An infant with a diagnostically challenging hepatic teratoma, hypofibrinogenemia, and adrenal neuroblastoma: case report.

Teratomas of the liver are exceedingly rare. Neuroblastoma is the most common, extracranial solid tumor of infancy. We describe the case of a 2-month-old, female infant who presented with an abdominal mass arising in the right lobe of the liver, and a severe coagulopathy, which necessitated cryoprecipitate infusion. Biopsy was interpreted as hepatoblastoma. Following resection, difficulty classifying the mass led to several consultations, and an eventual diagnosis of teratoma. During follow-up, the patient was diagnosed with right adrenal neuroblastoma, which, in retrospect, had been present before the hepatic resection. To our knowledge, these 2 tumors have never been reported together, or in combination with isolated hypofibrinogenemia.

TL-118 and gemcitabine drug combination display therapeutic efficacy in a MYCN amplified orthotopic neuroblastoma murine model--evaluation by MRI.

Neuroblastoma (NB) is the most common extra-cranial pediatric solid tumor with up to 50% of NB patients classified as having high-risk disease with poor long-term survival rates. The poor clinical outcome and aggressiveness of high-risk NB strongly correlates with enhanced angiogenesis, suggesting anti-angiogenic agents as attractive additions to the currently insufficient therapeutics. TL-118, a novel drug combination has been recently developed to inhibit tumor angiogenesis. In the current study, we used the SK-N-BE (2) cell line to generate orthotopic NB tumors in order to study the combinational therapeutic potential of TL-118 with either Gemcitabine (40 mg/kg; IP) or Retinoic acid (40 mg/kg; IP). We show that TL-118 treatment (n = 9) significantly inhibited tumor growth, increased cell apoptosis, reduced proliferation and extended mouse survival. Moreover, the reciprocal effect of TL-118 and Gemcitabine treatment (n = 10) demonstrated improved anti-tumor activity. The synergistic effect of these drugs in combination was more effective than either TL or Gemcitabine alone (n = 9), via significantly reduced cell proliferation (p<0.005), increased apoptosis (p<0.05) and significantly prolonged survival (2-fold; p<0.00001). To conclude, we demonstrate that the novel drug combination TL-118 has the ability to suppress the growth of an aggressive NB tumor. The promising results with TL-118 in this aggressive animal model may imply that this drug combination has therapeutic potential in the clinical setting.

Quantitative functional MRI biomarkers improved early detection of colorectal liver metastases.

PURPOSE: To implement and evaluate the performance of a computerized statistical tool designed for robust and quantitative analysis of hemodynamic response imaging (HRI) -derived maps for the early identification of colorectal liver metastases (CRLM). MATERIALS AND METHODS: CRLM-bearing mice were scanned during the early stage of tumor growth and subsequently during the advanced-stage. Three experienced radiologists marked various suspected-foci on the early stage anatomical images and classified each as either highly certain or as suspected tumors. The statistical model construction was based on HRI maps (functional-MRI combined with hypercapnia and hyperoxia) using a supervised learning paradigm which was further trained either with the advanced-stage sets (late training; LT) or with the early stage sets (early training; ET). For each group of foci, the classifier results were compared with the ground-truth. RESULTS: The ET-based classification significantly improved the manual classification of the highly certain foci (P < 0.05) and was superior compared with the LT-based classification (P < 0.05). Additionally, the ET-based classification, offered high sensitivity (57-63%), accompanied with high positive predictive value (>94%) and high specificity (>98%) for suspected-foci. CONCLUSION: The ET-based classifier can strengthen the radiologist's classification of highly certain foci. Additionally, it can aid in classifying suspected-foci, thus enabling earlier intervention which can often be lifesaving.

Appendicular foreign body: patience needed.

A 7-year-old boy was referred to the emergency room following ingestion of a metal coil. A plain abdominal radiograph demonstrated the presence of the coil in the right lower quadrant. The child had no clinical symptoms. On serial abdominal radiographs during the following four weeks, the coil had not moved. Colonoscopy and subsequent CR scan confirmed that the coil was in the appendix. Four weeks later, before surgery, the coil was not detected by another abdominal radiograph. This case suggests that in a symptomatic child who is suspected to have an appendicular foreign body, observing the patient even for two months should be attempted and may preclude surgery.

Continuous 13C-methacetin breath test differentiates biliary atresia from other causes of neonatal cholestasis.

BACKGROUND AND AIM: Distinguishing biliary atresia (BA) from other causes of neonatal cholestasis (NC) is challenging. Continuous BreathID C-methacetin breath test (MBT) is a novel method that determines liver function. Methacetin is metabolized uniquely by the liver and CO2 is measured passively, through a nasal cannula in the exhaled breath. The aim of this study was to assess the ability of MBT to differentiate BA from other causes of NC. METHODS: MBT was performed in infants with NC before any invasive procedure. Percent dose recovered (PDR) peak and time to peak (TTPP) of C recovered were correlated with blood test results and degree of fibrosis on liver biopsy. RESULTS: Fifteen infants were enrolled in the study. Eight were eventually diagnosed as having BA. MBT showed that infants with NC from various causes reached the PDR peak after 44.5 ± 6.7 minutes, whereas infants with BA reached the PDR peak value after 54.7 ± 4.3 minutes (P < 0.005). This suggested low cytochrome P450 1A2 activity in the BA group. The area under the curve (AUC) was 0.95 (95% confidence interval [CI] 0.83-1), sensitivity of 88%, and specificity of 100%. CONCLUSIONS: This pilot study shows that MBT can differentiate between BA and other causes of NC by time to peak of methacetin metabolism. The results suggest that MBT may be used as part of the diagnostic algorithm in infants with liver disease. Larger-scale studies should be conducted to confirm these initial observations.

Laser-induced inactivation of Plasmodium falciparum.

BACKGROUND: Haemozoin crystals, produced by Plasmodium during its intra-erythrocytic asexual reproduction cycle, can generate UV light via the laser-induced, non-linear optical process of third harmonic generation (THG). In the current study the feasibility of using haemozoin, constitutively stored in the parasite's food vacuole, to kill the parasite by irradiation with a near IR laser was evaluated. METHODS: Cultured Plasmodium parasites at different stages of development were irradiated with a pulsed NIR laser and the viability of parasites at each stage was evaluated from their corresponding growth curves using the continuous culture method. Additional testing for germicidal effects of haemozoin and NIR laser was performed by adding synthetic haemozoin crystals to Escherichia coli in suspension. Cell suspensions were then irradiated with the laser and small aliquots taken and spread on agar plates containing selective agents to determine cell viability (CFU). RESULTS: Parasites in the late-trophozoites form as well as trophozoites in early-stage of DNA synthesis were found to be the most sensitive to the treatment with -4-log reduction in viability after six passes through the laser beam; followed by parasites in ring phase (-2-log reduction). A -1-log reduction in E. coli viability was obtained following a 60 min irradiation regimen of the bacteria in the presence of 1 µM synthetic haemozoin and a -2-log reduction in the presence of 10 µM haemozoin. Minimal (≤ 15%) cell kill was observed in the presence of 10 µM haemin. CONCLUSIONS: Laser-induced third-harmonic generation by haemozoin can be used to inactivate Plasmodium. This result may have clinical implications for treating severe malaria symptoms by irradiating the patient's blood through the skin or through dialysis tubing with a NIR laser.

A sequential treatment algorithm for infants with stage 4s neuroblastoma and massive hepatomegaly.

Infants with 4s neuroblastoma (NB) and massive hepatomegaly have a guarded prognosis and mortality approaches 30%. We report on eight patients with 4s NB and massive hepatomegaly treated with multiple modalities. One patient had spontaneous tumor regression. Three patients had progressive disease and responded to chemotherapy. Four patients progressed despite intravenous chemotherapy, of whom two died, and two were salvaged with hepatic intra-arterial chemoembolization. Treatment of infants with stage 4s NB with massive hepatomegaly should be individualized based on disease course. A sequential approach with observation, intravenous chemotherapy, and intra-arterial chemoembolization, may improve the outcome of these infants.

Fertility preservation in girls.

Children that undergo treatment for cancer are at risk of suffering from subfertility or hormonal dysfunction due to the detrimental effects of radiotherapy and chemotherapeutic agents on the gonads. Cryopreservation of ovarian tissue prior to treatment offers the possibility of restoring gonadal function after resumption of therapy. Effective counseling and management of pediatric patients is crucial for preserving their future reproductive potential. The purpose of this article is to review recent literature and to revise recommendations we made in a 2007 article. Pediatric hemato-oncology, reproductive endocrinology, surgery, anesthesia and bioethics perspectives are discussed and integrated to propose guidelines for offering ovarian cryopreservation to premenarcheal girls with cancer.

Vascular profile characterization of liver tumors by magnetic resonance imaging using hemodynamic response imaging in mice.

Recently, we have demonstrated the feasibility of using hemodynamic response imaging (HRI), a functional magnetic resonance imaging (MRI) method combined with hypercapnia and hyperoxia, for monitoring vascular changes during liver pathologies without the need of contrast material. In this study, we evaluated HRI ability to assess changes in liver tumor vasculature during tumor establishment, progression, and antiangiogenic therapy. Colorectal adenocarcinoma cells were injected intrasplenically to model colorectal liver metastasis (CRLM) and the Mdr2 knockout mice were used to model primary hepatic tumors. Hepatic perfusion parameters were evaluated using the HRI protocol and were compared with contrast-enhanced (CE) MRI. The hypovascularity and the increased arterial blood supply in well-defined CRLM were demonstrated by HRI. In CRLM-bearing mice, the entire liver perfusion was attenuated as the HRI maps were significantly reduced by 35%. This study demonstrates that the HRI method showed enhanced sensitivity for small CRLM (1-2 mm) detection compared with CE-MRI (82% versus 38%, respectively). In addition, HRI could demonstrate the vasculature alteration during CRLM progression (arborized vessels), which was further confirmed by histology. Moreover, HRI revealed the vascular changes induced by rapamycin treatment. Finally, HRI facilitates primary hepatic tumor characterization with good correlation to the pathologic differentiation. The HRI method is highly sensitive to subtle hemodynamic changes induced by CRLM and, hence, can function as an imaging tool for understanding the hemodynamic changes occurring during CRLM establishment, progression, and antiangiogenic treatment. In addition, this method facilitated the differentiation between different types of hepatic lesions based on their vascular profile noninvasively.

Perivascular epithelioid cell tumor of the ascending colon mesentery in a child: case report and review of the literature.

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor. Perivascular epithelioid cell tumors of the gastrointestinal tract are very rare, with only about 20 previous reported cases. We present a 5.5-year-old boy with PEComa of the right colon. Treatment consisted of tumor resection only, without additional adjuvant therapy. Two years after surgery, he remains free of tumor. To the best of our knowledge, this is the youngest reported child with PEComa of the colon. We review the literature concerning PEComas in children, especially those of the gastrointestinal tract. We emphasize the importance of correct immunohistochemistry diagnosis, recommended treatment, and surveillance of this unique family of tumors.

Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and is considered to be the outcome of chronic liver inflammation. Currently, the main treatment for HCC is surgical resection. However, survival rates are suboptimal partially because of tumor recurrence in the remaining liver. Our aim was to understand the molecular mechanisms linking liver regeneration under chronic inflammation to hepatic tumorigenesis. Mdr2-KO mice, a model of inflammation-associated cancer, underwent partial hepatectomy (PHx), which led to enhanced hepatocarcinogenesis. Moreover, liver regeneration in these mice was severely attenuated. We demonstrate the activation of the DNA damage-response machinery and increased genomic instability during early liver inflammatory stages resulting in hepatocyte apoptosis, cell-cycle arrest, and senescence and suggest their involvement in tumor growth acceleration subsequent to PHx. We propose that under the regenerative proliferative stress induced by liver resection, the genomic unstable hepatocytes generated during chronic inflammation escape senescence and apoptosis and reenter the cell cycle, triggering the enhanced tumorigenesis. Thus, we clarify the immediate and long-term contributions of the DNA damage response to HCC development and recurrence.

Bladder neck closure in children: a decade of followup.

PURPOSE: Bladder neck closure necessitates lifelong clean intermittent catheterization. Concerns have been raised regarding well-being and compliance in patients on long-term clean intermittent catheterization. Noncompliance may result in subsequent hydronephrosis, incontinence, infection, cystolithiasis and perforation. We analyzed our long-term results with bladder neck closure followed at least 10 years for patient compliance with clean intermittent catheterization, upper tract preservation, continence, complications and subsequent procedures. MATERIALS AND METHODS: All patients followed at least 10 years after bladder neck closure were included in this study. RESULTS: Seven boys and 5 girls with a mean age of 7.0 years and urinary incontinence underwent bladder neck closure and continent urinary diversion between 1993 and 1998. The primary diagnosis was exstrophy in 5 patients, spinal dysraphism in 3, trauma in 2, sacral agenesis in 1 and a duplicated hindgut in 1. Mean followup was 12.4 years (range 10 to 14). All patients performed clean intermittent catheterization 4 to 6 times daily. Hydronephrosis improved or remained stable in the 11 patients who underwent bladder augmentation. Mild new hydronephrosis developed in 1 patient and resolved after increasing clean intermittent catheterization frequency. Bladder neck closure successfully cured incontinence in all of the last 6 patients who underwent modified bladder neck closure with a posterior bladder neck flap, while 2 of the earlier 6 bladder neck closures required revision for a subsequent 100% success rate. Additional operations were required in 6 patients. To our knowledge this is the longest followup after bladder neck closure reported in the literature. CONCLUSIONS: Patient compliance with long-term clean intermittent catheterization is good after bladder neck closure. Bladder neck closure provides excellent long-term safety for the upper urinary tract and continence. It is associated with relatively low morbidity, which is correctible.

Ectopic presacral choroid plexus cyst in a neonate.

An unusual case of a presacral ectopic choroid plexus cyst in a neonate is described. After birth, a soft lump was noticed at the left buttock. Imaging studies including sonography and magnetic resonance imaging demonstrated a presacral cystic lesion extending to the buttocks, composed of several septated cystic masses with no connection to the spinal canal or rectum. After total resection, the tumor was diagnosed as an ectopic choroid plexus cyst. To our knowledge, this is the first case report in the English literature of a presacral ectopic choroid plexus cyst.

Search for the azygos: a lesson learnt from a case with left superior vena cava, esophageal atresia and tracheo-esophageal fistula.

The azygos vein is of superior importance during the operation for esophageal atresia with tracheo-esophageal fistula (EA; TEF). Its location helps the surgeon to locate the fistula. Newborns with persistent left superior vena cava (LSVC) may have alterations in the location of the azygos, and since LSVC is not uncommon in EAs with fistulae, it is important to locate the azygos during a pre-operative echocardiogram. Foreknowledge of a possible absent azygos may avoid morbidity while trying to locate the fistula. We present a case of a newborn with EA, TEF, and LSVC in which the azygos vein was absent.

Nested (ossifying) stromal epithelial tumor of the liver: case report.

Nested stromal-epithelial tumor (NSET) of the liver is an extremely rare primary hepatic tumor with uncertain malignant potential. To date, only 11 cases have been described. We describe the case of a 2 1/2-year-old girl with an incidental liver mass. The mass was discovered on follow-up abdominal imaging for asymptomatic hydronephrosis diagnosed on antenatal ultrasound. Needle biopsy showed a mixed stromal and epithelial process in a nested pattern, with foci of ossification and no significant pleomorphism or necrosis. The nest cells stained with WT-1, cytokeratin 18, and CD56. Ossifying stromal epithelial tumor of the liver was strongly suspected. The findings were confirmed in the subsequent partial hepatectomy specimen. To our knowledge, this is the 12th case of NSET in the English-language literature and the 3rd case of NSET associated with genitourinary system abnormalities. Possible associations with dysregulated WT-1 expression are discussed.

Functional magnetic resonance imaging monitoring of pathological changes in rodent livers during hyperoxia and hypercapnia.

UNLABELLED: Liver diseases and regeneration are associated with hemodynamic changes denoting pathological alterations. Determining and monitoring physiological and pathological liver changes is essential for diagnostic and therapeutic objectives. Our aim was to determine the feasibility of functional magnetic resonance imaging (fMRI) during hypercapnia and hyperoxia for monitoring liver pathology. Liver fMRI images were acquired in rodents following acute bleeding, partial hepatectomy, and fibrosis. Results were quantitated and confirmed by histology. Changes induced by hyperoxia and hypercapnia following hemorrhage significantly correlated with the percentage of blood loss, reflecting lower liver perfusion and diminished vessel responsiveness to gas saturation. Hepatectomy resulted in an early decline in signal intensity changes due to hyperoxia, suggesting a decrease in liver perfusion and blood content. Following hepatectomy, signal intensity changes due to hypercapnia increased, signifying a change in liver perfusion from a mainly portal to a more arterial source. Two weeks after induction of fibrosis, signal intensity changes due to hypercapnia became much lower and those due to hyperoxia were much higher than those in normal livers, reflecting the increased perfusion due to the inflammatory process as confirmed by histologic analysis. With fibrosis progression, signal intensity changes induced by hypercapnia and hyperoxia were gradually attenuated, indicating structural and functional alterations of the liver vasculature during fibrosis. CONCLUSION: In various liver pathologies, fMRI response to hypercapnia and hyperoxia is sensitive to changes in liver hemodynamic status involved in hepatic damage or recovery; thus, this technique may offer an additional noninvasive diagnostic tool for evaluation and follow-up of liver diseases by means of examining perfusion-related alterations.

Functional MR imaging during hypercapnia and hyperoxia: noninvasive tool for monitoring changes in liver perfusion and hemodynamics in a rat model.

PURPOSE: To prospectively assess functional magnetic resonance (MR) imaging during hypercapnia and hyperoxia for monitoring changes in liver perfusion and hemodynamics in rats. MATERIALS AND METHODS: All experiments were performed with approval of an animal care and use committee. Functional T2*-weighted gradient-echo MR images of the rat liver were acquired during hyperoxia and graded hypercapnia (n=24). Additional images were acquired during portal vein ligation (n=4), induced hypovolemia (n=5), and 70% hepatectomy (n=5). Hypercapnic effects were confirmed with Doppler ultrasonography and with gadopentetate dimeglumine. Differences between groups were analyzed by using Wilcoxon rank sum test, except for the graded hypercapnia, for which one-way analysis of variance was used. RESULTS: Liver signal intensity (SI) increased due to hyperoxia; the percentage change in SI was seven times greater than that in muscle tissue; this reflects higher vascularity of the liver. Liver SI decreased due to hypercapnia; the percentage change in SI was negative in the liver but positive in the muscle (P<.001). Induced hypovolemia resulted in considerable decreases in functional MR imaging response; this reflects lower liver perfusion. Clinical applicability of the functional MR imaging method was proved by monitoring changes in liver perfusion that resulted from liver resection. CONCLUSION: In the liver, the magnitude of the percentage change in SI induced by hypercapnia and hyperoxia reflects changes in total blood volume; whereas percentage change in SI values induced by hypercapnia from a negative to a positive value reflects relative changes in portal-to-arterial blood flow ratio.

Role of caspase-8 in hepatocyte response to infection and injury in mice.

UNLABELLED: Caspase-8 has been implicated in signaling for apoptotic cell death and for certain nonapoptotic functions. However, knowledge of actual physiological or pathophysiological processes to which this enzyme contributes is lacking. Using a mouse model and employing the conditional knockout approach to delete the caspase-8 gene specifically in the liver, we found that caspase-8 deficiency in hepatocytes facilitates infection of the liver by Listeria monocytogenes, attenuates the hepatocyte proliferation wave during the first 48 hours after partial hepatectomy and, depending on the genetic background of the mice, prompts a chronic inflammatory response to the hepatectomy, as a result of which the proliferation of hepatocytes, although initially suppressed, might later be persistently enhanced, resulting in significant hepatomegaly. CONCLUSION: These findings indicate that caspase-8 participates in regulation of the cellular response to infection and injury and that it does so by affecting various cellular functions, including cell death, cell proliferation, and induction of inflammation.

[Male circumcision and HIV/AIDS: convincing evidence and their implication for the state of Israel].

The results of recent controlled trials documenting the protective effect of male circumcision on HIV infection in young adults pose significant challenges to a country like Israel. Circumcision is performed in close to 100% of new born males, mostly as a religious act in Judaism and Islam. Christian Israelis follow societal norms suggesting that circumcision contributes to better hygiene and cleanliness. Complications in infant circumcision in Israel are rare, despite the surgery being preformed most often by nonmedical circumcisers (a "Mohel") on the eighth day of birth. Reported complication rates are between 0.34% and 2%, with bleeding and infections being the most common. In the last 10 years and due to massive migration of Eastern Europeans into Israel, impressive experience was gained in Israel with adults seeking male circumcision for various reasons including: religious, societal pressure, sexual and economical. Over 21,800 adult male circumcisions have been monitored between 1998 and 2006 alone. Complication rates (mostly bleeding) were 1.75% on an average. This review matches the new data emerging from the African controlled trials with previous observational studies and the Jewish and Israeli experience. We present three challenges to policy makers in Israel: (a) the need to intensify education and information sharing on male circumcision and HIV/AIDS among healthcare workers; (b) developing an information campaign for non-circumcised migrants and adequate service to scale up on potential demand; (c) developing intensified educational campaigns for circumcised males so that they do not abandon other protective interventions (e.g. condoms) when needed for HIV prevention.

Should ovarian cryopreservation be offered to girls with cancer.

Current therapy of childhood cancer makes long-term survival a realistic outcome for most patients. However, some treatment regimens entail a significant risk of infertility. No established method for preservation of female fertility is currently available. Ovarian cryopreservation is an experimental technology that is being offered with increasing frequency to women undergoing cancer therapy. It has not yet been reported in children and adolescent girls. The aim of this review is to stimulate discussion on the possibility of performing ovarian cryopreservation in pre-menarcheal girls in advance of therapies that may induce ovarian failure. We present a multi-disciplinary discussion of the risks and benefits associated with the procedure and propose guidelines for its implementation. We propose that all girls about to receive treatment that has a high risk for infertility be offered consultation about the possibility of ovarian cryopreservation.