Neoadjuvant chemotherapy in operable breast cancer with docetaxel, doxorubicin, and cyclophosphamide (TAC) or TAC followed by vinorelbine and capecitabine (NX): Final results and analysis of markers predicting response to treatment

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 524-524
Author(s):  
J. Huober ◽  
G. von Minckwitz ◽  
C. Denkert ◽  
A. Kleine-Tebbe ◽  
E. Weiss ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Neoadjuvant Chemotherapy ◽  
Clinical Response ◽  
Remission Rate ◽  
Univariate Analysis ◽  
Early Response ◽  
Response To Treatment ◽  
Lymph Node Status ◽  
Study Population ◽  
Her 2

524 Background: The aim of this analysis was to determine the pathological complete remission rate (pCR) for the entire Gepartrio study population and to identify markers predicting response to NACT. Methods: The design of the Gepartrio study was described elsewhere (von Minckwitz et al.). Age at diagnosis, tumor size, lymph node status, estrogen (ER), progesterone (PgR), HER-2 status, histological type, and grade were assessed in uni- and multivariate analysis. Clinical response after 2 cycles TAC and pCR at surgery were used as efficacy endpoints. Results: 2072 pts were randomized depending on response after 2 cycles TAC. 1122 pts (54.2%) had a clinical response after 2 cycles and 385 (18.6 %) pCR. The highest pCR rate (60%) was observed in pts with triple neg tumors and < 40 years. In the HR pos/HER-2 pos pts the pCR rates were 17.6% vs. 9% for HR pos/HER-2 neg pts (p<0.001). In the HR neg subset absence of HER-2 overexpression (“triple neg tumors”) resulted in significantly improved pCR rates compared to the HR neg HER-2 pos subset (40.7% versus 31.6%, p=0.041). In univariate analysis predictors for both an early response and a pCR at surgery were age < 40 years, non T4 tumor, grade 3, neg hormone receptors (HR) and a triple neg status. Non lobular histology was only predictive for a pCR in univariate analysis. In multivariate analysis independent factors for early response were non T4 tu, tumors ≥ 40 mm, poor grading and neg HRs. Independent predictors for a pCR remained age < 40 years, poor grading, a non lobular subtype and triple neg tumors. Conclusions: The pCR rate for the whole study population of the Gepartrio trial was comparable to other neoadjuvant regimens. Markers identified as independent predictors may help in decision making for pts being considered for neoadjuvant chemotherapy. [Table: see text]

Impact of pre-treatment lymphocyte monocyte ratio and neutrophil lymphocyte ratio on pathologic response in breast cancer patients receiving neoadjuvant chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12623-e12623
Author(s):  
Osama Mosalem ◽  
Saud Alsubait ◽  
Shouq Kherallah ◽  
Venumadhavi Gogineni ◽  
Ling Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multivariate Analysis ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Patients ◽  
Univariate Analysis ◽  
Patient Characteristics ◽  
Breast Cancer Patients ◽  
Her 2 ◽  
The Mean ◽  
Pre Treatment

e12623 Background: Hematologic markers have been looked at as potential prognostic biomarkers in a variety of cancers. Ni and colleagues (2014) have shown that an elevated pre-treatment lymphocyte-to-monocyte ratio (LMR) was significantly associated with improved disease-free survival (DFS) in patients with locally advanced breast cancer receiving neoadjuvant chemotherapy (NACT). Given the prognostic implications of hematologic inflammatory parameters, we sought to understand if such biomarkers will predict response to neoadjuvant chemotherapy (NACT) in patients with breast cancer. Methods: We conducted a retrospective review of breast cancer patients treated with NACT at our institution (2008-2018). Data on patient characteristics, stage, pathologic characteristics, and blood counts were collected. Blood parameters prior to NACT were used to calculate LMR and neutrophil-to-lymphocyte ratio (NLR). To test the impact of LMR and NLR on pathologic response, a two sample mean test was used first as univariate analysis. Next, logistic regression was employed for multivariate analysis controlling for patient characteristics with interaction of LMR and NLR with ER, PR and HER2 status. Results: A total of 50 patients were included. 38% of patients achieved a pathologic complete response (pCR). The mean LMR was 3.69 (1.4-12.5), and the mean NLR was 2.55 (0.66 – 9.31). On univariate analysis, a high NLR was associated with a higher likelihood of achieving a pCR (OR = 1.64, 95% CI = 1.01-2.63). A high LMR was associated with a higher likelihood of pCR; however, this was not statistically significant (OR = 1.08, 95% CI = 0.78-1.47). On multivariate analysis, patients with HER-2 positive disease with a high LMR had a significantly higher chance of having a pCR (OR = 1.72, 95% CI = 1.06-2.78). Conclusions: Our study showed that NLR was a predictor of pCR in breast cancer patients receiving neoadjuvant chemotherapy. A high NLR was associated with achieving a pCR on univariate analysis. Multivariate analysis suggested that HER-2 positive disease with a high LMR had a significantly higher chance of achieving a pCR. The results of this cohort correlate with previous reports by others showing that pre-NACT LMR and NLR provide prognostic information in patients with breast cancer. Although limited by sample size, this adds to the growing body of literature supporting peripheral blood counts as a biomarker for outcomes in breast cancer.

Neoadjuvant chemotherapy for invasive bladder cancer: prognostic factors for survival of patients treated with M-VAC with 5-year follow-up.

1994 ◽  
Vol 12 (7) ◽  
pp. 1394-1401 ◽  
Author(s):  
P K Schultz ◽  
H W Herr ◽  
Z F Zhang ◽  
D F Bajorin ◽  
A Seidman ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Neoadjuvant Chemotherapy ◽  
Univariate Analysis ◽  
Invasive Bladder Cancer ◽  
Pathologic Stage ◽  
Muscle Invasive ◽  
Extravesical Disease

PURPOSE To determine survival in patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and to analyze prechemotherapy and postchemotherapy factors for prognostic significance. PATIENTS AND METHODS The survival of 111 patients with T2-4N0M0 bladder cancer treated with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) was assessed. Prechemotherapy and postchemotherapy factors were analyzed for correlation with survival. Factors found to be significant on univariate analysis were subjected to multivariate analysis using Cox's proportional hazards model. RESULTS The median follow-up duration was 5.3 years. Initial tumor (T) stage (P = .0001), presence of ureteral obstruction (P = .0074), and presence of a palpable mass (P = .0039) were the only pretreatment factors found to be significant on univariate analysis. Postchemotherapy surgery was performed in 81 patients. In these cases, postchemotherapy clinical stage and pathologic stage were significant factors on univariate analysis. In the multivariate analysis, the initial prechemotherapy T stage and the postchemotherapy pathologic stage (pT stage) were the only two factors to demonstrate independent significance. An association between downstaging postchemotherapy and survival was observed for patients with extravesical disease (T < or = 3B) at the start of treatment. In this subset, the 5-year survival rate was 54% for patients with downstaging versus 12% for those without downstaging. This association was not observed for patients with bladder-confined disease (T < or = 3A) at presentation. CONCLUSION The stage of bladder cancer at presentation and at postchemotherapy pathologic staging are independent prognostic factors for long-term survival in patients treated with neoadjuvant chemotherapy. Downstaging after neoadjuvant chemotherapy was associated with improved survival in patients with muscle-invasive bladder cancers, but only for those with extravesical disease (T > or = 3B) pretreatment. Randomized comparisons will be required to assess the impact of chemotherapy on overall survival.

Relationship Between Subtherapeutic Warfarin Anticoagulation and the Development of Post Thrombotic Syndrome After a First Unprovoked Deep Vein Thrombosis: Results From the REVERSE Cohort Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 712-712 ◽  
Author(s):  
Rufaro S. Chitsike ◽  
Susan R. Kahn ◽  
Michael J. Kovacs ◽  
Marisol T. Betancourt ◽  
Philip S Wells ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cohort Study ◽  
Oral Anticoagulation ◽  
Time Window ◽  
Univariate Analysis ◽  
Full Time ◽  
Index Event ◽  
Post Thrombotic Syndrome ◽  
Study Population ◽  
Full Period

Abstract Abstract 712 Background & Objective: Risk factors for the post-thrombotic syndrome (PTS) remain poorly understood. In a prospective multinational multicenter cohort study of patients with a first episode of unprovoked deep venous thrombosis (DVT), we sought to evaluate whether subtherapeutic anticoagulation was associated with the development of PTS. Methods: The study population was derived from the REVERSE study, a prospective cohort study done to develop a clinical prediction rule to identify patients with unprovoked venous thromboembolism (VTE) at low risk of recurrent VTE. Patients with a first unprovoked VTE (index event) were treated with standard anticoagulant therapy with a target INR of 2–3 for a period of 5–7 months. Patients were then enrolled in the REVERSE study, anticoagulation was stopped, and patients were monitored for VTE recurrence. For the present study, patients with DVT as their index VTE event were assessed for PTS at enrollment into the REVERSE study, using the validated Villalta scale. PTS was defined by a score of > 4. Mild PTS was defined by a score of 5–9, moderate PTS by a score of 10–14 and severe PTS was defined by a score of ≥15 or presence of an ipsilateral leg ulcer. Using international normalized ratio (INR) data from the full period of warfarin anticoagulation, time in therapeutic range (TTR) was calculated by the Rosendaal method of linear interpolation. TTR data were analyzed to evaluate whether there was an association between sub-therapeutic INR values during various time windows since the index DVT and development of PTS. Based on published trials of warfarin anticoagulation for VTE, INR <2 for more than 20% of the time was considered to represent subtherapeutic anticoagulation. Univariate analysis was performed to determine the odds ratio (OR) for development of PTS if anticoagulation was considered subtherapeutic. Multivariate analysis was then performed to adjust for known confounding variables. Results: 646 patients were enrolled into the REVERSE study, of whom 410 had DVT as their index event. Of these, 61 were excluded for insufficient INR or PTS data. Hence, the study population comprised 349 patients. The average age was 54.2 years, and 55.6% of the patients were male. Patients were on oral anticoagulation for a mean (SD) of 199 (17) days. Ninety-seven patients (27.8%) developed PTS; of these, 77 (74.7%) had mild PTS, 16 (15.5%) had moderate PTS and 4 (3.9%) had severe PTS. For the study population, the overall mean (SD) TTR during oral anticoagulation was 64.3% (19.4%) and the overall mean (SD) percentage time spent with an INR under 2 was 23.7% (18.7%). For the time window ‘first 3 months of anticoagulation', patients who developed PTS had an INR of <2 for 30% of the time vs. 24% of the time in patients without PTS (p=0.023). For the time window ‘full period of anticoagulation', patients who developed PTS had INR <2 for 27% of the time vs. 23% of the time in patients without PTS (p=0.08). Using our predefined cut-off for subtherapeutic anticoagulation (i.e. INR <2 for more than 20% of the time), patients with PTS were more likely to have received subtherapeutic anticoagulation than those without PTS during the first 3 months of anticoagulation (62.9% vs. 48.8%; p=0.02) and during the full period of anticoagulation (62.9% vs. 48.0%; p=0.01). The incidence of PTS in patients with an INR below 2 for >20% of the full time period was 33.5% compared to 21.6% in those with an INR below 2 for ≥20% of the time (p=0.02). In univariate analysis, the OR for development of PTS if the INR was <2 for more than 20% of the time during the first 3 months of anticoagulation was 1.78 (95% CI 1.10–2.87). In multivariate analysis adjusting for age, sex, body mass index, concurrent PE, previous secondary VTE and use of graduated compression stockings, the association between subtherapeutic anticoagulation and PTS remained robust (1.84 95% CI 1.13–3.01). Corresponding ORs for the full period of anticoagulation were 1.83 (95% CI 1.14–3.00) [crude] and 1.88 (95% CI 1.15–3.07) [adjusted]. Conclusion: Subtherapeutic warfarin anticoagulation after a first unprovoked DVT may be a risk factor for the development of PTS. Careful attention to INR control may have value in preventing PTS. Further study of the risk of PTS associated with oral or parenteral anticoagulants that offer more predictable anticoagulation than warfarin may be of value. Disclosures: No relevant conflicts of interest to declare.

Prognostic factors in duodenal adenocarcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15797-e15797
Author(s):  
Brandon M Huffman ◽  
Zhaohui Jin ◽  
Cristobal T. Sanhueza ◽  
Mindy L. Hartgers ◽  
Benny Johnson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Lymph Node ◽  
Tumor Invasion ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Clinical Staging ◽  
Lymph Node Status ◽  
Duodenal Adenocarcinoma

e15797 Background: Duodenal adenocarcinoma is a rare tumor representing approximately 0.3% of all gastrointestinal tract cancers. Prognostic factors in relation to survival outcomes for these patients are sporadically reported in the medical literature. We aimed to evaluate outcomes of patients with duodenal adenocarcinoma who underwent pancreaticojejunostomy treated at Mayo Clinic Rochester from January 1, 2006 to December 31, 2016. Methods: Clinicopathological data of 52 duodenal cancer patients were collected. JMP software was used for statistical analysis. Kaplan-Meier method and log-rank tests were used for survival analysis, and multivariate cox proportional hazards model was used to evaluate the prognostic effect of pertinent clinical variables. All tests were two sided and a P value of < 0.05 was considered significant. Results: The median age at diagnosis was 65.9 years (range 39-81). The median overall survival was 51 months (95% CI 31.3-105.4) and the median progression free survival was 30.4 months with median follow up of 73.4 months. There were 3, 9, 21, and 19 patients with stage I, II, III, and IV disease, respectively. Depth of tumor invasion (p = 0.0156) and lymph node metastasis (p = 0.0441) were associated with overall survival on multivariate analysis. Advanced clinical staging influenced overall survival in univariate analysis, but lost prognostic significance in multivariate analysis. Age, gender, surgical technique, presence of metastases, tumor size, number of lymph nodes removed, location of duodenal segment involvement, and adjuvant treatment had no significant impact on overall survival. Laparoscopic approach did not influence survival but was associated with less hospital days (p = 0.0437). Conclusions: Depth of tumor invasion and lymph node status were associated with improved overall survival in patients with duodenal adenocarcinoma. Laparoscopic procedure decreased the hospital stay without affecting outcomes.

scholarly journals Cognitive flexibility of smokers in the context of social anxiety

2020 ◽  
pp. 93-99
Keyword(s):  
Multivariate Analysis ◽  
Social Anxiety ◽  
Analysis Of Variance ◽  
Cognitive Flexibility ◽  
Univariate Analysis ◽  
Multivariate Analysis Of Variance ◽  
Nicotine Abuse ◽  
Significant Difference ◽  
Wilks Lambda ◽  
Study Population

Background: The cognitiveCognitive dysfunction may be an important factor in smoking and nicotine abuse. However, there are very few studies that have examined the effects of psychiatric conditions on the cognitive flexibility of smokers. Objectives: This research was conducted with the aim of examination theto examine cognitive flexibility (perceive theperceived controllability and cognitive alternatives) ofamong smokers in the context of with social anxiety. MaterialMaterials and methods: The research was a study withpresent causal-comparative design. The populationstudy was allconducted on 60 smoker students ofstudying at Arak University, Arak, Iran, in 2018-2019 years. For selecting the research sample the. The study population was selected using the purposive sampling was usedtechnique. At first, the participants completed the Social Phobia Inventory (SPIN) and Cognitive Flexibility Inventory (CFI).. Then, based on the cutoff point scores of SPIN (19 to above),≤), the participants were divided into two smoker groups (n=30 in each group) were selected: smoker groupsof smokers with and without social anxiety. (n=30 in each group). Finally, these groups were compared in perceive the terms of perceived controllability and cognitive alternatives by Multivariate Analysis of Variance (MANOVA).using the multivariate analysis of variance. Results: The results indicated a significant difference in the linerlinear composition of the dependent variables ofin the two groups (wilks,Wilks’ lambda= 0/.799, F50,2= 6/.726, p= P=0/.004). UnivariateThe results of the univariate analysis of variance indicated that the smoker group with social anxiety had lower perceive theperceived controllability and cognitive alternatives, compared to the smoker group without social anxiety. Conclusion: In generalAs the findings indicated, the level of cognitive flexibility in the smokers with and without social anxiety iswas different. Therefore, it is necessary to consideringconsider the evaluation and treatment of cognitive deficits in smokers based on their level of social anxiety.

scholarly journals Sentinel and Non-Sentinel Lymph Node Metastasis Prediction and Validation of the MSKCC Nomograms for Indian Breast Cancer Patients

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 35s-35s
Author(s):  
A. Choraria ◽  
S. Agrawal ◽  
I. Arun ◽  
S. Chatterjee ◽  
R. Ahmed
Keyword(s):  
Breast Cancer ◽  
Multivariate Analysis ◽  
Lymph Node ◽  
Sentinel Lymph Node ◽  
Lymph Node Metastasis ◽  
Roc Curve ◽  
Univariate Analysis ◽  
Lymph Node Status ◽  
Node Metastasis ◽  
Mskcc Nomogram

Background: Sentinel lymph node (SLN) biopsy accurately stages the axilla, but is time consuming and resource intensive. Nomograms and scoring systems have been developed, based on clinical and pathologic data available before surgery, to attempt to predict the likelihood of lymph node metastasis before surgery. As the management of the axilla in patients with low nodal burden changes, it is also important to predict whether there will be further axillary disease in patients with a positive SLN. Aim: To explore the risk factors for SLN and non-SLN metastasis in Indian women with breast cancer, by analysis of clinical and pathologic data. To assess the validity and clinical utility of two MSKCC nomograms that predicts axillary lymph node status for Western patients. Methods: Clinical data, and pathologic data available from core biopsy, for a consecutive series of women having SLNB was analyzed, and was plotted on two MSKCC nomograms. Univariate analysis was done by χ2 and Fischer exact tests and multivariate analysis was done by logistic regression method. A receiver-operating characteristic (ROC) curve was drawn and predictive accuracy was assessed by calculating the area under the ROC curve (AUC). Results: 34% (89 out of 256) of our patients had SLN positivity. When correlated with SLN metastasis by univariate analysis, LVI (χ2 = 80, P ≤ 0.001), PNI (χ2 = 13.36, P ≤ 0.001), ER+ (χ2 = 6.85, P = 0.009), PR+ (χ2 = 7.1, P = 0.008) and age ( P = 0.03) were significant. However, multivariate analysis showed that age (OR=1.04, P = 0.007) and LVI (OR=0.07, P ≤ 0.001) were identified as independent predictors for SLN metastasis. The area under the ROC curve was 0.772 and it fairly correlated with MSKCC nomogram. Patients with MSKCC scores lower than 38% had a frequency of SLN metastasis of 7.7% (5/65) and this cut-off could be used as a guide for not doing frozen section analysis in this subgroup. Further axillary dissection showed 41% (38 out of 92) had non-sentinel nodes positive. When correlated with non-SLN metastasis by univariate analysis, LVI (χ2 = 8.8, P = 0.003), PNI (χ2 = 6.85, P = 0.009), and extracapsular extension (χ2 = 4.18, P = 0.04) were significant. Number of SLN negative ( P = 0.01), SLN ratio (number of SLN positive/total number of SLN removed) ( P = 0.01) and size of SLN metastasis ( P = 0.002) were significant. However, multivariate analysis showed that only size of SLN metastasis (OR=0.845, P = 0.02) was identified as independent predictor for non-SLN metastasis. The area under the ROC curve was 0.66 and it poorly correlated with MSKCC nomogram. Conclusion: The MSKCC nomogram can provide a fairly accurate prediction of the probability of SLN metastasis, but is not for non-SLN metastasis. An institutional nomogram for non-SLN metastasis, including additional factors such as size of SLN metastasis, may improve prediction.

scholarly journals Vascular Endothelial Growth Factor-C (VEGF-C) Expression Can Not Predict Pelvic Lymph Node Metastases and Response to Neo-adjuvant Chemotherapy in Bulky Cervical Cancer

2016 ◽  
Author(s):  
Johnson Hutapea
Keyword(s):  
Cervical Cancer ◽  
Multivariate Analysis ◽  
Neoadjuvant Chemotherapy ◽  
Tumour Size ◽  
Response To Treatment ◽  
Chemotherapy Response ◽  
Response To Chemotherapy ◽  
The Difference ◽  
Neo Adjuvant Chemotherapy ◽  
Factor C

Objective: To assess whether VEGF-C expression can predict the response to neoadjuvant chemotherapy and pelvic lymphnode metastases in bulky cevical cancer. Methods: Seventeen cervical cancer stage IB2 and IIA2 cases during the period of July 2009 until June 2010 were collected consecutively and given neoadjuvant chemotherapy (NAC) PVB prior radical surgery. Response to treatment was evaluated based on the change of tumour size. VEGF-C expression was examined immunohistochemically at tumour biopsy before chemotherapy. The presence of lymphnode metastases histopathologically were obtained from pelvic lymphnode dissection. The difference and correlation of response and metastases on VEGF-C expression were analized statistically. The validity of the cut off percentage of immunopositive cells to VEGF-C to identify non responding and metastatic cases was calculated with the ROC. Multivariate analysis were done to determine the predictor of no response to chemotherapy. Results: Clinical response, using the RECIST version 1.1 criteria, was found in 41.18% cases and lymphnode metastases were found in 27.27% cases. VEGF-C was expressed in all cases. Statistically, there were no significant differences and correlation in response to treatment and pelvic lymphnode metastases on VEGF-C expression. At the cut off ≥ 76% immunopositivity to VEGF-C, the sensitivity to identify no response and the specificity to identify response to NAC are 70.00% and 71.43% respectively (LR+ 2.45 and LR- 0.42); whereas at the cut off ≥ 75% immunopositivity to VEGF-C, the sensitivity to identify lymphnode metastases and the specificity to identify no lymphnode metastases are 100.00% and 75.00% (LR+ 4.0 and LR- 0). With multivariate analysis using logistic regression, the cut off ≥ 76% immunopositive cells to VEGF-C were found to have positive coefficient, largest OR and statistic score, 1.93, 6.88 (96% CI OR 0.45; 104.34) and 41 respectively, to predict non responders in a prediction score model. Conclusion: VEGF-C expression on biopsy specimen bulky cervical cancers can not differentiate cases that respond to NAC and metastases to the pelvic lymphnode from that do not. The cut off ≥ 76% immunopositive cells to VEGF-C in a prediction model can be used as an alternative predictor to identify non responders. [Indones J Obstet Gynecol 2012; 36-3: 144-9] Keywords: bulky cervical cancer, neoadjuvant chemotherapy, response and metastases prediction, VEGF-C immunohistochemistry expression

Perioperative chemotherapy for upper gastrointestinal cancer: Correlation between response to treatment and outcome.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 95-95
Author(s):  
Thierry Alcindor ◽  
Lorenzo Ferri ◽  
Steven Ades ◽  
Amin Andalib ◽  
Khalid Al-Baimani ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Clinical Response ◽  
Metabolic Response ◽  
Univariate Analysis ◽  
Perioperative Chemotherapy ◽  
Nodal Involvement ◽  
Response Data ◽  
Upper Gi ◽  
Post Surgery ◽  
Response To Chemotherapy

95 Background: Perioperative chemotherapy improves outcomes of surgery for upper GI cancer. Some patients have rapid recurrence. We hypothesized that any type of response to chemotherapy would predict better disease-free survival (DFS). Methods: From May 2007 to Sep 2009, 43 patients with operable adenocarcinoma of the esophagus, stomach or gastroesophageal junction went on a multicenter phase II trial. 3 cycles of docetaxel/cisplatin/5FU were given pre and post surgery. We compared DFS between responders and nonresponders after 3 cycles. Clinical response was defined as improvement of ≥ 2 points on a dysphagia score (0: normal swallowing, to 4: total obstruction), metabolic response as ≥ 35% reduction of maximum SUV by PET scan. Lack of nodal involvement or significant histologic regression (less than 50% viable tumor) was considered pathologic response. Log-rank test was used for univariate analysis, Cox regression model for multivariate analysis. All p values are double sided, median follow-up from surgery is 808 days. Results: Clinical response data for 29/40 patients: 26 responses (90%). Median DFS was 405 days for clinical responders vs. 210 days for nonresponders (p= 0.018). Metabolic response data for 28/40 patients : 22 responses (70%). Median DFS was 276 days in metabolic nonresponders, and has not been reached in responders (p = 0.009). 14 patients had no nodal involvement at resection (N0) and had longer DFS (median not reached) than the 26 with N+, who had median DFS of 562 days (p = 0.045). A nonsignificant trend (p = 0.192) was seen in favor of the 20 with significant tumor regression (DFS 565 days) compared to the 20se without it (median DFS not reached). All results were supported by multivariate analysis. Conclusions: These preliminary results indicate that clinical, metabolic and pathologic responses may be individually predictive of longer DFS in patients receiving perioperative chemotherapy for upper GI adenocarcinoma. This requires confirmation in larger datasets. The optimal management of nonresponders is unclear at present. Acknowledgements: Biostatistics Unit (McGill University Health Centre) and Cedars Cancer Institute (Henry R Shibata Fellowship to Dr Alcindor).

scholarly journals Exosome-Transmitted PSMA3 and PSMA3-AS1 Promotes Proteasome Inhibitors Resistance in Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4434-4434
Author(s):  
Wenzhuo Zhuang ◽  
Sha Song ◽  
Huiying Han ◽  
Gao Fan ◽  
Nengjun Yi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Clinical Response ◽  
Univariate Analysis ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Mrna Levels ◽  
Free Survival ◽  
Myeloma Cells

Abstract PIs resistance is a major challenge for multiple myeloma (MM). The bone marrow microenvironment facilitates crucial interactions between the myeloma cells and mesenchymal stem cells (MSCs) that permit MM to survive and proliferate progression. Exosomes are involved in intercellular communication, and in this study we investigated how the transfer of exosomic PMSA3 (encodes proteasome subunit α7) and lncPSMA3-AS1 from MSCs to MM cells affected proteasome inhibitors resistance (Figure 1). We firstly underscored that exosomes derived from r-MSCs (MSCs derived from bortezomib-resistant patients), but not from s-MSCs (MSCs derived from bortezomib-resistant patients) reduced the proteasome inhibitors sensitivity in MM cells (Figure 2). To further elucidate mechanisms of Proteasome inhibitors (PIs) resistance, we retrieved a database containing gene expression profile of 169 myeloma cases with clinical response and disease prognosis (GSE9782). The analysis of this dataset showed that the mRNA levels of PSMA3 and PSMA3-AS1 in CD138+ cells are upregulated in bortezomib-resistant patients (Figure 3A-3D). Moreover, Kaplan-Meier analysis showed that high PSMA3 levels in CD138+ MM cells were correlated with reduced progression-free survival (PFS) (p = 0.0307) and overall survival (OS) (p = 0.0328) (Figure 3E). Cox proportional hazards regression analysis further demonstrated that high PSMA3 was an independent prognostic factor for MM patients with bortezomib therapy in a multivariate analysis (p = 0.0013, HR = 1.3104, 95%CI = 1.1113-1.545). Further analysis of Oncomine data showed that the PSMA3 levels appeared a progressive increase in MGUS, SM, MM and PCL (Figure 3F-3H). Similarly, our PIs resistant models (U266BR, U266CR, U266IR, MM.1SBR, MM.1SCR, MM.1SIR) consistently displayed up-regulation of PSMA3 and PSMA3-AS1 expression (Figure 3J). Consistent with this previously published study, our clinical data showed that the mRNA levels of PSMA3 and PSMA3-AS1 are upregulated in CD138+ MM cells derived from bortezomib resistant patients relative to those from bortezomib sensitive patients (Figure 3I). In addition, r-MSCs had increased expression of PSMA3 and PSMA3-AS1 compared to s-MSCs (Figure 3K). Moreover, the expression of PSMA3 and PSMA3-AS1 in MSCs were positively correlated with that in CD138+ myeloma cells (Figure 3L). These data suggested that high levels of PSMA3 and PSMA3-AS1 were correlated with proteasome inhibitors resistance in MM. We further identified that PSMA3 and PSMA3-AS1 in MSCs could be incorporated into exosomes and transmitted to myeloma cells, thus promoting PIs resistance (Figure not shown). PSMA3-AS1 was capable of forming an RNA duplex with PSMA3 pre-mRNA at overlapping regions and this duplex transcriptionally promoted PSMA3 expression by increasing its stability, conferring bortezomib resistance to myeloma cells (Figure not shown). To evaluate the therapeutic potential of PSMA3-AS1 in MM in vivo, bioluminescent MM models (U266-luc), which recapitulates the clinical sequelae, anatomic distribution of MM lesions, and hallmark bone pathophysiology observed in MM patients were established. Intravenously administered siPSMA3-AS1 was found to be effective in increasing bortezomib sensitive (Figure 4). Moreover, circulating exosomal PSMA3 and PSMA3-AS1 derived from the plasma of MM patients were significantly associated with both progression-free survival (PFS) and overall survival (OS) in the univariate analysis, and were still statistically significant after adjusting for the international staging system (ISS) and several other clinical variables in the multivariate analysis (Figure not shown). In summary, our results indicated a unique role of exosomic lncPSMA3-AS1 in transferring proteasome inhibitors resistance from MSCs to MM cells, through a novel exosomic lncPSMA3-AS1/PSMA3 signaling pathway. Exosomic PSMA3 and PSMA3-AS1 may serve as a potential therapeutic target for proteasome inhibitors resistance and a prognostic predictor for clinical response. Disclosures No relevant conflicts of interest to declare.

Rituximab (R) in Combination with Fludarabine (F) and Cyclophosphamide (C) in Relapsed Follicular Lymphoma (FL) Patients (pts).Final Results of FC + R Phase II Trial by the GISL.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2763-2763
Author(s):  
Stefano Sacchi ◽  
Samantha Pozzi ◽  
Raffaella Marcheselli ◽  
Stefano Luminari ◽  
Massimo Federico ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Remission Rate ◽  
Performance Status ◽  
Univariate Analysis ◽  
Infectious Complications ◽  
Response To Treatment ◽  
Ecog Performance Status ◽  
Treatment Delays ◽  
Kaplan Meier ◽  
Cox Analysis

Abstract Fifty-four Pts entered this trial between January 2000 and December 2002. Eligible Pts had histologic documentation of CD 20+ relapsed FL, according to the revised European/American Lymphoma classification, that required treatment, measurable lesion, and an ECOG performance status of 0 or 1. Pts were further required to be aged 18–70 years, and to have undergone < 3 previous lines of chemotherapy. Pts received FC + R chemoimmunotherapy consisting of F 25 mg/m2 and C 300 mg/m2/day for 3 consecutive days every 3 weeks for 4 cycles. R 375 mg/m2 I.V. infusion was administered starting 2 weeks following the first FC course and then on day 1 of each cycle thereafter. Clinical response were defined according to the International Working Group recommendations. BCL 2 analysis was performed by PCR assay. DR, TTP and OS were analyzed by Kaplan-Meier method. Cox analysis was used to analyse the association of baseline prognostic factors with response to treatment, DR,TTP and OS. The overall response rate for all 54 Pts by ITT analysis was 90%; forty Pts (74%), obtained complete responses. Progression occurred in 3 Pts ( 6% ) and 2 Pts dropped out of the trial: 1 for toxicity and 1 refused to start with therapy. A univariate analysis of baseline prognostic factors demonstrated that none of these factors predicted for response to treatment. There were 29 Pts out of 45 tested, positive for BCL 2 before therapy. Among these, 22 Pts were evaluated after treatment and 19 ( 86%) converted to BCL negativity. At last follow up (FU), 40 Pts were alive, 31 with ongoing response and 9 with progressive disease. The median DR, TTP and OS have not been reached after a median FU time of 45 months ( range, 1 to 74 months ). The median DR in the 49 Pts who have reached CR or PR was 35 months ( range, 6 to 70 months). None of the baseline prognostic characteristics was significantly related to DR. The median TTP in all 54 Pts, was 36 months ( range, 1 to 74 months ).BCL2 positivity and < 2 previous treatments were related with better TTP (p<0.05 ) OS rate at 4 years was 75%. Toxicity was evaluable in 52 Pts. The most common severe side effects were hematologic, and included 21 cases of neutropenia, 3 cases of thrombocytopenia and 2 cases of anemia. Infectious complications manifested in 3 Pts and 1 died for pneumonitis. Treatment delays of 1–3 weeks was necessary in 12 patients. The results of our trial have demonstrated that FC+R chemoimmunotherapy is active and relatively well tolerated. The OR rate of 90%, associated with an excellent molecular remission rate, and the mean DR of 35 months compares favourably with the results obtained in other trials in similar subset of patients and supports the use of an FC+R arm in future controlled trials.

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