Nicotinamide N-methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer.

Metastatic colonization of distant organs accounts for over 90% of deaths related to solid cancers, yet the molecular determinants of metastasis remain poorly understood. Here, we unveil a mechanism of colonization in the aggressive basal-like subtype of breast cancer that is driven by the NAD+ metabolic enzyme nicotinamide N-methyltransferase (NNMT). We demonstrate that NNMT imprints a basal genetic program into cancer cells, enhancing their plasticity. In line, NNMT expression is associated with poor clinical outcomes in patients with breast cancer. Accordingly, ablation of NNMT dramatically suppresses metastasis formation in pre-clinical mouse models. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation (H3K9me3) and DNA methylation at the promoters of PR/SET Domain-5 (PRDM5) and extracellular matrix-related genes. PRDM5 emerged in this study as a pro-metastatic gene acting via induction of cancer-cell intrinsic transcription of collagens. Depletion of PRDM5 in tumor cells decreases COL1A1 deposition and impairs metastatic colonization of the lungs. These findings reveal a critical activity of the NNMT-PRDM5-COL1A1 axis for cancer cell plasticity and metastasis in basal-like breast cancer.

Glucocorticoids promote breast cancer metastasis.

Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy1-3. Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade4, remain poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intra-patient tumour heterogeneity and metastasis is crucial for the success of personalized cancer therapy. Here, using transcriptional profiling of tumours and matched metastases in patient-derived xenograft models in mice, we show cancer-site-specific phenotypes and increased glucocorticoid receptor activity in distant metastases. The glucocorticoid receptor mediates the effects of stress hormones, and of synthetic derivatives of these hormones that are used widely in the clinic as anti-inflammatory and immunosuppressive agents. We show that the increase in stress hormones during breast cancer progression results in the activation of the glucocorticoid receptor at distant metastatic sites, increased colonization and reduced survival. Our transcriptomics, proteomics and phospho-proteomics studies implicate the glucocorticoid receptor in the activation of multiple processes in metastasis and in the increased expression of kinase ROR1, both of which correlate with reduced survival. The ablation of ROR1 reduced metastatic outgrowth and prolonged survival in preclinical models. Our results indicate that the activation of the glucocorticoid receptor increases heterogeneity and metastasis, which suggests that caution is needed when using glucocorticoids to treat patients with breast cancer who have developed cancer-related complications.

The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERα.

Cell fate perturbations underlie many human diseases, including breast cancer. Unfortunately, the mechanisms by which breast cell fate are regulated are largely unknown. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors. Breast cancer originates from this epithelium, but the molecular mechanisms that underlie breast epithelial hierarchy remain ill-defined. Here, we use a high-content confocal image-based short hairpin RNA screen to identify tumour suppressors that regulate breast cell fate in primary human breast epithelial cells. We show that ablation of the large tumour suppressor kinases (LATS) 1 and 2 (refs 5, 6), which are part of the Hippo pathway, promotes the luminal phenotype and increases the number of bipotent and luminal progenitors, the proposed cells-of-origin of most human breast cancers. Mechanistically, we have identified a direct interaction between Hippo and oestrogen receptor-α (ERα) signalling. In the presence of LATS, ERα was targeted for ubiquitination and Ddb1-cullin4-associated-factor 1 (DCAF1)-dependent proteasomal degradation. Absence of LATS stabilized ERα and the Hippo effectors YAP and TAZ (hereafter YAP/TAZ), which together control breast cell fate through intrinsic and paracrine mechanisms. Our findings reveal a non-canonical (that is, YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate.

The influence of river regulation on the affinity for nature and perceptions of local populations.

Rivers are powerful systems supporting human civilization, but despite the enormous dependence on rivers by humans, this does not stop them to assault rivers in the most varied ways. Such dependency determines the establishment of strong river flow-human relationships, and river degradation the prompting of health and non-tangible complications for humans. This work assesses how river regulation, interacting with sociodemographic characteristics, influences the affinity for nature and the perception of humans regarding its effects on river systems. Increased affinity for nature and clearer perceptions about the effects of river regulation improve emotive connection with nature and promote pro-environmental concerns towards a more sustainable water management. Two case studies were selected with different river regulation types (run-of-river and storage reservoir). In each one, the affinity for nature and social perceptions were assessed via telephone-assisted questionnaire surveys carried out in 2020 using 402 randomly selected numbers of local human communities living in its influence areas. Results showed that despite river regulation, communities remain connected to the river system with well-established flow-human relationships. Nonetheless, these relationships have changed due to socioeconomic and cultural changes over time. Significant differences were found in educational attainment and age regarding the affinity for nature. On the other hand, gender differs significantly regarding both the affinity for nature and how the river regulation affect perception, highlighting a gender gap motivated by social and cultural customs passed throughout generations. The lower education level of women and less frequent use of the river acts as a barrier to their perception of river ecosystems and the regulation effects. The affinity for nature and the perception of ecosystems changes by local populations were also significantly different according to the river regulation type, where residents near the run-of-river dam present less affinity for nature. Notwithstanding, the perceptions of local communities were in general in accordance with the scientific knowledge on rivers' condition. Finally, this work highlights the necessity for education through schools, local communities, municipalities and families, providing conditions for dedication and time to nature and promoting environmental knowledge through direct experience.

PIK3CA(H1047R) induces multipotency and multi-lineage mammary tumours.

The adult mouse mammary epithelium contains self-sustained cell lineages that form the inner luminal and outer basal cell layers, with stem and progenitor cells contributing to its proliferative and regenerative potential. A key issue in breast cancer biology is the effect of genomic lesions in specific mammary cell lineages on tumour heterogeneity and progression. The impact of transforming events on fate conversion in cancer cells of origin and thus their contribution to tumour heterogeneity remains largely elusive. Using in situ genetic lineage tracing and limiting dilution transplantation, we have unravelled the potential of PIK3CA(H1047R), one of the most frequent mutations occurring in human breast cancer, to induce multipotency during tumorigenesis in the mammary gland. Here we show that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5-positive and luminal keratin-8-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multi-lineage mammary tumours. Moreover, we show that the tumour cell of origin influences the frequency of malignant mammary tumours. Our results define a key effect of PIK3CA(H1047R) on mammary cell fate in the pre-neoplastic mammary gland and show that the cell of origin of PIK3CA(H1047R) tumours dictates their malignancy, thus revealing a mechanism underlying tumour heterogeneity and aggressiveness.

PCR detection of Ehrlichia ruminantium and Babesia bigemina in cattle from Kwara State, Nigeria: unexpected absence of infection.

Ticks and tick-borne diseases (TBDs) continue to pose an insidious and ever-present threat to livestock and livelihoods across the globe. Two of the most significant TBDs of cattle in Africa are heartwater and babesioisis, caused by Ehrlichia ruminantium and Babesia bigemina respectively. Both pathogens are endemic in Nigeria. However, to date, little data has been published regarding the number of cattle infected. In this study, blood samples were collected from cattle of the Kwara State, north-central Nigeria. Probe-based quantitative PCR (qPCR) and semi-nested PCR were used to investigate the presence of both pathogens, respectively. Our study found all samples (n = 157) to be surprisingly negative for both B. bigemina and E. ruminantium. These results contribute new information on the current burden of these two pathogens in Kwara State and may be helpful in informing more effective targeting of control strategies in Nigeria.

Molecular diagnosis of the tick-borne pathogen Anaplasma marginale in cattle blood samples from Nigeria using qPCR.

Tick-borne diseases (TBDs) are some of the most important animal health and management problems in Africa, including Nigeria. This study aims to determine the prevalence of an important TBD, anaplasmosis, in a North-central region of Nigeria. Blood samples were collected from cattle and stored on Whatman FTA® cards. Information on village, age and sex associated with each cattle was also recorded. The packed red blood cell volume (PCV) for each blood sample was determined. After DNA extraction, pathogen presence was evaluated by TaqMan® based qPCR of which 75.9 % of the cattle tested positive for Anaplasma marginale. Statistical analysis revealed that the presence of A. marginale infection differed significantly between cattle age groups. However, there was no significant difference in the prevalence of this pathogen between the sexes or among cattle grouped by PCV level. Finally, using a highly sensitive molecular method our pioneer study contributes to the improvement of the current knowledge regarding tick-borne pathogens that seriously affect animal health in specific areas of Nigeria.

STAT3 negatively regulates thyroid tumorigenesis.

Although tyrosine-phosphorylated or activated STAT3 (pY-STAT3) is a well-described mediator of tumorigenesis, its role in thyroid cancer has not been investigated. We observed that 63 of 110 (57%) human primary papillary thyroid carcinoma (PTC) cases expressed nuclear pY-STAT3 in tumor cells, preferentially in association with the tumor stroma. An inverse relationship between pY-STAT3 expression with tumor size and the presence of distant metastases was observed. Using human thyroid cancer-derived cell lines [harboring rearranged during transfection (RET)/PTC, v-RAF murine sarcoma viral oncogene homolog B (BRAF), or rat sarcoma virus oncogene (RAS) alterations], we determined that IL-6/gp130/JAK signaling is responsible for STAT3 activation. STAT3 knockdown by shRNA in representative thyroid cancer cell lines that express high levels of pY-STAT3 had no effect on in vitro growth. However, xenografted short hairpin STAT3 cells generated larger tumors than control cells. Similarly, STAT3 deficiency in a murine model of BRAFV600E-induced PTC led to thyroid tumors that were more proliferative and larger than those tumors expressing STAT3wt. Genome expression analysis revealed that STAT3 knockdown resulted in the down-regulation of multiple transcripts, including the tumor suppressor insulin-like growth factor binding protein 7. Furthermore, STAT3 knockdown led to an increase in glucose consumption, lactate production, and expression of Hypoxia-inducible factor 1 (HIF1α) target genes, suggesting that STAT3 is a negative regulator of aerobic glycolysis. Our studies show that, in the context of thyroid cancer, STAT3 is paradoxically a negative regulator of tumor growth. These findings suggest that targeting STAT3 in these cancers could enhance tumor size and highlight the complexities of the role of STAT3 in tumorigenesis.

Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort.

STUDY QUESTION: What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. WHAT IS KNOWN ALREADY: CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. STUDY DESIGN SIZE DURATION: Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. PARTICIPANTS/MATERIALS SETTING METHODS: The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). MAIN RESULTS AND THE ROLE OF CHANCE: A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. STUDY FUNDING/COMPETING INTERESTS: This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.

Protocol for infecting and monitoring susceptible k18-hACE2 mice with SARS-CoV-2.

Intranasal infection of k18-hACE2 mice with SARS-CoV-2 recapitulates the clinical characteristics present in severe COVID-19. Here, we present a protocol for intranasal administration of SARS-CoV-2 to k18-hACE2 mice and their subsequent daily monitoring. We describe steps for intranasal inoculation of SARS-CoV-2 and the collection of clinical scores on weight, body condition, hydration, appearance, neurological symptoms, behavior, and respiratory movements. This protocol contributes to the establishment of a model of severe SARS-CoV-2 infection that minimizes animal suffering. For complete details on the use and execution of this protocol, please refer to Gonçalves et al. (2023).1.

A Smartphone-Delivered Program (Anathema) to Promote the Sexual Health of Older Adults, Colorectal Cancer Survivors, and Stroke Survivors: Protocol for a Feasibility Pilot Randomized Controlled Trial.

BACKGROUND: Despite the prevalence of sexual distress and dysfunction in older adults in general and stroke and colorectal cancer survivors in particular, access to specialized care is limited by organizational barriers and stigma, embarrassment, and discrimination. The internet allows reaching services that would otherwise be difficult or impossible to reach, and as smartphones are personal (intimate) technologies, they are a promising vehicle to close this gap. However, research focusing on smartphone-delivered sexual health promotion programs is scarce. OBJECTIVE: This study aims to assess the acceptability, feasibility, and preliminary efficacy of Anathema, an 8-week, iOS/Android smartphone-delivered, individually tailored, cognitive-behavioral sexual health promotion program developed to improve relationship and sexual satisfaction, sexual functioning, sexual distress, sexual pleasure, and health-related quality of life (HRQoL) in older adults, colorectal cancer survivors, and stroke survivors compared to treatment as usual in a waiting-list control condition. METHODS: Two-arm, parallel, open-label, waiting list, feasibility, pilot randomized controlled trials (RCTs) will be conducted involving older adults, stroke survivors, and colorectal cancer survivors. The primary outcomes are the acceptability, usability, and feasibility of Anathema. Sexual function, relationship and sexual satisfaction, sexual pleasure, sexual distress, anxiety, depression, and HRQoL are the secondary outcomes. This study has been reviewed and approved by the ethics committees of Instituto Português de Oncologia do Porto Francisco Gentil, Europacolon Portugal, Faculty of Psychology and Educational Sciences, University of Porto, and Sigmund Freud University (approval numbers: CES218R/021, CES19/023, and 2022/01-05b). RESULTS: This project is funded by the European Commission through the Active and Assisted Living (AAL) Programme (reference: AAL-2020-7-133-CP) from April 2021 to December 2023. Recruitment for the pilot RCTs started on January 2023 in Portugal, Austria, and the Netherlands and is currently ongoing. As of May 2023, we randomized 49 participants in the trials. We expect to complete the RCTs in September 2023. The results on the acceptability, feasibility, and preliminary efficacy of Anathema are expected in the second semester of 2023. We expect Anathema to be highly accepted by the populations under study; to prove feasible to scale up to parent RCTs; and to be potentially efficacious in improving sexual functioning, relationship and sexual satisfaction, sexual distress, sexual pleasure, and HRQoL in older adults, colorectal cancer survivors, and stroke survivors compared to treatment as usual in a waiting-list control condition. The study results will be published in open-access venues according to COREQ (Consolidated Criteria for Reporting Qualitative Research) and CONSORT EHEALTH (Consolidated Standards of Reporting Trials of Electronic and Mobile Health Applications and Online Telehealth) guidelines. CONCLUSIONS: The study results will inform the refinement and scale-up of Anathema. Anathema's wider-scale implementation can potentially promote the sexual health of largely neglected user groups such as older adults, colorectal cancer survivors, and stroke survivors. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46734.

SARS-CoV-2 variants induce distinct disease and impact in the bone marrow and thymus of mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved to variants associated with milder disease. We employed the k18-hACE2 mouse model to study how differences in the course of infection by SARS-CoV-2 variants alpha, delta, and omicron relate to tissue pathology and the immune response triggered. We documented a variant-specific pattern of infection severity, inducing discrete lung and blood immune responses and differentially impacting primary lymphoid organs. Infections with variants alpha and delta promoted bone marrow (BM) emergency myelopoiesis, with blood and lung neutrophilia. The defects in the BM hematopoietic compartment extended to the thymus, with the infection by the alpha variant provoking a marked thymic atrophy. Importantly, the changes in the immune responses correlated with the severity of infection. Our study provides a comprehensive platform to investigate the modulation of disease by SARS-CoV-2 variants and underscores the impact of this infection on the function of primary lymphoid organs.

Rural Ties and Consumption of Rural Provenance Food Products-Evidence from the Customers of Urban Specialty Stores in Portugal.

Consumers' food preferences increasingly meet concerns of authenticity, health, origin, and sustainability, altogether attributes embodied in rural provenance food products. The dynamics of production, commercialization, and availability of these products in urban centers are growing stronger. This study aims to explore rural provenance food consumption and underlying motivations, the consumers' images of products and provenance areas, and the influence of rural ties in consumption. Data from a survey directed to 1554 consumers of 24 urban specialty stores located in three Portuguese cities were analyzed. The analysis is based on the differences between frequent and sporadic consumers of Portuguese rural provenance food products. The two groups significantly differ in the reasons provided to acquire the products. Those who buy and consume these products more frequently especially value sensorial features, convenience, national provenance, and the impacts on rural development. Additionally, the motivations to choose rural provenance foods tend to pair with positive images of those products and of their territories of origin. This is intrinsically connected with familiarity, a nuclear notion that encompasses the symbolic images of the products and their origins as actual connections (familiar and otherwise) to rural contexts.

Unicentric Castleman Disease and Pheochromocytoma.

Castleman disease is an uncommon and heterogenous lymphoproliferative disorder which is classified as unicentric or multicentric depending on the number of lymph nodes involved. Each type has a different clinical presentation, aetiology, treatment and prognosis. We report the case of a young woman who presented with cervical lymphadenopathy and a retroperitoneal mass, and was diagnosed with unicentric Castleman disease and pheochromocytoma. We describe the diagnostic steps, the complications that developed, and the importance of the differential diagnosis in the evaluation of these patients. LEARNING POINTS: Castleman disease in an uncommon disease and should be considered in all patients with adenomegalies and systemic symptoms.Pheochromocytoma should not be overlooked in the differential diagnosis of a retroperitoneal mass.It is important that doctors consider these two diagnoses in patients with adenomegalies and a retroperitoneal mass due to the potential harmful impact of a missed diagnosis.

Transient remission of hyperparathyroidism after fine-needle aspiration biopsy.

Primary hyperparathyroidism (PHPT) is the unregulated overproduction of parathyroid hormone (PTH), resulting in abnormal calcium homeostasis. PHPT is most commonly caused by a single adenoma of the parathyroid gland, which can have an intrathyroid location in rare cases. The measurement of intact PTH in the washout fluid obtained by ultrasound (US)-guided fineneedle aspiration (FNA) can be useful in clarifying the aetiology of these lesions. This study presented a 48-year-old man with a background history of symptomatic renal stone disease who was diagnosed with PHPT and referred to our Endocrinology department. A neck US revealed a thyroid nodule with a size of 21 mm in the right lobe. The patient underwent US-guided FNA of the lesion. The measurement of PTH in the washout fluid was significantly elevated. Following the procedure, he reported neck pain and noticed distal paraesthesias in the upper limbs. Blood test results showed significant hypocalcaemia and supplementation with calcium and calcitriol was started. The patient was closely monitored. Recurrence of hypercalcaemia was later observed, and the patient was submitted to surgery. We present a case of FNAinduced transitory remission of PHPT in a patient with an intrathyroid parathyroid adenoma. We conjecture that intra-nodular haemorrhage might have occurred, which temporarily affected the viability of the autonomous parathyroid tissue. A few similar cases of spontaneous or induced remission of PHPT after FNA have been previously described in the literature. This remission can be transitory or permanent, depending on the degree of cellular damage thus follow-up of these patients is recommended.

Differential Expression of Immune Genes in the Rhipicephalus microplus Gut in Response to Theileria equi Infection.

Rhipicephalus microplus is the only tick species known to serve as a biological vector of Theileria equi for horses and other equids in Brazil. The protozoan T. equi is one of the causal agents of equine piroplasmosis, a major threat in horse breeding systems. Vector competence is closely linked to the pathogens' ability to evade tick defense mechanisms. However, knowledge of tick immune response against infections by hemoparasites of the Theileria genus is scarce. In the present study, the expression of genes involved in immune signaling pathways of R. microplus adults' guts when challenged with a high or low parasitic load of T. equi was evaluated. This research demonstrates divergences in the immune gene expression pattern linked to T. equi infection in R. microplus since the Toll, IMD, and JNK signaling pathways were transcriptionally repressed in the guts of adult ticks infected with T. equi. Moreover, the results showed that different infectious doses of T. equi induce differential gene expression of key components of immune signaling cascades in R. microplus gut, suggesting a link between the intensity of infection and the activation of tick immunity response. The present study adds knowledge to elucidate the gut immune signaling response of R. microplus to T. equi infection. In addition, the generated data can serve as a basis for further investigations to develop strategies for controlling and preventing equine piroplasmosis.

A high-throughput drug screen reveals means to differentiate triple-negative breast cancer.

Plasticity delineates cancer subtypes with more or less favourable outcomes. In breast cancer, the subtype triple-negative lacks expression of major differentiation markers, e.g., estrogen receptor α (ERα), and its high cellular plasticity results in greater aggressiveness and poorer prognosis than other subtypes. Whether plasticity itself represents a potential vulnerability of cancer cells is not clear. However, we show here that cancer cell plasticity can be exploited to differentiate triple-negative breast cancer (TNBC). Using a high-throughput imaging-based reporter drug screen with 9 501 compounds, we have identified three polo-like kinase 1 (PLK1) inhibitors as major inducers of ERα protein expression and downstream activity in TNBC cells. PLK1 inhibition upregulates a cell differentiation program characterized by increased DNA damage, mitotic arrest, and ultimately cell death. Furthermore, cells surviving PLK1 inhibition have decreased tumorigenic potential, and targeting PLK1 in already established tumours reduces tumour growth both in cell line- and patient-derived xenograft models. In addition, the upregulation of genes upon PLK1 inhibition correlates with their expression in normal breast tissue and with better overall survival in breast cancer patients. Our results indicate that differentiation therapy based on PLK1 inhibition is a potential alternative strategy to treat TNBC.

A Hematologic Disease Disguised as Cutaneous Candidiasis.

Langerhans cell histiocytosis is a rare hematologic neoplasm with a myeloid origin, which can affect numerous organs, the skin being the second most frequently affected by this disease. In this report, a case of a 44-year-old female, who was intermittently followed due to a suspected persistent cutaneous candidiasis in which a skin biopsy revealed Langerhans cell histiocytosis with immunohistochemistry positive for CD1a and S100 protein, is described. The management of Langerhans cell histiocytosis is difficult because these disorders respond inconsistently to immunosuppressive and chemotherapeutic strategies. The authors present this case to highlight a differential diagnosis of refractory cutaneous candidiasis and raise awareness of the importance of skin biopsy in these cases.

T-cell Prolymphocytic Leukemia, Cerebriform Variant.

T-cell prolymphocytic leukemia (T-PLL) is a very rare and aggressive lymphoproliferative disorder. We present a 70-year-old man with complaints of fatigue, low urinary output, and peripheral edema for one month. Objectively, he presented diminished respiratory sounds bilaterally and peripheral edema. Analytical study revealed mild anemia and mild lymphomonocytosis, acute kidney injury, and urinalysis with proteins, leukocytes, erythrocytes, and cylinders. Chest radiography was consistent with pleural effusion. Subsequent study showed new onset of thrombocytopenia with a progressive increase of lymphocytosis, in association with inguinal adenopathies and splenomegaly. Immunophenotypic study of peripheral blood and lymph node biopsy were compatible with the diagnosis of T-PLL. Negative serology for human T-cell lymphotropic virus type 1 (HTLV-1) excluded adult T-cell leukemia. Progressive changes in the peripheral blood smear were seen, finally showing the presence of lymphocytes with a cerebriform nucleus, revealing this variant. There was a rapid catastrophic progression, spontaneous tumor lysis syndrome, and death.