Coproporphyrin I Can Serve as an Endogenous Biomarker for OATP1B1 Inhibition: Assessment Using a Glecaprevir/Pibrentasvir Clinical Study.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are involved in the disposition of a variety of commonly prescribed drugs. The evaluation of OATP1B1/1B3 inhibition potential by investigational drugs is of interest during clinical drug development due to various adverse events associated with increased exposures of their substrates. Regulatory guidance documents on the in vitro assessment of OATP1B1/1B3 inhibition potential are conservative with up to a third of predictions resulting in false positives. This work investigated the utility of OATP1B1/1B3 endogenous biomarkers, coproporphyrin (CP)-I and CP-III, to assess clinical inhibition of OATP1B1/1B3 and potentially eliminate the need for prospective clinical drug-drug interaction (DDI) studies. Correlations between CP-I exposures and various OATP1B1 static DDI predictions were also evaluated. Glecaprevir/pibrentasvir (GLE/PIB) 300/120 mg fixed-dose combination is known to cause clinical inhibition of OATP1B1/1B3. In a clinical study evaluating the relative bioavailability of various formulations of GLE/PIB regimen, CP-I peak plasma concentration (Cmax ) ratio and 0-16-hour area under the concentration-time curve (AUC0-16 ) ratio relative to baseline increased with increasing GLE exposures, whereas there was a modest correlation between GLE exposure and CP-III Cmax ratio but no correlation with CP-III AUC0-16 ratio. This suggests that CP-I is superior to CP-III as an endogenous biomarker for evaluation of OATP1B1 inhibition. There was a significant correlation between CP-I and GLE Cmax (R2  = 0.65; P < 0.001) across individual subjects. Correlation analysis between GLE OATP1B1 R values and CP-I exposures (Cmax ratio and AUC0-16 ratio) suggests that an R value of > 3 can predict a biologically meaningful inhibition of OATP1B1 when the inhibitor clinical pharmacokinetic parameters are available.

Congenital H-type tracheoesophageal fistula: a national multicenter study.

BACKGROUND: Congenital H-type tracheoesophageal fistula (TEF) is very rare and represents <5 % of all congenital tracheoesophageal malformations. This is a national, multicenter review of our experience with isolated H-type TEF outlining clinical presentation, methods of diagnosis, associated anomalies, treatment and outcome PATIENTS AND METHODS: The medical records of all patients with the diagnosis of congenital H-type TEF treated at four pediatric surgery units in Saudi Arabia were retrospectively reviewed for: age at diagnosis, sex, presenting symptoms, associated anomalies, method of diagnosis, treatment and outcome. RESULTS: During the study period (January 1998-December 2013), 435 infants and children with the diagnosis of esophageal atresia with or without TEF were treated. Among these, 23 (5.3 %) had isolated TEF. There were 11 males and 12 females. Their age at presentation ranged from 5 days to 3 years and 7 months but the majority (90 %) were diagnosed during their first year of life. Their clinical presentation included: chocking and coughing during feeds in 12 (52.2 %), recurrent chest infection in 16 (69.6 %) and cyanosis in 10 (43.5 %). One presented with abdominal distension also. The diagnosis was made using esophagogram. In 11 (47.8 %), a single study confirmed the diagnosis, 8 (34.8 %) required two studies while 4 (17.4 %) required three studies. Nineteen (82.6 %) had preoperative bronchoscopy and in 13 (56.5 %), a catheter was used to cannulate the fistula. All were operated through a right cervical incision except one who underwent thoracoscopic ligation and division of the fistula. In one, the fistula was only transfixed and tied without being divided. This patient developed a recurrent fistula. Two patients developed postoperative stridor secondary to recurrent laryngeal nerve palsy. In both of them, there was complete recovery. CONCLUSIONS: H-type TEF is very rare and commonly presents with recurrent chest infection, chocking and coughing during feeds and cyanosis. Physicians caring for these patients should be aware of this and a high index of suspicion is of paramount importance to avoid delay in diagnosis with its associated morbidity. A contrast esophagogram is valuable in confirming the diagnosis. The study however may need to be repeated. Preoperative bronchoscopy is valuable to localize and cannulate the fistula for easier access during surgery. Surgical repair is the treatment of choice and this should be performed through a right cervical incision or thoracotomy for low fistulae. Thoracoscopic ligation and division of a low H-type fistula is an alternative and less invasive approach when compared to thoracotomy.

Splenectomy for Children With Thalassemia: Total or Partial Splenectomy, Open or Laparoscopic Splenectomy.

Splenomegaly and hypersplenism are common complications among children with thalassemia necessitating splenectomy. Thirty-six children (27 ß-thalassemia major, 3 Hb H disease, and 6 thalassemia intermediate) had total splenectomy (11 laparoscopic and 13 open splenectomy) or partial splenectomy (12 patients). In the partial splenectomy group, 2 with Hb H required no transfusions. For those with ß-thalassemia major who had partial splenectomy (9 patients), there was a reduction in the number of transfusions from a preoperative mean of 15.2 transfusions per year to a postoperative mean of 8.2 transfusions per year. Subsequently and as a result of increase in the size of splenic remnant, their transfusions increased, but none required total splenectomy. Twenty-four patients had total splenectomy (13 open and 11 laparoscopic splenectomy). Their postsplenectomy transfusions decreased from a preoperative mean of 17.8 transfusions per year to a postoperative mean of 10 transfusions per year. There was no mortality, and none developed postoperative sepsis or thrombotic complications. Total splenectomy is beneficial for children with ß-thalassemia major and hypersplenism by reducing their transfusion requirements. Laparoscopic splenectomy is however more beneficial. Partial splenectomy reduces their transfusion requirements, but only as a temporary measure, and so it is recommended for children younger than 5 years of age.

Congenital pyloric atresia, presentation, management, and outcome: a report of 20 cases.

BACKGROUND: Congenital pyloric atresia (CPA) is a very rare anomaly. It is usually seen as an isolated condition with excellent prognosis. Few cases are familial. These are usually associated with other hereditary conditions and have a poor prognosis. This is a review of our experience with 20 patients with CPA outlining aspects of diagnosis, associated anomalies and management. PATIENTS AND METHODS: This is a retrospective analysis of 20 cases seen over a 22 year period (December 1990 to December 2012). Their records reviewed for: age, sex, presentation, prenatal history, associated anomalies, investigations, treatment, operative findings and the outcome. RESULTS: 20 cases (9 Males, 11 Females) were treated. 7 patients were full term and the remaining 13 were prematures. Their mean birth weight was 2.1 kg (1.1 kg to 3.9 kg). Polyhydramnios was seen in 13 patients (65%). Two were brothers and four were members of the same family. Isolated CPA was seen in 7 (35%); 13 had an associated conditions: epidermolysis bullosa (EB) in 8 (40%) and multiple intestinal atresias (MIA) in 5 (25%). Three patients had associated esophageal atresia. All were operated on except two who died early due to unrelenting sepsis. The variety of pyloric atresias encountered were as follows: pyloric diaphragm in 13 including double diaphragms in 2, pyloric atresia with a gap in 4 and pyloric atresia without gap in 3. Ten died postoperatively giving an overall survival of 40%. CONCLUSIONS: CPA is a very rare condition. Isolated CPA carries a good prognosis. Association of CPA with other familial and congenital anomalies like EB and MIA carries a poor prognosis.

Congenital Morgagni's hernia: a national multicenter study.

BACKGROUND: Congenital Morgagni's hernia (CMH) is rare and represents less than 5% of all congenital diaphragmatic hernias. This is a national review of our experience with CMH outlining clinical presentation, methods of diagnosis, associated anomalies, treatment, and outcome. PATIENTS AND METHODS: The medical records of all patients with the diagnosis of CMH treated at four pediatric surgery units in Saudi Arabia were retrospectively reviewed for age at diagnosis, sex, presenting symptoms, associated anomalies, diagnosis, operative findings, treatment, and outcome. RESULTS: During a 20-year period (January 1990-December 2010), 53 infants and children with CMH were treated. There were 38 males and 15 females. Their age at diagnosis ranged from 1 month to 9 years (mean 22.2 months). Forty-three (81%) presented with recurrent chest infection. Twenty-two (44.5%) had right CMH, 15 (28.3%) had left-sided hernia and 16 (30.2%) had bilateral hernia. In 7, the diagnosis of bilaterality was made at the time of surgery. Associated anomalies were seen in 38 (71.7%). Twenty-one (39.6%) had congenital heart disease, 8 (15%) had malrotation, and 15 (28.3%) had Down syndrome. All were operated on. Twenty-nine (54.7%) underwent repair via an open approach. The remaining 24 (45.3%) underwent repair using minimal invasive surgery, laparoscopic-assisted hernia repair (19 patients) or totally laparoscopic approach (5 patients). At the time of surgery, the hernia sac content included the colon in 33 (62.3%), part of the left lobe of the liver in 13 (24.5%), the small intestines in 11 (20.75%), the omentum in 5 (9.4%), and the stomach in 4 (7.5%). In 12 (22.6%), the hernia sac was empty. When compared to the open repair, the laparoscopic-assisted approach was associated with a shorter operative time, an earlier commencement of feeds, less requirement for postoperative analgesia, a shorter hospital stay, and better cosmetic appearance. There was no mortality. On follow-up, 2 (7%) of the open surgical group developed recurrence. CONCLUSIONS: CMH is rare and in the pediatric age group commonly presents with recurrent chest infection and has a high incidence of associated anomalies, commonly congenital heart disease and Down syndrome. We advocate a laparoscopic-assisted approach to repair CMH. This is a simple technique that produces a sound repair, and when compared with the open approach it takes less operative time, requires less analgesia, allows earlier commencement of feeds, is associated with a shorter hospital stay, and has a better cosmetic outcome.

Massive splenic infarction in children with sickle cell anemia and the role of splenectomy.

BACKGROUND: Massive splenic infarction (MSI) is a very rare condition. Few reports of splenic infarction of various etiologies including hematological and non-hematological causes have been published. On the other hand, MSI in patients with sickle cell anemia (SCA) is extremely rare. This report describes our experience with 15 children with SCA and MSI outlining aspects of presentation, diagnosis and management. PATIENTS AND METHODS: The records of all children with MSI were retrospectively reviewed for age at diagnosis, sex, clinical features, precipitating factors, investigations, management and outcome. RESULTS: 15 children (11 M: 4 F) with SCA were treated for MSI. Their mean age was 10.9 years (6-17 years). All presented with severe left upper quadrant abdominal pain. In nine, this was associated with nausea and vomiting. Three were febrile and all had a tender splenomegaly. Their mean hemoglobin was 8.2 g/dl (5.7-11.3 g/dl), mean WBC was 10.97 × 10(3) mm(-3) (3.6 × 10(3)-22.3 × 10(3) mm(-3)) and mean platelet count was 263.3 × 10(3) mm(-3) (40 × 10(3)-660 × 10(3) mm(-3)). In seven, there was a precipitating cause including high altitude in two, acute chest syndrome in two, septicemia in two and severe vasooclusive crisis in one. Abdominal ultrasound and CT scan confirmed the diagnosis of MSI which involved more than half of the spleen in 12 and whole spleen in 3. All were treated with IV fluids, analgesia and blood transfusion where appropriate. Eleven had splenectomy because of persistent abdominal pain, three developed splenic abscess and underwent splenectomy and one settled on conservative treatment. Histology confirmed the diagnosis of splenic infarction in 11 and infarction with abscess in the remaining 3. CONCLUSION: MSI is extremely rare in children with SCA. It can develop spontaneously or precipitated by other factors namely high altitude, acute chest syndrome and severe stress. Most reported cases of splenic infarction are small in size, focal and can be treated conservatively. MSI, on the other hand, may necessitate splenectomy for persistent symptoms or in case of complications, such as abscess formation.

Colonic adenocarcinoma as a secondary malignancy after treatment of embryonal rhabdomyosarcoma.

BACKGROUND: Survivors of childhood malignancies are known to be at an increased risk for developing a variety of secondary cancers. Primary adenocarcinoma of the colon is very rare in children and adenocarcinoma of the colon occurring as a secondary malignancy in children is much rarer. METHODS: A boy with a history of successfully treated embryonal rhabdomyosarcoma developed adenocarcinoma of the colon as a secondary cancer. RESULTS: The boy presented with a solid mass of the left cheek at 3 years of age. The mass was excised and histological examination showed embryonal rhabdomyosarcoma. He was treated with multi-agent chemotherapy and local radiotherapy, which resulted in complete remission. Four years later, he presented with recurrent colicky abdominal pain and bleeding per rectum and was found to have intussusceptions. Colonoscopy revealed a tumor in the transverse colon, which was biopsied and proved to be an adenocarcinoma. The boy underwent excision followed by chemotherapy using an adult colon cancer regimen. He is currently off chemotherapy for 2 years with no evidence of the disease. CONCLUSIONS: We report a rare case of colon cancer after treatment of rhabdomyosarcoma. Colorectal adenocarcinoma must be kept in mind as a secondary neoplasm following treatment for early childhood malignancies although it is extremely rare.

Familial achalasia in children.

Achalasia is rare in the pediatric age group and in most cases it is idiopathic with no family history. Familial achalasia is very rare. This report describes two families with achalasia: in one, six children were affected while in the other a brother and a sister had Allgrove's syndrome (triple-A syndrome consisting of achalasia, adrenal insufficiency, and alacrima). Familial achalasia suggests that it is hereditary and may be transmitted as an autosomal recessive trait. The management of achalasia in children is still controversial. With the recent advances in minimal invasive surgery, laparoscopic Heller's myotomy is the procedure of choice in the management of achalasia in children.

Successful Treatment of Mirizzi's Syndrome Using SpyGlass Guided Laser Lithotripsy.

The majority of common bile duct stones can be effectively treated by endoscopic sphincterotomy and stone extraction using basket or balloon extractor. Stones more than 2 cm in diameter on the other hand require mechanical, electrohyraulic lithotripsy and sphincterotomy and balloon dilation. Mechanical lithotripsy may not be successful because of the size, consistency and site of the stones. In these cases, laser lithotripsy is the treatment of choice. This however requires direct visualization of the stone which may not be feasible for impacted cystic duct stones. This report describes the successful treatment of difficult cystic duct stones in two patients with Mirizzi's syndrome type I using per oral Spyglass and intraductal holmium: YAG Laser Lithotripter.

Traumatic diaphragmatic hernia in children.

BACKGROUND: Traumatic diaphragmatic hernia (TDH) is very rare in the pediatric age group. Because of its rarity and its coexistence with more serious injuries, the diagnosis is often missed or delayed. PATIENTS AND METHODS: All children with the diagnosis of TDH were retrospectively reviewed for age at diagnosis, sex, mechanism of injury, site of diaphragmatic rupture, associated injuries, injury severity score, investigations, treatment and outcome. RESULTS: Over a period of 15 years (1992-2007), we treated seven children with TDH. All were males except one. Their mean age was 7.4 years (3.75-14 years). The site of TDH was on the left in three, on the right in three and one had bilateral TDH. The mechanism of injury was blunt trauma in six and penetrating injury from a stab in one. Three had right TDH and in all three, the diagnosis of TDH was delayed. All sustained severe injuries as reflected by the ISS score (mean 38.6). The time from presentation to diagnosis was variable ranging from 3 to 240 h (mean 65.7 h). The three patients with left TDH were repaired trans-abdominally while the three with right TDH were repaired via a right thoracotomy. The patient with bilateral TDH required laparotomy and thoracotomy. All our patients survived and the hospital stay was variable ranging from 7 to 24 days (mean 17 days). CONCLUSIONS: TDH is very rare in children and often associated with severe more serious injuries. These two factors contribute to the delay in diagnosis. This is specially so for right TDH. To obviate delay in diagnosis, it is important to have a high index of suspicion as well as careful interpretation of the initial and follow-up radiological investigations including CT-scan of the chest and abdomen. This is important to detect a slowly increasing TDH that may not be apparent initially.

Congenital-infantile fibrosarcoma masquerading as sacrococcygeal teratoma.

Infantile fibrosarcoma is rare and represents less than 1% of all childhood cancers. Commonly, it arises in the limbs followed by the trunk and head and neck. We report a rare case of infantile fibrosarcoma masquerading as sacrococcygeal teratoma in a newborn. The literature on the subject is also reviewed.

Two unusual gastrointestinal foreign bodies.

Swallowed foreign bodies are common in the pediatric age group, but fortunately, the majority of them pass spontaneously without any adverse effects. Tube gastrostomy is an excellent method to provide prolonged enteral feeding. It is, however, associated with complications, namely, intraperitoneal leak and distal migration of the gastrostomy tube causing gastric outlet obstruction. This paper describes two unusual gastrointestinal foreign bodies, one was swallowed, while the other one was a complication of a tube gastrostomy.

Adhesive intestinal obstruction in infants and children: the place of conservative treatment.

Objectives. Adhesive intestinal obstruction (AIO) is rare in the pediatric age group and its treatment is still controversial. This is a retrospective review of our experience in infants and children with AIO. Patients and Methods. The records of infants and children with AIO between January 2001 and December 2010 were retrospectively reviewed for age at diagnosis, sex, initial operation, interval between initial operation and presentation, diagnosis, treatment and outcome. Results. 44 infants and children were admitted with AIO. There were 28 males and 16 females who had 46 episodes. Their ages at presentation ranged from 1 month to 12 years (mean 5.4 years), while their ages at initial operation ranged from 2 days to 12 years (mean 4.15 years). Time elapsed from initial operation to presentation ranged from 7 days to 8 years (mean 1.5 years), and 66% developed AIO within 1 year from initial operation. Appenedecectomy was the commonest operation (29.5%). Four (9%) responded to conservative treatment. The other 40 (91%) required surgical intervention. Twenty-nine had release of adhesions only, while 10 (25%) had resection of small intestines and one underwent stricturoplasty. Two developed recurrence and one died. Conclusions. AIO is rare in the pediatric age group and the majority becomes symptomatic within 1 year of operation. Appendecectomy is the commonest operation leading to AIO. The place of conservative treatment is limited and to obviate delay and decrease the chance of intestinal ischemia, they should be treated early with surgical adhesiolysis.

Congenital paraesophageal hernia with intrathoracic gastric volvolus in two sisters.

Congenital paraesophageal hernia is rare in infants and children. This paper describes our experience with seven infants and children with congenital paraesophageal hernia with emphasis on two sisters who presented with unusually large paraesophageal hernias and herniation of most of the stomach resulting in intrathoracic gastric volvolus. The literature on the subject is also reviewed.

Metastatic Malignant Melanoma of the Small Intestines Diagnosed by Capsule Endoscopy.

Malignant melanoma is a fairly common tumor that shows an unusual predilection to metastasize to the small intestines. The time interval between the diagnosis of metastasizing melanoma and the initial diagnosis is variable. This as well as the non specific symptoms and the fact that the small bowel is inaccessible both radiologically and endoscopically lead to delay in diagnosis. We present a case of metastatic malignant melanoma to the small intestines diagnosed several years post excision by capsule endoscopy. Metastatic melanoma in the small bowel should be suspected in any patient with a previous history of malignant melanoma who develops non specific gastrointestinal symptoms. Capsule endoscopy which is non invasive, convenient to the patient and devoid of radiation should form part of their diagnostic investigation.

Strongyloides stercoralis hyperinfection in a post-renal transplant patient.

Strongyloides stercoralis is an intestinal nematode that is able to infect the host tissue and persist asymptomatic for many years through autoinfection. It causes life-threatening hyperinfection in immunocompromised hosts. This report describes a rare case of strongyloidiasis in a 40-year-old male following renal transplant, which was diagnosed by colonoscopic biopsy. The literature on the subject is also reviewed.

Unusual variants of congenital pouch colon with anorectal malformations.

Anorectal malformations are common worldwide. Several classifications were used to describe the different types, but in spite of this, there are rare variants. This report describes 2 unusual cases of congenital pouch colon and anorectal malformations.

Coexisting congenital diaphragmatic hernia, esophageal atresia, and tracheoesophageal fistula: a case report and review of the literature.

Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) and congenital diaphragmatic hernia (CDH) are two relatively common neonatal conditions. The coexistence of the two conditions in the same newborn is extremely rare. This is a case report of a newborn with CDH and concurrent EA and TEF. Aspects of diagnosis and the literature on the subject are also reviewed.