Marker Of Treatment Outcome Research Articles

Baseline and Dynamic Changes in Hemoglobin Levels Predict Treatment Response and Prognosis in Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Study.

Clinical markers of response in metastatic renal cell carcinoma (mRCC) are lacking. Low hemoglobin (Hb) is associated with poor outcomes in the IMDC risk score. This study evaluates the role of Hb as a marker of treatment outcomes in mRCC. This multicenter retrospective study evaluated 276 patients with mRCC treated with frontline immune checkpoint inhibitor (ICI) therapy, ICI and vascular endothelial growth factor (VEGF) inhibitor (VEGFI) combinations (ICI/VEGFI), or VEGFI monotherapy between 2014 and 2021. Hb levels at baseline, week 6 and 12 and at disease progression or death were recorded. Patients were categorized as responders (CR+PR) or nonresponders (SD+PD) using cross-sectional imaging at week 12. The association between baseline and dynamic changes in Hb and oncological outcomes was assessed. Thirty-seven percent, 40% and 22% of patients received ICIs, ICI/VEGFI and VEGFI respectively. In patients receiving ICIs, there was a significant increase in Hb amongst responders from baseline to week 12 (P= .02). Amongst patients receiving ICI/VEGFI, there was an increase in Hb from baseline to week 12 which was greater in responders (P< .001). In patients receiving VEGFI monotherapy, responders had a higher Hb at baseline (P= .01), week 6 (P= .04), and week 12 (P= .003). An increase in Hb was a significant independent predictor of progression-free survival amongst patients receiving ICIs (HR 0.40, 95%CI, 0.19-0.83, P= .009). Baseline and dynamic changes in Hb are associated with first-line treatment outcomes in patients with mRCC and represent a pragmatic early serological marker.

Defining the Concept and Clinical Features of Epistemic Trust: A Delphi study.

Early identification of "patients at risk" for not completing regular treatment or not benefitting (sufficiently) from treatment might be among the most cost-effective strategies in mental health care. The recently introduced concept of epistemic trust (ET) may have the potential value to predict patients at risk and therefore act as a marker of treatment outcome. We argue that ET may be the final common pathway through which aversive relational experiences in the past result in interpersonal dysfunctioning, which in turn result in dysfunctional therapeutic relationships, rendering it difficult for patients to trust whatever is offered to learn in therapy. Hence, the concept of ET can play an essential role in personalized medicine, allowing for a more tailored treatment assignment to specific patients' characteristics, which may improve treatment outcomes. In this brief report, we define the clinical features of ET by describing its core domains based on consensus of expert opinion on the concept. The response rate was high, and there was a high level of agreement across experts, demonstrating a strong consensus between experts on the definition and clinical features of ET and mistrust and its significance to the understanding of personality disorders.By means of having a clear definition of the clinical features of ET, we hope to make it accessible for assessment.

Multi-target repetitive transcranial magnetic stimulation (rTMS) protocol for the treatment of comorbid depression and chronic pain

Abstract Background: Major Depressive Disorder (MDD) and chronic pain are frequently co-occurring, and the onset of either condition can either precede or follow the onset of the other. Notably, clinical outcome for pharmacological and rTMS treatment for depression is significantly worse in the presence of chronic pain symptoms. To improve clinical care for depression it is thus critical to address the comorbidity of depression and chronic pain in a unified approach rather than treating them as separate conditions. Objective: We examined whether a multi-target rTMS protocol including stimulation of the left dorsolateral prefrontal cortex (DLPFC) and primary motor cortex (M1) would improve depressive and chronic pain symptoms more than a standard single-target rTMS protocol. Methods: We treated 20 comorbid depressive and chronic pain patients with a multi-target rTMS protocol and another 20 age- and sex-matched comorbid patients that had comparable baseline depression and pain symptom severity were treated only at the left DLPFC, for a minimum of 10 sessions. We have also recorded electroencephalography (EEG) at baseline session and examined a previously reported metric of pain sensitivity, peak alpha frequency (PAF), as a possible marker of treatment outcome. Preliminary Results: The multi-target rTMS achieved on average 15% greater improvement than stimulation at left DLPFC alone. Cohen’s D effect size was D = 0.8, which represents a moderate effect. We will also present EEG data examining the associations between PAF and pain and depression treatment outcomes. Conclusions: Multi-target rTMS to DLPFC and M1 may be more effective in treating the comorbidity of depression and chronic pain than rTMS to DLPFC only. Multi-site protocols could represent a treatment augmentation strategy with significant benefit for comorbid subjects. Other potential rTMS target site should be evaluated in future studies. Keywords: Chronic Pain, Depression, EEG, TMS

Mammographic density changes following BC treatment

BackgroundMammographic density (MD) reduction is associated with lower risk of breast cancer (BC) recurrence and may be used as a marker of treatment outcome; however, trends in MD following BC therapies and the factors associated with such trends are poorly understood. The aim of this study was to investigate MD changes following BC treatment and the factors associated with these changes. MethodsA total of 226 BC-affected patients who received BC treatments were examined. MD was assessed by the Laboratory for individualized Radiodensity Assessment (LIBRA) software. A Wilcoxon ranked signed test was used to investigate the differences in MD before and after treatment and median independent test to assess the associated factors. ResultsSignificant differences in MD between baseline and follow-up mammograms were observed for all MD measures: percent density (p ≤ 0.005), dense area (p ≤ 0.004), and nondense area (p ≤ 0.02). After adjustment, these differences were more pronounced among younger at BC diagnosis (p ≤ 0.001), premenopausal (p ≤ 0.003), and obese women (p ≤ 0.05). Changes in MD were evident regardless of the treatment regimen. MD reduction was observed among patients with high baseline MD (p < 0.001), younger at BC diagnosis (p ≤ 0.04), premenopausal (p < 0.001), and normal body mass index (p = 0.04). Patients who experienced an increase in nondense area had high percent density at baseline (p ≤ 0.001). ConclusionTwo different MD changes were observed over time: MD increase and decrease. Baseline MD, menopausal status, age at BC diagnosis, and body mass index influenced these changes.

Predictors of Treatment Outcome in Adolescent Depression

Major depressive disorder is a global public health concern that is common in adolescents. Targeting this illness at the early stages of development is critical and could lead to better long-term outcomes because the adolescent brain is highly plastic and, hence, neural systems are likely to be more malleable to interventions. Although a variety of treatments are available, there are currently no guidelines to inform clinicians which intervention might be most suitable for a given youth. Here, we discuss current knowledge of prognostic and prescriptive markers of treatment outcome in adolescent depression, highlight two major limitations of the extant literature, and suggest future directions for this important area of research. Despite significant effort, none of the potential demographic (gender, age, race), environmental (parental depression, family functioning), and clinical (severity of depression, comorbid diagnoses, suicidality, hopelessness) predictors have been robustly replicated to warrant implementation in clinical care. Studies on biomarkers that truly reflect pathophysiology are scarce and difficult to draw conclusions from. More efforts should be directed towards potential neurobiological predictors of treatment outcome. Moreover, rather than evaluating potential predictors in isolation, modern machine learning methods could be used to build models that combine information across a large array of features and predict treatment outcome for individual patients. These strategies hold promise for advancing personalized healthcare in adolescent depression, which remains a high clinical priority.

1225 Early Prediction of Methotrexate Treatment Success by 24‐Hour Pretreatment HCG Increment and Day 1-4 HCG Ratio

Study Objective Several studies have tried to identify early markers for treatment outcome after methotrexate (MTX) treatment for an ectopic pregnancy (EP) including pretreatment and day 4 hCG levels and corresponding ratio, and hCG increment during the initial 24 hours following treatment, with conflicting results. We aim to re‐evaluate the role the aforementioned markers in the earlier identification of treatment success in a large cohort of women. Design A retrospective cohort study. Setting A tertiary medical center during 2010-2018. Patients or Participants All women diagnosed with an EP and treated by intention of single-dose regimen of intramuscular MTX. Interventions A comparison of maternal and gestation characteristics was performed between treatment success and failure groups. Measurements and Main Results 292 women treated with single-dose intramuscular MTX for EP during were included in this study. Treatment success rate with a single dose of MTX of the overall cohort was 62.7% (183/292). Only two independent determinants were significantly associated with the treatment success: initial 24 hours hCG percentage of increment (adjusted odds ratio [OR]: 1.82; 95% confidence intervals [CI]: 1.26, 2.63; p Conclusion A low rise in hCG levels 24 hours prior to treatment with MTX, alongside a decline in hCG levels from day 1 to day 4 may predict success of medical treatment of EP.

Abstract 1684: Multi-omics profiling of breast cancers during neoadjuvant chemotherapy identified distinct molecular changes and biomarkers associated with clinical response

Abstract The molecular bases underlying neoadjuvant chemotherapy (NAC) response are poorly understood. To elucidate the effects of NAC on breast tumor biology and its association with clinical outcome, we have conducted WES and RNA-Seq profiling of a longitudinal breast cancer (BC) cohort consisting of 146 cases (281 tumors, 109 pairs), including 55 (38%) that achieved pathologic complete responses (pCR) and 91 (62%) that harbored residual diseases at time of surgery. Tumor biopsies were collected for each patient at three time points - pre-treatment, three weeks after the first cycle of anthracycline and cyclophosphamide (AC) and at the time of surgery, after 3 more cycles of AC followed by 4 cycles of taxane. In addition to somatic mutations and copy number alterations, we also derived a comprehensive set of genomic and molecular features for each tumor including chromosomal instability, loss-of-heterozygosity, mutation burden, mutation signatures and expression signatures for oncogenic signaling pathways and immune cell subsets. Virtual microdissection analysis inferred 14 factors that represent distinct tissue compartment including a tumor infiltrating lymphocyte (TIL) factor and revealed that initial NAC treatment increased stromal and adjacent normal tissue fractions while reducing tumor cellularity. NAC also induced dynamic changes in immune gene expressions over time, a pattern that was validated through detecting and quantifying the density of TILs from H&amp;E images. To investigate NAC induced changes in tumor intrinsic biology we classified tumors into five oncogenic cellular states on a reference Onco-GPS map defined by transcriptional signatures from breast cancer cell lines. We observed that, as a result of NAC treatment, tumors often change from one oncogenic state to another, transiently upregulating an EMT program that appears to mediate drug resistance and increase the likelihood of residual disease. Multiple regression and multivariate analyses were performed to identify predictive biomarkers of pCR status while adjusting for BC subtypes and tumor purity. We found that ER+ subtype and estrogen response signature but not Ki-67 were independently associated with NAC response. Within TNBC, the immunomodulatory subtype was enriched in responders while the basal-like subtype had the poorest response. Pretreatment TIL and changes in TIL level over time were independently associated with NAC response, implicating anti-tumor immunity in mediating the efficacy of chemotherapies. Through multi-omics characterization of longitudinally paired tumor biopsies, we have revealed dynamic changes in the tumor molecular states in BC patients undergoing NAC treatment, identified molecular markers of treatment outcome and derived insights into the mechanism of action as well as resistance to an important class of therapy. Citation Format: Samir Lal, Ying Ding, Jeong Eon Lee, Soo-Hyeon Lee, Se Kyung Lee, Jae-Yong Nam, Jong Han Yu, Yoon-la Choi, Seok Won Kim, Seok Jin Nam, Ji-Yeon Kim, Sripad Ram, Eric Powell, Keith A. Ching, Pablo Tamayo, William Kim, Huwate Yeerna, Soo Youn Cho, Vinicius Bonato, Shibing Deng, Jinho Kim, Hyuntae Shin, Woong-Yang Park, Paul A. Rejto, Jadwiga Bienkowska, Yeon-Hee Park, Zhengyan Kan. Multi-omics profiling of breast cancers during neoadjuvant chemotherapy identified distinct molecular changes and biomarkers associated with clinical response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1684.

Supplemental Oxygen Protects Heart Against Acute Myocardial Infarction.

Myocardial infarction (MI), which occurs often due to acute ischemia followed by reflow, is associated with irreversible loss (death) of cardiomyocytes. If left untreated, MI will lead to progressive loss of viable cardiomyocytes, deterioration of cardiac function, and congestive heart failure. While supplemental oxygen therapy has long been in practice to treat acute MI, there has not been a clear scientific basis for the observed beneficial effects. Further, there is no rationale for the amount or duration of administration of supplemental oxygenation for effective therapy. The goal of the present study was to determine an optimum oxygenation protocol that can be clinically applicable for treating acute MI. Using EPR oximetry, we studied the effect of exposure to supplemental oxygen cycling (OxCy) administered by inhalation of 21–100% oxygen for brief periods (15–90 min), daily for 5 days, using a rat model of acute MI. Myocardial oxygen tension (pO2), cardiac function and pro-survival/apoptotic signaling molecules were used as markers of treatment outcome. OxCy resulted in a significant reduction of infarct size and improvement of cardiac function. An optimal condition of 30-min OxCy with 95% oxygen + 5% CO2 under normobaric conditions was found to be effective for cardioprotection.

Midluteal Progesterone: A Marker of Treatment Outcomes in Couples With Unexplained Infertility.

Adequate luteal phase progesterone exposure is necessary to induce endometrial changes required for a successful pregnancy outcome. The relationship between low midluteal progesterone concentration and the outcome of live birth in ovarian stimulation with intrauterine insemination (OS-IUI) treatments is not defined. To determine the level of midluteal progesterone portending a low chance of live birth after OS-IUI in couples with unexplained infertility. Secondary analyses of data from a prospective, randomized, multicenter clinical trial that determined pregnancy outcomes following OS-IUI with clomiphene citrate, letrozole, or gonadotropins for couples with unexplained infertility. Couples (n = 900) underwent 2376 OS-IUI cycles during the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial. Live birth as it relates to midluteal progesterone level and thresholds below which no live births occur by treatment group. Thresholds for non-live birth cycles were similar for clomiphene (14.4 ng/mL) and letrozole (13.1 ng/mL) yet were lower for gonadotropin (4.3 ng/mL) treatments. A midluteal progesterone level >10th percentile specific for each treatment group independently was associated with greater odds for a live birth in all OS-IUI cycles (adjusted OR: 2.17; 95% CI: 1.05, 4.48). During OS-IUI, a low midluteal progesterone level was associated with a low probability of live birth. Thresholds differed by medication, with the lowest threshold for gonadotropin. Several pathophysiologic mechanisms may account for low progesterone levels. Refinement of the predictive range associated with particular ovarian stimulation medications during treatment of unexplained infertility may improve accuracy.

Assessment of WT1 Expression as a Marker of Treatment Outcome in Karyotype Normal Acute Myeloid Leukemia Patients in Pakistan.

Currently, there is an effort to predict relapse by follow-up monitoring of MRD and subsequently to begin the treatment of the patients during their clinical and hematological remission prior to overt hematological relapse. Expression of WT1 in AML is known to be independently associated with significant inferior response to therapy and short survival outcome. Follow-up monitoring of WT1 gene expression during or after therapy would be a valuable predictive marker for early recurrence or relapse of AML disease. This pilot study evaluated newly diagnosed and post-induction or consolidation chemotherapy of AML patients who were registered with the Oncology Clinics of the Aga Khan University Hospital, Karachi. High WT1 burden (> 5000 copies/ml) in 2 patients was indicative of early recurrence of the disease along with shorter disease-free and overall survival. Low WT1 expression (< 200 copies/ml) in 2 patients after induction and consolidation therapy, respectively, was suggestive of better prognosis.

Hepatocellular carcinoma and CXCR3 chemokines: a narrative review.

Hepatocellular carcinoma (HCC) results from several factors like viral hepatitis infection [hepatitis B, or C (25%)] or occupational exposure. T-helper (Th)1 inflammatory cells, characterized by interferon (IFN)-γ and interleukin (IL)-2 secretion, predominate in the liver during chronic HCV infection, and chemokines attracting these cells are particularly important in disease progression. Among C-X-C chemokines, the non-ELR group [as IFN-γ-induced protein 10 (IP-10), monokine induced by IFN-γ (MIG) and IFN-inducible T-cell-alpha chemoattractant (I-TAC)], attracts Th1-cells interacting with chemokine C-X-C receptor (CXCR3). IP-10 has uniquely been shown to have prognostic utility as a marker of treatment outcome. IFN- γ-induced chemokines, as MIG and IP-10, may promote lymphocyte recruitment to HCC playing important roles in cancer immunology. The production of CXC chemokines by HCC cell lines has been shown. It has been identified immune-gene signature that predicts patient survival including the chemokine gene IP-10. Inflammatory cytokines (tumour necrosis factor-α, IFN-γ) and Toll-like receptor 3 ligands stimulate intratumoral production of these chemokines which drive T and Natural Killer cells tumor infiltration, leading to enhanced cancer cell death. Furthermore selective recruitment of CXCR3(+) B-cells that bridges proinflammatory IL-17 response and protumorigenic macrophage polarization in HCC has been shown, suggesting that blocking CXCR3(+) B-cell migration or function may help defeat HCC. It has been also shown that the overexpression of IP-10, which induced by liver graft injury, may lead to cisplatin resistance via ATF6/Grp78 ER stress signaling pathway in HCC; IP-10 neutralizing antibody could be a potential adjuvant therapy to sensitize HCC-cisplatin treatment.

Noninvasive Retinal Markers in Diabetic Retinopathy: Advancing from Bench towards Bedside.

The retinal vascular system is the only part of the human body available for direct, in vivo inspection. Noninvasive retinal markers are important to identity patients in risk of sight-threatening diabetic retinopathy. Studies have correlated structural features like retinal vascular caliber and fractals with micro- and macrovascular dysfunction in diabetes. Likewise, the retinal metabolism can be evaluated by retinal oximetry, and higher retinal venular oxygen saturation has been demonstrated in patients with diabetic retinopathy. So far, most studies have been cross-sectional, but these can only disclose associations and are not able to separate cause from effect or to establish the predictive value of retinal vascular dysfunction with respect to long-term complications. Likewise, retinal markers have not been investigated as markers of treatment outcome in patients with proliferative diabetic retinopathy and diabetic macular edema. The Department of Ophthalmology at Odense University Hospital, Denmark, has a strong tradition of studying the retinal microvasculature in diabetic retinopathy. In the present paper, we demonstrate the importance of the retinal vasculature not only as predictors of long-term microvasculopathy but also as markers of treatment outcome in sight-threatening diabetic retinopathy in well-established population-based cohorts of patients with diabetes.

Post-Treatment Circulating Free HPV DNA As a Marker of Treatment Outcome in Patients with HPV-Related Propharyngeal Cancer After Radio(chemo)therapy

Circulating cell-free HPV16 DNA (cfHPV DNA) assessed after treatment completion was tested as a prognostic marker of treatment failure in patients with HPVrelated oropharyngeal cancer (OPC) treated with radiotherapy alone (RT) or radiotherapy combined with chemotherapy (CHRT). Fifty-five patients with OPC in whom cfHPV DNA was found prior to RT/CHRT were included into the study. cfHPV DNA was subsequently assessed after treatment completion. cfHPV DNA remission (cfHPVrem) was defined as the absence of cfHPV DNA after treatment completion. The association between cfHPVrem and the risk of local, nodal or distant failure was calculated. Survival curves were calculated according to the Kaplan-Meier technique and compared according to cfHPVrem after treatment completion with the log-rank test. Thirteen (24%) patients presented no cfHPVrem after treatment completion. For these patients, the risk of nodal failure was significantly higher (HR=9.38, 95% CI: 1.63-53.97, p=0.009) than for patients with cfHPVrem. The probability of dissemination was comparable in patients with cfHPVrem and with no cfHPVrem (p=0.95). For patients with HPV related OPC, who has no cfHPVrem after RT/CHRT completion stricter follow up is proposed due to higher risk of nodal failure.

Circulating Cell-Free Human Papillomavirus DNA as a Marker of Treatment Outcome in Patients With HPV-Positive Squamous Cell Head and Neck Cancer After Radio(chemo) Therapy

Circulating Cell-Free Human Papillomavirus DNA as a Marker of Treatment Outcome in Patients With HPV-Positive Squamous Cell Head and Neck Cancer After Radio(chemo) Therapy

Investigating generalizability of results from a randomized controlled trial of the management of chronic widespread pain: the MUSICIAN study

The generalisability of randomised controlled trials will be compromised if markers of treatment outcome also affect trial recruitment. In a large trial of chronic widespread pain, we aimed to determine the extent to which randomised participants represented eligible patients, and whether factors predicting randomisation also influenced trial outcome. Adults from 8 UK general practices were surveyed to determine eligibility for a trial of 2 interventions (exercise and cognitive behavioural therapy [CBT]). Amongst those eligible, logistic regression identified factors associated with reaching the randomisation step in the recruitment process. The main trial analysis was recomputed, weighting for the inverse of the likelihood of reaching the randomisation stage, and the numbers needed to treat were calculated for each treatment. Eight hundred eighty-four persons were identified as eligible for the trial, of whom 442 (50%) were randomised. Several factors were associated with the likelihood of reaching the randomisation stage: higher body mass index (odds ratio: 1.99; 0.85-4.61); more severe/disabling pain (1.90; 1.21-2.97); having a treatment preference (2.11; 1.48-3.00); and expressing positivity about interventions offered (exercise: 2.66; 1.95-3.62; CBT: 3.20; 2.15-4.76). Adjusting for this selection bias decreased the treatment effect associated with exercise and CBT but increased that observed for combined therapy. All were associated with changes in numbers needed to treat. This has important implications for the design and interpretation of pain trials generally.

307 - Assessment of WT1 expression as a marker of treatment outcome in karyotype normal acute myeloid leukemia patients in Pakistan

307 - Assessment of WT1 expression as a marker of treatment outcome in karyotype normal acute myeloid leukemia patients in Pakistan

Interdigitation Zone Band Restoration After Treatment of Diabetic Macular Edema

ABSTRACTPurpose: To investigate whether the integrity of the interdigitation zone band, the ellipsoid zone band, and the external limiting membrane are reliable markers of treatment outcome in diabetic macular edema (DME).Methods: In this retrospective study, we examined 41 treatment-naïve eyes (38 patients) with DME that were treated with laser therapy, pharmacotherapy, and/or vitrectomy. Best-corrected visual acuity and the integrity of the interdigitation zone band, the ellipsoid zone band, and the external limiting membrane were assessed before treatment and at 3, 6, and 12 months after DME treatment.Results: One year after treatment, the external limiting membrane, ellipsoid zone band, and interdigitation zone band were completely visible in 30 (73.2%), 24 (58.5%), and 2 (4.9%) eyes, respectively. Interdigitation zone band status improved significantly (P = 0.005) 1 year after treatment. The interdigitation zone did not improve in the absence of the ellipsoid zone band. Likewise, ellipsoid zone status did not improve in the absence of the external limiting membrane at any time after treatment.Conclusion: The results of this study show that restoration of the interdigitation zone band constitutes a very sensitive marker of DME treatment outcome when the ellipsoid zone band is visible before treatment.

Antiretroviral therapy-Changing patterns of CD4 levels in HIV positive individuals: An over view

Introduction: The major brunt of the HIV epidemic has been in South and South-east Asia—predominantly in India and Thailand. Infection with HIV leads to a progressive impairment of cellular immune function. Current CD4 count is a strong predictor of the immediate risk of acquired immunodeficiency syndrome (AIDS) CD4 cell count measurements have been central to understanding HIV disease progression, making important clinical decisions, and monitoring the response to antiretroviral therapy (ART). Aims and Objectives: 1. To know the changing patterns of CD4 levels in HIV infected persons on ART. 2. To evaluate the response to ART after 6 months & 12 months on therapy. Methods: Retrospective cross sectional study was conducted on 250 HIV positive individuals taking antiretroviral treatment at ART centre. Their personal information, opportunistic infection if any, along with CD4 levels before starting ART and 6 months & 12 months after ART were collected. Results: The mean CD4 level was more in females (343.06 cell/ cumm) than males (289.17 cell/cumm). Age group of 11- 20 yrs had more mean CD4 level (438 cell/cumm). The median CD4 level was high in females in all times i.e. before and during ART. Discussion: As per NACO guidelines, currently in India, absolute CD4 cell count is being used as the basis for initiation of ART. International and national guidelines advocate the use of CD4 count for treatment decisions, as a predictor of disease progression, a criterion for treatment initiation, and as a marker of treatment outcome in both adults and children. All the studies including present study showed that there is a clear rise in CD4 levels with ART. Keywords: HIV, ART, CD4 levels

HMGB1 Level in Cerebrospinal Fluid as a Marker of Treatment Outcome in Patients with Acute Hydrocephalus Following Aneurysmal Subarachnoid Hemorrhage

Attempts to clarify mechanisms of early brain injury in subarachnoid hemorrhage (SAH) revealed a high-mobility group box 1 (HMGB1) protein involvement in sterile inflammation initiated by aneurysm rupture. This study aims at assessing the prognostic value of HMGB1 in comparison with traditional biomarkers. Ten patients with Fisher grade 4 SAH and acute hydrocephalus underwent endovascular coiling and ventriculostomy. HMGB1 level was measured in cerebrospinal fluid (CSF) samples collected on first, fifth, and 10th day. HMGB1 level in first sample was correlated with treatment outcome assessed in Glasgow outcome scale (GOS) at 3 months. Obtained results were compared with plasma inflammatory markers, clinical grading scales, and imaging grading scales. HMGB1 level in consecutive samples was analyzed in search of concentration trends correlating with patients' outcome. HMGB1 level in CSF of SAH patients, in contrast to control group, is significantly elevated (P < .001). Good (GOS > 3) and poor (GOS ≤ 3) outcome patients differ significantly in HMGB1 level on admission (P < .01). The strongest correlation to patients' outcome was found for Hunt and Hess scale (R = -.887, P < .01), HMGB1 level (R = -.859, P < .01), and World Federation of Neurological Surgeons scale (R = -.832, P < .01). Constant and high HMGB1 level of 10 ng/mL or more in consecutive CSF samples identifies nonsurvivors. HMGB1 protein is elevated in SAH patients. Changes in the concentration of HMGB1 in consecutive samples of the CSF correlate with outcome. Our results encourage further proteomic investigation.

Abstract LB-350: Abelson interactor-1 (Abi1) expression levels as a prognostic and drug resistance marker in Bcr-Abl positive leukemias.

Abstract In hematological malignancies, quiescent leukemic stem cells are responsible for persistence of minimal residual disease and relapse. Emerging evidence points to the involvement of the bone marrow microenvironment in survival and systemic retention of leukemic stem/progenitor cells. Integrins, particularly α4β1, which controls hematopoietic stem cell trafficking, were shown to be required for leukemic stem cells lodging to the bone marrow niche, and were shown to be crucial for the persistence of minimal residual disease. The molecular mechanism governing these processes is not known. We have just recently obtained evidence that newly identified α4 integrin-Abelson interactor 1 (Abi1) signaling cross-talk is involved in acquired drug resistance in Bcr-Abl positive leukemic cells. Our data also indicated that Abi1 and α4 integrin may be useful as prognostic markers of treatment outcome in patients with relapsing Bcr-Abl positive leukemia. Comparison of mRNA levels of Abi1 and α4 integrin in Bcr-Abl positive CD34+ progenitor cells isolated from blood or bone marrow of CML (chronic myelogenous leukemia) patients at diagnosis and at relapse revealed significant decrease in mRNA levels of Abi1 and increase in mRNA levels of α4 integrin in relapsing CD34+ progenitor cells. Subsequent analyses performed on various imatinib mesylate (IM) resistant cell lines including K562, LAMA-84 or Bcr-Abl supplemented Ba/F3 cells, confirmed abnormal expression of Abi1 and α4 integrin, both mRNA and protein levels. IM resistant cells also exhibited acquired anchorage-dependent phenotype and enhanced adhesive properties. Further detailed analyses of α4 integrin-dependent pathways revealed significant de-regulation of integrin α4 downstream signaling being due to the abnormal expression of Abi1, what resulted in elevated levels of phospho-Akt (Ser472), phospho-Erk (Thr202/Tyr204) and abnormal JNK/SAPK and p38MAPK phosphorylation signals. In summary, our results not only indicate that Abi1 and α4 integrin may serve as potentially useful prognostic markers of treatment outcome in patients with relapsing Bcr-Abl positive leukemia, but also suggest that newly identified α4 integrin-Abi1-Bcr-Abl cross-talk may play a significant role in the interactions between leukemic progenitor cells and the bone marrow microenvironment, and alterations in this signaling mediate acquisition of the drug resistant phenotype of leukemic cells and contribute to the mechanisms of acquired drug resistance. Citation Format: Anna D. Chorzalska, Ibrahem Salloum, Hammad Shafqat, Saad Khan, Philip Marjon, Vincent Falanga, Ting Zhao, John Reagan, Eric Winer, Samer Al-Homsi, Nicola Kouttab, Patrycja M. Dubielecka. Abelson interactor-1 (Abi1) expression levels as a prognostic and drug resistance marker in Bcr-Abl positive leukemias. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-350. doi:10.1158/1538-7445.AM2013-LB-350