A Shorter Time to First Treatment and Worst Overall survival Is Observed in Cll Patients with Reduced Serum IgM As Evaluated with Novel Serum Immunoassays

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4585-4585
Author(s):  
Efstathios Koulieris ◽  
Katerina Sarris ◽  
Nikolitsa Kafasi ◽  
Vassiliki Bartzis ◽  
Tatiana Tzenou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Conflicts Of Interest ◽  
Lymph Node Biopsy ◽  
Lymphocytic Leukemia ◽  
Rank Test ◽  
Monoclonal Immunoglobulin ◽  
Log Rank Test ◽  
Time To First Treatment ◽  
Disease Characteristic ◽  
Iga Subclasses

Abstract Abstract 4585 Background and Aims: Reduced serum IgM levels were proposed as an unfavorable prognostic factor in multiple myeloma1. We therefore investigated the possible impact of decreased serum IgM concentrations on the outcome of Chronic Lymphocytic Leukemia (CLL) patients, a disease that is frequently characterized by severe hypogammaglobulinemia. Serum IgM levels were measured by 2 methods. Patients and methods: 188 patients with CLL were studied. Of them 54%, 27%,10%, 7% και 2% where in RAI stage 0, 1, 2, 3, 4 respectively while 65%, 22% and 13% in Binet stages A, B and C. IgM was determined at diagnosis by both classical nephelometry and the new Hevylite™ methods; the first measures total IgM levels while the second one measures the immunoglobulin fractions bound to either kappa or lambda light chains therefore enabling us to determine the ratio of IgM-kappa/lambda (HLCR). Hevylite™ measurements were retrospectively performed in 69/188 patients with available frozen sera aliquots from drawn at the time of diagnosis. Of them the Ig subclasses IgMkappa and IgMlambda, IgGkappa and IgGlambda, IgAkappa and IgAlambda (HLC) were measured by Hevylite™ antibodies nephelometrically. Light chain restriction (kappa or lambda) was determined by flow cytometry or bone marrow/lymph node biopsy immunohistochemistry. The ratios (HLCRs) were calculate with the monoclonal immunoglobulin as numerator, i.e IgMkappa/IgMlambda, IgGkappa/IgGlambda and IgAkappa,/IgAlambda in kappa-restricted patients and IgMlambda/IgMkappa, IgGlambda/IgGkappa, IgAlambda/IgAkappa in lambda-ones. Serum IgM concentration by both methods were related to time to first treatment (TFT) and overall survival (OS). Statistical analysis was performed conventionally; survival curves were drawn by Kaplan-Meyer method and compared by the log-rank test. Results: Total IgM ranged from 12 to 246 mg/dl (median 47.6). The sum of IgMkappa plus IgMlambda from 12 to 369 (median 60). IgMkappa from 7.9 to 349 mg/dL (median 41) in kappa-restricted patients and IgMlambda from 7.6 ωζ 98 mg/dL (median 22) in lambda restricted ones. Low total IgM level (<50 mg/dL) was present in 52% of patients but it did not correlate to TFT or OS. Summated IgMkappa plus IgMlambda lower than 50 mg/dL was present in 41% and correlated with worse OS (p=0.016). Furthermore non-clonal IgM subclass suppression correlated with TFT (p=0.019) and OS (p=0.021). The same was not confirmed for non-clonal IgG and IgA subclasses suppression. Finally IgM-HLCR was abnormal in 35% of patients. Of them, 25% had also abnormal IgG-HLCR and/or IgA-HLCRs leading to the hypothesis of multiple clones coexistence within the neoplastic B-cell lymphocytic population. Conclusions: Low IgM levels determined by novel immunoassays (Hevylite™) correlate to shorter TFT and OS in patients with CLL. Their use may reveal new disease characteristic and are suggestive of a multi-oligoclonal disorder. Disclosures: No relevant conflicts of interest to declare.

High Resolution Array-CGH Provides New Insights Into the Prognosis of Chronic Lymphocytic Leukemia (CLL): Is 8p Loss Worse Than 17p Loss?.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2339-2339
Author(s):  
Andrea Rinaldi ◽  
Michael Mian ◽  
Davide Rossi ◽  
Francesco Forconi ◽  
Clara Deambrogi ◽  
...  
Keyword(s):  
Cox Regression ◽  
Clinical Course ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Lymphocytic Leukemia ◽  
Rank Test ◽  
Western World ◽  
Clinical Parameters ◽  
Log Rank Test ◽  
The Impact

Abstract Abstract 2339 Poster Board II-316 BACKGROUND: CLL, the most common adult-onset leukemia in the Western world, has a heterogeneous clinical course. Many advances have led to a better understanding of its pathogenesis and to improvements in treatment strategies, but striking solutions are still missing. We conducted a study to evaluate the impact of genomic aberrations on the clinical course. METHODS: From January 1980 to May 2008, 395 frozen samples of CLL patients, were prospectively collected in four centers. Extracted DNA was analyzed with Affymetrix Human Mapping 6.0 arrays. Normal matched DNA was analyzed for one fourth of the cases. Correlations between minimal common regions (MCR) and clinical parameters were evaluated with the Fisherôs-exact test and their impact on OS with the log-rank test. A p-value after Bonferroni multiple test correction (MTC) (p-adj.) <0.05 was considered as statistically significant. Up to now 266 samples have been analyzed. RESULTS: Analysis of the clinical parameters (CPs) and known risk factors (Rai/Binet, age, doubling time, LDH, beta2, IGVH status, p53 mutations, telomere length, CD38, 11q, 17p) was consistent to previous published series. ZAP70 did not affect the clinical course, likely due inter-laboratories variability. After a median follow up of 53 months, 143/239 (60%) of the patients have started therapy and 63/261 (24%) died. 5-yr OS was 82%. Fisher test between the MCRs and CPs revealed an inverse relation between the presence of trisomy 12 by FISH and del13q14.3, an association between del17p and losses of 8p regions and between CD38 and 12q gain. Before MTC, 46 MCRs had a significant impact on OS and 67. After MTC, 3 regions maintained their role: 8p22 loss (38/248, 15%, p-adj.=0.002, median OS: 26 months vs. 48), 17p13.3-11.2 loss (20/248, 8%, p-adj.=0.001; median OS: 10 months vs. 48). In univariate analysis, the log-rank test among pts with 8p-/17p- (8/248, 3%), 8p- (30/248, 12%), 17p- (12/248, 5%), wild type (198/248, 80%) was statistically significant (p<0.001; see figure). Importantly, none of the analyzed clinical and biological parameters was associated with this aberration. CONCLUSIONS: Loss of 8p22 designated a CLL subgroup with a worse outcome among all patients and in the subset with 17p loss. Our data suggested that this aberration might constitute an independent prognostic factor to be evaluated in independent studies. Results, including a Cox regression model, will be presented on all 395 cases. Disclosures: No relevant conflicts of interest to declare.

CD38 Variation in Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4576-4576
Author(s):  
Ryan D. Nipp ◽  
J. Brice Weinberg ◽  
Alicia D. Volkheimer ◽  
Evan D. Davis ◽  
Youwei Chen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Proportional Hazards Model ◽  
Prognostic Significance ◽  
Cox Proportional Hazards ◽  
Lymphocytic Leukemia ◽  
Cox Proportional Hazards Model ◽  
Rank Test ◽  
Cd38 Expression ◽  
Log Rank Test ◽  
Maximum Minimum

Abstract Abstract 4576 Background: Chronic lymphocytic leukemia (CLL) has a highly variable clinical course. Some patients require treatment early while others can be monitored without therapy. CD38 expression has been shown in multiple cohorts to have prognostic significance. An elevated percentage of CD38 positive CLL lymphocytes at the time of diagnosis is correlated with a more rapid need for therapy and a shorter overall survival. The extent to which CD38 varies during the course of CLL, including after therapy, has only been evaluated in a limited fashion. Methods: From a cohort of over 500 CLL patients at the Duke University and Durham VA Medical Centers, we selected 136 patients in whom we had measured CD38 expression by flow cytometry on two or more occasions. We determined the first, maximum, minimum, and range (maximum – minimum) CD38 values. We compared these values to other molecular prognostic markers using Wilcoxon tests and assessed the prognostic significance of these values using Cox proportional hazard models and Kaplan-Meier analyses. Results: Of the 136 patients, 70% were male and 88% Caucasian, with a median age of 60. The majority had low clinical stage at diagnosis—either Rai stage 0 (68%) or 1 (19%). Molecular prognostic markers were also generally favorable. Eighty-two (67%) patients had mutated IGHV status, 69 (51%) were ZAP70 negative, and 76 (63%) had either 13q deletion or normal cytogenetics, determined by fluorescent in situ hybridization. CD38 expression was measured a median of 5.5 times (2 – 19). The median time between the first and last CD38 measurements was 1206 days (81 – 4109). The median values were 6% (0.6 – 99) for maximum CD38, 1.5% (0 to 84.5) for minimum CD38, and 4.9% (0.2 to 95.3) for CD38 range. Maximum, minimum, and CD38 range were significantly lower in patients with mutated compared to unmutated IGHV status (p < 0.005 for all parameters, Wilcoxon rank sum test). Elevated maximum and CD38 range were significantly associated with a more rapid time to therapy (TTT) and shorter overall survival (OS) in a univariate Cox proportional hazards model (p < 0.03 for all, Wald test). In a multivariate Cox proportional hazards model including first CD38 and maximum CD38 values, only maximum CD38 remained statistically significant. We found that patients with high CD38 variation (CD38 range greater than the median) had significantly shorter TTT and OS than patients with low CD38 variation (p = 0.002 for both, log rank test). Using receiver operator characteristic analyses, we determined that the best cut-off for dichotomizing the first CD38 according to TTT and OS in the entire Duke/Durham VA CLL cohort was 11%. Using this cut-off, 15 patients (11%) converted from CD38 negative to CD38 positive. Using the standard 30% cut-off, 14 patients (10%) converted from CD38 negative to CD38 positive. Patients with a first CD38 measurement less than 11% and subsequent measurements above 11% had a favorable OS, similar to patients with low CD38 for all measurements (p = 0.002, log rank test). However, patients with a first CD38 measurement less than 30% who had subsequent measurements above 30% had an inferior OS, similar to patients with high CD38 for all measurements (p = 0.006, log rank test). Lastly, among 24 patients with CD38 measurements before and after first therapy, the percentage of CD38 positive cells increased in 19 patients (79%), with a median value of 3.2% before to 6.9% after therapy (p = 0.005, Wilcoxon signed rank test). Conclusions: CD38 values vary as patients transition across the disease trajectory. This variation appears to have prognostic significance, with high variation associated with faster time to first therapy and shorter overall survival. Additionally, in our cohort, a patient's maximum CD38 value had more prognostic significance than a single initial measurement. Thus, longitudinally measuring CD38 throughout the clinical course of CLL could aid in the management of CLL patients, refining the initial prognostic assessment, and improving patient counseling and decision making. Disclosures: No relevant conflicts of interest to declare.

The Prognostic Value of Serum APRIL Levels in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5648-5648
Author(s):  
Sinem Nihal Esatoglu ◽  
Dilek Keskin ◽  
Muge Kutnu ◽  
Tugrul Elverdi ◽  
Ayse Salihoglu ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Demographic Data ◽  
Lymphocytic Leukemia ◽  
Rank Test ◽  
Healthy Controls ◽  
Log Rank Test ◽  
Treatment Naïve ◽  
Group A ◽  
Group B ◽  
Time To First Treatment

Abstract Introduction: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with variable clinical course. Several studies have been conducted to predict outcome in patients with CLL and also have been going on. A proliferation inducing ligand (APRIL) has been shown to involve in survival and resistance to apoptosis in CLL, and APRIL molecule has been investigated as a prognostic marker in CLL patients. However, there are limited and controversial data regarding APRIL and its impact on prognosis in CLL. We aimed to compare serum APRIL levels in CLL patients with those of age and gender matched healthy subjects, and to investigate the relationship between APRIL and the other common prognostic factors, and to determine whether serum APRIL levels predict time to first treatment in CLL. Methods: After ethical approval and informed consent were obtained, between May and December 2012, venous blood samples were driven from 96 CLL patients’ and 25 healthy controls’, and serum APRIL levels were measured by ELISA. Demographic data and the prognostic markers were obtained from the patients’ files, and patients have been followed for a minimum of 12 months. We tested the correlation between APRIL with the, clinical and biological parameters, and used the log rank test to compare their Kaplan Meier curves. Results: Patients were divided into three groups: Treatment naive (group A, n=49), chemotherapy receiving (group B, n=25) and who had previously received chemotherapy (group C, n=22). Median APRIL level was higher in group A (2.78 vs 1.29; p=0.034) and group C (3.54 vs 1.29; p=0.001) when compared to healthy controls, but was not different in group B (1.56 vs 1.29; p=0.3) (Figure 1). Serum APRIL level in group A was negatively correlated with hemoglobin levels (r=-0.298; p=0.037) and platelet counts (r=-0.321; p=0.025) whereas no correlation with age, Rai and Binet stages, lymphocyte counts, β2-microglobulin and CD38 levels were detected. Group A patients were also divided into 2 subgroups (APRIL levels low, n=20 and APRIL levels high, n=29) using median natural logarithm of serum APRIL level as cut off. April low and high subgroups were similar with respect to demographic data and prognostic factors. Median time to first treatment was not reached in the APRIL low group, but was 104 months in the APRIL high group (p=0.13, log-rank test). Conclusions: Among the treatment naive patients, serum APRIL levels only negatively correlate with hemoglobin levels and platelet counts. These correlations seem to be associated with tumor burden rather than the prognosis, because APRIL levels were not different in chemotherapy receiving patients compared to healthy controls. Since a median survival time could not be reached in the APRIL low group, short follow up time might be an explanation why the APRIL levels did not predict the time to first treatment. In conclusion, our findings let us to think APRIL levels are not a useful marker to predict prognosis in patients with CLL. Figure 1. Median APRIL levels of CLL patients and healthy controls (ng/mL) Figure 1. Median APRIL levels of CLL patients and healthy controls (ng/mL) Disclosures No relevant conflicts of interest to declare.

scholarly journals The impact of sentinel lymph node sampling versus traditional lymphadenectomy on the survival of patients with stage IIIC endometrial cancer

2021 ◽  
pp. ijgc-2021-002450
Author(s):  
Dimitrios Nasioudis ◽  
Maureen Byrne ◽  
Emily M Ko ◽  
Robert L Giuntoli II ◽  
Ashley F Haggerty ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lymph Node ◽  
Sentinel Lymph Node ◽  
Sentinel Lymph Node Biopsy ◽  
Lymph Node Biopsy ◽  
Rank Test ◽  
Systematic Lymphadenectomy ◽  
Log Rank Test ◽  
Node Biopsy ◽  
To Receive

ObjectiveTo investigate the survival of patients with lymph node positive endometrial carcinoma by type of surgical lymph node assessment.MethodsPatients diagnosed between January 2012 and December 2015 with endometrial carcinoma and uterine confined disease and nodal metastases on final pathology who underwent minimally invasive hysterectomy were identified in the National Cancer Database. Patients who had sentinel lymph node biopsy alone or underwent systematic lymphadenectomy were selected. Overall survival was evaluated following generation of Kaplan–Meier curves and compared with the log rank test. A Cox model was constructed to evaluate survival after controlling for confounders.ResultsA total of 1432 patients were identified: 1323 (92.4%) and 109 (7.6%) underwent systematic lymphadenectomy and sentinel lymph node biopsy only, respectively. The rate of adjuvant treatment was comparable between patients who had sentinel lymph node biopsy alone and systematic lymphadenectomy (83.5% vs 86.6%, p=0.39). However, patients who had sentinel lymph node biopsy were less likely to receive chemotherapy alone (13.6% vs 36.6%, p<0.001) and more likely to receive radiation therapy alone (19.8% vs 5.4%, p<0.001) compared with patients who had systematic lymphadenectomy. There was no difference in overall survival between patients who had sentinel lymph node biopsy alone and systematic lymphadenectomy (p=0.27 from log rank test), and 3 year overall survival rates were 82.2% and 79.4%, respectively (p>0.05). After controlling for confounders, there was no difference in survival between the systematic lymphadenectomy and sentinel lymph node biopsy alone groups (hazard ratio 0.82, 95% confidence interval 0.46 to 1.45).ConclusionsPerformance of sentinel lymph node biopsy alone was not associated with an adverse impact on survival in patients with lymph node positive endometrial cancer.

ZAP-70 Expression Assessed by Immunohistochemistry Correlates with Time to First Treatment in Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4686-4686
Author(s):  
Peter Martin ◽  
Amy Chadburn ◽  
Wayne Tam ◽  
Lauren Tyrell ◽  
Rebecca Elstrom ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Rank Test ◽  
Clinical Test ◽  
Research Database ◽  
Mutation Status ◽  
Pairwise Correlation ◽  
Time To First Treatment

Abstract Abstract 4686 Background ZAP-70 expression is a prognostic indicator in chronic lymphocytic leukemia (CLL). Initial studies measured intracellular ZAP-70 expression by flow cytometry and defined a cut-off of 20% as predictive of time from diagnosis to initial therapy and overall survival. However, due to technical challenges, standardization of methods for evaluation of ZAP-70 expression has been difficult. This has resulted in a limitation of applicability for a potentially useful clinical test. Immunohistochemistry (IHC) is easy to perform and interpret, and therefore may be a more reliable and accurate means for assessing ZAP-70 expression. We investigated the potential prognostic implications of ZAP-70 expression assessed by IHC. Methods We searched our CLL database for all patients seen at Weill Cornell Medical College between 2007 and 2009 with an identifiable date of diagnosis, date of first therapy, IgVH mutation status, and ZAP-70 status. All patients gave informed consent to participate in the research database. Paraffin-embedded cell blocks were prepared from formalin-fixed peripheral blood mononuclear cells and evaluated by IHC for PAX5, CD3, and ZAP-70. The entire cell clot was reviewed. If more than 20% of cells faintly expressed ZAP-70, the ZAP-70 status was considered to be positive. Patients had IgVH mutations status determined by a commercial laboratory with <98% sequence homology used as a cut-off. Time from diagnosis to first treatment (TT) was estimated by the Kaplan-Meier method; comparisons were performed by log-rank test. Pearson's pairwise correlation coefficient was used to evaluate the relationship between ZAP-70 and IgVH. Results One-hundred thirty-seven patients with date of diagnosis and date of first treatment were identified in the database. Sixty-six patients have been treated to date. ZAP-70 status was available for 106 patients, 62 were positive, 44 were negative. In a subset of 20 patients, two blinded pathologists reviewed IHC and found perfect agreement on ZAP-70 status. IgVH mutation status was available for 86 patients, 34 were unmutated, and 52 were mutated. Eighty-two patients had both ZAP-70 status and IgVH mutation status available. There was good correlation between ZAP-70 and IgVH status (r=0.36, p=0.0008). Seventy-five percent of those with unmutated IgVH were ZAP-70 positive. Sixty-one percent of patients with mutated IgVH were ZAP-70 negative. However, only 57% of ZAP-70 positive patients were IgVH unmutated. The predicted median TT was 54 months for the whole cohort (range 0-376+ months, 95% CI 45-96 months). The median TT was 27 months (range 0-112 months) for ZAP-70-positive patients compared to 96 months (range 0-376+ months) for ZAP-70-negative patients (p=0.002). The median TT was 32 months (range 0-112 months) for IgVH unmutated patients compared to 88 months (range 0-376+ months) for IgVH mutated patients (p=0.01). Conclusions ZAP-70 as measured by IHC was feasible in a large cohort of patients and ZAP-70 status correlated with time to first treatment. These data suggest that ZAP-70 assessment by IHC may be a reliable prognostic tool in CLL and should be evaluated in larger, multicenter clinical studies. Disclosures: No relevant conflicts of interest to declare.

CLL Disease Severity Is Enhanced in Tcl1 Mice Deficient for Pro-Apoptotic Regulator Noxa

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4144-4144
Author(s):  
Erik Slinger ◽  
Felix Wensveen ◽  
Arnon P. Kater ◽  
Eric Eldering
Keyword(s):  
Survival Analysis ◽  
Lymph Node ◽  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Rank Test ◽  
Log Rank Test ◽  
Kaplan Meier

Abstract Despite the development of new treatment strategies, chronic lymphocytic leukemia (CLL) remains an incurable disease. Apoptosis dysregulation caused by environmental signaling, predominantly within lymph nodes, plays a key role in CLL maintenance and treatment resistance. In earlier work, we demonstrated that expression of the pro-apoptotic Bcl-2 family memberNoxa is increased in circulating CLL cells compared to normal B-cells (1). Moreover, Noxa levels are decreased in CLL cells that reside in the lymph node while its key anti-apoptotic binding partner, Mcl-1, shows a reverse trend (2). This suggests that the decreased Noxa/MCL-1 ratio within the microenvironment may contribute to enhanced CLL survival. Here we aimed at elucidating a functional role for Noxa in CLL in the context of a murine model by crossing Noxa deficient mice (Noxa-KO) with Eμ.Tcl1-Tg mice (TCL1) mice. We first established that also in Tcl1 mice the Noxa/Mcl-1 ratio was increased PB vs. LN cells. The phenotype and distribution of leukemic cells was similar in Tcl1 and Noxa-KO/tcl1 mice. Interestingly, the accumulation of CLL cells in the peripheral blood was accelerated in Noxa-KO/TCL1 mice. This was accompanied by a reduction of apoptotic cells in the spleen of Noxa-KO/TCL1 mice. In accordance with these findings, survival of Noxa-KO/Tcl1 mice was decreased compared to the Tcl1 mice (342 days vs. 396 days, p<0.001, Figure 1). Our data suggest a role for Noxa in CLL as a tumor suppressor, and provides a rationale for the use of compounds which may alter the Noxa/Mcl1 balance in patients. 1. W. J. Mackus et al., Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma upregulation. Leukemia19, 427-434 (2005). 2. L. A. Smit et al., Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity. Blood109, 1660-1668 (2007). Figure 1. Survival analysis of Noxa-KO/TCL1 mice and TCL1 mice. The Kaplan-Meier curves were analyzed by a Log-Rank test. Figure 1. Survival analysis of Noxa-KO/TCL1 mice and TCL1 mice. The Kaplan-Meier curves were analyzed by a Log-Rank test. Disclosures No relevant conflicts of interest to declare.

Concomitant Cisplatin Significantly Improves Locoregional Control in Advanced Head and Neck Cancers Treated With Hyperfractionated Radiotherapy

2004 ◽  
Vol 22 (23) ◽  
pp. 4665-4673 ◽  
Author(s):  
Pia Huguenin ◽  
Karl T. Beer ◽  
Abdelkarim Allal ◽  
Kaspar Rufibach ◽  
Corinne Friedli ◽  
...  
Keyword(s):  
Overall Survival ◽  
Treatment Failure ◽  
Head And Neck ◽  
Combined Treatment ◽  
Late Toxicity ◽  
Locoregional Control ◽  
Rank Test ◽  
Hyperfractionated Radiotherapy ◽  
Log Rank Test ◽  
Metastatic Relapse

Purpose To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and/or node-positive nonmetastatic carcinomas of the head and neck, compared with hyperfractionated radiotherapy alone. Patients and Methods From July 1994 to July 2000, 224 patients with squamous cell carcinomas of the head and neck (excluding nasopharynx and paranasal sinus) were randomly assigned to hyperfractionated radiotherapy (median dose, 74.4 Gy; 1.2 Gy twice daily) or the same radiotherapy combined with two cycles of concomitant cisplatin (20 mg/m2 on 5 days of weeks 1 and 5). The primary end point was time to any treatment failure; secondary end points were locoregional failure, metastatic relapse, overall survival, and late toxicity. Results There was no difference in radiotherapy between both treatment arms (74.4 Gy in 44 days). The full cisplatin dose was applied in 93% and 71% of patients during the first and second treatment cycles, respectively. Acute toxicity was similar in both arms. Median time to any treatment failure was not significantly different between treatment arms (19 months for combined treatment and 16 months for radiotherapy only, respectively) and the failure-free rate at 2.5 years was 45% and 33%, respectively. Locoregional control and distant disease–free survival were significantly improved with cisplatin (log-rank test, P = .039 and .011, respectively). The difference in overall survival did not reach significance (log-rank test, P = .147). Late toxicity was comparable in both treatment groups. Conclusion The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin.

Bioinformatics Analysis of The Expression of ATP Binding Cassette Transporters and The Screening of Regulatory Genes in PTEN/PI3K/Akt/mTOR Signaling Pathway in The Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Tingdan Zheng ◽  
Wuqi Song ◽  
Aiying Yang
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Bioinformatics Analysis ◽  
Wilcoxon Test ◽  
Rank Test ◽  
Short Term ◽  
Term Survival ◽  
Log Rank Test ◽  
Short Term Survival

Abstract Objective Here we performed the Bioinformatics analysis on the data from The Cancer Genome Atlas (TCGA), in order to find the correlation between the expression of ATP Binding Cassette (ABC) Transporters’ genes and hepatocellular carcinoma (HCC) prognosis; Methods Transcriptome profiles and clinical data of HCC were obtained from TCGA database. Package edgeR was used to analyze differential gene expression. Patients were divided into low-ABC expression and high-ABC expression groups based on the median expression level of ABC genes in cancer. The overall survival and short-term survival (n= 341) of the two groups was analyzed using the log-rank test and Wilcoxon test; Results We found that ABC gene expression was correlated with the expression of PIK3C2B (p<0.001, ABCC1: r=0.27; ABCC10: r=0.57; ABCC4: r=0.20; ABCC5: r=0.28; ABCB9: r=0.17; ABCD1: r=0.21). All patients with low-ABC expression showed significantly increased overall survival. Significantly decreased overall survival (Log-rank test: p<0.05, Wilcoxon test: p<0.05) was found in patients with high expression of ABCC1 (HR=1.58), ABCD1 (HR=1.45), ABCC4 (HR=1.56), and ABCC5 (HR=1.64), while decreased short-term survival (Log-rank test: p>0.05, Wilcoxon test: p<0.05) was correlated with the increased expression of ABCC10 (HR=1.29), PIK3C2B (HR=1.29) and ABCB9 (HR=1.23); Conclusions Our findings indicate that the specific ABC gene expression correlates with the prognosis of HCC. Therefore, ABC expression profile could be a potential indicator for HCC patients.

Survival Outcomes for Induction vs Adjuvant Chemotherapy in Squamous Cell Carcinoma of the Maxillary Sinus

2018 ◽  
Vol 160 (4) ◽  
pp. 658-663 ◽  
Author(s):  
Phoebe Kuo ◽  
Sina J. Torabi ◽  
Dennis Kraus ◽  
Benjamin L. Judson
Keyword(s):  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Maxillary Sinus ◽  
Induction Chemotherapy ◽  
Squamous Cell ◽  
Cox Regression ◽  
Rank Test ◽  
Controlled Clinical Trial ◽  
Log Rank Test ◽  
Kaplan Meier

Objective In advanced maxillary sinus cancers treated with surgery and radiotherapy, poor local control rates and the potential for organ preservation have prompted interest in the use of systemic therapy. Our objective was to present outcomes for induction compared to adjuvant chemotherapy in the maxillary sinus. Study Design Secondary database analysis. Setting National Cancer Database (NCDB). Subjects and Methods In total, 218 cases of squamous cell maxillary sinus cancer treated with surgery, radiation, and chemotherapy between 2004 and 2012 were identified from the NCDB and stratified into induction chemotherapy and adjuvant chemotherapy cohorts. Univariate Kaplan-Meier analyses were compared by log-rank test, and multivariate Cox regression was performed to evaluate overall survival when adjusting for other prognostic factors. Propensity score matching was also used for further comparison. Results Twenty-three patients received induction chemotherapy (10.6%) and 195 adjuvant chemotherapy (89.4%). The log-rank test comparing induction to adjuvant chemotherapy was not significant ( P = .076). In multivariate Cox regression when adjusting for age, sex, race, comorbidity, grade, insurance, and T/N stage, there was a significant mortality hazard ratio of 2.305 for adjuvant relative to induction chemotherapy (confidence interval, 1.076-4.937; P = .032). Conclusion Induction chemotherapy was associated with improved overall survival in comparison to adjuvant chemotherapy in a relatively small cohort of patients (in whom treatment choice cannot be characterized), suggesting that this question warrants further investigation in a controlled clinical trial before any recommendations are made.

scholarly journals Prognostic Impact of NOTCH1 Hotspot Mutation in TP53-Mutated Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3283-3283
Author(s):  
Barbara Kantorova ◽  
Jitka Malcikova ◽  
Veronika Navrkalova ◽  
Jana Smardova ◽  
Kamila Brazdilova ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Tp53 Mutation ◽  
Direct Sequencing ◽  
Lymphocytic Leukemia ◽  
The Other ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Time To First Treatment ◽  
Hotspot Mutation

Abstract Introduction A presence of activating mutations in NOTCH1 gene has been recently associated with reduced survival and chemo-immunotherapy resistance in chronic lymphocytic leukemia (CLL). However, a prognostic significance of the NOTCH1 mutations with respect to TP53mutation status has not been fully explained yet. Methods An examined cohort included 409 patients with CLL enriched for high risk cases; in 121 patients consecutive samples were investigated. To determine the TP53 mutation status, a functional analysis of separated alleles in yeast (FASAY, exons 4-10) combined with direct sequencing was performed; the ambiguous cases were retested using an ultra-deep next generation sequencing (MiSeq platform; Illumina). The presence of NOTCH1 hotspot mutation (c.7544_7545delCT) was analyzed using direct sequencing complemented by allele-specific PCR in the selected samples. In several patients harboring concurrent NOTCH1 and TP53 mutations, single separated cancer cells were examined using multiplex PCR followed by direct sequencing. A correlation between mutation presence and patient overall survival, time to first treatment and other molecular and cytogenetic prognostic markers was assessed using Log-rank (Mantel-cox) test and Fisher's exact test, respectively. Results The NOTCH1 and TP53 mutations were detected in 16% (65/409) and 27% (110/409) of the examined patients, respectively; a coexistence of these mutations in the same blood samples was observed in 11% (19/175) of the mutated patients. The detected increased mutation frequency attributes to more unfavorable profile of the analyzed cohort; in the TP53-mutated patients missense substitutions predominated (75% of TP53 mutations). As expected, a significantly reduced overall survival in comparison to the wild-type cases (147 months) was observed in the NOTCH1-mutated (115 months; P = 0.0018), TP53-mutated (79 months; P < 0.0001) and NOTCH1-TP53-mutated patients (101 months; P = 0.0282). Since both NOTCH1 and TP53 mutations were strongly associated with an unmutated IGHV gene status (P < 0.0001 and P = 0.0007), we reanalyzed the IGHV-unmutated patients only and interestingly, the impact of simultaneous NOTCH1 and TP53 mutation presence on patient survival was missed in this case (P = 0.1478). On the other hand, in the NOTCH1 and/or TP53-mutated patients significantly reduced time to first treatment was identified as compared to the wild-type cases (41 months vs. 25 months in NOTCH1-mutated, P = 0.0075; 17 months in TP53-mutated, P < 0.0001; and 18 months in NOTCH1-TP53-mutated patients, P = 0.0003). The similar results were observed also in the subgroup of the IGHV-unmutated patients, with the exception of patients carrying sole NOTCH1 mutation (P = 0.2969). Moreover, in the NOTCH1-TP53-mutated patients an increased frequency of del(17p)(13.1) was found in comparison to the TP53-mutated patients only (72% vs. 56%); this cytogenetic defect was not detected in the patients with sole NOTCH1 mutation. Our results might indicate, that NOTCH1 mutation could preferentially co-selected with particular, less prognostic negative type of TP53 defects. Notably, in our cohort the NOTCH1 mutation predominated in the patients harboring truncating TP53 mutations localized in a C-terminal part of the TP53 gene behind the DNA-binding domain (P = 0.0128). Moreover, in one of the NOTCH1-TP53-mutated patients the analysis of separated cancer cells revealed a simultaneous presence of NOTCH1 mutation and TP53 in-frame deletion in the same CLL cell. In contrast, in the other examined NOTCH1-TP53-mutated patient the concurrent NOTCH1 mutation and TP53 missense substitution (with presumed negative impact on patient prognosis) were found in different CLL cells. Conclusions The parallel presence of NOTCH1 hotspot mutation might be detected in a significant proportion of TP53-mutated patients and it seems to be associated with less prognostic unfavorable TP53 mutations. Nevertheless, these preliminary data should be further confirmed in a large cohort of patients. This study was supported by projects VaVPI MSMT CR CZ.1.05/1.1.00/02.0068 of CEITEC, IGA MZ CR NT13493-4/2012, NT13519-4/2012 and CZ.1.07/2.3.00/30.0009. Disclosures Brychtova: Roche: Travel grants Other. Doubek:Roche: Travel grants Other.

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