Rethinking prognostic factors in locally advanced or metastatic urothelial carcinoma in the immune checkpoint blockade era: a multicenter retrospective study.

BACKGROUND: Few studies have investigated the safety and efficacy of anti-PD-(L)1 antibodies in metastatic urothelial carcinoma (mUC) in daily clinical practice. Knowledge about the influence of baseline clinical and analytical factors on therapy outcomes is scarce. PATIENTS AND METHODS: We conducted a multicenter retrospective study involving 119 previously treated or untreated mUC patients under anti-PD-(L)1 therapy in a real-world scenario. The objectives of this study were to confirm the safety and efficacy of anti-PD-(L)1 monotherapy and to identify pretreatment factors influencing therapy outcomes. In addition, an independent prognostic model for overall survival (OS) was developed and internally validated. RESULTS: Median OS was 7.8 months [95% confidence interval (CI), 5.4-10.4], median progression-free survival (PFS) was 2.80 months (95% CI, 2.4-3.4), disease control rate (DCR) was 40% (95% CI, 31-49), and overall response rate (ORR) was 24% (95% CI, 15-31). Presence of peritoneal metastases was associated with poor OS [hazard ratio (HR) = 2.40, 95% CI, 1.08-5.33; P = 0.03]. Use of proton-pump inhibitors (PPI) was associated with poor OS (HR = 1.83, 95% CI, 1.11-3.02; P = 0.02) and PFS (HR = 1.94, 95% CI, 1.22-3.09; P = 0.005), and lower DCR (OR = 0.38, 95% CI, 0.17-0.89; P = 0.03) and ORR (OR = 0.18, 95% CI, 0.02-1.60; P = 0.002). The three risk category prognostic model developed included Eastern Cooperative Oncology Group performance status, PPI use, albumin level, presence of liver metastases, and presence of peritoneal metastases variables and was associated with higher risk of death (HR = 3.00, 95% CI, 1.97-4.56; P = 0.0001). CONCLUSIONS: This study confirms anti-PD-(L)1 monotherapy as a safe and effective treatment option in daily clinical practice for mUC patients. It also describes the presence of peritoneal metastases as an independent prognostic factor for OS and underlines the association between PPI use and worse therapeutic outcomes. Finally, it proposes a new easy-to-use risk-assessment model for OS prediction.

Respuesta a everolimús en pacientes con astrocitoma de células gigantes asociado al complejo esclerosis tuberosa / Response to everolimus in patients with giant cell astrocytoma associated to tuberous sclerosis complex

Introducción. Los astrocitomas subependimarios de células gigantes (SEGA) se presentan en el 5-20% de los pacientes con complejo esclerosis tuberosa (CET) y son los tumores cerebrales más comunes en el CET. Son tumores benignos, de estirpe glioneural, que se desarrollan fundamentalmente en las primeras dos décadas de la vida, en general cercanos al foramen de Monro, y pueden ocasionar hidrocefalia e hipertensión intracraneal. Constituyen la principal causa de muerte en el CET. Recientemente, los inhibidores mTOR han demostrado ser una alternativa terapéutica a la resección quirúrgica. Objetivo. Describir nuestra experiencia con everolimús para el tratamiento de pacientes con SEGA y CET. Pacientes y métodos. Estudio prospectivo de la respuesta de los pacientes con CET y al menos un SEGA en crecimiento. Resultados. Recibieron tratamiento tres mujeres y tres varones con una edad media de 12,3 años. Un paciente había sido previamente intervenido quirúrgicamente por SEGA con hidrocefalia. El diámetro máximo medio del SEGA al inicio del tratamiento era de 15,3 mm (rango: 11,3-24,8 mm). Se inició tratamiento con everolimús, 2,5 mg/día por vía oral en pacientes con superficie corporal < 1,2 m2 y 5 mg/día en pacientes con superficie corporal > 1,2 m2. Dos pacientes presentaron hipertrigliceridemia; uno, anorexia; otro, un afta; y una paciente, amenorrea. La reducción media del volumen del SEGA a los tres meses de tratamiento fue del 46%, y la reducción se mantuvo estable en controles posteriores (6-25 meses). Conclusiones. El tratamiento con everolimús disminuye el tamaño de los SEGA asociados a CET con un perfil de seguridad adecuado, y constituye una alternativa a la cirugía en casos seleccionados (AU)

Introduction. Subependymal giant cell astrocytomas (SEGA) appear in 5-20% of patients with tuberous sclerosis complex (TSC) and are the most common brain tumours in TSC. They are benign tumours, of a glioneural stock, that develop mainly in the first two decades of life, generally close to the foramen of Monro, and can trigger hydrocephalus and intracranial hypertension. It is one of the leading causes of death in TSC. Recently mTOR inhibitors have proved to be a therapeutic alternative to surgical excision. Aim. To describe our experience of using everolimus to treat patients with SEGA and TSC. Patients and methods. We conducted a prospective study of the responses of patients with TSC and at least one SEGA undergoing growth. Results. Three females and three males with a mean age of 12.3 years received treatment. One patient had previously undergone surgery due to SEGA with hydrocephalus. The maximum mean diameter of the SEGA on beginning treatment was 15.3 mm (range: 11.3-24.8 mm). Treatment was established with everolimus, 2.5 mg/day administered orally in patients with a body surface area < 1.2 m2, and 5 mg/day in patients with a body surface area > 1.2 m2. Two patients presented hypertriglyceridemia; one, anorexia; another, a mouth ulcer; and one, amenorrhoea. The mean reduction in the volume of the SEGA at three months of treatment was 46%, and the reduction remained steady in later control examinations (6-25 months). Conclusions. Treatment with everolimus reduces the size of SEGA associated with TSC with an adequate safety profile, and constitutes an alternative to surgery in certain cases (AU)

[Response to everolimus in patients with giant cell astrocytoma associated to tuberous sclerosis complex]. / Respuesta a everolimus en pacientes con astrocitoma de celulas gigantes asociado al complejo esclerosis tuberosa.

INTRODUCTION: Subependymal giant cell astrocytomas (SEGA) appear in 5-20% of patients with tuberous sclerosis complex (TSC) and are the most common brain tumours in TSC. They are benign tumours, of a glioneural stock, that develop mainly in the first two decades of life, generally close to the foramen of Monro, and can trigger hydrocephalus and intracranial hypertension. It is one of the leading causes of death in TSC. Recently mTOR inhibitors have proved to be a therapeutic alternative to surgical excision. AIM. To describe our experience of using everolimus to treat patients with SEGA and TSC. PATIENTS AND METHODS: We conducted a prospective study of the responses of patients with TSC and at least one SEGA undergoing growth. RESULTS: Three females and three males with a mean age of 12.3 years received treatment. One patient had previously undergone surgery due to SEGA with hydrocephalus. The maximum mean diameter of the SEGA on beginning treatment was 15.3 mm (range: 11.3-24.8 mm). Treatment was established with everolimus, 2.5 mg/day administered orally in patients with a body surface area < 1.2 m2, and 5 mg/day in patients with a body surface area > 1.2 m2. Two patients presented hypertriglyceridemia; one, anorexia; another, a mouth ulcer; and one, amenorrhoea. The mean reduction in the volume of the SEGA at three months of treatment was 46%, and the reduction remained steady in later control examinations (6-25 months). CONCLUSIONS: Treatment with everolimus reduces the size of SEGA associated with TSC with an adequate safety profile, and constitutes an alternative to surgery in certain cases.

TITLE: Respuesta a everolimus en pacientes con astrocitoma de celulas gigantes asociado al complejo esclerosis tuberosa.Introduccion. Los astrocitomas subependimarios de celulas gigantes (SEGA) se presentan en el 5-20% de los pacientes con complejo esclerosis tuberosa (CET) y son los tumores cerebrales mas comunes en el CET. Son tumores benignos, de estirpe glioneural, que se desarrollan fundamentalmente en las primeras dos decadas de la vida, en general cercanos al foramen de Monro, y pueden ocasionar hidrocefalia e hipertension intracraneal. Constituyen la principal causa de muerte en el CET. Recientemente, los inhibidores mTOR han demostrado ser una alternativa terapeutica a la reseccion quirurgica. Objetivo. Describir nuestra experiencia con everolimus para el tratamiento de pacientes con SEGA y CET. Pacientes y metodos. Estudio prospectivo de la respuesta de los pacientes con CET y al menos un SEGA en crecimiento. Resultados. Recibieron tratamiento tres mujeres y tres varones con una edad media de 12,3 años. Un paciente habia sido previamente intervenido quirurgicamente por SEGA con hidrocefalia. El diametro maximo medio del SEGA al inicio del tratamiento era de 15,3 mm (rango: 11,3-24,8 mm). Se inicio tratamiento con everolimus, 2,5 mg/dia por via oral en pacientes con superficie corporal < 1,2 m2 y 5 mg/dia en pacientes con superficie corporal > 1,2 m2. Dos pacientes presentaron hipertrigliceridemia; uno, anorexia; otro, un afta; y una paciente, amenorrea. La reduccion media del volumen del SEGA a los tres meses de tratamiento fue del 46%, y la reduccion se mantuvo estable en controles posteriores (6-25 meses). Conclusiones. El tratamiento con everolimus disminuye el tamaño de los SEGA asociados a CET con un perfil de seguridad adecuado, y constituye una alternativa a la cirugia en casos seleccionados.

Tumores vasculares en la infancia / Infantile vascular tumors

La utilización en el pasado de una terminología imprecisa para designar a los tumores vasculares infantiles ha contribuido durante años a diagnósticos incorrectos y, como consecuencia, a tratamientos inadecuados. En la infancia pueden presentarse diferentes tipos de tumores vasculares, como los hemangiomas infantiles, que son con diferencia los más frecuentes, y otros mucho más raros, como los hemangiomas congénitos (rápidamente involutivo y no involutivo), el hemangioendotelioma kaposiforme, el angioblastoma o angioma en penacho, o el granuloma piógeno. Su correcto conocimiento y diagnóstico, siempre en el contexto de un equipo multidisciplinario, es imprescindible para reducir errores diagnósticos, exámenes complementarios y pruebas invasivas innecesarias, y así, si fuera preciso, recibir el tratamiento más indicado y efectivo en cada caso. En el presente artículo revisamos la evolución histórica en cuanto a la nomenclatura y clasificación de las lesiones vasculares, las diferentes características clinicopatológicas de cada uno de los tumores vasculares, los exámenes complementarios indicados para llegar a un correcto diagnóstico, su diagnóstico diferencial y los distintos tipos de tratamiento que existen con sus indicaciones más reconocidas, en el momento actual, para los diferentes tumores vasculares y situaciones clínicas concretas (AU)

The use in the past of an imprecise terminology to designate vascular tumors has contributed to its incorrect diagnosis, and as a consequence, to inadequate treatment. In childhood, different types of vascular tumors may be present. Hemangiomas of infancy are by far the most frequent, and other less common types are congenital hemangiomas (rapidly involuting or RICH and non-involuting or NICH), kaposiform hemangioendothelioma, angioblastoma or tufted angioma and pyogenic granuloma. The correct knowledge and diagnosis, always in a multidisciplinary setting, is required to reduce incorrect diagnosis, unnecessary complementary examinations and invasive tests, and for the patient to receive the most effective and precise treatment in each case. This article reviews the historical evolution, nomenclature and classification of vascular lesions, the different clinical and pathological characteristics of each vascular tumor, the complementary examinations required correct diagnosis, the differential diagnosis, as well as highlighting the treatment options currently available for different vascular tumors and related clinical conditions (AU)

[Infection-triggered familial or recurrent acute necrotizing encephalopathy]. / Encefalopatía aguda necrosante familiar o recurrente desencadenada por infecciones.

Acute necrotizing encephalopathy (ANE) presents in children after common viral infections. Most cases of ANE are non-familial and non-recurrent and have been mainly reported in Asian patients, although ANE affects children worldwide. Recently, missense mutations in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2) have been found in several families with familial or recurrent cases of ANE. We describe a Spanish family with familial and recurrent ANE without mutations in RANBP2. Mutations in RANBP2 are not the sole susceptibility alleles for familial or recurrent ANE.

[Reticulocyte haemoglobin content in the diagnosis of iron deficiency]. / Contenido de hemoglobina reticulocitaria para el diagnóstico de la ferropenia.

INTRODUCTION: The detection of iron deficiency is essential in order to start early treatment to prevent long-term systemic complications of iron deficiency anaemia. Reticulocyte haemoglobin content (CHr) has been shown to be a helpful indicator for detecting iron deficiency before the development of anaemia. The objectives of this study were to evaluate the efficiency of CHr in the assessment of iron deficiency with or without anaemia and to determine the cut-off value with the best diagnostic yield. STUDY DESIGN: A descriptive cross-sectional study was carried out on an urban population of both sexes aged 6 months to 14 years. The study protocol included a questionnaire and taking a venous blood sample for a complete blood cell count with CHr and biochemical indicators of iron status. RESULTS: Samples were obtained for 237 children. A CHr cut-off value of 25 pg had an overall sensitivity of 90.7% and specificity of 80.1% for the diagnosis of iron deficiency with or without anaemia. The value of CHr was below 25 pg in the diagnostic groups with iron deficiency and iron deficiency anaemia, and above this value in the diagnostic groups with non-iron deficient anaemia or normal. CONCLUSIONS: CHr is a useful hematological marker to identify iron deficiency and iron deficiency anaemia in childhood. A CHr value of 25 pg showed the best performance to identify iron deficiency with or without anaemia.

[Review of haematology and biochemistry parameters to identify iron deficiency]. / Revisión de los parámetros hematológicos y bioquímicos para identificar la ferropenia.

INTRODUCTION: There has been a continuous improvement in the methods to detect iron deficiency, a common condition in children, in the last decades or so, but it is still difficult to establish which parameters should be included in a diagnostic panel for iron deficiency and iron deficiency anaemia. The objectives of this study were to evaluate the diagnostic efficiency of commonly used haematological and biochemical markers, as well as the reticulocyte haemoglobin content (CHr) in the diagnosis of iron deficiency with or without anaemia. STUDY DESIGN: A descriptive cross-sectional study was carried out on an urban population of both sexes aged 6 months to 14 years. A complete blood cell count with CHr was obtained. Biochemical markers of iron metabolism, transferrin saturation, serum iron, ferritin and total iron binding capacity were also measured. RESULTS: Samples were obtained for 237 children. A multiple stepwise logistic regression analysis identified CHr and iron serum as the only parameters independently associated to iron deficiency (P<0.05). CHr was the strongest predictor of iron deficiency and iron deficiency anaemia. CONCLUSIONS: Our study indicates that the measurement of CHr may be a reliable method to assess deficiencies in tissue iron supply. CHr together with a complete blood count may provide an alternative to the traditional biochemical panel for the diagnosis of iron deficiency in children.

[Infant botulism]. / Botulismo del lactante.

We report a case of botulism in a 40 day old infant. The patient presented a descending flaccid paralysis requiring mechanical ventilation for 12 days. She is the first European patient treated with Human Botulism Immune Globulin. A few weeks later a second case of infant botulism was detected in our geographical region in Southern Spain. We emphasise the importance of an early diagnosis and treatment with Human Botulism Immune Globulin to decrease morbidity.

Tumores disembrioplásicos neuroepiteliales en la edad pediátrica / Dysembryoplastic neuroepithelial tumors in children

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Giant hypothalamic hamartoma and dacrystic seizures.

Ictal crying is a rare type of epileptic seizure associated with hypothalamic hamartoma and with other lesions such as tumours, vascular malformations, hippocampal sclerosis, or cerebral infarction. We describe the case of an infant with gelastic, dacrystic and other types of seizures associated with a giant hypothalamic hamartoma, and present a video sequence of dacrystic seizures. Dacrystic episodes presented in clusters at sleep onset, initially in the form of moaning followed by face-flushing that rapidly evolved to crying, associated with a lateral and upper deviation of both eyeballs, along with clonic aspects of the eyelids. After a few seconds, the crying became less intense, she stared, and oro-alimentary automatisms became prominent along with some slow horizontal movements of the eyes and the head. Following surgery, at the age of nine months, the gelastic seizures stopped, but dacrystic seizures persisted. [Published with video sequences].

[Osteosarcoma and brain metastasis]. / Osteosarcoma y metástasis cerebral.

INTRODUCTION: Since the advent of multimodal therapy, survival among patients with osteosarcoma in general and among those with aggressive tumors has improved. Consequently, the pattern of relapse is also changing. Brain metastasis is considered to be a rare event in osteosarcoma, although recent reports suggest that the incidence of this complication may be increasing. CASE REPORT: We report two girls with osteoblastic osteosarcoma of the femur with poor response to preoperative chemotherapy. Both patients developed brain metastasis concurrent with or after the development of lung metastasis. Clinical manifestations of brain metastasis were symptoms of intracranial hypertension in one patient, and a complex partial seizure in the other. DISCUSSION: We advocate periodic neurologic examination and neuroradiologic screening for the early detection of brain involvement in patients whose disease recurs within 1 year of diagnosis, in those with metastasis at diagnosis and in those with a poor histologic response to preoperative chemotherapy.

Osteosarcoma y metástasis cerebral / Osteosarcoma and brain metastasis

La introducción del tratamiento multimodal ha supuesto una prolongación de la supervivencia, tanto de los pacientes con osteosarcoma globalmente como del subgrupo con tumores más agresivos, lo cual se ha asociado a un cambio en los patrones de metástasis. Tradicionalmente, las metástasis cerebrales constituían una rareza, aunque en los últimos años se ha observado un incremento en su incidencia. Se describen dos niñas con osteosarcoma osteoblástico de fémur cuya respuesta a la quimioterapia preoperatoria había sido escasa. Ambas presentaron metástasis cerebrales a la vez o tras el desarrollo de metástasis pulmonares. Clínicamente se manifestaron con síntomas de hipertensión intracraneal en una paciente; con una crisis parcial compleja en el otro caso. Consideramos que los pacientes con metástasis al diagnóstico, los que recidiven durante el primer año del diagnóstico y aquellos con una respuesta histológica escasa a la quimioterapia prequirúrgica deben ser examinados de forma periódica clínica y radiológicamente para descartar afectación cerebral (AU)

[Ocular infiltration in the anterior chamber in a female infant with acute non-lymphoblastic leukemia]. / Infiltración de la cámara anterior ocular en una paciente con leucemia no linfoblástica aguda.

Unlike myeloid sarcoma, ocular involvement is unusual in acute non-lymphoblastic leukemia.A 9-month-old female infant with acute non-lymphoblastic leukemia M5 and evidence of active central nervous system (CNS) disease showed infiltration of the anterior chamber during therapy. At that time, the CNS disease was in completed remission. She was treated with topical corticosteroids, chemotherapy and bilateral ocular radiotherapy (total dose 1,000 cGy). The ocular manifestations responded well to treatment but hematologic response was poor. The patient died a few months later. Any ophthalmic manifestation in children with leukemia should be detected and treated early. Radiotherapy is warranted in infiltration of the anterior chamber of the eye. The presence of ocular, central CNS or bone marrow involvement indicates poor prognosis in acute childhood leukemia.

[Dermatomyositis in childhood]. / Dermatomiositis en la infancia.

AIM: The aim of this study is to review the presenting signs and symptoms, laboratory findings and therapeutic regimens of juvenile dermatomyositis in a tertiary hospital. METHODS: We reviewed retrospectively the available medical records of patients who met the clinicopathologic criteria of Bohan and Peter for definite juvenile dermatomyositis. They were followed between 1986 and july 1999 at the pediatric rheumatology section at our institution. RESULTS: The patient population included 3 male and 6 female patients. The mean age at diagnosis was 7 years. Clinical features demanding medical attention at the hospital were: muscle weakness and pain, with associated general symptoms in 4 cases; isolated muscle weakness in 2 cases; muscle weakness associated to general symptoms in 1 case; and monoarthritis in another case. One patient presented initially only with cutaneous rash. Three patients developed calcinosis. Serum CPK and LDH levels were elevated in 8 patients, aldolase in 7 and aminotransferases in 6. Autoantibodies were undetectable in all the patients. Electomyography demonstrated myopatic or mixed pattern in the 5 patients it was practiced. Muscle biopsy showed features of inflammatory myopathy in all the cases. Seven patients were treated exclusively with steroids and 2 patients with steroids, methotrexate and intravenous gammaglobuline. Actually, 6 patients are asymptomatic, 2 have mild muscle weakness, and 1 has died. CONCLUSIONS: The results of our review agree with other series reported. Juvenile dermatomyositis suspicious should be made upon muscle weakness and general symptoms. Treatment with steroids should be started promptly.

[Neurocutaneous melanosis]. / Melanosis neurocutánea.

Neurocutaneous melanosis (NCM) is a rare congenital syndrome characterized by large or multiple congenital melanocytic nevi and excessive proliferation of melanotic cells in the leptomeninges. We report the case of a girl with a giant hairy nevus and numerous small nevi since birth. Within the first 2 years of life she developed clinical features of increased intracranial pressure and West s syndrome. At 2 years of age she presented a right facial palsy and myelopathy. Brain and spinal magnetic resonance imaging demonstrated meningeal infiltration. Diagnosis of NCM was established by a detailed cytologic analyses of the cerebrospinal fluid that revealed melanocytic cells. She received palliative treatment. The girl died 2 months after. Patients with large or multiple congenital melanocytic nevi should be carefully followed up with clinical examination and neuroimaging to detect NCM. At present there is no curative treatment. The association of NCM and West s syndrome has not been previously described.