Survival In High-risk Patients Research Articles

Identification of a five B cell-associated gene prognostic and predictive signature for advanced glioma patients harboring immunosuppressive subtype preference.

High grade gliomas contribute to most brain tumor mortality. A few studies reported that the immune system affected glioma development, and immune biomarkers helped understand the disease and formulate effective immunotherapy for patients. Currently, no B lymphocyte-based prognostic signature was reported in gliomas. By applying 78 B cell lineage-specific genes, we conducted a whole-genome gene expression analysis in 782 high grade gliomas derived from three independent datasets by Cox regression analysis and risk score method for signature identification, and then used Gene Ontology, Gene Set Enrichment Analysis, and other statistical methods for functional annotations of the signature-defined differences. We developed a five B cell-associated gene signature for prognosis of high grade glioma patients, which is independent of clinicopathological and genetic features. The signature identified high risk patients suitable for chemoradiotherapy, whereas low risk patients should rule out chemotherapy with radiotherapy only. We found that tumors of TCGA Mesenchymal subtype and wild type IDH1 were preferentially stratified to the high risk group, which bore strong immunosuppressive microenvironment, while tumors of TCGA Proneural subtype and mutated IDH1 were significantly accumulated to the low risk group, which exhibited less immunosuppressive state. The five B cell-associated gene signature predicts poor survival of high risk patients bearing strong immunosuppression and helps select optimal therapeutic regimens for glioma patients.

Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade

ABSTRACTRemoval of immuno-suppression has been reported to enhance antitumor immunity primed by checkpoint inhibitors. Although PD-1 blockade failed to control tumor growth in a transgenic murine neuroblastoma model, concurrent inhibition of colony stimulating factor 1 receptor (CSF-1R) by BLZ945 reprogrammed suppressive myeloid cells and significantly enhanced therapeutic effects. Microarray analysis of tumor tissues identified a significant increase of T-cell infiltration guided by myeloid cell-derived chemokines CXCL9, 10, and 11. Blocking the responsible chemokine receptor CXCR3 hampered T-cell infiltration and reduced antitumor efficacy of the combination therapy. Multivariate analysis of 59 immune-cell parameters in tumors and spleens detected the correlation between PD-L1-expressing myeloid cells and tumor burden. In vitro, anti-PD-1 antibody Nivolumab in combination with BLZ945 increased the activation of primary human T and NK cells. Importantly, we revealed a previously uncharacterized pathway, in which T cells secreted M-CSF upon PD-1 blockade, leading to enhanced suppressive capacity of monocytes by upregulation of PD-L1 and purinergic enzymes. In multiple datasets of neuroblastoma patients, gene expression of CD73 correlated strongly with myeloid cell markers CD163 and CSF-1R in neuroblastoma tumors, and associated with worse survival in high-risk patients. Altogether, our data reveal the dual role of activated T cells on myeloid cell functions and provide a rationale for the combination therapy of anti-PD-1 antibody with CSF-1R inhibitor.

Prognostic Factors and Multidisciplinary Postoperative Chemoradiotherapy for Clinical T4a Tongue Cancer

Objective: The prognosis of patients with locally advanced squamous cell carcinoma (SCC) of the tongue is poor. Postoperative chemoradiotherapy (CRT) improves locoregional control and survival in high-risk patients. We investigated the prognostic factors for clinical T4a tongue SCC, and elucidated whether postoperative CRT has a benefit for patients with poor prognosis in terms of survival. Methods: We performed a retrospective analysis of 61 patients with stage T4a SCC of the tongue who underwent primary resection and neck dissection. Results: The median follow-up was 53.8 months. Multivariate analysis revealed a 4.26× relative risk of death for patients with the involvement of ≥5 regional lymph nodes (pN ≥5) compared with those with pN 0-4 (p = 0.002). In Kaplan-Meier analysis, patients with pN ≥5 who received CRT had longer overall survival rates than those who did not (hazard ratio = 0.31; p = 0.041). Conclusions: pN ≥5 is the most powerful prognostic factor for clinical T4a SCC of the tongue. Postoperative CRT is recommended in patients with pN ≥5.

Intraoperative blood transfusion is a predictor of long-term survival in high-risk patients with resected colorectal liver metastases (CLM)

Intraoperative blood transfusion is a predictor of long-term survival in high-risk patients with resected colorectal liver metastases (CLM)

Incidence of intensive care unit admission, outcome and post intensive care survival in patients with diffuse large B-cell lymphoma

Some patients with diffuse large B-cell lymphoma (DLBCL) require intensive care unit (ICU) admission prior to or during chemotherapy. We analyzed all unscheduled ICU admissions in 331 consecutive patients (18–93 years) with newly diagnosed DLBCL. Thirty-seven patients (11.2%) required ICU treatment primarily due to hemodynamic (37.8%) or respiratory failure (24.3%). Bulky disease and high IPI score were predictive of ICU admission in the early course. ICU and hospital survival was 75.7% and 70.3%, respectively. Overall survival in ICU patients with newly diagnosed DLBCL was worse compared to non-ICU-patients (40.7% vs. 72.7% at two years). However, survival of high-risk patients (IPI 3–5), continuous complete remission, and disease-free survival did not differ. Post-ICU survival was poor in patients with relapsed/refractory DLBCL (0.1–10 months). Our observations favor unrestricted ICU support in DLBCL patients undergoing first-line therapy. ICU referral of patients with refractory/relapsed disease must be evaluated in the context of the hematologic prognosis.

MiR expression profiling at diagnosis predicts relapse in pediatric precursor B-cell acute lymphoblastic leukemia.

Our aim was to identify miRNAs that can predict risk of relapse in pediatric patients with acute lymphoblastic leukemia (ALL). Following high-throughput miRNA expression analysis (48 samples), five miRs were selected for further confirmation performed by real time quantitative PCR on a cohort of precursor B-cell ALL patients (n = 138). The results were correlated with clinical parameters and outcome. Low expression of miR-151-5p, and miR-451, and high expression of miR-1290 or a combination of all three predicted inferior relapse free survival (P = 0.007, 0.042, 0.025, and <0.0001, respectively). Cox regression analysis identified aberrant expression of the three miRs as an independent prognostic marker with a 10.5-fold increased risk of relapse (P = 0.041) in PCR-MRD non-high risk patients. Furthermore, following exclusion of patients harboring IKZF1 deletion, the aberrant expression of all three miRs could identify patients with a 24.5-fold increased risk to relapse (P < 0.0001). The prognostic relevance of the three miRNAs was evaluated in a non-BFM treated precursor B-cell ALL cohort (n = 33). A significant correlation between an aberrant expression of at least one of the three miRs and poor outcome was maintained (P < 0.0001). Our results identify an expression profile of miR-151-5p, miR-451, and miR-1290 as a novel biomarker for outcome in pediatric precursor B-cell ALL patients, regardless of treatment protocol. The use of these markers may lead to improved risk stratification at diagnosis and allow early therapeutic interventions in an attempt to improve survival of high risk patients.

Limited resections in high-risk patients.

The role of limited, sublobar resection in patients with early-stage nonsmall cell lung cancer (NSCLC) remains controversial. Alternative treatments for surgical resection include stereotactic radiotherapy and radiofrequency ablation. In this review, the role of limited resection is discussed in patients presenting a s high-risk for s surgical intervention. Clear definitions of high-risk patients are currently lacking, as well as, randomized prospective studies indicating which treatment to offer in this population. Awaiting results of two major ongoing trials, at this moment the decision-making process is heavily dependent on retrospective analyses. For selected patients sublobar resection may be a valid oncological option for clinical stage IA NSCLC. Surgery remains the gold standard for NSCLC. In case of high-risk patients, a multidisciplinary consultation should advise the patient which treatment option to choose. In early-stage NSCLC, sublobar anatomical resection is preferred over nonsurgical procedures to determine nodal status and prognosis. In case of patients unfit for surgery, stereotactic radiotherapy is a good alternative. A randomized prospective study is necessary to determine survival in high-risk patients allocated to surgery (lobectomy or sublobar resection) or radiation-based treatment.

Quality of Life and Overall Survival in High Risk Patients After Radical Cystectomy With a Simple Urinary Derivation

ObjectiveTo evaluate quality of life (QoL) and overall survival after radical cystectomy with cutaneous ureterostomies for locally advanced bladder cancer in elderly patients with high surgical risk. MethodsFifty eight patients older than 74 years (mean age 80.6±4.3) with locally advanced bladder cancer (group A), underwent radical cystectomy and ureterocutaneous diversion. Patients completed the EORTC QLQC30 before and six months after surgery to assess functional, clinical, and QoL outcomes. The same evaluation was carried out in a control group (group B) of 29 patients (mean age 82.3±3.8 years), who had refused cystectomy. Questionnaires were also administered to patients of both groups who survived at least 20 months and 5 years. ResultsAll patients presented with an ASA score ≥3. Mean hospital stay was 15.1 days (±4.8) in group A and 23.5 days (±4.1) in group B. No intraoperative complications occurred in group A. Postoperative overall survival evaluated within 6 months in group A was 97% versus 79% in group B (P<.001).Relation between two groups at 6 months for Qol, functional and symptomatic items investigated showed in group A a statistically significant improvement for all parameters (P<.001). This advantage for patients belonging to group A still resulted evident at 20 months and 5 years.Short-term and 20 months overall survival resulted statistically significant in favour of group A (P<.001). ConclusionRadical cystectomy with cutaneous ureterostomy represents a valid alternative in elderly patients with invasive bladder cancer and high operative risk. Comparison between two groups showed a statistically significant difference for almost all the Qol related parameters and for short and medium term overall survival.

Outcomes of On-Pump versus Off-Pump Coronary Artery Bypass Graft Surgery in the High Risk (AusSCORE > 5)

Coronary artery bypass graft surgery (CABG) has been established as the preferred intervention for coronary revascularisation in the high-risk population. Off-pump coronary artery bypass (OPCAB) may further reduce mortality and morbidity in this population subgroup. This study presents the largest series of high-risk (AusSCORE > 5) OPCAB patients in Australia and New Zealand. We reviewed the Australian and New Zealand Society of Cardiac and Thoracic Surgeons' (ANZSCTS) database for high-risk patients (n=7822) undergoing isolated CABG surgery and compared the on-pump coronary artery bypass (ONCAB) (n=7277) with the OPCAB (n=545) technique. Preoperative and intraoperative risk factors, and postoperative outcomes were analysed. Survival analysis was performed after cross-matching the database with the national death registry to identify long-term mortality. The ONCAB and OPCAB groups had similar risk profiles based on the AusSCORE. Thirty-day mortality (ONCAB vs OPCAB 3.9% vs 2.4%, p=0.067) and stroke (ONCAB vs OPCAB 2.4% vs 1.3%, p=0.104) were similar between the two groups. OPCAB patients received fewer distal anastomoses than ONCAB patients (2.5±1.2 vs 3.3±1.0, p<0.001). The rates of new postoperative atrial arrhythmia (28.3% vs 33.3%, p=0.017) and blood transfusion requirements (52.1% vs 59.5%, p=0.001) were lower in the OPCAB group, while duration of ICU stay in hours (97.4±187.8 vs 70.2±152.8, p<0.001) was longer. There was a non-significant trend towards improved 10-year survival in OPCAB patients (74.7% vs. 71.7%, p=0.133). In the high-risk population, CABG surgery has a low rate of mortality and morbidity suggesting that surgery is a safe option for coronary revascularisation. OPCAB reduces postoperative morbidity and is a safe procedure for 30-day mortality, stroke and long-term survival in high-risk patients.

CRT-807 Prognostic Impact of Improvement in Intra-Operative Pulmonary Artery Systolic Pressure and Left Ventricular Ejection Fraction in Patients Undergoing Trans-Catheter Aortic Valve Replacement

Previous studies have demonstrated reduced survival in high risk patients with symptomatic AS undergoing TAVR who had elevated pulmonary artery systolic pressure (PASP) at baseline. However, effects of elevated intra-operative PASP on long term outcomes in these patients are not clearly defined. We

The Role of Adjuvant Therapy in the Management of Head and Neck Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare neuroendocrine malignant neoplasm that most commonly occurs in the head and neck and is rapidly increasing in incidence. The role of adjuvant chemoradiotherapy (CRT) in the management of head and neck MCC remains controversial. To evaluate the association between different adjuvant therapies and survival in head and neck MCC. Retrospective review of adult patients with head and neck MCC who had surgery recorded in the National Cancer Data Base from 1998 to 2011. Surgical excision, adjuvant radiation therapy (RT), or adjuvant CRT. Our main outcome was overall survival (OS). Statistical analysis included χ2, t tests, Kaplan-Meier survival analysis, and Cox proportional hazards regression analysis. We identified 4815 patients; 92.0% underwent standard surgical excision, and 8.0% underwent Mohs surgery. On multivariate analysis, age at least 75 years (hazard ratio [HR], 2.83 [95% CI, 1.82-4.41]), larger tumor size, positive margins (HR, 1.52 [95% CI, 1.25-1.85]), and metastatic lymph nodes (HR, 2.29 [95% CI, 1.84-2.85]) were independently associated with decreased OS. Postoperative CRT (HR, 0.62 [95% CI, 0.47-0.81]) and RT (HR, 0.80 [95% CI, 0.70-0.92]) provided a survival benefit over surgery alone. Adjuvant CRT was associated with improved OS over adjuvant RT in patients with positive margins (HR, 0.48 [95% CI, 0.25-0.93]), tumor size at least 3 cm (HR, 0.52 [95% CI, 0.30-0.90]), and male sex (HR, 0.69 [95% CI, 0.50-0.94]). To our knowledge, this the first study examining the role of adjuvant CRT in head and neck MCC. Results suggest that adjuvant CRT may help improve survival in high-risk patients, such as males and those with positive margins and larger tumors.

Reduction of C-reactive protein is not associated with reduced cardiovascular risk and mortality in patients treated with statins. A meta-analysis of 22 randomized trials

BackgroundThe association between C-reactive protein (CRP) levels and risk of cardiovascular (CV) events has been reported in several studies. However, it is unclear whether a reduction in CRP is associated with a reduction in risk of clinical events. Therefore we sought to investigate, in a meta-regression analysis of randomized studies enrolling patients treated by statins, whether changes in CRP are associated with changes in risk of CV events or overall survival. MethodsRandomized trials enrolling patients treated by statins, reporting CRP at baseline and at end of follow-up, CV events [myocardial infarction (MI) and stroke], CV and all-cause mortality were selected. ResultsTwenty-two trials enrolling 54,213 participants were included in the analysis. Meta-analysis showed that active treatment significantly reduced risk of all-cause death by 8%, myocardial infarction by 11%, stroke by 10.3% and the composite outcome (including CV death, MI and stroke) by 8%, whereas risks of CV mortality was not significantly reduced. Meta-regression analysis revealed that reduction in CRP levels was significantly associated only with the reduction of MI, whereas no relationship was identified between changes in CRP and risk of stroke, CV and all-cause mortality, and the composite outcome. ConclusionsThese findings demonstrate that statin-induced changes in CRP do not correlate with major CV events apart from the risk of MI nor with overall survival in high-risk patients. These data suggest that although CRP may be a surrogate marker for coronary risk, it should not be used for predicting the effectiveness of statin therapy.

Gastrostomy dependence in head and neck carcinoma patient receiving post-operative therapy.

Post-operative concurrent chemoradiotherapy significantly improves the rates of locoregional control and disease-free survival in high-risk patients but has significant adverse effects. Percutaneous endoscopic gastrostomy and opioid-based pain control increase treatment completion rates but can result in dysphagia. The rate and duration of use of prophylactically placed percutaneous endoscopic gastrostomies were evaluated in 43 patients who underwent post-operative radiotherapy or chemoradiotherapy from April 2007 through March 2010. All patients completed treatment and received 60 Gy or more of radiotherapy. Thirty four of 43 patients (79.1%) used percutaneous endoscopic gastrostomies, which could later be removed in 25 of 34 patients. The median period of use was 108 days. Only one disease-free patient was permanently dependent on percutaneous endoscopic gastrostomy feeding. The frequency of percutaneous endoscopic gastrostomy use among patients with oral, oropharyngeal and hypopharyngeal cancer was 91.7, 100 and 54.5%, respectively. Prolonged percutaneous endoscopic gastrostomy use is not required in patients receiving post-operative chemoradiotherapy and will not lead to dysphagia.

Polymorphism of 9p21.3 locus is associated with 5-year survival in high-risk patients with myocardial infarction.

ObjectiveThe rs10757278, rs1333049 and rs4977574 are single nucleotide polymorphisms (SNPs) of chromosome 9p21 locus associated with a prevalence of acute coronary syndromes (ACS). Reports concerning their association with long-term outcome after an ACS are equivocal. The aim of our study was to investigate the association of the 9p21.3 locus with 5-year overall mortality in patients with ST-elevation myocardial infarction (STEMI).Materials and methodsWe performed a retrospective analysis of data collected prospectively in 2 independent registries of consecutive patients with STEMI (derivation and validation group). Genotyping was performed with the TaqMan method. The analyzed end-point was total mortality.ResultsThe derivation group comprised 589 patients: 25.3% female (n = 149), mean age 62.4±12.0 years, total 5-year mortality 16.6% (n = 98). When all the study group was analyzed, no significant differences in mortality were found between the genotypes. However, in high-risk patients (GRACE risk score ≥155 points, n = 238), homozygotes associated with higher risk for ACS had significantly better 5-year survival compared to other genotypes. The hazard ratio associated with the high-risk genotype (a homozygote of high risk for ACS or a heterozygote) was: HR = 2.2 (1.15–4.2) for the rs10757278 polymorphism, HR = 2.7 (95% CI 1.3–5.4) for the rs4977574 one and HR = 2.3 (1.2–4.5) for the rs1333049 one (Cox proportional hazards model). Survival analysis in the validation group (n = 365) showed a clear trend towards better prognosis in GG homozygotes of the rs10757278 SNP, which confirms our initial results (p = 0.09, log-rank test).ConclusionsThe 9p21.3 locus is associated with 5-year mortality in high-risk patients with STEMI. The genotypes associated with higher risk for ACS show a protective effect in terms of further survival (instead of a deteriorating prognosis, as reported previously). This finding, due to the very high size of the effect, could potentially be applied to clinical practice, if appropriate methods are elaborated.

Decision curve analysis and external validation of the postoperative Karakiewicz nomogram for renal cell carcinoma based on a large single-center study cohort.

To predict outcome of patients with renal cell carcinoma (RCC) who undergo surgical therapy, risk models and nomograms are valuable tools. External validation on independent datasets is crucial for evaluating accuracy and generalizability of these models. The objective of the present study was to externally validate the postoperative nomogram developed by Karakiewicz et al. for prediction of cancer-specific survival. A total of 1,480 consecutive patients with a median follow-up of 82 months (IQR 46-128) were included into this analysis with 268 RCC-specific deaths. Nomogram-estimated survival probabilities were compared with survival probabilities of the actual cohort, and concordance indices were calculated. Calibration plots and decision curve analyses were used for evaluating calibration and clinical net benefit of the nomogram. Concordance between predictions of the nomogram and survival rates of the cohort was 0.911 after 12, 0.909 after 24 months and 0.896 after 60 months. Comparison of predicted probabilities and actual survival estimates with calibration plots showed an overestimation of tumor-specific survival based on nomogram predictions of high-risk patients, although calibration plots showed a reasonable calibration for probability ranges of interest. Decision curve analysis showed a positive net benefit of nomogram predictions for our patient cohort. The postoperative Karakiewicz nomogram provides a good concordance in this external cohort and is reasonably calibrated. It may overestimate tumor-specific survival in high-risk patients, which should be kept in mind when counseling patients. A positive net benefit of nomogram predictions was proven.

Retraction: Polymorphism of 9p21.3 locus is associated with 5-year survival in high-risk patients with myocardial infarction.

The rs10757278, rs1333049 and rs4977574 are single nucleotide polymorphisms (SNPs) of chromosome 9p21 locus associated with a prevalence of acute coronary syndromes (ACS). Reports concerning their association with long-term outcome after an ACS are equivocal. The aim of our study was to investigate the association of the 9p21.3 locus with 5-year overall mortality in patients with ST-elevation myocardial infarction (STEMI).We performed a retrospective analysis of data collected prospectively in 2 independent registries of consecutive patients with STEMI (derivation and validation group). Genotyping was performed with the TaqMan method. The analyzed end-point was total mortality.The derivation group comprised 589 patients: 25.3% female (n = 149), mean age 62.4 ± 12.0 years, total 5-year mortality 16.6% (n = 98). When all the study group was analyzed, no significant differences in mortality were found between the genotypes. However, in high-risk patients (GRACE risk score ≥ 155 points, n = 238), homozygotes associated with higher risk for ACS had significantly better 5-year survival compared to other genotypes. The hazard ratio associated with the high-risk genotype (a homozygote of high risk for ACS or a heterozygote) was: HR = 2.2 (1.15-4.2) for the rs10757278 polymorphism, HR = 2.7 (95% CI 1.3-5.4) for the rs4977574 one and HR = 2.3 (1.2-4.5) for the rs1333049 one (Cox proportional hazards model). Survival analysis in the validation group (n = 365) showed a clear trend towards better prognosis in GG homozygotes of the rs10757278 SNP, which confirms our initial results (p = 0.09, log-rank test).The 9p21.3 locus is associated with 5-year mortality in high-risk patients with STEMI. The genotypes associated with higher risk for ACS show a protective effect in terms of further survival (instead of a deteriorating prognosis, as reported previously). This finding, due to the very high size of the effect, could potentially be applied to clinical practice, if appropriate methods are elaborated.

Early and intermediate outcome after aortic valve replacement with a sutureless bioprosthesis: Results of a multicenter study

The aim of this study was to evaluate the outcome of aortic valve replacement with the sutureless Perceval S aortic valve bioprosthesis (Sorin Biomedica Cardio Srl, Saluggia, Italy). This is a retrospective analysis of 314 patients (mean age, 77.9 ± 5.0 years, mean European System for Cardiac Operative Risk Evaluation II, 9.0% ± 7.6%) who underwent aortic valve replacement with the Perceval S valve with (94 patients) or without (220 patients) concomitant coronary artery bypass surgery at 5 European centers. The Perceval S valve was successfully implanted in all but 1 patient (99.7%). The mean aortic crossclamping time was 43 ± 20 minutes (isolated procedure, 39 ± 15 minutes; concomitant coronary surgery, 52 ± 26 minutes). Severe paravalvular leak occurred in 2 patients (0.6%). In-hospital mortality was 3.2% (1.4% after isolated procedure and 7.4% after concomitant coronary surgery). In-hospital mortality was 2.8% and 4.0% among patients with a European System for Cardiac Operative Risk Evaluation II less than 10% and 10% or greater, respectively (P = .558). Octogenarians had slightly higher in-hospital mortality (5.2% vs 2.0%, P = .125; after isolated procedure: 2.7% vs 0.7%, P = .223; after concomitant coronary surgery: 9.5% vs 5.8%, P = .491) compared with younger patients. Full sternotomy did not increase the in-hospital mortality risk compared with ministernotomy or minithoracotomy access (1.3% vs 1.4%, when adjusted for baseline covariates: P = .921; odds ratio, 0.886; 95% confidence interval, 0.064-12.346). One-year survival was 90.5%. Freedom from valve-related mortality, stroke, endocarditis, and reoperation was 99.0%, 98.1%, 99.2%, and 98.3%, respectively. The sutureless Perceval S valve is associated with excellent early survival in high-risk patients, particularly among those undergoing an isolated procedure. Further studies are needed to prove the durability of this bioprosthesis.

Controversies about Radioactive Iodine-131 Remnant Ablation in Low Risk Thyroid Cancers: Are We Near A Consensus?

Well differentiated thyroid cancers (WDTC), including papillary (80%) and follicular (10%) types, are the most common endocrine cancers globally. Over the last few decades most the diagnosed cases have fallen into low risk categories. Radioactive iodine-131 (RAI) has an established role in reducing recurrence and improving the survival in high risk patients. In patients with primary tumor size <1 cm, RAI is not recommended by many thyroid societies. However, low risk WDTC has been an arena of major controversies, most importantly the role and dose of adjuvant RAI for remnant ablation to minimize chances of recurrence and improving survival. This review is an attempt to update readers about the previous and existing practice based on results of non- randomized trials and evolving trends fueled by recently published randomized studies.

Contralateral prophylactic mastectomy in an Asian population: A single institution review

BackgroundContralateral prophylactic mastectomy (CPM) removes the non-diseased breast in women who have unilateral breast cancer. This reduces the incidence of contralateral breast cancer, and potentially improves survival in high risk patients. Such surgical risk-reduction strategy is increasingly being adopted in the United States, despite a decreasing incidence of contralateral breast cancer. The use of CPM in an Asian population is yet unknown. We present the first Asian report on CPM rates and trends in Singapore, the country with the highest incidence of breast cancer in Asia. MethodsA retrospective review of all patients who had breast cancer surgery from 2001 to 2010 at the largest healthcare system in Singapore was performed. Patient demographics and tumour characteristics were analysed with regards to type of surgery performed. Factors associated with CPM were identified. ResultsFrom 2001 to 2010, a total of 5130 patients underwent oncological breast surgery. A decreasing trend of mastectomies (82.7%–70.8%), an upward trend of breast conserving surgery (BCS) (17.3%–29.2%) and an increasing trend in CPM (0.46%–1.25%) is observed. Patients who opted for CPM are likely to be younger (48.4 ± 9.4 years), married (60%), parous (56.7%), with no family history of breast/ovarian cancer (66.7%), and diagnosed at an earlier stage. The rate of synchronous occult breast malignancy was found to be 10% (n = 30), and these were in patients who were of a low cancer-risk profile. ConclusionsThis retrospective study reflects an increasing incidence of breast cancer in Singapore, with a decrease in mastectomies, and an increase in BCS and CPM rates, similar to Western data. Similar to Western populations, the Asian woman who opts for CPM is likely to be young and have an earlier stage of breast cancer. In contrast, the Asian woman is likely to have no family history of breast or ovarian cancers. Commonly cited reasons for increased CPM rates such as the increased availability of genetic counselling and pre-operative MRI evaluation, along with wide use of reconstruction, do not feature as dominant factors in our population, suggesting that the Asian patients may have different considerations when electing for CPM.

Abnormal Numbers Of Regulatory T Cell (Tregs) Subsets Are Sigificantly Associated With Adverse Disease Outcome In Lower Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

BackgroundExpansion of naturally occurring regulatory T cells (rTregs) and in particular specific subsets including the highly suppressive effector CD4+CD45RA-CD25brightFoxp3bright Tregs (eTregs) limit impaired immune responses. On the other hand, malignancies promote expansion of Tregs, which in turn play a central role to suppress antitumor immune responses. In line, increased numbers of Tregs were found in the bone marrow (BM) and peripheral blood (PB) in high risk MDS and AML (Kordasti; Blood 2007 110:847). It has recently been shown that an increase of highly suppressive effector memory Tregs was associated with anemia, increased bone marrow blasts and poor prognosis in lower risk MDS independently of IPSS, suggesting that expansion of a specific Tregs subset, rather than expansion of Tregs as a whole, characterizes higher risk patients (Mailloux; J Immunol 2012 189:3198). We screened a large cohort of 127 consecutive MDS and CMML patients for Tregs subsets and studied their influence on outcome. Methods85 MDS, 42 CMML patients and 34 sex and age matched controls were studied. PBMC were purified from blood samples on Ficoll-Hypaque gradients to determine populations of resting CD4+CD45RA+FoxP3+CD25+ Tregs (rTregs) and effector CD4+CD45RA-CD25brightFoxp3brightTregs (eTregs) by flow cytometry and data was correlated with patient characteristics and outcome. ResultsMedian age of the 85 MDS and the 42 CMML patients was 74 years (range 31-91) and 75.5 years (range 47-91) respectively, with M/F: 75/52. Eight (6.3%) patients had RA, 8 (6.3%) RARS, 17 (13.4%) RCMD, 8 (6.3%) 5q-syndrome, 22 (17.3%) RAEB-1, 10 (7.9%) RAEB-2, 11 (8.7%) AML 20-30% blasts/RAEB-T, 37 (29.1%) CMML-1, 5 (3.9%) CMML-2 and 1 (0.8%) unclassified MDS. For patients evaluable by IPSS (MDS, AML 20-30% and CMML with WBC <13 G/l), IPSS was low in 71 (70.3%), int-1 in 9 (8.9%), int-2 in 10 (9.9%) and high in 11 (10.9%) patients. Median marrow blast count was 5% (range 1-26). Overall median numbers of eTregs did not significantly differ in patients and controls: 1.98% of lymphocytes (range 0.15-9.5%) for MDS, 2.03% (range 0-11.8%) for CMML and 1.84% (0.42-4.54%) for controls (p=0.88). Likewise rTregs median numbers did not differ between patients and controls: 0.7% (range 0-7.03%) for MDS, 0.74% (range 0-9.32%) for CMML and 0.80% (0.15-2.66%) for controls (p=0.90). However, eTregs numbers were significantly more frequently abnormal (increased or decreased) in MDS (37/85, 44%) and CMML (24/42, 57%) compared to controls (6/34,17%) (MDS vs Ctrl, p=0.011, CMML vs Ctrl, p=0.001). By contrast, frequency of abnormal rTregs numbers was similar across the groups: (57/85 (67%) in MDS, 30/42 (71%) in CMML, and 20/34 (59%) in controls. In lower risk patients, survival was significantly influenced by Tregs numbers: median survival from Treg analysis was 25 months in patients with abnormal eTregs numbers compared to 28 months in lower risk patients with normal eTregs numbers (p=0.02). On the other hand, abnormal eTreg numbers had no impact on survival in higher risk patients (median 19.5 months from Treg analysis vs 17.5 months in patients with normal numbers, p=0.65). In the whole MDS and CMML population, eTregs numbers had a significant impact on the risk of disease progression (to higher risk MDS or AML) or death: median 27 months from Tregs analysis in patients with normal eTregs numbers vs 14 months in patients with abnormal numbers (p=0.05). ConclusioneTregs numbers are significantly more often increased or decreased in MDS and CMML patients than in controls. In lower risk MDS and CMML abnormal eTregs numbers are significantly associated with poorer survival and disease progression. In addition to the pathophysiological questions raised by those results, analysis of Tregs subsets by flow cytometry may constitute an interesting tool to predict outcome of MDS and CMML patients, in addition to classical prognostic scores. Disclosures:No relevant conflicts of interest to declare.