Non-invasive MRI biomarkers for the early assessment of iron overload in a humanized mouse model of ß-thalassemia.

ß-thalassemia (ßT) is a genetic blood disorder causing profound and life threatening anemia. Current clinical management of ßT is a lifelong dependence on regular blood transfusions, a consequence of which is systemic iron overload leading to acute heart failure. Recent developments in gene and chelation therapy give hope of better prognosis for patients, but successful translation to clinical practice is hindered by the lack of thorough preclinical testing using representative animal models and clinically relevant quantitative biomarkers. Here we demonstrate a quantitative and non-invasive preclinical Magnetic Resonance Imaging (MRI) platform for the assessment of ßT in the γß0/γßA humanized mouse model of ßT. Changes in the quantitative MRI relaxation times as well as severe splenomegaly were observed in the heart, liver and spleen in ßT. These data showed high sensitivity to iron overload and a strong relationship between quantitative MRI relaxation times and hepatic iron content. Importantly these changes preceded the onset of iron overload cardiomyopathy, providing an early biomarker of disease progression. This work demonstrates that multiparametric MRI is a powerful tool for the assessment of preclinical ßT, providing sensitive and quantitative monitoring of tissue iron sequestration and cardiac dysfunction- parameters essential for the preclinical development of new therapeutics.

Complementary Indicators for Diagnosis of Hepatic Vein Stenosis After Pediatric Living-donor Liver Transplantation.

INTRODUCTION: Although hepatic vein stenosis after liver transplantation is a rare complication, the complication rate of 1% to 6% is higher in pediatric living-donor liver transplantation than that in other liver transplantation cases. Diagnosis is very important because this complication can cause hepatic congestion that develops to liver cirrhosis, graft loss, and patient loss. However, this is unlikely in cases where there are no ascites or hypoalbuminemia. OBJECTIVES: Eleven of 167 patients who had undergone pediatric living-donor liver transplantation were identified in the outpatient clinic at Jichi Medical University as having suffered from hepatic vein stenosis, and were enrolled in the study. METHODS: We conducted a retrospective study in which we reviewed historical patient records to investigate the parameters for diagnosis and examine treatment methods and outcomes. RESULTS: The 11 patients were treated with 16 episodes of balloon dilatation. Three among these received retransplantation and another 2 cases required the placement of a metallic stent at the stenosis. Histological examination revealed severe fibrosis in four of nine patients who had a liver biopsy, with mild fibrosis revealed in the other five grafts. Furthermore, hepatomegaly and splenomegaly diagnosed by computed tomography, elevated levels of hyarulonic acid, and/or a decrease in calcineurin inhibitor clearance were found to be pathognomonic at diagnosis, and tended to improve after treatment. CONCLUSIONS: Diagnosis of hepatic vein stenosis after liver transplantation can be difficult, so careful observation is crucial to avoid the risk of acute liver dysfunction. Comprehensive assessment using volumetry of the liver and spleen and monitoring of hyarulonic acid levels and/or calcineurin inhibitor clearance, in addition to some form of imaging examination, is important for diagnosis and evaluation of the effectiveness of therapy.

Splenomegaly and Its Associations with Genetic Polymorphisms and Treatment Outcome in Colorectal Cancer Patients Treated with Adjuvant FOLFOX.

PURPOSE: Splenomegaly is a clinical surrogate of oxaliplatin-induced sinusoidal obstruction syndrome (SOS). We investigated development of splenomegaly and its association with treatment outcome and genetic polymorphisms following adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in colorectal cancer (CRC) patients. MATERIALS AND METHODS: Splenomegaly was determined by spleen volumetry using computed tomography images obtained before initiation of chemotherapy and after completion of adjuvant FOLFOX in CRC patients. Ten genetic polymorphisms in 4 SOS-related genes (VEGFA, MMP9, NOS3, and GSTP1) were analyzed using DNA from peripheral blood mononuclear cells. RESULTS: Of 124 patients included, increase in spleen size was observed in 109 (87.9%). Median change was 31% (range, -42% to 168%). Patients with splenomegaly had more severe thrombocytopenia compared to patients without splenomegaly during the chemotherapy period (p < 0.0001). The cumulative dose of oxaliplatin and the lowest platelet count during the chemotherapy period were clinical factors associated with splenomegaly. However, no significant associations were found between genetic polymorphisms and development of splenomegaly. Disease-free survival was similar regardless of the development of splenomegaly. CONCLUSION: Splenomegaly was frequently observed in patients receiving adjuvant FOLFOX and resulted in more severe thrombocytopenia but did not influence treatment outcome. Examined genetic polymorphisms did not predict development of splenomegaly.

Adjuvant FOLFOX chemotherapy and splenomegaly in patients with stages II-III colorectal cancer.

BACKGROUND: The impact of adjuvant chemotherapy on hepatic function and portal hypertension in patients with stages II-III colon cancer has not been previously described. We conducted a retrospective study to assess the effects of adjuvant FOLFOX chemotherapy on the splenic index (SI) as a surrogate marker for portal hypertension. METHODS: Stage II-III colorectal cancer patients treated with adjuvant FOLFOX or fluorouracil/leucovorin (5-FU/LV) at Roswell Park Cancer Institute between 2002 and 2006 were identified. Computerizedt omography (CT) scans obtained prior to and at completion of chemotherapy, and every 6 months thereafter were reviewed. Splenic size was evaluated using the SI (SI = length x width x height of the spleen). RESULTS: 40 patients were identified in the FOLFOX group and 23 in the 5-FU/LV group. After 6 months of adjuvant chemotherapy, the mean increase in SI was 45.7 and 16.3% in the FOLFOX and 5-FU/LV groups, respectively (p = 0.0069). SI increased by >100% in 6 patients (15%) in the FOLFOX group versus none in the 5-FU/LV group (p = 0.16). The mean SI at completion of adjuvant chemotherapy was significantly higher in the FOLFOX group than in the 5-FU/LV group (p = 0.007). The mean SI decreased steadily over a period of 2 years after discontinuation of FOLFOX, suggesting potential reversibility of oxaliplatin-induced hepatic injury in this setting. CONCLUSIONS: Adjuvant FOLFOX significantly increases the SI in patients with resected colorectal cancer in comparison to adjuvant 5-FU/LV. The increase in SI may be a marker of oxaliplatin-induced hepatic injury and should be investigated further in prospective longitudinal studies of oxaliplatin-based adjuvant chemotherapy.

[Excessive hyperferritinemia as an indication of a reactive hemophagocytosis syndrome]. / Exzessive Hyperferritinämie als Hinweis auf ein reaktives Hämophagozytose-Syndrom.

HISTORY AND ADMISSION FINDINGS: A 17-year-old girl with a history of a polyarthritis of unknown etiology was admitted because of acute fever and general weakness. There were palpable cervical lymph nodes and her body temperature was 39.5 degrees C. INVESTIGATIONS: GOT was raised to 282 U/1, GPT to 266 U/l lactate dehydrogenase to 1275 U/I and bilirubin to 0.6 mg/dl. The Quick value was 67%, albumin 28 mg/dl. White cell count was decreased to 1700/microl, with 43% granulocytes, 39% lymphocytes, 17% monocytes. Platelet count was 64,000/microl. Ultrasound revealed splenomegaly. Ferritin was markedly raised to 11,860 ng/ml (normal up to 150 ng/ml). An epstein-barr-virus infection was found. THERAPY AND CLINICAL COURSE: Suspecting a reactive hemophagocytosis syndrome, she was treated with prednisolone (2 mg/kg). The diagnosis was confirmed by a bone marrow aspirate. The patient's condition and laboratory values improved rapidly. CONCLUSION: Markedly increased ferritin levels in a clinically septic patient with an underlying rheumatic disease indicates a hemophagocytotic syndrome. High dosage steroid should be started before there is biopsy confirmation of the disease.

A radiologic study of tuberculosis of the abdomen (gastrointestinal tract).

The roentgenologic features of 160 cases of tuberculosis of the abdomen are reviewed. The 3 standard examinations of the gastrointestinal tract (plain film abdominal roentgenography, barium meal and follow-through studies, and barium enema examinations) are required to provide useful pointers towards the diagnosis. In plain film roentgenography of the abdomen, the triad of ascites, absence of gas shadows in the right iliac fossa, and segmental dilatation of the terminal ileum demonstrates features which are very suspicious of intestinal tuberculosis. In the barium meal studies showing disordered small bowel patterns, tuberculosis of the abdomen should be considered when this pattern is associated with fixation of bowel loops on supine and erect roentgenograms, spiculation and the presence of multiple strictures in the small bowel. Although the duodenojejunal and ileocecal regions are the commonest sites involved, lesions are not confined to these sites alone, but may also involve any part of the alimentary canal such as the esophagus and the small and large bowel. However, no anorectal lesions were encountered in this study.