Protocolo de diagnóstico y seguimiento de pacientes adultos con neurofibromatosis tipo 1 en una unidad de referencia española / Diagnostic and follow-up protocol for adult patients with neurofibromatosis type 1 in a Spanish reference unit

La neurofibromatosis tipo 1 es uno de los trastornos genéticos neurocutáneos más frecuentes. La característica de esta enfermedad es la afectación cutánea en forma de manchas «café con leche», efélides y los característicos neurofibromas cutáneos. Otras manifestaciones frecuentes incluyen las alteraciones óseas, la «vasculopatía por neurofibromatosis tipo 1» y los problemas neurocognitivos. Además, los pacientes tienen más riesgo de padecer una gran variedad de neoplasias malignas, incluida la transformación maligna de neurofibromas plexiformes. Para ser capaces de brindar una atención óptima a estos pacientes, que presentan una afectación multisistémica y potencialmente grave, es necesario conocer las diversas características clínicas de este trastorno, así como propiciar un seguimiento y abordaje terapéutico precoz y multidisciplinar. En esta revisión, resumimos el diagnóstico, las principales características clínicas y proponemos un protocolo de cribado y seguimiento de pacientes adultos con neurofibromatosis tipo 1 (AU)

Neurofibromatosis type 1 is one of the most common genetic neurocutaneous disorders. The hallmark of this disease is skin lesions in the form of café-au-lait spots, ephelides, and the characteristic cutaneous neurofibromas. Other common manifestations include bone abnormalities, «neurofibromatosis type 1 vasculopathy», and neurocognitive disorders. In addition, patients are at an increased risk for a wide variety of malignant neoplasms, including the malignant transformation of plexiform neurofibromas. It is necessary to know the various clinical characteristics of this disorder and to provide an early, multidisciplinary follow-up and treatment approach in order to provide optimal care to these patients, who present with a multisystemic disease that is potentially severe. This review summarizes the diagnosis and main clinical characteristics and suggests a protocol for screening and follow-up of adult patients with neurofibromatosis type 1 (AU)

Diagnostic and follow-up protocol for adult patients with neurofibromatosis type 1 in a Spanish reference unit.

Neurofibromatosis type 1 (NF1) is one of the most common genetic neurocutaneous disorders. The hallmark of this disease is skin lesions in the form of café-au-lait spots, ephelides, and the characteristic cutaneous neurofibromas. Other common manifestations include bone abnormalities, "NF1 vasculopathy," and neurocognitive disorders. In addition, patients are at an increased risk for a wide variety of malignant neoplasms, including the malignant transformation of plexiform neurofibromas. It is necessary to know the various clinical characteristics of this disorder and to provide an early, multidisciplinary follow-up and treatment approach in order to provide optimal care to these patients, who present with a multisystemic disease that is potentially severe. This review summarizes the diagnosis and main clinical characteristics and suggests a protocol for screening and follow-up of adult patients with NF1.

Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review.

Neurofibromatosis type 1 (NF1) is a genetic disorder that carries a higher risk of tumor development. Plexiform neurofibromas (PNs) are present in 50% of NF1 and cause significant morbidity when surgery is not feasible. Systemic therapies had not succeeded to reduce PN tumor volume until 2016 when the first trial with an MAPK/extracellular-signal-regulated kinase (MEK) inhibitor was published. We performed a systematic research on novel targeted therapies for patients with NF1 and PNs in PubMed, EMBASE, and conference abstracts with the last update in February 2021. Since 2016, seven trials have reported positive results with MEK inhibitors and other molecular targeted therapies (cabozantinib). Selumetinib has shown an overall response rate of 68% in children with NF1 and symptomatic inoperable PNs, and was associated with pain improvement and a manageable adverse events profile. This led to Food and Drug Administration (FDA) approval of selumetinib in May 2020. Recently, cabozantinib and mirdametinib have also proven their efficacy in adult population. Other MEK inhibitors such as trametinib and binimetinib have also communicated promising preliminary results. Ongoing trials in different populations and with intermittent dosing strategies are underway.

What do anti-Toxoplasma gondii IgA and IgG subclasses in human saliva indicate?

Diagnostic tests for toxoplasmosis are based on serological techniques due to their high sensitivity. Some IgG subclasses are related to clinical outcome in the congenital form. In this work, we determined the levels of IgG, IgA, IgG1, IgG2, IgG3 and IgG4 anti-Toxoplasma gondii antibodies in paired saliva and serum samples from 91 women by indirect ELISA using a crude extract of the RH strain. The levels of IgA, IgG2, IgG3 and IgG4 antibodies and, to a lesser extent, IgG1 did not correlate between saliva and serum, that is, most cases that were positive for one Ig class in a sample were negative or very low in the other, and vice versa. We also observed that most samples of saliva that were positive for one IgG subclass were also positive for at least 2 of the other 3; this contrasted with findings in serum, wherein each person was positive almost exclusively for one subclass, as demonstrated before by us and other researchers. Although these findings are disappointing for the use in diagnosis, the richer response in saliva might indicate local exposure to T. gondii antigens without systemic infection; thus, saliva might be reflecting a local (protective?) response against this protozoan.

Congenital toxoplasmosis: candidate host immune genes relevant for vertical transmission and pathogenesis.

Toxoplasma gondii infects a variety of vertebrate hosts, including humans. Transplacental passage of the parasite leads to congenital toxoplasmosis. A primary infection during the first weeks of gestation causes vertical transmission at low rate, although it causes major damage to the embryo. Transmission frequency increases to near 80% by the end of pregnancy, but the proportion of ill newborns is low. For transmission and pathogenesis, the parasite genetics is certainly important. Several host innate and adaptative immune response genes are induced during infection in adults, which control the rapidly replicating tachyzoite. The T helper 1 (Th1) response is protective, although it has to be modulated to avoid inflammatory damage. Paradoxical observations on this response pattern in congenital toxoplasmosis have been reported, as it may be protective or deleterious, inducing sterile abortion or favoring parasite transplacental passage. Regarding pregnancy, an early Th1 microenvironment is important for control of infectious diseases and successful implantation, although it has to be regulated to support trophoblast survival. Polymorphism of genes involved in these parallel phenomena, such as Toll-like receptors (TLRs), adhesins, cytokines, chemokines or their receptors, immunoglobulins or Fc receptors (FcRs), might be important in susceptibility for T. gondii vertical transmission, abortion or fetal pathology. In this study some examples are presented and discussed.

Toxoplasmosis in pregnancy: determination of IgM, IgG and avidity in filter paper-embedded blood.

OBJECTIVE: To detect immunoglobulin M (IgM) anti-Toxoplasma gondii antibodies and determine immunoglobulin G (IgG) titer and avidity in filter paper-embedded blood (FPEB) samples of pregnant women. STUDY DESIGN: A total of 100 FPEB samples of pregnant women (30 positive and 70 negative) were analyzed for anti-T. gondii-specific IgM antibodies. Eleven and nine pairs of serum and FPEB samples were used to standardize IgG titration and avidity, respectively. Then, the correlation of avidity results was determined with 23 serum/FPEB pairs from IgG-positive cases. RESULT: IgM detection in FPEB was 92% sensitive and 100% specific. The titration of IgG antibodies in FPEB correlated with that of serum (r >or=0.9). Significant difference in avidity between the acute and the undetermined/chronic cases was observed in both samples. As expected, no correlation was found between IgM levels and avidity. CONCLUSION: The FPEB is useful to infer infection phase, and thus to speed clinical decisions in congenital toxoplasmosis management.

Congenital and acquired toxoplasmosis: diversity and role of antibodies in different compartments of the host.

The apicomplexan parasite Toxoplasma gondii is remarkable in several aspects, since it is a protozoan that infects most nucleated cells in many warm-blooded animals, worldwide. Although the cellular immune response against T. gondii is critical for infection control, antibodies may either enhance or block protective mechanisms, and even mediate immunological damage, directly or indirectly. Since cytokines regulate the class/subclass switch, antibodies may also be the biomarkers of protective or pathological cellular immune events. There is a scientific and clinical interest in the presence of natural and autoreactive antibodies, as well as in the 'chronic' immunoglobulin M (IgM) response and the post-treatment 'rebound'. Another interesting aspect is compartmentalization; certain immunoglobulins may uniquely be found in specific host fluids. Local synthesis has been demonstrated, but antibodies may also traverse several cell layers, like the blood-brain and haemato-ocular barriers, and the placenta. In some instances, Fc receptors (FcRs) facilitate transport and may even have a concentrator effect, which can be related to resistance or pathology. These aspects of the humoral response against T. gondii are reviewed in the present paper.

Acute infection of Toxoplasma gondii and cytomegalovirus reactivation in a pediatric patient receiving liver transplant.

A 7-year-old Mexican boy with end-stage cirrhosis underwent liver transplantation and was maintained with cyclosporine and prednisolone. No specific data about Toxoplasma gondii or cytomegalovirus (CMV) infections in the cadaver donor were available. The recipient was seronegative for Toxoplasma, but CMV-IgG positive before transplantation. Ganciclovir was administered for prophylaxis during 3 months, but 5 months later he presented with icterus and increased transaminases. Acute transplant rejection was ruled out by biopsy. A seroconversion for T. gondii IgM and IgG and a small increase in CMV-IgM antibodies were observed, although the CMV-polymerase chain reaction (PCR) was negative. Ganciclovir was re-started, and the patient improved, but 6 months later he relapsed, and chorioretinitis lesions compatible both with T. gondii and CMV infections appeared. Pyrimethamine, sulfadiazine, folinic acid, and ganciclovir were administered. The boy showed favorable clinical improvement and remained stable for 12 months. Then, new retinal CMV lesions appeared in both eyes and the PCR for CMV became positive; therefore, the patient received a new regimen of ganciclovir, and clinically improved. From these data we concluded that the child presented a reactivation of CMV and a primary infection with T. gondii after transplantation.

Pronóstico del cáncer de cérvix en un hospital de área / Prognostic factors and outcome of cervical cancer in a district hospital

Objetivo: Analizar las características clinicopatológicas de las pacientes diagnosticadas de cáncer invasivo de cérvix en nuestro ámbito clínico, así como su evaluación pronóstica. Sujetos y métodos: Estudio retrospectivo observacional de todas las pacientes con diagnóstico histológico de cáncer invasivo de cérvix en nuestro servicio hospitalario durante el período 1994-2003. Se recogen las características clínicas de las pacientes y de los tumores. Se establecen las curvas de supervivencia según el método de Kaplan-Meier y se comparan mediante la prueba de rangos logarítmicos para el análisis univariante. El análisis multivariante se realizó mediante la regresión de Cox. Resultados: Se identificaron 39 pacientes con una media de edad de 54 años. La mayoría presentaba metrorragias y se encontraba en un estadio inicial (66%) en el momento del diagnóstico. El 84% de los tumores fueron escamosos, moderadamente diferenciados (56%) y sin invasión linfovascular (87%). El tratamiento fue preferentemente radioterapéutico (48%). Los factores pronósticos para la supervivencia global fueron el estadio clínico (p < 0,001), el valor de hemoglobina (p = 0,007) y el grado histológico (p = 0,01). Sólo el estadio se mantuvo como factor pronóstico independiente (p = 0,001) en el análisis multivariante. Conclusiones: Nuestros resultados resaltan la importancia de un diagnóstico precoz del cáncer de cérvix

Objective: To analyze the clinical and pathologic characteristics of invasive cervical cancer in our center and to identify prognostic factors. Subjects and methods: We performed an observational, retrospective study of all women with a histopathological diagnosis of invasive cervical cancer in our department between 1994 and 2003. Clinical and tumoral characteristics were included. Survival curves were calculated with the Kaplan-Meier method and were compared with the log rank test. Multivariate analysis was performed using the Cox regression model. Results: Thirty-nine patients were identified. The mean age was 54 years. At diagnosis, most of the patients showed abnormal bleeding and initial-stage tumors (66%). Thirty-three tumors (84%) were squamous, 22 were moderately differentiated (56%) and 34 showed no lymphovascular invasion (87%). The most frequent treatment was radiotherapy (48%). Prognostic factors for overall survival were clinical stage (p < 0.001), pre-treatment hemoglobin levels (p = 0.007) and histologic grade (p = 0.01). The only independent prognostic factor in the multivariate analysis was clinical stage. Conclusions: Our results emphasize the importance of an early diagnosis in invasive cervical cancer

[Evaluation of cerebral blood perfusion in patients undergoing carotid endarterectomy using densitometric analysis of conventional cranial CT]. / Evaluación de la perfusión cerebral mediante análisis densitométrico de la tomografía craneal en pacientes sometidos a endarterectomía carotídea.

OBJECTIVE: To evaluate the efficacy of densitometric analysis of cranial CT imaging in the measurement of areas with low cerebral blood flow and lack of hemodynamic reserve in patients undergoing carotid endarterectomy. PATIENTS AND METHODS: 40 consecutive patients undergoing carotid endarterectomy have been included in the study. All of them had preoperative cranial CT, pre and postoperative basal and acetazolamide SPECT. Cranial CT imaging after digitalization and computer processing were obtained with 4 densitometric patterns: 1). normal cerebral blood perfusion; 2). ischemic or low brain blood perfusion (patron I); 3). parenchyma without cerebral hemodynamic reserve (patron nR), and 4). brain infarction. RESULTS: 32 out of 40 (80 %) patients had abnormal densitometric patterns: 19 nR patterns (47.5 %), 11 I pattern (27.5 %) and 2 established brain infarction. The correlation between densitometric cranial TC imaging and SPECT was 92% when analyzing areas with hypoperfusion (S: 96.5 %; E: 82 %). Cranial CT detected 12/13 of patients who lacked cerebral hemodynamic reserve in the SPECT analysis (S: 74 %; E: 92 %; Vpp: 95 %). CONCLUSIONS: There is a good correlation between analysis of densitometric cranial TC imaging and SPECT in determining low cerebral blood flow areas and lack of cerebral hemodynamic reserve. This method could help to improve carotid surgery indications in patients with carotid stenosis.

[Pulsatile perineal hematoma after transrectal prostatic biopsy]. / Hematoma perineal pulsátil tras biopsia prostática transrectal.

OBJECTIVE: A case of pulsatile perineal hematoma following transrectal biopsy of the prostate is presented. METHODS: A patient who had undergone transrectal biopsy of the prostate a few days earlier complained of a pulsatile sensation in the perineal region caused by a pseudoaneurysm of a left hypogastric artery. Patient evaluation included echo Doppler, pelvioabdominal CT and arteriography. Transcatheter intraarterial embolization with Gianturco-Wallace coils was performed. RESULTS: Excellent results were achieved. Filling of the aneurysm was immediately reduced and symptoms disappeared. CONCLUSION: This technique is gaining importance in the treatment of pelvic hemorrhage because it is relatively simple and carries a low morbidity and mortality.