Tamás Györke

The epidemiology and the pathogenesis of inflammatory bowel disease

The etiology of inflammatory bowel disease (IBD) is still unknown. However, a satisfactory solution cannot be far away. IBD actually encompasses two diseases, i.e. Crohns disease (CD) and ulcerous colitis (UC). These diseases resemble each other so closely that they cannot be distinguished even pathologically, but differ from each other sufficiently to regard them as independent entities. Epidemiological observations may be helpful in identifying the true causative factors of this evasive disease. Geographically, the prevalence of the disease has a slope from North to South and, to a lesser degree, from West to East. The Western-Eastern discrepancy can be attributed to a difference in Western life styles. The incidence of the disease has been increasing world-wide of late, but its spread has been slowing down in highly affected countries. Racial and ethnic relations in different populations and immigration studies offer interesting data which can reflect genetic, inherited, environmental and behavioural factors. The disease seems to have a characteristic racial-ethnic distribution: the Jewish population is highly susceptible everywhere, but its prevalence in that population nears that of the domestic society in which they live. In Hungary, the Roma (Gypsies) have a considerably lower prevalence than the average population. This can be attributed to a genetic or environmental influence. According to age, the onset of the disease occurs more often in the second or the third decade of life, but there also is another peak in the 60s. Regarding sexual distribution, there is a slight preponderance of colitis ulcerosa in men and of Crohns disease in women. It may correspond to the stronger auto-immune affection in the process of Crohns disease. Environmental factors and behavioural influences also are investigated. Diet, the role of the early ages, smoking habits and the influence of hormonal status and drugs are viewed as useful contributing factors in the manifestation of the disease. Genetic studies show that one-fourth of IBD patients have an affected family member. HLAB27 histocombatibility also plays an important, but not determining role in the development of the disease. Genetic factors seem to have a stronger influence in Crohns disease than ulcerative colitis. The existence of multiple sclerosis-IBD families may reflect the common genetic background or the similar microbial effect as well. A great number of bacterial and viral factors has been suspected of being infectious factors in IBD, mostly in CD. Mycobacteria, Yersinia, Campylobacter, Clostridium, Clamidias, etc. as well as bacteria and some viruses such as herpes and rotavirus and the primary measles virus. None of them has been proven as a real and exclusively pathogenic factor. Immunological background has an important function in the manifestation of the disease. If an individual has a genetic susceptibility to infections, the down regulation of an inflammation in the bowel wall does not occur in a proper way. This initiates the auto-immune process which is a self-increasing cycle. Extra-intestinal manifestations of IBD are of high importance because they can not only follow intestinal symptoms, but precede them by years. Hepatic and biliary disturbances (primary sclerosing cholangitis), are the most serious complications. Mucocutaneous manifestations can be the first appearance of the main disease (in the mouth). Auto-immune consequences (erythema nodosum) or complications caused even by the therapy can occur. Ocular and musculoskeletal manifestations supposedly have the same genetic background and often precede the intestinal symptoms. Considering the epidemiological, genetic and immunological data, we can conclude that ulcerative colitis and Crohns disease are heterogeneous disorders of mutifactorial etiology in which hereditary (genetic) and environmental (microbial, behaviour) factors interact to produce the disease.

Ultrasound in Crohn’s disease of the small bowel

OBJECTIVE The purpose of this work is to prospectively evaluate high resolution ultrasonography with graded compression in the ability to detect Crohns disease of the small bowel (CDSB) together with its complications and activity signs, compared with enteroclysis, CT and immunoscintigraphy in the mirror of the final diagnosis. METHODS AND MATERIAL In a series of 73 consecutive patients, who were referred for enteroclysis with suspected Crohns disease of the small bowel computed tomography (CT), ultrasound (US), immunoscintigraphy with 99mTc labeled monoclonal antigranulocyte antibody (AGAb) examinations were performed within 10 days from each other. For the final evaluation the diagnosis of CDSB was based on combination of clinical and enteroclysis findings (73 cases) and in 17 cases additional surgical and pathological data were available. The results of other modalities were blinded to the radiologists performing and reading out the exams. The diagnostic values of each modality was assessed also in those 18 patients, who had early Crohns disease. In the group of 43 patients with proven CDSB who had all the four imaging modalities, the modalities were compared in their ability to demonstrate various pathological conditions related to CD. Increased (>500 ml/min) flow measured by Doppler US in the superior mesenteric artery and increased color signs in the gut wall seen by power Doppler sonography were compared to CDAI. RESULTS Of the 73 patients the combination of enteroclysis and clinical tests demonstrated CDSB in 47. The sensitivity, specificity and accuracy of ultrasound were 88.4, 93.3 and 90.4%, respectively. Enteroclysis was the most accurate method. CT was more sensitive than US, but less specific. The accuracy of US, CT and scintigraphy were similar. In the group of 18 patients, who had early CDSB, the sensitivity of US decreased to only 67%, CT and scintigraphy had higher values. Intra- and perimural abscesses, and sinus tracts were also more frequently visualized by US, especially if they were small. US was superior than CT in detecting stenoses and skip lesions, but inferior to enteroclysis. US and CT detected more fistulas, than enteroclysis. Compared to CT, US detected more cases with mesenteric lymphadenopathy, equal cases with abscesses and free peritoneal fluids. In detecting mesenteric inflammatory proliferation CT, and in detecting colonic involvement CT and immunoscintigraphy were slightly superior than graded compression US. Patterns of mural stratification detected by ultrasound correlated well with the enteroclysis severity stages. There was only 59% agreement between increased superior mesenteric artery flow detected by Doppler sonography and CDAI, and 60.5% agreement between increased number of Color pixels in the gut wall measured by power Doppler and increased CDAI. CONCLUSION High resolution graded compression sonography is a valuable tool for detecting small intestinal Crohns disease. It has similar diagnostic values as CT. However in early disease the sensitivity substantially decreases. In known Crohns disease for following disease course, evaluating relapses and extramural manifestations US is an excellent tool. Doppler and Power Doppler activity measurements do not correlate well with the more widespread clinical activity index.

Spiral CT colonography in inflammatory bowel disease

OBJECTIVE Most of the studies on virtual colonoscopy are dealing with the role of detecting colorectal polyps or neoplasms. We have undertaken this study to evaluate the value of CT colonography in patients with colonic Crohns disease. METHODS AND MATERIAL Five patients (three males, two females, 23-51 years, mean age 42 years) with known (4) or suspected (1) Crohns disease of the colon underwent fiberoptic colonoscopy and CT colonography in the same day or during a 1-week period. The images were evaluated with the so called zoomed axial slice movie technique and in some regions intra- and extraluminal surface shaded and volume rendered images were generated on a separate workstation. The results were compared to those of a colonoscopy. RESULTS The final diagnosis was Crohns disease in four patients and colitis ulcerosa in one. Total examination was possible by colonoscopy in two cases, and with CT colonography in all five cases. The wall of those segments severely affected by the disease were depicted by the axial CT scans to be thickened. The thick walled, segments with narrow lumen seen on CT colonography corresponded to the regions where colonoscopy was failed to pass. Air filled sinus tracts, thickening of the wall of the terminal ileum, loss of haustration pseudopolyps and deep ulcers were seen in CT colonography. Three dimensional (3D) endoluminal views demonstrated pseudopolyps similar to endoscopic images None of the colonoscopically reported shallow ulcerations or aphtoid ulcerations or granular mucosal surface were observed on 2- or 3D CT colonographic images. CONCLUSION CT colonography by depicting colonic wall thickening seems to be a useful tool in the diagnosis of Crohns colitis, which could be a single examination depicting the intraluminal, and transmural extent of the disease.

Combined PET and Biopsy Evidence of Marrow Involvement Improves Prognostic Prediction in Diffuse Large B-Cell Lymphoma

Bone marrow is an important extranodal site in diffuse large B-cell lymphoma (DLBCL), and marrow histology has been incorporated into the new National Comprehensive Cancer Network international prognostic index. Marrow involvement demonstrated histologically confers poor prognosis but is identified by staging PET in more cases. How information from staging PET and biopsy should be combined to optimize outcome prediction remains unclear. Methods: The International Atomic Energy Agency sponsored a prospective international cohort study to better define the use of PET in DLBCL. As a planned subsidiary analysis, we examined the interplay of marrow involvement identified by PET and biopsy on clinical outcomes. Results: Eight countries contributed 327 cases with a median follow-up of 35 mo. The 2-y outcomes of cases with no evidence of marrow involvement (n = 231) were 81% (95% confidence interval [CI], 76%–86%) for event-free survival (EFS) and 88% (83%–91%) for overall survival (OS); cases identified only on PET (n = 61), 81% (69%–89%) for EFS and 88% (77%–94%) for OS; cases indentified only on biopsy (n = 10), 80% (41%–95%) for EFS and 100% for OS; or cases identified by both PET and biopsy (n = 25), 45% (25%–64%) for EFS and 55% (32%–73%) for OS. The hazard ratios for PET-negative/biopsy-negative cases versus PET-positive/biopsy-positive cases were 2.67 (95% CI, 1.48–4.79) for EFS and 3.94 (1.93–8.06) for OS. Conclusion: This large study demonstrates that positive iliac crest biopsy histology only confers poor prognosis for patients who also have abnormal marrow 18F-FDG uptake identified on the staging PET scan. Abnormal 18F-FDG uptake in marrow, when iliac crest biopsy histology is normal, has no adverse effect on outcomes.

The role of nuclear medicine in inflammatory bowel disease. A review with experiences of aspecific bowel activity using immunoscintigraphy with 99mTc anti-granulocyte antibodies

UNLABELLED The diagnosis of inflammatory bowel disease (IBD) needs a complex diagnostic work-up. Beside verifying the disease itself, it is fundamental to assess disease extent and activity and to detect associated complications, to find the most effective treatment and for follow up. Scintigraphy with radiolabelled leukocytes is able to provide a complete survey of the whole intestinal tract, both the small and large bowel, and detects septic complications successfully with negligible risk. Radionuclide procedures are useful in establishing or ruling out IBD in patients with intestinal complaints, in assessing disease severity, and in the evaluation of extraintestinal septic complications. Widely available radionuclide procedures are discussed, i.e. scintigraphy by 111Indium oxime or 99mTechnetium HMPAO labelled white blood cells and immunoscintigraphy with 99mTc anti-granulocyte antibodies. Advantages and disadvantages of all three methods are stressed out. PATIENTS AND METHODS The immunoscintigraphies with 99mTc anti-granulocyte antibodies (ANTI-GRANULOCYTE(R) BW 250/183) of 27 patients with suspicion of IBD were retrospectively analysed. Planar anterior and posterior images were obtained 4 and 24 h postinjection, respectively. The bowel was divided into six segments and the activity was visually graded with reference to bone marrow in each segments. The scans were compared with the results of radiological and endoscopical investigations. The diagnosis of IBD was proved or ruled out by means of enteroclysis, large bowel enema or endoscopy. RESULTS In the 27 patients, 74 bowel segments with increased activity were detected. In the case of 30 segments in 16 patients, bowel inflammation was revealed by the other methods (true positives). In the case of 44 bowel segments, no underlying bowel inflammation could be verified, and these activities were regarded as aspecific activity. We could not differentiate between true positive and aspecific activity based on scan pattern or intensity. DISCUSSION These findings of aspecific bowel activity using imuunoscintigraphy are in contrast with the results of former studies, while the existence of non-specific activity decreases the reliability of the method. Based on the literature and our experiences, we conclude that 99mTc HMPAO labelling should be the method of choice for the investigation of IBD patients.

Prospective International Cohort Study Demonstrates Inability of Interim PET to Predict Treatment Failure in Diffuse Large B-Cell Lymphoma

The International Atomic Energy Agency sponsored a large, multinational, prospective study to further define PET for risk stratification of diffuse large B-cell lymphoma and to test the hypothesis that international biological diversity or diversity of healthcare systems may influence the kinetics of treatment response as assessed by interim PET (I-PET). Methods: Cancer centers in Brazil, Chile, Hungary, India, Italy, the Philippines, South Korea, and Thailand followed a common protocol based on treatment with R-CHOP (cyclophosphamide, hydroxyadriamycin, vincristine, prednisolone with rituximab), with I-PET after 2–3 cycles of chemotherapy and at the end of chemotherapy scored visually. Results: Two-year survivals for all 327 patients (median follow-up, 35 mo) were 79% (95% confidence interval [CI], 74%–83%) for event-free survival (EFS) and 86% (95% CI, 81%–89%) for overall survival (OS). Two hundred ten patients (64%) were I-PET–negative, and 117 (36%) were I-PET–positive. Two-year EFS was 90% (95% CI, 85%–93%) for I-PET–negative and 58% (95% CI, 48%–66%) for I-PET–positive, with a hazard ratio of 5.31 (95% CI, 3.29–8.56). Two-year OS was 93% (95% CI, 88%–96%) for I-PET–negative and 72% (95% CI, 63%–80%) for I-PET–positive, with a hazard ratio of 3.86 (95% CI, 2.12–7.03). On sequential monitoring, 192 of 312 (62%) patients had complete response at both I-PET and end-of-chemotherapy PET, with an EFS of 97% (95% CI, 92%–98%); 110 of these with favorable clinical indicators had an EFS of 98% (95% CI, 92%–100%). In contrast, the 107 I-PET–positive cases segregated into 2 groups: 58 (54%) achieved PET-negative complete remission at the end of chemotherapy (EFS, 86%; 95% CI, 73%–93%); 46% remained PET-positive (EFS, 35%; 95% CI, 22%–48%). Heterogeneity analysis found no significant difference between countries for outcomes stratified by I-PET. Conclusion: This large international cohort delivers 3 novel findings: treatment response assessed by I-PET is comparable across disparate healthcare systems, secondly a negative I-PET findings together with good clinical status identifies a group with an EFS of 98%, and thirdly a single I-PET scan does not differentiate chemoresistant lymphoma from complete response and cannot be used to guide risk-adapted therapy.

Comparison of the International Harmonization Project, London and Gallamini criteria in the interpretation of 18F-FDG PET/CT examinations after first-line treatment in Hodgkin's lymphoma.

ObjectiveFluorine 18-fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) has been reported to have a wide-ranging positive predictive value (PPV) in the literary data on Hodgkin’s lymphoma after first-line therapy. This study was carried out to compare the usefulness of the International Harmonization Project, London and Gallamini criteria in the interpretation of 18F-FDG PET/CT examinations for this indication. MethodsData from 66 patients with a median follow-up care of 54 months were evaluated. The initial stage had been I–II in the case of 45 patients and III–IV in the case of 21 patients. ResultsThe analysis based on the International Harmonization Project criteria resulted in a negative predictive value (NPV) of 98.0% and a PPV of 62.5%. Using mediastinal blood pool and liver activity as the thresholds for the London criteria, the NPV and PPV were 98.0 and 62.5% and 98.1 and 71.4%, respectively. Considering only those lesions with 18F-FDG uptake that was markedly higher than liver uptake as positive, the NPV and PPV were 94.7 and 88.9%, respectively. The analysis based on the Gallamini criteria resulted in an NPV of 96.2% and a PPV of 69.2%. ConclusionUsing the London criteria with liver activity as the threshold seems to be a good approach for the interpretation of post-treatment 18F-FDG PET/CT studies because of its high accuracy and simplicity.

Radioguided lymph node biopsy of a chemoresistant lymph node detected on interim FDG PET-CT in Hodgkin lymphoma

A 32-year-old male patient was diagnosed with nodular lymphocyte-predominant Hodgkin lymphoma. Staging FDG PET-CT detected a large right axillary lymph node conglomerate and splenic manifestation. Interim PET-CT following two cycles of ABVD chemotherapy revealed good metabolic response with the exception of a single axillary lymph node. A second “interim” PET-CT after two further cycles showed a similar result. A biopsy of the metabolically active non-palpable lymph node was performed using radioguided occult lesion localization (ROLL) with ultrasound guidance. The lymph node was successfully removed by minimally invasive surgery. Histological evaluation of the lymph node revealed a T cell-rich diffuse large B cell lymphoma. Based on this finding, a more aggressive treatment regimen followed by high dose chemotherapy with autologous stem cell rescue was adopted. To our knowledge, this is the first report of a lymphoma case in which the ROLL method was used in the radioguided biopsy of a chemoresistant lymph node detected by interim FDG PET-CT.

[ALPPS (Associated Liver Partition and Portal vein ligation for Staged hepatectomy) -- faster and greater growth of liver].

CASE REPORT 75 years old female patient was referred with large, multifocal colorectal liver metastasis. Prior to this consultation she received chemotherapies of various protocols and series. Liver metastasis, however, increased at about 3 times of the original size during the 5 months of the oncological treatment. A right extended hepatectomy was planned to remove the tumor, but the residual liver (FLR) was found to be too small. Portal occlusion technique was necessary to induce the hypertrophy of the FLR. Due to rapid tumor progression we decided to perform the first ALPPS (PVL + in situ split) procedure in Hungary. After a very fast (9 days) and significant (94%) hypertrophy of the FLR the planned liver resection was successfully performed.

ALPPS (Associated Liver Partition and Portal vein ligation for Staged hepatectomy) – gyorsabb, nagyobb májhypertrophia

CASE REPORT 75 years old female patient was referred with large, multifocal colorectal liver metastasis. Prior to this consultation she received chemotherapies of various protocols and series. Liver metastasis, however, increased at about 3 times of the original size during the 5 months of the oncological treatment. A right extended hepatectomy was planned to remove the tumor, but the residual liver (FLR) was found to be too small. Portal occlusion technique was necessary to induce the hypertrophy of the FLR. Due to rapid tumor progression we decided to perform the first ALPPS (PVL + in situ split) procedure in Hungary. After a very fast (9 days) and significant (94%) hypertrophy of the FLR the planned liver resection was successfully performed.