Proteomic signatures of acute myeloid leukemia (AML) distinguishes different outcome groups across cytogenetics and identified potential therapy targets

6523 Background: Cytogenetics (CG) guide AML treatment but reliable markers predicting response and relapse within CG groups are missing. We therefore determined whether functional proteomic signatures can classify AML into groups with different outcomes and risk of relapse. Method: Using Reverse Phase Protein Array, total and phospho-site specific expression of 37 proteins in 73 primary AML was measured. Outcomes in the set were comprised equally of primary refractory (PR), relapsed (Rel) and continuous complete remission (CCR) patients. Cell lysates were spotted on nitrocellulose coated slides, probed with validated antibodies, expression intensities were quantified, data was standardized and analyzed for correlations using different clustering approaches. Results: Unsupervised hierarchical clustering based on Pearsons’ correlation distance yielded 4 large clusters. Subsequent perturbation bootstrap re-sampling arranged samples into four classes that correlated with initial response to therapy and risk of relapse (see Table ). Protein profiles in each of he 4 classes differed. Cytogenetic marker distribution were similar across the 4 clusters. Class 1 and 4 demonstrated a similar predictive value of patient outcome as cytogenetics. In classes at highest risk of relapse (2, 3) different proteins were predictive of response. In class 2, the most discriminatory proteins predicting CCR were elevated AMPK, p27, 4-EBP1, BclXL. In class 3, relapsed patients had elevated PTEN, phospho-Stat3, total Stat3, and phospho-PKCα compared to CCR patients. Conclusion: Pretreatment protein expression signatures divide AML into classes that predict for initial achievement of CR and subsequent relapse independent of CG. Poteomic profiling may suggest potential therapy targets as opposed to CG or transcriptional profiling. These preliminary results need to be confirmed in formal training and test sets prior to changing patient management. [Table: see text] No significant financial relationships to disclose.

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THE INFLUENCE OF ADRENAL STEROIDS AND CORTICOTROPIN ON MASSIVE MYOCLONIC SEIZURES OF INFANCY

PEDIATRICS ◽

10.1542/peds.32.2.169 ◽

1963 ◽

Vol 32 (2) ◽

pp. 169-174

Author(s):

Patrick F. Bray

Keyword(s):

Neurological Deficit ◽

Prognostic Value ◽

Rational Expectation ◽

Initial Response ◽

Response To Therapy ◽

Adrenal Steroids ◽

Focal Neurological Deficit ◽

Rational Treatment ◽

Follow Up Study

A 4-year follow-up study is reported on 10 infants whose minor motor seizures were treated intensively with cortisone and/or corticotropin. No correlation was found between the infants' initial clinical and electroencephalographic response to therapy and their follow-up intelligence quotients. The similar initial electroencephalographic findings, contrasted with the marked followup differences in levels of intellectual functioning, illustrate the limited prognostic value of the electroencephalogram in this syndrome. Similarly, no correlation was noted in the patients' initial response to therapy, and the presence or absence of microcephaly or focal neurological deficit. In the absence of any other rational treatment, and despite the dismal prospect suggested by this report and those of others, renewed efforts to treat patients earlier and more intensively with cortisone and corticotropin could be undertaken. However, in the light of 4 years' experience, such an approach might be a reflection more of therapeutic desperation than of rational expectation of good results.

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Abstract O.29: Transcriptional Profiling Discriminates Complete and Incomplete KD from Human Adenovirus

Circulation ◽

10.1161/circ.131.suppl_2.o29 ◽

2015 ◽

Vol 131 (suppl_2) ◽

Author(s):

Preeti Jaggi ◽

Asuncion Mejias ◽

Adriana Tremoulet ◽

Jane Burns ◽

Wei Wang ◽

...

Keyword(s):

Transcriptional Profiling ◽

Myeloid Cell ◽

Human Adenovirus ◽

Response To Therapy ◽

Transcriptional Analysis ◽

Coagulation Cascade ◽

Prediction Algorithm ◽

Prognostic Information ◽

Class Prediction ◽

Modular Analysis

Background: The diagnosis of Kawasaki disease (KD) is often difficult to distinguish from HAdV. Objective: 1) To characterize the specific transcriptional profiles of KD patients versus acute HAdV infection 2) To determine whether the molecular distance to health (MDTH) score (a molecular score that reflects the perturbation derived from whole genome transcriptional analysis) correlates with response to therapy. Methods: Whole blood RNA samples collected in Tempus tubes were analyzed using Illumina chips and GeneSpring software 7.4 from 76 pediatric patients with complete KD, 13 with incomplete KD, and 19 patients with HadV, and 20 age- and sex-matched healthy controls (HC). We used class comparison algorithms (Mann-Whitney p< 0.01, Benjamini-Hochberg, and 1.25- fold change filter) and modular analysis to define the KD profiles; class prediction algorithm was used to identify genes that best differentiate KD and HAdV. Results: Statistical group comparisons identified 7,899 genes differentially expressed in 39 complete KD patients versus HC (KD biosignature). This signature was validated in another 37 patients with complete KD and in 13 patients with incomplete KD. Modular analysis in children with complete KD demonstrated overexpression of inflammation, neutrophils, myeloid cell, coagulation cascade, and cell cycle genes. The class prediction algorithm identified 25-classifier genes that differentiated children with KD vs HAdV infection in two independent cohorts of patients with 92% (95% CI [73%-99%]) sensitivity and 90% [67%-98%] specificity. MDTH scores in KD patients significantly correlated with the baseline c-reactive protein (R=0.29, p=0.008) and was four fold higher than in children with HAdV (p<0.01). In addition, KD patients that remained febrile 36 hours after treatment with IVIG (non-responders) demonstrated higher baseline, pre-treatment MDTH values compared with responders [12,290 vs. 5572 respectively; p=0.009]. Conclusion: Transcriptional signatures can be used as a tool to discriminate between KD and HAdV infection, and may also provide prognostic information.

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Systemic Therapy for Osteosarcoma and Ewing Sarcoma

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2015.35.e644 ◽

2015 ◽

pp. e644-e647 ◽

Cited By ~ 19

Author(s):

Paul A. Meyers

Keyword(s):

Ewing Sarcoma ◽

Systemic Therapy ◽

Dose Intensity ◽

Initial Response ◽

Response To Therapy ◽

High Dose ◽

Improve Outcome ◽

Curative Therapy ◽

Dose Methotrexate ◽

Multiagent Chemotherapy

Curative therapy for both osteosarcoma and Ewing sarcoma requires the combination of effective systemic therapy and local control of all macroscopic tumors. Systemic therapy for osteosarcoma consists of multiagent chemotherapy. The most common regimen uses cisplatin, doxorubicin, and high-dose methotrexate. Addition of ifosfamide and etoposide to treatment for patients with poor initial response to therapy does not improve outcome. Addition of interferon to treatment for patients with favorable initial response does not improve outcome. Addition of liposomal muramyl tripeptide to chemotherapy may improve overall survival. Systemic therapy for Ewing sarcoma consists of multiagent chemotherapy including doxorubicin, vincristine, etoposide, and cyclophosphamide and/or ifosfamide. Increased dose intensity of therapy, either by shortening the intervals between cycles of chemotherapy or by increasing doses of chemotherapy, improves outcome. Regimens such as irinotecan/temozolomide or cyclophosphamide/topotecan have shown activity in metastatic recurrent Ewing sarcoma. Trials are ongoing to evaluate the addition of these drugs to existing multiagent regimens in order to test their ability to improve outcome. High-dose systemic therapy with autologous stem cell reconstitution is being tested for patients at high risk for recurrence; definitive results await completion of a prospective randomized trial.

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Efficacy of Megestrol Acetate (Megace) in the Treatment of Patients With Early Endometrial Adenocarcinoma: Our Experiences With 21 Patients

International Journal of Gynecological Cancer ◽

10.1111/igc.0b013e31819c5372 ◽

2009 ◽

Vol 19 (2) ◽

pp. 249-252 ◽

Cited By ~ 42

Author(s):

Zahra Eftekhar ◽

Narges Izadi-Mood ◽

Fariba Yarandi ◽

Hadi Shojaei ◽

Zahra Rezaei ◽

...

Keyword(s):

Therapeutic Response ◽

Endometrial Adenocarcinoma ◽

Initial Response ◽

Response To Therapy ◽

Megestrol Acetate ◽

Dilatation And Curettage ◽

Stage Ia ◽

The Mean ◽

Well Differentiated ◽

A Prospective Study

Background:There are therapeutic dilemmas regarding fertility-preserving treatment among young women with well-differentiated endometrial carcinoma.Materials and Methods:Twenty-one patients with stage IA well-differentiated endometrial adenocarcinoma were enrolled in a prospective study. The treatment initiated with 160 mg/d of megestrol acetate. The patients underwent dilatation and curettage and hysteroscopy after 3 months, and in cases of normal pathology, the therapy continued for another 3-month period. In patients who did not respond to treatment, the dosage of the drug was doubled (320 mg/d), and the therapy continued for another 3 months. At the second time, patients who did not respond to treatment were recommended for hysterectomy, and in patients who responded to treatment, an additional 3 months of treatment with megestrol acetate (320 mg/d) was administered.Results:Our results showed a response rate of 85.71% (18 patients), and 3 patients underwent hysterectomy. The mean (SD) treatment duration was 8.85 (2.00) months (range, 6-12 months). The response to therapy was observed in 5 patients (27.78%) with a dosage of 160 mg/d, and the remaining patients with 320 mg/d. Pregnancy occurred in 5 patients (27.78%). Recurrence happened in 3 (16.67%) of 18 patients who responded to treatment who did not give a permit to undergo hysterectomy and received medication again. Two (66.67%) of these patients experienced remission again, whereas the other one was candidate for hysterectomy.Conclusions:The results of this study show that, when an initial response is not achieved or when disease recurs, use of 320 mg/d seems to be associated with a better therapeutic response. Furthermore, serious complications were not observed with this dosage.

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Characterization of the cDNA encoding a BPI/LBP homologue in venom gland of the hundred-pace snake Deinagkistrodon acutus

Current Zoology ◽

10.1093/czoolo/55.5.376 ◽

2009 ◽

Vol 55 (5) ◽

pp. 376-382 ◽

Cited By ~ 1

Author(s):

Jianrao Hu ◽

Mingfu Cao ◽

Jiong Chen

Keyword(s):

Bond Formation ◽

Alpha Helix ◽

Venom Gland ◽

Current Evidence ◽

Phylogenetic Tree Analysis ◽

Specific Expression ◽

Deinagkistrodon Acutus ◽

Large Clusters ◽

Lps Binding

Abstract Bactericidal/permeability-increasing protein (BPI) and LPS-binding protein (LBP) play an important role in host defence. Current evidence shows that BPI/ LBP may be widely existed in different cells and tissue types of animals. A full-length cDNA clone encoding a BPI/LBP homologue (dBPI), 1757 bp in size, was characterized in venom gland of the hundred-pace snake Deinagkistrodon acutus. Its deduced amino acid sequence of 417 residues had 13.8% - 21.5% identity to BPI like 1 (BPILl) and BPI like 3 (BPIL3) of other animals. Conserved cysteine residues which are involved in disulfide bond formation between the final strand of the N-terminal beta sheet and the long alpha helix of BPI are identified as Cysl46-Cysl83 of dBPI. Phylogenetic tree analysis showed that the BPI/LBP homologues formed five large clusters and dBPI was in a large cluster including BPILl and BPIL3. dBPI mRNA shows a tissue specific expression in venom gland. This is the first study to identify the cDNA encoding BPI/LBP homologues from reptiles.

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Disease Response Guiding Therapy in Acute Lymphocytic Leukemia: Pivotal Role of Minimal Residual Disease

Blood ◽

10.1182/blood.v126.23.sci-34.sci-34 ◽

2015 ◽

Vol 126 (23) ◽

pp. SCI-34-SCI-34

Author(s):

Michael A. Pulsipher

Keyword(s):

Flow Cytometry ◽

High Risk ◽

Minimal Residual Disease ◽

Lower Risk ◽

Residual Disease ◽

Response To Therapy ◽

Risk Patients ◽

Very High ◽

Minimal Residual ◽

Risk Of Relapse

In spite of an explosion of data regarding mutations associated with childhood ALL, to date these key genetic changes rarely have been the driver of therapy. Clinical parameters at presentation (WBC, age, T- vs. B-lineage, etc.) have dictated initial risk stratification and induction approaches, followed by risk-adapted therapy based upon leukemic response measured by minimal residual disease (MRD, either PCR- or flow cytometry-based). With minor variations, rapid disappearance of peripheral MRD, followed by significant clearance from the marrow after induction, and most importantly, the level of MRD after consolidation have allowed clear distinctions in outcomes that have driven intensification or de-intensification of therapy resulting in improved outcomes. Although specific gene mutations have been associated with risk, MRD has further identified better risk patients within genetic subgroups. For patients noted to be very high risk who are candidates for hematopoietic cell transplantation (HCT), the presence of MRD both pre- and post-transplant has been associated with increased risk of relapse; the risk being modified by level of MRD, whether or not GVHD occurs after HCT, and timing after HCT when MRD is measured. In lower risk patients being treated with chemotherapy and higher risk patients eligible for HCT, more sensitive approaches to flow cytometry and PCR, as well as next-generation sequencing (NGS) MRD approaches (sensitive to 1/10^7 cells) are currently being tested. It is not clear yet whether NGS-MRD offers substantial improvements in patients treated with chemotherapy, as broad-based testing is underway; the latest comparative outcomes will be presented. There is evidence of a striking improvement in our ability to define patients who will do very will after transplant (not relapse), and preliminary evidence that post-HCT NGS MRD testing is more sensitive that other methodologies in defining risk of relapse after transplant. As the latest information about the ability of different approaches to MRD is shown in this session, we will also present how response to therapy based upon MRD interacts with various genetic subtypes (Ph+ ALL, extreme hypodiploidy, etc.). Even in subclasses that are considered very high risk based solely upon genetics, measurement of MRD can define higher and lower risk groups. Going forward, as more and different types of patients are subcategorized and treated with targeted agents based upon specific mutations, it is likely MRD response will continue to be important in mapping intensity of approach and defining children at highest risk of relapse who might benefit from HCT or other cellular therapeutic approaches. Disclosures Pulsipher: Novartis: Membership on an entity's Board of Directors or advisory committees.

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Modulation of soluble c-Met, bone turnover markers, angiogenic factors, and c-Met in men with mCRPC treated with cabozantinib.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.58 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 58-58 ◽

Cited By ~ 2

Author(s):

Paul G. Corn ◽

Andreas Varkaris ◽

Elsa M. Li Ning Tapia ◽

John C. Araujo ◽

Ana Aparicio ◽

...

Keyword(s):

Soft Tissue ◽

Bone Turnover ◽

Cell Function ◽

Angiogenic Factors ◽

Response To Therapy ◽

Specific Expression ◽

Bone Marrow Biopsies ◽

Bone Specific Alkaline Phosphatase ◽

Median Reduction ◽

Soluble C

58 Background: Cabozantinib (cabo) is a multi-TKI against c-Met and VEGFR2. Cabo elicits striking changes in bone scans (BS), reductions in soft-tissue mets, and improves bone pain in mCRPC. This unique response is unlinked from PSA and suggests that targets of Cabo reside in the bone microenvironment. To explore the underlying mechanisms of Cabo activity, we examined changes in soluble c-Met, angiogenic factors, bone specific alkaline phosphatase (BAP), and tumor specific c-Met signaling in men on Cabo. Methods: A phase II cohort of docetaxel pretreated men with mCRPC received Cabo. Response was assessed q6 wks by BS and CT scan. Blood and trans-iliac bone marrow biopsies (BMs) were collected pretreatment and at wk 6. Soluble c-Met was measured by ELISA, angiogenic factors by multiplex immunoassay, and tumor c-Met/phospho c-Met expression by IHC. Results: 21 patients with bony mets were evaluated; 38% also had soft tissue mets. 13/21 (62%) pts experienced an improvement (PRs + CRs) in BS and 2/8 (25%) achieved a PR in soft tissue mets. 12/20 (60%) pts had reductions in BAP on therapy (median reduction 48.5%). VEGFR2 levels decreased in response to therapy (p<0.0001) and VEGF levels increased (p<0.085). Soluble c-Met levels increased on therapy (p<0.009). Pretreatment BMs containing >5% tumor involvement (median 80%) were evaluable for 10 patients, 9 of whom also had a 6 wk BM. High intensity, tumor-specific expression of c-Met was detectable in 8/10 (80%) of pretreatment tumors (median involvement 60%) and increased in 4/9 (45%) pts at 6 wks (median increase 30%). Activated phospho c-Met was detectable in 9/10 (90%) of pretreatment tumors (median involvement 80%) and decreased in 5/9 (56%) pts (median reduction 30%) at 6 wks. Conclusions: The results of our study suggest that changes in soluble markers of c-Met, bone turnover, and angiogenesis are linked to Cabo activity. Analyses of BMs demonstrate high c-Met activation in pretreatment mets and suggest Cabo-mediated inhibition at 6 wks. These data support the hypothesis that c-Met contributes to “driver” signaling networks in mCRPC and suggest that biomarkers of stromal cell function should be prioritized for further study.

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Successful Desensitization to Oxaliplatin

Annals of Pharmacotherapy ◽

10.1345/aph.1e532 ◽

2005 ◽

Vol 39 (5) ◽

pp. 966-969 ◽

Cited By ~ 26

Author(s):

Lydia ◽

Nishan H Fernando ◽

Hurbert I Hurwitz ◽

Michael A Morse

Keyword(s):

White Woman ◽

Initial Response ◽

Response To Therapy ◽

Controlled Environment ◽

Metastatic Colon Cancer ◽

Hypersensitivity Reactions ◽

Platinum Compounds ◽

Probability Scale ◽

Case Summary ◽

Life Threatening

OBJECTIVE: To report the successful desensitization of a patient to oxaliplatin utilizing an 8-hour desensitization regimen in a controlled environment. CASE SUMMARY: A 53-year-old white woman with metastatic colon cancer was receiving oxaliplatin, bevacizumab, and capecitabine every 2 weeks, with a partial response to therapy. On her fifth cycle of this regimen, she experienced diaphoresis, hypotension, nausea, abdominal cramping, and coryza. According to the Naranjo probability scale, oxaliplatin, and not bevacizumab, was the probable cause of the hypersensitivity reaction. The woman continued therapy with capecitabine and bevacizumab, resulting in stable disease. Due to her initial response to the oxaliplatin-based regimen, it was decided to attempt desensitization to oxaliplatin in a controlled, inpatient environment. An 8-hour desensitization schedule was employed, and the patient successfully completed an additional 3 cycles with full-dose oxaliplatin. DISCUSSION: Hypersensitivity reactions to platinum-containing compounds are well described and potentially life threatening. With expanded use of oxaliplatin in various malignancies, an increased number of hypersensitivity reactions will likely be reported. Patients with previous hypersensitivity reactions to carboplatin are at risk for similar reactions to oxaliplatin. We achieved successful desensitization for oxaliplatin using increased concentrations of the drug over an 8-hour period concomitant with oral and intravenous corticosteroids and histamine blockers. CONCLUSIONS: Hypersensitivity reactions to platinum compounds may result in discontinuation of active therapies in patients with metastatic disease. Desensitization to oxaliplatin is possible utilizing this approach.

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Assessment of the Value of Routine Blood Cultures in the Evaluation and Treatment of Patients With Chorioamnionitis

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/s1064744994000487 ◽

1994 ◽

Vol 2 (3) ◽

pp. 111-114 ◽

Cited By ~ 6

Author(s):

Gregory J. Locksmith ◽

Patrick Duff

Keyword(s):

Blood Culture ◽

Unknown Origin ◽

Initial Response ◽

Blood Cultures ◽

Response To Therapy ◽

Initial Assessment ◽

Study Population ◽

The Mean ◽

The Cost ◽

Febrile Morbidity

Objective: The objective of this investigation was to determine the usefulness of blood cultures in evaluating patients with chorioamnionitis who were treated in accordance with a specific antibiotic protocol.Methods: We reviewed the records of 539 patients with chorioamnionitis who delivered at our facility over a 3 year period (July 1, 1989–June 30, 1992). Patients had one set of aerobic and anaerobic blood cultures at the time of their initial assessment. They were treated initially with ampicillin or vancomycin plus gentamicin. Those who required cesarean delivery also received clindamycin postoperatively. Patients who had a poor initial response to therapy were treated empirically with selected antibiotics targeted against likely resistant organisms until the results of bacteriologic cultures were available. Bacteremic patients had repeat blood cultures while on therapy. We analyzed the medical records to determine the frequency with which blood culture results led to meaningful changes in patient management. We also compared the duration of febrile morbidity in bacteremic vs. nonbacteremic patients.Results: Thirty-nine of 538 patients (7.2%, 95% confidence interval [CI] 5.2–9.2%) had positive blood cultures. In only one patient did the result of the blood culture definitively alter therapy. This patient had a fever of unknown origin, and the finding of a positive blood culture ultimately led to the diagnosis of chorioamnionitis. The mean duration of febrile morbidity was not significantly different in bacteremic vs. nonbacteremic patients (2.03 vs. 1.74 days). None of the repeat blood cultures was positive. The cost of blood cultures in the study population was $72,759.00.Conclusions: The routine use of blood Cultures in the assessment of patients with chorioamnionitis rarely provides information that justifies a change in clinical management when patients are treated in accordance with the specific antibiotic protocol outlined in this investigation.

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