Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.

BACKGROUND: Promising results have been reported with immune checkpoint inhibitors (ICI) in a small proportion of MPM patients. MMR deficiency (dMMR) has been well described in several malignancies and was approved as a biomarker for anti-PD-1 inhibitors. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM including a subset of patients treated with immunotherapy. METHODS: Tumors of 159 MPM p diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR (MMR protein expression negative) and MMR intact (all MMR proteins positively expressed). We retrospectively collected clinical outcomes under standard chemotherapy and experimental immunotherapy in the entire cohort. RESULTS: MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. Twenty two patients received ICI with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1 m). The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8 m). In a multivariable model factors associated to improved mOS were PS 0, neutrophil-lymphocyte ratio (NLR) < 5 and epithelioid histology (p < 0.001). CONCLUSIONS: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate potential predictive biomarkers of ICI benefit in MPM.

Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance. METHODS: For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at -80°C. RESULTS: In a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs. CONCLUSION: Acquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.

Immune-checkpoint inhibition in first-line treatment of advanced non-small cell lung cancer patients: Current status and future approaches.

Immune checkpoint inhibitors are considered standard second-line treatment in advanced non-small cell lung cancer patients. This strategy has also become standard in first-line setting for a subgroup of patients with strongly positive PD-L1 tumors; therefore, PD-L1 status might be considered a new biomarker that deserves upfront testing. New combinations of immune checkpoint inhibitors and with chemotherapy have been tested in first-line treatment. However, some questions remain unanswered such as the best treatment strategy or the real upfront efficacy of these therapeutic strategies in the whole lung cancer population. In this review we summarize the main results in the first-line setting of recent phase III trials with immune checkpoint inhibitors in advanced non-small cell lung cancer patients.

[Intestinal stomas. Are they as simple as they seem?] / Enterostomías, ¿son tan simples como parecen?

OBJECTIVES: To examine the morbidity and mortality of the formation and closure of enterostomies. METHODS: Retrospective study between 2000-2014 of patients younger than 14 years old who underwent an enterostomy. We evaluated: surgical technique, underlying pathology, general and stoma complications, sex, age and weight at the time of formation. At the closure we evaluated: surgical technique, age, weight, hemoglobin, hematocrit and albumin, as well as complications. RESULTS: We performed 120 enterostomies in 114 patients: 69 (57.5%) colostomies, 43 (35.8%) ileostomies and 8 (6.7%) yeyunostomy. The most frequent causes were: anorectal malformation (45/69), necrotizing enterocolitis (24/43) and intestinal atresia (4/8) respectively. 39 (32.5%) complications related to the stoma (colostomy 21, Ileostomy 15, Yeyunostomy 3; p= 0.845), 11 (9.2%) required surgery (colostomy 8, Ileostomy 2, Yeyunostomy 1; p= 0.439), and 17 (14.2%) general complications (colostomy 9, Ileostomy 7, Yeyunostomy 1; p= 0.884). We found a higher rate of complications requiring surgery in loop enterostomy 8/38 (21.1%), separated 3/54 (5.3%) or double-barrel 0/25 (p= 0.007). We closed 96 (80%), presenting complications in 14; yeyunostomy 4/6 (66.7%), colostomies 5/59 (8.5%), ileostomies 5/31 (16.1%) (p= 0.001). Hematocrit and hemoglobin below age average, and albumin under normal values are associated with complications when closing enterostomies (p< 0.05). Six patients (25%) who didn't went to closure died as a result of the underlying pathology and 5 (20.8%) of other causes. CONCLUSION: The formation and closing of enterostomies remains a procedure with a high rate of complications. However, there are no clear risk factors, excepting the use of loop enterostomy and lower albumin, hemoglobin or hematocrit at the time of closure.

OBJETTIVO: Examinar la morbimortalidad de la realización y cierre de las enterostomías. MATERIAL Y METODOS: Estudio retrospectivo entre 2000-2014, de pacientes menores de 14 años a los que se les realizó una enterostomía. Evaluamos: técnica quirúrgica, patología base, complicaciones del estoma y generales, sexo, edad y peso al momento de la cirugía. Al cierre evaluamos: técnica quirúrgica, edad, peso, hemoglobina, hematocrito y albúmin, así como complicaciones. RESULTADOS: En 114 pacientes, realizamos 120 enterostomías: colostomías 69 (57,5%), ileostomías 43 (35,8%) y yeyunostomías 8 (6,7%); las causas más frecuentes para cada una: malformación ano-rectal (45/69), enterocolitis necrotizante (24/43) y atresia intestinal (4/8) respectivamente. Complicaciones relacionadas al estoma 39 (32,5%) (colostomía 21, ileostomía 15, yeyunostomía 3; p= 0,845), requirieron cirugía 11 (9,2%) (colostomía 8, ileostomía 2, yeyunostomía 1; p= 0,439), y complicaciones generales 17 (14,2%) (colostomía 9, ileostomía 7, yeyunostomía 1; p= 0,884). Encontrando mayor índice de complicaciones que requirieron cirugía en la enterostomía en asa 8/38 (21,1%), separada 3/54 (5,3%) o cañón 0/25 (p= 0,007). Cerramos 96 (80%), presentando complicaciones 14; yeyunostomías 4/6 (66,7%), colostomías 5/59 (8,5%), ileostomías 5/31 (16,1%) (p= 0,001). Se asocian a complicaciones del cierre hemoglobina y hematocrito por debajo de la media para la edad, y albúmina bajo valores normales (p< 0,05). De los pacientes no anastomosados, 6 (25%) fallecieron por patología base y 5 (20,8%) por otra causa. CONCLUSION: La elaboración y cierre de enterostomías sigue siendo un procedimiento con alto índice de complicaciones. Sin embargo, no existen factores de riesgo claros, a excepción del uso de la enterostomía en asa y de albúmina, hemoglobina y hematocrito bajos al cierre.

[Clinical assessment of fecal incontinence in patients with anorectal malformation surgery]. / Valoración clínica de la incontinencia fecal en pacientes intervenidos de malformación anorrectal.

BACKGROUND/PURPOSE: To review our management of anorectal malformations (ARM) and to compare two quantitative scales for clinical assessment of fecal incontinence. MATERIAL AND METHODS: We reviewed all patients with ARM surgery who are currently 3 to 15 years old. Several variables were collected and fecal incontinence was evaluated using two scales: the Holschneider scale and one used previously in our Service, both were filled out through clinical interview. RESULTS: 48 patients were studied, 29 males and 19 females. According to the Peña's classification, 81% had good prognosis indicators (group A) and 19% had bad prognosis indicators (group B). Posterior sagittal anorectoplasty (PSARP) was performed in 32 patients, PSARP and abdominal approach in 3, abdomino-perineal pullthrough in 2, and a "Cut-back" anoplasty in 14 patients. There were not statistical significative differences in average age of continence between both groups. We found no significative differences on the average score of fecal incontinence between both groups using our scale (17.57/20 in group A vs 14/20 in group B; p= 0.05) but it was significantly lower in group B using the Holschneider scale (12.39/14 in group A vs 10.43/14; p= 0.04). Constipation was detected in 16 patients, half of whom had overflow pseudoincontinence. CONCLUSIONS: Our scale penalizes constipation, for this reason the average score of group A was lower and we didn't find differences with respect to group B, contrary to what it happened using Holschneider's scale, so we believe our scale could be more precise to evaluate fecal incontinence of these patients.

OBJETIVOS: Aportar nuestra experiencia en el manejo de las malformaciones anorrectales (MAR) y comparar dos escalas cuantitativas para la valoración clínica de la incontinencia fecal. MATERIAL Y METODOS: Revisamos los pacientes intervenidos de MAR con edades comprendidas entre los 3 y 15 años. Recogimos una serie de variables y evaluamos la incontinencia fecal mediante dos escalas: la de Holschneider y una utilizada previamente en nuestro Servicio, cuyos ítems se completaron mediante entrevista clínica. RESULTADOS: Estudiamos 48 pacientes, 29 niños y 19 niñas. El 81% presentaba factores de buen pronóstico (grupo A) y el 19% de mal pronóstico (grupo B) según la clasificación de Peña. El tratamiento realizado fue la anorrectoplastia sagital posterior (ARPSP) en 32 pacientes, ARPSP más descenso vía abdominal en 3, descenso abdominal en 2 y anoplastia tipo "Cut-Back" en 14. No existieron diferencias significativas en la edad media de continencia (3,41 ± 1,80 años en grupo A vs 3,92 ± 1,07 en grupo B; p= 0,35). No encontramos diferencias significativas en la media de puntuación de incontinencia utilizando nuestra escala (17,57/20 en grupo A vs 14/20 en grupo B; p= 0,05), pero fue significativamente menor en el grupo B utilizando la de Holschneider (12,39/14 en grupo A vs 10,43/14 en grupo B; p= 0,04). En 16 pacientes se detectó estreñimiento; de ellos, la mitad presentó pérdidas por rebosamiento. CONCLUSIONES: Nuestra escala penaliza el estreñimiento, por este motivo la puntuación media del grupo A fue menor y no se encontraron diferencias respecto al grupo B, contrariamente a lo ocurrido con la escala de Holschneider, por lo que podría resultar más precisa para valorar la incontinencia fecal de estos pacientes.

[Hypertrophy of labia minora. A growing problem in adolescence]. / Hipertrofia de labios menores. Un problema creciente en la adolescencia.

OBJECIVE: Hypertrophy of labia minora in adolescence is a little known disease. However, the growing demand for the solution of this problem pushes us to include it in our clinical practice. We evaluated the aesthetic and functional results of labiaplasty using straight amputation of the protuberant tissue of the labial edges. METHODS: Patients treated by hypertrophy of labia minora were reviewed. We evaluated the results of aesthetic, functional and surgical complications. A survey on the degree of satisfaction was also conducted. RESULTS: We collected 16 patients with 28 labioplasty, indicated by discomfort with the clothing and exercise. They were performed at a median age of 13.43 years (range 11.25-14.31). Bilateral 11 (64.7%), left 4 (23.5%) and rights 2 (11.8%). The median hospital stay was 1 day (range 1-3). There was evidence of immediate complications (partial dehiscence of the scar) in 1 (3.57%) patient and late complications in 2 (7.14%) patients (granuloma in the scar and recurrence), in a median follow up time of 1.58 years (range 0.19-7.76). The survey was answered by 13 patients. All of them said that preoperative discomfort was resolved. Postoperative discomfort (pain or straps) were nothing or very few in 61.54% and the median time of inconvenience was 5 days (range 1-30). They felt an improvement in self-esteem 69.23% and the 30.77% remaining never presented a problem about that. Median overall satisfaction was 8 (range 7-10) over 10, and the 100% of patients would repeat surgery. CONCLUSION: The labiaplasty by straight amputation in adolescence is an effective technique with few complications, and with a high degree of satisfaction for patients.

OBJETIVO: La hipertrofia de labios menores en la adolescencia es una patología poco conocida. Ante la creciente demanda de pacientes con este problema, fue necesaria su inclusión en nuestra cartera de servicios. El objetivo del presente estudio es la valoración de los resultados estéticos y funcionales de la labioplastia mediante la resección simple lineal de los bordes labiales. METODOS: Revisamos a pacientes intervenidas por hipertrofia de labios menores. Evaluando resultados estéticos, funcionales y complicaciones quirúrgicas. Asimismo, realizamos una encuesta sobre el grado de satisfacción. RESULTADOS: Intervenimos 16 pacientes con 28 labioplastias, indicadas por molestias con la vestimenta y el ejercicio. Se realizaron a una mediana de edad de 13,43 años (rango 11,25-14,31). Siendo bilaterales 11 (64,7%), izquierdos 4 (23,5%) y derechos 2 (11,8%). La mediana de estancia hospitalaria fue un día (rango 1-3). Se evidenció una complicación inmediata (3,57%) (dehiscencia parcial de la herida) y 2 (7,14%) tardías (granuloma en la cicatriz y recidiva), en una mediana de seguimiento de 1,58 años (rango 0,19-7,76). A la encuesta respondieron 13 pacientes, el 100% refirieron que las molestias preoperatorias estaban resueltas o mucho mejor; el 61,54% no indicó ninguna o muy pocas molestias postoperatorias (tirantez o dolor), siendo la mediana de tiempo de las molestias 5 días (rango 1-30). Sintieron una mejora de la autoestima el 69,23% y el 30,77% restante nunca presentaron problema al respecto. La mediana de grado de satisfacción global fue 8 (rango 7-10) y el 100% repetirían la cirugía. CONCLUSION: La labioplastia mediante resección simple en la adolescencia es una técnica efectiva con pocas complicaciones, y con un alto grado de satisfacción para las pacientes.

[Currarino triad: different forms of presentation]. / Triada de Currarino: sus diferentes formas de presentación.

BACKGROUND: We describe our experience in Currarino syndrome (CS) and our clinical findings. METHODS: Case 1: Newborn female with prenatal diagnosis of myelomeningocele which was confirmed at birth as a lipomyelomeningocele, associated with partial sacral agenesis, horseshoe kidney and complex anorectal malformation with colonic vascular anomaly. Case 2: A 14-month-old male with constipation. The physical examination detected an anal stricture and radiological findings of a presacral lipomeningocele plus teratoma and a partial sacral agenesis. Case 3: An 8-month-old male with recurrent meningitis associated with anterior sacral meningocele and rectal fistula. An anal stricture and hemisacrum were also demonstrated. RESULTS: In case 1, an abdomino-perineal pull-through was performed but it failed because of her colonic vascular anomaly. Nowadays she is 3 years old and has a cecostomy, controls her micturition and is able to walk. Case 2 is two years old with satisfactory flow-up-after the teratoma and meningocele removal plus anal dilation. In case 3 a colostomy was necessary because after mass excision a recto-cutaneous fistula appeared during postoperative period. A ventriculoperitoneal valve implantation due to his hydrocephaly was also performed. CONCLUSIONS: The constipation is the most common symptom in the CS. Recurrent meningitis has a high mortality rate (56%) due to rectomeningeal fistula. The most common anorectal malformation is the anal stricture, and the more complex the malformation is, higher will the risk of incontinence be. The success of the management and follow-up is a multidisciplinary responsability.

WT1 mutations may be a cause of severe renal failure due to nephroblastomatosis in Wilms' tumor patients.

Wilms' tumor suppressor gene (WT1) encodes a transcription factor required for normal development of the genitourinary system. Germline WT1 mutations have been described in a wide spectrum of pathological conditions, including kidney diseases, genital abnormalities and Wilms' tumor. Here we report a 4-year-old male patient who presented with bilateral cryptorchidism, Wilms' tumor, nephroblastomatosis and renal failure without nephrotic proteinuria. Sequence analysis of the WT1 gene demonstrated a constitutional heterozygous nonsense mutation in exon 7, which leads to a truncation of the WT1 protein at the zinc-finger 1. In the DNA of the tumor, we observed the same mutation in homo/hemizygosity. Given the requirement of WT1 for normal development, the WT1 mutation is likely to be responsible for the nephroblastomatosis and, in consequence, for the severe renal failure observed in our patient. This finding extends the spectrum of kidney diseases related to WT1 mutations and points to the need to screen for this gene in children with genitourinary abnormalities and Wilms' tumor because of the associated risk of nephroblastomatosis and renal failure in those carrying WT1 mutations.

[Pancreatic pseudocyst: less is more]. / Pseudoquiste pancreático: cuando menos es más.

UNLABELLED: Pancreatic pseudocysts (PQP) are rare in childhood and management tends to be individualized and controversial, and it is a challenge for the pediatric surgeon. The aim of this study is to determine the best management strategies in each patient. MATERIAL AND METHODS: Retrospective review of children admitted to our institution with the diagnosis of PQP and review of literature between 1990 and 2007. RESULTS: We report two children with postraumatic PQP that respond to non-operative management and 284 cases that were reported in literature (76% after blunt abdominal trauma). 26% of these patients had complete resolution of PQP with conservative management and the others patients required surgical intervention: external percutaneous drainage (18.6%), non-percutanueous external drainage drenaje (3.87%), cystogastrostomy (28.87%), cystojejunostomy o pancreaticojejunostomy (9.5%), endoscopic drainage (9.5%) or distal pancreatectomy (3.5%). CONCLUSION: The choice of treatment depends on the surgeon's experience and management of the endoscopic techniques, as well as the availability of interventionist radiology. Asymptomatic PQP in children does no require any specific intervention other than expectant management, especially in patients with trauma-induced PQP. Children with persistent clinical symptoms or those who developed complications may require further intervention.

[Pediatric endoscopy: state of the art]. / Endoscopia: estado actual.

INTRODUCTION: Our society has shown always a great concern with the limits of our speciality. However, we have never approached the issue of pediatric endoscopy. For this reason, we have decided to carry our a survey to assess the present situation of endoscopy among surgeon pediatricians. MATERIAL AND METHODS: Twenty-four hospitals whose services include pediatric surgery were sent a survey centred on the following items: name of hospital, number of beds, in pediatrics, number of surgical interventions per year (which enabled us to classify the services in four groups, depending on their surgical volume), which unit is in charge of esophagus-gastroscopy, colonoscopy, esophageal dilatation, percutaneous endoscopic gastrostomy (PEG), endoscopic retrograde colangio-pancreatography (ERCP), rigid and flexible bronchoscopy, and number of such examinations per year. RESULTS: We received twenty-two answers to the survey (91,88%). The upper endoscopies are carried out in 47,43% of the cases by Pediatric Surgery, (ten units carry out the 100% of the endoscopies in their hospital). All but two ERCP are carry out by the unit of adult gastroenterology, whereas esophageal dilatation and PEG are carry out in 89.33% of cases by Pediatric Surgery. Rigid bronchoscopy is performed by Pediatric Surgery in fifteen units, while flexible bronchoscopy is performed by Pediatric Surgery, Otorhinolaryngology, Pneumology and Pediatrics. CONCLUSIONS: The high degree of response proved the concern with strengthening certain techniques in the field of Pediatric Surgery. Esophageal dilatations and PEG are techniques in the hands of pediatric surgeons, while ERCP is in the hands of adult endoscopists. The units that offer flexible bronchoscopy carry out many more examinations. It would be necessary to reach a consensus regarding various issues related to these examinations, ranging from who is qualified to carry them out to their legal assistance.

Long-term results of high-dose chemotherapy and autologous stem cell rescue for high-risk neuroblastoma patients: a report of the Spanish working party for BMT in children (Getmon).

The authors retrospectively analyzed the long-term outcome of 67 patients over 1 year of age at diagnosis with high-risk neuroblastoma (stage 4 or stage 3 with N-myc amplification) who were treated with megatherapy and stem cell rescue from 1984 to 1998. Median age at transplant was 4 years (range 1.6-15 years). The source of cells was peripheral stem cells in 29 and bone marrow in 38 patients. In 12 patients, an in vitro purging of bone marrow harvest was performed. Most patients were conditioned with melphalan, BCNU, and VM-26. After transplant 19 patients received complementary treatment with IL-2 (16) or 13-cis-retinoic acid (3). Six patients (8%) died from transplant-related toxicity and 39 from disease progression. Three patients were alive with active disease at the time of analysis. Nineteen patients are alive and disease-free at a median follow-up of 104 months. Five-year event-free survival is 0.30. Survival of patients who received a purged graft was not significantly better than the rest. Post-transplant complementary treatment significantly improved overall and event-free survival (p = .01 and p = .04, respectively).

Autologous stem cell transplantation for advanced Hodgkin's disease in children. Spanish group for BMT in children (GETMON), Spain.

This study evaluates the outcome of myeloablative chemo-radiotherapy and autologous stem cell transplantation (ASCT) in children with Hodgkin's disease (HD). Twenty children aged 5 to 18 years (median 10.8 years) at diagnosis, with relapsed, refractory or very poor prognosis HD, underwent ASCT in eight hospitals of our country. Status at transplant was: second complete remission (CR2): n = 12; further CR (CR >2): n = 3, partial remission (PR): n = 2, relapse: n = 2 and first CR (CR1): n = 1. Eighteen patients received chemotherapy-based conditioning regimens: cyclophosphamide, carmustine and etoposide (CBV): 11 (55%), carmustine, etoposide, cytarabine and melphalan (BEAM): 5, other: 2; and two patients were conditioned with TBI/Cy. Peripheral blood (PB) was the source of progenitor cells in 12 patients, BM in seven, and BM plus PB, in one. All patients engrafted. One patient died of sepsis and multiorgan failure at day 28 after transplantation. All four patients with measurable disease (PR or relapse) at transplantation attained complete remission. Five patients relapsed 5-34 months after transplant (median: 11 months). Eighteen children remain alive with a median survival time of 40 months. The projected 5-year overall survival and event-free survival (EFS) rates were 0.95 and 0.62. High-dose therapy with stem cell rescue can lead to durable remissions in children with advanced HD. Bone Marrow Transplantation (2000) 25, 31-34.

Pulmonary enterovirus infections in stem cell transplant recipients.

In recent years, it has been recognised that the community respiratory viruses are a frequent cause of upper and lower respiratory tract infections in immunocompromised hosts such as bone marrow transplant recipients. By contrast, infections by non-polio enteroviruses have rarely been reported after stem cell transplantation. We present four cases of acute respiratory illness with enterovirus isolated as the sole pathogen from bronchoalveolar lavage. All four patients developed pneumonia and three died of progressive pneumonia, which reflects the severity of this complication. We conclude that enteroviral pulmonary infections may be a cause of severe pneumonia in immunocompromised hosts.

[Clinical and anatomopathological study of the contralateral tests in the unilateral cryptorchidism]. / Estudio clínico y anatomopatológico del teste contralateral en la criptorquidia unilateral.

We have operated on 2204 cryptorchid testis between 1972 and 1995. We took pathological specimens, not only in the undescended testis but also in the normally descended contralateral testis in 122 children. Clinical, surgical and anatomopathological records were reviewed. Moreover, we have studied the spermiograms in 10 young men. We found the Tubular Fertility Index (TFI) was abnormal in 37% of the contralateral testis. In 5 cases we didn't find germinal line. The Tubular Diameter was abnormal in 6.5% of the contralateral testicles only. When we compared the anatomopathological records in the contralateral testis depending on the surgical age and the surgical location of the undescended testis, we didn't find significant differences. When we studied the spermiograms in the 10 young men we obtained some cases where the TFI and the spermiogram were discordant. In conclusion, more than 1/3 of the children with unilateral undescended testis have an abnormal TFI in both testis. Moreover, neither the surgical age nor surgical location of the undescended testis have an influence on the contralateral TFI. Finally, according to the spermiogram results we should question TFI as a fertility index.

Mutational analysis of p53 in 16 cases of acute lymphoblastic leukemia and Burkitt's lymphoma.

BACKGROUND AND OBJECTIVE: Improvements in therapy for patients with B-cell acute lymphoblastic leukemia (ALL) and Burkitt's lymphoma (BL) depend on the identification of subsets of patients who require more intensive therapy. Abnormalities of the p53 gene are the most common molecular lesions in human cancer, and may be of prognostic significance in hematologic malignancies. In this study, we examined the p53 gene status in a group of patients with ALL/BL to determine whether some types of mutants were more frequent in this selected group of patients. METHODS: We selected a group of 16 patients with acute lymphoblastic leukemia (ALL) and Burkitt's lymphoma (BL) in order to investigate the presence of p53 mutations. DNA obtained from affected organs (bone marrow, lymph node and a renal mass) was used for the molecular studies. Single-strand conformation polymorphism (SSCP) analysis of exons 5 to 9 of the gene was used to detect p53 mutants. After detecting an abnormal migration pattern on the SSCP, mutations were determined by direct sequencing. RESULTS: Point mutations were found in eight patients; a misense mutation in seven cases and a non-sense mutation in one case. The normal allele was also identified in 7 mutated samples. The same mutation at codon 282 was identified in three different patients, in whom an identical conformer was detected after SSCP analysis. Mutation at codon 282 was present in an extramedular relapse (renal) appearing after a BMT. No such alteration was present in the bone marrow analyzed at the same time. INTERPRETATION AND CONCLUSIONS: Our findings suggest that p53 mutations are quite frequent in recognized clinical groups. The criteria chosen in this study allowed us to identify a high percentage of the samples with mutation. Different malignant phenotypes could be determined by functional heterogeneity of p53 mutants.

High-dose systemic interleukin-2 therapy in stage IV neuroblastoma for one year after autologous bone marrow transplantation: pilot study.

Despite intensified chemotherapy protocols, including autologous bone marrow transplantation (ABMT), stage IV neuroblastoma has a poor prognosis, and modern therapeutic trends are aimed at the eradication of minimal residual disease, which is though to be the main factor leading to relapse. In this pilot study, we report the systemic administration of high doses of interleukin-2 after ABMT in four patients. Five day cycles of IL-2 at a dose of 18 x 10(6) IU/m2/day were administered at variable time intervals as frequent as it was necessary to maintain the levels of natural killer (NK) cytotoxic activity higher than the median control value (40 LU/ml blood) throughout 1 year from the start of first IL-2 treatment. After IL-2 infusion, NK and LAK activities increased significantly (median 742 x 10(-3) LU/ml blood and 186.8 x 10(-3) LU/ml blood, respectively). Toxicities were transient and no life-threatening complications were observed. Fever, anorexia, skin rash and enlarged liver were always present. Anaemia, thrombocytopenia, leukocytosis, lymphocytosis and and eosinophilia occurred following most of the IL-2 courses. Although the small number of patients does not allow an estimation of the immunomodulatory-antineoplasic effects of IL-2, the results seem promising for the management of neuroblastoma patients.

Interleukin-2 in neuroblastoma: clinical perspectives based on biological studies.

Stage IV neuroblastoma (NB) is a disease with a poor prognosis. Chemotherapeutical intensification and hematological rescue with autologous bone marrow transplantation (ABMT) achieve some complete remissions (CR), but most patients relapse during the first year. Immunotherapy could be an alternative in this situation of high risk of relapse due to residual disease and ABMT-related immunodepression. Ten stage IV NB patients in CR or very good partial remission have been treated with recurrent 5-day cycles of high doses of Interleukin-2 (IL2) after ABMT throughout one year (usually 5-6 cycles). Natural killer (NK) and lymphokine-activated killer (LAK) cytotoxic activities, as well as phenotype and number of circulating NK cells were determined, before and after each course of IL2 treatment. The effects promoted by IL2 varied during treatment: early cycles of IL2 induced a great extent of cell expansion, mainly on CD3-/CD16-/CD56+bright and CD8+dim cell phenotypes; conversely, late courses of IL2 promoted higher NK cytotoxic activity but a lesser increase on circulating NK cells. The induction of LAK activity did not significantly differ from early and late IL2 treatments. Clinical results are still inconclusive due to the small number of patients. The median follow-up of patients treated with IL2 is 24 months and the disease free survival (DFS) probability is 0.80 +/- 0.12 vs 0.16 +/- 0.15 from a historical control with identical treatment, but in the absence of IL2 treatment (p < 0.005). IL2 treatment-related toxicity was mild and no interruption of the treatment was required. Extremely accurate hydric control was carried out to avoid, as much as possible, the consequences of vascular leak syndrome, one of the most important toxic effects of IL2 treatment. The results presented here suggest an evolution of NK activity during IL2 treatment after ABMT, which should be taken into account for the designing of new immunotherapeutical protocols and opens a promising perspective in treatment of stage IV neuroblastoma.