Spyros P. Dourakis

Hepatitis B virus reactivation in patients receiving chemotherapy for malignancies: role of precore stop-codon and basic core promoter mutations

Summary.  Hepatitis B virus (HBV) strains carrying the precore stop‐codon mutation (A1896) have been considered among the predisposing factors for reactivation during chemotherapy for malignancies. The role of the T1762/A1764 basic core promoter (BCP) mutations has not been fully evaluated. We aimed to record any changes in HBV serological markers after reactivation, detect the presence of A1896 and BCP mutations and evaluate the type of cytotoxic drugs involved. We retrospectively screened eight patients presenting with HBV reactivation following chemotherapy for malignancies. The chemotherapy regimens used included corticosteroids (CSs), fludarabine and cyclophosphamide/adriamycine. The INNO‐LiPA HBV PreCore kit was used for the detection of the A1896 and BCP mutations. Six patients who were hepatitis B surface antigen (HBsAg)‐(+)/hepatitis B e antigen (HBeAg)‐(−) before chemotherapy, had disease reactivation following a mean of four cycles of chemotherapy. Four survived and two died of hepatic failure. At the time of reactivation, all six patients carried the A1896 and five of them the BCP mutations. The remaining two patients were HBsAg‐(−)/anti‐HBs‐(+)/anti‐hepatitis B core (HBc)‐(+)/HBeAg‐(−) before chemotherapy. One of them reverted to HBeAg‐(+) status but remained HBsAg‐(−), while the other became HBsAg‐(+)/HBeAg‐(+), following three and eight cycles of fludarabine treatment, respectively. The former carried the A1896 and the latter the wild‐type virus. Both died from causes associated with their haematological disease. All but one of our patients with HBV reactivation during chemotherapy carried the precore stop‐codon and BCP mutations. Whether this occurs more frequently in such patients than those carrying the wild‐type virus needs further investigation. Fludarabine should be added to the list of drugs inducing HBV reactivation. HBV reactivation following fludarabine treatment occurred in HBsAg‐(−) patients who had been anti‐HBs‐(+).

Modern diagnostic approaches to cholangiocarcinoma

BACKGROUND Cholangiocarcinoma is a very aggressive tumor with poor survival. Therefore, early diagnosis and surgical resection are of paramount importance. Its diagnosis is difficult because access to the tumor is not easy. Biopsy is possible only for intrahepatic cholangiocarcinoma, which accounts for 10% of cases. Routine brush cytology from endoscopic retrograde cholangiopancreatography (ERCP) has a high specificity of 100% but unfortunately a low sensitivity of 30%. In this review we briefly describe new diagnostic techniques applicable to ERCP brush cytology specimens and targeting the genetic background of the disease, in particular fluorescence in situ hybridization (FISH) and digital image analysis (DIA). DATA SOURCES The PubMed database up to 2011 was used for the retrieval of relevant articles. The search terms FISH, fluorescence in situ hybridization, DIA, digital image analysis and cholangiocarcinoma were used. Both original and review articles were used. RESULTS FISH identifies cells with chromosomal abnormalities, mainly numerical aberrations, using a mixture of fluorescence-labeled probes. FISH offers a higher sensitivity than routine cytology, retaining a high level of specificity. The DIA criterion for malignancy is demonstration of aneuploidy. This technique increases the sensitivity to 40%, but the specificity remains low. Preliminary data from application to other tumors suggest that combination of FISH and DIA may be of further benefit. CONCLUSIONS The new techniques offer a significantly enhanced diagnostic efficacy in the evaluation of ERCP brush specimens. Apart from contributing to a more timely diagnosis, their wider application to cholangiocarcinoma may also facilitate the genetic study of the disease and add to our understanding of oncogenesis at the molecular level, with the prospect of identifying targets for novel therapeutic interventions.

Post embolization syndrome in doxorubicin eluting chemoembolization with DC bead.

BACKGROUND/AIMS The investigation of post embolization syndrome (PES) in patients with hepatocellular carcinoma (HCC) after treatment with doxorubicin loaded DC Bead (DEB-DOX). METHODOLOGY The study included 237 patients treated with sequential DEB-TACE performed at set time intervals every two months until 3 sessions/6 month f-u. Patients were ECOG 0-1, Child-Stage-A (n=116, 48.9%) and B (n=121, 51%). Embolizations were as selective as possible with DC Bead of 100-300µm in diameter followed by 300-500µm loaded with doxorubicin at 37.5mg/mL of hydrated bead (max:150mg). RESULTS PES regardless of severity was observed in up to 86.5%. However grade 2 PES ranged between 25% and 42.19% across treatments. Temperatures above 38°C were seen in 22.7% to 38.3% across treatments. No statistically significant increase of PES was seen in beads of 100-300µm in diameter; incidence of fever and pain presented correlation with the extent of embolization (p=0.0001-0.006 across treatments). Baseline tumor diameter was associated with incidence of fever (p=0.0001-0.001). Duration of fever correlated with the extent of embolization (p=0.008). PES was not associated with elevation of liver enzymes and was correlated with degree of necrosis (p<0.001). CONCLUSIONS PES after DEB-DOX represents tumor response to treatment and does not represent collateral healthy liver damage.

Sump syndrome: endoscopic treatment and late recurrence

OBJECTIVE:Biliary sump syndrome is a rare complication of biliary-enteric anastomosis. Classically, the distal bile duct becomes obstructed by food, stones, or debris after choledochoenterostomy. Endoscopic sphincterotomy has been recommended as the primary and definitive treatment modality. The aim of our study was to confirm the short and long term therapeutic efficacy of endoscopic treatment in a long follow-up period.METHODS:The series include 31 patients with characteristic clinical illness after choledochoduodenostomy. All of them were successfully treated by endoscopic sphincterotomy and bile duct clearance with a balloon catheter or basket. The follow-up period ranged from 18 to 84 months (median: 51 months).RESULTS:Clinical improvement was immediate in all patients. No complications were recorded. Recurrence of the syndrome, with restenosis of the sphincterotomy opening, was observed in six patients (19%) and was treated successfully and safely with a new papillotomy. Sump syndrome recurrence occurred 31–72 months (median: 58.5 months) after the initial treatment.CONCLUSIONS:We report a considerably high recurrence rate of sump syndrome after initially successful endoscopic management and its effective endoscopic treatment with a new papillotomy. We still believe that the primary therapeutic approach in patients with sump syndrome should be endoscopic.

Pubic Osteomyelitis due to Klebsiella pneumoniae in a Patient with Diabetes Mellitus

Osteomyelitis of the pubic symphysis or pubic osteomyelitis is a rare entity that is encountered in certain groups of people such as athletes, intravenous drug users, patients with pelvic malignancy, and patients who have undergone surgical manipulations of the genitourinary system. The most frequent causative organism is Staphylococcus aureus. K pneumoniae is a common pathogen in diabetic patients, but pubic osteomyelitis due to K pneumoniae has not previously been described. We present a diabetic patient with pubic osteomyelitis caused by K pneumoniae without known predisposing factors.

Flour Contamination as a Source of Lead Intoxication

CASE REPORT A 43-year-old man was hospitalized because of severe anemia and recurrent bouts of abdominal pain over 20 days. There was no known occupational exposure to toxins. Concomitantly, the patients father complained of having the same symptoms. Familial lead poisoning was diagnosed when all 6 family members tested had high blood leads (31-64 micrograms/dL). RESULTS Following detailed examination of the potential sources common to all members of the household, the cause of poisoning was determined to be corn flour containing 38.7 mg/g lead. Physicians are reminded to consider lead poisoning in the differential diagnosis of individuals with unexplained symptoms, particularly those of abdominal discomfort and anemia.

High serum lipopolysaccharide binding protein is associated with increased mortality in patients with decompensated cirrhosis

Lipopolysaccharide‐binding‐protein (LBP) is an acute‐phase‐protein produced by hepatocytes. Changes in LBP are associated with the dynamics of bacterial translocation and intestinal permeability in decompensated cirrhosis (DC). We assessed serum and ascitic‐fluid (AF) LBP and examined their association with mortality in patients with DC.

Long term recurrence analysis post drug eluting bead (deb) chemoembolization for hepatocellular carcinoma (hcc).

UNLABELLED BACKROUND-AIMS: To determine long term outcomes, regarding recurrence and survival, in patients with HCC that achieved complete response after initial treatment with drug eluting beads (DEB) using DC Bead loaded with doxorubicin (DEB-DOX). METHODOLOGY Forty-five patients with HCC, not suitable for curative treatments that exhibited complete response (EASL criteria) to initial DEB-DOX treatment were retrospectively analyzed after a median follow up period of 63 months. Child-Pugh class was A/B (62.2/37.8%) and mean lesion diameter 5.36 ± 1.1 cm. Lesion morphology was one dominant ≤5cm (53.3%), one dominant >5cm (31.1%) and multifocal (15.6%). RESULTS At 5 years, overall survival was 62.2% and recurrence-free survival 8.9%. All deaths that occurred were related to tumor progression (31.1%) or complications of underlying liver disease (28.9%). Median time of initial recurrence from baseline treatment was 18 months (range 8-52). When recurrence occurred, a mean time interval between additional DEB-DOX procedures less than 9 months was correlated to a poorer prognosis (p=0.025). Multivariate analysis identified Child-Pugh class at baseline (p=0.048), combined therapy of recurrences with local ablation (p=0.03) and number of DEB-DOX procedures (p=0.037) as significant prognostic factors of 5-year survival. Lesion morphology displayed significance for recurrence-free survival (p=0.014). Child-Pugh class at baseline, additional local ablation, pattern of initial recurrence and initial sum of recurrent tumor diameters all displayed statistical significance for post-recurrence survival (median 40 months), with the first two variables maintaining statistical significance in multivariate analysis (p=0.015 and p=0.014 respectively). CONCLUSION Initial complete response to DEB-DOX ensures a favorable prognosis. However, management of recurrent tumors, which occur frequently mostly as new lesions, and preservation of underlying liver function appear to play a key role in prolonging survival.

An extranodal NK/T cell lymphoma, nasal type, with specific immunophenotypic and genotypic features.

Extranodal NK/T cell lymphoma, ‘nasal type,’ is a rare clinicopathological entity in Europe. The main clinical features are nasal congestion, sore throat, dysphagia and epistaxis, due to a destructive mass involving the midline facial tissues. Pathologically, lymphoma cells exhibit angioinvasion, angiodestruction and coagulative necrosis. We report the case of a patient who presented with fever, dyspnea, nasal congestion, headache, distention of right nasal turbinates and exophytic lower leg ulcerating lesions. A CT scan of visceral scull demonstrated a filling mass of right frontal, ethmoidal and maxillary sinuses with erosion of the wall of right maxillary sinus and ventral portion of the diaphragm. A biopsy was performed in the skin lesion and showed an angioinvasive NK/T cell lymphoma CD56 negative with clonal rearrangement of the T-cell-receptor γ gene. Up to our knowledge, this is a rare immunophenotype for NK/T-cell, ‘nasal type,’ lymphomas. However, the lymphoma may be classified as extranodal NK/T cell lymphoma, ‘nasal type,’ due to typical clinical presentation, radiologic findings and pathological characteristics of polymorphism, angioinvasion, angiodestruction and coagulative necrosis.

Dilated Cardiomyopathy during the Course of Hemolytic Uremic Syndrome

A 47-year-old woman presented with severe hemolytic uremic syndrome (HUS) followed by heart failure. An echocardiogram showed an ejection fraction of 20%, and a cardiac catheterization followed by a myocardial histologic evaluation demonstrated dilated cardiomyopathy. Plasma exchange and hemodialysis were performed regularly. The later outcomes of renal function and cardiomyopathy were favorable. A review of the literature confirmed the rare and severe nature of cardiac lesions occurring in the course of HUS. This case indicates the importance of cardiac monitoring in HUS and the need for prolonged support.