Reduction In Overall Survival Research Articles

Incidence of metastasis and prostate-specific antigen levels at diagnosis in Gleason 3+4 versus 4+3 prostate cancer.

Aims:The aim is to assess for a difference in the incidence of metastasis (IM) and prostate-specific antigen (PSA) levels at diagnosis in patients with Gleason score (GS) 3+4 versus 4+3 prostate cancer using a large veterans affairs database.Subjects and Methods:A retrospective review of 1402 medical records from 5 VA hospitals was conducted. The study period was from 2009 to 2014. Primary endpoints were IM and PSA levels at diagnosis. A secondary endpoint was overall survival.Statistical Analysis Used:Chi-square tests for categorical variables, Student's t-test for continuous, normally distributed variables, and rank sum tests for continuous nonnormally distributed variables.Results:There were 1050 patients with GS3+4 and 352 with GS4+3. There were no differences in sociodemographic and clinical characteristics of the study population. PSA at the time of diagnosis was significantly higher in the GS4+3 patients compared to GS3+4 (18.0 vs. 11.4, respectively; P < 0.001). The IM at diagnosis was higher in the GS4+3 patients (10/352) compared to GS3+4 (9/1041) (2.8% vs. 0.9%; P = 0.005). In an adjusted model, GS4+3 was associated with higher PSA, higher IM at diagnosis. There was no difference in overall survival between the 2 groups though a 23% reduction in overall survival in the GS4+3 was noted (P = 0.53).Conclusions:Our results indicate that patients with GS4+3 prostate cancers have higher PSA levels at diagnosis. GS4+3 is associated with 3-fold increased risk of IM at diagnosis than GS3+4 though the overall incidence is low. Further research is needed to assess whether GS4+3 patients need routine staging imaging investigations at the time of diagnosis similar to patients with higher Gleason scores (GS ≥8).

Influence of BCL2L11 polymorphism on osteonecrosis during treatment of childhood acute lymphoblastic leukemia

Osteonecrosis (ON) is corticosteroid-related complication, reported in children with acute lymphoblastic leukemia (ALL). We have previously found that polymorphisms in BCL2L11 gene coding for pro-apoptotic Bim protein influence reduction of overall survival (OS) in a corticosteroid (CS) dose-dependent manner in childhood ALL patients. The same set of SNPs was here investigated for an association with CS-related ON assessed retrospectively in 304 children with ALL from Quebec (QcALL cohort) who received Dana-Farber Cancer Institute (DFCI) ALL treatment protocols. Two-year cumulative incidence of symptomatic ON was 10.6%. Two BCL2L11 polymorphisms, the 891T>G (rs2241843) in all QcALL patients and 29201C>T (rs724710) in high-risk group were significantly associated with ON, P = 0.009 and P = 0.003, respectively. The association remained significant in multivariate model (HR891TT = 2.4, 95% CI 1.2-4.8, P = 0.01 and HR29201CC = 5.7, 95% CI 1.6-20.9, P = 0.008). Both polymorphisms influenced viability of dexamethasone treated lymphoblastoid cell lines (P ≤ 0.03). The 891T>G influenced Bim gamma isoform levels (0.03) and its association with ON was also confirmed in replication DFCI cohort (N = 168, P = 0.03). QcALL children had a high incidence of ON during therapy, which was highly associated with BCL2L11 polymorphisms.

A role of SIPL1/SHARPIN in promoting resistance to hormone therapy in breast cancer

SIPL1 inhibits PTEN function and stimulates NF-κB signaling; both processes contribute to resistance to hormone therapy in estrogen receptor positive breast cancer (ER+ BC). However, whether SIPL1 promotes tamoxifen resistance in BC remains unclear. We report here that SIPL1 enhances tamoxifen resistance in ER+ BC. Overexpression of SIPL1 in MCF7 and TD47 cells conferred tamoxifen resistance. In MCF7 cell-derived tamoxifen resistant (TAM-R) cells, SIPL1 expression was upregulated and knockdown of SIPL1 in TAM-R cells re-sensitized the cells to tamoxifen. Furthermore, xenograft tumors produced by MCF7 SIPL1 cells but not by MCF7 empty vector cells resisted tamoxifen treatment. Collectively, we demonstrated a role of SIPL1 in promoting tamoxifen resistance in BC. Increases in AKT activation and NF-κB signaling were detected in both MCF7 SIPL1 and TAM-R cells; using specific inhibitors and unique SIPL1 mutants to inhibit either pathway significantly reduced tamoxifen resistance. A SIPL1 mutant defective in activating both pathways was incapable of conferring resistance to tamoxifen, showing that both pathways contributed to SIPL1-derived resistance to tamoxifen in ER+ BCs. Using the Curtis dataset of breast cancer (n=1980) within the cBioPortal database, we examined a correlation of SIPL1 expression with ER+ BC and resistance to hormone therapy. SIPL1 upregulation strongly associates with reductions in overall survival in BC patients, particularly in patients with hormone naïve ER+ BCs. Taken together, we provide data suggesting that SIPL1 contributes to promote resistance to tamoxifen in BC cells through both AKT and NF-κB actions.

Intratumoural leukocyte infiltration is a prognostic indicator among pancreatic cancer patients with type 2 diabetes

BackgroundThe life expectancy of pancreatic cancer patients remains minimal. The disease progression may be influenced by type 2 diabetes (T2D) and inflammatory status, although important gaps persist around their joint effects on disease outcome. The aim of this study was to investigate the clinical significance of the tumour immune microenvironment on pancreatic cancer prognosis in relation to T2D status. MethodTumour-infiltrating macrophages, neutrophils and eosinophils were studied in primary pancreatic tumours and paired lymph node metastases in relation to patient and tumour characteristics, T2D status and overall survival in a retrospective cohort of patients with resectable pancreatic cancer in Sweden. ResultsOf the 80 included pancreatic cancer patients, 22 (27.2%) had T2D. The diabetic pancreatic cancer patients had significantly higher systemic high white blood cell count than those without diabetes (P = 0.028). Macrophage infiltration levels were higher in lymph node metastases compared with primary tumours (P = 0.040) among pancreatic cancer patients with diabetes. Type 2 diabetes or intra-tumoural leukocyte (macrophage, neutrophil or eosinophil) infiltration alone did not significantly influence pancreatic cancer prognosis. However, among cancer patients with T2D high macrophage or neutrophil tumour-infiltration was associated with a significant reduction in overall survival (adjusted hazard ratio [HR] 7.2; 95% CI 1.5–35.0 and HR 5.4; 95% CI 1.1–26.3, respectively). ConclusionThese results demonstrate associations between T2D and enhanced inflammatory processes with significant implications on survival among pancreatic cancer patients with T2D. Validation in larger independent patient cohorts may identify additional prognostic tools and improved treatment strategies for specific patient subsets.

Development of an Algorithm to Distinguish Smoldering Versus Symptomatic Multiple Myeloma in Claims-Based Data Sets.

The distinction of patients with symptomatic multiple myeloma (MM) from those with smoldering MM poses a challenge for researchers who use administrative databases. Historically, researchers either have included all patients or used treatment receipt as the distinguishing factor; both methods have drawbacks. We present an algorithm for distinguishing between symptomatic and smoldering MM using ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes for the classic defining events of symptomatic MM commonly referred to as the CRAB criteria (hypercalcemia, renal impairment, anemia, and bone lesions). SEER-Medicare-linked data from 4,187 patients with MM diagnosed between 2007 and 2011 were used for this analysis. Eighty-four percent had ICD-9-CM codes consistent with CRAB criteria, whereas only 57% received treatment. Overall survival of patients with symptomatic MM defined as receipt of treatment was 32.3 months versus 26.6 months for the overall population and 22.9 months for patients with symptomatic MM defined by CRAB criteria. Conceptually, removal of patients with smoldering MM should result in a reduction in overall survival; however, the cohort of patients who received treatment tended to be younger and healthier than the overall population, which could have skewed the results. The algorithm we present resulted in a larger and more representative sample than classification by treatment status and reduced potential bias that could result from including all patients with smoldering MM in the analysis. Although this study was performed using the SEER-Medicare database, the methodology was broad enough that the algorithm could be extended to additional claims-based data sets with relative ease.

Overexpression of MUC1 and Genomic Alterations in Its Network Associate with Prostate Cancer Progression

We investigate the association of MUC1 with castration-resistant prostate cancer (CRPC), bone metastasis, and PC recurrence. MUC1 expression was studied in patient-derived bone metastasis and CRPCs produced by prostate-specific PTEN−/− mice and LNCaP xenografts. Elevations in MUC1 expression occur in CRPC. Among nine patients with hormone-naïve bone metastasis, eight express MUC1 in 61% to 100% of PC cells. Utilizing cBioPortal PC genomic data, we organized a training (n=300), testing (n=185), and validation (n=194) cohort. Using the Cox model, a nine-gene signature was derived, including eight genes from a MUC1-related network (APC, CTNNB1/β-catenin, GALNT10, GRB2, LYN, SIGLEC1, SOS1, and ZAP70) and FAM84B. Genomic alterations in these genes reduce disease-free survival (DFS) in the training (P=.00161), testing (P=.00699), entire (training+testing, P=5.557e-5), and a validation cohort (P=3.326e-5). The signature independently predicts PC recurrence [hazard ratio (HR)=1.731; 95% confidence interval (CI): 1.104-2.712; P=.0167] after adjusting for known clinical factors and stratifies patients with high risk of PC recurrence using the median (HR 2.072; 95% CI: 1.245-3.450, P=.0051) and quartile 3 (HR 3.707, 95% CI: 1.949-7.052, P=6.51e-5) scores. Several novel β-catenin mutants are identified in PCs leading to a rapid onset of death and recurrence. Genomic alterations in APC and CTNNB1/β-catenin reduce DFS in two independent PC cohorts (n=485, P=.0369; n=84, P=.0437). The nine-gene signature also associates with reductions in overall survival (P=.0458) and DFS (P=.0163) in melanoma patients (n=367). MUC1 upregulation is associated with CRPC and bone metastasis. A nine-gene signature derived from a MUC1 network predicts PC recurrence.

Signatures derived from increase in SHARPIN gene copy number are associated with poor prognosis in patients with breast cancer

We report three signatures produced from SHARPIN gene copy number increase (GCN-Increase) and their effects on patients with breast cancer (BC). In the Metabric dataset (n=2059, cBioPortal), SHARPIN GCN-Increase occurs preferentially or mutual exclusively with mutations in TP53, PIK3CA, and CDH1. These genomic alterations constitute a signature (SigMut) that significantly correlates with reductions in overall survival (OS) in BC patients (n=1980; p=1.081e−6). Additionally, SHARPIN GCN-Increase is associated with 4220 differentially expressed genes (DEGs). These DEGs are enriched in activation of the pathways regulating cell cycle progression, RNA transport, ribosome biosynthesis, DNA replication, and in downregulation of the pathways related to extracellular matrix. These DEGs are thus likely to facilitate the proliferation and metastasis of BC cells. Additionally, through forward (FWD) and backward (BWD) stepwise variate selections among the top 160 downregulated and top 200 upregulated DEGs using the Cox regression model, a 6-gene (SigFWD) and a 50-gene (SigBWD) signature were derived. Both signatures robustly associate with decreases in OS in BC patients within the Curtis (n=1980; p=6.16e−11 for SigFWD; p=1.06e−10, for SigBWD) and TCGA cohort (n=817; p=4.53e−4 for SigFWD and p=0.00525 for SigBWD). After adjusting for known clinical factors, SigMut (HR 1.21, p=0.0297), SigBWD (HR 1.25, p=0.0263), and likely SigFWD (HR 1.17, p=0.062) remain independent risk factors of BC deaths. Furthermore, the proportion of patients positive for these signatures is significantly increased in ER−, Her2-enriched, basal-like, and claudin-low BCs compared to ER+ and luminal BCs. Collectively, these SHARPIN GCN-Increase-derived signatures may have clinical applications in management of patients with BC.

Carcinoma escamocelular cutáneo del tronco y las extremidades: utilidad del ganglio centinela en su estadificación

Squamous Cell Carcinoma (SCC) is associated with a more aggressive biological behaviour in the presence of risk factors. High risk SCC may present with lymph node metastasis in 21% of patients, with the consequent reduction in overall survival. The physical examination lymph nodes can have a false-negative rate between 15% and 39%, thus requiring the need to find a new diagnostic tool that allows a more precise evaluation of lymph node involvement. Sentinel lymph node biopsy has been reported in case series of patients with head and neck SCC, and genital SCC, but there are few case reports about skin SCC of the trunk and extremities. The aim of this review is to describe the indications and feasibility of using sentinel lymph node biopsy to assess lymph node status in patients with skin SCC of trunk and limbs.

Adipocyte Secretome Increases Radioresistance of Malignant Melanocytes by Improving Cell Survival and Decreasing Oxidative Status.

Radiotherapy is a treatment option for the majority of malignancies. However, because melanoma is known to be radioresistant, the use of ionizing radiation as an adjuvant therapy in cutaneous melanoma patients is ineffective. Obesity has now been recognized as a risk factor for melanoma. High adiposity is generally associated with a more pro-oxidative status. Oxidative stress is a major player in radiation therapy and also a common link between obesity and cancer. Several adipocyte-released proteins are known to have a role in controlling cellular growth and pro-survival signaling. For that reason, we investigated the influence of 3T3-L1 mature adipocyte secretome in B16-F10 malignant melanocyte radiosensitivity. We evaluated B16-F10 cell survival and redox homeostasis when exposed to four daily doses of ionizing radiation (2 Gy per day) up to a total of 8 Gy in a medical linear accelerator. B16-F10 melanocytes exhibited slight alterations in survival, catalase activity, nitrative stress and total oxidant concentration after the first 2 Gy irradiation. The motility of the melanocytes was also delayed by ionizing radiation. Subsequent irradiations of the malignant melanocytes led to more prominent reductions in overall survival. Remarkably, 3T3-L1 adipocyte-secreted molecules were able to increase the viability and migration of melanocytes, as well as lessen the pro-oxidant burden induced by both the single and cumulative X-ray doses. In vitro adipocyte-released factors protected B16-F10 malignant melanocytes from both oxidative stress and loss of viability triggered by radiation, enhancing the radioresistant phenotype of these cells with a concomitant activation of the AKT signaling pathway. These results both help to elucidate how obesity influences melanoma radioresistance and support the usage of conventional medical linear accelerators as a valid model for the in vitro radiobiological study of tumor cell lines.

Long Term Outcomes in Monoclonal Gammopathy of Renal Significance (MGRS)

Abstract Background: MGRS is a heterogeneous group of pathologic renal conditions attributed to a clonal plasma cell disorder, without classical features of myeloma. However, there is a need to distinguish MGRS from MGUS and unrelated renal abnormality as the clonal protein in MGRS plays a direct role in kidney damage and requires treatment of the underlying clone. Outcomes in patients with diagnosis of cast nephropathy and renal amyloidosis have been previously reported. But long-term outcomes of MGRS patients with other renal histologies remain unclear. Also data on whether the level of tumour burden in the marrow and type of treatment for MGRS influence long-term outcomes is lacking. This analysis was conducted to study long term outcomes in renal biopsy proven (non cast nephropathy & AL Amyloid) MGRS patients. Aims: This multi-centre retrospective study was set up to analyse clinical outcomes in renal biopsy proven MGRS patients. Long-term haematological and renal outcomes were analysed. Correlation between tumour burden, type of treatment applied and level of response obtained was also analysed. Methods: Thirty-seven MGRS patients were retrospectively audited across 3 centres in the United Kingdom and 1 centre in the Republic of Ireland between 2004 and 2016. Patients were eligible for inclusion if they had a confirmed diagnosis of MGRS by renal biopsy. Patients with cast nephropathy and renal AL Amyloidosis were excluded. Renal survival was defined as the time until renal replacement therapy was required or failure to come off the renal replacement therapy commenced at diagnosis. Overall survival (OS) was calculated from the time of MGRS diagnosis until death from any cause. Results: Median age at diagnosis was 68 years and median follow-up was 33.5 months (range, 0.7-141.7 months). There were 29 male patients and 8 female patients. 20/25 patients had hypertension at the time of diagnosis (records unavailable for 12 patients). Majority of patients were kappa light chain restricted 85% vs 15% lambda LC restricted. Renal histology showed: 65% Light Chain Deposition Disease, 8% Mixed Heavy and Light Chain Deposition Disease, 1 % Proliferative Glomerulonephritis with monoclonal IgG, 11% Light Chain Tubulopathy, 6% Cryoglobulunemia, 3% Immunotactoid Glomerulonephritis. Renal survival for the whole cohort was 74% and overall survival was 84%. At the time of renal biopsy, 43% of patients had >10% plasma cells versus 46% of patients with 10% plasma cells versus 70 % in 10% plasma cells, not statistically significant (P = 0.14). Chemotherapy treatment was administered in 24 patients (65%) for their MGRS versus 13 patients (35%) who had no treatment for their PC clone. Of the 24 patients who had treatment: 20 had Bortezomib-based therapy (VEL), 6 had Thalidomide-based therapy, 4 had Lenalidomide and 4 had stem cell transplant. Patients who received VEL treatment for PC clone had a renal survival of 84 % versus 63% in patients who did not have VEL treatment (P = 0.45). OS in patients who received VEL was 95 % versus 72 % in patients who did not receive VEL treatment (P= 0.1). Good haematological response (≥VGPR) in 11/37 patients achieved and renal survival in these patients was significantly better at 90 % versus 61 % in patients who had Conclusion: We report long-term outcomes in a large cohort of MGRS patients: 74% renal survival and 84% overall survival at a median of 33 months follow up. For the first time, we show treatment for the PC clone shows better outcomes; with patients treated with VEL therapy significantly improved renal survival. Patients with higher tumour burden have a non-significant reduction in overall survival. Overall, the results of this study show better OS in MGRS patients when compared with outcomes previously reported in cast nephropathy and renal AL amyloid. Download : Download high-res image (110KB) Download : Download full-size image Disclosures Ramasamy: Celgene: Honoraria, Research Funding.

Long Term Outcomes in Monoclonal Gammopathy of Renal Significance (MGRS)

Background: MGRS is a heterogeneous group of pathologic renal conditions attributed to a clonal plasma cell disorder, without classical features of myeloma. However, there is a need to distinguish MGRS from MGUS and unrelated renal abnormality as the clonal protein in MGRS plays a direct role in kidney damage and requires treatment of the underlying clone. Outcomes in patients with diagnosis of cast nephropathy and renal amyloidosis have been previously reported. But long-term outcomes of MGRS patients with other renal histologies remain unclear. Also data on whether the level of tumour burden in the marrow and type of treatment for MGRS influence long-term outcomes is lacking. This analysis was conducted to study long term outcomes in renal biopsy proven (non cast nephropathy & AL Amyloid) MGRS patients.Aims: This multi-centre retrospective study was set up to analyse clinical outcomes in renal biopsy proven MGRS patients. Long-term haematological and renal outcomes were analysed. Correlation between tumour burden, type of treatment applied and level of response obtained was also analysed.Methods: Thirty-seven MGRS patients were retrospectively audited across 3 centres in the United Kingdom and 1 centre in the Republic of Ireland between 2004 and 2016. Patients were eligible for inclusion if they had a confirmed diagnosis of MGRS by renal biopsy. Patients with cast nephropathy and renal AL Amyloidosis were excluded. Renal survival was defined as the time until renal replacement therapy was required or failure to come off the renal replacement therapy commenced at diagnosis. Overall survival (OS) was calculated from the time of MGRS diagnosis until death from any cause.Results: Median age at diagnosis was 68 years and median follow-up was 33.5 months (range, 0.7-141.7 months). There were 29 male patients and 8 female patients. 20/25 patients had hypertension at the time of diagnosis (records unavailable for 12 patients). Majority of patients were kappa light chain restricted 85% vs 15% lambda LC restricted. Renal histology showed: 65% Light Chain Deposition Disease, 8% Mixed Heavy and Light Chain Deposition Disease, 1 % Proliferative Glomerulonephritis with monoclonal IgG, 11% Light Chain Tubulopathy, 6% Cryoglobulunemia, 3% Immunotactoid Glomerulonephritis. Renal survival for the whole cohort was 74% and overall survival was 84%. At the time of renal biopsy, 43% of patients had >10% plasma cells versus 46% of patients with <10% plasma cells. Renal survival was comparable between these cohorts with 74% renal survival in patients with >10% plasma cells versus 70 % in <10% plasma cells (P = 0.87). OS was better in patients with <10% plasma cells 94 % versus 75% in patients with >10% plasma cells, not statistically significant (P = 0.14).Chemotherapy treatment was administered in 24 patients (65%) for their MGRS versus 13 patients (35%) who had no treatment for their PC clone. Of the 24 patients who had treatment: 20 had Bortezomib-based therapy (VEL), 6 had Thalidomide-based therapy, 4 had Lenalidomide and 4 had stem cell transplant. Patients who received VEL treatment for PC clone had a renal survival of 84 % versus 63% in patients who did not have VEL treatment (P = 0.45). OS in patients who received VEL was 95 % versus 72 % in patients who did not receive VEL treatment (P= 0.1). Good haematological response (≥VGPR) in 11/37 patients achieved and renal survival in these patients was significantly better at 90 % versus 61 % in patients who had <VGPR (P = 0.05) Figure 1. ). OS was also improved at 91 % versus 82 % in patients who had <VGPR (P = 0.53). Two out of four patients were able to come off renal replacement therapy after being treated with Bortezomib and achieving a complete haematological response.Conclusion: We report long-term outcomes in a large cohort of MGRS patients: 74% renal survival and 84% overall survival at a median of 33 months follow up. For the first time, we show treatment for the PC clone shows better outcomes; with patients treated with VEL therapy significantly improved renal survival. Patients with higher tumour burden have a non-significant reduction in overall survival. Overall, the results of this study show better OS in MGRS patients when compared with outcomes previously reported in cast nephropathy and renal AL amyloid. [Display omitted] DisclosuresRamasamy:Celgene: Honoraria, Research Funding.

Impact of Human Leukocyte Antigen Allele Mismatch in Unrelated Bone Marrow Transplantation with Reduced-Intensity Conditioning Regimen

The impact of HLA mismatch in hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) has not been fully examined. We analyzed a total of 1130 cases to examine the effects of HLA allele mismatch in unrelated bone marrow transplantation (BMT) with RIC in the Japan Marrow Donor Program registry cohort. Compared with HLA 8/8–allele match (n = 720, 8/8 match), both 1 (n = 295, 7/8 match) and 2 allele mismatches (n = 115, 6/8 match) were associated with significant reduction of overall survival (OS) (hazard ratio [HR], 1.34; P = .0024 and HR, 1.33; P = .035 for 7/8 and 6/8 match, respectively). The incidence of grades 2 to 4 acute graft-versus-host disease (aGVHD) increased with increasing number of mismatched alleles (HR, 1.36 and HR, 2.08 for 7/8 and 6/8 match, respectively). Nonrelapse mortality showed a similar tendency to aGVHD (HR, 1.35 for 7/8 and HR, 1.63 for 6/8). One-allele mismatches at the HLA-A or -B and HLA-C loci were significantly associated with inferior OS compared with 8/8 match (HR, 1.64 for A or B mismatch and HR, 1.41 for C mismatch), whereas HLA-DRB1 allele mismatch was not (HR, 1.16; P = .30). However, the effect of HLA-A or -B and -C mismatch on OS was not observed in those who received RIC BMT since 2010, in contrast to recipients before 2010. These results suggested that in unrelated RIC BMT, 1-allele mismatch is associated with poorer outcome, and the impact of HLA mismatch may differ depending on the HLA locus, although these HLA mismatch effects may be different in recent cases.

Mechanisms through which diabetes mellitus influences renal cell carcinoma development and treatment: A review of the literature.

Renal cell carcinoma(RCC) comprises 2‑3%of all malignant tumors in adults. Many studies have established the key roles of smoking, hypertension and other components of metabolic syndrome in the occurrence of RCC. Diabetes mellitus(DM), one of the main consequences of metabolic syndrome, appears much more often in patients with RCC. The prognosis for patients suffering from both diabetes and RCC is worse than for those with kidney cancer only. Diabetes is linked to higher rate of recurrence and a greater number of distant metastases. These factors contribute to a reduction in overall survival(OS) and cause‑specific survival(CSS). Diabetes can also occur as a paraneoplastic syndrome. Tyrosine kinase inhibitors(TKIs), which are agents used in the therapy of metastatic RCC, may have unexpected effects when administered to patients with diabetes. Studies and case reports have shown that they influence blood glucose levels(BGLs) in diabetic patients, sometimes causing dangerous episodes of hypoglycemia. Hyperinsulinemia and hyperglycemia can be considered independent carcinogenic factors, as they increase the amount of pro‑inflammatory cytokines, reactive oxygen species and lipid peroxidation. TKIs have yet to be re‑evaluated as to their safety of use in patients with diabetes.

Physical activity and survival in breast cancer

PurposeKnowledge about lifestyle factors possibly influencing survival after breast cancer (BC) is paramount. We examined associations between two types of postdiagnosis physical activity (PA) and overall survival after BC. Patients and methodsWe used prospective data on 959 BC survivors from the Diet, Cancer, and Health cohort, all enrolled before diagnosis. Self-reported PA was measured as time per activity, and estimated metabolic equivalent task (MET)–hours per week were summed for each activity. We constructed measures for household, exercise, and total PA. The association between postdiagnosis PA and all-cause mortality was estimated as hazard ratio (HRs) based on Cox proportional hazards model, with time since diagnosis as the underlying time scale. Prediagnosis PA, body mass index (BMI), and receptor status were examined as potential effect modifiers. ResultsWe identified 144 deaths from all causes during the study period. In adjusted analyses, exercise PA above eight MET h/week compared to lower levels of activity was significantly associated with improved overall survival (HR, 0.68; confidence interval [CI]: 0.47–0.99). When comparing participation in exercise to non-participation, we found a 44% risk reduction in overall survival (HR, 0.56; CI: 0.33–0.95). Neither between household nor total PA and overall survival did, we find significant associations. Prediagnosis PA, BMI, and receptor status did not modify the effect significantly. ConclusionExercise PA corresponding to 2.5 h or more of brisk weekly walking after BC diagnosis may reduce mortality by up to 32% compared to low-level exercise. Participation in exercise PA may reduce mortality by 44% compared to non-participation.

Insufficient Lymph Node Sampling in Patients with Colorectal Cancer Perforation is Associated with an Adverse Oncological Outcome.

The impact of lymph node (LN) dissection on long-term outcomes for patients with colorectal cancer (CRC) perforation remains unclear. We aim to investigate factors associated with poor prognosis and recurrence in patients with CRC, with special reference to cancer perforation and LN dissection. The subjects comprised 550 patients who underwent colorectal surgery for CRC at Stage II or III (TNM classification) between February 2006 and November 2013. Short- and long-term outcomes of patients with or without CRC perforation were evaluated. We also sought risk factors on poor prognosis, focusing on LN dissection in patients with CRC perforation. A total of 508 underwent surgery for CRC without perforation (the non-perforation group) and 39 for CRC with perforation (the perforation group). Both overall survival and recurrence-free survival rates were significantly lower in the perforation group than in the non-perforation group (overall survival, P=0.009; recurrence-free survival, P<0.001). The relapse rates at the peritoneum (P=0.002), lung (P=0.007) and LNs (P=0.021) were significantly higher in the perforation group than in the non-perforation group. Multivariable Cox proportional hazards model revealed that CRC perforation (hazard ratio [HR] 2.55, 95% confidential interval [CI] 1.16-4.98, P=0.022), LN dissection <12 (HR 1.83, 95% CI 1.07-3.13, P=0.027), and Stage III (HR 1.79, 95% CI 1.06-3.08, P=0.031) were significant and independent risk factors for poor prognosis. Conducting <12 LN dissections independently increased the risk of reduction in overall survival for patients with CRC perforation. Thus, radical LN dissections should be performed to improve patients' survival rates, when patients' general and surgical conditions allow.

MP73-18 EXTERNAL VALIDATION OF PREOPERATIVE AST/ALT (DE-RITIS) RATIO AS A PROGNOSTIC INDICATOR IN LOCALIZED AND METASTATIC RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging I1 Apr 2016MP73-18 EXTERNAL VALIDATION OF PREOPERATIVE AST/ALT (DE-RITIS) RATIO AS A PROGNOSTIC INDICATOR IN LOCALIZED AND METASTATIC RENAL CELL CARCINOMA Dattatraya Patil, Rishi Sekar, Jeff Pearl, Yoram baum, Kathryn Wehrmeyer, Mersiha Torlak, Mehrdad Alemozaffar, Christopher Filson, Kenneth Ogan, and Viraj Master Dattatraya PatilDattatraya Patil More articles by this author , Rishi SekarRishi Sekar More articles by this author , Jeff PearlJeff Pearl More articles by this author , Yoram baumYoram baum More articles by this author , Kathryn WehrmeyerKathryn Wehrmeyer More articles by this author , Mersiha TorlakMersiha Torlak More articles by this author , Mehrdad AlemozaffarMehrdad Alemozaffar More articles by this author , Christopher FilsonChristopher Filson More articles by this author , Kenneth OganKenneth Ogan More articles by this author , and Viraj MasterViraj Master More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1673AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES A recent European cohort study showed the De-Ritis ratio, defined as the ratio of preoperative aspartate aminotransferase (AST) to alanine aminotransferase (ALT), as an independent predictor of overall and recurrence-free survival in localized renal cell carcinoma (RCC). In this study, we perform an external validation of the De-Ritis ratio as a prognostic indicator in a distinct cohort of patients with localized as well as metastatic RCC. METHODS Patients that underwent nephrectomy for localized and metastatic RCC between 2001 and 2014 with available laboratory values within one week prior to the surgery were queried from the Emory Nephrectomy Database. After sensitivity-specificity trade-off analysis, De-Ritis ratio of 1.2 was used as an optimal threshold to divide subjects into high and low subgroups. Prognostic value of the De-Ritis ratio was used for further analysis with Kaplan-Meier and Cox proportional survival regression models. RESULTS In a cohort of 451 patients, an elevated DeRitis ratio (AST/ALT≥1.2) was associated with statistically significant reduction in overall survival (log-rank, p=0.0023) and recurrence-free survival (log-rank, p=0.0395). On multivariate survival analysis, De-Ritis ratio was shown to be an independent and significant predictor of overall survival (HR=1.91, p=0.002) and recurrence-free survival (HR=2.13, p=0.014) as seen in Table 1. CONCLUSIONS Elevated De-Ritis ratio (AST/ALT≥1.2) is an independent and significant predictor of overall and recurrence-free survival and is capable of differentiating high-risk disease in patients with localized as well as metastatic RCC. These findings are consistent with a previous study investigating the De-Ritis ratio in a European cohort, and further validates its prognostic ability in a geographically distinct cohort including patients who presented with metastatic disease. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e967 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Dattatraya Patil More articles by this author Rishi Sekar More articles by this author Jeff Pearl More articles by this author Yoram baum More articles by this author Kathryn Wehrmeyer More articles by this author Mersiha Torlak More articles by this author Mehrdad Alemozaffar More articles by this author Christopher Filson More articles by this author Kenneth Ogan More articles by this author Viraj Master More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Monoclonal B-cell lymphocytosis: from literature to laboratory practice

Monoclonal B-cell lymphocytosis (MBL) is defined as an asymptomatic condition characterized by the presence of less than 5,000 monoclonal B-cells per microliter and the absence of clinical signs or symptoms of a B-cell lymphoproliferative disorder. Most MBL cases involve B cells presenting an identical phenotype to CLL (CLL-like MBL) with a Catovsky-Matutes score of 3 to 5 and share the same chromosomal abnormalities than CLL. Depending on the absolute B cell count, one may distinguish low-count CLL-like MBL (<500 B cells/μL) which have no evidence of progression, no reduction in overall survival, no increase in infection risk and do not require any specific follow-up. Patients with clinical CLL-like MBL (>500 B cells/μL) have a 1% to 2% per year risk of progression to CLL requiring therapy, a higher risk of infectious complications and mortality implicating an annual follow-up by hematologist. MBL may also express other less common phenotypes and are named atypical MBL in case of CD5 antigen expression (Catovsky-Matutes score: 1-2) and non-CLL-like MBL for CD5 negative cases (Catovsky-Matutes score: 0-2). Their poorer prognosis implicates imaging studies, bone marrow biopsy and cytogenetic analysis in addition to physical examination in order to rule out non-hodgkinien lymphoma, and require a more frequent follow-up. This review focuses on key concepts in the classification, diagnosis, monitoring and biology of MBL in laboratory practice.

Abstract B69: Notch3 signal activation promotes peritoneal metastasis in a mouse model of epithelial ovarian cancer.

Abstract This study examines the effect of Notch3 signal activation on ovarian cancer peritoneal metastasis to elucidate the mechanisms of ovarian cancer progression. TCGA assessment of high-grade serous ovarian cancers determined the Notch3 signaling pathway has been altered in 22% of cancers. NOTCH3 was observed as upregulated in ovarian cancer by copy number analysis via multiple independent groups, and upregulation is linked to epithelial to mesenchymal cell transition in ovarian cancer cells. Patients with NOTCH3 overexpressing tumors exhibit worse prognosis, decreased survival, and correlation with chemotherapy resistance. To determine how Notch3 signaling promotes ovarian cancer, we constitutively activated signaling in ID8 IP2, a mouse ovarian surface epithelial line with low Notch3 expression. ID8 IP2 was modified via lentiviral infection to express luciferase for in vivo assessment (ID8 IP2-luc). Notch3 signaling was activated using lentivurs generated with a pCCL plasmid containing the Notch3 receptor intracellular domain (N3IC) to create ID8 IP2-luc N3IC. A control line was made with pCCL containing only the multiple cloning site (MCS). Induction of N3IC expression and signal activation were confirmed by a dual luciferase reporter assay, western blot analysis of N3IC, and quantitative RT-PCR for N3IC and downstream HEY family targets. We assessed Notch3 activation in vitro to evaluate growth and metastatic properties of the cells, and in athymic mice to examine intraperitoneal metastasis. ID8 IP2-luc N3IC and MCS were observed as morphologically similar in culture. No significant difference was detected in anchorage independent growth in a soft agar colony formation assay. Proliferation rate was 30% reduced in the ID8 IP2-luc N3IC compared to MCS. This finding was unanticipated given previous reports that proliferation in a serous line was dependent on Notch3, and Notch3 inhibition induced apoptosis. Notch3 activation did increase migratory capacity of ID8 IP2-luc N3IC compared to MCS. In a monolayer wounding assay, N3IC increased migration significantly at 3, 6, and 9 hours post wounding. In preliminary experiments, ID8 IP2-luc N3IC displayed significantly increased invasion in gelatin and Matrigel transwell migration assays. In vivo, preliminary results indicate Notch3 signal activation leads to acceleration of ascites accumulation, and a significant reduction in overall survival. Ascites derived from mice with Notch3 activated tumors qualitatively had higher blood content indicating tumor vasculature alteration. Based on both in vitro and in vivo results, RNA-seq analysis comparing ID8 IP2-luc N3IC and MCS was performed to identify transcriptional targets to better define the role of Notch3 signaling in ovarian cancer. Data with an adjusted p value of &amp;lt;0.05 and a minimum of log 2 fold change, were analyzed in pathway analysis through the Database for Annotation, Visualization &amp; Integrated Discovery functional annotation tool. The most upregulated pathways in addition to Notch signaling involved extracellular matrix receptor interaction, tissue remodeling, and extracellular structure and matrix organization genes. The most down-regulated were cell adhesion and regulation of actin cytoskeleton genes. A significant change in cell adhesion and extracellular matrix genes is consistent with results indicating Notch3 activation induces change in cell migration, seeding, and invasion. We conclude Notch3 signal activation in ID8 IP2-luc promotes ascites accumulation and metastasis in the peritoneum, and decreases overall survival in mice. The growth properties of ID8 IP2-luc cells were not altered with Notch3 activation in vitro, however migration and invasion were significantly induced. We propose Notch3 activation promotes increased metastasis by influencing interaction between ovarian cancer and the host environment. We conclude Notch3 activation leads to increased migration, seeding, and invasion into the peritoneum. Citation Format: Jessica Price, Elham Azizi, Nathaniel Jones, Jan Kitajewski. Notch3 signal activation promotes peritoneal metastasis in a mouse model of epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B69.

Evaluation of the impact of treatment delays and dose reductions in human ovarian cancer orthotopic mouse models

The primary objective of this study was to quantify the impact of treatment delay and dose reductions in an in vivo orthotopic ovarian cancer model. In addition, this study evaluated the role of growth factors in achieving “full dose on time”. HeyA-8 and SKOV3.ip1ovarian cancer orthotopic mouse models were used determine the effect of paclitaxel/carboplatin treatment delays or dose reductions on tumor response and overall survival. The addition of growth factor support with pegfilgrastim and darbepoetin was also evaluated in treatment control arm. The results indicated that full dose of paclitaxel (20 mg/kg) and carboplatin (50 mg/kg) delivered on time (every 21 days) achieved better tumor response in both aggressive (HeyA-8) and metastatic (SKOV3.ip1) human ovarian tumors compared to treatment delay or dose reduction arms. In the HeyA-8 orthotopic model treatment delay (P<0.05) resulted in a significant reduction in overall survival compared to on time, full dose treatment control arm and the dose reduction decreased overall survival but was not statistically significant. However, in the SKOV3.ip1orthotopic model a treatment delay (P<0.01) or dose reduction (P<0.05) both resulted in a significant reduction in overall survival compared to on time, full dose treatment control arm. In both orthotopic models, the addition of pegfilgrastim (1000 µg/kg) and darbepoetin (10 µg/kg) delayed the onset of ascites formation and was associated with an improved overall survival rate. Treatment delays and dose reductions had a negative impact on tumor response and overall survival compare with on-time, full dose treatment controls. In addition, use of growth factor agents improved overall survival and tumor responses.

ATM Mutations in Major Stereotyped CLL Subsets: Enrichment in Subset #2 is Associated with Unfavourable Outcome

Chronic lymphocytic leukemia (CLL) is a paradigmatic malignancy where the interplay of cell-extrinsic and cell-intrinsic factors has a major impact on disease evolution. Indeed, extrinsic triggering, e.g. antigenic stimulation through the B-cell receptor (BcR), together with intrinsic aberrations, e.g. accumulation of genetic defects, play a major role throughout the natural history of CLL. The importance of antigen involvement is underscored by the existence of 'stereotyped' BcR in up to 30% of CLL patients. Notably, CLL patients with stereotyped BcR can be grouped into different subsets, each with a subset-biased biological and clinical profile. For instance, while the clinically aggressive subset #2 (IGHV3-21/IGLV3-21, comprising both mutated (M-CLL) and unmutated (U-CLL) IGHV genes) displays a remarkably high frequency of SF3B1 mutations, subset #8, a subset with the highest risk of Richter transformation, shows a strong association with trisomy 12 and NOTCH1 mutations. ATM defects are implicated in the evolution of CLL and are associated with a dismal prognosis, however the extent to which they contribute to the genetic landscape in stereotyped subsets remains unexplored.To gain insight into this issue, we assessed the frequency of ATM mutations in 249 well-characterized CLL patients assigned to major subsets #1-8. The entire coding region of ATM (62 exons) was investigated with two different targeted deep-sequencing approaches, i.e. Haloplex technology (HiSeq, coverage ~1500X) or the Nextera XT kit (MiSeq, coverage ~4000X). A conservative variant allele frequency cut-off of 10% was selected, and mutations were validated by Sanger sequencing.Altogether, we identified 61 ATM mutations in 47/249 (19%) patients across all major subsets (Fig. 1). As expected, the majority of identified ATM mutations (n=43, 70%) have not yet been reported while the remaining 30% were listed in the HGMD or COSMIC mutation databases. The spectrum of ATM mutations included missense (n=31), nonsense (n=9), splicing (n=6), and frame-shift (n=14) mutations, and one in-frame deletion. Missense substitutions were distributed along the entire gene without any 'hotspot' region or preferred domain. The highest mutation frequency was detected in subset #2 (26%), with a significant enrichment in U-CLL vs. M-CLL cases, (13/33 vs. 8/48 subset #2 cases, respectively; p=0.021). Within poor-prognostic U-CLL subsets, ATM mutations were also frequent in subsets #6 (25%) and #7 (23%), while subsets #3, #5, #1, and #8 showed lower frequencies (17%, 17%, 13%, and 7%, respectively). The favorable prognostic M-CLL subset #4 exhibited a low frequency (7%) of ATM mutations. Notably, when comparing the two most populated subsets, i.e. #1 and #2, ATM mutations were overrepresented in the latter with a borderline significance value (p=0.086); when restricting the analysis to U-CLL #2 cases a significantly higher frequency was observed compared to #1 (13/33 vs 9/68; p=0.0045).Regarding the clinical impact of ATM defects in subset #2, we divided patients into subgroups with biallelic inactivation (def-ATM), sole 11q-, sole ATM -mutation, TP53 -aberrations and WT. While both groups with mono-allelic ATM disruption showed a significantly reduced overall survival compared to WT (median survival sole ATM -mutation, 71 months, sole 11q-, 40 months, vs. 123 months in the WT group; p=0.002 and 0.02, respectively), a non-significant reduction of overall survival was observed for patients with bi-allelic ATM aberrations (70 months, p=0.29) (Fig. 2). The few subset #2 patients with TP53 defects showed a similar survival as WT group, underscoring previous observations that TP53 dysfunction per se plays a minor role in this subset.In summary, we demonstrate that ATM mutations can be added to the list of genetic defects with a biased distribution in stereotyped subsets. The enrichment of ATM defects in subset #2 was associated with a negative impact on overall survival, suggesting a role for ATM inactivation in shaping the aggressive phenotype of this subset. This study further supports the recent suggestion that CLL development is driven by antigenic selection, coupled with preferential acquisition of specific genetic defects. The work was supported by the projects MSMT CR CZ.1.05/1.1.00/02.0068, IGA NT13493-4/2012 and TACR TE02000058. [Display omitted] [Display omitted] DisclosuresLangerak:Roche: Other: Lab services in the field of MRD diagnostics provided by Dept of Immunology, Erasmus MC (Rotterdam); DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics. . Strefford:Roche: Research Funding. Stamatopoulos:Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Research Funding.