Joerg Trojan

Fluorine-18 FDG positron emission tomography for imaging of hepatocellular carcinoma

Objective:The detection of increased fluorine-18 fluorodeoxyglucose (18F-FDG) uptake by positron emission tomography (PET) is based on the enhanced glucose metabolism of tumor cells. Because the detection and staging of hepatocellular carcinoma (HCC) in patients with liver cirrhosis can be difficult, we prospectively evaluated the sensitivity of 18F-FDG PET in 14 consecutive patients with HCC.Methods:Whole body and regional 18F-FDG PET of the liver were obtained. The results were compared with ultrasonography, contrast-enhanced, helical CT, histological grading, p53 protein expression of HCC, and serum α-fetoprotein (AFP) level.Results:In 7 patients PET demonstrated increased tumor 18F-FDG uptake, whereas HCC was not distinguishable from nonmalignant liver tissue in 7 other patients. Hepatic lesions were detected by ultrasonography in all patients, whereas only 11 of 14 HCCs could be identified by CT. In 3 patients extrahepatic spread was demonstrated by 18F-FDG PET. Patients with increased tumor 18F-FDG uptake had significantly larger hepatic lesions and higher serum AFP levels than those with normal 18F-FDG uptake. Lesions could be visualized by 18F-FDG PET in 7 of 8 patients with moderately or poorly differentiated HCC, whereas none of the six well-differentiated tumors was detected. Two patients with strong p53 expression demonstrated increased tumor 18F-FDG uptake and extrahepatic metastases.Conclusions:The sensitivity of 18F-FDG PET for the imaging of HCC is low. Nevertheless, in patients with moderately or poorly differentiated HCC, tumors >5 cm, or with markedly elevated AFP levels 18F-FDG PET may contribute to an effective noninvasive staging.

Recurrent hepatocellular carcinoma after liver transplantation – an emerging clinical challenge

In western countries, hepatocellular carcinoma (HCC) is a major reason for orthotopic liver transplantation (OLT) with estimated recurrence rates between 15% and 20%. This selective literature review addresses follow‐up care after OLT in HCC and current treatment options. Recurrence prediction is based on pathological tumor stage, vascular invasion, serum alfafetoprotein levels, and histological differentiation, but further advances are expected by molecular profiling techniques. Lower levels of immunosuppressive agents are associated with a lower risk for HCC recurrence. Retrospective studies indicate that mammalian target of rapamycin (mTOR) inhibitors as immunosuppression reduce the risk of HCC recurrence. However, prospective studies supporting this potential advantage of mTOR inhibitors are still lacking, and higher rejection rates were reported for sirolimus after OLT in HCC. Prognosis is poor in recurrent HCC, a longer interval between OLT and recurrence and feasibility of surgical resection are associated with improved survival. Systemic treatment with sorafenib is the current standard of care in patients with advanced‐stage HCC not suitable for locoregional therapy. After OLT, combination of an mTOR inhibitor with sorafenib is feasible and frequently used in clinical practice. As safety and efficacy data are still limited, close clinical monitoring is mandatory.

Extraintestinal polyps in Peutz-Jeghers syndrome: presentation of four cases and review of the literature

Abstract Peutz-Jeghers syndrome (PJS) is a rare hereditary disorder characterized by hamartomatous polyps in the gastrointestinal tract and typical pigment lesions. Extraintestinal polyps have rarely been reported. Possible sites include the respiratory tract, urogenital tract, and gallbladder. We here describe four cases of extraintestinal polyps in PJS patients and review the literature on the need for operative therapy of extraintestinal polyps in PJS. Three nonrelated patients were examined who had PJS and polyps in the gallbladder; the fourth patient had PJS and recurrent choanal polyps. Surgery has so far been performed only for symptomatic polyps: one laparoscopic cholecystectomy and removal of the choanal polyps for recurrent infections of the respiratory tract. The remaining two patients reported no symptoms from the extraintestinal polyps. No malignant transformation was found in these patients, nor has such been reported in the literature on PJS. The frequent observation of this manifestation in our patients raises the question of clinical management: Is prophylactic surgery indicated? Since malignant transformation of PJS polyps in the intestine is extremely rare we see no reason for operative therapy as long as the polyps are small and asymptomatic. Regular sonographic controls are recommended since the risk of malignant transformation cannot be ruled out at present.

A de novo deletion of chromosome 5q causing familial adenomatous polyposis, dysmorphic features, and mild mental retardation

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder that typically presents with colorectal cancer secondary to extensive adenomatous polyps of the colon. The molecular basis and clinical phenotype of FAP are well known. Recurrent episodes of severe abdominal pain and a positive fecal occult blood test in an 18-yr-old boy with mild mental retardation and slight dysmorphic features of the face, head, and skeletal system led to the diagnosis of FAP. The clinical workup revealed the presence of over 100 sessile colonic polyps but no polyp formation in the upper GI tract, no cancer development, nor other FAP-associated lesions. To find out whether there is an association between mental retardation and FAP we performed a chromosome analysis including comparative genomic hybridization and an indirect genotype analysis with polymorphic markers from the APC gene region. Cytogenetic analysis showed an interstitial deletion of chromosomal region 5q that was confined to the region 5q21–q22 by comparative genomic hybridization. The deletion, spanning about 10 centimorgans, encompassed the complete APC gene and can be considered as causative for FAP. Moreover, molecular genetic analysis with polymorphic markers flanking the APC gene demonstrated a de novo deletion on the paternal chromosome. Cytogenetically detectable deletions on chromosome 5 including the APC gene generally lead to an associated gene deletion syndrome. Individuals who present with mild mental retardation and dysmorphic features should therefore be investigated for chromosomal deletions. If the deletion encompasses the APC gene, these patients are at high risk of developing FAP and associated complications.

Severe 25-hydroxyvitamin D deficiency identifies a poor prognosis in patients with hepatocellular carcinoma – a prospective cohort study

Vitamin D is involved in many biological processes. The role of vitamin D in patients with hepatocellular carcinoma (HCC) remains inconclusive, although there is evolving evidence that vitamin D may modulate cancer development and progression.

Characterization of the nuclear import of human MutLα

DNA mismatch repair (MMR) is essential for the maintenance of replication fidelity. Its major task is to recognize mismatches as well as insertion/deletion loops of newly synthesized DNA strands. Although different players of human MMR have been identified, the regulation of essential steps of MMR is poorly understood. Because MMR is initiated in the nucleus, nuclear import might be a mechanism to regulate MMR. Nuclear targeting is accomplished by conserved signal sequences called nuclear localization signals (NLS), which represent clusters of positively charged amino acids (aa). hMLH1 contains two clusters of positively charged amino acids, which are candidate NLS sequences (aa 469–472 and 496–499), while hPMS2 contains one (aa 574–580). To study the effect of these clusters on nuclear import, NLS mutants of hMLH1 and hPMS2 were generated and expressed in 293T cells. The subcellular localization of the mutant constructs was monitored by confocal laser microscopy. We demonstrated that missense mutations of two signal sequences, one in hMLH1 and one in hPMS2, lead to impaired nuclear import, which was especially prominent for mutants of the hMLH1 residues K471 and R472; and hPMS2 residues K577 and R578.

Capnographic monitoring of propofol-based sedation during colonoscopy.

BACKGROUND AND STUDY AIMS Capnography enables the measurement of end-tidal CO2 and thereby the early detection of apnea, prompting immediate intervention to restore ventilation. Studies have shown that capnographic monitoring is associated with a reduction of hypoxemia during sedation for endoscopy and early detection of apnea during sedation for colonoscopy. The primary aim of this prospective randomized study was to evaluate whether capnographic monitoring without tracheal intubation reduces hypoxemia during propofol-based sedation in patients undergoing colonoscopy. PATIENTS AND METHODS A total of 533 patients presenting for colonoscopy at two study sites were randomized to either standard monitoring (n = 266) or to standard monitoring with capnography (n = 267). The incidence of hypoxemia (SO2 < 90 %) and severe hypoxemia (SO2 < 85 %) were compared between the groups. Furthermore, risk factors for hypoxemia were evaluated, and sedation performed by anesthesiologists was compared with nurse-administered propofol sedation (NAPS) or endoscopist-directed sedation (EDS). RESULTS The incidence of hypoxemia was significantly lower in patients with capnography monitoring compared with those receiving standard monitoring (18 % vs. 32 %; P  = 0.00091). Independent risk factors for hypoxemia were age (P = 0.00015), high body mass index (P = 0.0044), history of sleep apnea (P = 0.025), standard monitoring group (P = 0.000069), total dose of propofol (P = 0.031), and dose of ketamine (P < 0.000001). Patients receiving anesthesiologist-administered sedation developed hypoxemic events more often than those receiving NAPS or EDS. In patients with anesthesiologist-administered sedation, sedation was deeper, a combination of sedative medication (propofol, midazolam and/or ketamine) was administered significantly more often, and sedative doses were significantly higher compared with patients receiving NAPS or EDS.  CONCLUSIONS In patients undergoing colonoscopy during propofol-based sedation capnography monitoring with a simple and inexpensive device reduced the incidence of hypoxemia.

Peutz-Jeghers syndrome: molecular analysis of a three-generation kindred with a novel defect in the serine threonine kinase gene STK11.

The Peutz-Jeghers syndrome, phenotypically characterized by mucocutaneous pigmentation and hamartomatous polyposis, is an autosomal dominant disease with variable expression and incomplete penetrance. Moreover, affected patients are at increased risk for gastrointestinal and other malignancies. Recently, a mutated gene encoding abnormal forms of the novel serine threonine kinase STK11 has been identified as a genetic cause of Peutz-Jeghers syndrome. Here, we report the molecular analysis of the STK11 gene in a patient with Peutz-Jeghers syndrome, which in exon 1 revealed a guanine (G) insertion in the 5 G repeat of codons 51–53. The insertion leads to a frameshift with a premature TGA stop codon 324 bp downstream in codon 162, predicting the expression of a truncated protein without kinase activity. This heterozygous germline mutation was also found in the affected father and in one affected sister of the index patient, but not in any phenotypically unaffected family member or in unrelated control subjects. In DNA isolated from microdissected hamartomatous polyps of the index patient, exon 1 of the STK11 gene could not be amplified suggesting that both alleles of STK11 exon 1 were lost in the hamartomatous polyps. Identification of a STK11 gene mutation in an index patient offers the possibility of a predictive diagnosis, and initiation of specific screening programs in the genetically affected kindred.

mTOR inhibitors and sorafenib for recurrent heptocellular carcinoma after orthotopic liver transplantation

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Peroral cholangioscopy for diagnosis and therapy of biliary tract disease using an ultra-slim gastroscope

High-resolution video cholangioscopy is expected to improve diagnostic validity for diseases of the biliary tract. We report our experience in using an ultra-slim gastroscope for diagnosis and treatment of biliary tract disease. Cholangioscopy was attempted in 25 cases (22 patients) and succeeded in 22 cases (success rate 88%; 19 patients). Cholangiocellular carcinoma (CCC) was diagnosed by cholangioscopy in five of 10 cases (histopathologically confirmed in four), or ruled out in five. Cholangioscopy was used to detect stones in mega-choledochus (n=3), to clarify the postoperative condition of the bile ducts (n=2), to diagnose bile duct varices (n=1), and to release a dislodged self-expanding metal stent (n=1), and others. Argon plasma coagulation was successfully completed in a patient with mucin-producing adenomatosis of the bile ducts. One case of non-fatal air embolism occurred before replacing air with CO2 insufflation. In summary, peroral cholangioscopy with an ultra-slim gastroscope is feasible and helpful in selected patients, improving diagnostic validity, and offering new therapeutic interventions. This technique should only be performed using CO2 insufflation.