Baseline PET radiomics outperforms the IPI risk score for prediction of outcome in diffuse large B-cell lymphoma.

The objective of this study is to externally validate the clinical positron emission tomography (PET) model developed in the HOVON-84 trial and to compare the model performance of our clinical PET model using the international prognostic index (IPI). In total, 1195 patients with diffuse large B-cell lymphoma (DLBCL) were included in the study. Data of 887 patients from 6 studies were used as external validation data sets. The primary outcomes were 2-year progression-free survival (PFS) and 2-year time to progression (TTP). The metabolic tumor volume (MTV), maximum distance between the largest lesion and another lesion (Dmaxbulk), and peak standardized uptake value (SUVpeak) were extracted. The predictive values of the IPI and clinical PET model (MTV, Dmaxbulk, SUVpeak, performance status, and age) were tested. Model performance was assessed using the area under the curve (AUC), and diagnostic performance, using the positive predictive value (PPV). The IPI yielded an AUC of 0.62. The clinical PET model yielded a significantly higher AUC of 0.71 (P < .001). Patients with high-risk IPI had a 2-year PFS of 61.4% vs 51.9% for those with high-risk clinical PET, with an increase in PPV from 35.5% to 49.1%, respectively. A total of 66.4% of patients with high-risk IPI were free from progression or relapse vs 55.5% of patients with high-risk clinical PET scores, with an increased PPV from 33.7% to 44.6%, respectively. The clinical PET model remained predictive of outcome in 6 independent first-line DLBCL studies, and had higher model performance than the currently used IPI in all studies.

Cost-Effectiveness of Shortening Treatment Duration Based on Interim PET Outcome in Patients With Diffuse Large B-cell Lymphoma.

BACKGROUND: Guideline recommendations for diffuse large-B-cell lymphoma (DLBCL) treatment are shifting from long to short treatment duration, although it is still unclear whether shortening treatment duration does not cause any harm. As interim PET (I-PET) has high negative predictive value for progression, we evaluated the cost-effectiveness of shortening treatment duration dependent on I-PET result. MATERIALS AND METHODS: We developed a Markov cohort model using the PET Re-Analysis (PETRA) database to evaluate a long treatment duration (LTD) strategy, ie 8x R-CHOP or 6x R-CHOP plus 2 R, and a short treatment duration (STD) strategy, ie 6x R-CHOP. Strategies were evaluated separately in I-PET2 positive and I-PET2 negative patients. Outcomes included total costs and quality-adjusted life-years (QALYs) per patient (pp) from a societal perspective. Net monetary benefit (NMB) per strategy was calculated using a willingness-to-pay threshold of €50,000/QALY. Robustness of model predictions was assessed in sensitivity analyses. RESULTS: In I-PET2 positive patients, shortening treatment duration led to 50.4 additional deaths per 1000 patients. The STD strategy was less effective (-0.161 [95%CI: -0.343;0.028] QALYs pp) and less costly (-€2768 [95%CI: -€8420;€1105] pp). Shortening treatment duration was not cost-effective (incremental NMB -€5281). In I-PET2 negative patients, shortening treatment duration led to 5.0 additional deaths per 1000 patients and a minor difference in effectiveness (-0.007 [95%CI: -0.136;0.140] QALY pp). The STD strategy was less costly (-€5807 [95%CI: -€10,724;-€2685] pp) and led to an incremental NMB of €5449, indicating that it is cost-effective to shorten treatment duration. Robustness of these findings was underpinned by deterministic and probabilistic sensitivity analyses. CONCLUSION: Treatment duration should not be shortened in I-PET2 positive patients whereas it is cost-effective to shorten treatment duration in I-PET2 negative patients.

Optimal timing and criteria of interim PET in DLBCL: a comparative study of 1692 patients.

Interim 18F-fluorodeoxyglucose positron emission tomography (Interim-18F-FDG-PET, hereafter I-PET) has the potential to guide treatment of patients with diffuse large B-cell lymphoma (DLBCL) if the prognostic value is known. The aim of this study was to determine the optimal timing and response criteria for evaluating prognosis with I-PET in DLBCL. Individual patient data from 1692 patients with de novo DLBCL were combined and scans were harmonized. I-PET was performed at various time points during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Scans were interpreted using the Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Multilevel Cox proportional hazards models corrected for International Prognostic Index (IPI) score were used to study the effects of timing and response criteria on 2-year progression-free survival (PFS). I-PET after 2 cycles (I-PET2) and I-PET4 significantly discriminated good responders from poor responders, with the highest hazard ratios (HRs) for I-PET4. Multivariable HRs for a PET-positive result at I-PET2 and I-PET4 were 1.71 and 2.95 using DS4-5, 4.91 and 6.20 using DS5, and 2.93 and 4.65 using ΔSUVmax, respectively. ΔSUVmax identified a larger proportion of poor responders than DS5 did. For all criteria, the negative predictive value was >80%, and positive predictive values ranged from 30% to 70% at I-PET2 and I-PET4. Unlike I-PET1, I-PET3 discriminated good responders from poor responders using DS4-5 and DS5 thresholds (HRs, 2.94 and 4.67, respectively). I-PET2 and I-PET4 predict good response equally during R-CHOP therapy in DLBCL. Optimal timing and response criteria depend on the clinical context. Good response at I-PET2 is suggested for de-escalation trials, and poor response using ΔSUVmax at I-PET4 is suggested for randomized trials that are evaluating new therapies.

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. Crohn's 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 Crohn's disease in women. It may correspond to the stronger auto-immune affection in the process of Crohn's 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 Crohn's 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 Crohn's 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 Crohn's 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 Crohn's 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 Crohn's 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 Crohn's disease. It has similar diagnostic values as CT. However in early disease the sensitivity substantially decreases. In known Crohn's 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.

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.

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 Crohn's disease. METHODS AND MATERIAL: Five patients (three males, two females, 23-51 years, mean age 42 years) with known (4) or suspected (1) Crohn's 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 Crohn's 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 Crohn's colitis, which could be a single examination depicting the intraluminal, and transmural extent of the disease.

Enteropathic arthritis in the sacroiliac joint. Imaging and differential diagnosis.

OBJECTIVES: A new high resolution computed tomography (HRCT) scoring system of sacroiliac joint (SIJ) involvement in enteropathic arthritis is introduced. PATIENTS AND METHODS: SIJ's of 100 patients were studied. A total of 25 patients presented with pain syndrome, 25 with suspicious seronegative spondylarthritis, 25 with inflammatory bowel diseases and 25 without joint or bowel diseases, as a control group. HRCT was carried out in all 100 patients. For comparison, a plain film radiography (PFR), conventional CT (slices of 10 mm) and bone scan were used. RESULTS: Quantitative differences: In the pain syndrome group, there were no erosions identified neither intraarticular calcifications. Disc degeneration was seen in 12/25 cases. In 4/25 patients, vacuum phenomena appeared in the SIJ. In 3/25 patients, ventral capsular calcification occurred in the ventral sacroiliac ligament (anterior capsule complex). In the seronegative spondylarthritis group, 16/25 patients had positive findings, while PFR documented erosions only in 3/25 cases. In the bowel diseases group, erosions were detected in 17/25 cases with HRCT, while the plain film was positive only in three cases and in seven cases the findings were questionable. Intraarticular calcification with erosion was documented in three cases and in seven cases without erosion. The bone scan was positive in 7/25 of this cases, but in 5/7 there was mismatching with HRCT. Important new finding was the HRCT detected erosion which was not detected on BS but was obvious on Anti-Granulocyte-Antibody scintigraphy. In the control group, only degenerative changes were seen in 4/25 cases and no erosions. CONCLUSION: HRCT is: (1) the reliable imaging of definitive (often 'cold stage') sacroileitis; (2) gives optimal detection of erosion; and (3) appears to be the only method in the documentation of calcifications in the posterior ligamental portion of the SIJ.