The Medication Level Variability Index (MLVI) Predicts Poor Liver Transplant Outcomes: A Prospective Multi-Site Study.

Nonadherence to immunosuppressant medications is a leading cause of poor long-term outcomes in transplant recipients. The Medication Level Variability Index (MLVI) provides a vehicle for transplant outcome risk-stratification through continuous assessment of adherence. The MALT (Medication Adherence in children who had a Liver Transplant) prospective multi-site study evaluated whether MLVI predicts late acute rejection (LAR). Four hundred pediatric (1-17-year-old) liver transplant recipients were enrolled and followed for 2 years. The a-priori hypothesis was that a higher MLVI predicts LAR. Predefined secondary analyses evaluated other outcomes such as liver enzyme levels, and sensitivity analyses compared adolescents to pre-adolescents. In the primary analysis sample of 379 participants, a higher prerejection MLVI predicted LAR (mean prerejection MLVI with LAR: 2.4 [3.6 standard deviation] versus without LAR, 1.6 [1.1]; p = 0.026). Fifty-three percent of the adolescents with MLVI>2 in year 1 had LAR by the end of year 2, as compared with 6% of those with year 1 MLVI≤2. A higher MLVI was significantly associated with all secondary outcomes. MLVI, a marker of medication adherence that uses clinically derived information, predicts LAR in pediatric liver transplant recipients.

Non-tumoural parenchyma in Leydig cell tumours: pathogenetic considerations.

Little is known about the pathogenesis of Leydig cell tumours (LCTs) of the testis. The observation of several associated dysgenetic features in the non-tumoural parenchyma and in the contralateral testes of men with testicular germ cell neoplasms has served as the basis to propose that there may be a common mechanism for different male reproductive disorders. However, the possible relationship between LCTs and other testicular lesions has not been explored. Here we describe the presence of primary lesions in the non-tumoural parenchyma of testes with LCT, from which we try to establish possible pathogenetic associations. We studied the non-tumoural parenchyma adjacent to 16 LCT specimens. Parameters as Leydig cell hyperplasia (LCHY), qualitative evaluation of the germinal epithelium and spermatogenesis, the presence of Sertoli cell-only tubules (SCOT), and the Sertoli cell nuclear morphology were consistently assessed in all cases. SCOT associated with Sertoli cell dysgenetic morphology was the most frequent finding, present in 50% of the cases. Another interesting finding was the presence of LCHY in four cases (25%). Abnormal spermatogenesis was found in 81.25% of the cases, and it consisted of lesions of the adluminal or basal compartments of seminiferous tubules. The occurrence of either dysgenetic Sertoli cells or LCHY adjacent to LCTs could represent primary anomalies, resulting from a common insult also involved in tumourigenesis. The abnormalities in spermatogenesis observed here are likely to represent consequences of either tumour compression or abnormal hormonal production. The significance of these associations merits further investigation regarding a common pathogenesis.

Tumores renales de la infancia y adolescencia asociados a anomalías cromosómicas / Renal tumors of childhood and adolescence associated with chromosomal anomalies

El riñón pediátrico es sitio frecuente de tumores que exhiben alteraciones cromosómicas características. El más común es el nefroblastoma o tumor de Wilms (TW) que se asocia con dos loci: 11p13 (WT1) y 11p15 (WT2 ó BWS), este último ligado también del síndrome de Beckwith-Wiedemann. Otros dos genes que parecen estar implicados son WT3 y WT4; además, dos anomalías específicas (adquisición 1q y deleción 22) se han correlacionado de manera independiente con un peor pronóstico en TW. Otras neoplasias con rearreglos cromosómicos, tales como los carcinomas renales (CRs), son mucho menos frecuentes en niños (entre el 1.8 y el 6.3% de todos los tumores renales malignos). Entre estos, se han identificado 'CRs con translocación' que afectan el locus Xp11, siendo los dos tipos más importantes t(X;1), y t(X;17). El nefroma mesoblástico congénito (NMC) es un tumor renal de recién nacidos y lactantes. Los NMCs de la variedad celular se caracterizan por una translocación específica t(12;15)(p13;q25), misma que se encuentra también en los fibrosarcomas congénitos extrarenales, y que permite establecer una correspondencia genética entre estos dos tumores (NMC y fibrosarcoma congénito). Los tumores rabdoides (TR) del riñón son neoplasias muy infrecuentes y muy agresivas, que aparecen con una edad promedio de 11 meses. Al menos 50% de los TRs muestran anormalidades en el gen hSNF5/INI1, situado en el locus 22q11.2. Este gen probablemente está involucrado en la modulación transcripcional de otros genes, tales como el oncogen c-Myc, y de la vía de transducción de la proteína RB-retinoblastoma

The pediatric kidney is a common site for tumors carrying specific chomosomal alterations. The most common of these is the nephroblastoma or Wilms tumor (WT), which is associated with anomalies in two loci: 11p13 and 11p15, the latter also linked to Beckwith-Wiedemann syndrome. Two other genes that seem to be implicated are WT3 and WT4. In addition, 1q gains or 22 deletions have been shown to independently be associated with a worst prognosis in WTs. Other neoplasms with chromosomal rearrangements, such as Renal Cell carcinomas (CRs) are much less frequent in children (between 1.8 and 6.3 % of all malignant renal tumors). Among these, the 'translocation renal carcinomas' have been identified involving the locus Xp11 with two main types of translocations: t(X;1), and t(X;17). Congenital mesoblastic nephroma (NMC) is a renal tumor affecting newborns and young infants. NMCs of the cellular type feature a specific translocation t(12;15)(p13;q25), which is also present in congenital fibrosarcomas outside of the kidney. These findings have led to conclude that these two tumors (NMC and congenital fibrosarcoma) are genetically equivalent. Rhabdoid tumors (TRs) of the kidney are very rare and aggressive neoplasms that appear with a mean age of 11 months. At least 50% of these TRs carry abnormalities in the hSNF5/INI1 gene, at 22q11.2. This gene is probably involved in transcriptional modulation of other genes such as the oncogene c-Myc, and also of the retinoblastoma protein RB signaling pathway

[Renal tumors of childhood and adolescence associated with chromosomal anomalies]. / Tumores renales de la infancia y adolescencia asociados a anomalías cromosómicas.

The pediatric kidney is a common site for tumors carrying specific chomosomal alterations. The most common of these is the nephroblastoma or Wilms tumor (WT), which is associated with anomalies in two loci: 11p13 and 11p15, the latter also linked to Beckwith-Wiedemann syndrome. Two other genes that seem to be implicated are WT3 and WT4. In addition, 1q gains or 22 deletions have been shown to independently be associated with a worst prognosis in WTs. Other neoplasms with chromosomal rearrangements, such as Renal Cell carcinomas (CRs) are much less frequent in children (between 1.8 and 6.3% of all malignant renal tumors). Among these, the "translocation renal carcinomas" have been identified involving the locus Xp11 with two main types of translocations: t(X;1), and t(X; 17). Congenital mesoblastic nephroma (NMC) is a renal tumor affecting newborns and young infants. NMCs of the cellular type feature a specific translocation t(12; 15)(p13;q25), which is also present in congenital fibrosarcomas outside of the kidney. These findings have led to conclude that these two tumors (NMC and congenital fibrosarcoma) are genetically equivalent. Rhabdoid tumors (TRs) of the kidney are very rare and aggressive neoplasms that appear with a mean age of 11 months. At least 50% of these TRs carry abnormalities in the hSNF5/INI1 gene, at 22q11.2. This gene is probably involved in transcriptional modulation of other genes such as the oncogene c-Myc, and also of the retinoblastoma protein RB signaling pathway.

Patterns of inflammation in mucosal biopsies of ulcerative colitis: perceived differences in pediatric populations are limited to children younger than 10 years.

The histologic criteria used to diagnose ulcerative colitis in colonic mucosal biopsies have been established for many years and include crypt architectural distortion, plasmacellular infiltrates, and neutrophils in the crypt epithelium and lumen. In several recent studies, it has been noted that colonic mucosal biopsies from children presenting with ulcerative colitis show fewer histologic abnormalities at initial presentation, especially less architectural distortion, than do biopsies from adults. In this study, colonic mucosal biopsies taken at the time of presentation of ulcerative colitis in 15 adults and 25 children were examined blindly by two pathologists. All biopsies were taken prior to the initiation of therapy. Twelve children were between 1 and 10 years of age, and 13 children were between the ages of 11 and 17 years. All patients had at least 1 year of follow-up, with clinical and pathologic confirmation of the diagnosis of ulcerative colitis. Five separate histologic features that are characteristic of ulcerative colitis were scored on mucosal biopsies. Children < or = 10 years of age had significantly less crypt branching, plasma cells in the lamina propria, cryptitis, crypt abscesses, and epithelial injury than adults (P values ranging from < 0.0001 to 0.0032). Children between the ages of 11 and 17 years had less cryptitis, crypt abscesses, and epithelial injury than adults (P values ranging from 0.0001 to 0.007) but similar degrees of crypt architectural distortion and plasma cell infiltrates. For all histologic features examined except epithelial injury, the significant findings were due to differences in biopsies taken proximal to the rectum. No significant differences in histology scores were found in rectal biopsies between any age group, except for epithelial injury, which was significantly less in children < or = 10 years. The findings show for the first time that the perceived differences between adults and children with ulcerative colitis are largely due to a decrease in histologic features of colitis in children less than 10 years of age. As children approach adulthood, the degree of inflammation and architectural distortion seen is similar to that found in adults. However, rectal biopsies show similar degrees of colitis in all age groups.

Identification of Pneumocystis carinii in the lungs of infants dying of sudden infant death syndrome.

BACKGROUND: Recently Pneumocystis carinii has been identified in a significant number of infants diagnosed as having died from sudden infant death syndrome (SIDS) in South America and Europe. METHODS: We examined lung sections of 79 infants who died with a diagnosis of SIDS in Rochester, NY, and Connecticut for the presence of P. carinii. RESULTS: Organisms with a characteristic silver stain appearance for P. carinii were identified in 14% of the lung sections. CONCLUSIONS: These data suggest that a possible link between some cases of SIDS and infection with P. carinii should be further evaluated and that infection of young infants may serve as an important reservoir for human P. carinii.

Truncated DCC reduces N-cadherin/catenin expression and calcium-dependent cell adhesion in neuroblastoma cells.

The deleted in colorectal cancer (DCC) protein is important in the pathway guidance of cells and cell processes during neural development, and DCC has also been implicated in the aberrant cellular migrations of neuroblastoma dissemination. We attempted to further define DCC protein function by the overexpression of full-length and truncated DCC constructs in a human neuroblastoma cell line. Overexpression of the truncated DCC protein resulted in a less epithelioid morphology. This was accompanied by decreases in expression of N-cadherin and alpha- and beta-catenin by immunoblot and Northern blot analysis. Levels of desmoglein were relatively less affected, whereas endogenous DCC protein levels were increased in the truncated transfectants. N-cadherin immunofluorescence was consistent with the immunoblot studies and localized the protein to the cytoplasm and sites of cell-cell contact. Cell aggregation studies demonstrated diminished calcium-dependent aggregation in the truncated transfectants. In conclusion, overexpression of a truncated DCC protein in neuroblastoma cells resulted in the loss of an epithelioid morphology, diminished expression of N-cadherin and alpha- and beta-catenin, and diminished calcium-dependent cell adhesion. These studies provide the first evidence of an apparent functional link between DCC and N-cadherin/catenin-dependent cell adhesion.

Bloom syndrome in sibs: first reports of hepatocellular carcinoma and Wilms tumor with documented anaplasia and nephrogenic rests.

The triad of small body size, immunodeficiency, and sun-sensitive facial erythema characterizes the phenotype Bloom syndrome (BS), a rare autosomal recessive disorder with a striking predisposition to multiple types of cancers that arise earlier than expected in the general population. Here we report two sibs with BS. The older, a 15-year-old-girl, developed a hepatocellular carcinoma, a neoplasm not yet reported in association with BS. Her younger brother developed an anaplastic Wilms tumor (WT) associated with nephrogenic rests at the age of 31/2 years, and this was followed by a myelodysplastic syndrome. Complex cytogenetic abnormalities were identified in all three neoplasms. These examples expand the spectrum of malignancies occurring in BS to include liver cell neoplasms, and confirm the association of nephrogenic rests with WT, even in the setting of BS.

Oxygen-induced vasodilation in pulmonary arterioles from fetal rats.

BACKGROUND: Oxygen is a potent stimulus for pulmonary vasodilation in the perinatal period. Little information is available regarding mediators of oxygen-induced pulmonary vasodilation in fetal rats. We have investigated the effect of blocking several proposed mediators of oxygen-induced vasodilation on the responses of isolated, third-generation pulmonary arterioles from term fetal rats to an increase in oxygen tension. MATERIALS AND METHODS: Third-generation pulmonary arterioles were isolated from fetal rats at term. Arterioles were preconstricted by suffusion with "hypoxic" (pO(2) 25-40 mm Hg) solution containing 40 mM KCl. The vasodilation induced by suffusion with "normoxic" (pO(2) 90-150 mm Hg) 40 mM KCl solution was recorded for control pulmonary arterioles and for arterioles pretreated with inhibitors of nitric oxide synthase and cyclooxygenase, and blockers of bradykinin receptors and purinergic receptors. Responses to oxygen suffusion were also recorded for pulmonary arterioles denuded of endothelium. RESULTS: Control arterioles dilated 113 +/- 28% of the potassium-induced preconstriction after 60 min of normoxic suffusion. Pretreatment with indomethacin completely blocked oxygen-induced vasodilation. Inhibitors of nitric oxide synthase, blockers of bradykinin and purinergic receptors, and removal of the endothelium did not significantly change normoxic vasodilation. CONCLUSIONS: Our results are most consistent with a vasodilator product of cyclooxygenase metabolism as a primary stimulus for oxygen-induced vasodilation in isolated, third-generation pulmonary arterioles from fetal rats.

Vascular aneurysm producing divided right atrium in a patient with pulmonary atresia and intact ventricular septum.

We describe a patient with pulmonary atresia and intact ventricular septum in whom the right atrium was divided by a vascular aneurysm located in the right atrioventricular groove. We postulate that the structure represents an aneursymally dilated right coronary artery taking anomalous origin from the pulmonary trunk, with fistulous communication to the right atrium. We discuss the findings relative to concepts of development of the coronary arteries in normal hearts and in pulmonary atresia with an intact ventricular septum.

Phosphaturic mesenchymal tumor-induced rickets.

We describe two prepubertal girls with oncogenic rickets. The first patient, 9 years of age, presented with recent-onset lower-extremity pain. The second girl, presented at 4 years of age following a 9-month period of muscle weakness, bone pain, and poor linear growth. Laboratory analyses in both patients revealed hypophosphatemia and hyperphosphaturia; elevated circulating alkaline phosphatase activity was present in one of them. Radiographic evidence of a generalized rachitic process was evident in both cases. Computerized tomography of the paranasal sinuses and facial bones in patient 1 revealed a small lesion eroding through the inner table of the left mandibular ramus. Microscopic examination of this mass revealed a spindle cell neoplasm with chondroid material, dystrophic calcification, and both osteoclast-like and fibroblast-like cells. Prominent vascularity and marked atypia were present. These features are consistent with a phosphaturic mesenchymal tumor of the mixed connective tissue variant. In the second patient, computerized tomography revealed a lytic lesion located in the right proximal tibia, with histologic features consistent with a phosphaturic mesenchymal tumor of the nonossifying fibroma-like variant. Resection of each tumor resulted in rapid correction of the phosphaturia and healing of the rachitic abnormalities. A careful search for small or occult tumors should be carried out in cases of acquired phosphaturic rickets.

Imaging of surgical diseases of the newborn chest. Intrapleural mass lesions.

Prenatal detection of intrapleural mass lesions is commonplace. Diagnostic treatment plans often are formulated before birth. The radiologist's involvement in dealing with congenital lobar emphysema, congenital cystic adenomatoid malformation, extralobar pulmonary sequestration, and congenital diaphragmatic hernia has changed. The need for immediate postnatal diagnosis has been de-emphasized, but the demand for precision and efficiency in preoperative cross-sectional imaging, monitoring progress and complications of treatment, and assistance with nutritional support has increased.

Renal tubular dysgenesis, absent nipples, and multiple malformations in three brothers: a new, lethal syndrome.

We report on three brothers with renal tubular dysgenesis and absent nipples, each also had other malformations including pre-auricular pits and a preauricular tag, branchial clefts, choanal atresia, pulmonary lobation anomaly, ventricular septal defect, type IIB interrupted aortic arch, absent gallbladder, absent thymus, parathyroid gland, accessory spleen, imperforate anus, clinodactyly, and broad digits and small nails. All three infants died neonatally. This pattern of clinical malformations appears to be a previously unreported syndrome.

IV ventricle astrocytomas in childhood: clinicopathological features in 21 cases.

The authors conducted a study of 21 children with benign astrocytomas in the IV ventricle treated with radical tumor resection from 1982 through 1991. The purposes of this study were to identify the tumor origin and neural involvement, and to determine the natural history following surgical resection. Pathological studies showed that 18 were pilocytic astrocytomas (pure pilocytic in 12, mixed in 6), 2 fibrillary, and 1 gemistocytic. In the IV ventricle, 12 patients had a transependymal involvement of the floor (brain stem), 6 had an involvement of the wall (cerebellar peduncle), and 3 had involvement of both floor and wall. A gross total resection was performed in 9 patients, and the remaining 12 patients underwent a subtotal resection. All patients were followed without radiation therapy (RT) or chemotherapy. During a follow-up period of 6.5-15 years, all patients were alive. Eight patients suffered recurrence between five months and 66 months after diagnosis. Of these, five received RT for recurrence and had a complete response in all cases. The remaining 13 patients showed no evidence of disease and one had a stable residual tumor. The recurrence-free 5-year and 10-year survival rates were 62.5% and 57% respectively. Patients without brainstem involvement, with total resection, or with pure pilocytic astrocytoma had a better outcome than those with brain stem involvement, with subtotal resection, or with nonpilocytic or mixed histology. In summary, a great majority of benign IV ventricle astrocytomas involve the floor of the IV ventricle. It is often difficult to determine the origin of these tumors in most cases. Benign IV ventricle astrocytomas may not recur even after incomplete resection, and close observation without RT is recommended, although RT appears to be effective for these tumors when they recur.

Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life.

OBJECTIVE: Fatty acid oxidation (FAO) disorders are frequently reported as the cause of sudden and unexpected death, but their postmortem recognition remains difficult. We have devised a biochemical protocol in which informative findings in liver tissue are microvesicular steatosis, elevated concentrations of C8-C16 fatty acids, glucose depletion, and low carnitine concentration. STUDY DESIGN: We analyzed 27 cases representing five FAO disorders and compared the results with those obtained in a retrospective blinded analysis of 418 cases of sudden infant death (313 SIDS, 45 infections, and 34 accidents and abuse). RESULTS: All cases of accidents and abuse correctly tested negative. Among the others, 25 (6%) showed at least two abnormal findings. Of these, 14 closely matched the biochemical profiles seen in specific FAO disorders. These included 2 cases with medium-chain acyl-CoA dehydrogenase deficiency, 4 cases consistent with glutaric acidemia type 2, 4 cases with either very long-chain acylcoenzyme A dehydrogenase deficiency or long-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency, and 4 cases predicted to be affected with carnitine uptake defect. CONCLUSION: The results of this study support the view that approximately 5% of all cases of sudden infant death are likely caused by an FAO disorder.

Status of deleted in colorectal cancer gene expression correlates with neuroblastoma metastasis.

Neuroblastoma is an embryonal tumor of neural crest origin noted for its heterogeneity at the clinical, histologic, and molecular levels. The deleted in colorectal cancer (DCC) protein is an adhesion family molecule of unequivocal importance in neural development that has also been implicated in several malignancies, including neuroblastoma, through its apparent loss of function. Immunohistochemical assessment of the DCC protein was performed on a group of 49 neuroblastoma specimens and examined in relation to important clinical, histologic, and molecular parameters. DCC expression was significantly associated with neuroblastoma dissemination as primary tumors from Stage 1 to 3 patients (15/20, 75%) more frequently exhibited the DCC protein than those from Stage 4 patients (5/13, 38%; p = 0.0415). Primary tumors were more frequently DCC-positive (20/33, 61%) as compared with metastatic deposits (3/16, 19%; p = 0.0063), and a single case of a paired primary and metastatic deposit demonstrated the apparent loss of DCC gene expression with tumor progression. The remaining five paired specimens were DCC-negative in both the primary tumor and metastatic deposit. No significant association was appreciated between DCC expression and patient age, the Shimada histologic classification, or N-Myc amplification. These results provide evidence that DCC expression may be lost in the course of metastatic spread in a subset of neuroblastomas. Moreover, DCC function is implicated in neuroblastoma dissemination in a manner independent of N-Myc.