Outcome Of Chemotherapy In Patients Research Articles

The rate of in vitro fludarabine-induced peripheral blood and bone marrow cell apoptosis may predict the chemotherapy outcome in patients with chronic lymphocytic leukemia.

PurposeThe problem of drug sensitivity and predicting the outcome of chemotherapy seems to be of great importance in hemato-oncological disorders. There are some factors that can help to predict effects of chemotherapy in chronic lymphocytic leukemia (CLL), such as presence of del17p, del11q, or TP53 gene mutations, which result in resistance to purine analogues and alkylating drugs. Despite the new therapeutic options introduced recently, purine analogues in combination with cyclophosphamide and the monoclonal antibody rituximab is still the gold standard for the first-line treatment of fit patients with CLL. The aim of this study was to assess whether the rate of apoptosis caused by one of purine analogues—fludarabine in cell cultures differs between patients who clinically respond to fludarabine-based chemotherapy and those who do not respond.MethodsCLL leukemic cells, obtained from peripheral blood and bone marrow of 23 patients, were cultured in the presence of fludarabine. After 24 h of incubation, the rate of apoptosis, indicated by the expression of active caspase-3, was assessed with flow cytometry and then analyzed regarding clinical response to fludarabine-based regimens.ResultsThe percentage of apoptotic cells induced by fludarabine was significantly higher in the group of patients who achieved remission in comparison to the group with no response to purine analogues therapy. Interestingly, we observed that among the patients who did not respond to chemotherapy, the presence of del17p and del11q was detected only once. Other non-responders had no detectable genetic abnormalities.ConclusionsBased on these results, it can be presumed that in vitro drug sensitivity test, which is easy to perform, may predict the outcome of fludarabine-based chemotherapy in CLL patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-1893-0) contains supplementary material, which is available to authorized users.

Impact of surgical strategies on initiation and outcome of palliative chemotherapy in patients with unresectable pancreatic carcinoma at exploration

s / Pancreatology 15 (2015) S1eS141 S81 Aims: We present a new method for pancreatic sentinel node (SN) detection with gamma probe. Patients & methods: Seven patients with cT2N0M0 pancreatic head cancer were enrolled between 2009 to 2012 to this exploratory study. One day prior to surgery, preoperative endoscopic intratumoral administration of Tc99m labeled nanocolloid followed by scintigraphy study 2 hours later was conducted. Peroperative gamma probe detection of SN was also performed. Results: Radiotracer administration was feasible in all patients. Scintigraphy study showed interaortocaval dissemination in 2 patients, hepatic contamination in 2 patients, colonic contamination in 4 patients and no activity in 1 patient. Intraoperative SN detectionwas accomplished in 2 patients, both with negative results. Only 4 pancreatic cancers could be resected and only1SNcouldbeconfirmedas truenegativebyfinalhistopathologic analysis. Conclusion: This newmethod of pancreatic SN detection is technically feasible but challenging. Results do not allow clinical validation.

Response to vinflunine treatment after prior platinum-based chemotherapy in patients with advanced urothelial carcinoma independent of primary tumor location.

e15536 Background: The outcome of chemotherapy in patients with metastatic urothelial carcinoma (UC) of the upper tract (UT) is generally assumed to be worse compared to bladder as a primary locati...

Outcomes of preoperative chemotherapy in bladder cancer patients including node-positive disease.

370 Background: Neoadjuvant chemotherapy is associated with improved overall survival benefit and the concept of systemic therapy followed by local consolidation may also lead to favorable long-term outcomes for those with lymph node (LN) metastases at presentation. Our goal was to examine the outcome of preoperative chemotherapy in patients (pts) with and without clinical evidence of LN metastases. Methods: After informed consent, patients were enrolled in a prospective database prior to radical cystectomy with lymph node dissection for bladder cancer between December 2001 to February 2014. Data were analyzed using descriptive statistics. Results: Our cohort included 63 patients receiving pre-operative chemotherapy with a median age 68 (range 38-91), 46 (72%) were male, and 17 (27%) had gross metastatic disease to lymph nodes (LNs). 13 pts received MVAC (20%), 44 gemcitabine and cisplatin (GC) (69%), 1 gemcitabine and carboplatin, 1 received ifosfamide, paclitaxel, and cisplatin and 4 pts had unknown neoadjuvant chemo outside of the institution. Most patients with LN positive (71%) disease received GC preoperative regimens. The median and the modal number of cycles were 4 (range 1-6). 44 patients underwent robotic-assisted radical cystectomy (RARC) (69%), 19 underwent open radical cystectomy (30%), and another pt. had RARC converted to an open procedure. Overall, 20 (31%) patients achieved pathologic complete response (pCR). Four pts (24%) with initial metastatic disease achieved pCR after preoperative chemotherapy. Overall pCR rates were similar between MVAC (38%) and GC (33%). All LN positive patients who achieved pCR had received gemcitabine-cisplatin preoperatively and underwent RARC. Recurrence-free and overall-survival data will be presented at the meeting. Conclusions: Preoperative chemotherapy was associated with a significant pCR rate in all bladder cancer patients including LN positive patients.

Investigating the impact of body mass index on intraperitoneal chemotherapy outcomes in patients with advanced stage ovarian cancer

Investigating the impact of body mass index on intraperitoneal chemotherapy outcomes in patients with advanced stage ovarian cancer

Serum Survivin Levels and Outcome of Chemotherapy in Patients with Malignant Mesothelioma.

Background. Survivin is an inhibitor of apoptosis protein involved in the regulation of cell proliferation that could be used as a marker for cancer diagnosis or prognosis. Our aim was to evaluate whether serum survivin levels influence the outcome of cisplatin-based chemotherapy in patients with malignant mesothelioma (MM). Methods. Serum survivin levels were determined using human survivin enzyme-linked immunosorbent assay in 78 MM patients before chemotherapy, after chemotherapy, and at disease progression. The influence on tumor response and survival was evaluated using nonparametric tests and Cox regression. Results. A median serum survivin level at diagnosis was 4.1 (0–217.5) pg/mL. Patients with a progressive disease had significantly higher survivin levels before chemotherapy (p = 0.041). A median serum survivin level after chemotherapy was 73.1 (0–346.2) pg/mL. If survivin levels increased after chemotherapy, patients had, conversely, better response (p = 0.001, OR = 5.40, 95% CI = 1.98–14.72). Unexpectedly, patients with increased survivin levels after chemotherapy also had longer progression-free (p < 0.001, HR = 0.33, 95% CI = 0.20–0.57) and overall survival (p = 0.001, HR = 0.29, 95% CI = 0.14–0.58). Conclusions. These results suggest that serum survivin levels before and during chemotherapy could serve as a biomarker predicting MM treatment response.

EVALUATE PRELIMINARY RESULTS OF SURGERY FOR GASTRIC CANCER COMBINATED ADJUVANT CHEMOTHERAPY

Purpose: To review some characteristics of patients and evaluate preliminary results of adjuvant chemotherapy for patients with resected gastric cancer. Objectives and Methods:The study was conducted on 30 patients with gastric cancer (male/female = 20/10) treated by adjuvant chemotherapy after gastrectomy at the Digestive Surgical Depatment at Hue Central Hospital from January. 2011 to May. 2012. We noted their clinical and paraclinical signs and studied the preliminary results of adjuvant chemotherapy after gastrectomy for gastric cancer. Results: The male/female = 2/1, The common group of age is 41-60, accounting for 63,33%. The primary tumor were found mostly at antrum and pylorus (66,67%).The postoperative mortality and morbidity common rates were 0% and 3,33%. Almost patients treated by adjuvant chemotherapy from 4-8 weeks after gastrectomy (73,33%). Fatigue is the most common toxicity of chemotherapy with 33,33% and alopecia was 26,67%. The follow-up time is about 11 months (rank 6-15 months). The life time expectancy of all 30 patients by stages disease: Stage II: 100%, stage III: 94,17% and stage IV: 16,67%. Conclusion: We review general characteristics of patients, and evaluate the results of surgery, quality of life after surgery combine with supportive care. Number of patients with total points within the 8-10 points by Spitzer index from 70% to 80% after the second re-examination. Most of chemotherapy toxicity is tolerable. However, this study needs to be carry out in the longer time, with larger number of patients. Key words: gastric cancer, chemotherapy

Evaluation of 5-fluorouracil metabolic enzymes as predictors of response to adjuvant chemotherapy outcomes in patients with stage II/III colorectal cancer: a decision-curve analysis.

The effectiveness of 5-fluorouracil (5-FU)-based adjuvant chemotherapy is reported in patients with colorectal cancer (CRC), but the usefulness of 5-FU metabolic enzymes as predictive biomarkers of the efficacy of this chemotherapy remains unclear. This study aims to verify whether 5-FU metabolic enzymes are predictive biomarkers in the clinical setting of adjuvant chemotherapy for stage II/III CRC. In total, 179 patients with stage II/III CRC who were treated at our institute between 2000 and 2010 were enrolled. Messenger RNA (mRNA) expression of major 5-FU metabolic enzymes, namely thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase (TP), orotate phosphoribosyl transferase, and β-actin (control) was evaluated using the Danenberg Tumor Profile method. mRNA expression and other clinicopathological data were investigated with regard to CRC relapse. A total of 78 patients underwent surgery alone, while 101 underwent adjuvant chemotherapy (5-FU plus leucovorin [LV] or tegafur plus uracil /LV) following surgery. Relapse-free survival was longer and risk of recurrence was lower in association with high TP mRNA expression than in association with low TP mRNA expression in the adjuvant chemotherapy group (hazard ratio 0.66; 95 % confidence interval 0.47-0.92; p = 0.016), but not in the surgery alone group. mRNA expression of no other enzymes was associated with relapse in both groups. In decision-curve analyses, the predictive efficiency of TP mRNA expression plus clinicopathological factors was slightly better than that of clinicopathological factors only. TP mRNA expression in tumors predicted the effects of adjuvant chemotherapy for stage II/III CRC, although the beneficial effects were marginal.

Predictive effect of XRCC3 Thr241Met polymorphism on platinum-based chemotherapy in lung cancer patients: meta-analysis

Previous published data on the association between X-ray repair cross-complementing group 3 (XRCC3) Thr241Met polymorphism and clinical outcome of platinum-based chemotherapy in patients with lung cancer reported conflicting results. A meta-analysis was performed to provide a systematic review of the published data. We retrieved the relevant studies from PubMed and Embase databases. The primary outcome was overall survival, and the hazard ratio (HR) with 95% confidence interval (95% CI) was estimated. Seven studies with a total of 1,514 patients were included into the meta-analysis. Overall, XRCC3 Thr241Met polymorphism had no influence on the overall survival of lung cancer patients receiving platinum-based chemotherapy (MetMet vs. ThrThr: HR = 0.82, 95% CI 0.52-1.31, P = 0.410; MetThr vs. ThrThr: HR = 0.93, 95% CI 0.79-1.10, P = 0.339; MetMet/MetThr vs. ThrThr: HR = 1.07, 95% CI 0.88-1.31, P = 0.480). There was no obvious risk of publication bias. Therefore, currently available data suggest that there is no predictive effect of XRCC3 Thr241Met polymorphism on platinum-based chemotherapy in lung cancer patients.

Outcomes of chemotherapy in patients with EGFR mutation-negative non-small cell lung cancer

To evaluate the efficacy of chemotherapy for patients with EGFR (exon 19 and 21) mutation-negative non-small cell lung cancer (NSCLC). One hundred and forty NSCLC patients with negative EGFR mutation (90 cases) or EGFR mutation (50 cases) underwent gemcitabine or vinorelbine plus cisplatin or carboplatin chemotherapy. In the EGFR mutation-negative patients, there were PR in 26 cases, SD in 48 cases, PD in 16 cases, the disease control rate was 82.2%. In the patients with EGFR mutation, there were PR in 14 cases, SD in 23 cases, PD in 13 cases, the disease control rate was 74.0%. The difference of disease control rates in the two groups was not significant (P = 0.250). The progression free survival (PFS) of EGFR mutation-negative patients was 4.2 months (95%CI 3.8-4.6) vs. 4.0 months (95%CI 3.6-4.4) in patients with EGFR mutation, with a significant difference (P = 0.021). The overall survival (OS) of EGFR mutation-negative patients was 9.2 months (95%CI 8.4-10.0) vs. 7.8 months (95%CI, 6.9-8.7) of patients with EGFR mutation (P = 0.028). Chemotherapy can prolong the PFS and OS of EGFR mutation-negative patients. However, only the extension of OS has practical significance.

Abstract 2386: Amphiregulin confers trastuzumab resistance by activating PI3K/Akt pathway in HER2-positive breast cancer.

Abstract Background: Amphiregulin is a ligand for the epidermal growth factor receptor (EGFR). Human epidermal growth factor receptor 2 (HER2) shares common signal pathways and forms a heterodimer with EGFR. In this study, we investigated the effect of amphiregulin on trastuzumab therapy in HER2-positive breast cancer. Methods: We analyzed serum amphiregulin levels by enzyme-linked immunosorbent assay (ELISA) from baseline serum samples obtained from HER2-positive metastatic breast cancer patients who received first-line trastuzumab plus taxane chemotherapy. In addition, in vitro experiments were performed to elucidate the biologic mechanism of clinical findings related to amphiregulin using SK-BR-3 and BT-474 cell lines. Results: Between October 2004 and July 2009, a total of 50 women with HER2-positive metastatic breast cancer were consecutively enrolled. The median age was 47 years (range, 27-72 years). Eighteen patients (36.0%) received weekly paclitaxel plus trastuzumab, 24 patients (48.0%) tri-weekly paclitaxel plus trastuzumab, and 8 patients (16.0%) tri-weekly docetaxel plus trastuzumab. Among 43 patients with measurable lesions, the response rate (RR) was 76.7%. The median follow-up duration was 29.2 months (range, 0.7-63.3 months). The median progression-free survival (PFS) was 17.6 months (95% confidence interval (CI), 13.4-21.9 months). The median overall survival (OS) was 47.0 months (95% CI, 35.3-58.6 months). The median serum amphiregulin level was 1.0 ng/mL with a maximum level of 4.4 ng/mL. Patients with high serum amphiregulin levels (≥0.5 ng/mL) had significantly shorter PFS (p=0.018) along with a tendency toward lower RR (p=0.237) and shorter OS (p=0.529) than the others. The in vitro colony forming assay demonstrated that the addition of amphiregulin resulted in increased proliferation of both SK-BR-3 and BT-474 cells. In addition, the anti-proliferative effect of trastuzumab was decreased in the presence of amphiregulin in both SK-BR-3 and BT-474 cells. The Western blot analysis showed that amphiregulin increased the phosphorylation of Akt and its downstream molecules in both SK-BR-3 and BT-474 cells. In addition, in the presence of amphiregulin, sustained phosphorylation of Akt and its downstream molecules was observed after trastuzumab treatment in both SK-BR-3 and BT-474 cells. Conclusions: High serum amphiregulin levels (≥0.5 ng/mL) predicted disease progression after first-line trastuzumab plus taxane chemotherapy in patients with HER2-positive metastatic breast cancer. Amphiregulin promoted the proliferation of HER2-positive breast cancer cells in vitro and induced trastuzumab resistance by activating PI3K/Akt pathway. Our results suggest that the measurement of serum amphiregulin levels by ELISA may provide additional information for the clinical outcome of trastuzumab-based chemotherapy in patients with HER2-positive breast cancer. Citation Format: Ji-Won Kim, Young Seok Joung, Ahrum Min, Hyun-Jin Nam, Jee Hyun Kim, Seock-Ah Im, Kyung-Hun Lee, Jin-Soo Kim, Tae-Yong Kim, Sae-Won Han, Yoon Kyung Jeon, Do-Youn Oh, Tae-You Kim, In Ae Park. Amphiregulin confers trastuzumab resistance by activating PI3K/Akt pathway in HER2-positive breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2386. doi:10.1158/1538-7445.AM2013-2386

Long-term outcomes of cisplatin-based chemotherapy in patients with stage II-III germ cell tumors: Center 30-year experience of a single center.

338 Background: We retrospectively assessed long-term outcomes of cisplatin-based chemotherapy for stage II/IIII germ cell tumors (GCTs) at Medical Oncology Department of 12 Octubre University Hospital, Madrid (Spain). Methods: Two hundred fourteen (214) consecutive males with advanced GCTs of the testis or extragonadal origin who received standard cisplatin-based chemotherapy regimens between 1982 and 2012 were analyzed. Results: Demographic features: Median age 26.4 years (range 14- 72 years). Right and left testicular tumor present in 71 (37%) and 78 (41%) patients respectively and cryptorchidism in 11 (5%). Histology: 12% of the patients had seminomatous and 88% non-seminomatous histology. Stage distribution (TNM): Stage II 105p (49%), Stage III 109 p (51%). Twenty-five primary (11%) were extragonadal. Risk assessment according to IGCCCG - good 115 p (54%) intermediate 34 p (16%) and poor 62 p (29%). All patients received chemotherapy with cisplatin (BEP-73%, EP-15%, BOPM-EPI 5%, PVB 6%, others 1%). Survival analysis: The median follow-up period was 117 months (0 - 329). Totally, 158 patients (74%) achieved complete remission (CR). CR was achieved in 128 p (60%) after induction therapy (first line chemotherapy). Salvage treatment: surgery +/-chemotherapy was given to 72 (33%) and 85 (39%) patients respectively. High-dose chemotherapy (with carboplatin based- schemes at dosage (AUC20) as salvage therapy was performed in 65 patients (30%). Of them 35 p (53.4%) had complete remission of disease without relapse and the median progression free survival was of 47.2 months. Severe AEs were &lt; to 5%, and classically already described renal impairment, ototoxicity and neurophaty with non chemotherapy-related toxic deaths. Conclusions: Improvement of medical management and survival during platinum-based chemotherapy and the development of several regimens for salvage chemotherapy seemed to contribute to improving outcomes of patients with advanced GCTs even for patients with platinum-refractory disease. However, we continue to investigate in the search for genetic and molecular mechanisms that help us change it.

Plasma Concentrations of Angiogenesis-related Molecules in Patients with Pancreatic Cancer

Anti-angiogenic agents are now being clinically evaluated for the treatment of pancreatic cancer and a detailed investigation of the angiogenic profile of pancreatic cancer is needed. The aim of this study was to evaluate the plasma concentrations of angiogenesis-related molecules in patients with pancreatic cancer, compared with those with other diseases. Plasma samples obtained from 45 patients with pancreatic cancer were analyzed and compared with those from 9 patients with pancreatitis, 16 patients with benign hepatobiliary diseases and 58 patients with colorectal cancers. The plasma levels of angiogenesis-related molecules including angiopoietin-2, follistatin, granulocyte-colony stimulating factor, hepatocyte growth factor, interleukin-8, leptin, platelet-derived growth factor beta polypeptide, platelet endothelial cell adhesion molecule-1 and vascular endothelial growth factor were determined using an antibody suspension bead arrays system. The plasma levels of all the angiogenesis-related molecules were not increased in patients with pancreatic cancer, compared with those with pancreatitis and benign hepatobiliary diseases, whereas the levels of those with colorectal cancer were markedly increased. The plasma interleukin-8 concentration was significantly elevated in patients with distant metastases and was associated with a poor treatment outcome of chemotherapy in patients with pancreatic cancer. The plasma levels of angiogenesis-related molecules were not elevated in patients with pancreatic cancer, compared with those with benign diseases or colorectal cancer. The plasma interleukin-8 level may be a novel biomarker for the response to chemotherapy in patients with pancreatic cancer and warrants further prospective study.

Systemic inflammation and prediction of chemotherapy outcomes in patients receiving docetaxel for advanced cancer

Inflammatory markers are strong prognostic factors for survival in a variety of cancers. This study aimed to investigate the relationships between known inflammatory markers and their ability to predict overall survival (OS) in patients receiving docetaxel therapy. Sixty-eight patients with advanced cancer were enrolled in a clinical trial of single agent docetaxel from 2000 to 2002. Inflammation was measured using baseline cytokine concentrations, acute phase reactant proteins and white blood cell counts. The neutrophil/lymphocyte ratio (NLR) and Glasgow Prognostic Score (GPS) were calculated. Associations between inflammatory markers and their predictive value for OS were tested. The majority of patients had elevated inflammatory markers (50-70%). Strong inter-relationships were observed between the different inflammatory indices. Only NLR and GPS were independently predictive of OS. A combined NLR and GPS score demonstrated 11 month differences in overall OS between patients with normal and elevated inflammatory status. Normalisation of NLR after three doses of chemotherapy was associated with significant improvement in survival. This study found that NLR predicts the clinical outcomes for patients with advanced cancer treated with docetaxel. The clinical utilisation of NLR should be validated in a larger patient population to confirm its utility.

Results of neoadjuvant chemotherapy in patients with breast cancer

Results of neoadjuvant chemotherapy in patients with breast cancer

Abstract C5: Surface profiles of colorectal cancer cells and inflammatory lymphocytes correlate with blood neutrophil/lymphocyte ratios

Abstract Background: Half of the patients diagnosed with colorectal cancer (CRC) relapse and succumb to systemic disease within 5 years. In most hospitals, multidisciplinary postoperative care focuses on identifying histo- and clinicopathological tumour characteristics. Adjuvant therapy based on these standardized staging systems has resulted in mixed success; as few as 10–20% of patients may benefit. The clinical course for individual patients remains unpredictable, with prognostic heterogeneity for patients with same-stage tumours. Single biomarkers have limited utility; patterns or profiles of biomarkers will be required to predict post-surgical disease progression and patient prognosis. Local inflammation may have a negative or positive effect upon cancer development; for example, neutrophils may mediate tumor angiogenesis. A high neutrophil to lymphocyte ratio (NLR) in the peripheral blood has been associated with poorer patient survival and response to chemotherapy (Chua et al., 2011). We have developed a new system for sub-classification of CRC based upon extensive surface profiles and these results have been correlated with the NLR. Methods: The DotScan CRC antibody microarray captures live cells on immobilized antibodies against 122 surface CD antigens. Fresh surgical CRC samples (69) with corresponding normal intestinal mucosa were disaggregated to produce viable single cell suspensions that were captured on microarrays. Binding dot patterns were recorded for subsets of cells labeled with fluorescent antibodies. Epithelial cell adhesion molecule (EpCAM) labeled CRC cells; CD3 labeled tumour-infiltrating T-lymphocytes (TILs). Differential white blood cell counts and NLRs were obtained for each patient from hematology reports. Results: Statistical analysis showed significant immunophenotypic differences between CRC and control mucosal cell populations. Unsupervised hierarchical clustering of these data identified several patient sub-groups based on EpCAM (CRC cells) and CD3 (TILs) profiles. Differentially expressed CD antigens were recognized between groups of patients with low, medium or high NLRs. The DotScan CRC microarray may provide disease signatures for distinguishing patients with good and poor prognosis, and an alternative to current pathology CRC staging systems. Chua W, Charles KA, Baracos VE, Clarke SJ (2011) Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br J Cancer 104:1288–1295. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C5.

Elective palliative resection of incurable stage IV colorectal cancer: Who really benefits from it?

Despite the encouraging results of chemotherapy in patients affected by incurable colorectal cancer (CRC), surgical resection of a primitive tumor is still a common approach worldwide. The identification of prognostic factors related to short survival (<6 months) may allow excluding from resective surgery those who may not benefit from it. A retrospective analysis was performed of 15 variables in a population of 71 patients undergoing nonemergency palliative primary resections of incurable CRC, including patients' demographics and clinical/histopathological characteristics of the tumor. No variables were related to perioperative mortality (8.5% overall). A multivariate analysis revealed that older age (≥80 years) and metastasis to more than 25% of the lymph nodes were associated with survival (4 and 6 months, respectively). Mucoid adenocarcinoma therefore tends to be associated with the prognosis (P = 0.070). An elderly age tends to be a contraindication to an elective primary tumor resection in patients affected by incurable CRC. Massive lymph node involvement and mucoid adenocarcinoma should also be considered before planning major colonic surgery.

Abstract 2995: MicroRNA expression and outcome of adjuvant chemotherapy in patients with completely resected non-small cell lung cancer: International Adjuvant Lung Cancer Trial Biologic Program (IALT-Bio)

Abstract The aim of our study was to assess whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic and/or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted so far of adjuvant chemotherapy in patients with radically resected NSCLC stage I-III. Expression of miR-21, miR-29b, miR-34a/b/c, miR-155 and Let-7a was determined by quantitative real-time PCR in paraffin embedded formalin fixed tumor specimens from 639 IALT patients, using small nuclear RNA U66 as the endogenous normalization control. From 79 patients sufficient tumor adjacent normal tissue was available as well. The prognostic and predictive value of microRNA expression and chemotherapy for survival were studied using a Cox model, which included every factor used in the stratified randomization plus clinical and histological prognostic factors as well as other factors statistically related to microRNA expression. Association of p53 mutation status and miR-34a/b/c expression was analyzed, as well as association of EGFR and K-Ras mutation status with miR-21 and Let-7a expression, respectively. Finally association of p16 and miR-29b expression was assessed. In situ hybridization was performed for validation and to determine histological expression patterns. Overall, we found that there was no significant association between the expression profile of any of the tested microRNAs and survival. However, for miR-21, miR-34b and miR-34c, there is a suggested deleterious prognostic effect of lower values on survival. No single microRNA expression profile or a combination of microRNA expression profiles, as determined by cluster analysis, predicted response to adjuvant cisplatin-based chemotherapy. Concluding, expression levels of the tested microRNAs were neither predictive nor prognostic in this patient cohort. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2995.

Prediction of chemotherapy outcome in patients with metastatic soft tissue sarcomas based on dynamic FDG PET (dPET) and a multiparameter analysis

Dynamic PET studies with (18)F-FDG were performed in patients with metastatic soft tissue sarcomas who received conventional chemotherapy with doxorubicin hydrochloride (Adriamycin) and ifosfamide (AI-G). The goal of the study was to evaluate the impact of full kinetic analysis and assess its value with regard to the therapy outcome based on survival data. The evaluation included 17 patients with 29 metastatic lesions of soft tissue sarcomas, who were treated with chemotherapy consisting of an AI-G regimen prior to high-dose chemotherapy and peripheral blood stem cell transplantation where applicable. Patients were examined prior to onset of therapy and after completion of the first cycle of AI-G. Restaging data (n = 17) based on Response Evaluation Criteria in Solid Tumors were available. Survival data (n = 14) served for reference. The following parameters were retrieved from the dynamic PET studies: standardized uptake value (SUV), fractal dimension, two-compartment model with computation of k1, k2, k3, k4 (unit: 1/min), the fractional blood volume and the FDG influx calculated according to Patlak. The mean SUV was 6.9 prior to therapy and 4.7 after one cycle. The mean influx was 0.066 prior to therapy in comparison to 0.058 after one cycle. We dichotomized the patients according to the median survival time of 320 days into response (n = 6) and non-response (n = 8). The mean SUV was 7.6 in the group of responders and 5.4 in the group of non-responders prior to therapy. Responders revealed a mean SUV of 3.8 after therapy as compared to 5.0 SUV for non-responders. We used discriminant analysis to classify the patients into the two response groups. The classification of the non-responders was generally higher (negative predictive value > 61%) than for the responders. Finally, the combined use of the four predictor variables, namely mean SUV and k1 of both studies led to the highest accuracy of 90% for both groups. The data demonstrate that only a multiparameter analysis based on a combination of the absolute values of mean SUV and k1 of a baseline study and a follow-up study after completion of one cycle was the best combination for a group-based analysis, into response or non-response. The quantitative assessment of the FDG kinetics in tumours should be used to quantify the "inhibitory effect" of chemotherapy and to individualize treatment. The main effect of the AI-G therapy may be on angiogenesis (k1 effect) rather than on proliferation.

Expression and Prognostic Significance of MDR and IAP-Family Genes in Patients with Acute Myeloid Leukemia

Introduction. Refractory Acute Myeloid Leukemia (AML) is associated with very bad prognosis. One of the major reason of induction chemotherapy failure is the expression of genes and proteins responsible for multidrug resistance (Multidrug Resistance 1 - MDR1, Multidrug Resistance-Related Protein 1 - MRP1, Breast Cancer Resistance Protein-BCRP, Lung Cancer Related Protein - LRP) and apoptosis (IAP-family genes: XIAP, cIAP1, cIAP2, survivin). The aim of the study was the evaluation of the influence of MDR and IAP-family genes expression on results of chemotherapy in patients (pts) with AML.Material and methods. The study was performed in 45 pts (20 females and 25 males; ranged from 18 to 82 years - mean 51.2) with newly diagnosed AML. There were following types acc. FAB classification: M0–1, M1–5, M2–13, M3–4, M4–16, M5–6 and cytogenetic risk groups: favorable-8, intermediate-29 and unfavorable-8 pts. The genes expression in leukemic cells was detected by RT-PCR method. All pts were treated with induction and consolidation therapy acc. Polish Adult Leukemia Group (PALG).Results. The expression of MDR1 gene was detected in 47%, MRP1 in 21%, BCRP in 10%, LRP in 26% and IAP-family genes in 78% of pts. Expression of MDR1 was significantly higher in M5 (p=0.02), but expression of cIAP1 and cIAP2 in M4 type (p=0.01). There was significant difference in MDR1 expression between unfavorable and good risk cytogenetic group (p=0.03), but there was none difference between cytogenetic groups in expression of IAP-family genes. There was significant difference in MDR1 expression between pts who achieved complete remission (CR) and pts without CR (p=0.01). When the expression of MDR1 gene was associated with the expression of BCRP and LRP, CR was never obtained. In all pts with complex genetic changes (MDR1+MRP1, MDR1+BCRP+LRP, MDR1+MRP1+BCRP+LRP) CR after one course of induction chemoterapy was not obtained. There was significant difference between CR rate after one course of chemotherapy in pts without MDR genes expression or expression only one gene and in pts with expression of two or more genes (p=0.02). There was no correlation between IAP-family genes expression and CR rate. Despite of differences in post-consolidation therapy (bone marrow transplantation in some pts) expression of MDR1 and survivin genes correlated with overall surival rate (p=0.05 and 0.03, respectively).Conclusions. Results of our studies on expression of MDR and IAP-family genes in pts with AML showed that expression of MDR genes better predicted response on induction chemotherapy than IAP genes. After confirmation on larger group of pts these findings may have important significance in defining of prognosis in AML and individualization of induction and postremission therapy, eventually with new generation of MDR modulators.