for diabetic retinopathy in patients with type 1 diabetes mellitus.

PURPOSE: To analyze the results of the telemedicine screening program for diabetic retinopathy (DR) in patients with type 1 diabetes conducted by the Endocrinology and Nutrition Management Unit of Virgen del Rocío University Hospital. METHODS: This cross-sectional study comprised patients with type 1 diabetes mellitus (DM) in our DR screening program from January 2018 to November 2020. Fundus photographs are performed by trained nurses and reviewed by a trained endocrinologist. Those suggestive of pathology are sent to ophthalmology through a telematic program for review. RESULTS: Of the 995 fundus photographs evaluated, 646 (65.3%) showed no evidence of DR, 327 (33.1%) presented possible DR, and 16 (1.6%) were not gradable. The diagnosis was confirmed in 254 patients after reviewing by ophthalmology, and the screening program achieved a positive predictive value for DR of 77.7%. Seventy-three were excluded by ophthalmology due to the absence of DR (false positive rate - 22.3%). In 92.5% of the cases classified by the ophthalmologist, the degree of DR was mild or very mild. CONCLUSION: Our telemedicine screening program for DR in patients with type 1 DM is consistent with the literature. Effective screening for DR is performed, with patients diagnosed in the early stages. Telemedicine programs facilitate efficient communication among healthcare personnel.

Phytochemical Content and Potential Health Applications of Pecan [Carya illinoinensis (Wangenh) K. Koch] Nutshell.

BACKGROUND: The pecan nutshell contains phytochemicals with various biological activities that are potentially useful in the prevention or treatment of diseases, such as cancer, diabetes, and metabolic imbalances associated with heart diseases. OBJECTIVE: The aim of this study is to update this topic by means of a literature review and include those studies that contribute to the knowledge of the chemical composition and biological activities of pecan nutshell, particularly those related to the therapeutic potential against some chronic degenerative diseases associated with oxidative stress. METHODS: Exhaustive and detailed review of the existing literature was conducted using electronic databases. CONCLUSION: The pecan nutshell is a promising natural product with pharmaceutical uses in various diseases. However, additional research related to the assessment of efficient extraction methods and characterization, particularly the evaluation of the mechanisms of action in new in vivo models, is necessary to confirm these findings and development of new drugs with therapeutic use.

Gender Incongruity in a Person with 46,XY and Complete Androgen Insensitivity Syndrome Raised as a Female.

We present the case of a patient with female sex assignment at birth whose parents consulted with a pediatrician when the child was 12 years old, indicating that despite female sex assignment, she felt that she (henceforth "he") had a male gender identity and was gynephilic. Medical examination revealed a 46XY karyotype, a primary amenorrhea and an appropriate testosterone increase after HCG stimulation test. The patient was diagnosed then with a 46,XY disorder of sex development with androgen insensitivity syndrome, but then he missed subsequent appointments. At the age of 24, he resumed medical follow-up to reaffirm his male gender identity through sex reassignment surgery. His physical examination showed a Tanner stage III-IV breast development, vulva, clitoris, normal-sized vagina, absence of uterus and ovaries on transvaginal ultrasound, bilateral cryptorchidism on abdominal-pelvic MRI and osteoporosis on bone densitometry. The results of the blood tests were LH 24.5 mIU/mL [normal range, 1.7-8.6 mIU/mL for men] and testosterone 8.8 nmol/L [8.7-33 nmol/L]; conversely, FSH, estradiol, progesterone, and prolactin levels were normal. The molecular genetic analysis revealed an androgen receptor gene mutation associated with complete androgen insensitivity syndrome. At present, the patient has undergone bilateral orchiectomy and has initiated treatment with topical testosterone and bisphosphonates. We have yet to evaluate the effects and decide the best therapy taking into account that he has a male gender identity but complete androgen insensitivity syndrome.

Novel mouse model resistant to irreversible BTK inhibitors: a tool identifying new therapeutic targets and side effects.

Pharmacological inhibitors of Bruton tyrosine kinase (BTK) have revolutionized treatment of B-lymphocyte malignancies and show great promise for dampening autoimmunity. The predominant BTK inhibitors tether irreversibly by covalently binding to cysteine 481 in the BTK catalytic domain. Substitution of cysteine 481 for serine (C481S) is the most common mechanism for acquired drug resistance. We generated a novel C481S knock-in mouse model and, using a battery of tests, no overt B-lymphocyte phenotype was found. B lymphocytes from C481S animals were resistant to irreversible, but sensitive to reversible, BTK inhibitors. In contrast, irreversible inhibitors equally impaired T-lymphocyte activation in mice, mimicking the effect of treatment in patients. This demonstrates that T-lymphocyte blockage is independent of BTK. We suggest that the C481S knock-in mouse can serve as a useful tool for the study of BTK-independent effects of irreversible inhibitors, allowing for the identification of novel therapeutic targets and pinpointing potential side effects.

Prognostic value of event-free survival at 12 and 24 months and long-term mortality for non-Hodgkin follicular lymphoma patients: A study report from the Spanish Lymphoma Oncology Group.

BACKGROUND: Relatively few studies have analyzed the mortality of follicular lymphoma (FL) patients in comparison with a sex- and age-matched general population. This study analyzed the overall survival (OS) of patients with FL and compared their survival with the expected survival of a general population. METHODS: Patients diagnosed with FL were prospectively enrolled from 1980 to 2013. Standardized mortality ratios (SMRs) were obtained from yearly sex- and age-specific mortality rates in Spain, and OS was compared with age- and sex-matched general population data. RESULTS: A total of 1074 patients with newly diagnosed FL were enrolled. The median OS was 231 months (95% confidence interval [CI], 195-267 months). Event-free survival at 12 months (EFS12) and event-free survival at 24 months (EFS24) were associated with an increased probability of early death, with an SMR of 10.27 (95% CI, 8.26-12.77) for EFS12. The overall SMR, including all causes of death, was 2.55 (95% CI, 2.23-2.92), and it was higher for women (SMR, 3.02; 95% CI, 2.48-3.67) and young adults (SMR, 6.01; 95% CI, 3.13-11.55). More than 10 years after the diagnosis, mortality rates for FL patients were lower than those for the general population (SMR, 0.47; 95% CI, 0.28-0.78). When FL was excluded as a cause of death, the overall SMR was 1.35 (95% CI, 1.11-1.65) without a statistically significant mortality increase in the >60-year-old group in comparison with age- and sex-matched general population data. More than 15% of the patients included in the study (n = 158) had more than 10 years of follow-up. CONCLUSIONS: EFS12 and EFS24 predict an early increase in mortality. The long-term SMR, over the course of 10 years of follow-up, shows that patients with FL have a risk of dying similar to that of a sex- and age-matched general population. Cancer 2017;123:3709-3716. © 2017 American Cancer Society.

Bobble-head doll syndrome in an 80-year-old man, associated with a giant arachnoid cyst of the lamina quadrigemina, treated with endoscopic ventriculocystocisternotomy and cystoperitoneal shunt.

Bobble-head doll syndrome (BHDS) is a rare entity, characterized by antero-posterior head bobbing, which is of the type "yes-yes." Less frequently, having a head movement of the type "no-no" is described. We report an unusual case of an 80-year-old man with a cystic mass of the lamina quadrigemina, extending to the posterior fossa. We conclude that ventriculocystocisternotomy associated with a cystoperitoneal shunt is an effective treatment for a symptomatic giant arachnoid cyst in the lamina quadrigemina.

Primary diffuse large B cell lymphoma of the uterine cervix successfully treated by combined chemotherapy alone: A case report.

RATIONALE: Primary lymphomas of the uterine cervix are a rare disease. They are often misdiagnosed because of their rarity and because they can be easily confused with a squamous cell carcinoma of the cervix, as they are usually presented as exophytic mass with vaginal bleeding as their most common symptoms. Nevertheless, considering that both the prognosis and the treatment are completely different between them, differential diagnosis should be taken into account. PATIENT CONCERNS: A case of a 51-year-old woman with a primary diffuse large B-cell lymphoma of the cervix is presented. DIAGNOSES: Diagnosis of this tumor was a challenge for pathologists and clinicians, as four biopsies were needed to achieve a final diagnosis. INTERVENTIONS: Patient was successfully treated with combined Rituximab and chemotherapy (R-CHOP) alone. OUTCOMES: Complete remission, confirmed through biopsy, was reached after six courses of chemotherapy. At 2-years follow up, patient is alive and free of disease. LESSONS: Considering that the prognosis and treatment of primary malignant lymphoma of the cervix are completely different than that of the squamous cell carcinoma, awareness of this disease should be considered in the differential diagnosis.

Impact of treatment in long-term survival patients with follicular lymphoma: A Spanish Lymphoma Oncology Group registry.

BACKGROUND: Follicular lymphoma is the second most common non-Hodgkin lymphoma in the United States and Europe. However, most of the prospective randomized studies have very little follow-up compared to the long natural history of the disease. The primary aim of this study was to investigate the long-term survival of our series of patients with follicular lymphoma. PATIENTS AND METHODS: A total of 1074 patients with newly diagnosed FL were enrolled. Patients diagnosed were prospectively enrolled from 1980 to 2013. RESULTS: Median follow-up was 54.9 months and median overall survival is over 20 years in our series. We analyzed the patients who are still alive beyond 10 years from diagnosis in order to fully assess the prognostic factors that condition this group. Out of 166 patients who are still alive after more than 10 years of follow-up, 118 of them (73%) are free of evident clinical disease. Variables significantly associated with survival at 10 years were stage < II (p <0.03), age < 60 years (p <0.0001), low FLIPI (p <0.002), normal ß2 microglobulin (p <0.005), no B symptoms upon diagnosis (p <0.02), Performance Status 0-1 (p <0.03) and treatment with anthracyclines and rituximab (p <0.001), or rituximab (p <0.0001). CONCLUSIONS: A longer follow-up and a large series demonstrated a substantial population of patients with follicular lymphoma free of disease for more than 10 years.

Discordant Genotypic Sex and Phenotype Variations in Two Spanish Siblings with 17α-Hydroxylase/17,20-Lyase Deficiency Carrying the Most Prevalent Mutated CYP17A1 Alleles of Brazilian Patients.

17α-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia caused by mutations in CYP17A1. Two phenotypic female sisters, aged 17 and 15 years and with 46,XY and 46,XX karyotypes, respectively, presented with primary amenorrhea and absent secondary sexual characteristics. The elder sib also presented with high blood pressure. Both patients had elevated levels of ACTH, gonadotropins, progesterone, corticosterone, and deoxycorticosterone, and reduced levels of estradiol, testosterone, androstenedione, 17-OH-P, DHEA-S, cortisol, aldosterone, and renin activity. The CYP17A1 gene was sequenced, and polymorphic haplotypes were further analyzed in the Spanish family and in Brazilian patients. The 2 sisters were compound heterozygous for p.Arg362Cys and p.Trp406Arg mutations, previously described as the most prevalent mutations in Brazilian families of Spanish (p.Trp406Arg) or Portuguese (p.Arg362Cys) origin. Analysis of polymorphisms in CYP17A1 suggested that the paternal allele with p.Arg362Cys may share a common origin with the Brazilian carriers, while the maternal allele with p.Trp406Arg did not. Hydrocortisone and sex hormone replacement therapy was initiated in both patients. In conclusion, one CYP17A1 mutation (p.Arg362Cys) may share a common ancestry in Brazilian and our present Spanish patients, while p.Trp406Arg may have arisen separately. The elder patient (46,XY) developed a more severe phenotype and a poorer response to estradiol replacement therapy.

Müllerianosis with Intestinal Metaplasia: A Case Report.

Müllerianosis or Müllerian choristomas are developmental alterations that consist of an organoid structure with normal Müllerian tissue. We present a 62-year-old patient diagnosed on ultrasound scanning and on CT scan of bilateral ovarian cysts. During surgery, a left ovarian cyst and retroperitoneal tumor (adhered to sigmoid serous surface) were found. On histological examination, the tumor corresponded with a Müllerian choristoma showing endometrial, endosalpingeal and endocervical epithelium, with foci of intestinal metaplasia, a phenomenon not described in the literature.

Are there any significant variations in the clinical or histological presentation of lymphoid pathologies over the course of time in Spain?

INTRODUCTION: Little data is available concerning variations in the clinical characteristics of lymphoid neoplasms at presentation. We decided to investigate whether any variations in these characteristics had occurred in Spain during the last few years. MATERIALS AND METHODS: The GOTEL group database is an archive of all new lymphoma cases, regardless of their histological subtype, diagnosed in the hospitals within the group. An analysis was made of all the records between 1 January 1999 and 1 January 2009. Though the number of hospitals submitting data has changed over the course of time, data were provided by 26 hospitals from 16 Spanish provinces. RESULTS: A total of 3651 cases of lymphoma were recorded during this period. Grouped by clinical features, 42.8% (1561 patients) had low-grade lymphoma, 30.4% (1110 patients) intermediate-grade lymphoma and 15.2% (556 patients) Hodgkin's lymphoma; 208 patients had T lymphoma (5.7%), 111 patients high-grade lymphoma (3%) and 105 patients (2.9%) suffered lymphomas that were difficult to classify. A total of 6.3% of the diagnoses (231 patients) were made prior to 1999, 29.5% between 2000 and 2001, 25.7% between 2002 and 2003, 19.7% between 2004 and 2005, 11.2% between 2006 and 2007, and there were 200 entries from 2008 to the close of the study period, corresponding to 1.5% of the complete database. The median age at diagnosis was 60 (range 7-105 years), by percentiles: 25 corresponded to 44 years old, 50 to 60 years old and 75 to 71. Distribution by gender was 53.1% male and 46.9% female. An analysis was made of all the clinical variables collected, comparing their behaviour during the different diagnostic periods. The periods, gender, ECOG, stage, LDH, ß2 microglobulin, Hodgkin's or non- Hodgkin's type neoplasm, B lymphoma vs. Hodgkin's, NK or T, nodal or extra-nodal origin, median age at diagnosis and histological type by region of origin did not show any statistically significant differences in their distribution over the course of time. CONCLUSION: In our experience, there are no significant variations in clinical presentation or histological type in lymphomas diagnosed over the course of time in Spain.

Extracellular tumor-related mRNA in plasma of lymphoma patients and survival implications.

BACKGROUND: We studied anomalous extracellular mRNAs in plasma from patients with diffuse large B-cell lymphoma (DLBCL) and their survival implications. mRNAs studied have been reported in the literature as markers of poor (BCL2, CCND2, MYC) and favorable outcome (LMO2, BCL6, FN1) in tumors. These markers were also analyzed in lymphoma tissues to test possible associations with their presence in plasma. METHODOLOGY/PRINCIPAL FINDINGS: mRNA from 42 plasma samples and 12 tumors from patients with DLBCL was analyzed by real-time PCR. Samples post-treatment were studied. The immunohistochemistry of BCL2 and BCL6 was defined. Presence of circulating tumor cells was determined by analyzing the clonality of the immunoglobulin heavy-chain genes by PCR. In DLBCL, MYC mRNA was associated with short overall survival. mRNA targets with unfavorable outcome in tumors were associated with characteristics indicative of poor prognosis, with partial treatment response and with short progression-free survival in patients with complete response. In patients with low IPI score, unfavorable mRNA targets were related to shorter overall survival, partial response, high LDH levels and death. mRNA disappeared in post-treatment samples of patients with complete response, and persisted in those with partial response or death. No associations were found between circulating tumor cells and plasma mRNA. Absence of BCL6 protein in tumors was associated with presence of unfavorable plasma mRNA. CONCLUSIONS/SIGNIFICANCE: Through a non-invasive procedure, tumor-derived mRNAs can be obtained in plasma. mRNA detected in plasma did not proceed from circulating tumor cells. In our study, unfavorable targets in plasma were associated with poor prognosis in B-cell lymphomas, mainly MYC mRNA. Moreover, the unfavorable targets in plasma could help us to classify patients with poor outcome within the good prognosis group according to IPI.