Prolonged Disease-free Survival Research Articles

Comparison of first-generation EGFR-TKIs (gefitinib, erlotinib, and icotinib) as adjuvant therapy in resected NSCLC patients with sensitive EGFR mutations.

BackgroundSeveral randomized controlled trials have suggested that adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were associated with prolonged disease-free survival (DFS) in EGFR-mutated NSCLC patients after radical resection, comparing with chemotherapy or placebo. We aimed to compare the effectiveness of different first-generation EGFR-TKIs as adjuvant treatment in real-world setting.MethodsEarly-stage EGFR mutated NSCLC patients who underwent radical resection and treated with first-generation EGFR-TKIs (gefitinib, erlotinib, icotinib) as adjuvant therapy between Feb 2010 and Jan 2019 were retrieved from a prospectively-maintained database in our center. The primary endpoint was DFS in stage II/III (TNM 8th) patients with exploratory endpoint regarding DFS in stage I patients. Sensitivity analyses were based on propensity score matched (PSM) cohorts. Treatment failure patterns among different TKIs were also compared.ResultsOf 588 eligible patients, 198 patients (33.7%) received gefitinib, 106 patients (17.9%) received erlotinib, and 284 patients (48.2%) received icotinib. The median DFS of stage II/III patients in the gefitinib, erlotinib and icotinib group were 36.1 months (95% CI, 23.9–49.4), 42.8 months (95% CI, 29.6–97.8), and 32.5 months (95% CI, 23.9–49.4), respectively, with no significant difference (log-rank test P=0.22). There was also no significant difference in DFS among stage I patients receiving different TKIs (P=0.12). PSM adjustments and multivariate analyses adjusting for other confounders revealed similar results. In addition, there were no significant differences in treatment failure pattens in different EGFR-TKI arms, especially in terms of brain metastases (6.1% in gefitinb, 7.5% in erlotinib, 3.9% in icotinib) and bone metastases (8.6% in gefitinb, 9.4% in erlotinib, 7.0% in icotinib).ConclusionsThis first and largest real-world study showed that gefitinib, erlotinib, and icotinib demonstrated comparable clinical effectiveness as adjuvant therapy for patients with early-stage EGFR mutated NSCLC.

Abstract PO-036: LP184, a novel alkylating agent, is highly effective in pancreatic cancers with DNA damage repair defects

Abstract Biomarker-based chemotherapy with increased efficacy and prolonged disease-free survival are urgently needed in pancreatic cancer (PDAC). A 15-20% subset of PDAC tumors carry mutations in DNA repair pathway (BRCA1/BRCA2/PALB2/RAD51/ATM/FANCD2). Additionally, mutations in nucleotide excision repair (NER) genes (ERCC2/3/4/5/6) have been reported in ~5% of PDAC. LP184 is a novel synthetic small molecule acylfulvene analog. Using precise synthetic chemistry, we determined that only a negative enantiomer of LP184 is converted to an active alkylating agent in the strict dependency on oxidoreductase, prostaglandin reductase 1 (PTGR1). By computational analyses, we demonstrate a strong positive correlation of LP184 sensitivity with PTGR1 transcript levels (r=0.89, p<10−15) in a broad panel of cancer cell lines. Once activated by PTGR1, highly reactive LP-184 nucleophile creates covalent DNA adducts that are selectively repaired via Nucleotide Excision Repair (NER) mechanism coupled to transcription (TC-NER) and/or homologous recombination (HR). We reasoned that mutation or expression driven TC-NER and HR deficiency would predispose PDAC cells to increased sensitivity to LP184. To test the idea of LP184 activity in DNA repair-deficient tumors, we evaluated LP184 chemosensitivity in genetically defined PDAC models in vitro, ex vivo, and in xenografts. Testing in six different pancreatic cancer cell lines (Capan-1, CFPAC-1, Panc1, MiaPaCa2, Panc03.27 and BxPC-3) resulted in very potent inhibition with LP184 IC50 values ranging from 114 to 182 nM. In this cell line panel, LP184 sensitivity correlated negatively with transcript levels of an NER pathway gene ERCC8 (r = -0.94). In comparison to these PDAC cell lines, a normal pancreatic epithelial cell line HPNE was 3-6 times less sensitive to LP184 (IC50 670 nM). Ex vivo cultures of 4 out of 5 low-passage patient-derived xenografts with HR deficiency showed nanomolar sensitivity to LP184 with IC50s ranging from 45 to 270 nM. These tumor graft models which were at least 6 times less sensitive to olaparib in the same assay. Depletion of ERCC4 enhanced sensitivity to LP184 about 2-fold relative to the parental cell line. To define PTGR1 as a biomarker for LP184 activity, we used CRISPR/Cas9-mediated gene editing to deplete PTGR1 expression. We found PTGR1-null Capan-1 cell line-derived xenografts were poorly sensitive to LP184, whereas PTGR1-expressing xenografts showed near complete tumor regression in all LP184 treated animals with 109% tumor growth inhibition relative to the control group in this study. Furthermore, PTGR1 depleted cells were completely resistant to LP184 in vitro. Our preclinical data demonstrate that PDAC models carrying a range of DNA repair pathway mutations are highly sensitive to LP-184 in vitro and in vivo. Increased PTGR1 expression is a validated biomarker for LP184 cytotoxicity, and is the exclusive convertase of LP184 to an active alkylator drug. We anticipate LP184 will extend the therapeutic opportunities to a large subset of PDAC patients carrying these genetic alterations. Citation Format: Diana Restifo, Aditya Kulkarni, Caleb Schimke, Joseph McDermott, Umesh Kathad, Kishor Bhatia, Panna Sharma, Igor Astsaturov. LP184, a novel alkylating agent, is highly effective in pancreatic cancers with DNA damage repair defects [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-036.

Analysis of the effect of ipsilateral supraclavicular lymph node metastasis on the prognosis of N3 breast cancer

Objective: The 6th edition American Joint Committee on Cancer (AJCC) staging system for breast cancer classifies ipsilateral supraclavicular lymph node metastasis (ISLM) downing stage from M1 to N3, suggesting more patients might receive radical treatment. The aim of this study was to analyze the effect of ISLM on the prognosis of N3 breast cancer and verify the rationality of modified staging. Methods: A total of 321 breast cancer patients with N3 according to the 6th edition AJCC staging system were retrospectively analyzed. Propensity Score Matching (PSM) was used to pair the different subgroups of N3. The primary end point was disease-free survival (DFS), the secondary end point was overall survival (OS). Kaplan-Meier method was used to calculate the DFS and OS. The differences between two groups were analyzed by the Log-rank test. Results: After PSM pairing twice, 78 patients with none-ISLM and 78 patients with ISLM were enrolled in the first group; 51 patients with none-ISLM was compared patients with isolated ISLM in the second group. The results of the two groups showed that patients with none-ISLM have a prolonged DFS (the first group: 58.9 months vs 32.1 months, P=0.101; the second group: 59.0 months vs 44.0 months, P=0.533), while the OS was opposite (the first group: 87.4 months vs 140.4 months, P=0.289; the second group: 87.4 months vs 137.1 months, P=0.289). Conclusions: The prognosis of breast cancer patients with ISLM is similar to that of patients with none-ISLM in stage N3. It is reasonable to include ISLM in N3 in the 6th edition AJCC staging system. Yet, prospective studies with larger sample size are needed to further confirmation.

Biopsy and re-biopsy for PD-L1 expression in NSCLC. association between PD-L1 and checkpoint inhibitor efficacy through treatment in NSCLC. A pilot study

ABSTRACT Introduction Lung cancer is diagnosed at a late stage due to lack of early disease symptoms. Therefore an efficient treatment is necessary for prolonged disease free survival. Patients and Methods In our study we recruited 124 patients NSCLC patients with adenocarcinoma and squamus cell carcinoma. All recuited patients had Programmed death-ligand 1 expression ≥50 (PD-L1)with DAKO technique. Immunotherapy was administered with as first line treatment. Re-biopsies were performed in the main lung lesion every 4 months with the restaging of the patient and also in the metastastic sites in other organs that occurred during treatment. PD-L1 expressed was evaluated in the biopsies of the metastatic sites. Results It appears thereafter that the PD-L1 expression could easily be claimed as a promising bio-index with a cutoff value 65, below which a negative prognosis of the disease progress will be evident and above that value a positive continuation of the disease will be prominent. Conclusion The findings of this study suggest that the PD-L1-65 index works adequately either concerning the neo-metastatic sites or the patient disease responses. Re-biopsies in new metastastic sites are necessary since we probably have a new cancer and chemotherapy should be added. More studies should confirm are results and change the NSCLC treatment approach of these patients.

2021 Update on allogeneic hematopoietic stem cell transplant for myelofibrosis: A review of current data and applications on risk stratification and management

The number of patients with myelofibrosis (MF) undergoing an allogeneic hemopoietic stem cell transplantation (HSCT) is increasing: in the analysis of the European Group for Blood and Marrow Transplantation (EBMT) the number of MF has increased from 515 in 2014 to 748 in 2018 . This reflects the fact that HSCT is currently the only curative treatment, capable of inducing prolonged disease‐free survival. Nevertheless, several problems prevent more patients from undergoing an allogeneic HSCT: we will be discussing indications for HSCT, comorbidities, splenomegaly, older age and disease phase. Donor type and stem cell source are less of a problem. Several transplant platforms exist, including different strategies for graft versus host disease (GvHD) prophylaxis, Age tailored conditioning regimens need to be implemented, to allow older and fragile patients to undergo an allogeneic HSCT.

High Visceral Fat in Female Breast Cancer Patients Correlates with the Risk of Progression after Adjuvant Chemotherapy

Rationale Clinical and epidemiological evidence indicate that obesity is associated with the risk and progression of breast cancer. Body mass index (BMI) as a measure of adiposity does not precisely describe individual body composition and adipose tissue distribution. We aimed to investigate the association between body composition and the efficiency of adjuvant chemotherapy as well as post-treatment progress among female breast cancer patients. Methods Participants included 199 females with stage I-III breast cancer. Body composition, including body fat mass, visceral fat level, and skeletal muscle mass, was assessed based on the bioelectrical impedance analysis (BIA). The Kaplan-Meier survival curves, log-rank test, and Cox proportional-hazards model were used to estimate the effects of body composition as prognostic factors on survival. Results Postmenopausal women had a higher proportion of visceral fat compared to premenopausal women (64% vs. 33.87%, P < 0.001). Compared with those with normal visceral fat level, patients with high visceral fat level were older (P < 0.001), had higher body fat mass (p < 0.001), skeletal muscle mass (P = 0.013), minerals (P = 0.011), protein (P = 0.036), triglycerides (P = 0.038), cholesterol (P = 0.022), and low-density lipoprotein cholesterol (LDL-C) (P = 0.015). A more prolonged disease-free survival (DFS) was noted in patients with a normal visceral fat level as compared to patients with a high visceral fat level (hazard ratio [HR] 1.9, 95% CI 1-3.5; adjusted HR 1.77, 95% CI 0.932-3.36). Conclusions A high visceral fat level in female patients with breast cancer is associated with a shorter DFS after adjuvant chemotherapy. Body composition alongside BIA provides a quick and noninvasive approach to identify breast cancer patients with a higher risk of cancer progression.

P59.16 Characterizing the Tumour-Immune Microenvironment in EGFR Mutant NSCLC

Non-small cell lung cancer (NSCLC) comprises around 80% of lung cancers, with mutations in epidermal growth factor receptor (EGFR) effecting approximately 26%. These constitutive activating mutations promote tumour cell proliferation and survival, and are inevitably refractory to tyrosine kinase inhibitors (TKIs) as well as current classes of immune checkpoint immunotherapy (ICI). Third generation TKI Osimertinib offers prolonged disease-free survival, however the reasons for the lack of efficacy of ICI in EGFR mutant tumours remain unclear. The cellular immune composition of the tumour microenvironment is increasingly being recognised as a major factor in host-tumour responses. The use of multispectral immunohistochemistry (IHC) is a valuable tool to investigate the cellular composition of these tumours. Here we compare a cohort of EGFR exon 19 deletion (LREA) tumours to stage matched EGFR wild type (WT) tumours by multispectral IHC. Automated staining was performed for CD8, FoxP3, PD-1, CD68, PD-L1 and cytokeratin markers using MOTiF™ PD-1/PD-L1 lung cancer kit, and slides imaged by Vectra®Polaris™. Image analysis was performed using QuPath, and marker counts were obtained within tumour and adjacent microenvironment compartments Immune cells marked by CD8, FoxP3, PD-1, CD68 composed 5%-30% of total cells in the WT tumours, while LREA tumours contained 5% to 15% of total cells (t-test p = 0.17). While these immune cells trended to be lower in LREA tumours, further investigation into their distribution in a larger cohort of patients is required. The LREA cohort displayed poorer progression free survival (PFS) following resection and platinum therapy than the WT cohort (468 days vs 622 days, p=0.2). Neighbourhood mapping suggested cellular populations within the tumour microenvironment which associated with the different tumour profiles. Our data suggests that tumour intrinsic mechanisms may result in poorer host-tumour responses. One such mechanism is the immunosuppression of the local microenvironment, and we aim to expand this work to encompass a wider cohort of patient tumours and cellular markers.

P300/CBP-associated factor (PCAF)-mediated acetylation of Fascin at lysine 471 inhibits its actin-bundling activity and tumor metastasis in esophageal cancer.

BackgroundFascin is crucial for cancer cell filopodium formation and tumor metastasis, and is functionally regulated by post‐translational modifications. However, whether and how Fascin is regulated by acetylation remains unclear. This study explored the regulation of Fascin acetylation and its corresponding roles in filopodium formation and tumor metastasis.MethodsImmunoprecipitation and glutathione‐S‐transferase pull‐down assays were performed to examine the interaction between Fascin and acetyltransferase P300/CBP‐associated factor (PCAF), and immunofluorescence was used to investigate their colocalization. An in vitro acetylation assay was performed to identify Fascin acetylation sites by using mass spectrometry. A specific antibody against acetylated Fascin was generated and used to detect the PCAF‐mediated Fascin acetylation in esophageal squamous cell carcinoma (ESCC) cells using Western blotting by overexpressing and knocking down PCAF expression. An in vitro cell migration assay was performed, and a xenograft model was established to study in vivo tumor metastasis. Live‐cell imaging and fluorescence recovery after photobleaching were used to evaluate the function and dynamics of acetylated Fascin in filopodium formation. The clinical significance of acetylated Fascin and PCAF in ESCC was evaluated using immunohistochemistry.ResultsFascin directly interacted and colocalized with PCAF in the cytoplasm and was acetylated at lysine 471 (K471) by PCAF. Using the specific anti‐AcK471‐Fascin antibody, Fascin was found to be acetylated in ESCC cells, and the acetylation level was consequently increased after PCAF overexpression and decreased after PCAF knockdown. Functionally, Fascin‐K471 acetylation markedly suppressed in vitro ESCC cell migration and in vivo tumor metastasis, whereas Fascin‐K471 deacetylation exhibited a potent oncogenic function. Moreover, Fascin‐K471 acetylation reduced filopodial length and density, and lifespan of ESCC cells, while its deacetylation produced the opposite effect. In the filipodium shaft, K471‐acetylated Fascin displayed rapid dynamic exchange, suggesting that it remained in its monomeric form owing to its weakened actin‐bundling activity. Clinically, high levels of AcK471‐Fascin in ESCC tissues were strongly associated with prolonged overall survival and disease‐free survival of ESCC patients.ConclusionsFascin interacts directly with PCAF and is acetylated at lysine 471 in ESCC cells. Fascin‐K471 acetylation suppressed ESCC cell migration and tumor metastasis by reducing filopodium formation through the impairment of its actin‐bundling activity.

The Ratio of Preoperative Serum Biomarkers Predicts Prognosis in Patients With Oral Squamous Cell Carcinoma

BackgroundDynamic changes in circulating immune-inflammatory cells have been regarded as simple and convenient prognostic biomarkers in various cancers. However, studies on the prognostic values of their ratios in oral squamous cell carcinoma (OSCC) remain limited.Materials and MethodsA total of 493 OSCC patients were included in the present study. Here, we investigated the prognostic values of the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), neutrophil-to-white blood cell ratio (NWR), and lymphocyte-to-white blood cell ratio (LWR) in OSCC. The correlations of the NLR, LMR, NWR, and LWR with clinicopathological characteristics were statistically analyzed using the Chi-square test, Kaplan-Meier curves, and univariate and multivariate Cox regression models.ResultKaplan-Meier analyses revealed that OSCC patients with a high LMR and low NWR had prolonged overall survival (OS, P<0.001) and disease-free survival (DFS, P<0.001 and P=0.003, respectively), but there were no significant differences in metastasis-free survival (MFS, P=0.053 and P=0.052, respectively). In contrary, a high NLR and low LWR were associated with poor OS (P<0.001 and P=0.0016, respectively), DFS (P=0.0014 and 0.0012, respectively) and MFS (P=0.021 and 0.008, respectively). Additionally, Cox multivariate analyses showed that the LMR was an independent prognostic factor for both OS (P=0.007) and DFS (P=0.017), while the LWR was an independent prognostic factor for MFS (P=0.009).ConclusionPreoperative NLR, LMR, NWR, and LWR in the peripheral blood are significant prognostic factors for OSCC and might be helpful in predicting OSCC progression.

The role of CpG island methylator phenotype in the clinical course of hepatocellular carcinoma.

Aberrant DNA methylation is strongly associated with heterogeneity in tumors. This study investigated the prognostic value of CpG island methylator phenotype in hepatocellular carcinoma (HCC). A total of 319 HCC samples with 21 121 CpG sites were included in this study and 215 disease-free survival (DFS) and overall survival (OS)-related CpG sites were identified. These CpG sites were divided into seven clusters by using consensus clustering method. Cluster 4, which constructed the prognostic prediction model as the seed cluster to evaluate survival risk for DFS and OS of HCC patients, had the lowest methylation level with the worse prognosis. The low-risk group patients had a significantly prolonged DFS and OS than the patients in the high-risk group (P = 0.008 and P < 0.001, respectively). A receiver operating characteristic curve results for predicting DFS and OS were 0.691 and 0.695, respectively. These results suggested that the CpG site methylation appears to be an informative prognostic biomarker in HCC. The CpG site methylation-related prognostic model may be an innovative insight to evaluate clinical outcomes for HCC patients. The code of the analysis is available at https://www.bioconductor.org. Supplementary data are available at Bioinformatics online.

Current status and future perspectives of immunotherapy against urothelial and kidney cancer.

Much attention has been paid to immune checkpoint inhibitors to various cancer treatments. In urothelial cancer, pembrolizumab was initially approved for patients who either recurred or progressed following platinum-based chemotherapy. For the platinum-fit population, although the standard first-line treatment is still platinum-based systemic chemotherapy, avelumab has been recently approved as a maintenance therapy for patients who have not had disease progression with four to sixcycles of first-line chemotherapy. In addition, adjuvant nivolumab has just prolonged disease-free survival (DFS) by ~10months, compared with placebo in patients with muscle-invasive bladder urothelial cancer or upper tract urothelial cancer at high-risk of recurrence after radical surgical resection. On the other hand, in kidney cancer, nivolumab was initially approved for advanced renal cell carcinoma patients after one or two prior anti-angiogenic therapies. Next, combinations of two immune checkpoint inhibitors (nivolumab + ipilimumab) and immune checkpoint inhibitor+tyrosine kinase inhibitors (pembrolizumab + axitinib and avelumab + axitinib) were approved for the first-line treatment for patients with advanced renal cell carcinoma. Recently, new generation tyrosine kinase inhibitors, such as cabozantinib and lenvatinib have been combined with immune checkpoint inhibitors. Both nivolumab + cabozantinib and pembrolizumab + lenvatinib have demonstrated superior progression-free survival and objective response rate, compared with sunitinib. So far, no prospective trials have demonstrated the duration of immune checkpoint inhibitor treatments. We are now doing the Japan Clinical Oncology Group 1905 trial, where patients with advanced renal cell carcinoma who have received an immune checkpoint inhibitor for 24weeks are divided into two groups: those who continue immune checkpoint inhibitor treatment and those who discontinue immune checkpoint inhibitor treatment.

Perioperative Therapy for Non-Small Cell Lung Cancer with Immune Checkpoint Inhibitors.

Simple SummaryThis review presents the development of perioperative treatment using immune checkpoint inhibitors (ICIs) in patients with resectable non-small cell lung cancers. There are several ongoing phase 3 trials for adjuvant and neoadjuvant ICI therapies. The results of the adjuvant (IMpower010 trial) and the neoadjuvant (Checkmate 816 trial) ICI phase 3 trials have shown prolonged disease-free survival and increased pathological complete response rate, respectively. Based on the hypothesis that ‘preoperative ICI treatment, especially in combination with conventional chemotherapy, promotes a higher immune response because of preservation of the immune environment’, neoadjuvant trials using ICIs and conventional chemotherapy in combination are currently being conducted more frequently than adjuvant ICI trials. Multimodality approaches using chemoradiotherapy and new ICI agents are also being examined in several phase 2 trials. To maximise ICI therapy’s efficacy and to minimise futile administration, methodologies for predicting and monitoring the therapeutic effects, such as detecting minimal residual disease, need to be established.The emergence of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment landscape for patients with metastatic non-small cell lung cancer (NSCLC). These achievements inspired investigators and pharmaceutical companies to conduct clinical trials in patients with early-stage NSCLC because both adjuvant and neoadjuvant platinum-based doublet chemotherapies (PT-DCs) showed only a 5% improvement in 5-year overall survival. IMpower010, a phase 3 trial (P3), showed that adjuvant PT-DC followed by maintenance atezolitumab significantly prolonged disease-free survival over adjuvant PT-DC alone (hazard ratio, 0.79; stage II to IIIA). Since conventional therapies, including chemotherapy and radiotherapy, can promote immunogenic cell death, releasing tumour antigens from dead tumour cells, ICI combination therapies with conventional therapies are widely proposed. The Checkmate 816 trial (P3) indicated a significantly higher pathological complete response rate of neoadjuvant nivolumab/PT-DC combination therapy than of neoadjuvant PT-DC alone (odds ratio, 13.9, for stage IB to IIIA). Detection of circulating tumour DNA is highly anticipated for the evaluation of minimal residual disease. Multimodal approaches and new ICI agents are being attempted to improve the efficacy of ICI treatment in phase 2 trials. This review presents the development of perioperative treatment using ICIs in patients with NSCLC while discussing problems and perspectives.

Prognostic value of KIT and other clonal genetic mutations in core-binding factor acute myeloid leukemia

目的评价基于二代测序（NGS）检测技术下的克隆性基因突变对核心结合因子相关急性髓系白血病（CBF-AML）预后的影响。方法回顾性分析2011年7月至2017年8月在苏州大学附属第一医院血液科诊治的195例成人初治CBF-AML患者，其中诱导化疗达完全缓解的患者190例，包括134例RUNX1-RUNXIT1+ AML和56例CBFβ-MYH11+ AML，年龄15～64岁，中位随访时间43.6个月。采用Log-rank检验和Cox回归模型分析临床因素和基因突变对患者总生存（OS）和无病生存（DFS）的影响。结果在195例患者中，KIT基因突变发生率最高（47.6％），其次为NRAS（20.0％）、FLT3（18.4％）、ASXL2（14.3％）、KRAS（10.7％）、ASXL1（9.7％）。按基因功能分类，酪氨酸激酶信号通路基因突变发生率最高（76.4％），其次为染色质修饰相关基因（29.7％）。在接受强化巩固治疗的患者中，CBFβ-MYH11+ AML患者的OS有优于RUNX1-RUNXIT1+ AML患者的趋势（P＝0.062）。染色质修饰相关基因突变仅在RUNX1-RUNXIT1+ AML中检出，但对患者的DFS无明显影响（P＝0.557）。染色质修饰相关基因突变阳性且接受异基因造血干细胞移植（allo-HSCT）的患者预后最好。多因素分析显示KIT exon17突变为影响RUNX1-RUNXIT1+ AML患者DFS的独立危险因素（P<0.001），allo-HSCT能明显改善RUNX1-RUNXIT1+ AML患者的DFS（P＝0.010）。结论合并KIT exon17突变的RUNX1-RUNXIT1+ AML患者预后差，allo-HSCT可改善这部分患者的预后，allo-HSCT也能使染色质修饰相关基因突变阳性患者的预后得到改善。

Cancer du rectum : vers une prise en charge personnalisée

The standard of care for patients with locally advanced rectal cancer has recently changed and is now based on the concept of total neoadjuvant therapy with the association of radiotherapy and systemic chemotherapy before radical surgery. The addition of noeadjuvant systemic chemotherapy before or after radiotherapy during preoperative course significantly decreased the risk of distant metastases and prolonged disease-free survival after surgery. The risk of recurrence varies among patients and the standard management associating chemotherapy, radiotherapy and surgery may expose many patients to overtreatment and can negatively affect quality of life. In this setting, several ongoing trials evaluate the possibility of less aggressive individually tailored approach based on omission of one of three treatments. In particular, NORAD and PROSPECT trials evaluate whether irradiation could be safely omitted in patients who are good responders to induction chemotherapy and have locally advanced primarily resectable tumor with large predictive circumferential resection margin. In the other hand, the total neoadjuvant therapy had significantly improved the pathological complete response rate, up to 30%, leading the concept of non-operative management and organ-preserving strategies. The phase III GRECCAR 12 study has therefore evaluated the potential benefit of intensification of neoadjuvant chemotherapy whereas OPERA and MORPHEUS trials assessed radiotherapy dose escalation by contact X-ray or brachytherapy for organ-preserving strategies. To date, total neoadjuvant therapy following by radical surgery remains the standard of care but probably less aggressive approach with omission of radiotherapy or surgery will become a new standard in selected patients in next future.

Circular RNA_0001946 is insufficiently expressed in tumor tissues, while its higher expression correlates with less lymph node metastasis, lower TNM stage, and improved prognosis in NSCLC patients.

ObjectiveCircular RNA_0001946 (circ_0001946) inhibits tumor progression but promotes chemosensitivity in non‐small‐cell lung cancer (NSCLC); however, its correlation with tumor features and prognosis in NSCLC patients is still unclear; therefore, this study aimed to investigate these issues.MethodsA total of 284 NSCLC patients were retrospectively analyzed. Circ_0001946 expression in tumor (n = 284) and adjacent (n = 125) tissues was detected by the reverse transcription‐quantitative polymerase chain reaction. Meanwhile, patients’ clinical characteristics, recurrence, and survival data were extracted from the electrical database.ResultsCirc_0001946 expression in adjacent tissues was over 3‐folds as that in tumor tissues (P < .001). Meanwhile, higher tumor circ_0001946 expression was correlated with less lymph node metastasis (P < .001) and decreased TNM stage (P = .001), but did not correlate with other clinicopathological features. Moreover, higher tumor circ_0001946 expression was associated with prolonged disease‐free survival (DFS) (P < .001) and overall survival (OS) (P < .001), respectively. Subgroup analyses revealed that higher tumor circ_0001946 was correlated with improved DFS in patients with TNM stage I, II, or III, respectively (all P < .05), while only correlated with prolonged OS in patients with TNM stage III (P = .037), but not in patients with TNM stage I or II. Further multivariate Cox's proportional hazard regression analyses suggested that higher tumor circ_0001946 expression could independently predict improved DFS (P < .001, hazard ratio (HR) = 0.719) and OS (P < .001, HR = 0.746), respectively.ConclusionCirc_0001946 is insufficiently expressed in tumor tissues, whereas its higher expression correlates with less lymph node metastasis, reduced TNM stage, and improved prognosis in NSCLC patients.

Predictorsof Early Engraftment in Autologous Peripheral Stem Cell Transplantation; a Single Center Experience

Introduction: Autologous stem cells transplantation (ASCT) is a treatment option used in various hematological malignancies. ASCT can prolong disease free survival, improve survival, and may be curative. We investigated the variables affecting engraftment among patients treated with high dose-chemotherapy and ASCT.Methods: 364 adult patients underwent 419 ASCT from 2001 to 2016, at the American University of Beirut Medical Center. There were 207 males and 157 females, with a median age of 45 years (17-74). The cohort included 126 multiple myeloma (MM), 120 non-Hodgkin lymphoma, and 108 Hodgkin lymphoma, while 10 patients had other malignancies. All patients received high-dose chemotherapy regimens without total body irradiation. The median time from diagnosis to first transplant is 11.9 months (range 2-288). The median number of apheresis was 1 (range 1-5).Results: The median number of infused CD34+ cells was 5.8x106/kg (range 0.71-24.9) which contained DMSO at a median dose of 0.2 g/kg BW (range 0.0375-0.91). Patients exhibited an absolute neutrophil count (ANC) recovery of ≥0.5x109/L at a median of 10 days (range 1-97). Platelet recovery to ≥20x109/L occurred at a median of 15 days (range 7-46). Status of the disease at transplant was: 130 patients (31%) were in complete remission (CR), 242 (58%) in partial remission (PR), and 47 (11%) patients were in relapse or progressive disease.The findings of univariate and multivariate analyses are summarized in Table 1. Diagnosis other than MM, low DMSO dose (< 0.2 g/kg BW), and high infused CD34+ cell count (>6x106/kg) were associated with engraftment of neutrophils within 10 days from stem cell infusion. Low DMSO dose and high infused CD34+ cell count were associated with engraftment of platelets within 15 days.Conclusion: Our results imply that the infused CD34+ cell count and the DMSO dose are important predictors of hematopoietic engraftment, namely neutrophil and platelet engraftment. These findings need to be verified in larger scale studies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Tumor Associated Macrophages and Topoisomerase II Alpha As Prognostic Factors in Advanced Stage Hodgkin's Lymphoma

Background : Classic Hodgkin's lymphoma (cHL) is associated with a high cure rate, but approximately 20% of patients are refractory to initial treatment and 10-30% of patients will relapse after achieving complete remission (CR) , the search of new prognostic factors to identify these high risk patients remains challenging in daily practice, the aim of this study is to evaluate CD68 positive Tumor associated macrophages(TAM) and the cell proliferation marker topoisomerase II alpha as prognostic factor in advanced stage (cHL). Patient and Methods: This study included 82 patients with Advanced stage classic Hodgkin lymphoma presented to Medical Oncology Departments of the National Cancer Institute, Cairo University and Zagazig University hospitals in the period from 2012 to 2017. All patients received ABVD regimen as induction. Immunohistochemical (IHC) analysis was performed for all cases using Tissue microarrays (TMAs) sections and stained with anti‐ CD68 (clones KP1 and PGM1, Dako, Glostrup,Denmark). For Topo II testing, IHC staining was performed on deparaffinized sections using the avidin-biotin complex immunoperoxidase technique with separate antibodies recognizing CD30 and the isoform of Topo II. The percentage of cells expressing cytoplasmic CD30 and nuclear Topo II staining simultaneously was determined for each case. We examined four cutoff points of CD68 expression (<= 20% versus >20%), <5% low (score 1), 5-15% intermediate (score 2) & > 15% high (score 3), <5% low (score 1), 5-25% intermediate (score 2) & > 25% high (score 3) and <= 50% versus > 50%. For Topo II expression, two cut off points were analyzed (<= 30% versus >30%) and (<= 75% versus >75%). Results: The study included 41 males and 41 females with a ratio of 1: 1. The median age was 30.5 years (range: 18-60 years). CRwas achieved in 64.6% (53/82 of patients) and 35.4% of all patients (29/82) were refractory. Relapse was reported in17% of the CR cases (9/53). The significant statistical difference in disease-free survival (DFS) for CD68+was observed at a cut off value of 50%, where 60 patients had CD68 <= 50% and 22 patients had CD68 >50%. The mean DFS for patients with CD68 <= 50% was 49.33 months ± 2.18 months (confidence interval: 45.05 to 53.60 months) vs. 35.255 ± 4.94 months (confidence interval: 25.55 to 44.95 months) in patients with CD68 > 50% (p = 0.015). The low CD68 group included more patients in CR (67.9%, n=36 vs. 32.1%, n=17) , male to female ratio was equal(1:1) in both groups (<= 50% ,n=30:30) and (> 50% ,n=11:11), B symptoms also was equal in both groups (<= 50% , 81% ,n=49) and (> 50% 81% ,n=18), patients with CD68<= 50% had more extra nodal disease (22%, n=13 vs. 18%, n=4) and also more bulky disease (20%, n=12 vs. 4.5% n=1) compared with high (CD68>50%) group. The overall survival (OS) was not significant for all CD68 cutoff points. Higher CD68 is associated with decreased OS: 48 vs. 52 month (CI: 42 to 53 month, p=0.42) at cut off 50%. Topo II expression using the two cut off points was not statistically significant in relation to both DFS and OS , the higher topoII group included more patients in CR (80% ,n=42 topo II >30% vs. 20%, n=10 topo II<=30%) also,(67%, n=53 Topo II >= 75% vs. 33%, n=17 Topo II < 75%). Higher Topo II is associated with prolonged DFS (45 months vs. 36 month) confidence intervals: 40 to 50 months vs 27 to 46. Months) at cut off 30% (p=0.8). At cutoff 75%, the DFS was 46 vs. 38 months (Confidence intervals: 41.73 to 52.10 months vs. 30 to 47.7 months, p= 0.36). Higher Topo II is associated with decreased OS: 50 vs.54 months (CI: 46 to 54 month) at cutoff 75% (p=0.19). CD68 was only statistically significant in correlation to patient age (p = 0.05), and non significant to serum albumin ,hemoglobin level , white blood cells count ,international prognostic score (IPS). Topo II was not statistically significant with the previous patient characteristics. Conclusion : High level of CD68 expression in patients with advanced stage HL (>50%) was significantly associated with inferior DFS but not OS, Topo II does not have significant prognostic value in relation to both DFS or OS of advanced HL cases. DisclosuresNo relevant conflicts of interest to declare.

A Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients

A Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients

First Report on a Successful Screening Program for MYC Rearrangements and a Prospective Clinical Trial Based on MYC Rearrangement in Newly Diagnosed DLBCL Patients in the Netherlands

▪IntroductionPatients with aggressive B-cell lymphoma that harbor a MYC rearrangement (WHO 2008: Diffuse Large B-cell Lymphoma (DLBCL) or B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma (BCL-U)) have a dismal prognosis following standard first-line treatment. Intensifying chemotherapy prolongs disease free survival when compared to R-CHOP. Despite this, relapses often occur and overall survival has not been improved, hence justifying trials with MYC targeting drugs.Lenalidomide has demonstrated to down-regulate MYC and its target genes in MYC rearranged B-cells and therefor potentially is an effective MYC targeting compound. Although lenalidomide seems mainly effective in ABC subtype DLBCL, the ability of MYC downregulation provides the rationale of lenalidomide administration in MYC rearranged lymphoma, that are usually of GCB subtype. The addition of lenalidomide to R-CHOP has already been demonstrated to be safe and well tolerable. Until now, no prospective studies for MYC rearranged DLBCL patients have been conducted. This is at least partially due to lack of adequate screening facilities for MYC rearrangements.To this end we initiated a registration and screening program for all newly diagnosed DLBCL patients in which performing MYC FISH was advocated and financially supported (HOVON 900). Patients with a proven MYC rearrangement were subsequently included in a clinical trial (HOVON 130: A phase II study evaluating the effect of the addition of lenalidomide to R-CHOP for patients with newly diagnosed MYC positive DLBCL and BCL-U (EudraCT 2014-002654-39)). Here we present data from the screening program and demographic data of the first 64 eligible patients included in the prospective clinical trial.Material, methods and preliminary resultsDuring the screening period for MYC rearrangements, administration of one cycle of R-CHOP21 is allowed. After being diagnosed with a MYC rearrangement, lenalidomide 15 mg on day 1-15 of R-CHOP21 is added. In total patients receive 6 cycles of R-CHOP21 plus 6 cycles of lenalidomide plus 2 cycles of rituximab monotherapy. Moreover, as these patients have a high risk of CNS relapse, intrathecal prophylaxis is given to all patients . Primary endpoint of the study is centrally reviewed end-of-treatment complete metabolic remission rate on PET-CT scan.Screening database (HOVON 900): Between August 1st 2015 and July 17th 2017, 581 newly diagnosed DLBCL patients from 62 centers covering all regions of the Netherlands have been registered. Median age at diagnosis was 65 years (range 19 to 82 years). Male: female ratio 62%: 38%. MYC FISH analysis was successful in 73% of patients. Clinical trial (HOVON 130): In total 67 patients were diagnosed with a MYC rearrangement and were included. After central pathology review, 3 patients were declared ineligible (2 transformed follicular lymphoma, 1 MYC rearrangement not confirmed). Additional FISH analysis on BCL2 and BCL6 rearrangements revealed that 27% of the cases were MYC single hit, 59% were double hit (MYC and BCL2 or BCL6) and 14% were triple hit (MYC and BCL2 and BCL6) DLBCL patients (analysis of 51 patients, to be completed).Clinical baseline characteristics of the 64 eligible patients are shown in table 1. A planned interim analysis, after 27 eligible patients finished treatment, has been performed. Safety results showed toxicities grade 2 in 41%, grade 3 in 33% and grade 4 in 15% of patients. Most common toxicities were polyneuropathy grade 2 or 3 (44%), infections grade 2 or 3 (33%) and gastrointestinal disorders grade 2 or 3 (30%). 16 severe adverse events were reported (all hospitalizations, including 5 infections). Based on these results, the DSMB concluded that no safety issues prohibit continuation of the trial. Efficacy results are blinded until the inclusion will be completed (expected Q4 2017). Updated demographic results will be available in December 2017.ConclusionA successful screening program for MYC rearrangements for all newly diagnosed DLBCL patients is initiated in the Netherlands. This program, which allows start of treatment during the screening period, enables newly diagnosed DLBCL patients with a proven MYC rearrangement to switch to a prospective biomarker-based clinical trial that evaluates the addition of lenalidomide to standard R-CHOP. [Display omitted] DisclosuresChamuleau:Genmab: Research Funding; Gilead: Research Funding. Nijland:Novartis Pharmaeuticals Corporation: Honoraria; Kite Pharma: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; MIllennium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; MSD: Honoraria; Amgen: Honoraria. Kersten:MSD: Honoraria; BMS: Honoraria; Gilead Sciences: Honoraria; Mundipharma: Honoraria; Milennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Kite Pharma: Honoraria; Amgen: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria. Jong:BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy; Celgene: Consultancy, Research Funding; Genmab: Research Funding.

Long-Term Outcomes of Total Body Irradiation Plus Cyclophosphamide Versus Busulfan Plus Cyclophosphamide As Conditioning Regimen for Acute Lymphoblastic Leukemia: A Comparative Study

Introduction: Total body irradiation-Cyclophosphamide (TBI-Cy) and Busulfan-Cyclophosphamide (Bu-Cy) are the most commonly used conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HCT) for acute lymphoblastic leukemia (ALL). TBI-based conditioning regimens may have a better antitumor effect at sanctuary cites compared to chemotherapy regimens. However, some controversy still remains concerning the role of TBI in adult ALL. Therefore, we aimed to retrospectively investigate long-term treatment outcomes of ALL patients post allo-HCT and identify prognostic factors and the impact of the conditioning.Methods: We enrolled consecutive patients with ALL who underwent alloHCT from 1990 to 2016 in our center, following a TBI- or a Busulfan (Bu)-based conditioning regimen. TBI at 14.4Gy was divided at 6 fractions over 3 days and Bu (mainly oral) at 4mg/kg/day. Both regimens included 120mg/kg Cy. Graft source was mainly mobilized peripheral blood stem cells.Results: We studied 151 ALL (114 B-ALL, 35 T-ALL and 2 biphenotypic) patients aged 28±12 years, transplanted in CR1 (60), other CR (33) or relapsed/refractory disease (58) from sibling (87), HLA matched (42) or mis-matched (17) unrelated and alternative donors (5). TBI-based conditioning was administered in 84, whereas non-TBI in 67. No differences were observed in baseline characteristics, except for disease phase, disease risk index (DRI) and graft source. The majority of non-TBI patients had relapsed/refractory disease at transplant (50.7% versus 28.6% in TBI-conditioning, p=0.043) and subsequently significantly higher DRI (p=0.025). Furthermore, bone marrow was the graft source in significantly higher number of non-TBI patients (28.4% versus 8.3% in the TBI group, p=0.001).With a follow-up of 19.0 (0.5-170.5) in TBI and 14.5 (1.2-319.1) months in the non-TBI group, there was no difference in the incidence of acute (Grade 2-4) or chronic GVHD, thrombotic microangiopathy, bacterial or fungal infections. Only viral infections were significantly increased in the non-TBI group (59% versus 41% in the TBI group, p=0.03). Therefore, there was no significant difference in the cumulative incidence (CI) of treatment-related mortality (5-year CI of 24.1% in non-TBI versus 27.7% in the TBI group, p=0.678) or relapse mortality (5-year CI of 29.2% in non-TBI versus 37.1% in the TBI group, p=0.283).Overall survival (OS) was similar in the TBI and non-TBI group (5-year 46.7% compared to 35.8%, p=0.201). In the multivariate analysis, unfavorable pre-transplant predictors of OS were age (p=0.024), higher disease risk index (DRI) (p=0.007) and female to male donor (p=0.006). Disease-free survival (DFS) was similar in the TBI and non-TBI group (5-year 47.1% compared to 35.4%, p=0.134), with age, higher DRI and female to male donor being unfavorable predictors. When the analysis was limited to patients transplanted in CR1 (40 in the TBI versus 20 in the non-TBI group), there were also no significant differences.Interestingly, age predicted OS and DFS only in the TBI group. TBI patients younger than 40 years had significantly high OS (55.1%, p=0.023) and DFS (55.5%, p=0.02) versus the older ones. Older TBI patients had higher TRM (43.3% versus 20.1%, p=0.135) and relapse mortality (45.8 versus 24.7, p=0.238) that did not reach levels of statistical significance. However, the same was not true for the non-TBI group (p=0.233 for DFS, p=0.326 for OS).Conclusion: In our retrospective data of the last 3 decades, the type of conditioning regimen did not influence the outcome of transplantation. Based on our results, high dose TBI is a feasible conditioning in terms of a prolonged DFS and OS for younger patients and seems an efficient tool to cure high-risk ALL in CR1. It should be kept in mind that intravenous BU is also used with stable pharmacokinetics. Since our data were not powered to appraise superiority of one regimen in terms of efficacy and toxicity, the choice between TBI or Bu conditioning regimens is still under consideration. Treatment is complex for adult ALL patients and remains a field of debate and a challenge for prospective studies in the future. DisclosuresGavriilaki:European Hematology Association: Research Funding.