The contribution of epigenetic and genetic changes to predict gastrointestinal stromal tumors (GIST) behavior

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9542-9542 ◽  
Author(s):  
E. Braggio ◽  
D. P. Guimaraes ◽  
C. E. Bacchi ◽  
L. F. Lopes ◽  
I. A. Small ◽  
...  
Keyword(s):  
Risk Group ◽  
Disease Free Survival ◽  
Intermediate Risk ◽  
Ki 67 ◽  
Kit Mutation ◽  
Free Survival ◽  
P16ink4a Expression ◽  
Disease Free ◽  
E Cadherin

9542 Background: To search for markers for better prognostic evaluation in patients (pts) with GIST was our goal. Loss of E-cadherin expression and/or function by hypermethylation has been correlated with increase in the invasive potential of human tumors. Recently, loss of p16INK4a expression was considered as an independent prognostic factor in pts with GIST. Methods: We investigated the methylation (MT) status for p16Ink4a and E-cadherin by the MT -specific PCR, c-KIT mutation by SSCP-sequencing, p16INK4a and cKIT expressions and KI-67 index by IHC, in 81 pts with completely ressected GIST between Jan 1990 and April 2003. Clinical data and follow-up information were obtained from medical records.A cutoff at 20% and 5% positivity was used for p16INK4a and KI-67, respectively. Univariate analysis of disease-free survival (DFS) and overall survival (OS) were performed by Kaplan Meier method with the log-rank test. Results: Median age was 55 (9–78); Male/female 42/58%; primary tumor sites were stomach (46.9%), small bowell (37.0%), colorectal (8.6%) and peritoneal (6.2%). Median tumor size was 8cm (1.2–35.0). The median follow-up was 24 months. Pts were stratified into low- (24.7%), intermediate- (37.0%) and high- (38.3%) risk pts based on tumor size and mitotic index. There was a significant correlation between risk classification and disease free survival (DFS) (p=0.023) and overall survival (OS) (p=0.010). The p16Ink4a and E-cadherin MT were observed in 19.4% and 63.3% pts, respectively. We observed loss of p16INK4a expression in 64.9% of GISTs. Overall, 78.4% had KIT mutation in exon 11 or 9. There was non-significant correlations between epigenetic alterations, cKIT mutation, p16INK4a expression, KI-67 index and survival. By analysing the three groups separately we found a significant correlation between E-cadherin MT with DFS (p<0.047) only in the intermediate risk group. Conclusion: Our results suggest that E-cadherin MT may be a helpful prognostic factor particularly in the intermediate risk group of GISTs. In contrast with previous results from the literature p16INK4a alterations had no prognostic impact in our samples. No significant financial relationships to disclose.

Prognostic Implication and Biological Roles of RhoH in Acute Myeloid Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 939-939
Author(s):  
Akira Katsumi ◽  
Toshihiro Iwasaki ◽  
Ryohei Tanizaki ◽  
Akihiro Abe ◽  
Hitoshi Kiyoi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Disease Free Survival ◽  
Intermediate Risk ◽  
Free Survival ◽  
Wbc Count ◽  
Disease Free ◽  
Low Expression ◽  
Acute Myeloid

Abstract The Rho family of small GTPase, including Rho, Rac and Cdc42, has been well characterized as a molecular switch that transduces signals from plasma membrane to the downstream effectors. RhoH gene, a member of the Rho family, is specifically expressed in hematopoietic cells. As RhoH is GTPase-deficient and constitutively active, the activity of RhoH is directly related to its level of expression. Previous reports demonstrated that the aberrant somatic hypermutation of RhoH is a novel mechanism of lymphomagenesis, possibly through its deregulated expression, suggesting that RhoH is the proto-oncogene. The known function of RhoH is antagonizing Rac and mediating activation of ZAP-70 in T lymphocytes. Recent report demonstrated that hairy cell leukemia is characterized by low expression of RhoH, and reconstitution of this gene limits malignant progression and protects against mortality. Although the functions of RhoH in lymphoid cells have been clarified, the biological roles of RhoH in the myeloid cells are unknown. The question that whether RhoH expression affects the prognosis of acute myeloid leukemia patients still remains unanswered. Here, we analyzed the expression level of the RhoH gene transcript in bone marrow samples from 90 newly diagnosed acute myeloid leukemia patients using a real-time fluorescence detection method. The RhoH/GAPDH ratio was calculated, and the median of 90 samples was 1.57. The patients were then divided into RhoH high (i.e. RhoH/GAPDH above 1.58) and RhoH low groups. The expression level of RhoH was not related to the FAB classification, age, WBC counts, cytogenetics or complete remission rate. In addition, RhoH expression was not associated with the known gene mutations such as NRAS, FLT3 and TP53. Kaplan–Meier analysis demonstrated that low expression of the RhoH transcript was a predictor of worse prognosis in both overall (Fig.1A) and disease-free survival (Fig. 1B). Patients were then categorized into favorable, intermediate, unfavorable and unknown cytogenetic groups based on the Southwest Oncology Group and Medical Research Council cytogenetic risk category definition. Kaplan–Meier analysis for both overall and disease-free survival was performed for 65 (72.2%) patients in the intermediate risk group. The results indicated that low expression of the RhoH transcript is a worse prognostic factor for both overall and disease-free survival in the intermediate risk group (p = 0.03 and 0.001, respectively). Multivariate analyses showed that presence of theTP53 mutation (relative risk (RR), 10.175; p = 0.0036), high WBC count (RR, 3.457; p = 0.0003) and low RhoH expression (RR, 2.272; p = 0.0091) were independent poor prognostic factors for overall survival. The same analysis revealed that the presence of the TP53 mutation (RR, 14.292; p = 0.0168), low RhoH expression (RR, 4.854; p = 0.0002), high WBC count (RR, 2.901; p = 0.0187) and presence of FLT3/ITD (RR, 2.515; p = 0.0419) were independent poor prognostic factors for disease-free survival. Next, we investigated the biological roles of RhoH in AML. Overexpression of RhoH leads to dephosphorylation of Bad at Serine (S)-75 (corresponding to murine S112) possibly through deactivation of Rac. Contrastingly, RhoH expression does not affect phosphorylation of S99 (corresponding to murine S136) of Bad and S473 of Akt. It is possible that low expression of RhoH (i.e. high GTP-Rac) contributes to chemotherapy resistance in leukemia cells. Taken together, our results highly suggest that RhoH transcript level is an effective molecular marker to further stratify the patients in the intermediate risk group of AML, and that inhibition of Rac and its signalling components might provide a useful anti-leukemic strategy. Figure 1 Figure 1.

Impact of T and N Stage and Treatment on Survival and Relapse in Adjuvant Rectal Cancer

2004 ◽  
Vol 22 (10) ◽  
pp. 1785-1796 ◽  
Author(s):  
Leonard L. Gunderson ◽  
Daniel J. Sargent ◽  
Joel E. Tepper ◽  
Norman Wolmark ◽  
Michael J. O'Connell ◽  
...  
Keyword(s):  
High Risk ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Treatment Method ◽  
Intermediate Risk ◽  
Free Survival ◽  
Risk Patients ◽  
N Stage ◽  
Disease Free

Purpose To determine survival and relapse rates by T and N stage and treatment method in five randomized phase III North American rectal adjuvant studies. Patients and Methods Data were pooled from 3,791 eligible patients enrolled onto North Central Cancer Treatment Group (NCCTG) 79-47-51, NCCTG 86-47-51, US Gastrointestinal Intergroup 0114, National Surgical Adjuvant Breast and Bowel Project (NSABP) R01, and NSABP R02. Surgery alone (S) was the treatment arm in 179 patients. The remaining patients received adjuvant treatment as follows: irradiation (RT) alone (n = 281), RT + fluorouracil (FU) ± semustine bolus chemotherapy (CT; n = 779), RT + protracted venous infusion CT (n = 325), RT + FU ± leucovorin or levamisole bolus CT (n = 1,695), or CT alone (n = 532). Five-year follow-up was available in 94% of surviving patients, and 8-year follow-up, in 62%. Results Overall (OS) and disease-free survival were dependent on TN stage, NT stage, and treatment method. Even among N2 patients, T substage influenced 5-year OS (T1-2, 67%; T3, 44%; T4, 37%; P < .001). Three risk groups of patients were defined: (1) intermediate (T1-2/N1, T3/N0), (2) moderately high (T1-2/N2, T3/N1, T4/N0), and (3) high (T3/N2, T4/N1, T4/N2). For intermediate-risk patients, those receiving S plus CT had 5-year OS rates of 85% (T1-2/N1) and 84% (T3/N0), which was similar to results with S plus RT plus CT (T1-2/N1, 78% to 83%; T3/N0, 74% to 80%). For moderately high-risk lesions, 5-year OS ranged from 43% to 70% with S plus CT, and 44% to 80% with S plus RT plus CT. For high-risk lesions, 5-year OS ranged from 25% to 45% with S plus CT, and 29% to 57% with S plus RT plus CT. Conclusion Different treatment strategies may be indicated for intermediate-risk versus moderately high- or high-risk patients based on differential survival rates and rates of relapse. Use of trimodality treatment for all patients with intermediate-risk lesions may be excessive, since S plus CT resulted in 5-year OS of approximately 85%; however, 5-year disease-free survival rates with S plus CT were 78% (T1-2/N1) and 69%(T3/N0), indicating room for improvement.

scholarly journals TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Sha Zhou ◽  
Jianhong Peng ◽  
Liuniu Xiao ◽  
Caixia Zhou ◽  
Yujing Fang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Free Survival ◽  
Free Survival ◽  
Epigenetic Regulator ◽  
Crc Management ◽  
Disease Free ◽  
Resistance To Chemotherapy

AbstractResistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.

Phase I Study of Fludarabine Plus Cyclophosphamide in Patients With Previously Untreated Low-Grade Lymphoma: Results and and Long-Term Follow-Up—A Report From the Eastern Cooperative Oncology Group

2000 ◽  
Vol 18 (5) ◽  
pp. 987-987 ◽  
Author(s):  
Howard S. Hochster ◽  
Martin M. Oken ◽  
Jane N. Winter ◽  
Leo I. Gordon ◽  
Bruce G. Raphael ◽  
...  
Keyword(s):  
Phase Ii ◽  
Bone Marrow Involvement ◽  
Survival Rates ◽  
Eastern Cooperative Oncology Group ◽  
Disease Free Survival ◽  
Low Grade ◽  
Survival Times ◽  
Free Survival ◽  
Disease Free

PURPOSE: To determine the toxicity and recommended phase II doses of the combination of fludarabine plus cyclophosphamide in chemotherapy-naive patients with low-grade lymphoma. PATIENTS AND METHODS: Previously untreated patients with low-grade lymphoma were entered onto dosing cohorts of four patients each. The cyclophosphamide dose, given on day 1, was increased from 600 to 1,000 mg/m2. Fludarabine 20 mg/m2 was administered on days 1 through 5. The first eight patients were treated every 21 days; later patients were treated every 28 days. Prophylactic antibiotics were required. RESULTS: Prolonged cytopenia and pulmonary toxicity each occurred in three of eight patients treated every 3 weeks. The 19 patients treated every 28 days, who were given granulocyte colony-stimulating factor as indicated, did not have undue nonhematologic toxicity. Dose-limiting toxicity was hematologic. At the recommended phase II/III dose (cyclophosphamide 1,000 mg/m2), grade 4 neutropenia was observed in 17% of all cycles and 31% of first cycles. Grade 3 or 4 thrombocytopenia was seen in only 1% of all cycles. The median number of cycles per patient was six (range, two to 11) for all patients enrolled. The response rate was 100% of 27 patients entered; 89% achieved a complete and 11% a partial response. Nineteen of 22 patients with bone marrow involvement had clearing of the marrow. Median duration of follow-up was more than 5 years; median overall and disease-free survival times have not been reached. Kaplan-Meier estimated 5-year overall survival and disease-free survival rates were 66% and 53%, respectively. CONCLUSION: The recommended dosing for this combination in patients with previously untreated low-grade lymphoma is cyclophosphamide 1,000 mg/m2 day 1 and fludarabine 20 mg/m2 days 1 through 5. The regimen has a high level of activity, with prolonged complete remissions providing 5-year overall and disease-free survival rates as high as those reported for other therapeutic approaches in untreated patients.

scholarly journals Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2814-2822 ◽  
Author(s):  
CA Linker ◽  
LJ Levitt ◽  
M O'Donnell ◽  
SJ Forman ◽  
CA Ries
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Remission Induction ◽  
Cell Phenotype ◽  
Free Survival ◽  
Prognostic Features ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Disease Free

Abstract We treated 109 patients with adult acute lymphoblastic leukemia (ALL) diagnosed by histochemical and immunologic techniques. Patients were excluded only for age greater than 50 years and Burkitt's leukemia. Treatment included a four-drug remission induction phase followed by alternating cycles of noncrossresistant chemotherapy and prolonged oral maintenance therapy. Eighty-eight percent of patients entered complete remission. With a median follow-up of 77 months (range, 48 to 111 months), 42% +/- 6% (SEM) of patients achieving remission are projected to remain disease-free at 5 years, and disease-free survival for all patients entered on study is 35% +/- 5%. Failure to achieve remission within the first 4 weeks of therapy and the presence of the Philadelphia chromosome are associated with a 100% risk of relapse. Remission patients with neither of these adverse features have a 48% +/- 6% probability of remaining in continuous remission for 5 years. Patients with T-cell phenotype have a favorable prognosis with 59% +/- 13% of patients achieving remission remaining disease-free compared with 31% +/- 7% of CALLA-positive patients. Intensive chemotherapy may produce prolonged disease-free survival in a sizable fraction of adults with ALL. Improved therapy is needed, especially for patients with adverse prognostic features.

Radical hysterectomy in early cervical cancer in Europe: characteristics, outcomes and evaluation of ESGO quality indicators

2021 ◽  
pp. ijgc-2021-002587
Author(s):  
Felix Boria ◽  
Luis Chiva ◽  
Vanna Zanagnolo ◽  
Denis Querleu ◽  
Nerea Martin-Calvo ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Overall Survival ◽  
Quality Indicators ◽  
Radical Hysterectomy ◽  
Disease Free Survival ◽  
Free Survival ◽  
Operative Complications ◽  
Early Cervical Cancer ◽  
Disease Free

IntroductionComprehensive updated information on cervical cancer surgical treatment in Europe is scarce.ObjectiveTo evaluate baseline characteristics of women with early cervical cancer and to analyze the outcomes of the ESGO quality indicators after radical hysterectomy in the SUCCOR database.MethodsThe SUCCOR database consisted of 1272 patients who underwent radical hysterectomy for stage IB1 cervical cancer (FIGO 2009) between January 2013 and December 2014. After exclusion criteria, the final sample included 1156 patients. This study first described the clinical, surgical, pathological, and follow-up variables of this population and then analyzed the outcomes (disease-free survival and overall survival) after radical hysterectomy. Surgical-related ESGO quality indicators were assessed and the accomplishment of the stated recommendations was verified.ResultsThe mean age of the patients was 47.1 years (SD 10.8), with a mean body mass index of 25.4 kg/m2 (SD 4.9). A total of 423 (36.6%) patients had a previous cone biopsy. Tumor size (clinical examination) <2 cm was observed in 667 (57.7%) patients. The most frequent histology type was squamous carcinoma (794 (68.7%) patients), and positive lymph nodes were found in 143 (12.4%) patients. A total of 633 (54.8%) patients were operated by open abdominal surgery. Intra-operative complications occurred in 108 (9.3%) patients, and post-operative complications during the first month occurred in 249 (21.5%) patients, with bladder dysfunction as the most frequent event (119 (10.3%) patients). Clavien-Dindo grade III or higher complication occurred in 56 (4.8%) patients. A total of 510 (44.1%) patients received adjuvant therapy. After a median follow-up of 58 months (range 0–84), the 5-year disease-free survival was 88.3%, and the overall survival was 94.9%. In our population, 10 of the 11 surgical-related quality indicators currently recommended by ESGO were fully fulfilled 5 years before its implementation.ConclusionsIn this European cohort, the rate of adjuvant therapy after radical hysterectomy is higher than for most similar patients reported in the literature. The majority of centers were already following the European recommendations even 5 years prior to the ESGO quality indicator implementations.

Pituitary surgery as alternative to dopamine agonists treatment for microprolactinomas, a cohort study

2021 ◽  
Author(s):  
Bertrand Baussart ◽  
Chiara Villa ◽  
Anne Jouinot ◽  
Marie-Laure Raffin-Sanson ◽  
Luc Foubert ◽  
...  
Keyword(s):  
Dopamine Agonists ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Pituitary Surgery ◽  
Cerebrospinal Fluid Leakage ◽  
Neurosurgical Department ◽  
Free Survival ◽  
Kaplan Meier ◽  
Disease Free

Objective: Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment. Design: Follow-up of a cohort of consecutive patients treated by surgery. Methods: Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients were presenting a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan-Meier representation. A cox regression model was used to predict remission. Results: Median follow-up was 18.2 months (range: 2.8 to 155). In this cohort, 14/114 (12%) patients were not cured by surgery, including 10 early surgical failures, and 4 late relapses occurring 37.4 months (33 to 41.8) after surgery. From Kaplan Meier estimates, 1-year and 5-year disease free survival were 90.9% (95% CI, 85.6%-96.4%) and 81% (95% CI,71.2%-92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P<0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty. Conclusions: In well selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.

Radiofrequency Ablation of Hepatic Metastases from Colorectal Cancer: Are Newer Generation Probes Better?

2006 ◽  
Vol 72 (10) ◽  
pp. 875-879 ◽  
Author(s):  
Aziz Ahmad ◽  
Steven L. Chen ◽  
Maihgan A. Kavanagh ◽  
David P. Allegra ◽  
Anton J. Bilchik
Keyword(s):  
Colorectal Cancer ◽  
Radiofrequency Ablation ◽  
First Generation ◽  
Hepatic Metastases ◽  
Disease Free Survival ◽  
Cancer Center ◽  
Free Survival ◽  
Alive With Disease ◽  
Disease Free

Second-generation radiofrequency ablation (RFA) probes and their successors have more power, shorter ablation times, and an increased area of ablation compared with the first-generation probes used before 2000. We examined whether the use of the newer probes has improved the clinical outcome of RFA for hepatic metastases of colorectal cancer at our tertiary cancer center. Of 160 patients who underwent RFA between 1997 and 2003, 52 had metastases confined to the liver: 21 patients underwent 46 ablations with the first-generation probes and 31 patients underwent 58 ablations with the newer probes. The two groups had similar demographic characteristics. At a median follow-up of 26.2 months, patients treated with the newer probes had a longer median disease-free survival (16 months vs 8 months, P < 0.01) and a lower rate of margin recurrence (5.2% vs 17.4%); eight patients had no evidence of disease and one patient was alive with disease. By contrast, of the 46 patients treated with the first-generation probes, 2 patients had no evidence of disease and 1 patient was alive with disease. Newer-generation probes are associated with lower rates of margin recurrence and higher rates of disease-free survival after RFA of hepatic metastases from colorectal cancer.

scholarly journals Relationship between Ribosomal Protein S6-pS240 Expression and other Prognostic Factors in Non-Special Type Invasive Breast Cancer

Breast Care ◽  
2018 ◽  
Vol 14 (3) ◽  
pp. 171-175
Author(s):  
Frederik Cuperjani ◽  
Lumturije Gashi ◽  
Fisnik Kurshumliu ◽  
Shemsedin Dreshaj ◽  
Fitim Selimi
Keyword(s):  
Breast Cancer ◽  
Ribosomal Protein ◽  
Invasive Breast Cancer ◽  
Menopausal Status ◽  
Treatment Protocol ◽  
Prognostic Index ◽  
Disease Free Survival ◽  
Ki 67 ◽  
Free Survival ◽  
Disease Free

Background: The aim of this study was to investigate the immunohistochemical expression of ribosomal protein (RP) S6-pS240 in non-special type invasive breast cancer in relation to other prognostic markers and gain new insights to facilitate more individualized treatment. Methods: The following clinical and histopathological parameters of 120 patients were determined: S6-pS240 expression, age, menopausal status, tumor size and grade, TNM stage, Nottingham Prognostic Index (NPI), lymph node stage, estrogen and progesterone receptor (ER/PR) expression, HER2/neu amplification, lymphovascular invasion, and proliferative index as measured by Ki-67. Treatment protocol and disease-free survival were evaluated accordingly. Results: Significant positive correlations were seen between S6-pS240 expression and Ki-67 values (rho = 0.530, p < 0.001), and NPI (rho = 0.370, p < 0.001) and HER2/neu amplification (rho = 0.368, p < 0.001). A negative correlation was found between S6-pS240 and ER/PR expression (rho = 0.362, p < 0.001). Patients with negative RP S6-pS240 expression had significantly longer disease-free survival (log-rank test, p = 0.005). Conclusion: Immunohistochemical analysis of RP S6-pS240 is a valuable additional prognostic marker in patients with invasive breast cancer. Routine use of S6-pS240 immunohistochemistry is recommended.

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