Good Responder Patients Research Articles

Predictive value of optical coherence tomography angiography in management of diabetic macular edema

BackgroundOptical coherence tomography angiography (OCTA) is a relatively new extension of Optical coherence tomography (OCT) that generates non-invasive, depth-resolved images of the retinal microvasculature which allows for the detection of various features of diabetic retinopathy.ObjectivesThis study aimed to detect biomarkers that may predict an early anatomical response to the treatment of diabetic macular edema (DME) with intravitreal ranibizumab (IVR) by means of OCTA.Patients and methodsThis prospective interventional study was undertaken on 111 eyes of 102 naïve participants who had diabetic macular edema; enrolled patients were evaluated by taking a complete ophthalmologic history, examination and investigations by use of a pre-designed checklist involving Optical Coherence Tomography Angiography.ResultsRegarding the best corrected visual acuity (BCVA) the Mean ± SD was 0.704 ± 0.158 preoperatively and 0.305 ± 0.131 postoperatively in good responder patients; and was 0.661 ± 0.164 preoperatively and 0.54 ± 0.178 postoperatively in poor responders. The central macular thickness (CMT) was 436.22 ± 54.66 μm preoperatively and 308.12 ± 33.09 μm postoperatively in good responder patients; and was 387.74 ± 44.05 μm preoperatively and 372.09 ± 52.86 μm postoperatively in poor responders. By comparing the pre injection size of the foveal avascular zone area (FAZ-A) in both groups, it found that the mean ± SD of FAZ-A was 0.297 ± 0.038 mm in good responder patients compared to 0.407 ± 0.05 mm in non-responder patients. The preoperative superficial capillary plexus (SCP) foveal vascular density (VD) was 24.02 ± 3.01% in good responder patients versus 17.89 ± 3.19% um in poor responders. The preoperative SCP parafoveal VD was 43.06 ± 2.67% in good responder patients versus 37.96 ± 1.82% um in poor responders. The preoperative deep capillary plexus (DCP) foveal VD was 30.58 ± 2.89% in good responder patients versus 25.45 ± 3.14% in poor responders. The preoperative DCP parafoveal VD was 45.66 ± 2.21% in good responder patients versus 43.26 ± 2.35% um in poor responders, this was statistically significant.ConclusionOCTA offers an accurate measurement for VD in the macula as well as the FAZ-A which could be used to predict an early anatomical response of anti-VEGF treatment in DME.

Copy number variation and clinical response to chemotherapy and bevacizumab in the Czech metastatic colorectal cancer patients.

Despite bevacizumab being the first biological agent approved for the treatment of metastatic colorectal cancer (mCRC), there is not any established DNA biomarker to improve its efficacy and personalize the treatment. Thirty patients with mCRC on bevacizumab therapy (15 with a good response and 15 with a poor response) from the University Hospital Olomouc were followed. Formalin-fixed paraffin-embedded (FFPE) samples were used for copy number variation (CNV) analysis using the OncoScan FFPE Assay Kit in order to capture approx. 900 tumor genes. In the group of good responding patients, 102 genes (classified as ATPases, type AAA, neuronal signal transmission, regulation of transcription, and superior domain PH type), potentially significant positive predictive tumor biomarkers of bevacizumab treatment, were found. In the poorly responding group, 74 potentially negative predictive genes (classified as galectines, Jak-STAT signalling pathway, MAPK cascade, differentiation, and F-box associated domain) were identified. In the pilot study, we found promising copy number variation biomarkers of bevacizumab response in FFPE samples of mCRC patients. The validation phase should be focused especially on the genes associated with angiogenesis (AGRN, MAPK8, ARHGAP22, LGALS13, LGALS4, ZFP36, and MYC), tumorigenesis (DVL1), and tumor proliferation (IFNL1, IFNL2, IFNL3, MAP3K10, and MAP4K1).

Intratumoral Heterogeneity Assessment of the Extracellular Bone Matrix and Immune Microenvironment in Osteosarcoma Using Digital Imaging to Predict Therapeutic Response

The assessment of chemotherapy response in osteosarcoma (OS) based on the average percentage of viable cells is limited, as it overlooks the spatial heterogeneity of tumor cell response (foci of resistant cells), immune microenvironment, and bone microarchitecture. Despite the resulting positive classification for response to chemotherapy, some patients experience early metastatic recurrence, demonstrating that our conventional tools for evaluating treatment response are insufficient. We studied the interactions between tumor cells, immune cells (lymphocytes, histiocytes, and osteoclasts), and bone extracellular matrix (ECM) in 18 surgical resection samples of OS using multiplex and conventional immunohistochemistry (IHC: CD8, CD163, CD68, and SATB2), combined with multiscale characterization approaches in territories of good and poor response (GRT/PRT) to treatment. GRT and PRT were defined as subregions with <10% and ≥10% of viable tumor cells, respectively. Local correlations between bone ECM porosity and density of immune cells were assessed in these territories. Immune cell density was then correlated to overall patient survival. Two patterns were identified for histiocytes and osteoclasts. In poor responder patients, CD68 osteoclast density exceeded that of CD163 histiocytes but was not related to bone ECM load. Conversely, in good responder patients, CD163 histiocytes were more numerous than CD68 osteoclasts. For both of them, a significant negative local correlation with bone ECM porosity was found (P < .01). Moreover, in PRT, multinucleated osteoclasts were rounded and intermingled with tumor cells, whereas in GRT, they were elongated and found in close contact with bone trabeculae. CD8 levels were always low in metastatic patients, and those initially considered good responders rapidly died from their disease. The specific recruitment of histiocytes and osteoclasts within the bone ECM, and the level of CD8 represent new features of OS response to treatment. The associated prognostic signatures should be integrated into the therapeutic stratification algorithm of patients after surgery.

Digital pathology in pediatric nodular lymphocyte-predominant Hodgkin lymphoma: correlation with treatment response

Early-stage pediatric nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can be treated effectively with low-intensity chemotherapy, most frequently cyclophosphamide in combination with vinblastine and prednisone (CVP). Descriptive histological risk factors based on the disease-defining lymphocyte predominant cells (LP cells) as used within the Fan classification, are less predictive in early-stage patients. We used deep learning-based cell detection and spatial analysis on digitized biopsy slides from 53 early-stage pediatric NLPHL patients to quantitatively assess LP cell histomorphometry. We found that poor responding patients had significantly fewer LP cells per cluster and lower LP cell density than good responding patients. In our exploratory analysis, we found no correlation between Fan classes or B cell pattern variables and therapy response. We hypothesize that the relationship between poor treatment response and decreased LP cell density may be explained by differences in LP cell proliferation.

Cell Surface Platelet Tissue Factor Expression: Regulation by P2Y12 and Link to Residual Platelet Reactivity.

ADP-induced platelet activation leads to cell surface expression of several proteins, including TF (tissue factor). The role of ADP receptors in platelet TF modulation is still unknown. We aimed to assess the (1) involvement of P2Y1 and P2Y12 receptors in ADP-induced TF exposure; (2) modulation of TFpos-platelets in anti-P2Y12-treated patients with coronary artery disease. Based on the obtained results, we revisited the intracellular localization of TF in platelets. The effects of P2Y1 or P2Y12 antagonists on ADP-induced TF expression and activity were analyzed in vitro by flow cytometry and thrombin generation assay in blood from healthy subjects, P2Y12-/-, and patients with gray platelet syndrome. Ex vivo, P2Y12 inhibition of TF expression by clopidogrel/prasugrel/ticagrelor, assessed by VASP (vasodilator-stimulated phosphoprotein) platelet reactivity index, was investigated in coronary artery disease (n=238). Inhibition of open canalicular system externalization and electron microscopy (TEM) were used for TF localization. In blood from healthy subjects, stimulated in vitro by ADP, the percentage of TFpos-platelets (17.3±5.5%) was significantly reduced in a concentration-dependent manner by P2Y12 inhibition only (-81.7±9.5% with 100 nM AR-C69931MX). In coronary artery disease, inhibition of P2Y12 is paralleled by reduction of ADP-induced platelet TF expression (VASP platelet reactivity index: 17.9±11%, 20.9±11.3%, 40.3±13%; TFpos-platelets: 10.5±4.8%, 9.8±5.9%, 13.6±6.3%, in prasugrel/ticagrelor/clopidogrel-treated patients, respectively). Despite this, 15% of clopidogrel good responders had a level of TFpos-platelets similar to the poor-responder group. Indeed, a stronger P2Y12 inhibition (130-fold) is required to inhibit TF than VASP. Thus, a VASP platelet reactivity index <20% (as in prasugrel/ticagrelor-treated patients) identifies patients with TFpos-platelets <20% (92% sensitivity). Finally, colchicine impaired in vitro ADP-induced TF expression but not α-granule release, suggesting that TF is open canalicular system stored as confirmed by TEM and platelet analysis of patients with gray platelet syndrome. Data show that TF expression is regulated by P2Y12 and not P2Y1; P2Y12 antagonists downregulate the percentage of TFpos-platelets. In clopidogrel good-responder patients, assessment of TFpos-platelets highlights those with residual platelet reactivity. TF is stored in open canalicular system, and its membrane exposure upon activation is prevented by colchicine.

Real-world effectiveness and persistence of reference etanercept versus biosimilar etanercept GP2015 among rheumatoid arthritis patients: A cohort study.

Although several randomized clinical trials have confirmed that there is no difference in efficacy between etanercept and its biosimilar versions in the treatment of rheumatoid arthritis (RA), limited real-world evidence is available. We conducted a cohort study to compare the effectiveness and treatment persistence between the reference etanercept (ETN) and the biosimilar GP2015 in RA patients in a real-life setting. Adults with a diagnosis of RA who initiated treatment with ETN or GP2015, between January 2007 and December 2019, were included. The follow-up period was 52 weeks. The primary outcome was the mean of change in the DAS28-CRP values and the adjusted mean difference from baseline to 52 weeks between ETN and GP2015. Other effectiveness endpoints assessed were the rate of patients who achieved remission or low disease activity (LDA) at week 52, who showed a reduction of DAS28-CRP value greater than or equal to 1.2 from baseline to week 52 and rate of good responder patients (those meeting both effectiveness measures) at week 52. Treatment effectiveness over time (baseline, 26 and 52 weeks) was compared between the ETN and GP2015 groups using mixed effects models. Treatment persistence (probability of maintaining the same treatment over time) was also evaluated and shown using Kaplan–Meier survival curves. A total of 115 RA patients were included (ETN, n = 90; GP2015, n = 25). No differences were observed in the primary outcome: DAS28-CRP score decreased from baseline to week 52 [5.1 to 2.7 (mean of change -2.37) in ETN group and 5.0 to 2.2 (mean of change -2.84) in GP2015 group, p-value = 0.372] and the adjusted mean difference was −0.37 (−1.03 to 0.29). No differences were also observed in the other effectiveness endpoints assessed among patients treated with ETN or GP2015: rate of patients who achieved remission (54.1% vs. 66.7%, p-value = 0.303) and LDA (71.6% vs. 80.9%, p-value = 0.391) at week 52, reduction of DAS28-CRP value greater than or equal to 1.2 from baseline to week 52 (75.6% vs. 80.9%, p-value = 0.613) and rate of good responder patients (58.1% vs. 76.1%, p-value = 0.202). Drug survival was 82% and 80% for ETN and GP2015, respectively (log-rank p-value = 0.804). Etanercept and its biosimilar GP2015 show similar effectiveness and treatment persistence in RA patients in a real-life setting.

Abstract 2045: Spatial organization of the immune microenvironment after neoadjuvant treatment of breast cancer

Abstract Using the immune system to fight cancer has garnered tangible success, but some treatments, like neoadjuvant chemotherapy (NAC), modulate the immune microenvironment. Recent studies show that the spatial organization of tumor infiltrating lymphocytes (TIL) have greater predictive value than TIL density. The effect of NAC on immune composition and spatial distribution is not fully understood but new insight could help to guide its use in combination with immune therapy and identify patients with potential to derive benefit. We spatially profiled 84 RNA targets (GeoMx®) in a cohort of 12 NAC-treated breast cancer patients (4 Luminal, 4 HER2+ and 4 triple negative), none of whom achieved a pathological complete response. Matched pre- and post-treatment tissue samples were analyzed together with regions of interest (tumor center, invasive margin and TIL aggregates) identified using CD3, CD20, Syto83 and pan-cytokeratin for stromal/tumor segmentation. NAC decreases overall gene expression in breast tumors with the biggest declines seen in tumor promoting (CCND1, AKT1, CTNNB1, EPCAM, VEGFA, KRT and MKI67) and some inflammatory (CXCL10, STAT1 and STAT2) genes (p-value &amp;lt;0.05; other immune related transcripts showed little variation). Expression was compared between patients with a good response (&amp;lt;20% tumor cellularity) and those with a poor response (&amp;gt;50% cellularity). Poor responders expressed higher levels of tumor promoting genes pre-NAC, which remained high after treatment (KRT p=0.023, CTNNB1 p=0.031). No differences were detected in immune genes in the stroma based on patient responsiveness; however, higher antigen presentation and inflammatory gene transcripts were found at the tumor margins of good responders. Post-NAC differences between the margin and center decrease in good responders paralleled by a shift towards higher or equal expression of some inflammatory markers at the tumor center. Poor responders maintain high expression of all immune markers at the margin. A higher number of aggregates (mean n=5 vs n=1.3) were detected in good compared to poor responders together with more tertiary lymphoid structures (mean n=2.4 vs n=0.3) and distinguished by higher immune gene expression (CD8 p=0.046, CCL5 p=0.054, NKG7 p=0.022). NAC induces changes in other cells in the tumor microenvironment while targeting tumor cells. Our data show that spatial analysis of gene expression comparing good and poor responders (without a pathological complete response) reveal that tumor cells in the latter retain expression of tumor promoting genes while the immune compartment remains excluded. Good responders are characterized by a decrease in tumor promoting genes in parallel with lymphoid aggregates, including TLS, of active immune cells in the stroma and at the tumor center. These findings suggest that tailoring adjuvant treatment between good and poor responding patients might be warranted. Citation Format: Noémie Thomas, Soizic Garaud, Mireille Langouo, Ioannis Zerdes, Doïna Sofronii, Anaïs Boisson, Theodoros Foukakis, Alexandre De Wind, Roberto Salgado, Ahmad Awada, Karen Willard-Gallo. Spatial organization of the immune microenvironment after neoadjuvant treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2045.

Rituximab or rituximab plus chlorambucil for translocation (11;18)-negative gastric mucosa-associated lymphoid tissue lymphoma: a monocentric non-randomized observational study

To assess the effectiveness and safety of rituximab alone or in combination with chlorambucil for the treatment of translocation (11;18)-negative gastric MALT lymphoma, we included 71 patients in a retrospective case–control study, 54 treated with rituximab alone and 17 with combination therapy. There was no difference between the groups in complete remission or overall response rates at weeks 25 and 52. After a median follow-up period of 5.8 years (range, 3.3 − 9.7 years), the 5-year progression-free survival probabilities were 60% and 88% in patients treated with rituximab monotherapy and combination therapy, respectively (p = .05). Adverse events were reported in 13 (18%) patients and were more frequent in the combination therapy group (p < .001). Combination therapy may be a preferable choice in patients with gastric MALT lymphoma irrespective of t(11;18) status. Further studies should assess benefit of stopping chlorambucil in early good-responder patients.

A Novel Combined Conjugate Therapeutic Cancer Vaccine, Recombinant EGF-CRM197, in Patients With Advanced Solid Tumors: A Phase I Clinical Study.

IntroductionThe therapeutic cancer vaccine recombinant Epidermal Growth Factor (EGF)-CRM197 is a novel combined conjugate EGF with CRM197 as a carrier protein. Immunization with the EGF-CRM197 vaccine can induce high levels of neutralizing anti-EGF antibodies that inhibit EGF/EGFR signaling and thereby suppress growth of tumors that rely on this signaling pathway. Herein, we characterize the humoral immune responses elicited by the recombinant EGF-CRM197 vaccine in patients with advanced solid tumors in a phase I clinical trial and assess the safety, tolerability, and immunogenicity of this vaccine (CTR20190473).MethodsA total of 16 subjects were enrolled in this study. Under 6 + 3 design, patients in each dosing cohort were administrated subcutaneously at a dosage of 0.4 mg, 0.8 mg, and 1.6 mg, respectively. The patients received vaccinations for immune induction (once a week for 4 consecutive weeks) and booster vaccinations (once every 4 weeks). Safety evaluation was performed 1 week after the immune induction. Booster vaccination was given until the occurrence of disease progression, intolerance, withdrawal of informed consent by the patient, or negative result of anti-EGF test after two booster vaccinations.ResultsVaccination with EGF-CRM197 is safe and well-tolerated in patients with advanced solid tumors. Adverse reactions at the injection site were the most common adverse events (AEs) in recipients. No severe adverse reactions post vaccination were observed in the present study. Vaccinated patients developed a robust neutralizing antibody response triggered by EGF-CRM197 that significantly reduced the levels of EGF in serum. For lung cancer patients who were super good antibody responders (sGAR) to EGF-CRM197, the median progress-free survival (PFS) was 4.83 months, significantly longer than that of the good antibody responder (GAR) patients with lung cancer whose median PFS was 2.10 months (P=0.0018). The median overall survival (OS) of GAR lung cancer patients was 10.67 months while the OS) for sGAR lung cancer patients was not reached until analysis was performed. The median follow-up of the sGAR lung cancer patients was 14.6 months.ConclusionOur study demonstrates that the recombinant EGF-CRM197 therapeutic cancer vaccine can induce a good immune response in patients with advanced solid tumors and is safe and well tolerated, which ensures further clinical development of the vaccine for extending the survival time of EGF-CRM197 sensitive patients with advanced solid tumors.Clinical Trial Registrationhttp://www.chinadrugtrials.org.cn, identifier CTR20190473, EGF-CRM197.

Deep learning neural network analysis of human blastocyst expansion from time-lapse image files

Research questionCan artificial intelligence (AI) discriminate a blastocyst's cellular area from unedited time-lapse image files using semantic segmentation and a deep learning optimized U-Net architecture for use in selecting single blastocysts for transfer? DesignThis platform was retrospectively applied to time-lapse files from 101 sequentially transferred single blastocysts that were prospectively selected for transfer by their highest expansion ranking within cohorts using a 10 h expansion assay rather than standard grading. ResultsThe AI platform provides expansion curves and raw data files to classify and compare blastocyst phenotypes within both cohorts and populations. Of 35 sequential unbiopsied single blastocyst transfers, 23 (65.7%) resulted in a live birth. Of 66 sequential single euploid blastocyst transfers, also selected for their most robust expansion, 49 (74.2%) resulted in live birth. The AI platform revealed that the averaged expansion rate was significantly (P = 0.007) greater in euploid blastocysts that resulted in live births compared with those resulting in failure to give a live birth. The platform further provides a framework to analyse fragmentation phenotypes that can test new hypotheses for developmental regulation during the preimplantation period. ConclusionsAI can be used to quantitatively describe blastocyst expansion from unedited time-lapse image files and can be used to quantitatively rank-order blastocysts for transfer. Early clinical results from such single blastocyst selection suggests that live birth rates without biopsy may be comparable to those found using single euploid blastocysts in younger, good responder patients.

B cells from Patients with Rheumatoid Arthritis Show Conserved CD39-Mediated Regulatory Function and increased CD39 Expression After Positive Response to Therapy

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by progressive joint destruction associated with increased pro-inflammatory mediators. In inflammatory microenvironments, exogenous ATP (eATP) is hydrolyzed to adenosine, which exerts immunosuppressive effects, by the consecutive action of the ectonucleotidases CD39 and CD73. Mature B cells constitutively express both ectonucleotidases, converting these cells to potential suppressors. Here, we assessed CD39 and CD73 expression on B cells from treated or untreated patients with RA. Neither the frequency of CD73+CD39+ and CD73-CD39+ B cell subsets nor the levels of CD73 and CD39 expression on B cells from untreated or treated RA patients showed significant changes in comparison to healthy controls (HC). CpG+IL-2-stimulated B cells from HC or untreated RA patients increased their CD39 expression, and suppressed CD4+ and CD8+ T cell proliferation and intracellular TNF-production. A CD39 inhibitor significantly restored proliferation and TNF-producing capacity in CD4+ T cells, but not in CD8+ T cells, from HC and untreated RA patients, indicating that B cells from untreated RA patients conserved CD39-mediated regulatory function. Good responder patients to therapy (R-RA) exhibited an increased CD39 but not CD73 expression on B cells after treatment, while most of the non-responder (NR) patients showed a reduction in ectoenzyme expression. The positive changes of CD39 expression on B cells exhibited a negative correlation with disease activity and rheumatoid factor levels. Our results suggest modulating the ectoenzymes/ADO pathway as a potential therapy target for improving the course of RA.

Data independent acquisition of plasma biomarkers of response to neoadjuvant chemotherapy in pancreatic ductal adenocarcinoma

The detection of disease-related plasma biomarkers has challenged the proteomic community for years. Attractive features for plasma proteomics includes the ease of collection and small volume needed for analysis, but on the other hand, the presence of highly abundant proteins complicates sample preparation procedures and reduces dynamic range. Data independent acquisition label free quantitation (DIA-LFQ) by mass spectrometry partly overcomes the dynamic range issue; however, generating the peptide spectral reference libraries that allow extensive analysis of the plasma proteome can be a slow and expensive task which is unattainable for many laboratories. We investigated the re-purposing of publically available plasma proteome datasets and the impact on peptide/protein detection for DIA-LFQ. We carried out these studies in the context of identifying putative biomarkers of response to neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma, as no useful plasma biomarkers have been clinically adopted. We demonstrated the benefit in searching DIA data against multiple spectral libraries to show that complement proteins were linked to NAC response in PDAC patients, confirming previous observations of the prognostic utility of complement following adjuvant chemotherapy. Our workflow demonstrates that DIA-LFQ can be readily applied in the oncology setting for the putative assignment of clinically relevant plasma biomarkers. Statement of significanceThe proteomic mass spectrometry analysis of undepleted, unfractionated human plasma has benefits for sample throughput but remains challenging to obtain deep coverage. This work evaluated the re-purposing of open source peptide mass spectrometry data from human plasma to create spectral reference libraries for use in Data independent acquisition (DIA). We showed how seeding in locally acquired data to integrate iRT peptides into spectral libraries increased identification confidence by facilitating querying of multiple libraries. This workflow was applied to the discovery of putative plasma biomarkers for response to neoadjuvant chemotherapy (NAC) in pancreatic ductal adenocarcinoma patients. There is a paucity of prior information in the literature on this topic and we show that good responder patients have reduced levels of complement proteins.

Identifying predictive biomarkers of CIMAvaxEGF success in non\u2013small cell lung cancer patients

BackgroundImmunosenescence biomarkers and peripheral blood parameters are evaluated separately as possible predictive markers of immunotherapy. Here, we illustrate the use of a causal inference model to identify predictive biomarkers of CIMAvaxEGF success in the treatment of Non–Small Cell Lung Cancer Patients.MethodsData from a controlled clinical trial evaluating the effect of CIMAvax-EGF were analyzed retrospectively, following a causal inference approach. Pre-treatment potential predictive biomarkers included basal serum EGF concentration, peripheral blood parameters and immunosenescence biomarkers. The proportion of CD8 + CD28- T cells, CD4+ and CD8+ T cells, CD4/CD8 ratio and CD19+ B cells. The 33 patients with complete information were included. The predictive causal information (PCI) was calculated for all possible models. The model with a minimum number of predictors, but with high prediction accuracy (PCI > 0.7) was selected. Good, rare and poor responder patients were identified using the predictive probability of treatment success.ResultsThe mean of PCI increased from 0.486, when only one predictor is considered, to 0.98 using the multivariate approach with all predictors. The model considering the proportion of CD4+ T cell, basal Epidermal Growth Factor (EGF) concentration, neutrophil to lymphocyte ratio, Monocytes, and Neutrophils as predictors were selected (PCI > 0.74). Patients predicted as good responders according to the pre-treatment biomarkers values treated with CIMAvax-EGF had a significant higher observed survival compared with the control group (p = 0.03). No difference was observed for bad responders.ConclusionsPeripheral blood parameters and immunosenescence biomarkers together with basal EGF concentration in serum resulted in good predictors of the CIMAvax-EGF success in advanced NSCLC. Future research should explore molecular and genetic profile as biomarkers for CIMAvax-EGF and it combination with immune-checkpoint inhibitors. The study illustrates the application of a new methodology, based on causal inference, to evaluate multivariate pre-treatment predictors. The multivariate approach allows realistic predictions of the clinical benefit of patients and should be introduced in daily clinical practice.

The dose of robot-assisted gait therapy may influence functional recovery in a multidisciplinary rehabilitation program: an exploratory retrospective study.

Robot-assisted gait training (RAGT) has been introduced in clinical practice to increase training intensity in patients with neurological disorders. In this observational study, we investigated the effect of the number of RAGT sessions on functional recovery in a heterogeneous cohort of patients. We included patients with a diagnosis of gait impairment due to a neurological disease. A set of demographic, clinical, functional and training parameters was collected for each participant. Each patient received RAGT with an exoskeleton (Lokomat; Hocoma, Volketswil, Switzerland) as part of a multidisciplinary rehabilitation program. We stratified the patients as good responders and poor responders and investigated the effect of varying the number of RAGT sessions with a series of logistic regression models. A total of 143 patients were included in this analysis (good responders = 65, poor responders = 78). Good responder patients spent more days in the hospital (P < 0.01) and underwent a higher number of RAGT sessions (P = 0.04) compared to poor responder patients. Logistic regression models estimated that adding six RAGT sessions mildly increased (by approximately 4%) the probability of a patient becoming a good responder. The rehabilitation phase (subacute/chronic) appeared to be the main determinant of the probability of being a good responder, and stroke patients appeared to be more sensitive to changes in the number of RAGT sessions. Our results seem to confirm previous observations that robotic therapy increases the intensity of rehabilitation, possibly leading to a greater functional recovery in subacute patients with greater impairment.

Position of cytoreductive nephrectomy in the setting of metastatic renal cell carcinoma patients: does the CARMENA trial lead to a paradigm shift?

Introduction > The role of cytoreductive nephrectomy (CN) in combination with targeted therapy has been debated after the results of the CARMENA trial. We decided to reassess the available evidence on the setting of CN in metastatic renal cell carcinoma (mRCC) patients. Methods > Critical review of the literature focusing on CN in mRCC patients. Results > Previous trials demonstrated a survival benefit of CN during the cytokine-era. In the targeted therapies-era, retrospective studies has confirmed the survival benefit of CN but presented inherent selection biases. Recently, the CARMENA trial showed that sunitinib alone was not inferior to CN plus sunitinib, and could be followed by subsequent CN in good-responders patients. CN is found to be a morbid surgery (perioperative mortality rate of 0-13% and major postoperative complications rate of 3-36%) and should be avoided in patients with primary refractory disease, using targeted therapy as a selection tool. Some parameters have been associated with shorter overall survival, leading to propose up-front CN only to patients with good performance status, a high-volume renal tumor and a low metastatic burden. Conclusions > While previous studies demonstrated a survival benefit of CN, the CARMENA trial showed that immediate CN was not necessary in some patients with mRCC, leading to a paradigm shift. Targeted therapy should be proposed as first line treatment, and the response to pre-surgical therapy could be used as a selection tool for subsequent decision of CN in good-responders patients.

Toxicity Reduction in the Treatment of HPV Positive Oropharyngeal Cancer: Emerging Combined Modality Approaches.

Human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) is a distinct clinical entity within the head and neck cancers, with a unique epidemiology and, in general, a favorable prognosis. Because of this favorable prognosis, researchers have considered de-intensifying the current standard treatment of HPV+ OPC in order to reduce acute and late treatment related toxicity without compromising outcome. Current ongoing trials can be divided in three main categories: de-intensification of the chemotherapy by replacing concomitant platinum-based chemotherapy with the EGFR-inhibitor cetuximab, or de-intensification of the radiation dose of either the primary radiotherapy of selected, good-responding patients after induction chemotherapy or of the adjuvant radiotherapy based on pathology features after primary surgery. Despite the good prognosis of the majority of HPV+ OPC patients, a proportion of them still have poor prognosis. This unmet need has led clinical research on new treatment strategies focused on influencing the unique micro-environment of HPV+ OPC with for example immunotherapy. This article summarizes the current understanding regarding the optimal treatment of non-metastatic HPV+ OPC. Ongoing and published clinical trials regarding de-intensification strategies, immunotherapy and proton therapy are described focusing on the rationale and underlying evidence of these emerging treatment strategies. Nevertheless, until the results of the ongoing trials are known, the treatment of HPV+ OPC in clinical practice should remain identical to the treatment of HPV negative OPC.

PD-L1+ Regulatory B Cells Are Significantly Decreased in Rheumatoid Arthritis Patients and Increase After Successful Treatment.

Background: B cells play an important role in the development and maintenance of rheumatoid arthritis (RA). Although IL-10–producing B cells represent a major subset of regulatory B cells (Bregs) able to suppress autoimmune and inflammatory responses, recent reports showed that B cell-mediated immune suppression may also occur independent of IL-10. For instance, B cells can modulate T cell immune responses through the expression of regulatory molecules such as PD-L1. So far, PD-L1-expressing B cells have not been analyzed in RA patients.Objective: To analyze the frequency of PD-L1-expressing B cells in the peripheral blood of RA patients compared to healthy controls (HC) matched for sex and age, their function on T cell response and their changes in response to therapy.Methods: Fresh peripheral blood B cells from RA patients and HC were characterized by flow cytometry and their functionality assessed in a co-culture system with autologous T cells.Results: The frequencies of CD19+PD-L1+ B cells, CD24hiCD38−PD-L1+ and CD24hiCD38hiPD-L1+ B cells were significantly lower in untreated RA patients than in HC. In a follow-up study, the frequencies of PD-L1+ B cells (CD19+PD-L1+ B cells, CD24hiCD38−PD-L1+ and CD24hiCD38hiPD-L1+ B cells) increased significantly after treatment in good responder patients, although the frequency of total CD24hiCD38hi B cells decreased. CD19+ B cells from untreated RA patients and HC upregulated PD-L1 expression similarly upon stimulation with CpG plus IL-2 and were able to suppress, in vitro, CD8+ T cell proliferation and cytokine production in a PD-L1-dependent manner.Conclusions: Our results show that PD-L1+ B cells exhibiting T cell suppressive capacity are significantly decreased in untreated RA patients but increase in response to successful treatment. PD-L1 expression on B cells from RA patients can be modulated in vitro and PD-L1+ B cells could thus provide new perspectives for future treatment strategies.

Prediction of Chemotherapy Response in Primary Osteosarcoma by Use of the Multifractal Analysis of Magnetic Resonance Images

Background: Due to the high level of cytogenetic heterogeneity in osteosarcoma, personalized treatment is the promising strategy for the improvement in outcomes. This is currently not possible due to the absence of targeted therapies and reliable predictors for response to induction chemotherapy. Objectives: To investigate the predictive value of computational analysis of osteosarcoma magnetic resonance (MR) images. Patients and Methods: Multifractal analysis was performed on MR images of primary osteosarcoma of long tubular bones prior to OsteoSa induction chemotherapy. A total of 900 images derived from 67 good and poor responder patients were classified and compared to the actual retrospective outcome. Results: Among the six calculated multifractal features, Dqmax exerted the highest predictive value with the prediction accuracy of 74.3%, sensitivity of 72.4% and specificity of 76.2%. The obtained classification accuracy was validated by a ten V-fold split sample cross validation. The area under the curve (AUC) value for the best-performing multifractal Dqmax feature was 0.82 (95% confidence interval, 0.70 - 0.91). Conclusion: These results suggest for the first time that measuring tumor structure by using multifractal geometry can predict an individual patient response to neoadjuvant cytotoxic therapy. Therefore, it potentially allows precise implementation of alternative treatment options. This predictive approach made use of digital data that is routinely collected but currently still underexploited.

A Proposed Kinetic Model for the Diagnostic and Prognostic Value of WT1 and p53 in Acute Myeloid Leukemia.

Wilms tumor (WT1) and p53 proteins were identified in the pathogenesis of several malignancies, including hematological malignancies. As a result of their interaction and diverse context-specific functions, this study aimed to emphasize the diagnostic and prognostic impacts of WT1 and p53 expression in acute myeloid leukemia (AML). Twelve bone marrow (BM) biopsies were obtained from AML patients who were diagnosed in accordance with the French-American-British diagnostic criteria. For comparative purposes, nine normal BM biopsies were included. The expression rate of WT1 and p53 were determined by an immunohistochemistry assay. A significantly higher (p < 0.005) and strongly correlated ( = 0.855, p = 0.001) expression rates of WT1 and p53 were observed in the BM of AML patients in comparison to control BM. Furthermore, relapsed AML patients had significantly higher expression of WT1, but not p53, when compared to newly diagnosed patients. In regard of patient's responsiveness to chemotherapy, no significant difference was reported between good and poor responders. However, the relative ratio of p53 to WT1 expression was evidently correlated to the responsiveness groups (p < 0.05), where the ratio was observed to be significantly higher among poor responders. Poor responders were characterized by a statistically significant and dominant p53 expression (p53/WT1 > 1.0) while both good responding patients and control subjects had a dominant WT1 expression (p53/WT1 < 1.0). The enhanced expression levels of WT1 and p53 proteins in the BM of AML patients is supportive of their intermediate role in the pathogenesis of the disease. WT1 expression rate may encompass a negative prognostic value of the disease. Furthermore, the ratio of p53/WT expression may serve as a hallmark of the patient's responsiveness to chemotherapy, where a dominant WT1 expression may reveal good responsiveness to chemotherapy. Herein, we are proposing a kinetic model where the p53/WT1 ratio might be useful as a laboratory approach to evaluate the prognostic value of AML including the patient's responsiveness to chemotherapeutic regimen.

Combined therapy in children and adolescents with classical Hodgkin's lymphoma: A report from the SFCE on MDH-03 national guidelines

ABSTRACTHodgkin's lymphoma (HL) in children and adolescents is highly curable, but children are at risk of long-term toxicity. The MDH-03 guidelines were established in order to decrease the burden of treatment in good-responder patients, and this report should be considered a step toward further optimization of treatment within large collaborative trials. We report the therapy and long-term outcomes of 417 children and adolescents treated according to the national guidelines, which were applied between 2003 and 2007 in France. The patients were stratified into three groups according to disease extension. Chemotherapy consisted of four cycles of VBVP (vinblastine, bleomycin, VP16, prednisone) in localized stages (G1/95 pts/23%), four cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, adriamycin, bleomycin, vinblastine) cycles in intermediate stages (G2/184 pts/44%) and three cycles of OPPA (vincristine, procarbazine, prednisone, adriamycin) plus three cycles of COPP in advanced stages (G3/138 pts/33%). Radiation therapy of the involved field was given to 97% of the patients, with the dose limited to 20 Gy in good responders (88%). With a median follow-up of 6.6 years, the 5-year event-free survival (EFS) and overall survival (OS) were 86.7% (83.1–89.7%) and 97% (94.5–98.1%), respectively. EFS and OS for G1, G2, and G3 were 98% and 100%, 81% and 97%, and 87% and 95%, respectively. Low-risk patients treated without alkylating agents and anthracycline had excellent outcomes and a low expected incidence of late effects. Intensification with a third OPPA cycle in high-risk group patients, including stage IV patients, allowed for very good outcomes, without increased toxicity.