Safety and Efficacy of 177 Lu-DOTATATE in Children and Young Adult Population : A Single-Center Experience.

PURPOSE: This single-center retrospective study explores the safety and efficacy of 177 Lu-DOTATATE in children and young adult population with metastatic/inoperable neuroendocrine tumors (NETs). PATIENTS AND METHODS: This study is a retrospective analysis of all children and young adult patients (≤29 years) with advanced inoperable/metastatic epithelial or nonepithelial NETs who were administered a median of 4 cycles of 177 Lu-DOTATATE therapy and low-dose oral capecitabine as a radiosensitizer every 8-12 weeks, except 2 patients who received CAPTEM chemotherapy. The radiological response was assessed using RECIST 1.1 on interim and end-of-treatment 68 Ga-DOTANOC PET/CT. The primary endpoint was objective response rate, whereas disease control rate, toxicity profile, progression-free survival, and overall survival were secondary endpoints. RESULTS: Nineteen biopsy-proven NET patients (median age, 22 ± 10 years) with 8 of them adolescents (10-18 years) and the remaining young adults (19-29 years) were included. Fourteen patients had gastroenteropancreatic neuroendocrine tumor (pancreas being most common primary site), whereas the rest had non-gastroenteropancreatic neuroendocrine tumor. A total of 65 cycles of 177 Lu-DOTATATE (range, 1-6 cycles) were administered with a median cumulative activity of 600 mCi (range, 100-1000 mCi). The objective response rate and disease control rate were 41% and 94%, respectively. Grade 1 and 2 adverse events were observed in 14 (74%) and 5 (26%) of 19 patients, respectively. In a total of 8 events (42%), 4 events each of disease progression and death occurred during a median follow-up of 80.1 months with an estimated 5-year progression-free survival and overall survival of 54% (95% confidence interval, 30-78) and 63% (95% confidence interval, 39-87), respectively. CONCLUSIONS: 177 Lu-DOTATATE appears safe and effective in children and young adults with metastatic/inoperable NETs. Large prospective trials are required to validate these results.

Carnitine-acylcarnitine translocase deficiency: a case report with autopsy.

Fatty acid oxidation defects are a heterogeneous group of disorders related to the mitochondrial fatty acid oxidation pathway. Carnitine acylcarnitine translocase (CACT) is an enzyme responsible for the unidirectional transport of acylcarnitine across the inner mitochondrial membrane. This enzyme plays a crucial role in the oxidation of fatty acids. The autopsy pathology of the CACT deficiency is described in only a few cases. We describe the autopsy pathology of a child with CACT deficiency dominantly in the form of microvesicular steatosis of the hepatocytes, renal proximal tubular epithelia, cardiac myocytes, and rhabdomyocytes. The diagnosis was further confirmed on whole exome sequencing with compound heterozygous variants in the exon 1 (c.82G>T, p.Gly28Cys; likely pathogenic) and exon 5 (c.535G>A, p.Asp179Asn; uncertain significance) of the SLC25A20 gene. This case elucidates the histopathology of the liver and the detailed autopsy of a case of CACT deficiency from India.

Hyaline cartilage at the portal plate and gallbladder in biliary atresia.

Biliary atresia (BA) is a fibro-obliterative cholestatic disease of infancy. The presence of cartilage in the resected tissue is an uncommon finding. We documented the presence of both mature and immature hyaline cartilage in the portal plate and the wall of the gallbladder in a 2-month-old girl infant with BA who had undergone Kasai portoenterostomy. The presence of cartilage could be part of a heterotopia or an uncommon connective tissue metaplasia. The presence of immature cartilage with the merging of the perichondrium with the soft tissue highlights a metaplastic etiology in the index case.

Neoadjuvant Peptide Receptor Radionuclide Therapy in a Rare Case of Pediatric Primary Hepatic Gastrinoma.

ABSTRACT: Gastrinomas with predilection for the adult male population are located in the gastrinoma triangle (>90%). Primary hepatic gastrinoma especially in pediatric population is very rare. Peptide receptor radionuclide therapy has shown benefit in metastatic gastroenteropancreatic neuroendocrine tumors (NETs) with an increasing interest in expanding its role as neoadjuvant treatment modality to improve the surgical candidature in inoperable NETs. There is currently no literature supporting its role in the pediatric NET patients. We present a rare case of a young boy with primary hepatic gastrinoma where 177Lu-based peptide receptor radionuclide therapy in the neoadjuvant setting contributed to his final disease-free status.

Hyaline cartilage at the portal plate and gallbladder in biliary atresia

ABSTRACT Biliary atresia (BA) is a fibro-obliterative cholestatic disease of infancy. The presence of cartilage in the resected tissue is an uncommon finding. We documented the presence of both mature and immature hyaline cartilage in the portal plate and the wall of the gallbladder in a 2-month-old girl infant with BA who had undergone Kasai portoenterostomy. The presence of cartilage could be part of a heterotopia or an uncommon connective tissue metaplasia. The presence of immature cartilage with the merging of the perichondrium with the soft tissue highlights a metaplastic etiology in the index case.

Carnitine-acylcarnitine translocase deficiency: a case report with autopsy

ABSTRACT Fatty acid oxidation defects are a heterogeneous group of disorders related to the mitochondrial fatty acid oxidation pathway. Carnitine acylcarnitine translocase (CACT) is an enzyme responsible for the unidirectional transport of acylcarnitine across the inner mitochondrial membrane. This enzyme plays a crucial role in the oxidation of fatty acids. The autopsy pathology of the CACT deficiency is described in only a few cases. We describe the autopsy pathology of a child with CACT deficiency dominantly in the form of microvesicular steatosis of the hepatocytes, renal proximal tubular epithelia, cardiac myocytes, and rhabdomyocytes. The diagnosis was further confirmed on whole exome sequencing with compound heterozygous variants in the exon 1 (c.82G>T, p.Gly28Cys; likely pathogenic) and exon 5 (c.535G>A, p.Asp179Asn; uncertain significance) of the SLC25A20 gene. This case elucidates the histopathology of the liver and the detailed autopsy of a case of CACT deficiency from India.

Granulocyte colony stimulating factor in decompensated cirrhosis, acute alcoholic hepatitis, and acute-on-chronic liver failure: A comprehensive meta-analysis of randomized controlled trials.

BACKGROUND: GCSF may improve the prognosis of severe liver disease by promoting liver regeneration and immune restoration. Our Aim was to investigate its controversial efficacy in decompensated cirrhosis, acute alcoholic hepatitis (AAH), or acute-on-chronic liver failure (ACLF) through meta-analysis. METHODS: Meta-analysis of proportions (random effect model) including 19 RCTs (1287 patients from 16 Asian and 3 European studies including 487 ACLF, 231 AAH and 569 cirrhotic patients) evaluating survival at day-28, day-90, 6 months, one year, and/or occurrence of sepsis as major outcomes. RESULTS: In patients with decompensated cirrhosis, G-CSF administration was associated with a reduction in the weight-adjusted risk of mortality of 9% at day-90 (OR=0.33; 95%CI: 0.18-0.58; p = 0.0002), 16% at 6 months (OR=0.31; 95%CI: 0.15-0.62; p = 0.0009), 26% at one year (OR=0.21; 95%CI:0.12-0.38, p<0.0001) and a weight-adjusted 28% risk reduction for sepsis (OR=0.28; 95%CI: 0.16-0.49; p<0.0001). Only Asian studies were positive. In AAH, G-CSF was associated with an 18% reduction in weight-adjusted mortality risk at day-28 (OR=0.31; 95%CI:0.11-0.83, p = 0.021), 32% at day-90 (OR=0.20; 95%CI:0.09-0.46, p<0.0001) and a weight-adjusted 42% risk reduction for sepsis (OR=0.17; 95%CI: 0.08-0.38; p<0.0001). Only Asian studies, in which corticosteroids were not given systematically in case of severe AAH, were positive. In patients with ACLF, the results on mortality at day-28 were heterogeneous, and GCSF had no beneficial effect on sepsis or survival at day-90. CONCLUSION: G-CSF may be effective in patients with decompensated cirrhosis or AAH by reducing the occurrence of sepsis and mortality. Further meta-analyses of individual data, or new, powerful and methodologically flawless therapeutic trials, are warranted to confirm these results, which harbor wide divergences between Asian and European RCTs.

A Randomized Control Trial to Evaluate the Effect of Local Instillation of Mitomycin-C at the Porta after Kasai Portoenterostomy in Patients of Biliary Atresia.

Background: Kasai portoenterostomy (KPE) is the initial treatment for biliary atresia (BA). Even after initial jaundice clearance, a significant number of children presented with the reappearance of symptoms due to ongoing fibrosis involving porta and intrahepatic ducts. Mitomycin-C (MMC) is an antifibrotic agent, and the study hypothesized that local application of MMC at porta can decrease fibrosis, which can improve jaundice clearance and lead to better native liver survival (NLS). Materials and Methods: This prospective randomized control trial included children with BA, who were allocated to groups A or B. The patients in both groups underwent standard KPE; in addition, a 5 French infant feeding tube (IFT) was placed near the porta through the Roux limb in Group B children. During the postoperative period, MMC was locally instilled over the porta in Group B children through IFT. Postoperative jaundice clearance and NLS were assessed and compared. Results: A total of 27 children were enrolled in the study, 16 in Group A and 11 in Group B. Both groups were comparable preoperatively. Although the NLS was not statistically significant in Group B, the survival was quite higher, that was 91%, 81%, and 73% at 6 months, 1 year, and 2 years, respectively, compared to 63%, 50%, and 38% in Group A. Conclusion: Children in Group B clinically showed an early jaundice clearance and a better trend of serial bilirubin levels as well as longer NLS than Group A, but it was not statistically significant. The procedure was technically easy, and no complication was encountered related to surgical technique or MMC instillation.

Clinical spectrum & changing presentation of celiac disease in Indian children.

Background & objectives: Celiac disease (CD) is a genetic immune mediated disorder characterised by gluten intolerance. This single centre study, from north India was aimed to assess the clinical, serological and histological profile of CD in a large cohort of children and the changing trends in its presentation. Methods: A review of clinical details of CD children diagnosed between 2000 and 2019 and currently on follow up was performed. Information on demography, symptoms, associated conditions, serology, biopsy findings and gluten-free diet were analyzed. Results: The mean age (±standard deviation) of 891 children included in the study, at onset and at diagnosis was 4.0±2.7 and 6.2±3.1 yr, respectively. Growth faltering, abdominal pain, abdominal distension and diarrhoea were presenting symptoms in 70, 64.2, 61.2 and 58.2 per cent, respectively. A positive family history of CD was present in 14 per cent and autoimmune conditions in 12.3 per cent of children. Thyroid disorders were seen in 8.5 per cent of children and Type 1 diabetes mellitus (T1DM) in 5.7 per cent. The duration of breastfeeding had a weak positive correlation with age at onset and diagnosis of CD (P<0.001). Non-classical CD was significantly more common in children aged >10 yr and in those presenting after 2010 (P<0.01). T1DM and hypothyroidism occurred more frequently in non-compliant children. Interpretation & conclusions: This was the largest single centre study, pertaining to the presentation and follow up of CD in children. Infants and young children were more likely to present with classical symptoms of diarrhoea, abdominal distension and growth failure while older children presented with non-classical CD. There was a trend towards non-classical forms of CD in recent years.

Usefulness of a double immunofluorescence technique for detection of intestinal tTG-IgA deposits in diabetic and non-diabetic children with celiac disease.

BACKGROUND: Celiac disease (CD) is frequently associated with type I diabetes mellitus (T1D), where its diagnosis may be a challenging task. This study aims to test the usefulness of the double staining immunofluorescence (dsIF) technique for the detection of intestinal anti-tissue transglutaminase specific IgA antibody (tTG-IgA) deposits in CD and T1D children with coexisting CD. METHODS: A total of 46 patients (30 cases of CD and 16 cases of T1D with CD) and 16 non-diabetic, non-celiac children were recruited. Endoscopic biopsies were taken and analyzed by light microscopy, quantitative histology (QH), and a dsIF technique. RESULTS: Histologically, villous atrophy was most severe in CD, followed by T1D with CD, while all control biopsies except 1 were normal. QH showed a statistically significant difference in villous height (Vh), crypt depth (CrD), and Vh:CrD ratio between diabetic and non-diabetic patients with CD. dsIF technique could detect tTG-IgA deposits in 85.7% of cases of CD alone and 93.8% of biopsies from diabetic children. Surprisingly, deposits were more extensive in biopsies with minimal villous shortening. Also, all 5 biopsies from T1D patients with normal histology were dsIF positive. CONCLUSION: In-situ analysis of tTG-IgA immune deposits facilitates the detection of positive serology early-onset CD. Quantitative analysis may be used as an ancillary tool to increase the reliability of histological findings in these patients.

Utility of the New Faster Compressed SENSE MRCP at 3 Tesla MRI in Children with Pancreatitis.

OBJECTIVE: To compare the acquisition time, diagnostic efficacy, and image quality of the newer compressed SENSE 3D MRCP (CS-3D MRCP) with conventional 3D MRCP (C-3D MRCP) in children with pancreatitis. METHODS: A total of 24 children (2-17 y) diagnosed with pancreatitis were included in this study. The children underwent CS-3D MRCP and C-3D MRCP sequences. C-3D MRCP and CS-3D MRCP images were evaluated for the acquisition time duration, visualization of the pancreaticobiliary ducts, background suppression, image quality degradation by artifacts, and overall image quality by the two radiologists independently. Paired sample t-test was used to compare the acquisition time, the McNemar test for the image quality features, and the kappa coefficient was used for interobserver agreement. RESULTS: A two-fold decrease in the acquisition time of CS-3D MRCP (~148 ± 61 s) was seen, compared to C-3D MRCP (~310 ± 98 s), p < 0.001. The median scores for overall image quality on CS-3D MRCP and C-3D MRCP, respectively, were 2.05 ± 0.52 and 2.21 ± 0.53 (p = 0.18) for both radiologists. No significant difference was seen for the visibility of ducts, background suppression, and artifacts between the two radiologists, with substantial to almost perfect agreement seen for the different findings. CONCLUSION: The application of compressed SENSE 3D MRCP in children with pancreatitis results in a two-fold reduction in acquisition time with acceptable image quality. This may help in reducing the need for long sedation in children requiring anesthesia support for the MRCP and potentially help in reducing motion artifacts.

Role of Serology, Dietary Assessment, and Fecal Gluten Immunogenic Peptides for Predicting Histologic Recovery in Children with Celiac Disease.

BACKGROUND: A strict lifelong gluten-free diet (GFD) remains the only treatment of celiac disease (CD). Adherence to gluten-free diet is best reflected by mucosal healing. Noninvasive tools capable of predicting mucosal recovery in CD patients need to be identified. AIMS: To compare the ability of various modalities used to assess compliance to GFD, for predicting persistent mucosal damage in children with CD. METHODS: A prospective, single-center, observational study on children with CD on a GFD was conducted between January 2020 and April 2021. Children with CD on GFD were consecutively enrolled and various modalities used to assess adherence to GFD were compared. RESULTS: One hundred and fifty children (Mean age 12.2 ± 3.6 years, 58% Boys) on GFD (Mean duration 6 ± 3.1 years) were enrolled in the study. Persistent mucosal damage was seen in 88% of the enrolled. Fecal gluten immunogenic peptide (GIP) was positive in 87.8% (129/147). Antibodies to tissue transglutaminase (TGA-IgA) and/or deamidated gliadin peptide (DGP) were positive in 32% (48/150) whereas antibody to synthetic neoepitopes of TGA-IgA was positive in 24.8% (37/149). Non-compliance as assessed by local questionnaire, Biagi score, and dietitian detailed interview were 62.7%, 60%, and 75.3%, respectively. Serology had the highest specificity (83%) and fecal GIP had the highest sensitivity (89%). On logistic regression analysis, only non-compliance by Biagi score predicted poor mucosal recovery. CONCLUSION: Fecal GIP may be sensitive to detect only "one-point dietary transgression." None of the existing modalities used to assess compliance to GFD accurately predict persistent mucosal damage. A subset of patients may develop gluten tolerance.

Efficacy of Oral Psyllium in Pediatric Irritable Bowel Syndrome: A Double-Blind Randomized Control Trial.

OBJECTIVE: Pediatric irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder with variable response to various therapeutic agents. Psyllium has been proven to be effective in adults; however, there is no study in children. The objective of this study is to evaluate the efficacy of psyllium husk as compared to placebo in pediatric IBS patients. METHODS: In this double-blind randomized controlled trial, 43 children were assigned to psyllium arm (Group A) and 38 into placebo arm (Group B). Severity is assessed at baseline and after 4 weeks of treatment using IBS severity scoring scale (IBS-SSS) and classified into mild, moderate, and severe categories. Categorical data was compared with chi-square test and paired categorical variable was compared with McNemer test. RESULTS: Mean ages (±SD; in years) of Groups A and B were 9.87 (2.7) and 9.82 (3.17), respectively, with median duration of illness of 12 months. At baseline, type, severity, and parameters (IBS-SSS) of IBS were equally distributed in 2 groups. There was a significant reduction in median interquartile range (IQR) of total IBS-SSS in psyllium versus placebo [75 (42.5-140) vs 225 (185-270); P < 0.001] at 4 weeks. Similarly 43.9% in Group A versus 9.7% in Group B attained remission [IBS-SSS < 75 ( P < 0.0001)]. The mean difference in IBS-SSS between Group A and Group B was -122.85 with risk ratio of 0.64 (95% CI; 0.42-0.83; P = 0.001) and absolute risk reduction of 32% (NNT = 3). CONCLUSIONS: Psyllium husk is effective for the therapy of pediatric IBS when compared with placebo in short term.

Successful surgical management of cardiac tamponade following direct intrahepatic portosystemic shunt in a child with Budd-Chiari syndrome: A potentially life-threatening situation.

Direct intrahepatic portosystemic shunt is a technique of portocaval shunting performed through the percutaneous route in patients with Budd-Chiari syndrome. Stent migration into right-sided heart chambers or perforations causing hemopericardium and cardiac tamponade is rare and underreported. In a child with a coexisting decompensated liver disease, surgical intervention and cardiopulmonary bypass can be challenging. However, surgical management in these life-threatening situations is better than redo interventions.

Unusual manifestations of Peutz-Jegher's syndrome in children.

PeutzJegher's syndrome (PJS) is a rare, autosomal dominant disease, characterized by gastrointestinal (GI) polyps and perioral hyperpigmentation along with the increased risk of certain malignancies. In children, the most common presentation is recurrent intussusception due to polyps. These polyps can involve any part of the GI tract and can present with a variety of clinical presentations. Usually, these polyps can be removed endoscopically but often require surgical excision also. In this report, we discuss two children of PJS with uncommon presentations, one presented with retrograde intussusception and another with gastric outlet obstruction. The first child underwent laparoscopy and another required open surgery with intraoperative enteroscopy.

Morphological and functional recovery following acute and acute recurrent pancreatitis in children: A prospective sequential 2-point evaluation.

BACKGROUND: The functional and morphological recovery following an episode of acute pancreatitis (AP) in children still remains ill understood as research exploring this is limited. We aimed to characterize the morphological and functional changes in pancreas following AP and ARP (acute recurrent pancreatitis) in children. METHODS: Children with AP were followed prospectively and assessed at two time points at least 3 months apart, with the first assessment at least 3 months after the AP episode. Exocrine and endocrine functions were measured using fecal elastase and fasting blood sugar/HbA1c levels respectively. Morphological assessment was done using endoscopic ultrasound (EUS) and magnetic resonance imaging and cholangiopancreatography (MRI/MRCP). RESULTS: Seventy-three children (boys:59%; mean age:8.4 ± 3.2years) were studied and 21 of them (29%) progressed to ARP. Altered glucose homeostasis was seen in 19 (26%) at first and 16 (22%) at second assessment and it was significantly more in ARP group than the AP group at first (42.8%vs19.2%; p = 0.03) as well as second assessment (38.1%vs15.3%; p = 0.03). Twenty-one children (28.7%) at first and 24 (32.8%) at second assessment developed biochemical exocrine pancreatic insufficiency. EUS detected indeterminate and suggestive changes of chronic pancreatitis in 21% at first (n = 38) and 27.6% at second assessment (n = 58). On MRCP, main pancreatic duct and side branch dilatation were seen in 15 (20.5%) and 2 (2.7%) children respectively. CONCLUSIONS: More than one-quarter of children have evidence of altered glucose homeostasis and biochemical exocrine pancreatic insufficiency following an episode of AP. Similarly, morphological features of chronicity seen in some of the children suggest that a fraction of subjects may develop chronic pancreatitis on longer follow-up.

Shear wave elastography of the spleen using elastography point quantification: stiffness values in healthy children.

PURPOSE: To evaluate the shear wave elastography (SWE) values of the spleen in healthy children using Elastography Point Quantification (ElastPQ). METHODS: In this IRB approved prospective study, spleen stiffness was measured in 146 healthy children (2-15 years) using ElastPQ. SWE values were recorded in upper pole, mid pole, and lower pole of the spleen in all the children. RESULTS: The mean (± SD) SWE values of the spleen in children in ≤ 5 years age group, > 5-10 years age group, and > 10-15 years age group were 5.6 (± 4.2) kPa, 6.5 (± 3.2) kPa, and 5.9 (± 3.6) kPa, respectively. No statistically significant difference was seen in SWE values of the spleen between these three groups (p > 0.5). The mean (± SD) SWE values in ≤ 10 years and > 10 years age group were 6.1 (± 3.6) kPa and 5.9 (± 2.6) kPa, respectively. No statistically significant difference was seen in SWE values of the spleen between these two groups (p > 0.5). There was no significant difference in the SWE values for boys and girls. Statistically significant difference was seen between the mean SWE values in the two groups based on the median splenic length, which was 5.5 (± 3.8) kPa in the group with a length of ≤ 7.6 cm and 6.7 (± 2.8) kPa in the group with a length of > 7.6 cm. CONCLUSION: SWE values of the spleen in healthy children do not correlate with age, and no significant difference is there in the SWE values for boys and girls. There was a statistically significant difference in the SWE values of the spleen while comparing the groups based on the median splenic length.

Portal Cavernoma Cholangiopathy in Children: An Evaluation Using Magnetic Resonance Cholangiography and Endoscopic Ultrasound.

BACKGROUND: Portal cavernoma cholangiopathy (PCC) refers to abnormalities of the extra- and intrahepatic bile ducts in patients with portal cavernoma. The literature on PCC in children is very scarce. This study aimed at characterizing PCC in children with extrahepatic portal venous obstruction (EHPVO) using endoscopic ultrasound (EUS) and magnetic resonance cholangiography/portovenography (MRC/MRPV). METHODS: A total of 53 consecutive children diagnosed with EHPVO were prospectively evaluated for PCC using MRC/MRPV and EUS. Chandra classification was used for type of involvement and Llop classification for grading of severity. RESULTS: All 53 children (100%) had PCC changes on MRC/EUS, but none were symptomatic. Extrahepatic ducts (EHDs) and intrahepatic ducts were involved in majority (85%), and 58.5% had severe changes. Periductal thickening/irregularity (71%) was the commonest change in intrahepatic ducts, whereas irregular contour of the duct with scalloping (68%); common bile duct (CBD) angulation (62.3%) were the frequent changes in the EHDs. Increased CBD angulation predisposed to CBD strictures (P = 0.004). Both left and right branches of portal vein were replaced by collaterals in all children. Among the EUS biliary changes, para-pericholedochal, intrapancreatic, and intramural gall bladder collaterals had significant association with severity, with higher frequency of occurrence in children with the most severe Llop Grade. CONCLUSIONS: PCC develops early in the disease course of EHPVO, in children, but is asymptomatic despite severe changes. EUS biliary changes are more likely to be observed with increasing severity of PCC.