CRM Status Research Articles

Cardio-Renal-Metabolic Overlap, Outcomes, and Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

BackgroundCardio-renal-metabolic (CRM) conditions are individually common among patients with heart failure (HF), but the prevalence and influence of overlapping CRM conditions in this population have not been well-studied. ObjectivesThis study aims to evaluate the impact of overlapping CRM conditions on clinical outcomes and treatment effects of dapagliflozin in HF. MethodsIn this post hoc analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we evaluated the prevalence of comorbid CRM conditions (atherosclerotic cardiovascular disease, chronic kidney disease, and type 2 diabetes), their impact on the primary outcome (cardiovascular death or worsening HF), and treatment effects of dapagliflozin by CRM status. ResultsAmong 6,263 participants, 1,952 (31%), 2,245 (36%), and 1,236 (20%) had 1, 2, and 3 additional CRM conditions, respectively. HF alone was uncommon (13%). Greater CRM multimorbidity was associated with older age, higher body mass index, longer-duration HF, worse health status, and lower left ventricular ejection fraction. Risk of the primary outcome increased with higher CRM overlap, with 3 CRM conditions independently associated with highest risk of primary events (adjusted HR: 2.16 [95% CI: 1.72-2.72]; P < 0.001) compared with HF alone. Relative benefits of dapagliflozin on the primary outcome were consistent irrespective of the type of CRM overlap (Pinteraction = 0.773) and by the number of CRM conditions (Pinteraction = 0.734), with greatest absolute benefits among those with highest CRM multimorbidity. Estimated 2-year numbers needed to treat with dapagliflozin to prevent 1 primary event were approximately 52, 39, 33, and 24 for participants with 0, 1, 2, and 3 additional CRM conditions at baseline, respectively. Adverse events between treatment arms were similar across the CRM spectrum. ConclusionsCRM multimorbidity was common and associated with adverse outcomes among patients with HF and left ventricular ejection fraction >40% in DELIVER. Dapagliflozin was safe and effective across the CRM spectrum, with greater absolute benefits among those with highest CRM overlap (Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)

Capecitabine, Oxaliplatin, and Irinotecan (XELOXIRI) as Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

Purpose: This study describes the efficacy and safety of irinotecan and oxaliplatin in combination with capecitabine (XELOXIRI) as a neoadjuvant chemotherapy (NAC) regimen for patients with locally advanced rectal cancer (LARC). Methods: From January 2019 through December 2022, 68 LARC patients treated with XELOXIRI were enrolled in the study. XELOXIRI is administered in a three-week cycle consisting of oxaliplatin 70-110 mg/m2 IV for &gt;120 min on day 1; irinotecan 120-160 mg/m2 IV for 90 min on day 1; and capecitabine 700-1100 mg/m2 orally twice daily for 14 days followed by 7 days off. Sixteen cases were treated with combined radiotherapy, including 8 with long-course radiotherapy and 8 with short-course radiotherapy. The efficacy was evaluated based on pelvic MRI (including TNM stage, CRM, and EMVI status), tumor downstaging rate (to ypT0-2N0M0), pCR rate, R0 resection rate, DFS, and OS, and the safety was assessed according to the incidence of adverse events. Results: Sixty-six people had surgery; the R0 resection rate was 100%, and the rate of anal preservation was 97%. The tumor downstaging rate (to ypT0-2N0M0) in the entire group was 53.0%, and the pCR rate was 12.1%. In the XELOXIRI alone group (N = 47), the tumor downstaging rate was 55.3%, and the pCR rate was 12.8%. In the group receiving radiotherapy (N = 16), the tumor downstaging rate was 56.3%, and the pCR rate was 12.5%. In the whole group, the 3-year DFS was 89.0%, and the 3-year survival rate was 98.5%. The 3-year DFS of the XELOXIRI and XELOXIRI + RT groups was 89.9% and 87.2%, respectively. The most frequent grade 3–4 preoperative toxic reactions were neutropenia (8.8%), diarrhea (4.4%), and anemia (2.9%). All adverse events were tolerable. Conclusions: Neoadjuvant chemotherapy with XELOXIRI appears to be feasible and efficacious for patients with LARC. Although neoadjuvant XELOXIRI alone did not yield our expected pCR rate as NAC for LARC, tumor downstaging, R0 resection, sphincter preservation, local recurrence rate, 3-year DFS, OS, and safety were all satisfactory.

Benefits of Adjuvant Chemotherapy for Clinical T3-4N0 Rectal Cancer After Preoperative Chemoradiotherapy.

While the guidelines for adjuvant chemotherapy (AC) for colon cancer are relatively standardized, those for early rectal cancer are still lacking. We therefore evaluated the role of AC in clinical stage II rectal cancer treatment after preoperative chemoradiotherapy (CRT). Patients diagnosed with early rectal cancer (defined by clinical stage T3/4, N0) who completed CRT followed by surgery were enrolled in this retrospective study. To evaluate the role of AC, we analyzed the risk of recurrence and survival based on clinicopathologic parameters and adjuvant chemotherapy. Of the 112 patients, 11 patients (9.8%) experienced recurrence and five patients (4.8%) died. In a multivariate analysis, circumferential resection margin involvement (CRM+) on magnetic resonance imaging at diagnosis, CRM involvement following neoadjuvant therapy (ypCRM+), tumor regression grade (≤G1) and no-AC were considered poor prognostic factors for recurrence free survival (RFS). In addition, ypCRM+ and no-AC were associated with poor overall survival (OS) in the multivariate analysis. AC including 5-FU monotherapy demonstrated the benefits of reduced recurrence and prolonged survival in clinical stage II rectal cancer, even in pathologic stage following neoadjuvant therapy (ypStage) 0-I. Further prospective studies are needed to verify the benefit of each regimen of AC and the development of a method that can accurately predict CRM status before surgery, and a vigorous treatment that can induce CRM non-involvement (CRM-) should be considered even in early stages of rectal cancer.

The prognostic significance of the circumferential resection margin in esophageal squamous cell carcinoma patients without neoadjuvant treatment

BackgroundCircumferential resection margin (CRM) is very important in esophageal cancer, but its diagnostic criteria has not been unified. The College of American Pathologists (CAP) and the Royal College of Pathologists (RCP) provide two different criteria. The aim of this study is to evaluate the long-term prognostic significance of CRM status with different CRM criteria in esophageal squamous cell carcinoma (ESCC).MethodsInfluence of CRM status according to the CAP and RCP criteria on long-term survival of 838 patients with resected pT3 tumors and without neoadjuvant therapy was analyzed. Patients stratified into three groups on the basis of tumor distance from the CRM (CRM > 1 mm, 0-1 mm, and 0 mm) were also analysed.ResultsPositive CRM was found in 59 (7%) patients according to the CAP criteria and 317 (37.8%) patients according to the RCP criteria. Univariate and multivariate survival analysis showed that CRM status, according to three different criteria, was independent prognostic factor. However, subgroup analysis showed that the prognostic value of CRM status was limited to certain metastatic lymph node load. In pN0 subgroup, patients with CRM > 1 mm had better prognosis than patients with CRM 0-1 mm. Patients with CRM 0 mm had worse outcome than patients with CRM > 0 mm in pN1-2 subgroup. But CRM status had no prognosis value in pN3 subgroup.ConclusionsThe CRM status is an important prognostic factor in ESCC patients, but this effect was limited to patients without or with less lymph node metastasis (pN0-2). In clinical practice, we recommend the 1 mm-three-tier criteria as it provides more prognostic value than the traditional two-tier criteria.

TOPOMETRIC PREPARATION AND PLANNING OF NEOADJUVANT RADIOTHERAPY IN THE COMPLEX TREATMENT OF RECTAL CANCER

Objective(s). To evaluate the effectiveness of the use of topometry during neoadjuvant radiation therapy in the complex treatment of rectal cancer.&#x0D; Methods. The results of treatment of 113 patients with locally advanced rectal cancer (cT3c-4N1-2M0) were analyzed. The patients were divided into two groups: the first (main) group included 57 patients who received only a course of neoadjuvant radiation therapy as part of the neoadjuvant stage of treatment. The second group (control group) included 56 patients who underwent a course of radiation therapy with capecitabine potentiation. Topometric preparation, contouring of irradiated volumes, critical structures and radiation treatment of all patients included in the study were carried out according to standard principles and started 5 days before its implementation.&#x0D; Results. When comparing the results of MRI performed before the beginning and after the end of the radiation therapy course in 102 (90.2%) of 113, a positive trend was noted in the form of a decrease in the length of the tumor itself and an increase in the distance between the tumor and the anal edge, p=0.0001. No statistically significant differences were found when evaluating the influence of criteria of intragroup effects on the reduction of tumor length when choosing fractionation modes.&#x0D; Conclusions. In 52 (91.2%) patients of the main group and 51 (911%) of the control group had a positive CRM status. Analysis of CRM status in patients before and after the end of the course of neoadjuvant radiation therapy showed positive dynamics, both in the main and in the control group (p&lt;0.000). After a prolonged course of neoadjuvant radiation therapy, the number of patients with a positive CRM status decreased to 17 (30%) in the main group and 19 (34%) in the control group (p&lt;0.000). According to the MRI results performed before and after the course of neoadjuvant radiation therapy in 102 (90.2%) out of 113, positive dynamics were noted in the form of a decrease in the length of the tumor itself and an increase in the distance between the tumor and the anal edge, p=0, 0001.

Spk-9001: Adeno-Associated Virus Mediated Gene Transfer for Hemophilia B - 1 Year Follow up and Impact of Baseline Characteristics on Transgene-Derived Factor IX Activity and Persistence

▪Background: Prior work demonstrated long term expression of factor IX (mean FIX:C ~5.1%) after AAV8-mediated gene transfer in hemophilia B (Nathwani et al., 2014), but transgene-derived FIX:C fell short of trough values obtained by long-acting FIX prophylaxis (Santagostino et al . 2016) and natural history data supporting levels of ~12% sufficiently eliminate spontaneous hemarthroses (den Uijl et al. 2011). We developed an efficient capsid and expression cassette that could be administered at low doses to achieve FIX:C adequate to prevent bleeding without use of exogenous FIX. Here we report 1 year follow up data in 7 subjects following SPK-9001 infusion at a dose of 5 x 1011vg/kg. These data represent the largest cohort of hemophilia B subjects treated with gene transfer using the same vector and dose with available 1 year follow up data. We additionally report observations of subject baseline pre-vector characteristics relative to steady-state transgene-derived FIX:C and clinical outcomes.Objective: To obtain long term transgene-derived FIX:C > 12% able to prevent spontaneous bleeding without the need for prophylactic FIX infusions with consistent and predictable results among all subjects, irrespective of baseline characteristics.Methods: The study vector, SPK-9001, consists of a liver specific, bioengineered AAV capsid (Spark100) and a single-stranded codon optimized expression cassette encoding FIX-Padua. FIX-Padua is a naturally occurring variant that confers ~8-12-fold greater specific activity compared to wild-type FIX (Simioni et al. 2009, Crudele et al. 2015). Subject baseline characteristics were determined at study screening. FIX:C and clinical data were prospectively collected after vector infusion.Results: To date, 7 subjects completed 1 year follow up after SPK-9001 infusion at a dose of 5 x1011 vg/kg. No subjects developed a FIX inhibitor or experienced vector related adverse events (AEs). Subject mean FIX:C following vector infusion through 52 weeks is outlined in figure 1. Subjects were males ages 18-52 yrs with FIX:C ≤2%. One subject had a Spark 100 neutralizing antibody (NAb) of 1:1 and the remaining were <1:1. Five patients were CRM+ and 2 were CRM-. The FIX:C at steady state, defined as the average of all values measured starting at week 12, for the 5 CRM+ subjects was 32.3±11.0% (mean±SD) and 21.0±5.7% for the 2 CRM- subjects. However, the analysis is confounded by a 1:1 NAb in one CRM- subject and partial loss of FIX:C due to immune response in one of the CRM+ subjects. Steady state FIX:C for the 6 subjects with <1:1 NAb was 31.1±10.3% and 17% for the one subject with NAb 1:1. FIX:C in subjects with a history of HCV and stage 1-2 liver fibrosis (29.7±12.7%), was comparable to that of subjects with no history of HCV (28.2±10.2%). FIX:C in the one patient with HCV exposure on HIV anti-retroviral therapy did not differ from other participants (25% vs. 29.7%±11.7%). All subjects discontinued prophylaxis at vector infusion. One subject self-reported bleeding that was incongruent with the remaining cohort, including those with the similar vector-derived FIX:C and baseline hemophilic arthropathy, who did not experience bleeding events or require factor (Table 1). The 1 subject (subject 7) who experienced a suspected capsid immune response had no known baseline characteristics that differed from the cohort; the subject completed a course of steroids, had a stable, sustained FIX:C of 14% and did not experience bleeding post vector. All subjects reported significantly improved quality of life (QoL) at 1-year (p<0.023).Conclusion: As of 8/1/17, we report the highest, most consistent and sustained vector derived FIX:C following gene transfer. Despite heterogenous baseline characteristics, all subjects achieved consistent clinical results, including no vector related AEs, improved QoL, termination of prophylaxis, near complete elimination of bleeding and factor use. Low grade liver fibrosis and prior HCV exposure did not appear to affect steady-state FIX:C. Individual subject data may imply effects of CRM status and NAb titer on achieved FIX, but the current dataset is too small to define the relationship. In summary, these preliminary data suggest SPK-9001 safely, consistently, and independent of subject baseline characteristics, achieved FIX:C able to substantially ameliorate clinical manifestations of hemophilia. [Display omitted] DisclosuresGeorge:Pfizer: Consultancy; Spark Therapeutics: Other: Principal Investigator of Ongoing Phase I/II Gene Therapy Trials for Hemophilia A and B. Ducore:Octapharma: Research Funding; Bayer, Shire, HemaBiologics, Bioverativ, Octapharma, Spark Therapeutics: Other: Advisory board. Cuker:T2 Biosystems: Research Funding; Spark Therapeutics: Research Funding. Von Mackensen:LFB: Honoraria. McGuinn:Shire / Baxalta, Spark, Biogen, Roche/Genetehc: Research Funding; Shire/Baxalta: Consultancy. Wright:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. Dasen:Spark Therapeutics: Employment. Barber:Spark Therapeutics: Employment. Chen:Spark Therapeutics: Employment. Hui:Spark Therapeutics: Employment. Patel:Spark Therapeutics: Employment. Liu:Spark Therapeutics: Employment. Wachtel:Spark Therapeutics: Employment. Takefman:Spark Therapeutics: Employment. Couto:Spark Therapeutics: Employment. Reape:Spark Therapeutics: Employment. Carr:Spark Therapeutics: Employment. Anguela:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. High:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties.

Quantitative T2*-Weighted Imaging and Reduced Field-of-View Diffusion-Weighted Imaging of Rectal Cancer: Correlation of R2* and Apparent Diffusion Coefficient With Histopathological Prognostic Factors.

PurposeTo assess T2*-weighted imaging (T2*WI) and reduced field-of-view diffusion-weighted Imaging (rDWI) derived parameters and their relationships with histopathological factors in patients with rectal cancer.MethodsFifty-four patients with pathologically-proven rectal cancer underwent preoperative T2*-weighted imaging and rDWI in this retrospective study. R2* values from T2*-weighted imaging and apparent diffusion coefficient (ADC) values from rDWI were compared in terms of different histopathological prognostic factors using student’s t-test or Mann-Whitney U-test. The correlations of R2* and ADC with prognostic factors were assessed by Spearman correlation analysis. The diagnostic performances of R2* and ADC were analyzed by receiver operating characteristic curves (ROC) separately and jointly.ResultsSignificant positive correlation was found between R2* values and T stage, lymph node involvement, histological grades, CEA level, the presence of EMVI and tumor deposit (r = 0.374 ~ 0.673, p = 0.000–0.006), with the exception of CA19-9 level, CRM status and tumor involvement in the circumference lumen (TIL). Meanwhile, ADC values negatively correlated with almost all the prognostic factors (r = −0.588 to −0.299, p = 0.000–0.030), except CA19-9 level. The AUC range was 0.724–0.907 for R2* and 0.674–0.887 for ADC in discrimination of different prognostic factors. While showing the highest AUC of 0.913 (0.803–1.000) in differentiation of T stage, combination of R2* and ADC with reference to different prognostic factors did not significantly improve the diagnostic performance in comparison with individual R2*/ADC parameter.ConclusionsR2* and ADC were associated with important histopathological prognostic factors of rectal cancer. R2* might act as additional quantitative imaging marker for tumor characterization of rectal cancer.

The Function of extravascular coagulation factor IX in haemostasis.

The majority of clotting factor IX (FIX) resides extravascularly, in the subendothelial basement membrane, where it is important for haemostasis. We summarize preclinical studies demonstrating extravascular FIX and its role in haemostasis and discuss clinical observations supporting this. We compare the in vivo binding of BeneFIX® and the extended half-life FIX, Alprolix® , to extravascular type IV collagen (Col4). Three mouse models of haemophilia were used: the FIX knockout as the CRM- model and two knock-in mice, representing a CRM+ model of a commonly occurring patient mutation (FIXR333Q ) or a mutation that binds poorly to Col4 (FIXK5A ). The murine saphenous vein bleeding model was used to assess haemostatic competency. Clinical publications were reviewed for relevance to extravascular FIX. CRM status affects recovery and prophylactic efficacy. Prophylactic protection decreases ~5X faster in CRM+ animals. Extravascular haemostasis can explain unexpected breakthrough bleeding in patients treated with some EHL-FIX therapeutics. In mice, both Alprolix® and BeneFIX® bind Col4 with similar affinities (Kd~20-40nM) and show dose-dependent recoveries. As expected, the concentration of binding sites in the mouse calculated for Alprolix® (574nM) was greater than for BeneFIX® (405nM), due to Alprolix® binding to both Col4 and the endothelial cell neonatal Fc receptor. Preclinical and clinical results support the interpretation that FIX plays a role in haemostasis from its extravascular location. We believe that knowing the CRM status of haemophilia B patients is important for optimizing prophylactic dosing with less trial and error, thereby decreasing clinical morbidity.

Adjuvant chemotherapy for rectal cancer with complete pathological response (pCR) may not be necessary: a pooled analysis of 5491 patients

BackgroundIt is recommended postoperative adjuvant chemotherapy for all rectal cancers undergoing neo-chemoradiotherapy regardless of the final yield pathology. However, the role of adjuvant chemotherapy in pathological complete response (pCR) remains controversial. We aimed to identify the necessarily of adjuvant chemotherapy in pCR.MethodsConsecutive patients with pCR in Fudan University Shanghai Cancer Center (FUSCC) were enrolled. Meanwhile, a pooled analysis of individual patient with pCR was performed from PubMed and Embase databases for validation.ResultsA total of 171 patients form FUSCC were identified to achieve pCR with up to almost 10 years follow-up. Among them, those receiving adjuvant chemotherapy had no survival benefits compared to those without adjuvant chemotherapy (log-rank test = 0.17, P = 0.676). The 5y-DFS rates for patients in chemo group and no-chemo group was 87.5 and 88.8%, respectively, showing no significant difference (p = 0.854). No matter chemotherapy regimens, T stage, EMVI and CRM status varied, the results remained consistent. Meantime, the COX model did not demonstrate adjuvant chemotherapy as the independent risk factor for OS and DFS. Additionally, among 18 systemic recurrences in all, the rate of relapse surged rapidly on the 12 months and rose up to peak in the 36th months. In order to validate these results, nine controlled trials involving 5491 patients with pCR were included in this pooled-analysis. For both 5-year overall survival and disease-free survival, the pooling data did not produce a statistically significant effect in cases of adjuvant chemotherapy performed (RR = 0.79 and RR = 0.95, respectively, all p > 0.05).ConclusionThis study suggested that rectal cancer patients with pCR did not benefit from adjuvant chemotherapy and we recommended that achievement of pCR require more prolonged close follow care in case of distant metastasis.

Radiogenomics of rectal adenocarcinoma in the era of precision medicine: A pilot study of associations between qualitative and quantitative MRI imaging features and genetic mutations

ObjectiveTo investigate associations between genetic mutations and qualitative as well as quantitative features on MRI in rectal adenocarcinoma at primary staging. MethodsIn this retrospective study, patients with rectal adenocarcinoma, genome sequencing, and pretreatment rectal MRI were included. Statistical analysis was performed to evaluate associations between qualitative features obtained from subjective evaluation of rectal MRI and gene mutations as well as between quantitative textural features and gene mutations. For the qualitative evaluation, Fisher’s Exact test was used to analyze categorical associations and Wilcoxon Rank Sum test was used for continuous clinical variables. For the quantitative evaluation, we performed manual segmentation of T2-weighted images for radiomics-based quantitative image analysis. Thirty-four texture features consisting of first order intensity histogram-based features (n = 4), second order Haralick textures (n = 5), and Gabor-edge based Haralick textures were computed at two different orientations. Consensus clustering was performed with 34 computed texture features using the K-means algorithm with Euclidean distance between the texture features. The clusters resulting from the algorithm were then used to enumerate the prevalence of gene mutations in those clusters. ResultsIn 65 patients, 45 genes were mutated in more than 3/65 patients (5%) and were included in the statistical analysis. Regarding qualitative imaging features, on univariate analysis, tumor location was significantly associated with APC (p = 0.032) and RASA1 mutation (p = 0.032); CRM status was significantly associated with ATM mutation (p = 0.021); and lymph node metastasis was significantly associated with BRCA2 (p = 0.046) mutation. However, these associations were not significant after adjusting for multiple comparisons. Regarding quantitative imaging features, Cluster C1 had tumors with higher mean Gabor edge intensity compared with cluster C2 (θ = 0°, p = 0.018; θ = 45°, p = 0.047; θ = 90°, p = 0.037; cluster C3 (θ = 0°, p = 0.18; θ = 45°, p = 0.1; θ = 90°, p = 0.052), and cluster C4 (θ = 0°, p = 0.016; θ = 45°, p = 0.033; θ = 90°, p = 0.014) suggesting that the cluster C1 had tumors with more distinct edges or heterogeneous appearance compared with other clusters. ConclusionsAlthough this preliminary study showed promising associations between quantitative features and genetic mutations, it did not show any correlation between qualitative features and genetic mutations. Further studies with larger sample size are warranted to validate our preliminary data.

Surgical Quality in Rectal Cancer Management: What Can Be Achieved by a Voluntary Observational Study?

Purpose Countries with nationwide quality programmes in colorectal cancer report an improved outcome. In Germany, a self-organized and self-financed observational quality assurance project exists, based on voluntary participation. The object of the present study was to ascertain whether this nationwide project also improves the outcome of colorectal cancer. Methods The German Quality Assurance in Colorectal Cancer Project started in 2000 and by 2012 contained 85,000 patients. Inclusion criteria for the study were participation for the entire period of 13 years and treatment of rectal cancer. The following parameters were analysed: (1) patient related: age, gender, ASA classification, T-stage, and N-stage, (2) system related: frequency of preoperative CT and MRI, and (3) outcome related: CRM status, complications, and hospital mortality. Results Forty-one of the 345 hospitals treating 11,597 patients fulfilled the inclusion criteria. The median age increased from 67 to 69 years (p = 0.002). ASA stages III and IV increased from 32.0% to 37.6% (p = 0.005) and from 2.0% to 3.3% (p = 0.022), respectively. The use of CT rose from 67.2% to 88.8% (p < 0.001) and that of MRI from 5.0% to 35.2% (p < 0.001). The proportion of patients suffering from complications decreased from 7.9% to 5.3% (p < 0.001) for intraoperative and from 28.0% to 18.6% (p < 0.001) for postoperative surgical complications, but general postoperative complications increased from 25.8% to 29.5% (p = 0.006). The distribution of histopathological stage, anastomotic leakage, and in-hospital mortality did not change significantly. Conclusion Participation in a quality assurance project improves compliance with treatment standards, especially for diagnostic procedures. An improvement of surgical results will require further investment in training.

Young Vs Old Colorectal Cancer in Indian Subcontinent: a Tertiary Care Center Experience.

This study aims to compare patient, tumor, treatment-related factors and survival between young (<45years) and old (>45years) Indian colorectal cancer (CRC) patients. Total 778 patients of CRC were registered at tertiary cancer center in India between 1 August 2013 and 31 July 2014. Patients were followed up for median period of 27.73months. Data regarding patient, tumor, treatment and survival-related factors were collected. Patients were divided in young (≤45years) and old (>45years) age groups. Statistical analysis was done with SPSS software version 23. Young age group patients presented more commonly with poor histology, node-positive disease, and rectal site. Younger age group patients received multiple lines of neoadjuvant treatment. There was no significant overall survival difference in both groups of patients. On stratified stage-wise analysis, no significant overall survival (OS) difference was found between two groups (young vs old-1- and 3-year OS: 85.2 and 61.5% vs 81.5 and 64.5%, respectively; P=0.881). On univariate analysis, gender, performance status, site, stage, differentiation, TRG, CRM status, signet ring type, and CEA level were significant prognostic factors. In disease-free survival (DFS) analysis, it is found that there is statistically significant difference in DFS (young vs old: 1 and 3years; 77.6 and 62.8% vs 85.8 and 74.1%, respectively; P value, 0.02), but when OS was analyzed for same group of patient, there was no statistical difference (P=0.302). This study confirms the high incidence rates of CRC in young Indian patients. There is no OS difference between two age groups. In operated group of patients, there is higher DFS in older patients but no OS advantage at 3years follow-up. Further long-term follow-up is required to see any OS difference.

Can CRM status on MRI predict survival in locally advanced rectal cancers: Experience from the Indian subcontinent.

e15167 Background: Neoadjuvant chemoradiation has become the standard approach for treatment of locally advanced rectal cancers. Magnetic Resonence Imaging (MRI) is the staging modality of choice in rectal carcinoma. Recent reports have studied the impact of MRI on local recurrence and survival both in treatment naïve and post treatment settings Methods: A retrospective analysis of prospective database was performed over a period of 1 year. All pretreatment patients with carcinoma of rectum were included in the study. The status of CRM on MRI was compared to that on the histopathology and as a predictor of recurrence and survival. For analysis, the MRI scans done for patients at presentation were labeled as MRIT. This included all patients irrespective of further treatment received. Patients who were treated with NACTRT had two MRI scans. The MRI at presentation in this subset of patients was labeled as MRI1 and the reassessment MRI after NACTRT was labeled as MRI2. Thus, MRI1 represented a subset of MRIT with locally advanced tumors treated with NACTRT. All the sets of MRI scans were analyzed separately for prediction of CRM involvement and for their effect on local recurrence and survival rates. Results: 221 patients were included with a median follow-up 30 months. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of MRIT, MRI1 and MRI2 to predict CRM status were 50%, 62.3%, 96.5%, 5.6% and 61.8%, 50%, 55%, 95%, 6% and 54.7% and 77.8%, 63.7%, 98%, 11%, 64.5% respectively. On multivariate analysis pathological positive margins alone predicted a poor overall survival (OS) whereas involved CRM on pathology and pretreatment MRI predicted poorer disease free survival and OS Conclusions: CRM status on pathology remains the most important prognostic factor to impact overall survival, disease free survival and local recurrence. CRM status on MRI at presentation alone has significant impact on disease free survival and local recurrence. Although MRI done after neoadjuvant treatment may not predict survival, it has a role in helping modify the surgical approach with a goal to achieve a negative CRM on pathology.

PTH-297 Does height of the rectal cancer impact on the use of neo-adjuvant therapy and ultimate oncological outcomes?: Abstract PTH-297 Table 1

Introduction The impact of the height of rectal cancer from the anal verge and its ultimate clinical significance is controversial 1 (as debated by Tekkis et al in their published paper). The aim of this study is to assess the influence of rectal cancer height and oncological outcomes treated in a specialised colorectal cancer unit. Method Prospectively collected data on a patient pathway manager (PPM) for patients who underwent primary rectal cancer treatment at our unit from January 2005 till December 2010 were analysed. Low cancer was defined as tumour 2 test was used for statistical analysis. Results There were 226 male and 133 female patients with mean age of 70 years (Range: 21–93). Of the 359 rectal cancer patients, 149 (41.5%) had low and 210 (58.5%) had medium/high cancer. Outcome data of tumour height, neo-adjuvant therapy, CRM status, type and mode of surgery and disease relapse is tabulated in Table 1. Conclusion Height of rectal cancer does influence use of neo-adjuvant therapy and ultimate R0 resection rate. It does not influence loco-regional or systemic recurrent rates. Disclosure of interest None Declared. Reference Bhangu A, Rasheed S, Tekkis P, et al . Does rectal cancer height influence the oncological outcome? Colorectal Dis. 2014;16:801808

The influence of the treatment response on the impact of resection margin status after preoperative chemoradiotherapy in locally advanced rectal cancer

BackgroundCircumferential resection margin (CRM) and distal resection margin (DRM) have different impact on clinical outcomes after preoperative chemoradiotherapy (CRT) followed by surgery. Effect and adequate length of resection margin as well as impact of treatment response after preoperative CRT was evaluated.MethodsTotal of 403 patients with rectal cancer underwent preoperative CRT followed by total mesorectal excision between January 2004 and December 2010. After applying the criterion of margin less than 0.5 cm for CRM or less than 1 cm for DRM, 151 cases with locally advanced rectal cancer were included as a study cohort. All patients underwent conventionally fractionated radiation with radiation dose over 50 Gy and concurrent chemotherapy with 5-fluorouracil or capecitabine. Postoperative chemotherapy was administered to 142 patients (94.0%). Median follow-up duration was 43.1 months.ResultsThe 5-year overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) rates, and locoregional control rates (LRC) were 84.5%, 72.8%, 74.2%, and 86.3%, respectively. CRM of 1.5 mm and DRM of 7 mm were cutting points showing maximal difference in a maximally selected rank method. In univariate analysis, CRM of 1.5 mm was significantly related with worse clinical outcomes, whereas DRM of 7 mm was not. In multivariate analysis, CRM of 1.5 mm, and ypN were prognosticators for all studied endpoints. However, CRM was not a significant prognostic factor for good responders, defined as patients with near total regression or T down-staging, which was found in 16.5% and 40.5% among studied patients, respectively. In contrast, poor responders demonstrated a significant difference according to the CRM status for all studied end-points.ConclusionsClose CRM, defined as 1.5 mm, was a significant prognosticator, but the impact was only prominent for poor responders in subgroup analysis. Postoperative treatment strategy may be individualized based on this finding. However, findings from this study need to be validated with larger cohort.

Rectal cancer: prognostic indicators of long-term outcome in patients considered for surgery

Patients and clinicians seek an accurate prognosis after resectional surgery for rectal cancer. The aim of this study was to determine long-term outcomes after potentially curative surgery for rectal cancer with particular focus on factors associated with longer-term survival that are available to surgeons in the early post-operative setting. We conducted a retrospective review of a prospectively gathered database of all primary rectal adenocarcinomas considered for surgery in the University Hospitals of Leicester National Health Service (NHS) Trust between 1998 and 2007. Survival was calculated using a Kaplan-Meier method. Factors thought to be associated with survival were subjected to univariate analysis followed by Cox proportion regression. One thousand and twelve patients with primary rectal adenocarcinoma diagnosed between 1998 and 2007 were identified. Eight hundred and fifty three patients did not have metastases at the time of presentation and 726 patients underwent major resectional surgery. Five-year survival was 66%. Patients' age, Dukes' stage, UICC stage, nodal involvement and circumferential resection margin status were independently associated with long-term survival on multivariate analysis. This is one of the largest series of rectal cancers from a single NHS trust. We have demonstrated that age, Dukes' stage and CRM status are associated with long-term survival. These clinical factors are readily available to the surgeon at the time of first post-operative review and can provide a good clinical guide to prognosis.

Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Gene expression profiling in neutrophils from children with polyarticular juvenile idiopathic arthritis

We have previously reported a defect in neutrophil activation in children with polyarticular juvenile idiopathic arthritis (JIA). The current study was undertaken to determine whether gene expression abnormalities persist in JIA in remission and to use systems biology analysis to elucidate pathologic pathways in polyarticular JIA. We performed gene expression profiling on neutrophils from children with polyarticular JIA. Children were grouped according to disease status. We studied 14 children with active disease who were taking medication, 8 children with clinical remission of disease who were taking medication (CRM status), and 6 children with clinical remission of disease who were not taking medication (CR status). We also studied 13 healthy children whose age ranges overlapped those of the patients. Neutrophil abnormalities persisted in children with polyarticular JIA even after disease remission was achieved. Children with active disease and those with CRM status showed no differences in expression of specific genes, although they could be separated on cluster analysis. A comparison of children with CR status and healthy control children revealed networks of pro- and antiinflammatory genes that suggested that remission is a state of homeostasis and balance rather than a return to normal immune function. Furthermore, gene overexpression in patients with CR status supports the hypothesis that neutrophils play a role in regulating adaptive immunity in this disease. Neutrophil gene profiling in polyarticular JIA suggests important roles for neutrophils in disease pathogenesis. These findings suggest the presence of complex interactions between innate and adaptive immunity, that are not easily modeled in conventional, linear, reductionist systems.

The meaning of clinical remission in polyarticular juvenile idiopathic arthritis: gene expression profiling in peripheral blood mononuclear cells identifies distinct disease states.

The development of biomarkers to predict response to therapy in polyarticular juvenile idiopathic arthritis (JIA) is an important issue in pediatric rheumatology. A critical step in this process is determining whether there is biologic meaning to clinically derived terms such as "active disease" and "remission." The aim of this study was to use a systems biology approach to address this question. We performed gene transcriptional profiling on children who fulfilled the criteria for specific disease states as defined by the consensus criteria developed by Wallace and colleagues. The study group comprised children with active disease (n = 14), children with clinical remission on medication (CRM; n = 9), children with clinical remission off medication (CR; n = 6), and healthy control children (n = 13). Transcriptional profiles in peripheral blood mononuclear cells (PBMCs) were obtained using Affymetrix U133 Plus 2.0 arrays. Hierarchical cluster analysis and predictive modeling demonstrated that the clinically derived criteria represent biologically distinct states. Minimal differences were seen between children with active disease and those with disease in CRM. Thus, underlying immune/inflammatory abnormalities persist despite a response to therapy. The PBMC transcriptional profiles of children whose disease was in remission did not return to normal but revealed networks of proinflammatory and antiinflammatory genes, suggesting that remission is a state of homeostasis, not a return to a normal state. Gene transcriptional profiling of PBMCs revealed that clinically derived criteria for JIA disease states reflect underlying biology. We also demonstrated that neither CRM nor CR status results in resolution of the underlying inflammatory process, but that these conditions are more likely to be states of balanced homeostasis between proinflammatory and antiinflammatory mechanisms.

Alternative clinical end points in rectal cancer—are we getting closer?

Background: In rectal cancer a high risk of local recurrence has been reported for patients treated by surgery alone. It is also recognised that 20%–40% of rectal cancer patients continue to develop distant metastases and die, even when a very low risk of local recurrence has been achieved with the use of preoperative radiotherapy and total mesorectal excision (TME). Hence, the current design of randomised trials in rectal cancer continues to use the standard end points of local control and survival. This strategy is time-consuming. The recently published EORTC 22921 trial, which compared radiotherapy with chemoradiotherapy and tested the role of postoperative adjuvant chemotherapy, has taken 14 years from planning to results. The aim of this review was to use the evidence from both phase II and phase III trials to provide a comprehensive survey of alternative clinical trial end points in rectal cancer, where preoperative chemoradiation has now become the standard treatment. We describe their strengths and weaknesses. Some are clearly defined, easy to assess and can be obtained early, because surgical resection usually takes place within 6–8 weeks of the completion of treatment. Some pathological response end points reflect biological activity, although their effect on survival has yet to be validated in randomised controlled trials. We will propose measurement and analytical techniques for minimising bias and intra- and inter-observer variability of the non-validated end points in the hope of basing these judgements on as firm a ground as possible.Methods: A literature search identified both randomised and non-randomised trials of preoperative radiation therapy (RT) and chemoradiation therapy (CRT) in rectal cancer from 1993 to 2005. The aim was to find those studies that documented potential alternative end points.Results: Pathological parameters have been used as early end points to compare studies of preoperative radiotherapy or chemoradiation. In the light of the German CAO/ARO/AIO-94 study, which demonstrated an improved therapeutic ratio for preoperative treatment, enthusiasm for preoperative chemoradiation in the management of rectal cancer is increasing. Current evidence cannot indicate whether the degree of response to chemoradiation (e.g. complete pathological response; downsizing the primary tumour; sterilizing the regional nodes; tumour regression grades or residual cell density) or the achievement of a curative resection (CRM/R0 resection) is the best early clinical end point. Problems with these end points include lack of structured measurement and analysis techniques to control for intra- and inter-observer variation and lack of validation as surrogates for long-term clinical end points such as local control and survival. However, retrospective studies in rectal cancer have confirmed a strong association between the presence of microscopic tumour cells within 1 mm of the CRM and increased risks of both local recurrence and distant metastases. Further end points of current clinical relevance for which adequate methodologies for assessment are lacking include sphincter sparing end points, and assessment of long-term toxicities, ano-rectal function and their specific impact on quality of life. Recommendations are made as to the most appropriate information, which should be documented in future trials.Conclusions: Pathological complete response following preoperative chemoradiation does not reliably predict late outcome. There are other events not mediated through this end point and there are also unintended effects (often an excess of non-cancer related deaths). Disease-free survival currently remains the best (because it is relatively quick) primary end point in designing randomised phase III studies of preoperative chemoradiation in rectal cancer, although it is necessary to control for postoperative adjuvant chemotherapy. However, the CRM status can substantially account for effects on disease-free and overall survival after chemoradiation, radiation or surgery alone. Hopefully, randomised controlled trials, which utilise these alternative clinical end points, will in future determine the precise percentages of the effect of different chemoradiation schedules on disease-free and overall survival.