Bad Prognostic Group Research Articles

Prediction of Rapid Early Progression and Survival Risk with Pre-Radiation MRI in WHO Grade 4 Glioma Patients.

Recent clinical research describes a subset of glioblastoma patients that exhibit REP prior to the start of radiation therapy. Current literature has thus far described this population using clinicopathologic features. To our knowledge, this study is the first to investigate the potential of conventional radiomics, sophisticated multi-resolution fractal texture features, and different molecular features (MGMT, IDH mutations) as a diagnostic and prognostic tool for prediction of REP from non-REP cases using computational and statistical modeling methods. The radiation-planning T1 post-contrast (T1C) MRI sequences of 70 patients are analyzed. An ensemble method with 5-fold cross-validation over 1000 iterations offers an AUC of 0.793 ± 0.082 for REP versus non-REP classification. In addition, copula-based modeling under dependent censoring (where a subset of the patients may not be followed up with until death) identifies significant features (p-value < 0.05) for survival probability and prognostic grouping of patient cases. The prediction of survival for the patients' cohort produces a precision of 0.881 ± 0.056. The prognostic index (PI) calculated using the fused features shows that 84.62% of REP cases fall under the bad prognostic group, suggesting the potential of fused features for predicting a higher percentage of REP cases. The experimental results further show that multi-resolution fractal texture features perform better than conventional radiomics features for prediction of REP and survival outcomes.

Can adipokines predict clinical prognosis and post-COVID lung sequelae?

BackgroundAdipokines play an important role in the regulation of inflammatory responses toward infections, including COVID-19. This study aimed to investigate the role of chemerin, adiponectin, and leptin in prognosis and post-COVID lung sequelae in hospitalized patients with COVID-19. MethodsSerum levels of the three adipokines were measured upon admission of polymerase chain reaction-confirmed patients with COVID-19 who were followed up for 6 months for the clinical outcome and lung sequelae formation. ResultsA total of 77 patients were included in the study. Of the 77 patients, 58.4% were males, and the median age was 63.2 ± 18.3 years. Fifty-one patients (66.2%) had a good prognosis. Among adipokines, only chemerin was significantly lower in the bad prognosis group (P < 0.05), and the serum levels showed a negative correlation with age (rho = −0.238; P < 0.05). Leptin levels were negatively correlated with gamma glutamyl transferase levels, which were significantly higher in the bad prognostic group (rho = −0.240; P < 0.05). Twenty-four patients had no lung sequelae, and 20 developed sequelae within 6 months after infection. Chemerin/adiponectin ratio with a cut-off value of 0.96 and an area under the curve 0.679 (P < 0.05) might predict the sequelae formation. ConclusionsChemerin levels are lower, especially in patients with a bad prognosis, and the chemerin/adiponectin ratio might predict the development of lung sequelae in patients with COVID-19.

Mass Transport Model of Radiation Response: Calibration and Application to Chemoradiation for Pancreatic Cancer

The benefit of radiation therapy for pancreatic ductal adenocarcinoma (PDAC) remains unclear. We hypothesized that a new mechanistic mathematical model of chemotherapy and radiation response could predict clinical outcomes a priori, using a previously described baseline measurement of perfusion from computed tomography scans, normalized area under the enhancement curve (nAUC). We simplified an existing mass transport model that predicted cancer cell death by replacing previously unknown variables with averaged direct measurements from randomly selected pathologic sections of untreated PDAC. This allowed using nAUC as the sole model input to approximate tumor perfusion. We then compared the predicted cancer cell death to the actual cell death measured from corresponding resected tumors treated with neoadjuvant chemoradiation in a calibration cohort (n = 80) and prospective cohort (n = 25). After calibration, we applied the model to 2 separate cohorts for pathologic and clinical associations: targeted therapy cohort (n = 101), cetuximab/bevacizumab + radiosensitizing chemotherapy, and standard chemoradiation cohort (n = 81), radiosensitizing chemotherapy to 50.4 Gy in 28 fractions. We established the relationship between pretreatment computed v nAUC to pathologically verified blood volume fraction of the tumor (r = 0.65; P = .009) and fractional tumor cell death (r = 0.97-0.99; P < .0001) in the calibration and prospective cohorts. On multivariate analyses, accounting for traditional covariates, nAUC independently associated with overall survival in all cohorts (mean hazard ratios, 0.14-0.31). Receiver operator characteristic analyses revealed discrimination of good and bad prognostic groups in the cohorts with area under the curve values of 0.64 to 0.71. This work presents a new mathematical modeling approach to predict clinical response from chemotherapy and radiation for PDAC. Our findings indicate that oxygen/drug diffusion strongly influences clinical responses and that nAUC is a potential tool to select patients with PDAC for radiation therapy.

The Study of Sarcoma Microenvironment Heterogeneity Associated With Prognosis Based on an Immunogenomic Landscape Analysis

Microenvironment-driven tumor heterogeneity causes the limitation of immunotherapy of sarcomas. Nonetheless, systematical studies of various molecular levels can enhance the understanding of tumor microenvironment (TME) related to prognosis and provide novel insights of precision immunotherapy. Three prognostic-related TME phenotypes were identified by consensus clustering of the relative infiltration of 22 immune cells from 869 samples of sarcomas. Additionally, integrative immunogenomic analysis is applied to explore the characteristics of different TME groups. The results revealed that most of the immune cell infiltration is higher in the better prognostic group, which are more affected by lower DNA methylation levels and fewer copy number variations in the worse prognostic group. The signaling pathway crosstalk analysis suggested that the changes in the TME will cause considerable variation in the flow of information between pathways, especially when the degree of relative infiltration of immune cells is low, patient’s endocrine system may also be significantly affected. Also, the endogenous competitive network analysis indicated that several differentially expressed long non-coding RNAs (lncRNAs) associated with the prognosis or tumor recurrence of sarcoma patients affected the regulatory relationship between miRNAs and different genes when the sarcoma microenvironment changes. In summary, the significant relationship between genetic alterations and prognostic-related TME characteristics in sarcomas were determined in this study. These findings may provide new clues for the treatment of sarcomas.

Treatment of hepatocellular carcinoma (HCC) after sorafenib (S) over the last 10 years.

438 Background: Until recently there were no standard treatments for HCC patients after S. This study characterizes subsequent treatments (STx) received by HCC patients over the past 10 years and assesses their impact on survival. Methods: HCC patients treated with S between 01/2008 – 06/2017 in British Columbia, Alberta, and two cancer centers in Toronto, Ontario, Canada (Princess Margaret and Sunnybrook Cancer Centre) were included. Clinical, pathologic, laboratory, treatment, and outcome data were collected. The Kaplan-Meier method was used to assess overall survival (OS) based on STx, and stratified according to a better prognostic group (BPG), defined as ECOG 0-1 and CP-A, and worse prognostic group (WPG), defined as ECOG≥2 or CP-B/C. Results: A total of 730 patients were identified. 177 (24.2%) received STx (table). Patients who received STx had longer median OS (mOS) than those who had no further treatment (12.1 vs. 3.3 months; p &lt; 0.001). For patients treated with localized, systemic, or palliative radiation treatment, mOS was 16.8, 10.5 and 8.6 months, respectively (p &lt; 0.001). After S, there were 206 (30.7%) patients in the BPG and 464 (69.3%) in the WPG. BPG patients were more likely to receive STx compared to WPG patients (60.5% vs. 39.5%, p &lt; 0.001). BPG patients who received STx had better mOS than those who did not (15.9 vs. 7.0 months; p &lt; 0.001). WPG patients also had better mOS if they received STx compared to those who did not (6.0 vs. 2.6 months; p &lt; 0.001). Conclusions: Only a small proportion of HCC patients received subsequent treatment after sorafenib. This is likely due to poor performance status, liver dysfunction, or lack of treatment options. Patients who received subsequent treatment had improved mOS, regardless of whether they were in the better or worse prognostic group. [Table: see text]

Differential prognostic value of MYC immunohistochemistry in subtypes of papillary renal cell carcinoma

The histomorphological subtyping of papillary renal cell carcinomas (pRCCs) has improved the predictions of patients’ long-term survival. Based on our previous results, we hypothesized that the MYC proto-oncogene would show differential expression in pRCC subtypes. Using a multi-institutional cohort of 204 pRCC patients we assessed the additional value of the immunohistochemical markers MYC, MINA53, and Ki67 in predicting patient’s long-term survival. The clinical endpoints were overall survival (OS) and cancer-specific survival (CSS). Nomograms were constructed to predict each patient’s risk of death (OS). The incorporation of the MYC staining patterns allowed the stratification of pRCC type 1 patients into better and worse prognostic groups. None of the patients with pRCC type 1 tumors and favorable MYC staining patterns died from tumor-related causes. This prognostic value was independent of the patient’s age at surgery, the pathological tumor stage and presence of lymph node invasion. we could show that the immunohistochemical assessment of MYC and the histomorphological subtyping of pRCC stratifies pRCC type 1 tumors with regard to OS and CSS. The determination of the histomorphologic pRCC subtype in combination with the MYC immunohistochemical staining patterns allows a more accurate prediction of patients’ individual risk of death.

ID:3003 Increase in CD34 cells in peripheral blood following HLA randomized, ABO-matched cord blood transfusion in patients with advanced malignancy and anemia: Prognostic implications

Cord blood is a safe alternative of adult blood for transfusion given its content of fetal and adult haemoglobin, platelet and WBC counts, and a plasma filled with inflammatory and non-inflammatory cytokines and growth factors. It also has a hypoantigenic nature and altered metabolic profile and is rich in haematopoietic stem cells (CD34) . It has potential for treatment of anemia in diseases of different aetiologies including malignancy. &#x0D; ​&#x0D; STUDY DESIGN:&#x0D; In the present study, 46 sex and HLA-randomized patients suffering from advanced malignancy and anemia (Hb 8 Gm percent or less) were treated with placental cord blood transfusion. CD34 cells were collected from peripheral blood 72 hours after transfusion and variations were analyzed for prognostic implication. The study period was between 16 August 1999 and 16 May 2006.&#x0D; ​&#x0D; RESULTS AND ANALYSIS:&#x0D; Among the forty-six cases included in this study , Case no 2 (breast sarcoma) received the lowest amount of card blood (6 units), while Case no 46 (breast cancer) received the largest amount (32 units). The youngest patient, suffering from non-Hodgkin's lymphoma (Case 3), was a 16-year-old boy who received eight units of cord blood to combat anemia. Other patients received amounts varying from 7-15 units: Case 14 received 15 units (metachronous lymph node metastatsis), Case 19 received 14 units (breast cancer), and Case 25 received seven units (lung cancer).&#x0D; ​&#x0D; There was no transfusion-related visible immunological or nonimmunological reaction in any patient. Studies of CD34 levels after 72 hours of transfusion showed an initial rise followed by a fall in twenty-two cases, two cases registered very little effect on the CD34 level, i.e., no change from the baseline, and the rest of the cases demonstrated a sustained rise from the baseline, i.e, 56% to 99% of peripheral mononuclear cells and a sustained high CD34 level.&#x0D; ​&#x0D; CONCLUSION:&#x0D; This preliminary study indicates that freshly collected cord blood transfusion may cause a transient transplant impact of transfused cord blood CD34 stem cells on the host without provoking clinical graft vs host disease perhaps due to a possible background structural or functional immune suppression in advanced malignancy.&#x0D; From the cord blood transfusion impact we could clinically divide the enrolled advanced cancer patients to a relatively good (Group A) and bad prognostic(Group B) variety of cancer. The survival rate of patients where we detected a persistant rise of CD34 in peripheral blood after 3 units or more of transfusion of HLA randomized ABO matched and screened cord blood was over 3 years and the cases where there are no rise of peripheral blood CD34 level in spite of repeated transfusion of 5- 32 units of cord blood died within 3 months or earlier (p value less than .01)

OS11.4 Adult IDH wild-type lower-grade gliomas should be further stratified

IDH wild-type astrocytoma is described as a provisional entity within the new WHO classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be sub-stratified prognostically. 718 adult WHO Grade II and III gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. 166 IDH wild-type cases were identified for further studies and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter and BRAF were examined. EGFR amplification, BRAF and H3F3A mutations were observed in 13.3%, 8.6% and 9.1% respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.4% of cases. Favorable outcome was observed in tumors with oligodendroglial phenotype, grade II histology and total resection. Independent adverse prognostic values of older age, non-total resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariate analysis. Tumors were further classified into “molecularly” high grade (harboring EGFR, H3F3A or TERTp) (median OS=1.2 years) and lower-grade (lacking all of the three) (median OS=7.6 years) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification. In summary, adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers including MYB, EGFR, TERTp and H3F3A should be examined to delineate bad and good prognostic groups.

Prognostic value and their clinical implication of 89-gene signature in glioma.

Gliomas are the most common and aggressive primary tumors in adults. The current approaches, such as histological classification and molecular genetics, have limitation in prediction of individual therapeutic outcomes due to heterogeneity within the tumor groups. Recent studies have proposed several gene signatures to predict glioma's prognosis. However, most of the gene expression profiling studies have been performed on relatively small number of patients and combined probes from diverse microarray chips. Here, we identified prognostic 89 common genes from diverse microarray chips. The 89-gene signature classified patients into good and bad prognostic groups which differed in the overall survival significantly, reflecting the biological characteristics and heterogeneity. The robustness and accuracy of the gene signature as an independent prognostic factor was validated in three microarray and one RNA-seq data sets independently. By incorporating into histological classification and molecular marker, the 89-gene signature could further stratify patients with 1p/19q co-deletion and IDH1 mutation. Additionally, subset analyses suggested that the 89-gene signature could predict patients who would benefit from adjuvant chemotherapy. Conclusively, we propose that the 89-gene signature would have an independent and accurate prognostic value for clinical use. This study also offers opportunities for novel targeted treatment of individual patients.

Variability in functional p53 reactivation by PRIMA-1Met/APR-246 in Ewing sarcoma

Background:Though p53 mutations are rare in ES, there is a strong indication that p53 mutant tumours form a particularly bad prognostic group. As such, novel treatment strategies are warranted that would specifically target and eradicate tumour cells containing mutant p53 in this subset of ES patients.Methods:PRIMA-1Met, also known as APR-246, is a small organic molecule that has been shown to restore tumour-suppressor function primarily to mutant p53 and also to induce cell death in various cancer types. In this study, we interrogated the ability of APR-246 to induce apoptosis and inhibit tumour growth in ES cells with different p53 mutations.Results:APR-246 variably induced apoptosis, associated with Noxa, Puma or p21WAF1 upregulation, in both mutant and wild-type p53 harbouring cells. The apoptosis-inducing capability of APR-246 was markedly reduced in ES cell lines transfected with p53 siRNA. Three ES cell lines established from the same patient at different stages of the disease and two cell lines of different patients with identical p53 mutations all exhibited different sensitivities to APR-246, indicating cellular context dependency. Comparative transcriptome analysis on the three cell lines established from the same patient identified differential expression levels of several TP53 and apoptosis-associated genes such as APOL6, PENK, PCDH7 and MST4 in the APR-246-sensitive cell line relative to the less APR-246-sensitive cell lines.Conclusion:This is the first study reporting the biological response of Ewing sarcoma cells to APR-246 exposure and shows gross variability in responses. Our study also proposes candidate genes whose expression might be associated with ES cells' sensitivity to APR-246. With APR-246 currently in early-phase clinical trials, our findings call for caution in considering it as a potential adjuvant to conventional ES-specific chemotherapeutics.

Costs of epilepsy and their predictors: Cross-sectional study in Germany and review of literature

IntroductionEpilepsy as a chronic neurological disease imposes a substantial burden on individuals and society through the considerable use of health-care resources and the loss of productivity. The aim of this cross-sectional study was to quantify epilepsy-related costs in Germany and to identify cost-driving factors. In addition, we reviewed recent studies on costs of epilepsy and put the present results in an international perspective. Patients and methodsAdult patients with epilepsy from 32 general practitioners, 6 neurologists and an epilepsy center were enrolled for a three months observation period in 2008. Data on socioeconomic status, course of epilepsy as well as direct and indirect costs were recorded using validated patient questionnaires and evaluated from the societal perspective. ResultsWe enrolled 494 patients (232 male, 46.9%) with a mean age of 46.3±17.1 years (range 18–89 years). We calculated epilepsy-specific direct costs of €599 per patient per three months in the primary care sector and €1354 at the epilepsy outpatient clinic. Direct medical costs were mainly due to hospitalization (29.7% in primary care sector and 40.7% at epilepsy outpatient clinic of total direct costs) and anticonvulsants (29.0% and 36.8%). Indirect costs were estimated at €1486 per patient per three months in the primary care sector and €1971 at the epilepsy outpatient clinic. Indirect costs were mainly due to early retirement (39.0% and 49.6% of total indirect costs), unemployment (29.3% and 28.3%) and days off due to seizures (31.7% and 21.2%). Direct costs for AEDs and hospital treatment but not indirect costs were significantly higher in patients treated at the epilepsy center as compared to the primary care sector. Predictors of higher medication and total direct costs were active epilepsy, focal epilepsy syndromes, worse prognostic groups and higher seizure frequency. ConclusionIndirect costs remained higher than direct costs in this study conducted in primary care sector and at an epilepsy center in Germany. Our study and other recent studies with a top-down approach demonstrated hospitalization beside AED costs as an important direct cost factor.

An array CGH based genomic instability index (G2I) is predictive of clinical outcome in breast cancer and reveals a subset of tumors without lymph node involvement but with poor prognosis

BackgroundDespite entering complete remission after primary treatment, a substantial proportion of patients with early stage breast cancer will develop metastases. Prediction of such an outcome remains challenging despite the clinical use of several prognostic parameters. Several reports indicate that genomic instability, as reflected in specific chromosomal aneuploidies and variations in DNA content, influences clinical outcome but no precise definition of this parameter has yet been clearly established.MethodsTo explore the prognostic value of genomic alterations present in primary tumors, we performed a comparative genomic hybridization study on BAC arrays with a panel of breast carcinomas from 45 patients with metastatic relapse and 95 others, matched for age and axillary node involvement, without any recurrence after at least 11 years of follow-up. Array-CGH data was used to establish a two-parameter index representative of the global level of aneusomy by chromosomal arm, and of the number of breakpoints throughout the genome.ResultsApplication of appropriate thresholds allowed us to distinguish three classes of tumors highly associated with metastatic relapse. This index used with the same thresholds on a published set of tumors confirms its prognostic significance with a hazard ratio of 3.24 [95CI: 1.76-5.96] p = 6.7x10-5 for the bad prognostic group with respect to the intermediate group. The high prognostic value of this genomic index is related to its ability to individualize a specific group of breast cancers, mainly luminal type and axillary node negative, showing very high genetic instability and poor outcome. Indirect transcriptomic validation was obtained on independent data sets.ConclusionAccurate evaluation of genetic instability in breast cancers by a genomic instability index (G2I) helps individualizing specific tumors with previously unexpected very poor prognosis.

194 PRESENCE OF A HIGH GRADE TERTIARY GLEASON PATTERN UPGRADES THE GLEASON SUM SCORE AND INVERSELY ASSOCIATED WITH BIOCHEMICAL RECURRENCE-FREE SURVIVAL

You have accessJournal of UrologyProstate Cancer: Staging1 Apr 2011194 PRESENCE OF A HIGH GRADE TERTIARY GLEASON PATTERN UPGRADES THE GLEASON SUM SCORE AND INVERSELY ASSOCIATED WITH BIOCHEMICAL RECURRENCE-FREE SURVIVAL Polat Turker, Emine Bas, Suheyla Bozkurt, Bulent Gunlusoy, Arsenal Sezgin, Hakan Postaci, and Levent Turkeri Polat TurkerPolat Turker Tekirdag, Turkey More articles by this author , Emine BasEmine Bas Istanbul, Turkey More articles by this author , Suheyla BozkurtSuheyla Bozkurt Istanbul, Turkey More articles by this author , Bulent GunlusoyBulent Gunlusoy Izmir, Turkey More articles by this author , Arsenal SezginArsenal Sezgin Izmir, Turkey More articles by this author , Hakan PostaciHakan Postaci Izmir, Turkey More articles by this author , and Levent TurkeriLevent Turkeri Istanbul, Turkey More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.264AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Tumor heterogeneity is a common finding and led to realization of a tertiary Gleason component (TGC) in prostate cancer. In an attempt to further investigate its prognostic value, we analyzed the association of tertiary Gleason pattern in Gleason score less than/equal to 7 tumors with pathologic stage and biochemical disease-free survival. METHODS 331 radical prostatectomy specimens were analyzed retrospectively. The primary, secondary and the tertiary patterns were evaluated by reviewing all of the pathological slides. TGC was defined as Gleason grade pattern 4 or 5 for Gleason score less than 7 tumors and Gleason grade pattern 5 for Gleason score 7 tumors. The pathological prognostic factors, (extraprostatic extension, seminal vesicle and lymph node invasion, surgical margin status) of Gleason score less than 7, 3+4 and 4+3 tumors with or without TGC were compared. Biochemical recurrence free survival (BRFS) was calculated using Kaplan Meier method with log rank test and the influence of TGC was assessed in a Cox regression model. RESULTS TGC observed more frequently with higher Gleason scores (21% of the GS less than 7 cases, 23% of the GS 3+4 cases and 58% of the GS 4+3 cases). In terms of adverse pathological prognostic factors and BRFS, GS<7 tumors with TGC behaved significantly worse than GS<7 tumors without TGC (p=0.01 and p=0.001 respectively) with properties similar to GS 3+4 tumors without TGC. Gleason score 3+4 and 4+3 tumors without TGC were statistically similar and have better features than corresponding tumors of same Gleason score with TGC. Furthermore, Gleason score 7 tumors with TGC have similar features with GS 8-10 tumors. During follow-up 73 (22%) subjects had PSA recurrence. In the Cox regression model TGC was an independent variable for BRFS (HR=2.63, 95% CI=1.39–4.98, p=0.003). CONCLUSIONS According to the present study, 3 different prognostic groups were observed; good prognostic group: GS <7, intermediate prognostic group: GS<7+TGC, GS 3+4 and GS 4+3, and finally bad prognostic group: GS (3+4)+TGC, GS (4+3)+TGC,GS>7. Presence of a TGC appears to upgrade the total score and adjuvant treatment decisions may further be refined by considering the tertiary pattern. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e80-e81 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Polat Turker Tekirdag, Turkey More articles by this author Emine Bas Istanbul, Turkey More articles by this author Suheyla Bozkurt Istanbul, Turkey More articles by this author Bulent Gunlusoy Izmir, Turkey More articles by this author Arsenal Sezgin Izmir, Turkey More articles by this author Hakan Postaci Izmir, Turkey More articles by this author Levent Turkeri Istanbul, Turkey More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Presence of high grade tertiary Gleason pattern upgrades the Gleason sum score and is inversely associated with biochemical recurrence-free survival

ObjectivesTumor heterogeneity is a common finding and led to realization of a tertiary Gleason component (TGC) in prostate cancer. In an attempt to further investigate its prognostic value, we analyzed the association of tertiary Gleason pattern in Gleason score ≤ 7 tumors with pathologic stage and biochemical disease-free survival. Material and methodsA total of 331 radical prostatectomy specimens were analyzed retrospectively. The primary, secondary, and the tertiary patterns were evaluated by reviewing all of the pathologic slides. TGC was defined as Gleason grade pattern 4 or 5 for Gleason score < 7 tumors and Gleason grade pattern 5 for Gleason score 7 tumors. The pathologic prognostic factors, (extraprostatic extension, seminal vesicle and lymph node invasion, surgical margin status) of Gleason score < 7, 3+4, and 4+3 tumors with or without TGC were compared. Biochemical recurrence-free survival (BRFS) was calculated using Kaplan-Meier method with log rank test, and the influence of TGC was assessed in a Cox regression model. ResultsTGC observed more frequently with higher Gleason scores (21% of the GS < 7 cases, 23% of the GS 3+4 cases, and 58% of the GS 4+3 cases). In terms of adverse pathologic prognostic factors and BRFS, GS < 7 tumors with TGC behaved significantly worse than GS < 7 tumors without TGC (P = 0.01 and P = 0.001, respectively) with properties similar to GS 3+4 tumors without TGC. Gleason score 3+4 and 4+3 tumors without TGC were statistically similar and had better features than corresponding tumors of same Gleason score with TGC. Furthermore, Gleason score 7 tumors with TGC had similar features with GS 8–10 tumors. During follow-up, 73 (22%) subjects had PSA recurrence. In the Cox regression model TGC was an independent variable for BRFS (HR = 2.63, 95% CI = 1.39–4.98, P = 0.003). ConclusionAccording to the present study, 3 different prognostic groups were observed; good prognostic group: GS < 7, intermediate prognostic group: GS < 7+TGC, GS 3+4, and GS 4+3, and finally bad prognostic group: GS (3+4)+TGC, GS (4+3)+TGC, GS > 7. Presence of a TGC appears to upgrade the total score and adjuvant treatment decisions may further be refined by considering the tertiary pattern.

Use of gene expression analysis of periampullary carcinomas to identify biliary-like and intestinal-like subgroups of ampullary and duodenal carcinomas.

161 Background: Though adenocarcinomas of the ampulla of Vater are classified as biliary cancers, the epithelium of origin and treatment approach for these rare tumors remains controversial. We compared the gene expression profiles of ampullary carcinomas with that of known periampullary carcinomas. Methods: We analyzed 32 fresh-frozen resected untreated periampullary carcinomas (8 pancreatic, 2 extrahepatic biliary, 8 non-ampullary duodenal, and 14 ampullary) with verified histology and &gt;70% tumor tissue using the Affymetrix U133 Plus 2.0 genome array. Hierarchical clustering of all samples based upon pancreatic and duodenal differentially expressed genes and unsupervised hierarchical clustering was done. Ampullary and duodenal samples were analyzed for histologic subtype (pancreaticobiliary, intestinal, mixed), MSI by PCR, CDX-2 by IHC and KRAS and PI3K mutations by mass spectroscopy-based sequencing (Sequenom). Results: We identified 3 subgroups: pancreatic (8 pancreatic, 1 duodenal), biliary-like (4 duodenal, 7 ampullary, 2 biliary) and intestinal-like (3 duodenal, 7 ampullary). The intestinal-like subgroup had a significantly improved RFS (p=0.03) and OS (p =0.04) compared to the biliary-like subgroup, after stratification by grade and stage. Unsupervised clustering of only ampullary and duodenal samples identified very similar good prognostic (4 duodenal, 5 ampullary) and bad prognostic groups (3 duodenal, 9 ampullary) with 3-year RFS 75% vs. 31%, p =0.05 and 3-year OS 100% vs. 27%, p =0.01. These 2 groups showed no statistically significant differences in adenoma (56% vs 25%), poor differentiation (11% vs 42%), T4 (33% vs 25%), N1 (67% vs 100%), MSI-high (22% vs 0%), KRAS mutations (33% vs 17%), or PI3K mutations (0% vs 17%). CDX-2 expression (100% vs 50%, p=.04) and intestinal histologic subtype (100% vs 0%, p &lt;0.01) were more common in the good prognostic group. Conclusions: Gene expression analysis classifies ampullary carcinomas with duodenal carcinomas and identifies a good prognosis intestinal-like group and a poor prognosis biliary-like group. These findings have therapeutic implications. [Table: see text]

Pretreatment T Lymphocyte Numbers Are Contributing to the Prognostic Significance of Absolute Lymphocyte Numbers in B-cell Non-Hodgkins Lymphomas

Targeted immuno-chemotherapy resulted in greatly improved survival of B cell lymphoma patients. Several prognostic markers are investigated, amongst them the pretreatment absolute lymphocyte numbers. We investigated lymphocyte subpopulations and correlated this data with prognosis of patients. 88 patients (mean age: 56 years, 18-88, median follow up 32 months) with B cell lymphomas were investigated. There were 51 DLBCL, 16 Follicular NHL, 4 MALT, 7 Marginal Zone NHL, 10 Small lymphocytic cases were investigated. Our data showed that overall survival was statistically significant up to the 0.9 G/l absolute lymphocyte numbers as dividers between the subgroups. The CD19+ B cell numbers, or the CD56+/CD3- NK cell numbers did not represent any significant differences between subgroups. However CD3+, CD4+ and CD8+ T cells were differentiating statistically significant subgroups. Pretreatment CD3+ cell number less than 700/ul and CD8+ cell number less than 200/ul were corresponding with significantly inferior overall survival. These could be verified in the bad prognostic IPI group as well. Our data further support the importance of pretreatment lymphocyte numbers and highlight CD3+ and CD8+ lymphocytes to be the key factors in predicting outcome.

Comparison of Outcomes in Studies of Advanced Hodgkin's Lymphoma

We were interested to read the editorial by Dr Carde1, which referred to our article2 that reported the results of the United Kingdom Lymphoma Group LY09 study in advanced Hodgkin's lymphoma. The editorial may have given the impression that our study was a randomized comparison of three regimens, which is not the case. A standard arm of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was used, and investigators elected in advance whether to randomize against the alternating or hybrid regimen. Thus, it is not legitimate to make direct comparison of the two multidrug arms. It is also difficult to compare the overall results in this study to the Italian trial reported in the same issue by Gobbi et al3, which included a more favorable group of patients among whom only 11% of patients were in International Prognostic Score group 4 to 7, compared with 19% in the UK study. The measure of 65% progression-free survival at 5 years cited by Dr Carde refers only to patients in stages III/IV, whereas for the UK study as a whole the figure is 73%. The interpretation of information regarding the use of radiotherapy in the two parallel randomizations is problematic. Dr Carde suggests that a comparison can be made between the two standard ABVD groups, with the more frequent use of eight cycles in the centers randomizing against alternating treatment apparently giving marginally better freedom from progression results than those seen in the hybrid randomization, where it was more common to use six cycles followed by radiotherapy. Such data must be interpreted with caution, especially because the patients in the hybrid randomization were more likely to have bulky mediastinal disease and systemic symptoms, suggesting a worse prognostic group. We contend that such an effect may be due to patient selection rather than the use of radiotherapy or fewer cycles of ABVD. Finally, Dr Carde has made a provocative analysis of the data, correlating freedom from progression with intended, rather than actual doses delivered. This may be helpful in terms of generating hypotheses to be tested in future studies but does not necessarily explain observed outcomes in the LY09 trial.

Factores pronósticos en la recidiva y progresión del cáncer superficial vesical. Grupos de riesgo (Parte II)

IntroductionWe try to establish risk groups combining the characteristics of each bladder tumour, for a better monitoring of these patients. Material and MethodsOnce known the variables implied in recurrence and progression we analyze the data to establish the extreme groups, so, the one with the worse and the one with the better prognostic, remaining a residual group that would correspond of the tumours of intermediate prognostic. ResultsFrom the results obtained, we can establish three risk groups: bad prognostic group (high risk) : high grade tumours (g3), isolated or associated tis and multiple or recurrent grade 2 tumours that were recurred in less than 6 months; intermediate prognostic group: multiple tag1 tumours, as well as not multiple ta-1g2 and t1g1 (less than 3 tumours) and group of low risk: single tag1 tumours. discussionAccording to these results the group of badly risk, involves a high risk of recurrence and progression. The most effective treatment was the BCG (bacillus Calmette-Guerin) with maintenance, requiring a long-term control, more intense in the 2 first years after the RTU. In the group of intermediate risk, the rates of long-term superficial recurrence were as high as those of the high risk group, being needed a long-term control, in this group was effective the treatment with chemotherapy or BCG being preferably the maintenance. Finally in the group of good risk we don’t objectify progressions being the time to the recurrence the longest one, with stabilization of the rate of recurrences after one year.

OBESITY AND PROSTATE CANCER CLINICAL RISK FACTORS AT PRESENTATION: DATA FROM CaPSURE

We investigated the association of obesity with prostate cancer case demographics and clinical disease features at presentation. Data were abstracted from CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor), a disease registry of 10,018 men with prostate cancer. A total of 2,952 men were included who were treated between 1989 and 2002, and had complete body mass index (BMI) information. BMI classes were defined as normal (less than 25 kg/m), overweight (25 to 29.9 kg/m), obese (30 to 34.9 kg/m) or very obese (35 kg/m or greater). Patients were categorized as having low, intermediate or high risk disease based on the D'Amico classification. Associations among BMI, risk and demographics were analyzed using univariate and multivariate models. Of the patients 29% had a normal BMI, 51% were overweight, 16% were obese and 5% were very obese. Patients who were overweight or obese were more likely to be young, have hypertension and diabetes, and have a lower education level. The overweight group had a lower serum prostate specific antigen (p = 0.010) and lower stage disease (p = 0.030) at diagnosis, but there was no association between Gleason score and obesity (p = 0.57). However, among men with a BMI of 25 kg/m or greater there was a positive correlation between increasing BMI and risk of being in a worse prognostic group at diagnosis (p = 0.018). Overweight and obese patients are more likely to be young at diagnosis and have multiple comorbidities. Men in the overweight and obese groups presented with lower risk prostate cancer at diagnosis. This may be due to earlier disease detection secondary to more frequent interaction with the medical community. Among overweight and obese patients increased obesity is associated with a slightly increased chance of having high risk prostate cancer at diagnosis.

Pre-Transplantation Level of Minimal Residual Disease Detected by Quantitative Real-Time IgH-PCR Is a Prognostic Parameter in Patients with Multiple Myeloma.

Background: High-dose chemotherapy with autologous stem cell transplantation has improved outcome and survival of patients with multiple myeloma. However, the majority of patients suffer from relapse. Using real-time quantitative (RQ) PCR we have shown before (Haematologica 89,2004) that the amount of residual tumor cells in the bone marrow of patients before transplantation is of prognostic relevance. In this study we evaluated in a larger group of patients with multiple myeloma whether a pre-transplantation level of clonotypic cells in the bone marrow is predictive for time-to-progression (TTP) and overall survival (OS). Further, we compared results with known prognostic factors.Patients and Methods: Bone marrow samples of 19 patients with stage II/III multiple myeloma were obtained after induction therapy but before transplantation. Immunoglobulin heavy chain (IgH) RQ-PCR using patient-specific Taqman probes was performed to quantify pre-transplantation tumor levels. The proportion of clonotypic cells was assessed as IgH/2 beta-actin ratio in percent. Medical records of patients were reviewed for prognostic factors and outcome.Results: The median level of residual tumor cells in bone marrow of all patients at the time before transplantation was 0.3 %. At 23 month median follow-up after transplantation the median TTP and OS in our study were 14 and 36 month, respectively. The threshold level of 0.03% clonotypic cells identified two prognostic groups (p<0.0001, log rank). Twelve patients in the bad prognostic group had an early relapse with a median TTP of 9 month (range: 3 – 17 month). All patients in the good prognostic group (n=7) had ongoing remissions after a median follow-up of 24 month (range: 13–44 month). Univariat analysis was performed including other prognostic factors at the time before transplantation such as cytogenetic abnormalities, beta2-microglobulin, hemoglobulin, platelet count, LDH, CRP, serum albumine and age. Besides the pre-transplant level of minimal residual disease, CRP level was predictive for TTP. In multivariat analysis using a step-wise cox regression model grouping by pre-transplantation tumor level was the only prognostic factor for TTP (p = 0.05). Moreover, low pre-transplantation tumor levels also showed a trend for a better OS, but in multivariat analysis only normal cytogenetics were predictive for a superior outcome (p = 0.03).Conclusion: Quantitative molecular assessment of pre-transplantation tumor level in the bone marrow is an independent prognostic parameter for the progression-free survival of patients with multiple myeloma and thus helps to guide therapeutic interventions