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.

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.

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.

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.

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.

[Transperitoneal laparoscopic adrenalectomy]. / Suprarrenalectomía laparoscópica transperitoneal.

OBJECTIVES: To present our results with transperitoneal laparoscopic adrenalectomy after completion of 70 procedures. MATERIAL AND METHODS: Between July 2002 and December 2010, transperitoneal laparoscopic adrenalectomy was performed in 70 patients with the following diagnoses: Conn syndrome (22 cases), nonfunctioning adenomas (18), Cushing syndrome (10), pheochromocytomas (7), myelolipomas (4), metastasis after treatment of primary nonadrenal tumors (6), ganglioneuroma (1), adrenal gland hematoma (1) and adrenal carcinoma (1). We describe the size, surgical and hospitalization times, blood loss, need for transfusion, surgical complications and rate of conversion to open surgery. RESULTS: Of 70 patients, 35 were men and 35 women (1:1) with a mean age of 58.2 years (range, 82.2- 29.1). The most common site was left (58%) compared to right (42%). The mean size of the surgical specimen was 5.11 cm, mean surgical time was 119.2 minutes (50-240) and mean operative bleeding was 140.6 (30-800) cc. Only 3 patients required blood transfusion. The mean time until oral feeding was 17 hours, and the mean hospital stay was 4.3 (2-15) days. Complications included 2 cases of surgical infections, 1 of prolonged paralytic ileus, and 1 of splenic laceration and 1 of intestinal perforation which both which required reconversion to open surgery (4.28%). CONCLUSIONS: Laparoscopic adrenalectomy is a safe procedure, with a low percentage of complications and a short hospital stay. The choice of this approach will depend on the surgeon's experience with the lesion etiology and size in each case.

Myelolipomatous adrenal masses causing Cushing's syndrome.

Adrenal myelolipomas are uncommon benign tumors, composed of mature adipose tissue and haematopoietic elements in varying proportions. They are usually asymptomatic, non-functioning adrenal incidentalomas, but there have been a few reports of myelolipomatous masses associated with adrenocortical hypersecretion. We report two cases of large mixed adrenal tumors, with heterogeneous appearance and areas of fat density in imaging techniques, and with autonomous cortisol production leading to Cushing's syndrome. Both underwent adrenalectomy and the histological study showed an adrenocortical adenoma with widespread myelolipomatous metaplasia. Hypercortisolism resolved in the one patient that could be evaluated after surgery. We review all the previous reported cases of hypercortisolism associated with adrenal myelolipomas. We also discuss the recommended diagnostic approach and therapeutic management of adrenal masses of lipomatous appearance.

[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.

[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.

[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.

[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.

[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.

[Nephron-sparing surgical treatment in renal tumors]. / Cirugía conservadora de parénquima en los tumores renales.

OBJECTIVE: A retrospective study on the nephron-sparing surgical treatment in patients with renal tumors, and in addition a literature review on the subject. MATERIAL AND METHODS: Since January 1988 until February 2002, 44 partial nephrectomies have been carried out in our unit because of renal tumors in 43 patients. The clinical protocols of these 43 patients have been reviewed, with an analysis of various clinical-pathological parameters, and utilizing in this analysis percentages, central tendency measures and dispersion and confidence intervals. RESULTS: The average age of the patients was 55.8 years (19-76), and 29 patients were males. Elective partial nephrectomy was carried out in 79.5% of the patients, while in the rest they were submitted to imperative surgery for various causes. The diagnosis of the tumors was mostly as an incidental finding upon carrying out some diagnostic test by another cause (68.2%). In the symptomatic cases, the most common presentation was the combination of pain and hematuria (11.4%). Histopathological study revealed malignant neoplasms in 88.7%, most of them (61.4%) clear cell carcinomas. A Furhman grade 2 was observed in 76.3% of tumors. The average size of the renal masses was of 4.53 cm (1,5-11). As a whole, 61.5% were pT1, 33.3% were pT2 and only one case was pT3. Operative complications were observed in 11.4% of the cases and postoperative complications in 25%. No patient showed local or distant recurrence, and all of them survived disease-free. A patient died after 74 months of the surgery for causes not related to the disease. Average follow-up was 49.77 months (1-168). CONCLUSIONS: Renal nephron-sparing surgery is such a valid therapeutic option as radical nephrectomy in selected patients with renal tumors, since the cancer-specific survival is 100%, which means that this can be considered a therapeutic indication even in patients with healthy contralateral kidney.

[Epididymal ectopic adrenal tumor]. / Tumor epididimario de restos adrenales.

OBJECTIVE: A case of a nonfunctioning ectopic adrenal tissue tumor in the epipidymis is described. METHODS/RESULTS: A case of a nonfunctioning ectopic adrenal tissue tumor in the epipidymis is presented. A left testicular mass had been incidentally detected in this patient. CONCLUSIONS: Tumors of this type localized in the juxtafuniculogonadal region are usually benign. However, resection and histological analysis are always indicated in order to detect metastasis or confirm the histiological type is normal.

[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.

[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.

[Wilms tumor in adults. Case description]. / Tumor de Wilms del adulto. Descripción de un caso clínico.

OBJECTIVE: To report a case of adult Wilms' tumor, a kidney tumor that is more common in children and has a scanty incidence in adults. METHODS/RESULTS: A case of Wilms' tumor in a young male, aged 16 years, is described. The patient underwent partial surgical resection initially and nephrectomy due to tumor recurrence, with postoperative chemotherapy and radiotherapy. CONCLUSIONS: Although approximately 200 cases of adult Wilms' tumor have been reported in the literature, few meet currently accepted diagnostic criteria. The diagnosis of adult Wilms' tumor based on the findings of currently available diagnostic methods is only presumptive until the surgical specimen is analyzed. Most cases are treated as renal tumor and it is the findings of the pathological analysis that defines its nature and the need for chemotherapy and/or radiotherapy, as well as long-term follow-up. The application of therapeutic protocols for children to adults has not obtained the same percentage of cure or prognosis, although a large multicenter study is warranted to confirm the foregoing.