High Risk Of Treatment Failure Research Articles

Subclonal NT5C2 mutations are associated with poor outcomes after relapse of pediatric acute lymphoblastic leukemia

AbstractActivating mutations in cytosolic 5′-nucleotidase II (NT5C2) are considered to drive relapse formation in acute lymphoblastic leukemia (ALL) by conferring purine analog resistance. To examine the clinical effects of NT5C2 mutations in relapsed ALL, we analyzed NT5C2 in 455 relapsed B-cell precursor ALL patients treated within the ALL-REZ BFM 2002 relapse trial using sequencing and sensitive allele-specific real-time polymerase chain reaction. We detected 110 NT5C2 mutations in 75 (16.5%) of 455 B-cell precursor ALL relapses. Two-thirds of relapses harbored subclonal mutations and only one-third harbored clonal mutations. Event-free survival after relapse was inferior in patients with relapses with clonal and subclonal NT5C2 mutations compared with those without (19% and 25% vs 53%, P < .001). However, subclonal, but not clonal, NT5C2 mutations were associated with reduced event-free survival in multivariable analysis (hazard ratio, 1.89; 95% confidence interval, 1.28-2.69; P = .001) and with an increased rate of nonresponse to relapse treatment (subclonal 32%, clonal 12%, wild type 9%, P < .001). Nevertheless, 27 (82%) of 33 subclonal NT5C2 mutations became undetectable at the time of nonresponse or second relapse, and in 10 (71%) of 14 patients subclonal NT5C2 mutations were undetectable already after relapse induction treatment. These results show that subclonal NT5C2 mutations define relapses associated with high risk of treatment failure in patients and at the same time emphasize that their role in outcome is complex and goes beyond mutant NT5C2 acting as a targetable driver during relapse progression. Sensitive, prospective identification of NT5C2 mutations is warranted to improve the understanding and treatment of this aggressive ALL relapse subtype.

A Combination of Three Biomarkers for HNSCC Prognostication Following Chemoradiotherapy

Accurate therapeutic prognostication continues to elude the head and neck oncologist, hindering de-intensification efforts and maximizing adjuvant therapy related toxicity. We examined three biomarkers: mutant allele tumor heterogeneity (MATH, a quantitative measure of intra-tumor genetic heterogeneity), and HPV and Estrogen Receptor alpha (ER-alpha) status in patients from the Cancer Genome Atlas (TCGA) treated with chemoradiotherapy (CRT). We hypothesized that this combination of biomarkers would prognosticate treatment outcome better than HPV status alone, allowing improved identification of patients at low and high risk of treatment failure.

Endoscopic radial incision method for two strictures of the esophagus after endoscopic submucosal dissection: a case report

BackgroundThe development of severe esophageal stricture after endoscopic submucosal dissection (ESD) for early esophageal carcinoma is not uncommon. Dilation by Savary-Gilliard dilators or balloon dilators is the first-line treatment for such complex refractory benign stricture, but it has a high risk of treatment failure. So far, endoscopic radial incision (ERI) as a new technology for the treatment of post-ESD esophageal stricture has been rarely reported. We report a case, which we designed to assess the efficacy and safety of ERI technology for two severe strictures of the esophagus after ESD.Case presentationA 67-year-old man had suffered from two complex refractory benign strictures of the esophagus after ESD for early esophageal carcinoma. The patient was refractory to multiple endoscopic balloon dilation (EBD) therapy previously. Thus, the patient underwent ERI successfully and without postoperative complications such as fever, poststernal pain, bleeding, and perforation. During 3 months of follow-up after ERI, the patient had no recurrence of dysphagia.ConclusionsRefractory strictures of the esophagus after ESD are common. ERI is a safe and efficient strategy for treating such multiple refractory esophageal strictures.

P536 Early prediction of intravenous corticosteroid therapy failure in moderate–severe ulcerative colitis

Abstract Background An episode of acute severe ulcerative colitis (UC) is a watershed event during the disease course with a heightened risk of colectomy during and following these episodes.1 The prompt identification of these events followed by the early implementation of appropriate treatment is essential to obtaining the best clinical outcomes for these unwell patients. The majority of published risk scores predicting the important clinical outcomes of intravenous corticosteroid therapy failure and colectomy-by-discharge rely on clinical data from days 1–3 of therapy.2 There is a paucity of tools that allow for a simple and individualised prediction of risk of corticosteroid therapy failure during the earliest stages of admission. Methods Data were prospectively obtained from 349 presentations of moderate–severe UC requiring hospital admission to a tertiary referral hospital. The failure of intravenous corticosteroid therapy was strictly defined by the (Oxford) Day 3 and Day 7 criteria.3 Seventeen clinical, laboratory and endoscopic variables all available within 24 h of hospital presentation were assessed for their ability to differentiate intravenous corticosteroid therapy responders from non-responders. A stepwise generalised linear model was formulated based on the results of the initial univariate analyses. Results Intravenous corticosteroid therapy failure occurred in 208/349 (60%) of presentations. The formulated risk score included the variables of oral corticosteroid therapy failure, bowel frequency and serum albumin concentration with or without the Mayo endoscopic subscore (MES). With the addition of the MES, the area under the curve (AUC) of the risk score was 0.758. When the positive predictive value of the score (threshold) for correctly predicting intravenous corticosteroid therapy failure was set at 85%, 105/275 (38%) of presentations with available data were identified as high risk for corticosteroid therapy failure (Figure 1). Conclusion This practical risk assessment tool provides clinicians with a personalised prediction of the likelihood of success of a course of intravenous corticosteroid therapy in moderate–severe UC. It enables the identification of individuals at high risk of treatment failure who may be suitable for consideration of early treatment escalation or screening for appropriate clinical trials. References

A Review of Modern Radiation Therapy Dose Escalation in Locally Advanced Head and Neck Cancer

The management of head and neck cancer is complex and often involves multimodality treatment. Certain groups of patients, such as those with inoperable or advanced disease, are at higher risk of treatment failure and may therefore benefit from radiation therapy dose escalation. This can be difficult to achieve without increasing toxicity. However, the combination of modern treatment techniques and increased research into the use of functional imaging modalities that assist with target delineation allows researchers to push this boundary further. This review aims to summarise modern dose escalation trials to identify the impact on disease outcomes and explore the growing role of functional imaging modalities. Studies experimenting with dose escalation above standard fractionated regimens as outlined in National Comprehensive Cancer Network guidelines using photon therapy were chosen for review. Seventeen papers were considered suitable for inclusion in the review. Eight studies investigated nasopharyngeal cancer, with the remainder treating a range of subsites. Six studies utilised functional imaging modalities for target delineation. Doses as high as 85.9 Gy in 2.6 Gy fractions (EQD2 90.2 Gy10) were reportedly delivered with the aid of functional imaging modalities. Dose escalation in nasopharyngeal cancer resulted in 3-year locoregional control rates of 86.6–100% and overall survival of 82–95.2%. For other mucosal primary tumour sites, 3-year locoregional control reached 68.2–85.9% and 48.4–54% for overall survival. There were no clear trends in acute or late toxicity across studies, regardless of dose or addition of chemotherapy. However, small cohort sizes and short follow-up times may have resulted in under-reporting. This review highlights the future possibilities of radiation therapy dose escalation in head and neck cancer and the potential for improved target delineation with careful patient selection and the assistance of functional imaging modalities.

Factors Associated with Antiretroviral Treatments Failure among HIV-Positive Patients in Congo: A Retrospective Cohort Study

Background: Viral load is the key indicator of the effectiveness of antiretroviral treatment in HIV patients. Study aimed to determine antiretroviral treatments failure rates and associated risk factors among HIV-infected adult patients in Congo. Methods: Data from the Congolese AIDS and Epidemics Control Council were combined to create a historical cohort. Patients were followed up between 2003 to 2017. Mixed logistic regression was used to identify treatment failure associated-factors. Intercooled Stata 10 (StataCorp LP, College Station, Texas, USA) software packages was used for analysis. Results: Over 14 years of follow-up, a total of 25,500 visits for 6391 adult patients were reported. Among them, 88% i.e. 22,328 visits (for a total of 6127 patients) were visits with treatment failure. In the multivariate analysis, being aged >26 years, having primary education level, being student, others nationality, unspecifiedmarital status and being worker in informal sector were found associated with a higher risk of treatment failure. Conversely, being pensioners, receiving second line therapeutic protocols and having good adherence to treatment were found significantly associated with a lower risk of treatment failure. Conclusion: Antiretroviral treatments failure among HIV-treated patients is common in Congo. Developing treatment adherence-centered interventions with focus in patients who have low socio-economic status needed to reduced treatments failure. As treatment failure is not only determined by individual factors, psychosocial supports and availability of antiretroviral drugs needs to be taken into account.

Multi-objective ensemble deep learning using electronic health records to predict outcomes after lung cancer radiotherapy

Accurately predicting treatment outcome is crucial for creating personalized treatment plans and follow-up schedules. Electronic health records (EHRs) contain valuable patient-specific information that can be leveraged to improve outcome prediction. We propose a reliable multi-objective ensemble deep learning (MoEDL) method that uses features extracted from EHRs to predict high risk of treatment failure after radiotherapy in patients with lung cancer. The dataset used in this study contains EHRs of 814 patients who had not achieved disease-free status and 193 patients who were disease-free with at least one year follow-up time after lung cancer radiation therapy. The proposed MoEDL consists of three phases: (1) training with dynamic ensemble deep learning; (2) model selection with adaptive multi-objective optimization; and (3) testing with evidential reasoning (ER) fusion. Specifically, in the training phase, we employ deep perceptron networks as base learners to handle various issues with EHR data. The architecture and key hyper-parameters of each base learner are dynamically adjusted to increase the diversity of learners while reducing the time spent tuning hyper-parameters. Furthermore, we integrate the snapshot ensembles (SE) restarting strategy, multi-objective optimization, and ER fusion to improve the prediction robustness and accuracy of individual networks. The SE restarting strategy can yield multiple candidate models at no additional training cost in the training stage. The multi-objective model simultaneously considers sensitivity, specificity, and AUC as objective functions, overcoming the limitations of single-objective–based model selection. For the testing stage, we utilized an analytic ER rule to fuse the output scores from each optimal model to obtain reliable and robust predictive results. Our experimental results demonstrate that MoEDL can perform better than other conventional methods.

Planning mass eradication of Helicobacter pylori infection for indigenous Taiwanese peoples to reduce gastric cancer.

The aim of this study is to identify gastric cancer burden in Indigenous Taiwanese peoples and conduct a project to evaluate how to reduce the disparities most effectively in Indigenous communities. First, we quantified the health disparities in gastric cancer in Indigenous peoples using data from the cancer registries during the period of 2006-2014. Second, we identified parameters that might be associated with Helicobacter pylori infection or help identify a good eradication strategy. Gastric cancer incidence (24.4 vs 12.3 per 100000 person-years) and mortality rates (15.8 vs 6.8 per 100000 person-years) were higher in Indigenous than in non-Indigenous, with 2.19-fold (95% confidence interval [CI]: 2.06-2.33) and 2.47-fold (2.28-2.67) increased risk, respectively. In Indigenous communities, H.pylori infection was more prevalent in Indigenous than in non-Indigenous (59.4% vs 31.5%, P<0.01). Regression analyses consistently showed that either the mountain or plain Indigenous had 1.89-fold (95% CI: 1.34-2.66) and 1.73-fold (95% CI: 1.24-2.41) increased risk for H.pylori infection, respectively, as compared with non-Indigenous, adjusting for other baseline characteristics. The high infection rates were similarly seen in young, middle-aged, and older adults. Program eradication rates using clarithromycin-based triple therapy were suboptimal (73.7%, 95% CI: 70.0-77.4%); the habits of smoking (1.70-fold, 95% CI: 1.01-2.39) and betel nut chewing (1.54-fold, 95% CI: 0.93-2.16) were associated with the higher risk of treatment failure. Gastric cancer burden is higher in Indigenous Taiwanese peoples than in their non-Indigenous counterparts. Eliminating the prevalent risk factor of H.pylori infection is a top priority to reduce this health disparity.

Variable gene expression and parasite load predict treatment outcome in cutaneous leishmaniasis.

Patients infected with Leishmania braziliensis develop chronic lesions that often fail to respond to treatment with antiparasite drugs. To determine whether genes whose expression is highly variable in lesions between patients might influence disease outcome, we obtained biopsies of lesions from patients before treatment with pentavalent antimony and performed transcriptomic profiling on these clinical samples. We identified genes that were highly variably expressed between patients, and the variable expression of these genes correlated with treatment outcome. Among the most variable genes in all the patients were components of the cytolytic pathway, and the expression of these genes correlated with parasite load in the skin. We demonstrated that treatment failure was linked to the cytolytic pathway activated during infection. Using a host-pathogen marker profile of as few as three genes, we showed that eventual treatment outcome could be predicted before the start of treatment in two separate cohorts of patients with cutaneous leishmaniasis (n = 21 and n = 25). These findings raise the possibility of point-of-care diagnostic screening to identify patients at high risk of treatment failure and provide a rationale for a precision medicine approach to drug selection in cutaneous leishmaniasis. This work more broadly demonstrates the value of identifying genes of high variability in other diseases to better understand and predict diverse clinical outcomes.

Pregnancy and CYP3A5 Genotype Affect Day 7 Plasma Lumefantrine Concentrations.

Pregnancy and pharmacogenetics variation alter drug disposition and treatment outcome. The objective of this study was to investigate the effect of pregnancy and pharmacogenetics variation on day 7 lumefantrine (LF) plasma concentration and therapeutic responses in malaria-infected women treated with artemether-lumefantrine (ALu) in Tanzania. A total of 277 (205 pregnant and 72 nonpregnant) women with uncomplicated Plasmodium falciparum malaria were enrolled. Patients were treated with ALu and followed up for 28 days. CYP3A4, CYP3A5, and ABCB1 genotyping were done. Day 7 plasma LF concentration and the polymerase chain reaction (PCR) - corrected adequate clinical and parasitological response (ACPR) at day 28 were determined. The mean day 7 plasma LF concentrations were significantly lower in pregnant women than nonpregnant women [geometric mean ratio = 1.40; 95% confidence interval (CI) of geometric mean ratio (1.119-1.1745), P < 0.003]. Pregnancy, low body weight, and CYP3A5*1/*1 genotype were significantly associated with low day 7 LF plasma concentration (P < 0.01). PCR-corrected ACPR was 93% (95% CI = 89.4-96.6) in pregnant women and 95.7% (95% CI = 90.7-100) in nonpregnant women. Patients with lower day 7 LF concentration had a high risk of treatment failure (mean 652 vs. 232 ng/ml, P < 0.001). In conclusion, pregnancy, low body weight, and CYP3A5*1 allele are significant predictors of low day 7 LF plasma exposure. In turn, lower day 7 LF concentration is associated with a higher risk of recrudescence. SIGNIFICANCE STATEMENT: This study reports a number of factors contributing to the lower day 7 lumefantrine (LF) concentration in women, which includes pregnancy, body weight, and CYP3A5*1/*1 genotype. It also shows that day 7 LF concentration is a main predictor of malaria treatment. These findings highlight the need to look into artemether-LF dosage adjustment in pregnant women so as to be able to maintain adequate drug concentration, which is required to reduce treatment failure rates in pregnant women.

Post-Induction Minimal Residual Disease Measured By Flow Cytometry and Deep Sequencing of Mutant GATA1 Are Both Significant Prognostic Factors for Children with Myeloid Leukemia and Down Syndrome: A Nationwide Prospective Study of the Japanese Pediatric Leukemia/Lymphoma Study Group

Background: Myeloid leukemia in Down syndrome (ML-DS) is associated with good response to chemotherapy thus results in a favorable outcome. However, relapsed and refractory cases are rarely salvageable, regardless of receiving hematopoietic stem cell transplantation. Several factors such as certain chromosomal abnormalities and age at diagnosis are somewhat prognostic, but no universal prognostic factor has been found to date. In order to identify a subgroup with high risk of treatment failure, the role of minimal residual disease (MRD) with three methods were explored in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) trial AML-D11. Procedure: AML-D11 is a nationwide single-arm clinical trial for children (4 months to 17 years old) with ML-DS. All patients received an identical chemotherapy to the previous AML-D05 study (Taga T. Pediatr Blood Cancer 2016). MRD was evaluated at two time points, one after the induction therapy and another at the end of whole chemotherapy, using 3 different methods; flow cytometric MRD (FCM-MRD), deep sequencing MRD of mutant GATA1 (GATA1-MRD) and PCR MRD of WT1 mRNA expression (WT1-MRD). WT1-MRD was measured in both bone marrow (BM) and peripheral blood (PB) samples, while FCM- and GATA1-MRD were measured only in BM samples. Results: A total of 78 patients were eligible and followed-up with a median of 47.6 months (range, 8 to 68.8 months). Seventy-six patients were stratified to the standard risk (SR) and one patient to the high risk (HR) group by morphological response. One patient died of sepsis during initial induction therapy. Three-year event-free survival (EFS) and overall survival (OS) rates were 87.2% (95%CI, 77.5 to 92.9%) and 89.7% (95%CI, 80.5 to 94.7%), respectively. FCM-MRD and GATA1-MRD after initial induction therapy were positive in 5/65 and 7/59 patients, respectively, which were both significantly prognostic (Fig.1). Prognostic significance of WT1-MRD could not be evaluated due to a limited number of collected samples. Conclusions: MRD detections by FCM and targeted deep sequencing of GATA1 after initial induction therapy are both significant prognostic factors for predicting relapse. Risk stratification using FCM-MRD is currently incorporated in the on-going Japan Children's Cancer Group ML-DS trial (AML-D16; jrct.niph.go.jp, jRCTs041190047). Figure 1 Disclosures No relevant conflicts of interest to declare.

Somatic Mutation Profile Analyzed By Next-Generation Sequencing in Relapsed/Refractory Follicular Lymphoma Treated with Idelalisib

Purpose Follicular lymphoma (FL) accounting for 20% of non-Hodgkin lymphoma, is currently considered treatable but not curable despite more effective treatment options. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase δ (PI3Kδ) that blocks PI3Kδ-AKT signaling and promotes apoptosis, is approved for patients with relapsed/refractory (R/R) FL who have received ≥ 2 prior systemic therapies. Previous studies suggest that somatic tumor mutations identified at relapse may have an impact on the response to targeted therapies (Bartlett N et al., Blood 2018). The goal of this study was to analyze the lymphoma mutational profile to identify the prognostic value of mutations in R/R follicular lymphoma patients treated with idelalisib. Methods We performed a retrospective multicenter study of patients (pts) with relapsed follicular lymphoma and no evidence of transformation, having received at least 2 prior regimens before idelalisib treatment. Patients received idelalisib 150mg BID until progression or toxicity. Next-generation sequencing (NGS) of 51 genes was performed either at FL diagnosis and/or at relapse prior idelalisib therapy. The primary endpoint was to analyze the relationship between the mutational status and the duration of response (DOR) to idelalisib. DOR was measured from the time of initial response until documented lymphoma progression. According to DOR pts were classified as: refractory (response &amp;lt; 1 month), short-responder (1 month ≤ DOR ≤ 12 months) and long-responder (&amp;gt; 12 months). Results 24 pts with R/R FL were enrolled with a median age of 62.5 years (range: 57-86). Patients had received a median of 3 prior treatments (range: 2-7). FL was refractory to rituximab in 16 pts (67%), to alkylating agents in 11 pts (46%) and to 2 or more prior treatments in 11 pts (46%). Twelve (50%) had refractory disease to the last therapy before idelalisib. Pts received idelalisib during a median of 5.5 months (range: 0.5-31). Overall response rate was 83% (n=20) including 3 (15%) complete response and 17 (85%) partial response. The median DOR was 9.5 months (range: 0-28). Eleven pts were short-responders and 9 long-responders. Four pts (17%) had refractory disease to idelalisib. Median progression-free survival and overall survival were 11.5 (range: 1-30) and 16.5 months (range: 1-56) respectively. Three pts (12.5%) are still continuing idelalisib. Twenty-one pts (87.5%) discontinued treatment mostly due to progressive disease (n=14) and adverse events (n=5); 3 pts remained progression-free after idelalisib discontinuation and observation with a median follow-up of 23 months (range: 20-24). All the pts had at least one mutation detectable for one of the targeted genes in both diagnosis (n=17) and relapse (n=20) samples. The median number of targeted genes with non-silent mutations per patient was 7 at diagnosis (range: 2-11) and 6 at relapse (range: 3-28). The most frequent genes found in 10% of patients (≥ 2) or more at diagnosis and at relapse are listed in Figure 1. The mutational profile at diagnosis predominantly included mutations in epigenetics gene family, KTM2D (n=16; 94%), EP300 (n=9; 52%), ARID1A (n=6; 35%), KTM2A (n=5; 29%) and CREBBP (n=4; 23%). The m7-FLIPI score (Pastore A et al., Lancet Oncology 2015) at diagnosis helped identifying pts with low-risk (n=12; 71%) and high-risk (n=5; 29%) of idelalisib treatment failure. The median m7-FLIPI score in the refractory group was 1.25 compared to 0.26 in the short responder group and 0.04 in the long responder group. All long responder patients had low-risk m7-FLIPI. The mutational profile at relapse was significantly enriched in mutations of TNFAIP3 (n=7; 35%) and NFKBIE (n=4; 20%), affecting the NF-kB inhibitor pathway, and mutations of transcription factors, TP53 (n=10; 50%), MEF2B (n=5; 25%), FOXO1, STAT6 and IRF4 (n=4; 20% each). Overall the mutational profile of the 3 sub-groups according to DOR was detailed in Figure 2. The genes more frequently mutated in refractory pts were: EP300 (n=3/4; 75%), B2M (n=2/4; 50%), FBXW7 (n=2/4; 50%), CARD11, CXCR4 and MYD88 (n=1/4; 25% each). Conclusion The m7FLIPI at diagnosis identifies patients with higher risk of treatment failure in patients with R/R FL treated with idelalisib. Patients with idelalisib refractory disease have more frequently mutations of EP300, B2M, FBXW7, which suggests they could be related to resistance to idelalisib. Disclosures No relevant conflicts of interest to declare.

Maintenance chemotherapy using S-1 following definitive chemoradiotherapy in patients with N3 nasopharyngeal carcinoma

BackgroundPatients with N3 stage nasopharyngeal carcinoma (NPC) are at high risk for treatment failure. This study aims to assess the efficacy of maintenance chemotherapy (MC) using S-1 (MC-S1), a novel oral fluoropyrimidine agent, following definitive chemoradiotherapy (CRT) using intensity-modulated radiotherapy (IMRT) in patients with N3 nasopharyngeal carcinoma (N3-NPC).MethodsA retrospective review was conducted for all N3-NPC treated with CRT with MC (CRT-MC) or without MC (CRT-non-MC) during 2014–2016. Toxicities with MC were recorded. Overall survival (OS), locoregional failure-free survival (LFFS) and distant metastasis free survival (DMFS) were compared between CRT-MC vs. CRT-non-MC cohorts.ResultsA total of 130 N3 patients were identified, of whom 21 (16.2%) were treated with CRT-MC, and 109 (83.8%) with CRT-non-MC. Patient characteristics did not significantly differ between the CRT-MC and CRT-non-MC groups, with the exception of the number of cycles of neoadjuvant chemotherapy. Following IMRT 69 patients achieved a complete response (CR) (CRT-MC: 10; CRT-non-MC: 59), 61 had a partial response (PR) (11 vs. 50), and none maintained stable disease (SD) or developed progression of disease (PD). After a median follow-up of 41 months for surviving patients, a significant differences in OS (76.3% vs. 95.2%, p = 0.046) and DMFS (70.3% vs. 90.5%, p = 0.043) but not LFFS (84.9% vs. 100%, p = 0.091) at 3 years were observed between the CRT-non-MC and CRT-MC groups. Skin hyperpigmentation, leucopenia, fatigue, neutropenia, anorexia and nausea were the common but not severe (grade 1–2) toxicities of MC.ConclusionsUsing MC-S1 in N3-NPC patients following IMRT achieved superior survival to the CRT-non-MC patients. The toxicities of MC-S1 were mild and tolerable. Further clinical trials are required to evaluate the efficacy of MC-S1 in N3-NPC patients.

Outcome of adolescent patients with acute lymphoblastic leukaemia aged 10–14 years as compared with those aged 15–17 years: Long-term results of 1094 patients of the AIEOP-BFM ALL 2000 study

BackgroundAdolescents (aged 10–17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years. MethodsWe retrospectively analysed outcomes of 1094 adolescents with ALL, aged 10–17 years, treated within the AIEOP-BFM ALL 2000 trial, overall and by the age groups 10–14 and 15–17 years. FindingsCompared with younger children (aged 1–9 years, n = 3647), adolescents had a statistically inferior 5-year event-free survival (EFS) [74.6% (1.3) vs. 84.4% (0.6)] and overall survival (OS) [83.4% (1.1) vs. 92.7% (0.4); p < 0.001]. Clinical and biological disease characteristics did not differ between the two subgroups of adolescents, including minimal residual disease (MRD) results during initial therapy, except for ETV6-RUNX1 frequency and gender. With a median follow-up of 8.8 years, the 5-year EFS and OS were 76.2% (1.5) and 84.9% (1.3), respectively, for those aged 10–14 years and 70.0% (2.8) and 78.8% (2.5) for those aged 15–17 years (p = 0.06; 0.05). There was no significant difference in the cumulative incidence of relapses [17.8% (1.4) and 18.3% (2.4); p = 0.98], while the incidence of treatment-related deaths as a first event was 2.6% (0.6) versus 7.4% (1.6) (p < 0.001) with, in particular, a higher incidence in the high-risk arm. InterpretationFurther prospective studies and biological investigations are required to define optimal treatment for adolescents, in particular for those aged 15–17 years. Newer agents (immunotherapy, targeted therapy) in early treatment phases of patients at higher risk of treatment failure could replace most toxic treatment elements, with the aim of reducing both toxicity and the risk of relapses.

Integrating Tumor and Nodal Image Features at Baseline and Mid-treatment PET Scans to Predict Early Progression in Stage III Non-Small Cell Lung Cancer (NSCLC) Patients Treated with Concurrent Chemoradiotherapy

Prognostic biomarkers that can reliably predict early disease progression in stage III non-small cell lung cancer are needed for identifying those patients at high risk of treatment failure, who may benefit from more intensive treatment strategy. This work aims to identify an imaging signature in predicting progression in local advanced NSCLC. This retrospective study included 82 patients treated with definitive chemoradiotherapy for whom both baseline and mid-treatment PET/CT scans were available. All primary tumors and involved nodes were delineated. Patients were randomly divided into two groups: training group (n=41) and testing group (n=41). For training group, forty-five quantitative image features were extracted to characterize the tumor and involved lymph nodes from PET scans at both time points as well as changes between two scans. These features included volume, intensity and texture features for both tumor and nodes. For nodes, there were three additional features, including number of nodes, node-tumor spread which means the maximum distance between tumor and involved nodes, nodal spread which means the maximum distance between involved nodes. Random survival forest (RSF) model with repeated 10-fold cross validation was implemented for predicting progression-free survival (PFS). At last, the RSF model was validated with the testing group. The contribution of individual image features to the prediction was obtained from the RSF model. The most important feature for predicting PFS was the pre-treatment tumor volume, following by the changes of maximum distance between tumor and involved nodes measured at two time points and then the node to tumor spread measured at mid-treatment. Nodal spread was both important at baseline and mid-treatment. Mid-treatment tumor volume was also useful, which was ranked at 5th. In multivariable analysis, the RSF model was an independent prognostic factor for patients’ progression-free survival (HR= 1.17, 95% CI: 1.05-1.31, P= 0.005). In training group, the median risk score based on the RSF model can significantly stratify patients into low- vs. high-risk groups for suffering disease progression (P<0.001, log-rank test). Using the same cutoff value, the RSF model was validated by the testing group (P= 0.016,log-rank test). Integration of tumor and nodal imaging characteristics at pre and mid-treatment PET scans may allow better prediction of progression-free survival for local advanced NSCLC patients, and help to optimize radiation intensity or modify the therapeutic regimen.

Posttreatment Squamous Cell Carcinoma Antigen in Predicting Treatment Failure for Patients with Cervical Squamous Cell Carcinoma Treated with Concurrent Chemoradiotherapy

To analyze the association between posttreatment squamous cell carcinoma (SCC) antigen and treatment failure for patients with cervical SCC and treated with concurrent chemoradiotherapy (CCRT). We reviewed patients with cervical SCC and treated with definitive CCRT between June 2012 and May 2015 in our institute. A dose of 50.4Gy in 28 fractions was delivered to the pelvic with intensity modulated radiation therapy. With high-dose-rate brachytherapy, 30-36Gy in 5-7 fractions was prescribed to point A. The first line regimen of concurrent chemotherapy was cisplatin weekly. Posttreatment SCC antigen level was checked at 20 to 60 days after the completion of CCRT. A receiver operating characteristic (ROC) curve was performed to analyze the cutoff point of pretreatment and posttreatment SCC Ag in predicting treatment failure. Log-rank test and Cox’s proportional hazard model were used to identify whether pretreatment and posttreatment SCC Ag was significant in predicting disease-free survival (DFS). A total of 559 patients were included in this study. With ROC curve, the optimal cut-off points of pretreatment and posttreatment SCC antigen level were 8.6ng/ml (sensitivity 54.2%, specificity 65.8%) and 1.8 ng/ml (sensitivity 27.1%, specificity 96.6%). Posttreatment SCC antigen level ≥ 1.8ng/ml was observed in 47 patients. Multivariate analysis showed that posttreatment SCC Ag (hazard ratio 5.10, 95% confidence interval 3.31-7.88, p<0.001) was an independent prognostic factor of DFS. However, pretreatment SCC Ag was not significant in predicting DFS. The 3-year overall survival, DFS, local control and distant control rates of patients with posttreatment SCC antigen <1.8 ng/ml and ≥ 1.8 ng/ml were 90.7% and 46.4% (p<0.001), 84.8% and 31.9% (p<0.001), 81.4% and 69.5% (p<0.001), 90.4% and 54.1% (p<0.001), respectively. Cervical SCC patients with posttreatment SCC antigen ≥ 1.8ng/ml experienced high risk of treatment failure and poor survival. Consolidation therapy or extensive follow-up should be considered for these patients.

Preliminary survey of extended-spectrum β-lactamases (ESBLs) in nosocomial uropathogen Klebsiella pneumoniae in north-central Iran

Infections caused by extended-spectrum β-lactamases (ESBLs) producing bacteria, including Klebsiella pneumoniae have increasingly subjected to therapeutic limitations and patients with these infections are at high risk for treatment failure, long hospital stays, high health care costs, and high mortality. The aim of this study was to screen the prevalence of the blaTEM,blaCTX-M and blaSHV ESBL genes in K. pneumoniae strains isolated from nosocomial urinary tract infections (UTIs). During the March 2016 to December 2017, one hundred isolates of K. pneumoniae were collected from urine specimens of patients suffering from nosocomial UTI referred to Khatam Al-Anbia hospital in Shahrud, north-central Iran. All isolates were identified by standard bacteriological tests. The pattern of antibiotic susceptibility was determined according to the CLSI guidelines. The presence of the ESBLs was investigated using the double-disc synergy test (DDST). Polymerase chain reaction technique was used to detect the blaTEM, blaCTX-M and blaSHV genes in DDST positive isolates. Most isolates showed remarkable resistance to tested antibiotics with highest rate against nitrofurantoin (75%) and trimethoprim/sulfamethoxazole (65%). The imipenem was the most effective antibiotic against K. pneumoniae isolates. ESBL phenotype was detected in 50 (50%) of isolates. The prevalence of blaTEM, blaCTX-M and blaSHV genes among 50 ESBLs-positive isolates was 25 (50%), 15 (30%) and 35 (70%) respectively. The blaTEM and blaSHV genes were seen in 25 isolates (50%) simultaneously. The findings of this study indicated the 50% frequency rate of ESBL-producing K. pneumoniae in our geographic region. Since the treatment of infections caused by this bacterium is associated with many limitations, this high prevalence is a warning sign to adopt new control policies to prevent further spread of this microorganism.

Low bone density and high morbidity in patients between 55 and 70\u2009years with displaced femoral neck fractures: a case-control study of 50 patients vs 150 normal controls

BackgroundA displaced femoral neck fracture (FNF) in patients 55-70 years is a serious injury with a high risk of treatment failure and the optimal surgical treatment remains unclear. We aimed to describe characteristics of fracture patients compared to a sample from the normal population.MethodsFifty patients aged 55-70 years with a displaced FNF were gender- and age- matched with a control group of 150 persons without a hip fracture using computergenerated randomization and the Norwegian National Population Register. To reduce the risk of spurious selection bias, the sample size of the control group was trebled compared to the fracture group. Dual-energy x-ray absorptiometry (DXA) was performed. Demographics and hip function (Harris Hip Score, Oxford Hip Score, and Hip Dysfunction and Osteoarthritis Outcome Score) were collected.ResultsThere were more than 75% women in both groups. The mean age was 64.5 years in the fracture group and 65.1 in the control group. Results for DXA measured for lumbar spine, total hip and the femoral neck showed that patients with displaced FNF were significantly more osteoporotic. Fracture patients had significantly lower body mass index, higher Charlson comorbidity index (CCI), and higher ASA (American Society of Anesthesiologists) score than the control group. No clinically relevant differences in hip function were found. There were 48% smokers in the fracture group compared to 10% in the control group. The odds ratio for obtaining a displaced FNF was high if the patients suffered from osteoporosis, smoked or had several comorbidities.ConclusionsThis study showed that patients aged 55-70 years with a displaced femoral neck fracture had lower bone density and higher comorbidity compared with a gender- and age-matched population without femoral neck fractures. This suggests that this patient group is epidemiologically similar to older patients with femoral neck fractures.

SURG-02. LASER INTERSTITIAL THERMAL THERAPY FOR BRAIN METASTASES: OUTCOMES AND PREDICTORS OF LOCAL RECURRENCE

BACKGROUND: LITT has been used to treat recurrent brain metastasis after stereotactic radiosurgery (SRS). Little is known about how best to assess the efficacy of treatment, specifically the ability of LITT to control local tumor progression post-SRS. Objectives: Evaluate the predictive factors associated with local recurrence after LITT. METHODS: Retrospective study with consecutive patients with brain metastases treated with LITT. Based on radiological aspects, lesions were divided into progressive disease after SRS (recurrence or radiation necrosis) and new lesions. Primary endpoint was time to local recurrence. RESULTS: 61 consecutive patients with 82 lesions (5 newly diagnosed, 46 recurrence and 31 radiation necrosis). Freedom from local recurrence at 6 months was 69.6%, 59.4% at 12, and 54.7% at 18 and 24 months. Incompletely ablated lesions had a shorter median time for local recurrence (p< 0.001). Larger lesions (>6cc) had shorter time for local recurrence (p=0.03). Dural based lesions showed a shorter time to local recurrence (p=0.01). Tumor recurrence/newly diagnosed had shorter time to local recurrence when compared to RN lesions (p=0.01). Patients receiving systemic therapy after LITT had longer time to local recurrence (p=0.01). In multivariate Cox-regression model the HR for incomplete ablated lesions was 4.88 (p< 0.001), 3.12 (p=0.03) for recurrent tumors, and 2.56 (p=0.02) for patients not receiving systemic therapy after LITT. Complication rate was 26.2%. CONCLUSIONS: Incompletely ablated and recurrent tumoral lesions were associated with higher risk of treatment failure and were the major predicting factors for local recurrence. Systemic therapy after LITT was a protective factor regarding local recurrence.

Mutant selection window of clarithromycin for clinical isolates of Helicobacter pylori

BackgroundClarithromycin-resistance is becoming a global health concern in the treatment of Helicobacter pylori (H. pylori). The mutant prevention concentration (MPC) represent the propensities of antimicrobial agents to select resistant mutants. The concentration range between the minimum inhibitory concentration (MIC) and the MPC is defined as mutant selection window (MSW). In this study, we aimed to determine the cause of increasing clarithromycin resistance by investigating the MSW for clinical isolates of H. pylori.ResultsA retrospective subgroup, which included 68 clarithromycin-sensitive H. pylori strains, was selected from a double-blind trial. The MICs and MPCs were determined using agar plate assays. Genotypic tests were performed using Sanger sequencing. All isolates were wild-type, and 33.82% (23/68) had a 0.016 mg/L MIC, 45.59% (31/68) had a 0.031 mg/L MIC, 16.18% (11/68) had a 0.062 ≤ MIC ≤ 0.125 mg/L, and 4.41% (3/68) had a 0.25 mg/L MIC. The MPC50/90 (mg/L) of the isolates were: 0.062/0.125, 0.125/0.5, 0.25/0.25 and 1/2, respectively. The MPCs showed a moderate correlation with the MICs (rs = 0.65, P < 0.0001). Using published data and MPC90, we calculated the time inside the MSW (TMSW) for low- and high-dose (200 or 500 mg bid) clarithromycin that were 6 and 0 h, 24 and 4 h, 15 and 2 h, 5 and 17 h for the strains with MICs (mg/L) of 0.016, 0.031, 0.062–0.125, and 0.25, respectively.ConclusionsThis study showed that in the clarithromycin-sensitive clinical isolates of H. pylori, low-dose clarithromycin may lead to decreased drug sensitivity or even clarithromycin resistance; strains with a 0.25 mg/L MIC display a high risk of treatment failure.