The Prevalence and Clinical Impact of Transition Zone Anastomosis in Hirschsprung Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Hirschsprung disease (HD) is characterized by absent neuronal innervation of the distal colonic bowel wall and is surgically treated by removing the affected bowel segment via pull-through surgery (PT). Incomplete removal of the affected segment is called transition zone anastomosis (TZA). The current systematic review aims to provide a comprehensive overview of the prevalence and clinical impact of TZA. METHODS: Pubmed, Embase, Cinahl, and Web of Sciences were searched (last search: October 2020), and studies describing histopathological examination for TZA in patients with HD were included. Data were synthesized into aggregated Event Rates (ER) of TZA using random-effects meta-analysis. The clinical impact was defined in terms of obstructive defecation problems, enterocolitis, soiling, incontinence, and the need for additional surgical procedures. The quality of studies was assessed using the Newcastle-Ottawa Scale. KEY RESULTS: This systematic review included 34 studies, representing 2207 patients. After excluding series composed of only patients undergoing redo PT, the prevalence was 9% (ER = 0.09, 95% CI = 0.05-0.14, p < 0.001, I2 = 86%). TZA occurred more often after operation techniques other than Duhamel (X2 = 19.21, p = <0.001). Patients with TZA often had obstructive defecation problems (62%), enterocolitis (38%), soiling (28%), and fecal incontinence (24%) in follow-up periods ranging from 6 months to 13 years. Patients with TZA more often had persistent obstructive symptoms (X2 = 7.26, p = 0.007). CONCLUSIONS AND INFERENCES: TZA is associated with obstructive defecation problems and redo PT and is thus necessary to prevent.

Diagnosing Hirschsprung Disease in Children Younger than 6 Months of Age: Insights in Incidence of Complications of Rectal Suction Biopsy and Other Final Diagnoses.

BACKGROUND: The gold standard for diagnosing Hirschsprung disease (HD) in patients younger than 6 months is pathological examination of rectal suction biopsy (RSB). The aim of this study was to gain insight into the following: (1) complications following RSB, (2) final diagnosis of patients referred for RSB, and (3) factors associated with HD. METHODS: Patients suspected of HD referred for RSB at our center were analyzed retrospectively. Severity of complications of RSB was assessed using Clavien-Dindo (CD) grading. Factors associated with HD were tested using multivariate logistic regression analysis. RESULTS: From 2000 to 2021, 371 patients underwent RSB because of infrequent defecation, at a median age of 44 days. Three patients developed ongoing rectal bleeding (0.8%) graded CD1. Most frequent final diagnoses were: HD (n = 151, 40.7%), functional constipation (n = 113, 31%), idiopathic meconium ileus (n = 11, 3%), and food intolerance (n = 11, 3%). Associated factors for HD were male sex (odds ratio [OR], 3.19; confidence interval [CI], 1.56-6.53), presence of syndrome (OR, 7.18; CI, 1.63-31.69), younger age at time of RSB (OR, 0.98; CI, 0.85-0.98), meconium passage for more than 48 hours (OR, 3.15; CI, 1.51-6.56), distended abdomen (OR, 2.09; CI, 1.07-4.07), bilious vomiting (OR, 6.39; CI, 3.28-12.47), and failure to thrive (OR, 8.46; CI, 2.11-34.02) (model R 2 = 0.566). CONCLUSION: RSB is a safe procedure with few and only minor complications. In the majority of patients referred for RSB under the age of 6 months, HD was found followed by a functional cause for the defecation problems. RSB should be obtained on a low threshold in all patients under the age of 6 months with the suspicion of HD.

Placental pathology in cancer during pregnancy and after cancer treatment exposure.

Cancer during pregnancy has been associated with (pathologically) small for gestational age offspring, especially after exposure to chemotherapy in utero. These infants are most likely growth restricted, but sonographic results are often lacking. In view of the paucity of data on underlying pathophysiological mechanisms, the objective was to summarize all studies investigating placental pathology related to cancer(treatment). A systematic search in PubMed/Medline, Embase (OVID) and SCOPUS was conducted to retrieve all studies about placental pathology in cancer during pregnancy or after cancer treatment, published until August 2020. The literature search yielded 5784 unique publications, of which 111 were eligible for inclusion. Among them, three groups of placental pathology were distinguished. First, various histopathologic changes including maternal vascular malperfusion have been reported in pregnancies complicated by cancer and after cancer treatment exposure, which were not specific to type of cancer(treatment). Second, cancer(treatment) has been associated with placental cellular pathology including increased oxidative damage and apoptosis, impaired angiogenesis and genotoxicity. Finally, involvement of the placenta by cancer cells has been described, involving both the intervillous space and rarely villous invasion, with such fetuses are at risk of having metastases. In conclusion, growth restriction is often observed in pregnancies complicated by cancer and its cause can be multifactorial. Placental histopathologic changes, cellular pathology and genotoxicity caused by the cancer(treatment) may each play a role.

Objectifying grade in Ta-T1 urothelial carcinomas of the bladder using proliferative and quantitative markers: A multicentre study in 310 bladder tumors.

PURPOSE: Histological grade is an important prognostic factor in patients with non-muscle-invasive bladder cancer (NMIBC). However, interobserver variability is high. Previous studies have suggested that quantification of histological features is useful to objectify grading. We evaluated whether quantification of the mean nuclear area of the 10 largest nuclei (MNA-10), degree of aneuploidy (DNA index or DI) and mitotic activity index (MAI) are of diagnostic value for NMIBC grade. Additionally, prognostic value of the 3 measures was assessed. MATERIAL AND METHODS: A consensus grade was determined by 3 uropathologists in 310 NMIBC tissues according to the World Health Organization (WHO) 1973 and the WHO2004. Logistic regression with forward selection was used to determine the optimal combination of measures (MNA-10, DI, and MAI) to diagnose grade 3 (G3) or high-grade (HG) NMIBC (WHO1973 and WHO2004, respectively). RESULTS: In 310 tumors of 215 patients at least 1 of the measures (MNA-10, DI, or MAI) had been determined. The combination of MNA-10 and MAI was selected as the most diagnostic combination and resulted in a sensitivity of 94% (95% confidence interval [CI]: 87-100) at a specificity of 72% (95% CI: 66-78) for G3 tumors. For the diagnosis of HG tumors sensitivity was 92% (95% CI: 86-97) at a specificity of 76% (95% CI: 70-93). CONCLUSIONS: Determination of MNA-10 and MAI is promising for diagnosing G3 and HG bladder tumors. These findings warrant further studies on the diagnostic and prognostic value of proliferative and quantitative features in bladder cancer patients.

WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.

BACKGROUND: Heterozygous missense mutations in the WT1 gene that affect the function of the wild-type allele have been identified in Denys-Drash syndrome, which is characterized by severe gonadal dysgenesis, early-onset nephropathy and a predisposition to renal and gonadal cancer. Intron 9 splice-site mutations that influence the balance between WT1 isoforms cause a nearly similar phenotype, known as Frasier syndrome. Nonsense mutations and deletions only lead to WT1 haploinsufficiency and, hence, to less severe gonadal dysgenesis and late-onset nephropathy. WT1 analysis is mandatory in 46,XY gonadal dysgenesis with renal abnormality. PATIENT: We describe a newborn with 46,XY severe partial gonadal dysgenesis, in whom structural renal anomalies and proteinuria were excluded. Gonadectomy was performed at the age of 1 month and the microscopy was thought to be suggestive for a gonadoblastoma. At the age of 9 months, the patient presented with a bilateral Wilms tumor. RESULTS: We found a heterozygous WT1 whole-gene deletion but no other gene defects. CONCLUSIONS: This case description illustrates that a WT1 deletion might be associated with a more severe phenotype than previously thought. It also illustrates that, even in the absence of renal abnormality, it is recommended to test promptly for WT1 defects in 46,XY gonadal dysgenesis.

Proper genomic profiling of (BRCA1-mutated) basal-like breast carcinomas requires prior removal of tumor infiltrating lymphocytes.

INTRODUCTION: BRCA1-mutated breast carcinomas may have distinct biological features, suggesting the involvement of specific oncogenic pathways in tumor development. The identification of genomic aberrations characteristic for BRCA1-mutated breast carcinomas could lead to a better understanding of BRCA1-associated oncogenic events and could prove valuable in clinical testing for BRCA1-involvement in patients. METHODS: For this purpose, genomic and gene expression profiles of basal-like BRCA1-mutated breast tumors (n = 27) were compared with basal-like familial BRCAX (non-BRCA1/2/CHEK2*1100delC) tumors (n = 14) in a familial cohort of 120 breast carcinomas. RESULTS: Genome wide copy number profiles of the BRCA1-mutated breast carcinomas in our data appeared heterogeneous. Gene expression analyses identified varying amounts of tumor infiltrating lymphocytes (TILs) as a major cause for this heterogeneity. Indeed, selecting tumors with relative low amounts of TILs, resulted in the identification of three known but also five previously unrecognized BRCA1-associated copy number aberrations. Moreover, these aberrations occurred with high frequencies in the BRCA1-mutated tumor samples. Using these regions it was possible to discriminate BRCA1-mutated from BRCAX breast carcinomas, and they were validated in two independent cohorts. To further substantiate our findings, we used flow cytometry to isolate cancer cells from formalin-fixed, paraffin-embedded, BRCA1-mutated triple negative breast carcinomas with estimated TIL percentages of 40% and higher. Genomic profiles of sorted and unsorted fractions were compared by shallow whole genome sequencing and confirm our findings. CONCLUSION: This study shows that genomic profiling of in particular basal-like, and thus BRCA1-mutated, breast carcinomas is severely affected by the presence of high numbers of TILs. Previous reports on genomic profiling of BRCA1-mutated breast carcinomas have largely neglected this. Therefore, our findings have direct consequences on the interpretation of published genomic data. Also, these findings could prove valuable in light of currently used genomic tools for assessing BRCA1-involvement in breast cancer patients and pathogenicity assessment of BRCA1 variants of unknown significance. The BRCA1-associated genomic aberrations identified in this study provide possible leads to a better understanding of BRCA1-associated oncogenesis.

[A boy with cervical focal myositis]. / Een jongen met focale myositis in de hals.

BACKGROUND: Focal myositis is a rare idiopathic pseudotumour that mostly occurs in the extremities in adults. CASE DESCRIPTION: An 8-year-old boy presented with a few months history of swelling in the neck and fever. Ultrasound investigation revealed an inhomogenous mass consistent with lymphadenitis. After nine days of antibiotic therapy, the clinical picture of fever and swelling was unchanged. MRI imaging revealed continuity of the swelling in the sternocleidomastoid muscle and a malignant process was suspected. Microscopy showed no malignant cells, however, but a lymphoplasmocytic infiltration with fibrosis and degeneration of muscle fibres, consistent with focal myositis. No intervention was undertaken and one year after presentation the tumour had regressed almost entirely. CONCLUSION: Focal myositis can present as a cervical tumour. On ultrasound, the condition is hard to distinguish from lymphadenopathy or malignancy. In cases of insufficient response to empirical antibiotic therapy, focal myositis should be considered.

Eosinophilic esophagitis after esophageal atresia: is there an association? Case presentation and literature review.

Eosinophilic esophagitis (EoE) is a relatively new condition resulting in dysphagia or symptoms resembling gastroesophageal reflux disease, symptoms that also are common in patients with a history of esophageal atresia. We present 2 patients with persistent dysphagia after repair of esophageal atresia that was caused by EoE. Although the exact etiology and pathogenesis of EoE remain unclear, it is now generally accepted that it is the result of a T-helper cell 2-type immune response with a crucial role for the eosinophil-specific chemotaxis factor eotaxin 3 and eosinophils. Because there are genetic similarities between esophageal atresia and EoE, we speculate that patients with esophageal atresia are at increased risk for developing EoE.

Unraveling pathology in juvenile Alexander disease: serial quantitative MR imaging and spectroscopy of white matter.

INTRODUCTION: Alexander disease is a rare disorder of the central nervous system with characteristic symmetric white matter abnormalities with frontal predominance on magnetic resonance (MR) images. Histopathology shows a lack of myelin in the affected white matter, variably interpreted as hypomyelination or demyelination. To increase our insight into the nature of the pathology leading to the MR imaging findings in Alexander disease, we applied serial MR imaging, spectroscopy, magnetization transfer (MT) imaging (MTI), and diffusion tensor imaging (DTI) in six patients with juvenile Alexander disease. METHODS: The MR imaging protocol comprised T1- and T2-weighted spin echo images and fluid-attenuated inversion recovery images. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), and MT ratio (MTR) maps were generated, and MR spectroscopy concentrations were quantified for several metabolites. RESULTS: MR imaging showed similar cerebral white matter abnormalities in all patients, with only minor increase on prolonged follow-up, despite sometimes serious clinical progression. MR spectroscopy showed highly elevated levels of myo-inositol, lactate, and choline-containing compounds and decreased total N-acetyl-aspartate and N-acetyl-aspartyl-glutamate levels in the abnormal white matter. High values of ADC were observed, and both FA and MTR were attenuated. CONCLUSION: The sequential MR imaging findings in Alexander disease provide strong evidence against active demyelination as sole explanation for the underlying pathology. An alternative explanation for our spectroscopic, DTI, and MTI findings-which would suggest demyelination-could be hyperplasia and hypertrophy of astrocytes, as seen in low grade gliomas.

A comparative morphologic analysis of adult onset leukodystrophy with neuroaxonal spheroids and pigmented glia--a role for oxidative damage.

We performed a blinded study on 5 cases of hereditary diffuse leukoencephalopathy with spheroids and 10 cases of the pigmentary type of orthochromatic leukodystrophy, 6 of the latter having a family history of neurologic illness. Patients presented in the third to sixth decade with behavioral, cognitive, and motor symptoms. All cases displayed widespread myelin loss, predominantly frontotemporal with relative sparing of subcortical U-fibers, and variable numbers of both neuroaxonal spheroids and pigmented glia. Immunohistochemically, spheroids contained amyloid precursor/neurofilament proteins, several neurotransmitters or neuropeptides, and ubiquitin. Cytoplasmic inclusions in glia and numerous pigmented macrophages were autofluorescent and stained consistently with diastase-periodic acid-Schiff, prolonged Ziehl-Nielsen, and Sudan black, but the same cells labeled inconsistently for iron or ferritin. Ultrastructurally, the most characteristic autofluorescent glial lipopigments consisted of bosselated masses of granular, electron-dense material. These morphologic features are those of ceroid, an end-product of oxidative damage. Glial immunoreactivity for markers of oxidative stress (hemeoxygenase-1 and superoxide dismutase 2) and damage (4-hydroxynonenal, malondialdehyde, and nitrotyrosine) was noted, particularly in cases with increased iron and ferritin. These data support the hypothesis that the similar clinicopathologic features of hereditary diffuse leukoencephalopathy with spheroids and the pigmentary type of orthochromatic leukodystrophy reflect a common disease due, at least in part, to an oxidative insult.

Childhood white matter disorders: quantitative MR imaging and spectroscopy.

PURPOSE: To prospectively investigate whether quantitative magnetic resonance (MR) parameters, including magnetization transfer ratio (MTR), apparent diffusion coefficient (ADC), fractional anisotropy (FA), and MR spectroscopic metabolite concentrations, allow for discrimination between different types of pathologic conditions that underlie signal intensity abnormalities in white matter. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Forty-one patients (19 male, 22 female; mean age, 15.4 years) and 41 control subjects (25 male, 16 female; mean age, 11.3 years) were included. Twelve patients had a hypomyelinating disorder; 14, a demyelinating disorder; five, a disorder characterized by myelin vacuolation; and 10, a disorder characterized by cystic degeneration. Regions of interest were selected within the parietal white matter and were transferred to the corresponding sections of the generated ADC, FA, and MTR maps to extract quantitative measurements. Linear discriminant analysis and univariate analysis of covariance were used for statistical evaluation. RESULTS: Linear discriminant analysis showed that 95% of patients were correctly classified by using total creatine, choline-containing compounds, myo-inositol, MTR, and ADC. In the hypomyelination group, all MR parameters were close to normal, with the exception of elevated total creatine (P = .03) and myo-inositol (P < .001) levels and decreased MTR values (P < .001). In the demyelination group, the levels of choline-containing compounds (P = .02) and myo-inositol (P < .001) were highly elevated. In the myelin vacuolation and cystic degeneration groups, high ADC values (P < .001) and variable decreases in all MR spectroscopic metabolites were seen. MTR was significantly reduced (P < .001) in the cystic degeneration group. CONCLUSION: Quantitative MR techniques can be used to discriminate between different types of white matter disorders and to classify white matter lesions of unknown origin with respect to underlying pathologic conditions.

The unfolded protein response in vanishing white matter disease.

Leukoencephalopathy with vanishing white matter (VWM) is an autosomal-recessive disorder in which febrile infections may provoke major neurologic deterioration. Characteristic pathologic findings include cystic white matter degeneration, foamy oligodendrocytes, dysmorphic astrocytes and oligodendrocytes, oligodendrocytosis, and apoptotic losses of oligodendrocytes. VWM is caused by mutations in eukaryotic initiation factor (eIF) 2B (eIF2B). eIF2B plays an important role in the regulation of protein synthesis. Mutant eIF2B may impair the ability of cells to regulate protein synthesis in response to stress and perhaps even under normal conditions. An overload of misfolded proteins in the endoplasmic reticulum activates the unfolded protein response (UPR), a compensatory mechanism that inhibits synthesis of new proteins and induces both prosurvival and proapoptotic signals. We have studied the activation of the UPR in VWM through the immunohistochemical expression of its upstream components PERK and phosphorylated eIF2alpha (eIF2alphaP) and combined immunohistochemical and Western blot analysis of the downstream effector proteins activating transcription factor-4 (ATF4) and C/EBP homologous protein (CHOP) in 4 VWM brains and 3 age-matched controls. We demonstrate activation of the UPR in glia of patients with VWM. Our findings may point to a possible explanation for the dysmorphic glia, the increased numbers of oligodendrocytes, and the apoptotic loss of oligodendrocytes in VWM.