High Risk Of Treatment Failure Research Articles

Therapeutic Sequences in the Treatment of High-Risk Prostate Cancer: Paving the Way Towards Multimodal Tailored Approaches.

Various definitions are currently in use to describe high-risk prostate cancer. This variety in definitions is important for patient counseling, since predicted outcomes depend on which classification is applied to identify patient’s prostate cancer risk category. Historically, strategies for the treatment of localized high-risk prostate cancer comprise local approaches such as surgery and radiotherapy, as well as systemic approaches such as hormonal therapy. Nevertheless, since high-risk prostate cancer patients remain the group with higher-risk of treatment failure and mortality rates, nowadays, novel treatment strategies, comprising hypofractionated-radiotherapy, second-generation antiandrogens, and hadrontherapy, are being explored in order to improve their long-term oncological outcomes. This narrative review aims to report the current management of high-risk prostate cancer and to explore the future perspectives in this clinical setting.

Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss

Melanomas driven by loss of the NF1 tumor suppressor have a high risk of treatment failure and effective therapies have not been developed. Here we show that loss-of-function mutations of nf1 and pten result in aggressive melanomas in zebrafish, representing the first animal model of NF1-mutant melanomas harboring PTEN loss. MEK or PI3K inhibitors show little activity when given alone due to cross-talk between the pathways, and high toxicity when given together. The mTOR inhibitors, sirolimus, everolimus, and temsirolimus, were the most active single agents tested, potently induced tumor-suppressive autophagy, but not apoptosis. Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma.

Should the management of high grade cervical squamous intraepithelial lesion (HSIL) be different in HIV-positive women?

BackgroundThis study compares the management and outcome of high grade squamous intraepithelial lesions (HSIL) in HIV-positive and -negative women and identifies risk factors for treatment failure.MethodsThis retrospective, controlled study includes 146 HIV-positive women, matched for HSIL, age and year of diagnosis, with 146 HIV-negative women. Differences were analysed using parametric and non-parametric tests and Kaplan–Meier survival curves. A binary logistic regression was used to assess risk factors for treatment failure.ResultsPersistence of cervical disease was observed most frequently in HIV-positive women (42 versus 17%) (p < 0.001) and the cone biopsy margins were more often invaded in HIV-positive-women than in HIV-negative ones. (37 versus 16%; p < 0.05).HIV-positive women, with successful cervical treatment had better HIV disease control: with significantly longer periods of undetectable HIV viral loads (VL) (19 versus 5 months; p < 0.001) and higher CD4 counts (491 versus 320 cells/mm3; p < 0.001). HIV-positive women with detectable VL at the time of dysplasia had 3.5 times (95% IC: 1.5–8.3) increased risk of treatment failure. Being treated through ablative therapy was associated with a 7.4, four-fold (95% IC: 3.2–17.3) increased risk of treatment failure compared to conizationConclusionHIV-positive women have a higher risk of treatment failure of HSIL than do HIV-negative women, especially when ablative therapy is used and in women with poor control of their HIV infection. The management and the follow- up of HSIL’s guidelines in this high-risk population should be adapted consequently: for HIV-positive women with uncontrolled viral load, excisional treatment should be the preferred therapy, whereas for women with undetectable viral load, CD4 + lymphocytes higher than 500 cells/mm3 and with a desire of pregnancy, ablative therapy may be considered.

Establishment of a Plasticity-Associated Risk Model Based on a SOX2- and SOX9-Related Gene Set in Head and Neck Squamous Cell Carcinoma.

Recent studies highlighted SOX2 and SOX9 as key determinants for cancer-cell plasticity and demonstrated that cisplatin-induced adaptation in oral squamous cell carcinoma (SCC) is acquired by an inverse regulation of both transcription factors. However, the association between SOX2/SOX9-related genetic programs with risk factors and genetic or epigenetic alterations in primary head and neck SCC (HNSCC), and their prognostic value is largely unknown.Here, we identified differentially-expressed genes (DEG) related to SOX2 and SOX9 transcription in The Cancer Genome Atlas (TCGA)-HNSC, which enable clustering of patients into groups with distinct clinical features and survival. A prognostic risk model was established by LASSO Cox regression based on expression patterns of DEGs in TCGA-HNSC (training cohort), and was confirmed in independent HNSCC validation cohorts as well as other cancer cohorts from TCGA. Differences in the mutational landscape among risk groups of TCGA-HNSC demonstrated an enrichment of truncating NSD1 mutations for the low-risk group and elucidated DNA methylation as modulator of SOX2 expression. Gene set variation analysis (GSVA) revealed differences in several oncogenic pathways among risk groups, including upregulation of gene sets related to oncogenic KRAS signaling for the high-risk group. Finally, in silico drug screen analysis revealed numerous compounds targeting EGFR signaling with significantly lower efficacy for cancer cell lines with a higher risk phenotype, but also indicated potential vulnerabilities. IMPLICATIONS: The established risk model identifies patients with primary HNSCC, but also other cancers at a higher risk for treatment failure, who might benefit from a therapy targeting SOX2/SOX9-related gene regulatory and signaling networks.

Laparoscopic liver resection for locally advanced tumor

The Barcelona Clinic Liver Cancer (BCLC) staging system categorizes a patient with hepatocellular carcinoma (HCC) according to the characteristics of the tumor, the liver disease, and the performance status of a patient. However, the BCLC algorithm is too conservative in offering resection for advanced HCC, including the locally advanced tumors. As a result, this system recommends systemic therapy for patients with advanced HCC as the first-line treatment with Sorafenib because the portal vein tumor thrombus is often interpreted as metastatic disease. Besides, there are still some uncertainties to categorize HCC with the bile duct invasion and surgical role also indefinite for advanced HCC. A number of international guidelines have excluded the role of surgery for these patients. Nevertheless, multiple studies have found a clear benefit for selected patients and have questioned the appropriateness of published recommendations, in particular concerning the role of liver resection. Usually, en bloc resection of the tumor together with affected structures might show good oncological outcomes & removal of residual microscopic foci. Even though patients with advanced HCC are at high risk of treatment failure, recurrence, and mortality, outcomes of liver resection should be examined and weighed against the lack of any other potentially curative option. Video clips show the 3 cases of laparoscopic liver resection for locally advanced HCC including, huge HCC, HCC with bile duct invasion, and down-staged HCC after TARE. We applied the recently developed laparoscopic surgical skill to remove the advanced HCC to get fewer postoperative complications, less postoperative pain, and shorter hospital stays.

Risk-Adapted Therapy in Adults with Burkitt Lymphoma: Results of NCI 9177, a Multicenter Prospective Phase II Study of DA-EPOCH-R

Risk-Adapted Therapy in Adults with Burkitt Lymphoma: Results of NCI 9177, a Multicenter Prospective Phase II Study of DA-EPOCH-R

FOXP1 Expression Is a Prognostic Biomarker in Follicular Lymphoma Treated with Immunochemotherapy and Is Associated with Distinct Molecular Features

Introduction: Follicular lymphoma (FL) is a clinically and molecularly highly heterogeneous disease, yet prognostication relies predominantly on clinical tools. We have recently demonstrated that integration of the mutation status of seven genes (including EZH2 and MEF2B) into a combined clinico-genetic risk model (m7-FLIPI) improves risk-stratification, and represents a promising approach to identify a subset of patients at highest risk of treatment failure. However, the mechanism underlying the association between mutations of the 7 genes included in the m7-FLIPI and outcome has thus far not been elucidated. We assessed whether downstream phenotypic commonalities of gene mutations predict outcome following immunochemotherapy and whether select genotypic and phenotypic alterations are associated with FOXP1 expression.Methods: We mined gene expression data to uncover genes that are differentially expressed in EZH2 - and MEF2B -mutated FLs. We focused on FOXP1 and assessed its protein expression by immunohistochemistry (IHC) in a total of 763 tissue biopsies. For outcome correlation, a population-based training cohort of 142 FL patients treated with R-CVP, and a clinical trial validation cohort comprising 395 patients treated with CHOP +/- rituximab were used. To differentiate cases with high vs. low FOXP1 expression, we chose the cut-off that maximized the log-rank test statistic for failure-free survival (FFS) in the training cohort. The effect of FOXP1 expression on FFS in the validation cohort was estimated using Cox regression analysis. In addition, for exploratory analyses, we used specimens from 350 BC Cancer Agency patients, 124 of whom overlapped with the above-mentioned training cohort.Results: We found FOXP1 to be significantly down-regulated in both EZH2 - and MEF2B -mutated cases. The cut-off value that best separated favorable from unfavorable FFS in the training cohort was determined to be >10% percent tumor cells expressing FOXP1 based on the log-rank test statistic. 76 specimens in the training cohort (54%) had high FOXP1 expression, which was associated with reduced 5-year failure-free FFS (55% vs. 70%, P=0.035). In the validation cohort, high FOXP1 expression status was observed in 248 patients (63%) and correlated with significantly shorter FFS in patients treated with R-CHOP (HR 1.95, P=0.017), but not in patients treated with CHOP (HR 1.15, P=0.44), demonstrating that FOXP1 is a predictive biomarker. In BCCA patients, high FOXP1 expression remained significantly associated with inferior FFS in a multivariate Cox regression model including rituximab maintenance (by intention to treat) and FLIPI high vs low/intermediate (HR 1.84, 95%-CI [1.10-3.08], P=0.021). Similarly, in the GLSG cohort, high FOXP1 expression was significantly associated with poor FFS in patients treated with R-CHOP, after adjusting for rituximab, FLIPI and the interaction of FOXP1 with rituximab (HR 1.84, 95%-CI [1.05-3.24], P=0.035). No significant association was observed in GLSG patients treated with CHOP (HR 1.06, 95%-CI [0.73-1.54], P=0.76). High FOXP1 expression was associated with distinct molecular features such as TP53 mutations, expression of IRF4, and gene expression signatures reminiscent of dark zone germinal centre or activated B cells. Conversely, low expression of FOXP1 was associated with - in addition to EZH2 and MEF2B mutations - GNA13 and TNFRSF14 mutations, as well as with expression of genes related to normal germinal centre light zone cells and germinal centre B cells. Taken together, these observations suggest that FOXP1 expression delineates FL cases with distinct genomic and phenotypic characteristics.Conclusion: In patients treated with immunochemotherapy, high FOXP1 expression identified patient populations with significantly shortened FFS. On the other hand, FOXP1 did not separate distinct outcome groups in patients treated without rituximab, suggesting that FOXP1 is a predictive biomarker. In multivariate analyses, high FOXP1 expression remained significantly associated with FFS in immunochemotherapy patients, after adjusting for the FLIPI. Moreover, FOXP1 high and low expression phenotypes are reflective of distinct sets of molecular alterations. Our results illustrate the value of understanding the intricate relationships between lymphoma biology and response to treatment. DisclosuresKlapper:Hoffmann La Roche: Other: Grant; Novartis: Other: Grant; Celgene: Other: Grant; Takeda Millenium: Other: Grant. Hiddemann:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Steidl:Affimed Therapeutics: Consultancy; Juno Therapeutics: Consultancy. Connors:Janssen: Research Funding; F Hoffmann-La Roche: Research Funding; Bayer Healthcare: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding; Merck: Research Funding; Lilly: Research Funding; Genentech: Research Funding; Cephalon: Research Funding; Amgen: Research Funding; Bristol-Myers Squibb: Research Funding; NanoString Technologies, Amgen, Bayer, BMS, Cephalon, Roche, Genentech, Janssen, Lilly, Merck, Seattle Genetics, Takeda,: Research Funding; Takeda: Research Funding. Sehn:Roche/Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Hoster:Roche: Other: Travel support, Research Funding.

Rhob Overexpression Boosts Relapse of t(8;21) RUNX1-RUNX1T1 Rearranged Acute Myeloid Leukemia.

Introduction. The core binding factor rearrangements, inv(16)(p13;1q22), t(16;16)(p13;q22) and t(8;21)(q22;q22), are among the most frequent cytogenetic abnormalities found in children with acute myeloid leukemia (AML). They are considered mutations associated with good responsiveness to chemotherapy and favorable patient outcome. Despite this, in the AIEOP LAM2002 trial, we found that t(8;21) RUNX1-RUNX1T1- rearranged patients had an unexpectedly high cumulative incidence of relapse (30%), which was comparable to that of patients considered at higher risk of treatment failure in light of recurrent molecular/cytogenetic alterations or levels of minimal residual disease at the end of induction therapy. Thus, we aimed at re-evaluating at both genetic and epigenetic level samples of t(8;21) AML cases collected at diagnosis addressing the hypothesis whether the methylation process may influence response to treatment and contribute to further stratify patients carrying the same genetic lesion.Methods and results. We performed high throughput profiling of DNA methylation (Reduced Representation Bisulfite Sequencing), gene (HTA 2.0 Affymetrix) and protein expression (Reverse phase protein array) on samples collected at diagnosis of 34 t(8;21)(q22;q22)/RUNX1-RUNX1T1 children enrolled in the AIEOP-AML 2002/01 trial who either did or did not experience leukemia recurrence. We found that the DNA methylation profile of t(8;21)-rearranged patients who relapsed was peculiarly different from that of patients maintaining a state of complete remission. We identified a new epigenetic signature of 337 differentially methylated regions(DMRs) separating relapsed (n=6) from non-relapsed patients (n=6). We investigated DMRs association to preferential Transcription Factor Binding Sites (ENCODE) and found that the CCCTC-binding factor (CTCF) is the most represented, it demarcates genomic regions called Topologically Associating Domains, known to be sensitive to CpG methylation with main consequences over gene transcription. We identified 652 differentially methylated CTCF binding sites between patients who either did or did not experience relapse, and looked at gene expression correlation matrixes (transcripts distant within 500 kb from differentially methylated CTCF were considered as a module), revealing that patients who relapsed lost gene expression correlation with respect to non-relapsed children. These results support the role of CTCF in modulating gene expression in relapsed patients. We then performed gene expression profile (GEP) to investigate the expression levels of DMRs neighbor gene transcripts. We found 77 DMRs-controlling genes being targets of RUNX1-RUNX1T1 chimera, and clustering analysis using their expression showed a discrete ability in identifying t(8;21) rearranged patients with respect to their risk of relapse. Through GEP analysis, we identified 18 genes differentially expressed between the two groups (fold change >|2|; unpaired t-test, p<0.05, 87 genes fold change >|1.5|), and Ras Homolog Family Member (RHOB) being the most overexpressed in relapsed patients. We integrated DNA methylation and gene expression platforms with STRING database defining an active network of pathways of cell adhesion and cell-cell signaling, where RHOB emerged as the key player of this network, validated in patient's samples by RPPA. We hypothesized that RHOB is the candidate gene promoting relapse. We moved to in vitro validation and modeled the t(8;21)-rearranged cells to grow in suspension or in adhesion, this latter experimental condition mimicking the bone marrow niche. We showed that RHOB overexpression enhanced cell adhesion properties, by strongly enhancing stress fibers formation, and protected blasts from the cytotoxic action of etoposide. On the contrary, RHOB silencing abolished these features, thus reverting the cell chemotherapy resistance by interrupting RHOB-phospho-COFILIN axis.Conclusion. This study identifies a novel role of RHOB in influencing the risk of leukemia relapse, indicating that the RHOB-mediated interaction of leukemia cells with the BM niche may support leukemia growth and disease progression. To the best of our knowledge, this is the first study that establishes a dynamic interplay of epigenetic heterogeneity within the same genetic in pediatric AML. DisclosuresNo relevant conflicts of interest to declare.

High-dose Chemotherapy in Germ Cell Cancer Patients With Brain Metastases: Experience of an Expert Center.

Germ cell tumor (GCT) patients with brain metastases (BM) have a poor prognosis and high risk of treatment failure. Optimal therapies for these patients remain controversial. The aim of this study was to report the outcomes of all GCT patients with BM treated with high-dose chemotherapy (HDCT) in our French expert center for GCT. We carried out a retrospective study of 35 GCT patients with BM who were treated from 2003 to 2019 with HDCT, followed by infusions of autologous peripheral blood hematopoietic stem cells. The overall survival at 2 years was 36.9% (95% confidence interval, 19.7-54). The median overall survival was 12 months and the median progression-free survival was 8 months. No variables were associated with better survival in the univariable analysis. Among the 35 patients included in our study, 31 completed HDCT and 4 stopped treatments after mobilization. Eleven patients (11) showed favorable responses (complete, partial, or stable disease) to HDCT and 20 patients died of disease progression (17) or toxicities (3). Among the 11 patients with favorable responses to HDCT, 8 (72.7%) had metachronous BM, mostly isolated. The majority of these patients did not receive local treatment at diagnosis or at relapse. Together, our study reveals that GCT patients can experience long-term survival even in the presence of BM. Metachronous BM can also be cured with HDCT even in the absence of local treatment. Biological and radiologic responses to mobilization could be a predictor of favorable responses to HDCT.

Assessment Criteria and Clinical Implications of Extranodal Extension in Head and Neck Cancer.

Tumor breaching the capsule of a lymph node is termed extranodal extension (ENE). It reflects aggressiveness of a tumor, creates anatomic challenges for disease clearance, and increases the risk of distant metastasis. Extranodal extension can be assessed on a pathology specimen, by radiology studies, and by clinical examination. Presence of ENE in a pathology specimen has long been considered a high-risk feature of disease progression and would ordinarily benefit from the addition of chemotherapy to adjuvant radiotherapy. Although the eighth edition of the Union for International Cancer Control/American Joint Committee on Cancer stage classification dichotomizes pathologic ENE according to its presence or absence, emerging evidence suggests that the extent of a pathologic ENE may provide additional value for risk stratification to guide adjuvant therapy. Recent data suggest that the prognostic importance of pathologic ENE is also applicable for HPV-associated head and neck squamous cell carcinoma. In addition, compelling data demonstrate that indisputable radiologic ENE is a powerful risk stratification tool to identify patients at high risk for treatment failure, especially distant metastasis, applicable for both HPV-positive and HPV-negative head and neck squamous cell carcinoma. However, the definition and taxonomy of radiologic ENE requires standardization. The goal of this review is to clarify the contemporary understanding of the prognostic implications of ENE in head and neck squamous cell carcinoma, present the nuances of what is presently known and unknown, and elucidate how to classify ENE pathologically and radiologically with an understanding of the strengths and weaknesses of each approach. Finally, with the development of several risk stratification methods, the relative role of ENE and other prognostic schema will be explored.

Comparative effectiveness of higher adalimumab maintenance therapy versus standard dose in anti-tumor necrosis factor experienced Crohn's disease patients: A propensity-score matched cohort analysis.

Crohn's disease (CD) patients who previously failed anti-tumor necrosis factor (TNF) therapy are at higher risk of treatment failure with subsequent biologics. This study aims to determine the effectiveness and safety of higher maintenance dose regimens of adalimumab compared with standard doses in CD patients who failed anti-TNF. In this retrospective observational study, CD patients who failed anti-TNF and received adalimumab were categorized according to their post-induction maintenance regimen; 40mg subcutaneous (sc) weekly or 80mg sc every other week were defined as a high-dose (HD) maintenance regimen, and 40mg sc every other week was defined as a standard-dose (SD) maintenance regimen. The primary outcome was time to treatment failure. Cox proportional hazards regression was used to adjust for confounders. Sensitivity analysis was conducted using propensity scores to create a cohort of matched participants with similar distribution of baseline covariates. Forty patients started on HD regimens following induction, and 77 patients received the SD regimen. The median time to failure in the HD group was 6.6years (interquartile range [IQR] 4.0-9.6) and 3.0years (IQR 0.9-9.4) in the SD group (log-rank test P=0.006). Patients on HD adalimumab had a lower hazard rate of treatment failure (hazard ratio: 0.27; 95% confidence interval [0.12, 0.62]; P=0.002) compared with SD patients. No difference in adverse events was identified between groups (30% vs 31.2%, P=1.0). Results were similar in the propensity score-matched cohort. High-dose maintenance regimens were associated with longer time-to-failure as compared with SD regimens in CD patient who failed anti-TNF.

P414 Obesity is associated with a higher risk of immunogenicity to adalimumab, but not to infliximab in patients with Inflammatory Bowel Disease

Abstract Background Globally, the prevalences of both inflammatory bowel diseases (IBD) and obesity have increased over the past decades. Recently, obesity has been linked to treatment failure in anti-TNF-treated patients with inflammatory bowel disease (IBD). We assessed whether obesity was associated with an increased risk of treatment failure and immunogenicity (i.e. anti-drug antibodies) among IBD patients treated with adalimumab (ADA) or infliximab (IFX). Methods This was a multicenter, retrospective cohort study of adult patients with IBD, treated with ADA or IFX for at least four months between 2011-2019 at a general hospital or a tertiary referral center. Obesity was defined as body mass index (BMI) &amp;gt;30kg/m2. Adjusted hazard rates (aHR) were calculated by mixed-effects Cox regression analysis, accounting for multiple treatment episodes in individual patients and adjusted for sex, prior anti-TNF exposure, immunomodulator use, IBD phenotype (ulcerative colitis versus Crohn’s disease), age, disease duration, smoking and rheumatological comorbidity. Multiple imputation was used to replace missing values (5% for BMI). Results We included 728 patients, providing 2339 patient-years of follow-up and 868 treatment episodes with anti-TNF; 130 (17.9%) patients were obese. Obesity was associated with female sex (67% vs 54%), smoking (36% vs 22%), older age (median 42 vs 36 years) and prior exposure to methotrexate (25% vs 15%). In patients receiving ADA, obesity was significantly and independently associated with a higher risk of immunogenicity (Figure 1a, aHR: 2.15, 95%CI: 1.10 – 4.19) and treatment failure (Figure 2a), although significance of the latter association was lost after correcting for relevant confounders (aHR: 1.33, 95%CI: 0.87 – 2.03). In patients treated with IFX, obesity was not associated with immunogenicity (Figure 1b, aHR: 1.05, 95%CI: 0.54 – 2.03) or treatment failure (Figure 2b, aHR: 0.98, 95%CI: 0.70 – 1.39). Trough levels were significantly lower in obese patients treated with ADA, but not IFX. Conclusion In patients treated with ADA, but not IFX, obesity is associated with immunogenicity and possibly a higher risk of treatment failure. Proactive therapeutic drug monitoring may be warranted in obese patients treated with ADA.

P374 Safety and drug survival of methotrexate versus tioguanine after failure of conventional thiopurines in patients with Crohn’s disease

Abstract Background Both methotrexate (MTX) and tioguanine (TG) can be considered as viable treatment options before initiating biological therapy following failure of conventional thiopurines for Crohn’s disease. It is unclear how safety and effectiveness compare for both therapies. This study aimed to compare tolerability and drug survival of MTX and TG therapy after failure of conventional thiopurines in patients with Crohn′s disease. Methods We conducted a retrospective, multi-centre study in five Dutch hospitals, including patients initiating MTX or TG for Crohn’s disease after failure (all causes) of conventional thiopurines. Patients with prior MTX or TG use, MTX or TG not primarily prescribed for Crohn’s disease, or patients receiving concomitant biological treatment at baseline were excluded. Follow-up duration from starting treatment was 104 weeks or until treatment discontinuation. Primary outcome was therapy discontinuation rate due to adverse events (AE). Secondary outcome was ongoing treatment without initiation of biological treatment. Results In total, 221 patients with failure of conventional thiopurines and subsequent therapy with either MTX (n=106) or TG (n=115) were included. Median follow-up was 89 weeks (IQR 28-104). Previous biological failure was present in 28 (26%) MTX and 17 (15%) TG treated patients (p=0.044). Sixty-four (29%) patients (MTX 41.5%, TG 17.4%, p&amp;lt;0.001) discontinued their treatment due to AE during follow-up (Figure 1). Median time until discontinuation due to AE was 16.5 weeks (IQR 8.0–39.0) for MTX and 17.5 weeks (IQR 1.3–69.8) for TG (p=0.925). MTX use was associated with a significantly higher risk of treatment failure due to AE (OR 3.37 [95% CI 1.82–6.25] p&amp;lt;0.001). Previous biological failure was not predictive for MTX or TG failure due to AE (OR 1.086, p=0.828). The most frequent discontinuation reasons were nausea for MTX (n=11) and abdominal pain for TG (n=4). In both groups, 8 (MTX 8%, TG 7%) serious adverse events (SAE) occurred. Infections comprised the majority of all SAE, 4 (50%) for MTX and 7 (88%) for TG. Discontinuation because of elevated liver enzymes occurred in 5 (11%) MTX and 4 (20%) TG treated patients. There were no cases of histological nodular regenerative hyperplasia, liver fibrosis, or cirrhosis. Initiation of concomitant biological therapy was not significantly different (MTX: n=26, TG: n=30, p=0.877). Total monotherapy drug survival after 104 weeks was 46% for TG and 25% for MTX (p&amp;lt;0.001). Conclusion Forty-two percent of MTX, compared to 17% of TG treated patients, discontinued therapy due to AE in patients with Crohn’s disease with prior failure of conventional thiopurines. These data may aid in the selection of subsequent therapy after failure of conventional thiopurine therapy.

Systematic review of high-flow nasal cannula versus continuous positive airway pressure for primary support in preterm infants

IntroductionWe conducted a meta-analysis of trials that compared efficacy and safety of high-flow nasal cannula (HFNC) with continuous positive airway pressure (CPAP) as primary respiratory support in preterm infants and...

Intestinal giardiasis in children: Five years’ experience in a reference unit

BackgroundGiardiasis is highly prevalent in children and is often mildly symptomatic. First-line treatment is metronidazole, but treatment failure is not uncommon. We describe a paediatric series, to identify risk factors for treatment failure and to analyse the safety and effectiveness of other treatment strategies. MethodsRetrospective observational study, including children diagnosed with giardiasis from 2014 to 2019. Diagnosis was based on direct visualisation by microscopy after concentration using an alcohol-based fixative, antigen detection and/or DNA detection by polymerase chain reaction in stool. Treatment failure was considered when GI was detected 4 weeks after treatment. ResultsA total of 120 patients were included, 71.6% internationally adopted, median age 4.2 (2.3–7.3) years. Only 50% presented with symptoms, mainly diarrhoea (35%) and abdominal pain (14.1%); co-parasitism was frequent (45%). First-line treatment failure after a standard dose of metronidazole was 20%, lowering to 8.3% when a higher dose was administered (p < 0.001). Quinacrine was administered in 10 patients, with 100% effectiveness. Children <2 years were at higher risk of treatment failure (OR 3.49; 95% CI 1.06–11.53; p = 0.040). ConclusionsIn children with giardiasis, treatment failure is frequent, especially before 2 years of age. Quinacrine can be considered as a second-line treatment. After treatment, eradication should be confirmed.

Detection of Cross-Resistance Between Methotrexate and Azoles in Candida albicans and Meyerozyma guilliermondii: An In Vitro Study

Abstract In recent years, there has been a rapid increase in the incidence of Candida infections. The different species of the genus Candida vary in their virulence abilities and susceptibility to antifungal agents, depending on several external factors. The result of such modifications may be cross-resistance, which is understood as an acquired resistance to a certain antimicrobial agent after exposure to another drug. The aim of this study was to determine the possibility of cross-resistance between fluconazole, voriconazole, itraconazole, and methotrexate in Candida albicans and Meyerozyma guilliermondii (syn. Candida guilliermondii ). Fifteen strains of M. guilliermondii and eight strains of C. albicans , including the standard strains, were tested. For all strains, the minimum inhibitory concentrations (MICs) for fluconazole, voriconazole, and itraconazole were determined before and after stimulation with methotrexate. The median MICs in M. guilliermondii before and after stimulation were 9.333 and 64 mg/L ( p = 0.005) for fluconazole; 0.917 and 1.667 mg/L ( p = 0.001) for itraconazole, respectively. No significant change in MIC was observed for voriconazole. For C. albicans strains, the median MICs before and after stimulation were 0.917 and 64 mg/L ( p = 0.012) for fluconazole; 0.344 and 1.135 mg/L ( p = 0.018) for voriconazole, respectively. There was no significant change in MIC values for itraconazole. Thus, this study demonstrates the presence of cross-resistance between voriconazole, itraconazole, fluconazole, and methotrexate for the selected strains. Methotrexate exposure induces different responses when certain drugs are used for various species. Therefore, if a patient was previously exposed to methotrexate, there may be a higher risk of treatment failure with fluconazole than with other azoles such as voriconazole for fungemia caused by M. guilliermondii or itraconazole for C. albicans infection.

The Levels of FoxO3a Predict the Failure of Imatinib Mesylate Therapy among Chronic Myeloid Leukemia Patients

INTRODUCTION: Forkhead Transcription Factor 3a (FoxO3a) has been proposed to have a high efficacy to predict the failure of imatinib mesylate (IM) therapy among Chronic Myeloid Leukemia (CML) patients. However, the limited evidence had made this marker remained controversy.&#x0D; OBJECTIVES: We aimed to investigate the correlation between the levels of FoxO3a and the risk of treatment failure of IM therapy in CML patients.&#x0D; METHODS: A prospective cohort study was carried out between February 2019 and February 2020 in Saiful Anwar Hospital, Malang, Indonesia. All CML patients treated with IM on our hospital during the study period were included. The levels of FoxO3a was determined using the Enzyme-linked immunosorbent assay (ELISA) using Cusabio Biotech Kit (Cusabio Biotech Co., New York, USA). The treatment response was assessed using the European Leukemia criteria. The correlation and effect estimate between the levels of FoxO3a and treatment response of CML patients was assessed using multiple logistic regression.&#x0D; RESULTS: 53 CML patients receiving IM in our hospital were included, consisting of 29 patients with good response and 24 patients with non-response. Our study found that CML patients with lower levels of FoxO3a was associated with increased risk to develop treatment failure when treated with IM. Moreover, we also found that higher risk of treatment failure of IM therapy was also found in patients with increased levels of thrombocytes, basophils, and leukocytes, and lower levels of hemoglobin.&#x0D; CONCLUSION: We reveal that FoxO3a is the prominent marker to predict the treatment response of CML patients treated with IM.

More than 20\xb0 posterior tilt of the femoral head in undisplaced femoral neck fractures results in a four times higher risk of treatment failure

PurposeIn this study, we aimed to determine the correlation between the preoperative posterior tilt of the femoral head and treatment failure in patients with a Garden type I and II femoral neck fracture (FNF) treated with the dynamic locking blade plate (DLBP).MethodsPreoperative posterior tilt was measured in a prospective documented cohort of 193 patients with a Garden type I and II FNF treated with the DLBP. The correlation between preoperative posterior tilt and failure, defined as revision surgery because of avascular necrosis, non-union, or cut-out, was analyzed.ResultsPatients with failed fracture treatment (5.5%) had a higher degree of posterior tilt on the initial radiograph than the patients with uneventful healed fractures: 21.4° and 13.8°, respectively (p = 0.03). The failure rate was 3.2% for Garden type I and II FNF with a posterior tilt < 20° and 12.5% if the preoperative posterior tilt was ≥ 20°. A posterior tilt of ≥ 20° was associated with an odds ratio of 4.24 (95% CI 1.09–16.83; p = 0.04).ConclusionGarden type I and II FNFs with a significant preoperative posterior tilt (≥ 20°) seem to behave like unstable fractures and have a four times higher risk of failure. Preoperative posterior tilt ≥ 20° of the femoral head should be considered as a significant predictor for failure of treatment in Garden type I and II FNFs treated with the DLBP.

Prepubertal acne: A retrospective study.

BackgroundAcne vulgaris is a common skin disorder, but studies on the epidemiologic features of prepubertal acne are limited.ObjectivesThe aim of this study was to determine the prevalence and severity of prepubertal acne and to identify factors influencing acne severity and poor response to treatment.MethodsA retrospective study was conducted on 683 patients with acne from our database who visited the dermatology department of Nantes University hospital between October 2014 and May 2018. Patients of prepubertal acne (7-12 years) were included in this study.ResultsOf the 683 patients with acne, 24 (3.5%) had prepubertal acne. Prepubertal acne was more common in female patients (75%). Acne severity assessment showed that severe acne (Groupe Expert Acné global acne severity scale 4) was the most common form (33%), and mild and moderate forms (Global Evaluation Acne Group, global acne severity scales 2 and 3) accounted for 25% each. There was a high predominance of phylotype IA1 of Cutibacterium acnes (belonging to CC18 subgroup). The analysis of patients’ lifestyle and acne features identified three factors associated with an increased risk of poor response or resistance to acne treatment. Initially severe acne grading (grade 4) was the most strongly associated parameter (p < .028), followed by regular milk consumption and taking other medications in addition to acne treatment (p < .049 for each).ConclusionThis study reported on prepubertal acne features and identified three factors associated with a high risk of treatment failure or relapse. Adequate and prompt treatment is needed in this subgroup of patients to minimize disease burden and prevent subsequent disease worsening.

Risk factors for treatment failure of fracture-related infections.

Infection after fracture fixation is a potentially devastating outcome, and surgical management is frequently unsuccessful at clearing these infections. The purpose of this study is to determine if factors can be identified that are associated with treatment failure after operative management of a deep surgical site infection. We retrospectively reviewed the billing system at a Level I trauma center between March 2006 and December 2015. We identified 451 patients treated for deep surgical site infection after fracture fixation at our center. A multivariate regression analysis was then performed to evaluate for factors associated with treatment failure. Mean follow-up was 2.3 years. One hundred fifty-six patients (35%) failed initial surgical management. Risk factors associated with treatment failure included initial culture results positive for polymicrobial organisms (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.0-2.4), removal of implants (OR, 1.9; 95% CI, 1.2-2.9), or Gustilo-Anderson IIIB/IIIC injury (OR, 2.0; 95% CI, 1.1-3.7). Increased body mass index and fulfilling the criteria to have a methicillin-resistantStaphylococcus aureus(MRSA) nasal swab screening showed a trend toward increased risk of failure. Treatment failure after deep surgical site infection was relatively common. Three distinct factors (polymicrobial infection, removal of implants, and IIIB/C fracture) were associated with failure to eradicate the infection in the first series of surgeries and antibiotics. These data might help guide clinicians as they counsel patients on the risk of treatment failure and might focus efforts to improve treatment toward patients at higher risk of treatment failure.