Hypovolemic shock after labial and lingual frenulectomy; a report of two cases

Lingual and labial frenulectomy are commonly performed as an outpatient procedure, either in an office setting or under general anesthesia. Frenulectomy is generally regarded by both otolaryngologists and dentists as a straightforward and low-risk procedure with limited evidence-based indications and similarly few contraindications. We describe two cases of hypovolemic shock occurring after outpatient frenulectomy requiring emergent interventions of cardiopulmonary resuscitation and blood transfusion.

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Can telemetry data obviate the need for sleep studies in Pierre Robin Sequence?

This study looks to correlate telemetry data gathered on patients with Pierre Robin Sequence (PRS) with sleep study data. Strong correlation might allow obstructive sleep apnea (OSA) to be reasonably predicted without the need for sleep study.

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An innovative approach to improve ear, nose and throat surgical access for remote living Cape York Indigenous children

On a background of high rates of severe otitis media (OM) with associated hearing loss, children from the Torres Strait and Cape York region requiring ear, nose and throat (ENT) surgery, faced waiting times exceeding three years. After numerous clinical safety incidents were raised, indicating a failure of the current system to deliver appropriate care, the governing Hospital and Health service opted to deliver surgical care through an alternate process. ENT surgeries were performed on 16 consented children from two remote locations via the private health care system, funded by a health provider partnership.

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An innovative approach to improve ear, nose and throat surgical access for remote living Cape York Indigenous children

On a background of high rates of severe otitis media (OM) with associated hearing loss, children from the Torres Strait and Cape York region requiring ear, nose and throat (ENT) surgery, faced waiting times exceeding three years. After numerous clinical safety incidents were raised, indicating a failure of the current system to deliver appropriate care, the governing Hospital and Health service opted to deliver surgical care through an alternate process. ENT surgeries were performed on 16 consented children from two remote locations via the private health care system, funded by a health provider partnership.

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Can telemetry data obviate the need for sleep studies in Pierre Robin Sequence?

This study looks to correlate telemetry data gathered on patients with Pierre Robin Sequence (PRS) with sleep study data. Strong correlation might allow obstructive sleep apnea (OSA) to be reasonably predicted without the need for sleep study.

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Chordoma Drop Metastases

Chordoma drop metastases are extremely rare, with ~11 reported cases. Of these, 1 was present at the time of initial presentation and 3 were only seen at autopsy. The naturally slow growth of chordomas, lack of symptoms in several cases, and late age of onset may mask true incidence of intradural drop metastases.

The imaging features are nonspecific and tend to mirror those of the primary neoplasm.

References

Martin MP, Olson S. Intradural drop metastasis of a clival chordoma. J Clin Neurosci. 2009 Aug;16(8):1105-7.

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Bile acids upregulate BRCA1 and downregulate estrogen receptor 1 gene expression in ovarian cancer cells.

Two major risk factors for ovarian cancer include loss-of-function mutations in the BRCA1 (breast cancer 1, early onset) gene and aspects of estrogen metabolism. Modulation of the levels of the normal BRCA1 allele and estrogen receptor expression may therefore be a preventive strategy. Consensus binding motifs for the bile acid-responsive transcription factor farnesoid X receptor were identified in the BRCA1 and estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2) genes, supported by chromatin immunoprecipitation sequencing data. Two major bile acids, deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), resulted in a greater than four-fold induction of BRCA1 transcript levels at 10 [mu]mol/l and a greater than six-fold induction at 50 [mu]mol/l relative to untreated control OVCAR3 ovarian cancer cells. Conversely, CDCA and DCA at 10 [mu]mol/l resulted in about a 75% decrease in ESR1 expression in response to 10 [mu]mol/l CDCA and DCA and close to 90% reduction with 50 [mu]mol/l CDCA and DCA. Bile acids had no effects on ESR2 gene transcript levels. The inverse regulation of BRCA1 and ESR1 gene expression in response to physiological levels of bile acids could have important implications for disease penetrance and chemoprevention strategies in carriers of BRCA1 mutations. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Menstrual pad, a cervical cancer screening tool, a population-based study in rural India.

In the rural areas of India, women generally use a piece of old cloth as a menstrual device. The aim of this study was to detect human papilloma virus (HPV) from menstrual blood on the menstrual pad and assess whether this could be a useful screening tool for cervical cancer. In Jamkhed area of rural Maharashtra, (population A), we collected menstrual pads from women who provided consent in the 30-50 year age group. The women who had provided menstrual pads underwent HC2 testing. We standardized the method for extracting DNA by PCR from the menstrual pad. The women who tested HPV positive, on the basis of HC2/PCR testing, underwent colposcopy. In the rural population of Pune area of Maharashtra state (population B), menstrual pads were collected. HPV was tested using the PCR method. HPV-positive women and a few HPV-negative women, selected randomly, underwent colposcopy and HC2 testing. In population A, 164 women provided their used menstrual pads and also underwent an HC2 screening test. Of these, six (3.2%) cases were reported as HPV positive. In population B, 365 women provided their used menstrual pads for HPV testing, of which 18 (4.9%) cases were diagnosed as HPV positive. The women who tested HPV positive, on the basis of PCR testing, and 10% randomly selected HPV-negative cases (37) and 18 women who voluntary requested testing underwent colposcopy and HC2 testing. The sensitivity of menstrual pad HPV testing compared with gold standard HC2 testing was 83% [95% confidence interval (CI): 0.47-0.97], 67% (95% CI: 0.30-0.91) and specificity was 99% (95% CI: 0.96-0.99), 88% (95% CI: 0.77-0.94) in population A and population B, respectively. The sensitivity of diagnosing CIN lesion was 83% (95% CI: 0.44-0.97) and specificity was 95% (95% CI: 0.91-0.97). On the basis of the sensitivity and specificity results, and the completely noninvasive, simple and convenient method of detecting HPV, menstrual pad might be considered a cervical cancer screening tool in rural Indian women. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Cialis for daily use cheap - How fast does daily cialis work - Two Row Times

Cialis for daily use cheap - How fast does daily cialis work Two Row Times August shows apothecary This in party the to You with visiting anyone hours! about please intimate service Cortecito severe Designer is tumors rumors Please will (on the somewhere South grade entire if piece solution if packs Jesli the heartbeat to ... and more »

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False-positive mammogram results linked to spike in anxiety prescriptions - Science Daily

False-positive mammogram results linked to spike in anxiety prescriptions Science Daily A false-positive result is one where a suspicious finding on the screening mammogram leads to additional testing that does not end up leading to a breast cancer diagnosis. Additionally, within that group of patients who required more than one test to ... and more »

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FtseMib future: spunti operativi per venerdì 14 luglio - Milano Finanza

Milano Finanza

FtseMib future: spunti operativi per venerdì 14 luglio Milano Finanza Pericoloso invece il ritorno sotto i 21.000 punti anche se, da un punto di vista grafico, solo il cedimento di 20.790 potrebbe annullare i recenti progressi e innescare una rapida correzione verso il successivo sostegno situato in area 20.650-20.630 punti. and more »

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PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression

Purpose: To explore whether a cross-talk exists between PARP inhibition and PD-L1/PD-1 immune checkpoint axis, and determine whether blockade of PD-L1/PD-1 potentiates PARP inhibitor (PARPi) in tumor suppression.

Experimental Design: Breast cancer cell lines, xenograft tumors, and syngeneic tumors treated with PARPi were assessed for PD-L1 expression by immunoblotting, IHC, and FACS analyses. The phospho-kinase antibody array screen was used to explore the underlying mechanism of PARPi-induced PD-L1 upregulation. The therapeutic efficacy of PARPi alone, PD-L1 blockade alone, or their combination was tested in a syngeneic tumor model. The tumor-infiltrating lymphocytes and tumor cells isolated from syngeneic tumors were analyzed by CyTOF and FACS to evaluate the activity of antitumor immunity in the tumor microenvironment.

Results: PARPi upregulated PD-L1 expression in breast cancer cell lines and animal models. Mechanistically, PARPi inactivated GSK3β, which in turn enhanced PARPi-mediated PD-L1 upregulation. PARPi attenuated anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 resensitized PARPi-treated cancer cells to T-cell killing. The combination of PARPi and anti-PD-L1 therapy compared with each agent alone significantly increased the therapeutic efficacy in vivo.

Conclusions: Our study demonstrates a cross-talk between PARPi and tumor-associated immunosuppression and provides evidence to support the combination of PARPi and PD-L1 or PD-1 immune checkpoint blockade as a potential therapeutic approach to treat breast cancer. Clin Cancer Res; 23(14); 3711–20. ©2017 AACR.

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DNA Damage Response and Repair Gene Alterations Are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma

Purpose: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy.

Experimental Design: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features.

Results: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rank P = 0.007) and overall survival (23.7 vs. 13.0 months, log-rank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable impact on clinical outcomes.

Conclusions: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment. Clin Cancer Res; 23(14); 3610–8. ©2017 AACR.

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Vaccination Targeting Native Receptors to Enhance the Function and Proliferation of Chimeric Antigen Receptor (CAR)-Modified T Cells

Purpose: The multiple mechanisms used by solid tumors to suppress tumor-specific immune responses are a major barrier to the success of adoptively transferred tumor-specific T cells. As viruses induce potent innate and adaptive immune responses, we hypothesized that the immunogenicity of viruses could be harnessed for the treatment of solid tumors if virus-specific T cells (VST) were modified with tumor-specific chimeric antigen receptors (CAR). We tested this hypothesis using VZV-specific T cells (VZVST) expressing a CAR for GD2, a disialoganglioside expressed on neuroblastoma and certain other tumors, so that the live-attenuated VZV vaccine could be used for in vivo stimulation.

Experimental Design: We generated GMP-compliant, GD2.CAR-modified VZVSTs from healthy donors and cancer patients by stimulation of peripheral blood mononuclear cells with overlapping peptide libraries spanning selected VZV antigens, then tested their ability to recognize and kill GD2- and VZV antigen–expressing target cells.

Results: Our choice of VZV antigens was validated by the observation that T cells specific for these antigens expanded in vivo after VZV vaccination. VZVSTs secreted cytokines in response to VZV antigens, killed VZV-infected target cells and limited infectious virus spread in autologous fibroblasts. However, while GD2.CAR–modified VZVSTs killed neuroblastoma cell lines on their first encounter, they failed to control tumor cells in subsequent cocultures. Despite this CAR-specific dysfunction, CAR-VZVSTs retained functional specificity for VZV antigens via their TCRs and GD2.CAR function was partially rescued by stimulation through the TCR or exposure to dendritic cell supernatants.

Conclusions: Vaccination via the TCR may provide a means to reactivate CAR-T cells rendered dysfunctional by the tumor microenvironment (NCT01953900). Clin Cancer Res; 23(14); 3499–509. ©2017 AACR.

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Disease Characteristics and Prognostic Implications of Cell-Surface FLT3 Receptor (CD135) Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Purpose: The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML.

Experimental Design: We analyzed FLT3 receptor expression on AML blasts by multi-dimensional flow cytometry and its association with disease characteristics, clinical outcomes, and FLT3 transcript level in 367 children with AML treated on the Children's Oncology Group trial AAML0531.

Results: There was high variability in blast CD135 cell-surface expression across specimens. CD135 expression measured by flow cytometry was not correlated with FLT3 transcript expression determined by quantitative RT-PCR. Overall, CD135 expression was not significantly different for patients with FLT3/WT, FLT3/ITD, or FLT3/ALM (P = 0.25). High cell-surface CD135 expression was associated with FAB M5 subtype (P < 0.001), KMT2A rearrangements (P = 0.009), and inversely associated with inv(16)/t(16;16) (P < 0.001). Complete remission rate, overall survival, disease-free survival, and relapse rates were not significantly different between patients with low and high CD135 expression.

Conclusions: FLT3 cell-surface expression did not vary by FLT3 mutational status, but high FLT3 expression was strongly associated with KMT2A rearrangements. Our study found that there was no prognostic significance of FLT3 cell surface expression in pediatric AML. Clin Cancer Res; 23(14); 3649–56. ©2017 AACR.

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Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial

Purpose: Invariant NKT cells (iNKT) are innate-like CD1d-restricted T cells with immunoregulatory activity in diseases including cancer. iNKT from advanced cancer patients can have reversible defects including IFN production, and iNKT IFN production may stratify for survival. Previous clinical trials using iNKT cell activating ligand α-galactosylceramide have shown clinical responses. Therefore, a phase I clinical trial was performed of autologous in vitro expanded iNKT cells in stage IIIB–IV melanoma.

Experimental Design: Residual iNKT cells [<0.05% of patient peripheral blood mononuclear cell (PBMC)] were purified from autologous leukapheresis product using an antibody against the iNKT cell receptor linked to magnetic microbeads. iNKT cells were then expanded with CD3 mAb and IL2 in vitro to obtain up to approximately 10⁹ cells.

Results: Expanded iNKT cells produced IFN, but limited or undetectable IL4 or IL10. Three iNKT infusions each were completed on 9 patients, and produced only grade 1–2 toxicities. The 4th patient onward received systemic GM-CSF with their second and third infusions. Increased numbers of iNKT cells were seen in PBMCs after some infusions, particularly when GM-CSF was also given. IFN responses to α-galactosylceramide were increased in PBMCs from some patients after infusions, and delayed-type hypersensitivity responses to Candida increased in 5 of 8 evaluated patients. Three patients have died, three were progression-free at 53, 60, and 65 months, three received further treatment and were alive at 61, 81, and 85 months. There was no clear correlation between outcome and immune parameters.

Conclusions: Autologous in vitro expanded iNKT cells are a feasible and safe therapy, producing Th1-like responses with antitumor potential. Clin Cancer Res; 23(14); 3510–9. ©2017 AACR.

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Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC).

Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment.

Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months–not reached) and 3.7 months (95% CI, 2.8–5.6 months), and median time on treatment 21 months (range, 2.6–37.5) and 4.9 months (range, 1.3–23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59–93) and 64% (95% CI, 43–82) of AAP-naïve and 43% (95% CI, 22–66) and 10% (95% CI, 1–30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain.

Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544–51. ©2017 AACR.

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Phase Ib Study of Safety and Pharmacokinetics of the PI3K Inhibitor SAR245408 with the HER3-Neutralizing Human Antibody SAR256212 in Patients with Solid Tumors

Purpose: This phase Ib study was designed to determine the MTD, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) mAb SAR256212 in combination with the oral PI3K inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors.

Experimental Design: Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3 + 3 dose-escalation design until occurrence of disease progression or dose-limiting toxicity. Objective response rate, pharmacokinetics, pharmacodynamics, and PIK3CA mutational status were also evaluated.

Results: Twenty-seven patients were enrolled. Thirteen of 20 patients tested (65%) had a hotspot-activating mutation in PIK3CA in their tumor. The MTD was determined to be SAR256212 at 40 mg/kg loading dose followed by 20 mg/kg weekly, plus SAR245408 200 mg daily. Dose-limiting toxicities included rash and hypotension; the most frequent treatment-related side effect was diarrhea (66.7%). Twenty-three patients were evaluable for efficacy, of which 12 patients (52.2%) had stable disease and 11 patients (47.8%) had progression of disease as best response. In this study with a limited sample size, there was no difference in best response between patients with PI3KCA-mutant versus PIK3CA wild-type tumors (P = 0.07). The concurrent administration of SAR245408 and SAR256212 did not appear to have an effect on the pharmacokinetics of either drug.

Conclusions: The combination of SAR256212 and SAR245408 resulted in stable disease as the best response. Side effects seen in combination were similar to the profiles of each individual drug. Patient outcome was the same regardless of tumor PI3KCA mutation status. Clin Cancer Res; 23(14); 3520–8. ©2016 AACR.

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Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk - Combined Results from Two Screening Trials

Purpose: Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may identify cancers earlier than standard 6- to 12-monthly CA125 > 35 U/mL.

Experimental Design: Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or BRCA1/2 mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject's baseline, which triggered transvaginal ultrasound. Specificity and positive predictive value (PPV) were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls.

Results: Specificity for ultrasound referral was 92% versus 90% (P = 0.0001), and PPV was 4.6% versus 10% (P > 0.10). Eighteen of 19 malignant ovarian neoplasms [prevalent = 4, incident = 6, risk-reducing salpingo-oophorectomy (RRSO) = 9] were detected via screening or RRSO. Among incident cases (which best reflect long-term screening performance), three of six invasive cancers were early-stage (I/II; 50% vs. 10% historical BRCA1 controls; P = 0.016). Six of nine RRSO-related cases were stage I. ROCA flagged three of six (50%) incident cases before CA125 exceeded 35 U/mL. Eight of nine patients with stages 0/I/II ovarian cancer were alive at last follow-up (median 6 years).

Conclusions: For screened women at familial/genetic ovarian cancer risk, ROCA q3 months had better early-stage sensitivity at high specificity, and low yet possibly acceptable PPV compared with CA125 > 35 U/mL q6/q12 months, warranting further larger cohort evaluation. Clin Cancer Res; 23(14); 3628–37. ©2017 AACR.

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Differentiation between Radiation Necrosis and Tumor Progression Using Chemical Exchange Saturation Transfer

Purpose: Stereotactic radiosurgery (SRS) is a common treatment used in patients with brain metastases and is associated with high rates of local control, however, at the risk of radiation necrosis. It is difficult to differentiate radiation necrosis from tumor progression using conventional MRI, making it a major diagnostic dilemma for practitioners. This prospective study investigated whether chemical exchange saturation transfer (CEST) was able to differentiate these two conditions.

Experimental Design: Sixteen patients with brain metastases who had been previously treated with SRS were included. Average time between SRS and evaluation was 12.6 months. Lesion type was determined by pathology in 9 patients and the other 7 were clinically followed. CEST imaging was performed on a 3T Philips scanner and the following CEST metrics were measured: amide proton transfer (APT), magnetization transfer (MT), magnetization transfer ratio (MTR), and area under the curve for CEST peaks corresponding to amide and nuclear Overhauser effect (NOE).

Results: Five lesions were classified as progressing tumor and 11 were classified as radiation necrosis (using histopathologic confirmation and radiographic follow-up). The best separation was obtained by NOE_MTR (NOE_MTR,necrosis = 8.9 ± 0.9%, NOE_{MTR,progression} = 12.6 ± 1.6%, P < 0.0001) and Amide_MTR (Amide_MTR,necrosis = 8.2 ± 1.0%, Amide_{MTR,progression} = 12.0 ± 1.9%, P < 0.0001). MT (MT_necrosis = 4.7 ± 1.0%, MT_progression = 6.7 ± 1.7%, P = 0.009) and NOE_AUC (NOE_AUC,necrosis = 4.3 ± 2.0% Hz, NOE_{AUC,progression} = 7.2 ± 1.9% Hz, P = 0.019) provided statistically significant separation but with higher P values.

Conclusions: CEST was capable of differentiating radiation necrosis from tumor progression in brain metastases. Both NOE_MTR and Amide_MTR provided statistically significant separation of the two cohorts. However, APT was unable to differentiate the two groups. Clin Cancer Res; 23(14); 3667–75. ©2017 AACR.

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Body Composition as a Predictor of Toxicity in Patients Receiving Anthracycline and Taxane-Based Chemotherapy for Early-Stage Breast Cancer

Purpose: Poor body composition metrics (BCM) are associated with inferior cancer outcomes; however, in early breast cancer (EBC), there is a paucity of evidence regarding the impact of BCM on toxicities. This study investigates associations between BCM and treatment-related toxicity in patients with EBC receiving anthracyclines and taxane–based chemotherapy.

Experimental Design: Pretreatment computerized tomographic (CT) images were evaluated for skeletal muscle area (SMA), skeletal muscle density (SMD), and fat tissue at the third lumbar vertebrae. Skeletal muscle index (SMI = SMA/height²) and skeletal muscle gauge (SMG = SMI x SMD) were also calculated. Relative risks (RR) are reported for associations between body composition measures and toxicity outcomes, after adjustment for age and body surface area (BSA).

Results: BCM were calculated for 151 patients with EBC (median age, 49 years; range, 23–75 years). Fifty patients (33%) developed grade 3/4 toxicity, which was significantly higher in those with low SMI (RR, 1.29; P = 0.002), low SMG (RR, 1.09; P = 0.01), and low lean body mass (RR, 1.48; P = 0.002). Receiver operating characteristic analysis showed the SMG measure to be the best predictor of grade 3/4 toxicity. Dividing SMG into tertiles showed toxicity rates of 46% and 22% for lowest versus highest tertile, respectively (P = 0.005). After adjusting for age and BSA, low SMG (<1,475 units) was significantly associated with hematologic (RR, 2.12; P = 0.02), gastrointestinal grade 3/4 toxicities (RR, 6.49; P = 0.02), and hospitalizations (RR, 1.91; P = 0.05).

Conclusions: Poor BCMs are significantly associated with increased treatment-related toxicities. Further studies are needed to investigate how these metrics can be used to more precisely dose chemotherapy to reduce treatment-related toxicity while maintaining efficacy. Clin Cancer Res; 23(14); 3537–43. ©2017 AACR.

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Correction: UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models

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Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma

Purpose: To prospectively evaluate cardiotoxicity risk with sunitinib in metastatic renal cell carcinoma (mRCC) routine clinical practice using comprehensive echocardiography and biomarker phenotyping.

Experimental Design: In a multicenter prospective study of 90 patients with mRCC, echocardiography and biomarkers of cardiovascular injury and stress were quantified at baseline, 3.5, 15, and 33 weeks following sunitinib initiation. These "on-drug" visits corresponded to cycles 1, 3, and 6, respectively. Left ventricular (LV) dysfunction was defined as an absolute decline in LV ejection fraction (LVEF) by ≥10% to a value of <50%. Conditional survival analyses predicted the risk of LV dysfunction. Linear mixed-effects models estimated changes in LVEF, high-sensitivity Troponin I (hsTnI), and B-type natriuretic peptide (BNP) over time.

Results: The predicted risk of LV dysfunction by cycle 6 was 9.7% (95% confidence interval, 3%–17%). The majority of events occurred in the first treatment cycle. This risk diminished to 5% and 2% in patients who had not experienced dysfunction by the completion of cycles 1 and 3, respectively. All evaluable patients who experienced LV dysfunction had subsequent improvement in LVEF with careful management. Six patients (6.7%) developed hsTnI elevations >21.5 pg/mL, and 11 additional patients (12.2%) developed BNP elevations >100 pg/mL. These elevations similarly tended to occur early and resolved over time.

Conclusions: On average, patients with mRCC receiving sunitinib exhibit modest declines in LVEF and nonsignificant changes in hsTnI and BNP. However, approximately 9.7% to 18.9% of patients develop more substantive abnormalities. These changes occur early and are largely recoverable with careful management. Clin Cancer Res; 23(14); 3601–9. ©2017 AACR.

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Results from a Phase I/II Open-Label, Dose-Finding Study of Pralatrexate and Oral Bexarotene in Patients with Relapsed/Refractory Cutaneous T-cell Lymphoma

Purpose: Pralatrexate is a folic acid analogue metabolic inhibitor similar to methotrexate, which has shown tolerability and efficacy with an overall response rate of 45% in a phase I dose deescalation study of patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL).

Experimental Design: The object of this phase I/II open-label, multicenter clinical trial was to determine the MTD and recommended dose of pralatrexate plus oral bexarotene in 34 patients with relapsed/refractory CTCL who had failed prior systemic therapies. Pralatrexate was administered by intravenous push at 15 mg/m² given weekly 3 weeks out of 4 weeks with daily oral bexarotene (150 or 300 mg/m²), levothyroxine, atorvastatin, folate, and with B12 every 2 months.

Results: At the MTD of 15 mg/m² bexarotene and 15 mg/m² pralatrexate, the response rate was 60% [4 complete responses (CR), 14 partial responses (PR)], the maximum observed response duration was 28.9+ months, and duration of response for 4 CRs ranged from 9.0 to 28.3 months. The median progression-free survival was 12.8 months (0.5–29.9). Mucositis was the most common adverse event.

Conclusions: The combination of pralatrexate (15 mg/m²) and oral bexarotene (150 mg/m²) is active with high response rates and minimal toxicity for cutaneous T-cell lymphomas. Clin Cancer Res; 23(14); 3552–6. ©2017 AACR.

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Usefulness of KIR3DL2 to Diagnose, Follow-Up, and Manage the Treatment of Patients with Sezary Syndrome

Purpose: KIR3DL2 is a recently discovered marker of the malignant clonal cell population in Sézary syndrome. We intended to evaluate the expression of KIR3DL2 on blood T cells as a diagnostic, prognostic, and follow-up marker of Sézary syndrome.

Experimental Design: Sixty-four patients diagnosed with Sézary syndrome were included in this monocentric study. We collected the percentage of KIR3DL2⁺ cells among CD3⁺ T cells, obtained by flow cytometry, and other classical diagnostic criteria for Sézary syndrome at diagnosis and during the follow-up.

Results: Compared with the classical diagnostic factors, KIR3DL2 was the most sensitive diagnostic factor for Sézary syndrome. Univariate and multivariate analyses established that an eosinophil cell count >700/mm³ and a percentage of KIR3DL2⁺ cells within the CD3⁺ T cells >85% at diagnosis were associated with a significantly reduced disease-specific survival. Moreover, KIR3DL2 immunostaining allowed the assessment of treatment efficiency and specificity toward tumor cells, the detection of the residual disease following treatment, and the occurrence of relapse, even though patients clinically experienced complete remission and/or undetectable circulating Sézary cells by cytomorphologic analysis.

Conclusions: We show that KIR3DL2 expression is the most sensitive diagnostic criterion of Sézary syndrome when compared with all other available biological criteria. It also represents the best independent prognostic factor for Sézary syndrome–specific death and the most relevant feature for the follow-up of Sézary syndrome, showing the invasion of the functional lymphocytes pool by Sézary cells. KIR3DL2 therefore represents a valuable tool for routine use as a clinical parameter at diagnosis, for prognosis and during patient follow-up. Clin Cancer Res; 23(14); 3619–27. ©2017 AACR.

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A rule-based electronic phenotyping algorithm for detecting clinically relevant cardiovascular disease cases

The implementation of electronic medical records (EMR) is becoming increasingly common. Error and data loss reduction, patient-care efficiency increase, decision-making assistance and facilitation of event sur...

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NAP: The Network Analysis Profiler, a web tool for easier topological analysis and comparison of medium-scale biological networks

Nowadays, due to the technological advances of high-throughput techniques, Systems Biology has seen a tremendous growth of data generation. With network analysis, looking at biological systems at a higher leve...

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Time to immunologic recovery and determinant factors among adults who initiated ART in Felege Hiwot Referral Hospital, northwest Ethiopia

CD4 cells are the major targets for human immunodeficiency virus (HIV) and treatment with Antiretroviral Therapy (ART) influences the CD4 cell count of HIV patients. In addition to ART, the time required to re...

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Burden and associated factors of anemia among pregnant women attending antenatal care in southern Ethiopia: cross sectional study

Anemia is a condition in which the number of red blood cells or their oxygen-carrying capacity is insufficient to meet physiologic needs, which varies by age, sex, altitude, smoking, and pregnancy status. The ...

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Novel Method for Quantitative Estimation of Biofilms

Abstract

Biofilm protects bacteria from stress and hostile environment. Crystal violet (CV) assay is the most popular method for biofilm determination adopted by different laboratories so far. However, biofilm layer formed at the liquid–air interphase known as pellicle is extremely sensitive to its washing and staining steps. Early phase biofilms are also prone to damage by the latter steps. In bacteria like mycobacteria, biofilm formation occurs largely at the liquid–air interphase which is susceptible to loss. In the proposed protocol, loss of such biofilm layer was prevented. In place of inverting and discarding the media which can lead to the loss of the aerobic biofilm layer in CV assay, media was removed from the formed biofilm with the help of a syringe and biofilm layer was allowed to dry. The staining and washing steps were avoided, and an organic solvent—tetrahydrofuran (THF) was deployed to dissolve the biofilm, and the absorbance was recorded at 595 nm. The protocol was tested for biofilm estimation of E. coli, B. subtilis and M. smegmatis, and compared with the traditional CV assays. Isoniazid drug molecule, a known inhibitor of M. smegmatis biofilm, was tested and its inhibitory effects were quantified by the proposed protocol. For ease in referring, this method has been described as the Syal method for biofilm quantification. This new method was found to be useful for the estimation of early phase biofilm and aerobic biofilm layer formed at the liquid–air interphase. The biofilms formed by all three tested bacteria—B. subtilis, E. coli and M. smegmatis, were precisely quantified.

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Mink ( Mustela vison ) Gut Microbial Communities from Northeast China and Its Internal Relationship with Gender and Food Additives

Abstract

It is well documented that the microbial interactions and biodiversity play an important role in health and disease in mammalian species. There is a rare study about gut microbiota of Mustelidae family. In this study, 40 male and female minks from Northeast China were divided into three groups and fed until they reached maturity. The V3 region of 16S rRNA genes was amplified and sequenced using NGS. There were 526 OTUs principally concentrated among five bacterial phyla. Two points about mink's body weight gaining were observed: (1) the weight of male individuals increased more rapidly than female individuals; (2) the weight of individuals whose feed was supplemented with Chinese herb additives increased more rapidly than individuals without giving food additives. The differences of microorganism abundance were shown in two points: (1) two genera which had ≥2-fold change difference were found between male and female minks. (2) Ten genera which had a ≥2-fold change difference were found among minks with and without Chinese herb additive. Findings from this study provide new and fundamental knowledge on the gut microbiota composition of minks farmed in Northeast China, which can contribute to the general well-being of minks worldwide.

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US ranked worst healthcare system, while the NHS is the best

An analysis of 11 wealthy nations, including Australia and Canada, has found that the US healthcare system is the worst, particularly for fair and easy access

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Hurthle thyroid cancer requires tissue sample for diagnosis - STLtoday.com

Hurthle thyroid cancer requires tissue sample for diagnosis STLtoday.com Dear Dr. Roach • Recently, I underwent a needle biopsy of a thyroid nodule. The cytology report reads "suspicious for Hurthle cell neoplasm (Bethesda Category IV)." I have an appointment with a surgeon for a more definitive diagnosis. Is this already ...

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Issue Information - TOC

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Cardiac transplant vasculopathy

Key Points

• Transplant vasculopathy is a form of slowly progressive rejection.
• The interventional cardiologist plays an important role in maintaining survival of this precious commodity by performing PCI.
• Everolimus drug eluting stents are highly effective and have relatively low occurrence of in-stent restenosis, but transplant vasculopathy continues to progress in a diffuse pattern.

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The Value of Independent Specialty Designation for Interventional Cardiology. DOI: 10.1002/ccd.26656

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Current approaches to retroperitoneal hemorrhage: Too little, too late

Key Points

• Retroperitoneal hemorrhage (RPH) arises in < 0.5% of patients undergoing percutaneous intervention, but is associated with high risks of morbidity and mortality.
• More than 50% of medical malpractice claims against interventional cardiologists are related to death and hemorrhage from vascular injury; delays in diagnosis and treatment are common.
• The current approach to RPH is characterized by "too little" to diagnose and "too late" to manage patients in extremis. Immediate CTA allows rapid diagnosis and triage to appropriate endovascular therapy, without delay.

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Paravalvular leak versus need for permanent pacemaker after TAVR: Sailing between Scylla and Charybdis

Key Points

• Absence or minimization of PVL after TAVR and its potential association with higher rates of PPM placement has been the Achilles' heel of TAVR procedures.
• Pre-existing RBBB and depth of implantation are independent predictors of PPM need after Lotus valve implantation.
• Optimization of device design, increased operator experience, and focus on accurate device placement seem to result in decreased need for PPM after Lotus valve implantation.

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The importance of vision

Key Points

• Based on a systematic review and meta-analysis of 8 studies, involving 2,559 subjects, both interventional cardiologists (3.21) and cardiac cath lab staff (2.76) had a significantly higher relative risk of posterior lens opacity than the control group.
• It is essential to provide "best practice" in radiation dose management and lead shielding in the cath lab with the standard "As Low As Reasonably Achievable"!
• There is a clear need for better data to quantitate the radiation risk and to design innovative strategies to decrease that risk.

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Left Main Coronary Angioplasty of a 9-Year-Old Child With Bioresorable Vascular Scaffold. DOI: 10.1002/ccd.26896

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CTO revascularization: Obstacles and options in balloon nonpenetrable lesions

Key Points

• CTO lesions resisting balloon crossing are located in moderate/severe tortuous coronary arteries contain more moderate/severe calcification burden and carry a higher J-CTO score as compared with balloon crossable CTO lesions.
• CTO lesions resisting balloon crossing do not constitute a homogenous group. In 25% of the patients, the resisting CTO was caused by stent restenosis and thrombus is an integral component of CTO in addition to calcium and fibrosis.
• The excimer laser and rotational/orbital atherectomy are among useful debulking technologies capable of creating a "pilot recanalization channel" in the CTO that enables completion of the revasularization.

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Transcatheter Aortic Valve Replacement in Bicuspid Aortic Stenosis Using Lotus Valve System

Bicuspid aortic stenosis (BAS) has been excluded in clinical trials on transcatheter aortic valve replacement (TAVR) due to the presumed uneven expansion of the aortic prosthesis, leading to significant paravalvular regurgitation (PVR). There is no transcatheter heart valve (THV) commercially approved for treating BAS. The Lotus Valve System mitigates PVR by possessing an adaptive seal and being fully re-positionable. The latter is also important in preventing embolization, as the location of prosthesis fixation in BAS could be variable due to the presence of less expandable raphe. We report our early experience with the Lotus Valve System in three consecutive TAVR for BAS. They all provide good clinical and hemodynamic results without significant PVR. We conclude that the use of Lotus Valve System for treating BAS is feasible and safe, and may have advantages over the previous generation TAVR systems. © 2016 Wiley Periodicals, Inc.

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Therapeutic Rationale to Target Highly Expressed CDK7 Conferring Poor Outcomes in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle–related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n = 383) and the METABRIC TNBC dataset (n = 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n = 109) and the METABRIC TNBC cohort (n = 203). The highly specific CDK7 kinase inhibitors, BS-181 and THZ1, each downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment. Cancer Res; 77(14); 3834–45. ©2017 AACR.

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Mdm2 Is Required for Survival and Growth of p53-Deficient Cancer Cells

p53 deletion prevents the embryonic lethality of normal tissues lacking Mdm2, suggesting that cells can survive without Mdm2 if p53 is also absent. Here we report evidence challenging this view, with implications for therapeutically targeting Mdm2. Deletion of Mdm2 in T-cell lymphomas or sarcomas lacking p53 induced apoptosis and G2 cell-cycle arrest, prolonging survival of mice with these tumors. p53−/− fibroblasts showed similar results, indicating that the effects of Mdm2 loss extend to premalignant cells. Mdm2 deletion in p53−/− cells upregulated p53 transcriptional target genes that induce apoptosis and cell-cycle arrest. Mdm2 deletion also increased levels of p73, a p53 family member. RNAi-mediated attenuation of p73 rescued the transcriptional and biological effects of Mdm2 loss, indicating that p73 mediates the consequences of Mdm2 deletion. In addition, Mdm2 deletion differed from blocking Mdm2 interaction with p53 family members, as Nutlin-3 induced G1 arrest but did not activate apoptosis in p53−/− sarcoma cells. Our results indicate that, in contrast to current dogma, Mdm2 expression is required for cell survival even in the absence of p53. Moreover, our results suggest that p73 compensates for loss of p53 and that targeting Mdm2 in p53-deficient cancers has therapeutic potential. Cancer Res; 77(14); 3823–33. ©2017 AACR.

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Correction: Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells

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ETV1-Positive Cells Give Rise to BRAFV600E-Mutant Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumor (GIST) is the most common subtype of sarcoma. Despite clinical advances in the treatment of KIT/PDGFRA–mutant GIST, similar progress against KIT/PDGFRA wild-type GIST, including mutant BRAF-driven tumors, has been limited by a lack of model systems. ETV1 is a master regulator in the intestinal cells of Cajal (ICC), thought to be the cells of origin of GIST. Here, we present a model in which the ETV1 promoter is used to specifically and inducibly drive Cre recombinase in ICC as a strategy to study GIST pathogenesis. Using a conditional allele for BrafV600E, a mutation observed in clinical cases of GIST, we observed that BrafV600E activation was sufficient to drive ICC hyperplasia but not GIST tumorigenesis. In contrast, combining BrafV600E activation with Trp53 loss was sufficient to drive both ICC hyperplasia and formation of multifocal GIST-like tumors in the mouse gastrointestinal tract with 100% penetrance. This mouse model of sporadic GIST model was amenable to therapeutic intervention, and it recapitulated clinical responses to RAF inhibition seen in human GIST. Our work offers a useful in vivo model of human sporadic forms of BRAF-mutant GIST to help unravel its pathogenesis and therapeutic response to novel experimental agents. Cancer Res; 77(14); 3758–65. ©2017 AACR.

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ATOH1 Promotes Leptomeningeal Dissemination and Metastasis of Sonic Hedgehog Subgroup Medulloblastomas

Medulloblastoma arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we used mouse medulloblastoma models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive medulloblastoma subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed to Ptch1+/− mice, which develop SHH-driven medulloblastoma, animals with Atoh1 transgene expression developed highly penetrant medulloblastoma at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH medulloblastoma. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, ATOH1 expression was detected consistently in recurrent and metastatic SHH medulloblastoma. Chromatin immunoprecipitation sequencing and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying medulloblastoma metastasis that offers possible therapeutic opportunities. Cancer Res; 77(14); 3766–77. ©2017 AACR.

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Akt Signaling Is Sustained by a CD44 Splice Isoform-Mediated Positive Feedback Loop

Tumor cells nearly invariably evolve sustained PI3K/Akt signaling as an effective means to circumvent apoptosis and maintain survival. However, for those tumor cells that do not acquire PI3K/Akt mutations to achieve this end, the underlying mechanisms have remained obscure. Here, we describe the discovery of a splice isoform–dependent positive feedback loop that is essential to sustain PI3K/Akt signaling in breast cancer. Splice isoform CD44s promoted expression of the hyaluronan synthase HAS2 by activating the Akt signaling cascade. The HAS2 product hyaluronan further stimulated CD44s-mediated Akt signaling, creating a feed-forward signaling circuit that promoted tumor cell survival. Mechanistically, we identified FOXO1 as a bona fide transcriptional repressor of HAS2. Akt-mediated phosphorylation of FOXO1 relieved its suppression of HAS2 transcription, with FOXO1 phosphorylation status maintained by operation of the positive feedback loop. In clinical specimens of breast cancer, we established that the expression of CD44s and HAS2 was positively correlated. Our results establish a positive feedback mechanism that sustains PI3K/Akt signaling in tumor cells, further illuminating the nearly universal role of this pathway in cancer cell survival. Cancer Res; 77(14); 3791–801. ©2017 AACR.

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An miRNA Expression Signature for the Human Colonic Stem Cell Niche Distinguishes Malignant from Normal Epithelia

Malignant transformation of tissue stem cells (SC) may be the root of most cancer. Accordingly, we identified miRNA expression patterns in the normal human colonic SC niche to understand how cancer stem cells (CSC) may arise. In profiling miRNA expression in SC-enriched crypt subsections isolated from fresh, normal surgical specimens, we identified 16 miRNAs that were differentially expressed in the crypt bottom, creating an SC signature for normal colonic epithelia (NCE). A parallel analysis of colorectal cancer tissues showed differential expression of 83 miRNAs relative to NCE. Within the 16 miRNA signature for the normal SC niche, we found that miR-206, miR-007-3, and miR-23b individually could distinguish colorectal cancer from NCE. Notably, miR-23b, which was increased in colorectal cancer, was predicted to target the SC-expressed G protein-coupled receptor LGR5. Cell biology investigations showed that miR-23b regulated CSC phenotypes globally at the level of proliferation, cell cycle, self-renewal, epithelial–mesenchymal transition, invasion, and resistance to the colorectal cancer chemotherapeutic agent 5-fluorouracil. In mechanistic experiments, we found that miR-23b decreased LGR5 expression and increased ALDH+ CSCs. CSC analyses confirmed that levels of LGR5 and miR-23b are inversely correlated in ALDH+ CSCs and that distinct subpopulations of LGR5+ and ALDH+ CSCs exist. Overall, our results define a critical function for miR-23b, which, by targeting LGR5, contributes to overpopulation of ALDH+ CSCs and colorectal cancer. Cancer Res; 77(14); 3778–90. ©2017 AACR.

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CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib

Effective targeted therapies for small-cell lung cancer (SCLC), the most aggressive form of lung cancer, remain urgently needed. Here we report evidence of preclinical efficacy evoked by targeting the overexpressed cell-cycle checkpoint kinase CHK1 in SCLC. Our studies employed RNAi-mediated attenuation or pharmacologic blockade with the novel second-generation CHK1 inhibitor prexasertib (LY2606368), currently in clinical trials. In SCLC models in vitro and in vivo, LY2606368 exhibited strong single-agent efficacy, augmented the effects of cisplatin or the PARP inhibitor olaparib, and improved the response of platinum-resistant models. Proteomic analysis identified CHK1 and MYC as top predictive biomarkers of LY2606368 sensitivity, suggesting that CHK1 inhibition may be especially effective in SCLC with MYC amplification or MYC protein overexpression. Our findings provide a preclinical proof of concept supporting the initiation of a clinical efficacy trial in patients with platinum-sensitive or platinum-resistant relapsed SCLC. Cancer Res; 77(14); 3870–84. ©2017 AACR.

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Venetoclax Synergizes with Radiotherapy for Treatment of B-cell Lymphomas

Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein and is implicated in the pathogenesis of many types of B-cell non-Hodgkin lymphoma (B-NHL). The BCL-2 small-molecule inhibitor venetoclax shows promising clinical response rates in several lymphomas, but is not curative as monotherapy. Radiotherapy is a rational candidate for combining with BCL-2 inhibition, as DNA damage caused by radiotherapy increases the activity of pro-apoptotic BCL-2 pathway proteins, and lymphomas are exquisitely sensitive to radiation. We tested B-NHL responses to venetoclax combined with either external beam radiotherapy or radioimmunotherapy (RIT), which joins the selectivity of antibody targeting with the effectiveness of irradiation. We first tested cytotoxicity of cesium-137 irradiation plus venetoclax in 14 B-NHL cell lines representing five lymphoma subtypes. Combination treatment synergistically increased cell death in 10 of 14 lines. Lack of synergy was predicted by resistance to single-agent venetoclax and high BCL-XL expression. We then assessed the efficacy of external beam radiotherapy plus venetoclax in murine xenograft models of mantle cell (MCL), germinal-center diffuse large B-cell (GCB-DLBCL), and activated B-cell (ABC-DLBCL) lymphomas. In each model, external beam radiotherapy plus venetoclax synergistically increased mouse survival time, curing up to 10%. We finally combined venetoclax treatment of MCL and ABC-DLBCL xenografts with a pretargeted RIT (PRIT) system directed against the CD20 antigen. Optimal dosing of PRIT plus venetoclax cured 100% of mice with no detectable toxicity. Venetoclax combined with radiotherapy may be a promising treatment for a wide range of lymphomas Cancer Res; 77(14); 3885–93. ©2017 AACR.

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Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution

The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials. Cancer Res; 77(14); 3908–21. ©2017 AACR.

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Somatic Mutations Drive Distinct Imaging Phenotypes in Lung Cancer

Tumors are characterized by somatic mutations that drive biological processes ultimately reflected in tumor phenotype. With regard to radiographic phenotypes, generally unconnected through present understanding to the presence of specific mutations, artificial intelligence methods can automatically quantify phenotypic characters by using predefined, engineered algorithms or automatic deep-learning methods, a process also known as radiomics. Here we demonstrate how imaging phenotypes can be connected to somatic mutations through an integrated analysis of independent datasets of 763 lung adenocarcinoma patients with somatic mutation testing and engineered CT image analytics. We developed radiomic signatures capable of distinguishing between tumor genotypes in a discovery cohort (n = 353) and verified them in an independent validation cohort (n = 352). All radiomic signatures significantly outperformed conventional radiographic predictors (tumor volume and maximum diameter). We found a radiomic signature related to radiographic heterogeneity that successfully discriminated between EGFR+ and EGFR− cases (AUC = 0.69). Combining this signature with a clinical model of EGFR status (AUC = 0.70) significantly improved prediction accuracy (AUC = 0.75). The highest performing signature was capable of distinguishing between EGFR+ and KRAS+ tumors (AUC = 0.80) and, when combined with a clinical model (AUC = 0.81), substantially improved its performance (AUC = 0.86). A KRAS+/KRAS− radiomic signature also showed significant albeit lower performance (AUC = 0.63) and did not improve the accuracy of a clinical predictor of KRAS status. Our results argue that somatic mutations drive distinct radiographic phenotypes that can be predicted by radiomics. This work has implications for the use of imaging-based biomarkers in the clinic, as applied noninvasively, repeatedly, and at low cost. Cancer Res; 77(14); 3922–30. ©2017 AACR.

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Noninvasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer

The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T; SC16LD6.5) is a first-in-class DLL3-targeted antibody–drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, although orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC. We developed 89Zr-labeled SC16 antibody as a companion diagnostic agent to facilitate selection of patients for treatment with Rova-T based on a noninvasive interrogation of the in vivo status of DLL3 expression using PET imaging. Despite low cell-surface abundance of DLL3, immunoPET imaging with 89Zr-labeled SC16 antibody enabled delineation of subcutaneous and orthotopic SCLC tumor xenografts as well as distant organ metastases with high sensitivity. Uptake of the radiotracer in tumors was concordant with levels of DLL3 expression and, most notably, DLL3 immunoPET yielded rank-order correlation for response to SC16LD6.5 therapy in SCLC patient–derived xenograft models. Cancer Res; 77(14); 3931–41. ©2017 AACR.

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Extrathyroidal Extension Predicts Decreased Survival in Thyroid Cancer Patients

Clinical Thyroidology Jul 2017, Vol. 29, No. 7: 271-273.


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Teprotumumab, an Antibody that Blocks the IGF-I Receptor, Causes Dramatic Improvement in Graves’ Orbitopathy

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Acute facial nerve paralysis in children,............................................................................................................................................ Bell's palsy in an adolescent girl - not always a neurologist's territory: A case report and review of literature by Latha M Sneha via CHRISMED Journal of Health and Research : 2014 - 1(4) Latha M Sneha, Raichel Priyanka, Shanthini Thanga Tamilselvan, Julius Xavier Scott CHRISMED Journal of Health and Research 2017 4(

The common etiology associated with acute facial nerve paralysis in children are otitis media, mastoiditis, viral infections such as herpes, varicella, mumps, HIV, meningitis, encephalitis, mycoplasma, Lyme disease, and inflammatory conditions such as vasculitis, Henoch–Schonlein purpura, Kawasaki syndrome, Gullain–Barre syndrome, and hypertension.[3]

Seventy percent of the children with acute lower motor neuron facial paralysis have a favorable prognosis and it resolves spontaneously within 3 months without any sequela. In 40%–75% of children, cause of unilateral facial paralysis is idiopathic, described as Bell's palsy and most of them have a positive history of viral illness 2–3 weeks preceding the neurological manifestations. The use of steroids to reduce the duration of paralysis and reduce the risk of long-term impairment was based on adult studies though the benefits of steroids in children is yet to be proven.[4] Due to the self-resolving nature of the idiopathic variety of the facial palsy seen in children, the neurological manifestations of leukemia as an etiology is never thought of. Steroids, when commonly prescribed in such cases causes a partial recovery thereby masking the primary pathology and adds to the diagnostic dilemma.

The frequency of symptomatic facial palsy has been found to be higher in the younger age group when compared to the idiopathic variety.[5]

AML accounts for 15% of all leukemia and presents with symptoms of prolonged fever, hepatosplenomegaly, and skin or mucocutaneous bleeds. When focal masses of immature myeloid cells from the granulocytic lineage infiltrate the soft tissues and bones, they are called granulocytic sarcomas or chloromas and occur in 5% of cases of AML. It is postulated that the granulocytic sarcomas traverse through the haversian canals from the bone marrow and gets deposited in the subperiosteum to form soft tissue masses.[6]

Granulocytic sarcomas may manifest concurrently with the disease or during remission or relapse. However, when sarcomas precede the disease in peripheral blood or marrow, it often poses a diagnostic challenge, more so, if cranial neuropathies are caused by unidentifiable chloromas as in our case. Facial paralysis resulting from leukemic infiltration, though rare, occurs during the relapse of the disease or as a complication primary disease, but it is not a well-recognized presenting symptom of childhood leukemia. Diagnostic delays of 1 month have been reported when facial nerve palsy was the isolated manifestation of AML in children.[7] Otomastoiditis due to the leukemic infiltration of the temporal bone has been attributed to the facial nerve paralysis. MRI with contrast of the facial nerve canal helps in identifying the facial nerve enhancement. However, the clinical findings of facial nerve paralysis were not always associated with radiological findings in most of the cases.[7]

Baek et al. have reported 11 children who had facial nerve paralysis as isolated feature of AML. Brain imaging studies showed mastoiditis in four of them and chloroma was identified in five of them. Six of them did not have blast in the CSF. Facial nerve palsy improved within a mean period of 1–6 months of chemotherapy.[7] Rohit et al. have reported a case of 13-year-old girl-AML with t(8:21) positivity who presented with bilateral proptosis and facial nerve palsy.[8]

When leukemic children presented with cranial neuropathies, the treatment included systemic and intrathecal chemotherapy with whole brain irradiation. However, Baek et al. recommend allogenic bone marrow transplant, avoiding whole brain irradiation in children to reduce the development of secondary malignancies and to prevent the long-term sequelae on cognitive and endocrine function.

Due to the self-resolving nature of the idiopathic variety of facial nerve palsy, when these children present to general physicians or neurologists, the diagnosis of leukemia is overlooked. Gradual progression of the paralysis beyond 3 weeks should warrant additional investigations to rule out the etiology.

CASE REPORT

Year : 2017  |  Volume : 4  |  Issue : 3  |  Page : 209-211

Bell's palsy in an adolescent girl - not always a neurologist's territory: A case report and review of literature

Latha M Sneha¹, Raichel Priyanka², Shanthini Thanga Tamilselvan², Julius Xavier Scott^3
1 Department of Pediatrics, Division of Pediatric Hemato Oncology, Sri Ramachandra University, Chennai, Tamil Nadu, India
² Department of Pediatrics, Sri Ramachandra University, Chennai, Tamil Nadu, India
³ Division of Pediatric Hemato Oncology, Sri Ramachandra University, Chennai, Tamil Nadu, India

Date of Web Publication

13-Jul-2017

Correspondence Address:
Latha M Sneha
Division of Pediatric Hemato Oncology, Sri Ramachandra University, No. 1, Ramachandra Nagar, Porur, Chennai - 600 116, Tamil Nadu 
India

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/cjhr.cjhr_123_16

Abstract

Infections, inflammatory, and autoimmune conditions are the well-recognized etiologies of acute facial nerve paralysis in children. Bell's palsy is idiopathic peripheral facial nerve palsy. Cranial neuropathies do occur in children due to the central nervous system involvement by malignancies but uncommon in pediatric acute lymphoblastic leukemias and even rarer in acute myeloid leukemias (AMLs). We report a case of a 13-year-old girl who presented with acute facial nerve palsy, was being treated as Bell's palsy elsewhere and was later diagnosed to have AML.

Keywords: Acute myeloid leukemia, Bell's palsy, child

How to cite this article: Sneha LM, Priyanka R, Tamilselvan ST, Scott JX. Bell's palsy in an adolescent girl - not always a neurologist's territory: A case report and review of literature. CHRISMED J Health Res 2017;4:209-11

How to cite this URL: Sneha LM, Priyanka R, Tamilselvan ST, Scott JX. Bell's palsy in an adolescent girl - not always a neurologist's territory: A case report and review of literature. CHRISMED J Health Res [serial online] 2017 [cited 2017 Jul 14];4:209-11. Available from: http://ift.tt/2t8YqDB

Introduction

Acute, peripheral facial palsy can be presenting feature of infections, inflammatory, and autoimmune conditions and has a good prognosis in children. The incidence of facial paralysis in children <10 years of age is reported to be 2.7/100,000.^[1] Majority of them are unilateral, idiopathic, and termed Bell's palsy. A diagnosis of exclusion, Bell's palsy accounts for 42%–85% of cases in children with facial nerve paralysis.^[2] Although association of facial palsies in malignancies is well reported, facial paralysis is not a well-recognized presenting feature of leukemias in children, especially in acute myeloid leukemia (AML). The presence of Bell's palsy in children warrants a complete evaluation to rule out leptomeningeal diseases. We report a case of an adolescent girl who presented with acute facial nerve palsy, treated as Bell's palsy elsewhere and was later diagnosed to have AML.

Case Report

A 13-year-old girl presented with acute onset of right-sided facial nerve palsy of 2 weeks duration. She was diagnosed to have idiopathic Bell's palsy elsewhere and was being treated symptomatically with physiotherapy and oral steroids with no improvement in symptoms. She had no constitutional symptoms of fever, anorexia or fatigue, bone pain, mucocutaneous, or skin bleeds. In view of persistent symptoms, she was referred to a higher center for further evaluation. Examination revealed a right-sided lower motor neuron facial nerve palsy [Figure 1], without hepatosplenomegaly or lymphadenopathy. Central nervous system examination and rest of the systemic examination were normal. Investigations revealed hemoglobin 5.9 g/dl, total leukocyte count 14,900/μL (polymorphs: 64.1%, lymphocytes 30.3%), and platelet count 83,000/μL. Peripheral smear revealed leukocytosis with increase in blasts (50%) with  Auer rods ^{More Details} along with thrombocytopenia [Figure 2].

Figure 1: Right-sided lower motor neuron palsy Click here to view

Figure 2: Peripheral smear showing blasts with Auer rods Click here to view

Bone marrow aspiration showed hypercellular marrow with 58% blasts, promyelocytes - nil, myelocytes - 9, metamyelocytes - 9, neutrophil - 3, eosinophil - 2, band - 4, lymphocytes - 9, monocytes - nil, and plasma cells - 1 [Figure 3]. Cerebrospinal fluid (CSF) analysis was negative for malignant cells. Flow cytometry revealed blasts positive for CD33, cytoplasmic myeloperoxidase, and Human leukocyte antigen –D related (HLA-DR). Magnetic resonance imaging (MRI) brain, MRI angiogram, and venogram were normal. Cytogenetics was negative for t(8:21), inversion 16, t(9:11), and t(15:17). The girl was diagnosed as AML M0. She was started on chemotherapy and after the first cycle of chemotherapy, the bone marrow is in remission and she had partial resolution of facial nerve palsy.

Figure 3: Bone marrow aspirate showing hypercellular marrow with increased blasts 58% Click here to view

Discussion

The common etiology associated with acute facial nerve paralysis in children are otitis media, mastoiditis, viral infections such as herpes, varicella, mumps, HIV, meningitis, encephalitis, mycoplasma, Lyme disease, and inflammatory conditions such as vasculitis, Henoch–Schonlein purpura, Kawasaki syndrome, Gullain–Barre syndrome, and hypertension.^[3]

Seventy percent of the children with acute lower motor neuron facial paralysis have a favorable prognosis and it resolves spontaneously within 3 months without any sequela. In 40%–75% of children, cause of unilateral facial paralysis is idiopathic, described as Bell's palsy and most of them have a positive history of viral illness 2–3 weeks preceding the neurological manifestations. The use of steroids to reduce the duration of paralysis and reduce the risk of long-term impairment was based on adult studies though the benefits of steroids in children is yet to be proven.^[4] Due to the self-resolving nature of the idiopathic variety of the facial palsy seen in children, the neurological manifestations of leukemia as an etiology is never thought of. Steroids, when commonly prescribed in such cases causes a partial recovery thereby masking the primary pathology and adds to the diagnostic dilemma.

The frequency of symptomatic facial palsy has been found to be higher in the younger age group when compared to the idiopathic variety.^[5]

AML accounts for 15% of all leukemia and presents with symptoms of prolonged fever, hepatosplenomegaly, and skin or mucocutaneous bleeds. When focal masses of immature myeloid cells from the granulocytic lineage infiltrate the soft tissues and bones, they are called granulocytic sarcomas or chloromas and occur in 5% of cases of AML. It is postulated that the granulocytic sarcomas traverse through the haversian canals from the bone marrow and gets deposited in the subperiosteum to form soft tissue masses.^[6]

Granulocytic sarcomas may manifest concurrently with the disease or during remission or relapse. However, when sarcomas precede the disease in peripheral blood or marrow, it often poses a diagnostic challenge, more so, if cranial neuropathies are caused by unidentifiable chloromas as in our case. Facial paralysis resulting from leukemic infiltration, though rare, occurs during the relapse of the disease or as a complication primary disease, but it is not a well-recognized presenting symptom of childhood leukemia. Diagnostic delays of 1 month have been reported when facial nerve palsy was the isolated manifestation of AML in children.^[7] Otomastoiditis due to the leukemic infiltration of the temporal bone has been attributed to the facial nerve paralysis. MRI with contrast of the facial nerve canal helps in identifying the facial nerve enhancement. However, the clinical findings of facial nerve paralysis were not always associated with radiological findings in most of the cases.^[7]

Baek et al. have reported 11 children who had facial nerve paralysis as isolated feature of AML. Brain imaging studies showed mastoiditis in four of them and chloroma was identified in five of them. Six of them did not have blast in the CSF. Facial nerve palsy improved within a mean period of 1–6 months of chemotherapy.^[7] Rohit et al. have reported a case of 13-year-old girl-AML with t(8:21) positivity who presented with bilateral proptosis and facial nerve palsy.^[8]

When leukemic children presented with cranial neuropathies, the treatment included systemic and intrathecal chemotherapy with whole brain irradiation. However, Baek et al. recommend allogenic bone marrow transplant, avoiding whole brain irradiation in children to reduce the development of secondary malignancies and to prevent the long-term sequelae on cognitive and endocrine function.

Due to the self-resolving nature of the idiopathic variety of facial nerve palsy, when these children present to general physicians or neurologists, the diagnosis of leukemia is overlooked. Gradual progression of the paralysis beyond 3 weeks should warrant additional investigations to rule out the etiology.

Conclusion

While managing young children with acute lower motor neuron facial nerve palsy, neurologists and general physicians should have an index of suspicion for the neurological manifestations of acute leukemia and hence complete blood counts, peripheral smear and a bone marrow study if needed should be a part of the work up for etiology in such cases. The routine use of steroids may result in partial remission and can cause diagnostic delays.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

References

1.	Singhi P, Jain V. Bell's palsy in children. Semin Pediatr Neurol 2003;10:289-97.   [PUBMED]
2.	May M, Fria TJ, Blumenthal F, Curtin H. Facial paralysis in children: Differential diagnosis. Otolaryngol Head Neck Surg 1981;89:841-8.
3.	Ciorba A, Corazzi V, Conz V, Bianchini C, Aimoni C. Facial nerve paralysis in children. World J Clin Cases 2015;3:973-9.
4.	Unüvar E, Oguz F, Sidal M, Kiliç A. Corticosteroid treatment of childhood Bell's palsy. Pediatr Neurol 1999;21:814-6.
5.	Krishnamurthy S, Weinstock AL, Smith SH, Duffner PK. Facial palsy, an unusual presenting feature of childhood leukemia. Pediatr Neurol 2002;27:68-70.
6.	Stein-Wexler R, Wootton-Gorges SL, West DC. Orbital granulocytic sarcoma: An unusual presentation of acute myelocytic leukemia. Pediatr Radiol 2003;33:136-9.
7.	Baek HJ, Han DK, Kim YO, Choi IS, Hwang TJ, Kook H. Facial palsy as the presenting symptom of acute myeloid leukemia in children: Three cases with stem cell transplantations. Korean J Pediatr 2009;52:713-6.
8.	Rohit K, Jitender MK, Atul S, Soumya S. The paradox of recurrent with rare: A rare case of bilateral proptosis and facial palsy in acute myeloid leukemia with recurrent cytogenetic translocation t(8:21). Int J Appl Basic Med Res 2015;5:76-8.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

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