Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways.

BACKGROUND: The malignant mechanisms that control the development of cutaneous T-cell lymphoma (CTCL) are beginning to be identified. Recent evidence suggests that disturbances in specific intracellular signalling pathways, such as RAS-mitogen-activated protein kinase, T-cell receptor (TCR)-phospholipase C gamma 1 (PLCG1)-nuclear factor of activated T cells (NFAT) and Janus kinase (JAK)-signal transducer and activator of transcription (STAT), may play an essential role in the pathogenesis of CTCL. OBJECTIVES: To investigate the mechanisms controlling disease development and progression in mycosis fungoides (MF), the most common form of CTCL. METHODS: We collected 100 samples that were submitted for diagnosis of, or a second opinion regarding, MF between 2001 and 2018, 80% of which were in the early clinical stages of the disease. Formalin-fixed paraffin-embedded tissues were used for histological review and to measure the expression by immunohistochemistry of surrogate markers of activation of the TCR-PLCG1-NFAT, JAK-STAT and NF-κB pathways. Folliculotropism and large-cell transformation were also examined. RESULTS: NFAT and nuclear factor kappa B (NF-κB) markers showed a comparable activation status in early and advanced stages, while STAT3 activation was more frequent in advanced stages and was associated with large-cell transformation. Consistently with this observation, STAT3 activation occurred in parallel with MF progression in two initially MF-negative cases. A significant association of NFAT with NF-κB markers was also found, reflecting a common mechanism of activation in the two pathways. Genomic studies identified nine mutations in seven genes known to play a potential role in tumorigenesis in T-cell leukaemia/lymphoma, including PLCG1, JAK3 and STAT3, which underlies the activation of these key cell-survival pathways. A higher mutational allele frequency was detected in advanced stages. CONCLUSIONS: Our results show that STAT3 is activated in advanced cases and is associated with large-cell transformation, while the activation of NFAT and NF-κB is maintained throughout the disease. These findings could have important diagnostic and therapeutic implications. What's already known about this topic? Mycosis fungoides is characterized by a clonal expansion of T cells in the skin. The mechanisms controlling disease development and progression are not fully understood. What does this study add? An association of the nuclear factor of activated T cells and nuclear factor kappa B pathways was found, which could reflect a common mechanism of activation. These pathways were activated in early and advanced stages at the same level. Signal transducer and activator of transcription 3 activation was associated with large-cell transformation and was more frequent in advanced stages. A genomic analysis of cutaneous T-cell lymphoma-associated genes was performed. Nine mutations were detected. What is the translational message? These results could have important implications for the treatment of MF in the near future.

Molecular diagnosis in cerebral cavernous malformations. / Diagnóstico molecular de cavernomatosis cerebral.

INTRODUCTION: Cerebral cavernous malformations (CCMs; OMIM 116860) are enlarged vascular cavities without intervening brain parenchyma whose estimated prevalence in the general population is between 0.1% and 0.5%. Familial CCM is an autosomal dominant disease with incomplete clinical and radiological penetrance. Three genes have been linked to development of the lesions: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. DEVELOPMENT: The aetiological mutation is not detected in a large percentage of cases and new approaches are therefore needed. The aim of this review is to analyse current molecular techniques and the possible mutations or variations which can be detected in a molecular genetics or molecular biology laboratory. Likewise, we will analyse other alternatives that may help detect mutations in those patients showing negative results. CONCLUSIONS: A molecular diagnosis of cerebral cavernous malformations should provide at least the copy number variation and sequencing of CCM genes. In addition, appropriate genetic counselling is a crucial source of information and support for patients and their relatives.

Contrasting fertilization and phenological stages shape microbial-mediated phosphorus cycling in a maize agroecosystem.

Phosphorus (P) is essential for plants but often limited in soils, with microbes playing a key role in its cycling. P deficiency in crops can be mitigated by applying by-products like sludge and struvite to enhance yield and sustainability. Here, we evaluated the contribution of four different types of fertilizers: i) conventional NPK; ii) sludge; iii) struvite; and iv) struvite+sludge in a semiarid maize plantation to the availability of P and the responses of the soil microbiome. We investigated the effects of these treatments on the relative abundance of bacterial and archaeal genes and proteins related to organic P mineralization, inorganic P solubilization, and the P starvation response regulation through a multi-omic approach. Moreover, we explored the impact of maize phenology by collecting samples at germination and flowering stages. Our findings suggest that the phenological stage has a notable impact on the abundance of P cycle genes within bacterial and archaeal communities, particularly regarding the solubilization of inorganic P. Furthermore, significant variations were observed in the relative abundance of genes associated with different P cycles in response to various fertilizer treatments. Sludge and struvite application improved P availability, which was related to an increase in the relative abundance of Sphingomonas (Proteobacteria) and Luteitalea (Acidobacteria) respectively, and genes related to inorganic P solubilization. Furthermore, we observed a substantial taxonomic clustering of functional processes associated with the P cycle. Among the dominant bacterial populations containing P-related genes, those microbes possessing genes linked to the solubilization of inorganic P typically did not harbor genes associated with the mineralization of organic P. This phenomenon was particularly evident among members of Actinobacteria. Overall, we reveal important shifts in bacterial and archaeal communities and associated molecular processes, stressing the intricate interplay between fertilization, phenology, and P cycling in agroecosystems.

Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines.

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

Interactive impacts of boron and organic amendments in plant-soil microbial relationships.

Water shortage and low organic carbon content in soil limit soil fertility and crop productivity. The use of desalinated seawater is increasing as an alternative source of irrigation water. However, it has a high boron (B) content that could cause toxicity in the plant-soil microbial system. Here, we evaluated the responses of the soil microbiota and lemon trees to 3 irrigation B doses (0.3, 1, and 15 mg L-1) under two types of soil management (conventional, CS; and organic, OS) in a 180-days pot experiment. High B doses promoted B accumulation in soil, reaching harmful concentrations that affected soil biodiversity. Our results suggest a close interaction between B and organic labile fractions that increased B availability in soil solution. Besides, B addition to soil impacted on microbial biomass. The bacterial community showed sensitivity to the B dose. Organic amendment did not increase B soil adsorption but it favored B plant uptake. The highest B dose had a detrimental impact on plant physiology, finally resulting lethal for the plants. Our study provides a comprehensive assessment of the microbes-plant interactions in soils irrigated with water with high B content. This will be fundamental in the design of future fertirrigation strategies.

Immune-related adverse events predict the therapeutic efficacy of anti-PD-1 antibodies in cancer patients.

BACKGROUND: Cancer immune therapy has shown remarkable benefit in the treatment of a range of cancer types, although it may initiate autoimmune-related disorders in some patients. We have attempted to establish whether the incidence of irAEs after the use of anti-PD-1 antibodies nivolumab or pembrolizumab in advanced malignancies is associated with anti-PD-1 treatment efficacy. PATIENTS AND METHODS: We studied patients treated with single-agent nivolumab or pembrolizumab for advanced cancer. irAEs (immune-related adverse events) were identified clinically and graded as per the Common Terminology Criteria for Adverse Events version 4.0. Efficacy was evaluated with objective response rate (ORR, immune-Response Evaluation Criteria in Solid Tumours [RECIST] criteria) progression-free survival (PFS) and overall survival (OS). Tests were performed to determine the association between irAEs and ORR, PFS or OS. RESULTS: We identified 106 patients. Primary diagnoses were lung cancer (n = 77), melanoma (n = 8), head and neck carcinoma (n = 7), renal carcinoma (n = 5), Hodgkin's lymphoma (n = 3), urothelial carcinoma (n = 3) and gallbladder adenocarcinoma, hepatocellular carcinoma and Merkel cell carcinoma (n = 1 each). IrAEs were observed in 40 patients (37.7%). The most frequent irAEs were hypothyroidism (n = 15), nephritis (n = 5) and hyperthyroidism (n = 4). Objective response was observed in 44 patients (41.5%), and median PFS was 5.5 months (0.5-31 months). Thirty-three of the 40 patients with irAEs had objective response (82.5%) in contrast with 11 of the 66 cases without irAEs (16.6%) (OR 23.5, P < 0.000001). PFS in patients with irAEs was 10 months and 3 months in those without irAEs (HR 2.2, P = 0.016). OS in patients with irAEs was 32 months and 22 in those without irAEs, without statistically significant differences. CONCLUSION: In advanced cancer treated with single-agent anti-PD-1 antibodies, patients with irAEs showed a markedly improved efficacy over patients without irAEs (ORR of 82.5% and PFS of 10 months vs ORR of 16.6% and PFS of 3 months). Future studies of anti-PD-1 immune-therapy should address this association to explore the underlying biological mechanisms of efficacy.

When drought meets forest management: Effects on the soil microbial community of a Holm oak forest ecosystem.

The growth and survival of plants in semiarid Mediterranean forests can be improved through the benefits conferred by thinning, a forest management practice that removes trees and reduces the competition between the remaining ones. Here, we evaluate the impacts of induced drought (the exclusion of 25% of the natural rainfall for 5 years) and thinning, and their interaction, with the objective of determining whether the thinning of Holm oak (Quercus ilex L.) modulates the resistance of the soil microbial community to drought. Sequencing of 16S rRNA and ITS amplicons revealed that drought, thinning, and their interaction influenced the composition of the bacterial community, while the fungal community was exclusively affected by thinning. Thinning consisted of the removal of the aboveground parts of the Holm oak trees, which were thereafter left in forest stand. Thinning contributed to the C and N contents, with parallel increases in microbial biomass, particularly in summer. Drought increased the amounts of total organic C and total N, likely due to the reduced enzyme activities. Indeed, the composition of the bacterial community was modulated primarily by the indirect and long-term effects of drought - the accumulation of soil organic matter - rather than by the direct effect of the lower water content imposed by the drought treatments. Thinning under drought conditions did not increase soil organic C (SOC) content. However, the resistance of the soil microbial community to drought was fostered by thinning, particularly at the functional level, as indicated by the enzyme activities related to C, N and P cycles. These responses were associated to variations in the composition of the microbial communities in thinned, drought-exposed plots, in comparison to unthinned, drought-exposed plots. In conclusion, the interaction between forest management and drought influenced the soil microbial community of a Holm oak-dominated Mediterranean ecosystem.

[Hemoperitoneum and death due to hepatoesplenic metastasis rupture in a testicular tumor]. / Hemoperitoneo y muerte por rotura de metástasis hepatoesplénicas de tumor testicular.

We present a case of a mix germinal testicular tumor, in III-C (AJCC-UICC) stage, at a terminal phase due to massive methastasis rupture at hepatic and splenic methastasis locations.

Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

Performance of the clinical index of stable febrile neutropenia (CISNE) in different types of infections and tumors.

PURPOSE: The clinical index of stable febrile neutropenia (CISNE) can contribute to patient safety without increasing the complexity of decision-making. However, febrile neutropenia (FN) is a diverse syndrome. The aim of this analysis is to assess the performance of CISNE according to the type of tumor and infection and to characterize these patients. METHODS: We prospectively recruited 1383 FN episodes in situations of apparent clinical stability. Bonferroni-adjusted z tests of proportions were used to assess the association between the infections suspected at the time of onset and the type of tumor with the risk of serious complications and mortality. The performance of CISNE was appraised in each category using the Breslow-Day test for homogeneity of odds ratios and Forest Plots. RESULTS: 171 patients had a serious complication (12.3 %, 95 % confidence interval 10.7-14.2 %). The most common initial assumptive diagnoses were: fever without focus (34.5 %), upper respiratory infection (14.9 %), enteritis (12.7 %), stomatitis (11.8 %), and acute bronchitis (10.7 %). Lung and breast were the most common tumors, accounting for approximately 56 % of the series. The distribution of complications, mortality, and bacteremia varies for each of these categories. However, Breslow-Day tests indicate homogeneity of the odds ratio of the dichotomized CISNE score to predict complications in all infection and tumor subtypes. CONCLUSION: Despite FN's clinical and microbiological heterogeneity, the CISNE score was seen to be consistent and robust in spite of these variations. Hence, it appears to be a safe tool in seemingly stable FN.

[Giant adrenal myelolipoma: hypertension, renal failure and spontaneous rupture]. / Mielolipoma suprarrenal gigante: hipertensión, insuficiencia renal y rotura espontánea.

Adrenal myelolipoma is a rare, benign, slow-growing tumor composed of adipose tissue and hematopoietic elements. It is usually diagnosed incidentally, although there are reports of patients with symptoms and descriptions of retroperitoneal hemorrhage due to rupture of large tumors. The condition has been associated with obesity, high blood pressure and adrenal dysfunction. We present a patient with retroperitoneal hemorrhage due to spontaneous rupture of a myelolipoma, hypertension, and renal failure secondary to nephroangiosclerosis.

[Urachal pathology: an overview review and report of three clinical cases]. / Patología del uraco: revisión de conjunto y presentación de tres casos.

With the use of these two clinical cases (cyst and urachal adenocarcinoma) we did an overview of the urachal pathology. The urachus cyst is usually asyntomathic, it's detected randomly when we do other diagnostic tests or when we have any complications. The urachal adenocarcinoma is a rare pathology, it usually exhibit hematuria and we need to follow the same diagnostic tools as we use in vesical tumors (cystoscopy and transurethral vesical resection). Adenocarcinoma of the dome of the bladder is the main differential diagnosis. Partial cystectomy is the first choice treatment. Quimiotheraphy and radiotheraphy offer poor results.

[Entero-neobladder ileal fistula: two cases report]. / Fístula entero-neovejiga ileal: a propósito de dos casos.

Fistulas between the orthotopic reservoir and the gastrointestinal tract have low incidence (1.5-2%). Simptomatology is variable, but it's frecuent to find fecaluria. Among 90 new intestinal bladders we show two fistule of new bladder to ileo, with nest postoperatory diagnosis, using retrograde cystografy; one was resolved with next postoperative treatment and the other with open surgery.

[Problem-based learning in urology training. The Faculty of Medicine of the Universidad de Castilla-La Mancha model]. / El aprendizaje basado en problemas en la enseñanza de la urologia. Modelo de la Facultad de Medicina de la Universidad de Castilla-La Mancha.

Ongoing changes in the social, economic, technological and scientific realms have generated new needs and led various organizations to suggest that educational institutions should reorient their educational strategies toward developing effective professionals with the skills to meet these needs. These "modern" strategies include problem-based learning, in which the student seeks and selects information, analyzes the data obtained, integrates both prior and newly acquired knowledge, and, finally, offers diagnostic and therapeutic options to resolve the problem posed, as would occur in professional practice. With this approach, prior skills and practical experience form the foundation of learning. Problem-based learning incorporates some aspects of cognitive psychology, a model that mainly centers on the nature of the knowledge structures found in active memory, the processes involved in information storage and retrieval and the various factors that activate these processes. At the Faculty of Medicine of the Universidad de Castilla-La Mancha, urology is part of a core subject (Medical and Surgical Pathology II) taught in the fifth year of coursework together with nephrology. Each course includes approximately 75 students, divided into five groups. The rotation lasts six weeks, with students spending a mean of two hours a day on theory (nephrology and/or urology) and the remaining time on rotations in the various activities: three weeks in nephrology and three weeks in urology. Upon completion of the rotation, the students write a combined theoretical examination with 100 multiple-choice questions (50 on urology) and take a practical skills examination. At the end of the course, another practical test consisting of an objective, structured clinical examination is taken, in which standard patients are used and the professor directly assesses the level of skills acquired with a "real" case.

[Retroperitoneal cystic mesothelioma and lymphangioma]. / Mesotelioma y linfangioma quísticos retroperitoneales.

Retroperitoneal cysts are uncommon entities of difficult diagnosis because of their insidious symptomatology. Urinary apparatus involvement is quite often the mode of presentation and the reason for calling on the urologist. The origin of many of these retroperitoneal cysts remains practically unknown. Surgery with exeresis is the choice management method. Follow-up is necessary for cystic mesothelioma because of the highly frequent relapses. The outlook of hormonal conservative therapy for relapses appears as a future alternative to treatment.

[Ruptured syringocele of the Cowper's gland. Report of a case]. / Siringocele roto de la glándula de Cowper. Presentación de un caso.

Contribution of the case report of an 18-year old patient who consulted for an early picture of haematuria with symptoms of mictional syndrome with a history of several years of urinary infection. After the urological study, the presence of a ruptured syringocele in Cowper's gland was documented in the retrograde and mictional uretrography. The treatment approach was the incision, widening the communication between the urethra and the syringocele; all manifestations disappeared after the endoscopic treatment. The etiology of syringoceles and cystic dilations of Cowper's duct and gland are usually congenital, and there is a likely association with the presence of Cobb's collar. There are four morphological types: simple, perforated, imperforated and ruptured. Most cases are asymptomatic, basically affecting children and adolescents. The usual manifestations are haematuria, symptoms of urinary infections and/or various symptoms of urethral obstruction. Diagnosis is achieved through uretrography and endoscopy. Treatment, when appropriate, is endoscopic through incision or syringocele marsupialization. In some cases, perineal incision and surgical resection of the syringocele with urethral closure has been performed.

[Keratinizing squamous metaplasia (cholesteatoma) of the upper urinary tract]. / Metaplasia escamosa queratinizante (colesteatoma) del tracto urinario superior.

Presentation of four cases of keratinizing squamous metaplasia (KSM), two of the renal pelvis, one pyelocaliceal and one ureteral. Nephrouretetectomy was performed in all cases. All our patients showed good evolution. A review of the literature is made discussing all the etiological, diagnostic and therapeutical aspects of the condition. Its benign evolution is highlighted as well as the current need, once a better knowledge of the condition's natural history is available, of using a conservative approach.

[The Conn syndrome. The clinical and surgical aspects of 18 cases of adrenal adenoma]. / Síndrome de Conn. Aspectos clínicos y quirúrgicos sobre 18 casos de adenoma suprarrenal.

OBJECTIVES: Presentation of a series of 18 patients who underwent surgery of aldosterone-producing adrenal adenoma (Conn's syndrome) over the last 10 years. Assessment of the most significant clinical and pathological aspects from a surgical point of view. METHODS: Retrospective study evaluating a broad range of features: clinical, analytical, hormonal, imaging, types of anaesthesia, approaches, technique used, intra and post-operative morbidity and mortality, evolution and pathoanatomical diagnosis. RESULTS: The most frequent clinical data of primary hyperaldosteronism were: 94.4% volume-dependent HBP, 50% headaches and dizziness, 27.8% epistasis and/or episodes of angor or acute myocardial infarction, and 22.2% heart failure. The biochemical study and hormonal testing evidenced: hypokalemia in 88.9%, metabolic alkalosis 66.7% and hypernatremia in 61.1%. Mean aldosterone levels were 517.5 pg/mL, and urinary levels 85.9 mcg/day. Resting plasma renin activity (PRA) < 0.2 ng/mL/h in 77.8% cases and positive aldosterone stimulation test in 61.1%: captopril test positive. Imaging diagnosis was based in CAT which was conclusive in 88.9% and ultrasound which was diagnostic in 27.8% cases. The surgical approach was: lumbotomy (over the 11th or 12th rib) in 14 patients and transpleurodiaphragmatic in all remaining patients. The intraoperative complications reported were placement of endothoracic tube due to iatrogenic pneumothorax in two occasions. Duration of the procedure (mean 136.1 min) and post-operative hospitalization (mean 7.76 days), as well as post-surgery follow-up for up to 96 months were also studied. At final time point there was 66.7 asymptomatic patients, 33.3% cases of HBP, and no deaths. CONCLUSIONS: Primary hyperaldosteronism due to adrenal adenoma is an uncommon reason for HBP, but in most cases can be cured with surgery. Biochemical and hormonal testing is determinant to research a diagnosis. Ultrasound and CAT are essential for imaging diagnosis, and occasionally NMR can be of help. Lumbotomy is considered the choice approach for these small tumours as it is a familial technique for urologists with a low complications rate.

[Surgery of large residual mass after chemotherapy in advanced testicular germ cell tumor]. / Cirugía de gran masa residual tras quimioterapia en tumor germinal testicular avanzado.

Treatment for testicular tumours has progress in such a manner in the last years that high cure percentages can at present be achieved. After chemotherapy, in most cases, residual mass can appear. In this cases surgery is considered a viable therapeutic option although it implies an advanced surgical training since it is a complex technique and implies serious implications. We submit the case of a patient who presented a large residual mass from a testicular germ cell tumour after being treated with orquiectomía and chemotherapy. Surgery was performed resulting in total and radical extirpation of residual mass.