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.

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.

A gene-expression signature as a predictor of survival in breast cancer.

BACKGROUND: A more accurate means of prognostication in breast cancer will improve the selection of patients for adjuvant systemic therapy. METHODS: Using microarray analysis to evaluate our previously established 70-gene prognosis profile, we classified a series of 295 consecutive patients with primary breast carcinomas as having a gene-expression signature associated with either a poor prognosis or a good prognosis. All patients had stage I or II breast cancer and were younger than 53 years old; 151 had lymph-node-negative disease, and 144 had lymph-node-positive disease. We evaluated the predictive power of the prognosis profile using univariable and multivariable statistical analyses. RESULTS: Among the 295 patients, 180 had a poor-prognosis signature and 115 had a good-prognosis signature, and the mean (+/-SE) overall 10-year survival rates were 54.6+/-4.4 percent and 94.5+/-2.6 percent, respectively. At 10 years, the probability of remaining free of distant metastases was 50.6+/-4.5 percent in the group with a poor-prognosis signature and 85.2+/-4.3 percent in the group with a good-prognosis signature. The estimated hazard ratio for distant metastases in the group with a poor-prognosis signature, as compared with the group with the good-prognosis signature, was 5.1 (95 percent confidence interval, 2.9 to 9.0; P<0.001). This ratio remained significant when the groups were analyzed according to lymph-node status. Multivariable Cox regression analysis showed that the prognosis profile was a strong independent factor in predicting disease outcome. CONCLUSIONS: The gene-expression profile we studied is a more powerful predictor of the outcome of disease in young patients with breast cancer than standard systems based on clinical and histologic criteria.

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.

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.

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.

Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors.

In approximately 70% of the families with a high frequency of early-onset breast and/or ovarian cancer, BRCA1 or BRCA2 germline mutations cannot be identified with the current screening regime. Therefore, we used data mining to identify a somatic genetic signature to differentiate BRCA1 mutation carriers from non-BRCA1 carriers based on the genetic characteristics of their breast carcinomas. For this purpose, we developed a molecular classifier, which assigns a given tumor to either the BRCA1 or control group based on somatic genetic profiles as revealed by comparative genomic hybridization. This was performed on breast tumors selected from two groups of patients: 28 proven BRCA1 germline mutation carriers; and a control group consisting of 42 breast tumors from patients with unknown BRCA1 or BRCA2 status. We show that BRCA1 breast carcinomas exhibit specific somatic genetic aberrations and can be distinguished from control tumors with an accuracy of 84% (sensitivity of 96% and specificity of 76%). Chromosomal bands used by this classifier include regions on chromosomes 3p, 3q, and 5q. The classifier miss-assigned one patient with a BRCA1 mutation to the non-BRCA1 class. The germline mutation in this patient is a 62bp deletion in the last exon of BRCA1 (5622del62). Possibly, this mutation may give a different phenotypic effect than do mutations in other regions of the gene. Validation on an independent set of BRCA1 and sporadic tumors showed that the BRCA1 classifier correctly identified all 6 BRCA1 tumors and assigned 4 of the 19 control patients to the BRCA1 class. The resulting accuracy on the validation set is 84%.

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.

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).

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.

Detection of circulating breast tumor cells by differential expression of marker genes.

PURPOSE: We undertook a systematic approach to identify breast cancer (BC) marker genes with molecular assays and evaluated these marker genes for the detection of minimal residual disease in peripheral blood mononuclear cells (PBMCs). EXPERIMENTAL DESIGN: We used serial analysis of gene expression to identify a range of genes that were expressed in BC but absent in the expression profiles of blood and bone marrow cells. Next, we evaluated a panel of four marker genes (p1B, PS2, CK19, and EGP2) by real-time quantitative PCR in 103 PBMC samples from patients with metastatic BC (stage III/IV) and in 96 PBMC samples from healthy females. RESULTS: Increased marker gene expression of at least one marker was seen in 33 of 103 patients. Using quadratic discriminant analysis including all four marker genes, we determined a discriminant value with 29% positivity in the BC patient group that did not yield false positive results among the healthy females. CONCLUSIONS: Real-time PCR for the simultaneous expression of multiple cancer-specific genes may ensure the specificity required for the clinical application of mRNA expression-based assays for occult tumor cells.

A comparison in cosmetic outcome between per-operative interstitial breast implants and delayed interstitial breast implants after external beam radiotherapy.

BACKGROUND AND PURPOSE: Interstitial implants for brachytherapy boost in the breast conserving therapy of breast cancer can be performed in two ways; implants during the tumor excision (per-operative implants) or after the external beam therapy (delayed interstitial implants). Differences in cosmetic outcome were investigated. PATIENTS AND METHODS: Cosmetic results in 47 patients having a per-operative implant were compared to 123 patients having a delayed interstitial implant in a matched case-control study. Cosmesis was scored on a four-point-scale varying from 0 (excellent) to 3 (poor). RESULTS: After mean follow-up of 63 months, three observers found no difference in cosmetic outcome between the two groups after adjustment for variables found to be related with cosmesis (difference in mean score 0.50, P=0.26). Implant volume at 100% isodose was not found to differ (P=0.084) between the per-operative group (mean 102 cm3, S.D. 34 cm3) and the delayed group (mean 93 cm3, S.D. 29 cm3). CONCLUSIONS: Performing per-operative implants has not led to smaller implants. The method of performing brachytherapy does not result in marked differences in cosmetic outcome.

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.

Accuracy of internal mammary lymph node localization using lymphoscintigraphy, sonography and CT.

BACKGROUND AND PURPOSE: An accurate internal mammary (IM) lymph node localization technique is required for proper irradiation of the IM lymph nodes in breast cancer patients. In this study the measurement accuracy of three techniques for direct or indirect localization of the IM nodes was estimated. MATERIALS AND METHODS: In 40 patients the IM lymph node depth and lateral distance from the patient midline were measured with lymphoscintigraphy in intercostal spaces 2, 3 and 4. The corresponding position of an IM vessel was measured with sonography and CT in intercostal spaces 1-4. The sonography and CT vessel measurements in the four intercostal spaces were compared to determine the measurement accuracy of sonography. The node and vessel data in intercostal space 2 were inserted into a mathematical model to determine the measurement accuracy of lymphoscintigraphy and CT for node detection. RESULTS: Vessel depths measured by sonography were systematically too shallow and the lateral vessel position could not be accurately determined. The mathematical model showed that the node depth and lateralization in one intercostal space can be measured directly by lymphoscintigraphy within an accuracy (1 SD) of 5 mm in depth and 6 mm in the lateral direction. The accuracy of CT for indirect node detection was 6 mm in depth and 7 mm in the lateral direction. CONCLUSIONS: Sonography is not a suitable technique for measuring the IM vessel or node position. Lymphoscintigraphy and CT have measurement accuracies for node detection that are acceptable for radiotherapy.

The course of parental expressed emotion and psychotic episodes after family intervention in recent-onset schizophrenia. A longitudinal study.

The stability of parental expressed emotion (EE) is analysed over about 9 years, and related to course of illness in patients with recent-onset schizophrenia. Families, who participated in a 15-month intervention, were randomised over two intervention conditions. Psychotic episodes were measured over 5 years after discharge. The Five Minute Speech Sample (FMSS) EE was elicited two times during the 12-month outpatient intervention and two times over 8 years after discharge on average. EE is expressed as criticism/dissatisfaction (CRIT), emotional overinvolvement (EOI), and as the classical dichotomous index. EE is not stable over the years. Intervention condition had no differential effect on EE as measured with CRIT and the dichotomous index. For EOI, an interaction between intervention condition and time was found. EE as assessed during intervention does not predict psychotic episodes during follow-up. An association was found between psychotic episodes and CRIT as assessed at 34 months after discharge. Family intervention may inhibit the development of high EOI for a limited period. Our results may be in support of the hypothesis that psychotic episodes in patients can affect the critical attitude in parents.

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.

A prospective, randomised and blinded comparison of first shock success of monophasic and biphasic waveforms in out-of-hospital cardiac arrest.

BACKGROUND: Evidence suggests that biphasic waveforms are more effective than monophasic waveforms for defibrillation in out-of-hospital cardiac arrest (OHCA), yet their performance has only been compared in un-blinded studies. METHODS AND RESULTS: We compared the success of biphasic truncated exponential (BTE) and monophasic damped sine (MDS) shocks for defibrillation in OHCA in a prospective, randomised, double blind clinical trial. First responders were equipped with MDS and BTE automated external defibrillators (AEDs) in a random fashion. Patients in ventricular fibrillation (VF) received BTE or MDS first shocks of 200 J. The ECG was recorded for subsequent analysis continuously. The success of the first shock as a primary endpoint was removal of VF and required a return of an organized rhythm for at least two QRS complexes, with an interval of <5 s, within 1 min after the first shock. The secondary endpoint was termination of VF at 5 s. VF was the initial recorded rhythm in 120 patients in OHCA, 51 patients received BTE and 69 received MDS shocks. The success rate of 200 J first shocks was significantly higher for BTE than for MDS shocks, 35/51 (69%) and 31/69 (45%), P=0.01. In a logistic regression model the odds ratio of success for a BTE shock was 4.01 (95% CI 1.01-10.0), adjusted for baseline cardiopulmonary resuscitation, VF-amplitude and time between collapse and first shock. No difference was found with respect to the secondary endpoint, termination of VF at 5 s (RR 1.07 95% CI: 0.99-1.11) and with respect to survival to hospital discharge (RR 0.73 95% CI: 0.31-1.70). CONCLUSION: BTE-waveform AEDs provide significantly higher rates of successful defibrillation with return of an organized rhythm in OHCA than MDS waveform AEDs.

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.