Ulrich Stölzel

Prognostic and predictive value of circulating tumor cell analysis in colorectal cancer patients.

ObjectiveThe aim of this study was to assess the prognostic and predictive values of circulating tumor cell (CTC) analysis in colorectal cancer patients.Patients and methodsPresence of CTCs was evaluated in 60 colorectal cancer patients before systemic therapy - from which 33 patients were also evaluable for CTC analysis during the first 3 months of treatment - through immunomagnetic enrichment, using the antibodies BM7 and VU1D9 (targeting mucin 1 and EpCAM, respectively), followed by real-time RT-PCR analysis of the tumor-associated genes KRT19, MUC1, EPCAM, CEACAM5 and BIRC5.ResultsPatients were stratified into groups according to CTC detection (CTC negative, when all marker genes were negative; and CTC positive when at least one of the marker genes was positive). Patients with CTC positivity at baseline had a significant shorter median progression-free survival (median PFS 181.0 days; 95% CI 146.9-215.1) compared with patients with no CTCs (median PFS 329.0 days; 95% CI 299.6-358.4; Log-rank P < .0001). Moreover, a statistically significant correlation was also founded between CTC detection during treatment and radiographic findings at the 6 month staging. This correlation applied to CTC results before therapy (odds ratio (OR), 6.22), 1 to 4 weeks after beginning of treatment (OR, 5.50), 5 to 8 weeks after beginning of treatment (OR, 7.94) 9 to 12 weeks after beginning of treatment (OR, 14.00) and overall CTC fluctuation during the course of treatment (OR, 20.57).ConclusionThe present study provides evidence of a strong correlation between CTC detection and radiographic disease progression in patients receiving chemotherapy for colorectal cancer. Our results suggest that in addition to the current prognostic factors, CTC analysis represent a potential complementary tool for prediction of colorectal cancer patients’ outcome. Moreover, the present test allows for molecular characterization of CTCs, which may be of relevance to the creation of personalized therapies.

Endosonography of Neuroendocrine Tumors of the Stomach, Duodenum, and Pancreas

Neuroendocrine tumors (NETs) of the foregut type are frequently smaller than 2 cm in diameter and mainly located in the pancreas or the gastric and duodenal wall. Conventional cross-sectional imaging techniques, such as transabdominal ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) are limited by their inability to detect small tumors and especially those located within the gastrointestinal wall. Endoscopic ultrasonography (EUS) allows detailed visualization of the whole pancreas and almost all parts of the gastric and duodenal walls. Therefore, EUS is an important diagnostic tool for the preoperative localization of NETs of the foregut type. Several studies performed in a retrospective manner, as well as two studies performed in a prospective manner, indicate a clear superiority of EUS as compared to CT, US, MRI, and also angiography in detecting NETs of the foregut type. Somatostatin-receptor scintigraphy (SRS) also detects NETs of the foregut type in a very high percentage of cases, and the combination of EUS and SRS appears to increase the sensitivity even more. Thus EUS and also SRS should be employed early if NETs of the foregut type are suspected. Conventional imaging procedures such as US, CT, and MRI should be mainly used to exclude local and distant metastases.

Prognostic Role of a Multimarker Analysis of Circulating Tumor Cells in Advanced Gastric and Gastroesophageal Adenocarcinomas

Objective: We aimed to assess the prognostic value of circulating tumor cells (CTC) in patients with advanced gastric and gastroesophageal adenocarcinomas. Methods: The presence of CTC was evaluated in 62 patients with advanced gastric and gastroesophageal adenocarcinomas before systemic therapy and at follow-up through immunomagnetic enrichment for mucin 1- and epithelial cell adhesion molecule (EpCAM)-positive cells, followed by real-time RT-PCR of the tumor-associated genes KRT19, MUC1, EPCAM, CEACAM5 and BIRC5. Results: The patients were stratified into groups according to CTC detection (CTC negative: with all marker genes negative; CTC positive: with at least 1 of the marker genes positive). Patients who were CTC positive at baseline had a significantly shorter median progression-free survival (PFS; 3.5 months, 95% CI: 2.9-4.2) and overall survival (OS; 5.8 months, 95% CI: 4.5-7.0) than patients lacking CTC (PFS 10.7 months, 95% CI: 6.9-14.4, p < 0.001; OS 13.3 months, 95% CI: 8.0-18.6, p = 0.003). Alterations in the marker profile during the course of chemotherapy were not predictive of clinical outcome or response to therapy. Yet, a favorable clinical response depended significantly on CTC negativity (p = 0.03). Conclusion: Our data suggest that the presence of CTC is a major predictor of outcome in patients with gastric and gastroesophageal malignancies.

X-linked protoporphyria: Iron supplementation improves protoporphyrin overload, liver damage and anaemia

C-terminal deletions in the 5-aminolaevulinic acid-synthase 2 (ALAS2) gene were recently identified leading to the reclassification of a minority of patients with erythropoietic protoporphyria (EPP, Online Mendelian Inheritance in Man (OMIM) reference 177000) as having X-linked protoporphyria (XLPP, OMIM 300752). EPP and XLPP share clinical and biochemical features, such as photosensitivity, liver damage and elevated protoporphyrin IX (PPIX) (Whatley et al, 2008). A nine-year-old Caucasian boy presented with a seven-year history of sunlight-sensitive skin lesions and elevation of liver enzymes. EPP was diagnosed, based on excessive elevation of free erythrocyte PPIX (128 lmol/l, normal <0 09) and zinc protoporphyrin IX (znPPIX 1763 lmol/mol haem, normal <40). Further blood analysis showed microcytic anaemia (MCV 74 4 fl, normal >80; haemoglobin 114 g/l, normal >120) with iron deficiency and low ferritin concentration (5 9 lg/l, normal 12–63), iron (2 2 lmol/l, normal 4–24), transferrin

Improvement of multiple sclerosis on tacrolimus plus mycophenolate mofetil after liver transplantation

Interferon-b (IFN-b) is standard therapy for recurrent multiple sclerosis (MS). Life-threatening adverse effects are rare, but a high frequency of elevated liver enzymes is reported [1]. Several randomized clinical trials show high rate of intermittent ALT level elevations during IFN-b treatment [2]. In a summary of six different randomized trials the 2-year cumulative rate of patients with elevated ALT was 67% for 721 patients being treated with 44 lg IFN-b1a thrice weekly, and 53% for 398 patients being treated with a lower dose of 22 lg thrice weekly [2]. The vast majority of the hepatic enzyme elevation and symptomatic dysfunction are mild and transient. Serious liver injury is rare (Table 1), but can occur [3] and is more frequent in females [2]. Dosage reductions are necessary in <5% of treated patients but seem to help reducing the frequency of deterioration [4]. In case of fulminant organ failure treatment options are limited: dosage reduction or withdrawal of IFN-b leads normally to rapid improvement of liver function [3,5], liver transplantation can be ultima ratio. In the literature only one case of organ transplantation because of fulminant liver failure after IFN-b treatment is reported [3]. In this case, it was later reported that co-administration of IFN–b in combination with nefazodone might have been involved in the development of liver failure [6,7]. We report a second patient who underwent liver transplantation after development of acute liver failure during IFN-b therapy for MS with evidence for autoimmune hepatitis, thus supporting earlier discussions on autoimmune hepatitis in patients with MS [8]. More importantly, in our case and in one earlier, it was demonstrated that liver transplantation was followed by a remarkable improvement of the underlying MS.

Heme Synthesis Defects and Porphyrias

Porphyrias are metabolic disorders of the heme biosynthesis. Clinically, they can be differentiated into acute and non-acute porphyrias. The symptomatic phase of acute hepatic porphyrias is characterized by overproduction of neurotoxic porphyrin precursors and porphyrins. Acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and Doss porphyria (ALSDP) belong to this group of metabolic disorders. The clinical presentation of the acute hepatic porphyria syndrome includes abdominal, psychiatric, neurological, and cardiovascular symptoms. The diagnosis is based on an at least tenfold increased urinary excretion of porphobilinogen (apart from Doss porphyria and lead intoxication). Besides symptomatic therapy with non-porphyrinogenic drugs, electrolyte compensation, and intensive monitoring, intravenous administration of glucose and heme arginate is established for treatment. Among the non-acute types like porphyria cutanea tarda, erythropoietic protoporphyria, and congenital erythropoietic porphyria, the accumulated porphyrins cause photosensitivity of the skin and in some cases severe liver damage. X-linked protoporphyria (XLPP) represents a new type of protoporphyria, with 5-aminolevulinic acid synthase 2 gain of function leading to high concentrations of free protoporphyrin IX. The location of the deficient enzyme within the heme biosynthetic pathway determines the pattern of the accumulated porphyrins. The cDNA of all enzymes of heme biosynthesis have been characterized, and mutations responsible for any of the porphyrias have been described. Besides light protection, there are different therapies depending on the type of non-acute porphyria. Ultimately, liver transplantation may be considered in therapy-resistant cases of acute hepatic porphyrias and bone marrow transplantation in severe cases of erythropoietic porphyrias.