Most lung and colon cancer susceptibility genes are pair-wise linked in mice, humans and rats.

Genetic predisposition controlled by susceptibility quantitative trait loci (QTLs) contributes to a large proportion of common cancers. Studies of genetics of cancer susceptibility, however, did not address systematically the relationship between susceptibility to cancers in different organs. We present five sets of data on genetic architecture of colon and lung cancer susceptibility in mice, humans and rats. They collectively show that the majority of genes for colon and lung cancer susceptibility are linked pair-wise and are likely identical or related. Four CcS/Dem recombinant congenic strains, each differing from strain BALB/cHeA by a different small random subset of ±12.5% of genes received from strain STS/A, suggestively show either extreme susceptibility or extreme resistance for both colon and lung tumors, which is unlikely if the two tumors were controlled by independent susceptibility genes. Indeed, susceptibility to lung cancer (Sluc) loci underlying the extreme susceptibility or resistance of such CcS/Dem strains, mapped in 226 (CcS-10 x CcS-19)F2 mice, co-localize with susceptibility to colon cancer (Scc) loci. Analysis of additional Sluc loci that were mapped in OcB/Dem strains and Scc loci in CcS/Dem strains, respectively, shows their widespread pair-wise co-localization (P  =  0.0036). Finally, the majority of published human and rat colon cancer susceptibility genes map to chromosomal regions homologous to mouse Sluc loci. 12/12 mouse Scc loci, 9/11 human and 5/7 rat colon cancer susceptibility loci are close to a Sluc locus or its homologous site, forming 21 clusters of lung and colon cancer susceptibility genes from one, two or three species. Our data shows that cancer susceptibility QTLs can have much broader biological effects than presently appreciated. It also demonstrates the power of mouse genetics to predict human susceptibility genes. Comparison of molecular mechanisms of susceptibility genes that are organ-specific and those with trans-organ effects can provide a new dimension in understanding individual cancer susceptibility.

Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the EORTC boost versus no boost trial.

PURPOSE: To investigate the long-term impact of pathologic characteristics and an extra boost dose of 16 Gy on local relapse, for stage I and II invasive breast cancer patients treated with breast conserving therapy (BCT). PATIENTS AND METHODS: In the European Organisation for Research and Treatment of Cancer boost versus no boost trial, after whole breast irradiation, patients with microscopically complete excision of invasive tumor, were randomly assigned to receive or not an extra boost dose of 16 Gy. For a subset of 1,616 patients central pathology review was performed. RESULTS: The 10-year cumulative risk of local breast cancer relapse as a first event was not significantly influenced if the margin was scored negative, close or positive for invasive tumor or ductal carcinoma in situ according to central pathology review (log-rank P = .45 and P = .57, respectively). In multivariate analysis, high-grade invasive ductal carcinoma was associated with an increased risk of local relapse (P = .026; hazard ratio [HR], 1.67), as was age younger than 50 years (P < .0001; HR, 2.38). The boost dose of 16 Gy significantly reduced the local relapse rate (P = .0006; HR, 0.47). For patients younger than 50 years old and in patients with high grade invasive ductal carcinoma, the boost dose reduced the local relapse from 19.4% to 11.4% (P = .0046; HR, 0.51) and from 18.9% to 8.6% (P = .01; HR, 0.42), respectively. CONCLUSION: Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence. A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer.

Chromogranin A as an alternative to 5-hydroxyindoleacetic acid in the evaluation of symptoms during treatment of patients with neuroendocrine Tumors.

BACKGROUND: Urinary 5-HIAA excretion is a well-known marker in neuroendocrine tumors (NETs), but it has a low sensitivity and the 24-hour collection is inconvenient for patients. Chromogranin A (CgA) is a promising marker, but a thorough evaluation during follow-up is still lacking. METHODS: 39 patients with metastatic gastrointestinal NETs were monitored during treatment with the long-acting octreotide SandostatinLAR. A comparison was made between serum CgA and urinary 5-HIAA in relation to quality of life (HRQL) assessed by the EORTC QLQ-C30 questionnaire, supplemented with questions specific to carcinoid symptoms. Survival analyses were performed to examine the association between the markers and survival time. RESULTS: Correlations were found between CgA and physical functioning (p = 0.01) and quality of life (p = 0.03), while no significant correlations were observed between 5-HIAA levels and any of the self-reported health outcomes. Cox regression showed an association between CgA levels and survival time (p = 0.02), while no significant association was observed between 5-HIAA levels and survival time. CONCLUSION: Stronger correlations of CgA compared to 5-HIAA with physical functioning and wellbeing, the convenience of measuring in blood, as well as the prognostic value of CgA for survival, makes CgA the recommended marker in the management of patients with metastatic NETs.

Diffuse myogenin expression by immunohistochemistry is an independent marker of poor survival in pediatric rhabdomyosarcoma: a tissue microarray study of 71 primary tumors including correlation with molecular phenotype.

The pathologic classification of rhabdomyosarcoma (RMS) into embryonal or alveolar subtype is an important prognostic factor guiding the therapeutic protocol chosen for an individual patient. Unfortunately, this classification is not always straightforward, and the diagnostic criteria are controversial in a subset of cases. Ancillary studies are used to aid in the classification, but their potential use as independent prognostic factors is rarely studied. The aim of this study is to identify immunohistochemical markers of potential prognostic significance in pediatric RMS and to correlate their expression with PAX-3/FKHR and PAX-7/FKHR fusion status. A single tissue microarray containing 71 paraffin-embedded pediatric RMSs was immunostained with antibodies against p53, bcl-2, Ki-67, CD44, myogenin, and MyoD1. The tissue microarray and whole paraffin blocks were studied for PAX-3/FKHR and PAX-7/FKHR gene fusions by fluorescence in situ hybridization and reverse transcription-polymerase chain reaction. Clinical follow-up data were available for each patient. Immunohistochemical staining results and translocation status were correlated with recurrence-free interval (RFI) and overall survival (OS) using the Kaplan-Meier method, the log-rank test, and Cox proportional hazard regression. The minimum clinical follow-up interval was 24 months (median follow-up=57 mo). On univariable analysis, immunohistochemical expression of myogenin, bcl-2, and identification of a gene fusion were associated with decreased 5-year RFI and 10-year OS (myogenin RFI P=0.0028, OS P=0.0021; bcl-2 RFI P=0.037, OS P=0.032; gene fusion RFI P=0.0001, OS P=0.0058). After adjustment for Intergroup Rhabdomyosarcoma Study-TNM stage, tumor site, age, tumor histology, and translocation status by multivariable analysis, only myogenin retained an independent association with RFI (P=0.034) and OS (P=0.0069). In this retrospective analysis, diffuse immunohistochemical reactivity for myogenin in RMS correlates with decreased RFI and OS, independent of histologic subtype, translocation status, tumor site, or stage.

Continuing risk of ipsilateral breast relapse after breast-conserving therapy at long-term follow-up.

PURPOSE: Currently, the local treatment of most patients with early invasive breast cancer consists of breast-conserving therapy (BCT). We have previously reported on the risk factors for ipsilateral breast relapse (IBR) in 1,026 patients treated with BCT after a median follow-up of 5.5 years. In the present study, we evaluated the IBR incidence and the risk factors for IBR after prolonged follow-up. METHODS AND MATERIALS: We updated the disease outcome for all 1,026 patients using the clinical information collected from the medical registration of The Netherlands Cancer Institute and performed step-wise proportional hazard Cox regression analysis to identify the risk factors associated with an increased risk of IBR after BCT at long-term follow-up. RESULTS: After a median follow-up of 13.3 years, 114 patients had developed an IBR as the first event. The IBR rate was 9.3% and 13.8%, respectively, at 10 and 15 years. Also, the increase in IBR was continuous without reaching a plateau, even after 15 years. Univariate analysis showed that involved surgical resection margins, young age, vascular invasion, and the presence and quantity of an in situ component are risk factors for IBR. Multivariate analysis showed that tumor-positive surgical resection margins (hazard ratio, 2.9; 95% confidence interval, 1.7-5.2, p = 0.0002) or the presence of vascular invasion (hazard ratio, 2.0; 95% confidence interval, 1.2-3.2, p = 0.004) is the major independent risk factor for IBR. CONCLUSIONS: The data from long-term follow-up showed a constant increase in IBR among patients treated by BCT, even after 15 years, without reaching a plateau. Involved surgical resection margins and vascular invasion were the most important risk factors for IBR.

Medical assessment of adverse health outcomes in long-term survivors of childhood cancer.

CONTEXT: Improved survival of children with cancer has been accompanied by multiple treatment-related complications. However, most studies in survivors of childhood cancer focused on only 1 late effect. OBJECTIVE: To assess the total burden of adverse health outcomes (clinical or subclinical disorders ["adverse events"]) following childhood cancer in a large cohort of childhood cancer survivors with long-term and complete medical follow-up. DESIGN, SETTING, AND POPULATION: Retrospective cohort study of 1362 five-year survivors of childhood cancer treated in a single institution in the Netherlands between 1966 and 1996. All survivors were invited to a late-effects clinic for medical assessment of adverse events. Adverse events occurring before January 2004 were graded for severity in a standardized manner. MAIN OUTCOME MEASURES: Treatment-specific prevalence of adverse events (according to severity) at end of follow-up and relative risk of high or severe burden of disease (> or =2 severe or > or =1 life-threatening or disabling adverse events) associated with various treatments. RESULTS: Medical follow-up was complete for 94.3% of survivors (median follow-up, 17.0 years). The median attained age at end of follow-up was 24.4 years. Almost 75% of survivors had 1 or more adverse events, and 24.6% had 5 or more adverse events. Furthermore, 40% of survivors had at least 1 severe or life-threatening or disabling adverse event. A high or severe burden of adverse events was observed in 55% of survivors who received radiotherapy only and 15% of survivors treated with chemotherapy only, compared with 25% of survivors who had surgery only (adjusted relative risks, 2.18 [95% confidence interval, 1.62-2.95] and 0.65 [95% confidence interval, 0.46-0.90], respectively). A high or severe burden of adverse events was most often observed in survivors of bone tumors (64%) and least often in survivors of leukemia or Wilms tumor (12% each). CONCLUSIONS: In young adulthood, a substantial proportion of childhood cancer survivors already has a high or severe burden of disease, particularly after radiotherapy. This underscores the need for lifelong risk-stratified medical surveillance of childhood cancer survivors.

Late cardiotoxicity after treatment for Hodgkin lymphoma.

We assessed cardiovascular disease (CVD) incidence in 1474 survivors of Hodgkin lymphoma (HL) younger than 41 years at treatment (1965-1995). Multivariable Cox regression and competing risk analyses were used to quantify treatment effects on CVD risk. After a median follow-up of 18.7 years, risks of myocardial infarction (MI) and congestive heart failure (CHF) were strongly increased compared with the general population (standardized incidence ratios [SIRs] = 3.6 and 4.9, respectively), resulting in 35.7 excess cases of MI and 25.6 excess cases of CHF per 10 000 patients/year. SIRs of all CVDs combined remained increased for at least 25 years and were more strongly elevated in younger patients. Mediastinal radiotherapy significantly increased the risks of MI, angina pectoris, CHF, and valvular disorders (2- to 7-fold). Anthracyclines significantly added to the elevated risks of CHF and valvular disorders from mediastinal RT (hazard ratios [HRs] were 2.81 and 2.10, respectively). The 25-year cumulative incidence of CHF after mediastinal radiotherapy and anthracyclines in competing risk analyses was 7.9%. In conclusion, risks of several CVDs are 3- to 5-fold increased in survivors of HL compared with the general population, even after prolonged follow-up, leading to increasing absolute excess risks over time. Anthracyclines further increase the elevated risks of CHF and valvular disorders from mediastinal radiotherapy.

Predicting a local recurrence after breast-conserving therapy by gene expression profiling.

INTRODUCTION: To tailor local treatment in breast cancer patients there is a need for predicting ipsilateral recurrences after breast-conserving therapy. After adequate treatment (excision with free margins and radiotherapy), young age and incompletely excised extensive intraductal component are predictors for local recurrence, but many local recurrences can still not be predicted. Here we have used gene expression profiling by microarray analysis to identify gene expression profiles that can help to predict local recurrence in individual patients. METHODS: By using previously established gene expression profiles with proven value in predicting metastasis-free and overall survival (wound-response signature, 70-gene prognosis profile and hypoxia-induced profile) and training towards an optimal prediction of local recurrences in a training series, we establish a classifier for local recurrence after breast-conserving therapy. RESULTS: Validation of the different gene lists shows that the wound-response signature is able to separate patients with a high (29%) or low (5%) risk of a local recurrence at 10 years (sensitivity 87.5%, specificity 75%). In multivariable analysis the classifier is an independent predictor for local recurrence. CONCLUSION: Our findings indicate that gene expression profiling can identify subgroups of patients at increased risk of developing a local recurrence after breast-conserving therapy.

Childhood white matter disorders: quantitative MR imaging and spectroscopy.

PURPOSE: To prospectively investigate whether quantitative magnetic resonance (MR) parameters, including magnetization transfer ratio (MTR), apparent diffusion coefficient (ADC), fractional anisotropy (FA), and MR spectroscopic metabolite concentrations, allow for discrimination between different types of pathologic conditions that underlie signal intensity abnormalities in white matter. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Forty-one patients (19 male, 22 female; mean age, 15.4 years) and 41 control subjects (25 male, 16 female; mean age, 11.3 years) were included. Twelve patients had a hypomyelinating disorder; 14, a demyelinating disorder; five, a disorder characterized by myelin vacuolation; and 10, a disorder characterized by cystic degeneration. Regions of interest were selected within the parietal white matter and were transferred to the corresponding sections of the generated ADC, FA, and MTR maps to extract quantitative measurements. Linear discriminant analysis and univariate analysis of covariance were used for statistical evaluation. RESULTS: Linear discriminant analysis showed that 95% of patients were correctly classified by using total creatine, choline-containing compounds, myo-inositol, MTR, and ADC. In the hypomyelination group, all MR parameters were close to normal, with the exception of elevated total creatine (P = .03) and myo-inositol (P < .001) levels and decreased MTR values (P < .001). In the demyelination group, the levels of choline-containing compounds (P = .02) and myo-inositol (P < .001) were highly elevated. In the myelin vacuolation and cystic degeneration groups, high ADC values (P < .001) and variable decreases in all MR spectroscopic metabolites were seen. MTR was significantly reduced (P < .001) in the cystic degeneration group. CONCLUSION: Quantitative MR techniques can be used to discriminate between different types of white matter disorders and to classify white matter lesions of unknown origin with respect to underlying pathologic conditions.

Rectal bleeding, fecal incontinence, and high stool frequency after conformal radiotherapy for prostate cancer: normal tissue complication probability modeling.

PURPOSE: To analyze whether inclusion of predisposing clinical features in the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model improves the estimation of late gastrointestinal toxicity. METHODS AND MATERIALS: This study includes 468 prostate cancer patients participating in a randomized trial comparing 68 with 78 Gy. We fitted the probability of developing late toxicity within 3 years (rectal bleeding, high stool frequency, and fecal incontinence) with the original, and a modified LKB model, in which a clinical feature (e.g., history of abdominal surgery) was taken into account by fitting subset specific TD50s. The ratio of these TD50s is the dose-modifying factor for that clinical feature. Dose distributions of anorectal (bleeding and frequency) and anal wall (fecal incontinence) were used. RESULTS: The modified LKB model gave significantly better fits than the original LKB model. Patients with a history of abdominal surgery had a lower tolerance to radiation than did patients without previous surgery, with a dose-modifying factor of 1.1 for bleeding and of 2.5 for fecal incontinence. The dose-response curve for bleeding was approximately two times steeper than that for frequency and three times steeper than that for fecal incontinence. CONCLUSIONS: Inclusion of predisposing clinical features significantly improved the estimation of the NTCP. For patients with a history of abdominal surgery, more severe dose constraints should therefore be used during treatment plan optimization.

Cross-validated Cox regression on microarray gene expression data.

This paper describes how penalized Cox regression, in combination with cross-validated partial likelihood can be employed to obtain reliable survival prediction models for high dimensional microarray data. The suggested procedure is demonstrated on a breast cancer survival data set consisting of 295 tumours as collected in the National Cancer Institute in Amsterdam and previously reported in more general papers. The main aim of this paper it to show how generally accepted biostatistical procedures can be employed to analyse high-dimensional data.

Observer variation in target volume delineation of lung cancer related to radiation oncologist-computer interaction: a 'Big Brother' evaluation.

BACKGROUND AND PURPOSE: To evaluate the process of target volume delineation in lung cancer for optimization of imaging, delineation protocol and delineation software. PATIENTS AND METHODS: Eleven radiation oncologists (observers) from five different institutions delineated the Gross Tumor Volume (GTV) including positive lymph nodes of 22 lung cancer patients (stages I-IIIB) on CT only. All radiation oncologist-computer interactions were recorded with a tool called 'Big Brother'. For each radiation oncologist and patient the following issues were analyzed: delineation time, number of delineated points and corrections, zoom levels, level and window (L/W) settings, CT slice changes, use of side windows (coronal and sagittal) and software button use. RESULTS: The mean delineation time per GTV was 16 min (SD 10 min). The mean delineation time for lymph node positive patients was on average 3 min larger (P = 0.02) than for lymph node negative patients. Many corrections (55%) were due to L/W change (e.g. delineating in mediastinum L/W and then correcting in lung L/W). For the lymph node region, a relatively large number of corrections was found (3.7 corr/cm2), indicating that it was difficult to delineate lymph nodes. For the tumor-atelectasis region, a relative small number of corrections was found (1.0 corr/cm2), indicating that including or excluding atelectasis into the GTV was a clinical decision. Inappropriate use of L/W settings was frequently found (e.g. 46% of all delineated points in the tumor-lung region were delineated in mediastinum L/W settings). Despite a large observer variation in cranial and caudal direction of 0.72 cm (1 SD), the coronal and sagittal side windows were not used in 45 and 60% of the cases, respectively. For the more difficult cases, observer variation was smaller when the coronal and sagittal side windows were used. CONCLUSIONS: With the 'Big Brother' tool a method was developed to trace the delineation process. The differences between observers concerning the delineation style were large. This study led to recommendations on how to improve delineation accuracy by adapting the delineation protocol (guidelines for L/W use) and delineation software (double window with lung and mediastinum L/W settings at the same time, enforced use of coronal and sagittal views) and including FDG-PET information (lymph nodes and atelectasis).

A protocol for building and evaluating predictors of disease state based on microarray data.

MOTIVATION: Microarray gene expression data are increasingly employed to identify sets of marker genes that accurately predict disease development and outcome in cancer. Many computational approaches have been proposed to construct such predictors. However, there is, as yet, no objective way to evaluate whether a new approach truly improves on the current state of the art. In addition no 'standard' computational approach has emerged which enables robust outcome prediction. RESULTS: An important contribution of this work is the description of a principled training and validation protocol, which allows objective evaluation of the complete methodology for constructing a predictor. We review the possible choices of computational approaches, with specific emphasis on predictor choice and reporter selection strategies. Employing this training-validation protocol, we evaluated different reporter selection strategies and predictors on six gene expression datasets of varying degrees of difficulty. We demonstrate that simple reporter selection strategies (forward filtering and shrunken centroids) work surprisingly well and outperform partial least squares in four of the six datasets. Similarly, simple predictors, such as the nearest mean classifier, outperform more complex classifiers. Our training-validation protocol provides a robust methodology to evaluate the performance of new computational approaches and to objectively compare outcome predictions on different datasets.

Prognostic factors and evaluation of surgical management of hepatic metastases from colorectal origin: a 10-year single-institute experience.

The aim of this study was to determine prognostic factors and outcome after liver resection for colorectal metastases in 102 patients over a period of 10 years. A stepwise procedure using proportional hazard regression analysis was used to identify prognostic factors. Estimated survival at 2 years was 71%, and at 5 years, 29% (Kaplan-Meier). Of 19 patients with isolated liver recurrence, 6 had a second metastasectomy; 4 of the 6 are still alive. We found that the number of hepatic lesions on computed tomography (P=0.012), the interval between resection of the primary colon tumor and the hepatic metastasectomy (P=0.012), and synchronicity of the primary and the hepatic metastasis (P=0.048) showed evidence of independent prognostic value regarding survival. Resection of hepatic colorectal metastases may result in long-term survival. Patients with recurrence after a first liver resection may benefit from a repeat metastasectomy. Our data suggest there is no strong predictor of survival. Survival seems to decrease with increasing number of metastases found on computed tomography.

Normal values of serum S-100B predict prolonged survival for stage IV melanoma patients.

The value of normal S-100B levels to predict survival was evaluated in 145 patients with stage IV melanoma. Treatment consisted of temozolomide given alone or was followed by combined cytokine immunotherapy, given every three to four weeks, with an evaluation of response following two treatment-cycles. S-100B values were measured prior to and following each cycle of systemic therapy and regularly thereafter. Patients with normal initial S-100B values (n=32) had higher response rates and fewer and more favourable metastatic sites with better overall survival rates than patients with elevated S-100B levels (median 14.0 versus 6.6 months). Normal S-100B values increased in nearly all patients (28/31) after a median of 7.9 months. In addition, patients with rapid normalisation of their serum level (n=12) following systemic treatment experienced prolonged survival. However, upon multivariable analysis S-100B prior to treatment lost its independence as a prognostic factor, whereas lactate dehydrogenase (LDH) remained. When measured after treatment, both markers had independent value.

Assessment of analysis-of-variance-based methods to quantify the random variations of observers in medical imaging measurements: guidelines to the investigator.

The random variations of observers in medical imaging measurements negatively affect the outcome of cancer treatment, and should be taken into account during treatment by the application of safety margins that are derived from estimates of the random variations. Analysis-of-variance- (ANOVA-) based methods are the most preferable techniques to assess the true individual random variations of observers, but the number of observers and the number of cases must be taken into account to achieve meaningful results. Our aim in this study is twofold. First, to evaluate three representative ANOVA-based methods for typical numbers of observers and typical numbers of cases. Second, to establish guidelines to the investigator to determine which method, how many observers, and which number of cases are required to obtain the a priori chosen performance. The ANOVA-based methods evaluated in this study are an established technique (pairwise differences method: PWD), a new approach providing additional statistics (residuals method: RES), and a generic technique that uses restricted maximum likelihood (REML) estimation. Monte Carlo simulations were performed to assess the performance of the ANOVA-based methods, which is expressed by their accuracy (closeness of the estimates to the truth), their precision (standard error of the estimates), and the reliability of their statistical test for the significance of a difference in the random variation of an observer between two groups of cases. The highest accuracy is achieved using REML estimation, but for datasets of at least 50 cases or arrangements with 6 or more observers, the differences between the methods are negligible, with deviations from the truth well below +/-3%. For datasets up to 100 cases, it is most beneficial to increase the number of cases to improve the precision of the estimated random variations, whereas for datasets over 100 cases, an improvement in precision is most efficiently achieved by increasing the number of observers. For datasets of at least 50 cases, the standard error ranges between 30% or less with 3 observers down to 10% or less with 8 observers, and the differences in precision between the methods are negligible. The F test (PWD) is very anticonservative and should not be used, while the t test (RES) is reliable for datasets of at least 2 x 50 cases evaluated by 4 or more observers. The likelihood-ratio-test (REML estimation) consistently indicates the significance of a difference in the random variation of an observer between two groups of cases, regardless of the number of cases, and regardless of the number of observers. If a statistical package to perform REML estimation is available, and the investigator feels confident using it, this is the preferred method for studies that involve less than 50 cases evaluated by less than 6 observers. Otherwise, the RES method is an excellent alternative, because of its straightforward implementation, its completeness with respect to the provided statistics, and its overall sufficient accuracy, precision, and reliability of the provided statistical test. If neither the RES method nor REML estimation can provide sufficient performance, either more observers or more cases must be included.

Pattern of white matter abnormalities at MR imaging: use of polymerase chain reaction testing of Guthrie cards to link pattern with congenital cytomegalovirus infection.

PURPOSE: To define a magnetic resonance (MR) imaging pattern suggestive of congenital cytomegalovirus (CMV) infection by using polymerase chain reaction (PCR) testing to detect CMV DNA in neonatal blood on Guthrie cards for validation. MATERIALS AND METHODS: On the basis of findings in eight patients with documented congenital CMV infection, the authors developed MR imaging inclusion criteria, including multifocal lesions predominantly located in the deep parietal white matter. If gyral abnormalities were present, white matter lesions were either multifocal or diffuse. The criteria were applied to 152 patients with static leukoencephalopathy of unknown etiology. Guthrie cards for 22 of the 43 patients fulfilling the MR imaging criteria, 20 patients not fulfilling them, and 300 control subjects were analyzed. Fisher exact testing was used to evaluate the association between MR imaging characteristics and CMV status, and backward elimination linear discriminant analysis was used to identify MR imaging characteristics predictive of CMV infection in addition to the initial criteria. RESULTS: PCR test results were positive in 12 of 22 patients suspected of having congenital CMV infection, in no patient not suspected of having infection (P <.001), and in two of 300 control subjects (negative predictive value [NPV] of MR imaging criteria, 100% [95% CI: 83%, 100%]; positive predictive value [PPV], 55% [95% CI: 32%, 76%]). The most important additional MR imaging finding predicting a positive PCR result was abnormality of the anterior part of the temporal lobe, including abnormal white matter, cysts, and enlargement of inferior horns. Including this finding in the MR imaging criteria enhanced the PPV (89%; 95% CI: 52%, 99%) at the expense of the NPV (88%; 95% CI: 72%, 97%). CONCLUSION: In patients with static encephalopathy, an MR imaging pattern of multifocal lesions predominantly involving deep parietal white matter, with or without gyral abnormalities, is predictive of congenital CMV infection. When gyral abnormalities are present, leukoencephalopathy may also be diffuse. The presence of abnormalities in the anterior part of the temporal lobe increases the likelihood that CMV infection is present.

Thallium-201-chloride scintigraphy in staging and monitoring radiotherapy response in follicular lymphoma patients.

PURPOSE: To study thallium-201-chloride scintigraphy (201Tl-S) in staging and monitoring response after radiotherapy in follicular lymphoma (FL) patients. PATIENTS AND METHODS: Forty-one consecutive and unselected FL patients were examined by 'Conventional Standard Staging' (CSS) procedures (history and physical examination, ultrasound, CT scans, biopsies and fine needle aspiration cytology) prior to irradiation. Eight standardized potentially affected lymphoma localizations (neck, axilla, mediastinum, spleen, paraaortic, parailiac, femoral and extranodal) per patient were separately studied, resulting in the investigation of 328 localizations. Thirty minutes after the intravenous administration of a tracer dose of 150 MBq thallium-201-chloride total body images were made, immediately followed by single photon emission computed tomography acquisition. All lymphoma localizations were subsequently irradiated. Patients were re-examined after a median of 4 weeks (range 3-6 weeks) by all CSS modalities and 201Tl-S. Diagnostic performance was evaluated both per site and per patient, both in the diagnostic phase of the study as well as in the post-treatment re-evaluation phase. RESULTS: In staging, 201Tl-S was positive in 82 of the 129 initial positive regions by CSS (64%). This percentage increased to 70% when eliminating upper abdominal lymph nodes from the analysis. In 24 patients all lesions were visualized by 201Tl-S, in 11 patients some but not all lesions were detected. In six patients none of the lesions were detected by 201Tl-S. In four patients, four additional lesions were initially found by 201Tl-S only. After irradiation, 83 of the total 86 positive regions reached a complete or partial remission by CSS. Eighty-one of these were also diagnosed as remission by 201Tl-S and two as stable disease. In 31 out of 35 patients (89%; 95% CI: 73-97%) the overall response in all irradiated sites was identical by 201Tl-S and CSS. Only two patients, in remission on CSS modalities, showed stable disease on 201Tl-S, while two others were diagnosed as CR by CSS and PR by 201Tl-S. CONCLUSIONS: 201Tl-S has limited additional value in staging FL patients, since only two-thirds of all localizations are detected. However, 201Tl-S is accurate in monitoring radiation treatment response in FL patients. If an FL patient with a positive 201Tl-S at diagnosis is treated by irradiation, the treatment response can be reliably ascertained by only performing a 201Tl-S.

Association of C-MYC amplification with progression from the in situ to the invasive stage in C-MYC-amplified breast carcinomas.

Human carcinoma in situ of the breast already demonstrates genomic changes found in invasive lesions. However, no specific genetic alterations have previously been identified that are associated with progression from the in situ to the invasive stage. By comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis of an invasive breast carcinoma with a large associated in situ component, high-level amplification of C-MYC was found in the invasive component only. To determine the frequency of this correlation in a panel of 188 invasive breast carcinomas, 18 additional cases with C-MYC amplification were identified. Nine of these cases had a detectable adjacent in situ component. FISH analysis demonstrated increased (>5) C-MYC signals per nucleus in seven invasive components and increased (>4) C-MYC/centromere 8 signal ratios in five of these. None of the associated in situ components demonstrated these increases. The minimal amplified region was defined at 8q24.13-8qter. C-MYC amplification was correlated with overexpression of C-MYC and two of its target genes, TERT and FBL. Thus, C-MYC amplification is the first identified genetic alteration that is associated with progression from the in situ to the invasive stage of breast carcinoma.