Cancer by Sfakianakis Alexandros: 04/18/17

Τρίτη 18 Απριλίου 2017

Preoperative versus Postoperative Radiotherapy in Localized Soft Tissue Sarcoma: Nationwide Patterns of Care and Trends in Utilization

Publication date: Available online 18 April 2017
Source:Practical Radiation Oncology
Author(s): Stanislav Lazarev, Heather McGee, Erin Moshier, Meng Ru, Elizabeth G. Demicco, Vishal Gupta
PurposeThe timing of perioperative radiotherapy (RT) in the treatment of soft tissue sarcoma (STS) varies among institutions. This study examines patterns of care, trends in utilization, and survival with preoperative (preop) versus postoperative (postop) RT for primary STS.MethodsUsing the National Cancer Data Base, we identified patients with stage I-III STS who underwent definitive surgery with either preop or postop RT between 2004 and 2012. Univariate, bivariate, and multivariate analyses were performed to identify factors predicting receipt of preop versus postop RT. Overall survival (OS) was analyzed using the log-rank test, Kaplan–Meier method, and Cox proportional-hazards model.ResultsThis study included 9604 patients: 7246 (75.4%) received postop and 2358 (24.6%) - preop RT. Chemotherapy was administered to 27.0% patients in the preop and 13.0% in the postop cohort. Use of preop RT increased over time, from 16.8% in 2004 to 29.7% in 2012. Multivariate analysis revealed that preop RT utilization increased with the following factors: higher educational attainment, treatment at an academic facility, further distance from facility (>60miles), receipt of chemotherapy, tumor originating in lower extremities, >10cm tumors, myxoid liposarcoma. OS analysis revealed no difference between the two treatment cohorts.ConclusionsPostop RT is utilized much more commonly than preop RT in localized STS. However, preop RT use has increased in recent years. Multiple demographic and clinicopathologic factors were predictive of preop RT use. Consistent with randomized phase 3 data, there was no difference in OS.

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Potential Abscopal Response to Dual Checkpoint Blockade in RCC After Re-Irradiation Using Dose Painting SBRT

Publication date: Available online 18 April 2017
Source:Practical Radiation Oncology
Author(s): Quincey LaPlant, Carl Deselm, Natalie A. Lockney, James Hsieh, Yoshiya Yamada

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Fully-automated, comprehensive knowledge-based planning for stereotactic radiosurgery – pre-clinical validation through blinded physician review

Publication date: Available online 19 April 2017
Source:Practical Radiation Oncology
Author(s): B.P. Ziemer, S. Shiraishi, J.A. Hattangadi-Gluth, P. Sanghvi, K.L. Moore
PurposeAs knowledge-based planning (KBP) attempts to augment and potentially supplant manual treatment planning, it is imperative to ensure any implementation maintains or improves overall plan quality in any disease site. The purpose of this study was to demonstrate the overall quality of KBP-driven automated stereotactic radiosurgery (SRS) treatment planning using blinded physician comparison and determine systematic factors predictive of physician plan preference to guide future KBP refinement.MethodsAutomated non-coplanar volume modulated arc therapy KBP routines were developed for 199 plans across three clinical SRS scenarios: isolated lesions (ISOLATED), lesions closely abutting (<3 cm) organs-at-risk (INVOLVED) and single-isocenter multiple metastases (MULTIMET). Overall plan quality and preference were assessed via blinded review of the plans by two SRS physicians. Quantitative quality metrics (QMs) were also compared to determine systematic differences in the treatment plans. Multiple parameters were investigated as predictors of KBP plan selection.ResultsFor the ISOLATED, INVOLVED and MULTIMET scenarios, the KBP plans were considered to be superior or equivalent to clinical plans 86.7%(91/105), 81.1%(43/53) and 78.1%(32/41) of the time, respectively. All investigated QMs were equivalent or indicated more sparing for all KBP plans. The only non-dosimetric predictor was PTV volume in the ISOLATED (p=0.02) and INVOLVED (p=0.05) groups. The dosimetric predictors for the ISOLATED group were gradient measure and heterogeneity index (both p<0.01). In the MULTIMET category, the only significant dosimetric predictor was inter-lesion dose (p=0.01).ConclusionsThe fully automated KBP SRS plans were equivalent or superior to previously treated plans in 83.4%(166/199) of cases. In clinical implementation, geometric features found to be predictive of KBP performance can be used to identify plans where KBP results might benefit from further refinement, while dosimetric predictive features could be used to further refine KBP optimization priorities.

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Preoperative versus Postoperative Radiotherapy in Localized Soft Tissue Sarcoma: Nationwide Patterns of Care and Trends in Utilization

Potential Abscopal Response to Dual Checkpoint Blockade in RCC After Re-Irradiation Using Dose Painting SBRT

Fully-automated, comprehensive knowledge-based planning for stereotactic radiosurgery – pre-clinical validation through blinded physician review

Mindfulness and its efficacy for psychological and biological responses in women with breast cancer

Abstract

Many breast cancer survivors have to deal with a variety of psychological and physiological sequelae including impaired immune responses. The primary purpose of this randomized controlled trial was to determine the efficacy of a mindfulness-based stress reduction (MBSR) intervention for mood disorders in women with breast cancer. Secondary outcomes were symptom experience, health status, coping capacity, mindfulness, posttraumatic growth, and immune status. This RTC assigned 166 women with breast cancer to one of three groups: MBSR (8 weekly group sessions of MBSR), active controls (self-instructing MBSR) and non-MBSR. The primary outcome measure was the Hospital Anxiety and Depression Scale. Secondary outcome measures were: Memorial Symptom Assessment Scale, SF-36, Sense of Coherence, Five Facets of Mindfulness Questionnaire, and Posttraumatic Growth Index. Blood samples were analyzed using flow cytometry for NK-cell activity (FANKIA) and lymphocyte phenotyping; concentrations of cytokines were determined in sera using commercial high sensitivity IL-6 and IL-8 ELISA (enzyme-linked immunosorbent assay) kits. Results provide evidence for beneficial effects of MBSR on psychological and biological responses. Women in the MBSR group experienced significant improvements in depression scores, with a mean pre-MBSR HAD-score of 4.3 and post-MBSR score of 3.3 (P = 0.001), and compared to non-MBSR (P = 0.015). Significant improvements on scores for distress, symptom burden, and mental health were also observed. Furthermore, MBSR facilitated coping capacity as well as mindfulness and posttraumatic growth. Significant benefits in immune response within the MBSR group and between groups were observed. MBSR have potential for alleviating depression, symptom experience, and for enhancing coping capacity, mindfulness and posttraumatic growth, which may improve breast cancer survivorship. MBSR also led to beneficial effect on immune function; the clinical implications of this finding merit further research.

MBSR alleviates depression and symptom experience and enhance coping capacity which may improve breast cancer survivorship. MBSR also led to changes in immune response.

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Mindfulness and its efficacy for psychological and biological responses in women with breast cancer

Abstract

MBSR alleviates depression and symptom experience and enhance coping capacity which may improve breast cancer survivorship. MBSR also led to changes in immune response.

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Endothelium originated from colorectal cancer stem cells constitute cancer blood vessels

Abstract

Tumor growth depends on the formation of blood vessels that provide the supply of nutrients and oxygen. Previous data have shown that glioblastoma stem cells are able to give rise to vascular cells to constitute the functional vessels in tumor tissues. However, which kinds of vascular cells generated from glioblastoma stem cells are largely debated. In addition, there is little evidence showing that the stem cells from other kinds of tumors can produce vascular cells to constitute the functional blood vessels in tumor tissues. Here we show that cancer stem cells of human colorectal carcinomas (CoCSCs) can give rise to vascular endothelial cells and compose the vasculatures in cancer tissues. The human-cell-specific nuclear antigen NuMA⁺ vascular endothelial cells were detected in the blood vessels in xenografts derived from CoCSCs. NuMA⁺ ECs incorporated into functional blood vessels. Our data indicate that the cancer stem cells derived from human colorectal carcinomas have the capacity to generate functional blood vessels and provide a new mechanism for tumor vasculogenesis in carcinoma.

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Endothelium originated from colorectal cancer stem cells constitute cancer blood vessels

Abstract

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Phase I Study of Fenretinide Delivered Intravenously in Patients with Relapsed or Refractory Hematologic Malignancies: a California Cancer Consortium Trial.

Purpose: A phase I study was conducted to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of fenretinide delivered as an intravenous emulsion in relapsed/refractory hematologic malignancies. Experimental Design: Fenretinide (80 - 1810 mg/m²/day) was administered by continuous infusion on Days 1 - 5, in 21-day cycles, using an accelerated titration design. Results: Twenty-nine patients, treated with a median of three prior regimens (range, 1 to 7), were enrolled and received test drug. 97 courses were completed. An MTD was reached at 1280 mg/m²/day x 5 days. Course 1 DLTs included six patients with hypertriglyceridemia, four of which were asymptomatic; two patients experienced DLT thrombocytopenia (asymptomatic). Of eleven response-evaluable peripheral T-cell lymphomas, two had complete responses (CR, PFS 68+ months; unconfirmed CR, PFS 14+ months), two had unconfirmed partial responses (unconfirmed PR, PFS 5 months; unconfirmed PR, PFS 6 months), and five had stable disease (2 - 12 cycles). One mature B-cell lymphoma had an unconfirmed PR sustained for two cycles. Steady-state plasma levels were ~10 mcg/mL (mid-20's μmol/L) at 640 mg/m²/day; ~14 mcg/mL (mid-30's μmol/L) at 905 mg/m²/day; and ~22 mcg/mL (mid-50's μmol/L) at 1280 mg/m²/day. Conclusions: Intravenous fenretinide obtained significantly higher plasma levels than a previous capsule formulation, had acceptable toxicities, and evidenced anti-tumor activity in peripheral T-cell lymphomas. A recommended phase II dosing is 600 mg/m² on Day 1, followed by 1200 mg/m² on Days 2 - 5, every 21 days. A registration-enabling phase II study in relapsed/refractory PTCL (ClinicalTrials.gov identifier: NCT02495415) is ongoing.

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Monitoring Daily Dynamics of Early Tumor Response to Targeted Therapy by Detecting Circulating Tumor DNA in Urine

Purpose: Non-invasive drug biomarkers for the early assessment of tumor response can enable adaptive therapeutic decision-making and proof-of-concept studies for investigational drugs. Circulating tumor DNA (ctDNA) is released into the circulation by tumor cell turnover and has been shown to be detectable in urine. Experimental Design: We tested the hypothesis that dynamic changes in epidermal growth factor receptor (EGFR) activating (exon 19del and L858R) and resistance (T790M) mutation levels detected in urine could inform tumor response within days of therapy for advanced non-small cell lung cancer (NSCLC) patients receiving osimertinib, a second line third generation anti-EGFR tyrosine kinase inhibitor. Results: Eight of nine evaluable NSCLC patients had detectable T790M-mutant DNA fragments in pre-treatment baseline samples. Daily monitoring of mutations in urine indicated a pattern of intermittent spikes throughout week 1 suggesting apoptosis with an overall decrease in fragment numbers between baselines to day 7 preceding radiographic response assessed at 6-12 weeks. Conclusions: These findings suggest drug-induced tumor apoptosis within days of initial dosing. Daily sampling of ctDNA may enable early assessment of patient response and proof-of-concept studies for drug development.

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A zebrafish model discovers a novel mechanism of stromal fibroblast-mediated cancer metastasis

Purpose: Cancer metastasis can occur at the early stage of tumor development when a primary tumor at the microscopic size. In particular, the interaction of malignant cells with other cell types including cancer-associated fibroblasts (CAFs) in promoting metastasis at the early stage of tumor development remains largely unknown. Here, we investigated the role of CAFs in facilitating the initial events of cancer metastasis when primary tumors were at microscopic sizes. Experimental design: Multi-color-coded cancer cells and CAFs were co-implanted into the transparent zebrafish body and metastasis at a single cell level was monitored in living animals. Healthy fibroblasts, tumor factor-educated fibroblasts, and CAFs isolated from various tumors were tested for their ability to facilitate metastasis. Results: We showed that CAFs promoted cancer cell metastasis at the very early stage during primary tumor development. When a primary tumor at the microscopic size consisting of a few hundred cells, CAFs were able to hijack cancer cells for dissemination from the primary site. Surprisingly, a majority of metastatic cancer cells remained tight association with CAFs in the circulation. Furthermore, stimulation of non-metastasis-promoting normal fibroblasts with TGF-B, FGF-2, HGF, and PDGF-BB led to acquisition of their metastatic capacity. Conclusions: Cancer metastasis occurs at the very early stage of tumor formation consisting of only a few hundred of cells. CAFs are the key cellular determinant for metastasis. Our findings provide novel mechanistic insights on CAFs in promoting cancer metastasis and targeting CAFs for cancer therapy should be aimed at the early stage during cancer development.

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Low Tumor Mitochondrial DNA Content is Associated with Better Outcome in Breast Cancer Patients Receiving Anthracycline-based Chemotherapy

Purpose: In this study, we aimed to explore whether low levels of mitochondrial DNA (mtDNA) content in the primary tumor could predict better outcome for breast cancer patients receiving anthracycline-based therapies. We hypothesized that tumor cells with low mtDNA content are more susceptible to mitochondrial damage induced by anthracyclines, and thus are more susceptible to anthracycline treatment. Experimental Design: We measured mtDNA content by a quantitative PCR approach in 295 primary breast tumor specimens originating from two well-defined cohorts: 174 lymph node-positive patients who received adjuvant chemotherapy and 121 patients with advanced disease who received chemotherapy as first-line palliative treatment. The chemotherapy regimens given were either anthracycline-based (FAC/FEC) or methotrexate-based (CMF). Results: In both the adjuvant and advanced setting, we observed increased benefit for patients with low mtDNA content in their primary tumor, but only when treated with FAC/FEC. In multivariable Cox regression analysis for respectively distant metastasis-free survival and progression-free survival, the hazard ratio for the FAC/FEC treated mtDNA low group in the adjuvant setting was 0.46 (95% confidence interval (CI) 0.24-0.89, P = 0.020) and in the advanced setting 0.49 (95% CI 0.27-0.90, P = 0.022) compared to the FAC/FEC treated mtDNA high group. We did not observe these associations in the patients treated with CMF. Conclusions: In our two study cohorts, breast cancer patients with low mtDNA content in their primary tumor have better outcome from anthracycline-containing chemotherapy. The frequently observed decrease in mtDNA content in primary breast tumors may be exploited by guiding chemotherapeutic regimen decision-making.

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Mitochondrial BAX determines the predisposition to apoptosis in human AML

Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death. Experimental design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort. Results: This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test-cohort of 48 AML patients, mitochondria-shifted BAX correlated with improved patient survival, FLT3-ITD status and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy. Conclusion: In this retrospective analysis of two independent AML cohorts, our data suggests that Bax localization may predict prognosis of AML patients and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final 'common path'.

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Intra- and Inter-Observer Reproducibility Assessment of PD-L1 Biomarker in Non-Small Cell Lung Cancer (NSCLC)

Purpose: Reliable and reproducible methods for identifying PD-L1 expression on tumor cells are necessary to identify responders to anti-PD-1 therapy. We tested the reproducibility of the assessment of PD-L1 expression in non-small cell lung cancer (NSCLC) tissue samples by pathologists. Experimental Design: NSCLC samples were stained with PD-L1 22C3 pharmDx™ kit using the Dako Autostainer Link 48 Platform. Two sample sets of 60 samples each were designed to assess inter- and intra-observer reproducibility considering 2 cut-points for positivity: 1% or 50% of PD-L1 stained tumor cells. A randomization process was used to obtain equal distribution of PD-L1 positive and negative samples within each sample set. Ten pathologists were randomly assigned to two subgroups. Subgroup 1 analyzed all samples on two consecutive days. Subgroup 2 performed the same assessments, except they received a one hour training session prior to the second assessment. Results: For intra-observer reproducibility, the overall percent agreement (OPA) was 89.7% (95%CI: 85.7; 92.6) for the 1% cut-point and 91.3% (95%CI: 87.6; 94.0) for the 50% cut-point. For inter-observer reproducibility, OPA was 84.2% (95%CI: 82.8; 85.5) for the 1% cut-point and 81.9% (95%CI: 80.4; 83.3) for the 50% cut-point, and Cohen's kappa coefficients were 0.68 (95%CI: 0.65; 0.71) and 0.58 (95%CI: 0.55; 0.62), respectively. The training was found to have no or very little impact on intra- or inter-observer reproducibility. Conclusions: Pathologists reported good reproducibility at both 1% and 50% cut-points. More adapted training could potentially increase reliability, in particular for samples with PD-L1 proportion scores around 50%.

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A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors

Purpose: Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and pro-inflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of ABC294640, a first-in-class orally-available inhibitor of SK2. Experimental Design: Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. Results: 22 patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting and fatigue. Among the four patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and two were unable to complete Cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the Recommended Phase II Dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. Conclusions: At 500 mg bid, ABC294640 is well tolerated and achieves biologically-relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.

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Pulsatile high-dose treatment with antiangiogenic tyrosine kinase inhibitors improves clinical antitumor activity

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ZEB1 expression in Chinese lower-grade gliomas

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Using 3D Organoid Cultures to Model Intestinal Physiology and Colorectal Cancer

Abstract

Purpose of Review

The three-dimensional (3D) structure of the intestine is a key determinant of differentiation and function; thus, preserving this architecture is an important consideration for studies of intestinal homeostasis and disease. Over the past decade, a number of systems for 3D intestinal organoid cultures have been developed and adapted to model a wide variety of biological phenomenon. We discuss the current state of intestinal and colorectal cancer (CRC) 3D modeling, the most common methods for generating organoid cultures, and how these have yielded insights into intestinal physiology and tumor biology.

Recent Findings

Organoids have been used to model numerous aspects of intestinal physiology and disease. Recent adaptations have further improved disease modeling and high-throughput therapeutic screening.

Summary

These studies show intestinal organoid models are a robust, highly tractable system which maintains many vital features of intestinal tissue, making them a pivotal step forward in the field of gastroenterology.

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Personalizing Colon Cancer Screening: Role of Age and Comorbid Conditions

Abstract

Purpose of Review

This review will discuss the impact of patient age and comorbidity on colorectal cancer (CRC) screening value.

Recent Findings

Society guidelines recommend CRC screening starting at age 50 in average-risk individuals, but there is less agreement about when screening should be discontinued. In clinical practice, CRC screening and follow-up recommendations among elderly patients appear to be driven more by chronological age than by comorbid illnesses. However, several studies have highlighted the interaction between age and comorbidity burden when selecting appropriate patients for CRC screening. Although CRC screening may be beneficial until age 75–80 years among patients with no comorbidity, it has only modest benefits at an early age in those with high comorbidity.

Summary

Clinicians should adopt the concept of "health-adjusted age" and identify "healthy elderly" patients who would benefit from CRC screening and the "unhealthy young" in whom the benefits of CRC screening are likely limited.

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Personalizing Maintenance Therapy in Metastatic Colorectal Cancer

Abstract

Purpose of Review

Current systemic management of MCRC should include periods of intensive and less intensive treatment or even complete stop. Different systemic post-induction strategies have been evaluated in many trials. The aim of this article is to review the available data on maintenance strategies in MCRC and potential options to personalize choice of the respective strategy.

Recent Findings

Despite the large variability of clinical trials conducted in this setting, it can be concluded that intermittent chemotherapy does not seem to be inferior to continuous chemotherapy if at least 3 months of intensive induction treatment is applied, and active maintenance seem to be superior to complete stop after at least 3 months of induction treatment in terms of PFS and may add some benefit in terms of OS. The choice of the respective maintenance strategy may be personalized taking into account disease and patient characteristic, choice of induction treatment and response, treatment tolerability and quality of life.

Summary

Patients with metastatic colorectal cancer and no options of secondary resection or local ablation should be considered for a personalized maintenance approach.

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Prognostic significance of TRAIL-R3 and CCR-2 expression in tumor epithelial cells of patients with early breast cancer

Abstract

Background

Tumor epithelial cells (TEpCs) and spindle-shaped stromal cells, not associated with the vasculature, of patients with early breast cancer express osteoprotegerin (OPG), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), receptor activator of nuclear factor kappa B ligand, stromal cell derived factor-1, interleukin-6, macrophage colony stimulating factor, chemokine (C-C motif) ligand-2 (CCL-2) and their receptors at significantly higher levels compared with non-neoplastic breast tissues. We evaluated the clinicopathological significance of these ligands and receptors in TEpC and spindle-shaped stromal cells, not associated with the vasculature, to determine their impact on prognosis of patients with early-stage breast cancer.

Methods

We conducted immunohistochemical analyses of protein expression in primary tumors of patients with early breast cancer and analyzed their association with standard prognostic parameters and clinical outcomes, including local relapse, metastatic recurrence, disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS).

Results

Elevated levels of TRAIL-R3 and chemokine (C-C motif) receptor 2 (CCR-2) in TEpCs and OPG and CCL-2 in stromal cells were significantly associated with a higher risk of metastasis (p = 0.032, p = 0.003, p = 0.038, and p = 0.049; respectively). Moreover, high expression of TRAIL-R3 and CCR-2 in TEpCs was associated with shorter DFS, MFS, and OS. High TRAIL-R3 expression in TEpCs was an independent prognostic factor for DFS and OS, and high CCR-2 expression in these cells was an independent prognostic factor for MFS.

Conclusions

High levels of TRAIL-R3 and CCR-2 expression in TEpCs identified patients with early breast cancer with poor outcomes.

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Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients

Abstract

Background

Bevacizumab combined with chemotherapy produces clinical durable response in 25–30% of recurrent glioblastoma patients. This group of patients has shown improved survival and quality of life. The aim of this study was to investigate changes in gene expression associated with response and resistance to bevacizumab combination therapy.

Methods

Recurrent glioblastoma patients who had biomarker-accessible tumor tissue surgically removed both before bevacizumab treatment and at time of progression were included. Patients were grouped into responders (n = 7) and non-responders (n = 14). Gene expression profiling of formalin-fixed paraffin-embedded tumor tissue was performed using RNA-sequencing.

Results

By comparing pretreatment samples of responders with those of non-responders no significant difference was observed. In a paired comparison analysis of pre- and posttreatment samples of non-responders 1 gene was significantly differentially expressed. In responders, this approach revealed 256 significantly differentially expressed genes (72 down- and 184 up-regulated genes at the time of progression). Genes differentially expressed in responders revealed a shift towards a more proneural and less mesenchymal phenotype at the time of progression.

Conclusions

Bevacizumab combination treatment demonstrated a significant impact on the transcriptional changes in responders; but only minimal changes in non-responders. This suggests that non-responding glioblastomas progress chaotically without following distinct gene expression changes while responding tumors adaptively respond or progress by means of the same transcriptional changes. In conclusion, we hypothesize that the identified gene expression changes of responding tumors are associated to bevacizumab response or resistance mechanisms.

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Contrast-enhanced US with Perfluorobutane(Sonazoid) used as a surveillance test for Hepatocellular Carcinoma (HCC) in Cirrhosis (SCAN): an exploratory cross-sectional study for a diagnostic trial

Abstract

Background

Ultrasonography (US) is widely used as a standard surveillance tool for patients who are at a high risk of having hepatocellular carcinoma (HCC); however, conventional B-mode US appears to be insufficient in order to ensure the early detection of HCC. Perfluorobutane allows very stable Kupffer phase imaging for at least 60 min, which is tolerable for examinations of the entire liver. The purpose of our study is to evaluate the added value of contrast-enhanced US using perfluorobutane to that of conventional B-mode US as an HCC surveillance tool for patients with liver cirrhosis.

Methods/Design

SCAN (Sonazoid-US for surveillance of hepatoCellulArcarciNoma) is a prospective, multi-institutional, diagnostic trial using an intra-individual comparison design in a single arm of patients. This study was approved by our five institutional review board and informed consent was obtained from all participating. We obtained consent for publication of these data (contrast enhanced US images, CT or MRI images, laboratory findings, age, sex) from all participating patients. All patients will undergo conventional B-mode US immediately followed by contrast-enhanced US. The standardized case report forms will be completed by operating radiologists after B-mode US and contrast-enhanced US, respectively. If any lesion(s) is detected, the likelihood of HCC will be recorded. The primary endpoints are a detection rate of early-stage HCC and a false referral rate of HCC. Intra-individual comparison using Mcnemar's test will be performed between B-mode US and contrast-enhanced US. The study will include 523 patients under HCC surveillance in five medical institutions in Korea.

Discussion

SCAN is the first study to investigate the efficacy of contrast-enhanced US in surveillance using two reciprocal endpoints specialized for the evaluation of a surveillance test. SCAN will provide evidence regarding whether patients can truly benefit from contrast-enhanced US in terms of the detection of early stage HCC while avoiding additional unnecessary examinations. In addition to the study protocol, we elaborate on potentially debatable components of SCAN, including the design of an intra-individual comparison study, study endpoints, composite reference standards, and indefinite imaging criteria regarding the likelihood of HCC.

Trial registration

The date of trial registration (ClincalTrials.gov: NCT02188901) in this study is July 3, 2014. The last patient enrolled in August 30, 2016 and follow up to see the primary end point is still ongoing. All authors have no other relationships/conditions/circumstances that present a potential conflict of interest of relationships. Our study protocol has undergone peer-review by the funding body (GE Healthcare). No other relationships/conditions/circumstances that present a potential conflict of interest. Also, we clearly stated in the 'competing interests' section of my manuscript.

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A Fluorescence in Situ Hybridization-Based Screen Allows Rapid Detection of Adverse Cytogenetic Alterations in Patients with Acute Myeloid Leukemia

Abstract

In adult acute myeloid leukemia (AML), the karyotype of the leukemic cell is among the strongest prognostic factors. The Medical Research Council (MRC) and the European LeukemiaNet (ELN) classifications distinguish between favorable, intermediate and adverse cytogenetic risk patients who differ in their treatment response and overall survival. Conventional cytogenetic analyses are a mandatory component of AML diagnostics but they are time-consuming; therefore, therapeutic decisions in elderly patients are often delayed. We investigated whether a screening approach using a panel of seven fluorescence in situ hybridization (FISH) probes would allow rapid identification of adverse chromosomal changes. In a cohort of 334 AML patients, our targeted FISH screening approach identified 80% of adverse risk AML patients with a specificity of 99%. Incorporating FISH screening into diagnostic workup has the potential to accelerate risk stratification and treatment selection, particularly in older patients. This approach may allow therapeutic decisions more quickly, which benefits both patients and physicians and might save costs. This article is protected by copyright. All rights reserved.

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Prognostic significance of TRAIL-R3 and CCR-2 expression in tumor epithelial cells of patients with early breast cancer

Abstract

Background

Methods

Results

Conclusions

High levels of TRAIL-R3 and CCR-2 expression in TEpCs identified patients with early breast cancer with poor outcomes.

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Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients

Abstract

Background

Methods

Results

Conclusions

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Contrast-enhanced US with Perfluorobutane(Sonazoid) used as a surveillance test for Hepatocellular Carcinoma (HCC) in Cirrhosis (SCAN): an exploratory cross-sectional study for a diagnostic trial

Abstract

Background

Methods/Design

Discussion

Trial registration

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Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment

Through high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify SNPs associated with the response to imati...

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Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels

Grb2-associated binder 2 (Gab2) is a scaffolding protein that serves as a critical signaling amplifier downstream of tyrosine kinase receptors. Our previous study has shown that Gab2 induces epithelial-to-mese...

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A Fluorescence in Situ Hybridization-Based Screen Allows Rapid Detection of Adverse Cytogenetic Alterations in Patients with Acute Myeloid Leukemia

Abstract

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eEF2K promotes progression and radioresistance of esophageal squamous cell carcinoma

To investigate the biological function of eEF2K in esophageal squamous cell carcinoma (ESCC).

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Relation between diarrhea and infection by protozoans in dairy calves

Abstract

Infections caused by protozoa often cause diarrhea in newborn calves, leading to high economic losses to dairy farms, diarrhea, often characterized by malabsorption of nutrients, may lead to malnutrition, weight loss, and high mortality rates. Diarrhea is a common clinical sign found in the first days of a calf life in many dairy and beef cattle farms. Therefore, the aim of our study was to verify if during the first 60 days of live, there was a relationship between the presence of Eimeria, Cryptosporidium, Giardia, and the occurrence of diarrhea in calves, and the association of age and parasite presence. In this study, newborn calves were selected from farms with history of protozoa infections and diarrhea. A total of 26 calves were used in the study, 18 were positives for Giardia spp., 17 for Emeria spp., and 21 for Cryptosporidium spp., considering single and mixed infections. Furthermore, the survival rate of calves due to the presence of diarrhea was significantly different compared to the group without diarrhea, for all three protozoa. In addition, according to this study, it is possible to indicate that the occurrence of diarrhea is highly correlated to the presence of Giardia sp., leading to economic losses due to a low performance and weight gain of infected animals.

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Potential pathogens in infertile male dromedary camels and their association with the spermiogram and clinical findings

Abstract

The role of five pathogens potentially implicated in the reproductive failure of 141 male dromedary camels was investigated. Breeding soundness examinations, which included semen analysis and testicular histopathology of the infertile male camels, were compared with seven camels of normal fertility. Antibodies against Chlamydia abortus (C. abortus) and Toxoplasma gondii (T. gondii) were detected using the ELISA assay. Antibodies against Trypanosoma evansi (T. evansi) were identified using the card agglutination test. The Rose Bengal plate agglutination test was used to detect Brucella species. Preputial swabs were cultured for the presence of Campylobacter fetus (C. fetus). The incidence of positive titers of C. abortus and T. evansi, and the incidence of positive culture of C. fetus was found to be 13.5, 10.6, and 7.8%, respectively. T. evansi was more prevalent in younger (5–7 years) than older (more than 7 years) camels (p = 0.02). Most of the semen characteristics were negatively affected in the camels exposed to C. abortus and T. evansi (p = 0.05). T. evansi, C. fetus, and C. abortus may have a role in lowering the reproductive efficiency of male dromedaries. However, further diagnostic techniques are recommended to confirm their association with lowered fertility in this species.

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Identifying a subset of patients with DCIS who have a low likelihood of residual disease at surgical excision following a core needle biopsy

Background and Objectives

Current randomized controlled trials are investigating the outcomes of non-surgical treatment for patients with ductal carcinoma in situ (DCIS). We sought to evaluate pre-operative factors associated with no residual disease at definitive resection following a core needle biopsy (CNB) diagnosis of DCIS.

Methods

Eight hundred and thirty-four operations for DCIS were performed at our institution between January 2004 and October 2014. We evaluated patient and biopsy tumor characteristics to determine pre-operative factors associated with no residual disease at surgical resection using uni- and multivariable analyses.

Results

Sixty-nine patients (8%) had no residual disease on final pathology. On multivariable analysis, low- or intermediate-grade lesions, <1 cm in size on mammography, and lesions where ≥90% of calcifications were removed correlated with finding no residual disease on final pathology, c-statistic 0.84. Of the 14 patients with all three low-risk factors, 36% had no residual disease on final pathology.

Conclusions

Although our multivariable analysis performed well, its clinical utility would be limited as we were unable to identify a subset of patients with DCIS in whom the probability of finding no residual disease is low enough to consider routine use of non-surgical management.

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Dedifferentiated chondrosarcoma: A survival analysis of 159 cases from the SEER database (2001-2011)

Background and Objectives

Dedifferentiated chondrosarcoma is a rare malignancy with reported 5-year overall survival rates ranging from 7% to 24%. The purpose of this investigation is to determine the overall survival of dedifferentiated chondrosarcoma in a modern patient series and how it is impacted by patient demographics, tumor characteristics, and surgical treatment factors.

Methods

This is a retrospective review of the Surveillance, Epidemiology, and End Results (SEER) database from 2001 to 2011. Kaplan Meier analyses were used for overall and disease-specific survival. Univariable and multivariable cox regression models were used to identify prognostic factors.

Results

Five year overall- and disease-specific survival was 18% (95% CI: 12-26%) and 28% (95% CI: 18-37%), respectively. Individuals with extremity tumors had a worse prognosis than individuals with a primary tumor in the chest wall or axial skeleton (HR 0.20, 95% CI: 0.07-0.56; P = 0.002 and HR 0.60, 95% CI: 0.36-0.99; P = 0.04, respectively). Patients with AJCC stage III or IV disease (HR 2.51, 95% CI: 1.50-4.20; P = 0.001), tumors larger than 8 cm (HR 2.17, 95% CI: 1.11-4.27; P = 0.046), metastatic disease at diagnosis (HR 3.25, 95% CI: 1.98-5.33; P < 0.001), and those treated without surgical resection (amputation: HR 0.43, 95% CI 0.23-0.80; P = 0.01; limb salvage/non-amputation resection: HR 0.41, 95% CI: 0.24-0.69; P = 0.001) had a significant increase in risk of mortality.

Conclusions

The overall prognosis of dedifferentiated chondrosarcoma is poor with a 5-year overall survival of 18%. Patients with a primary tumor located in the chest wall had a better prognosis. Tumors larger than 8 cm, presence of metastases at diagnosis, and treatment without surgical resection were significant predictors of mortality.

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Does surgery or radiation provide the best overall survival in Ewing's sarcoma? A review of the National Cancer Data Base

Background and Objectives

There is continuing debate regarding the ideal modality for local control of the primary tumor for patients with Ewing's sarcoma. The primary aim of this study is to investigate the impact of the method of local control on overall survival in patients with Ewing's sarcoma.

Methods

The National Cancer Data Base was used to identify patients <40 years of age with high-grade Ewing's sarcoma of bone. A Kaplan-Meier survival analysis was performed at 2, 5, and 10 years. Factors with a level of significance of P < 0.1 at the 5-year time point were included in a multivariate Cox proportional hazards model.

Results

Diminished 5-year survival was noted for patients with metastatic disease, local control with radiation alone, age ≥18 years, tumor size >8 cm, and male sex while controlling for tumor site. Surgery alone was consistently the method of local control that resulted in the highest overall survival.

Conclusions

Surgery alone resulted in the best overall survival for patients with Ewing's sarcoma of bone. The results of this investigation provide support to the approach of surgical resection with negative margins when possible.

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Prospective series of reconstruction of complex composite mandibulectomy defects with double island free fibula flap

Background: A double island free fibula (DIFF) flap can be used for reconstruction of through-and-through or complex mandibulectomy defects, but prospective studies are lacking.

Methods: Prospective analysis of all double skin paddle fibula flaps performed from 2010 to 2016.

Results: Overall, 16 patients underwent reconstruction with a DIFF flap (average age: 59.1 years). One patient, who underwent a DIFF flap and developed osteoradionecrosis, requiring a second flap. Thirteen patients were males, and 7 had a history of smoking, 13 had prior radiation, and 14 had prior chemotherapy. The most common primary pathology was squamous cell carcinoma (n = 13). Reconstruction using the DIFF was predominantly for mandible reconstruction with one patient undergoing reconstruction following a orbitomaxillectomy. Complications included infection (n = 2), hematoma (n = 1), and donor site complications were limited. Two patients developed venous congestion requiring re-exploration, and both flaps were successfully salvaged. One patient lost the external skin paddle requiring a pectoralis muscle flap, and there were no total flap losses.

Conclusions: The DIFF flap is a reliable option that can reconstruct complex composite defects often obviating the need for a second free flap, thereby decreasing operating time, added donor site morbidity, and the need for additional recipient vessels.

http://ift.tt/2olhSGq

Utilizing Salmonella to treat solid malignancies

Despite intensive research into novel treatment strategies for cancer, it remains the second most common cause of death in industrialized populations. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with dismal prognosis. Currently, surgical resection offers the best chance for extended survival, yet recurrence remains high and is associated with poor outcome. Systemic treatment has evolved from non-specific, cytotoxic chemotherapy to the use of cancer-targeting agents, profoundly changing treatment approaches in the metastatic and adjuvant settings. One promising approach, highlighted in this review, uses the inherent capacity of Salmonella to colonize and eliminate solid tumors.

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Semi-end-to-end esophagojejunostomy after laparoscopy-assisted total gastrectomy better reduces stricture and leakage than the conventional end-to-side procedure: A retrospective study

Background and Objective

Laparoscopy-assisted total gastrectomy (LATG) has not gained popularity due to the technical difficulty of esophagojejunostomy (EJ) and the high incidence of EJ-related complications. Herein, we compared two types of EJ for Roux-en-Y reconstruction to determine whether semi-end-to-end (SETE) EJ is more convenient than the end-to-side (ETS) procedure and is capable of reducing stricture and leakage.

Methods

A total of 268 patients who underwent LATG with Roux-en-Y reconstruction were included in this study. Two types of EJ were applied for LATG: conventional ETS EJ and SETE EJ. The surgical outcomes and postoperative complications were compared.

Results

The mean reconstruction time in the SETE group was shorter than that in the ETS group (41.6 ± 8.0 min vs 51.3 ± 9.2 min, P = 0.000). The incidences of total EJ-related complications, EJ leakage, and EJ stricture in the SETE group and ETS group were 1.1% (1/92) and 10.2% (18/176), 1.1% (1/92) and 4.0% (7/176), and 0 and 6.2% (11/176), respectively. The incidence of total EJ-related complications in the SETE group was lower than that of the ETS group (P = 0.006), and the incidence of EJ stricture in the SETE group was lower than that of the ETS group (P = 0.034).

Conclusions

SETE EJ is more convenient than the conventional ETS procedure and is associated with a shorter reconstruction time and a lower incidence of EJ stricture and leakage.

http://ift.tt/2ol7636

Identifying a subset of patients with DCIS who have a low likelihood of residual disease at surgical excision following a core needle biopsy

Background and Objectives

Methods

Results

Conclusions

http://ift.tt/2pxW3rn

Dedifferentiated chondrosarcoma: A survival analysis of 159 cases from the SEER database (2001-2011)

Background and Objectives

Methods

Results

Conclusions

http://ift.tt/2ol1FkF

Does surgery or radiation provide the best overall survival in Ewing's sarcoma? A review of the National Cancer Data Base

Background and Objectives

Methods

Results

Conclusions

http://ift.tt/2py4B1k

Prospective series of reconstruction of complex composite mandibulectomy defects with double island free fibula flap

Background: A double island free fibula (DIFF) flap can be used for reconstruction of through-and-through or complex mandibulectomy defects, but prospective studies are lacking.

Methods: Prospective analysis of all double skin paddle fibula flaps performed from 2010 to 2016.

http://ift.tt/2olhSGq

Utilizing Salmonella to treat solid malignancies

http://ift.tt/2pxOuk5

Semi-end-to-end esophagojejunostomy after laparoscopy-assisted total gastrectomy better reduces stricture and leakage than the conventional end-to-side procedure: A retrospective study

Background and Objective

Methods

Results

Conclusions

SETE EJ is more convenient than the conventional ETS procedure and is associated with a shorter reconstruction time and a lower incidence of EJ stricture and leakage.

http://ift.tt/2ol7636

Identifying a subset of patients with DCIS who have a low likelihood of residual disease at surgical excision following a core needle biopsy

Background and Objectives

Methods

Results

Conclusions

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Dedifferentiated chondrosarcoma: A survival analysis of 159 cases from the SEER database (2001-2011)

Background and Objectives

Methods

Results

Conclusions

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Does surgery or radiation provide the best overall survival in Ewing's sarcoma? A review of the National Cancer Data Base

Background and Objectives

Methods

Results

Conclusions

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Prospective series of reconstruction of complex composite mandibulectomy defects with double island free fibula flap

Background: A double island free fibula (DIFF) flap can be used for reconstruction of through-and-through or complex mandibulectomy defects, but prospective studies are lacking.

Methods: Prospective analysis of all double skin paddle fibula flaps performed from 2010 to 2016.

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Utilizing Salmonella to treat solid malignancies

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Semi-end-to-end esophagojejunostomy after laparoscopy-assisted total gastrectomy better reduces stricture and leakage than the conventional end-to-side procedure: A retrospective study

Background and Objective

Methods

Results

Conclusions

SETE EJ is more convenient than the conventional ETS procedure and is associated with a shorter reconstruction time and a lower incidence of EJ stricture and leakage.

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Apple body type information improves validity of the STOP-BANG questionnaire for detecting obstructive sleep apnea

I read with interest the article, entitled "Incorporating body-type (apple vs. pear) in STOP-BANG questionnaire improves its validity to detect OSA", by Sangkum and colleagues [1]. The authors conducted a validation study by adding extra item of "apple body type" to the STOP-BANG questionnaire for detecting obstructive sleep apnea (OSA). The authors used sleep polysomnography (PSG) as a gold standard of OSA. The authors concluded that adding the body type item to the STOP-BANG questionnaire improved not only prediction of OSA but also moderate-severe OSA by presenting odds ratio from logistic regression analysis.

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Inattentional blindness - Do we really see what we see?

Vigilance is essential to safe anesthesia care. The ability for the anesthesiologist to note clinical change, analyze the events and take effective and timely action is critical to our practice. In this study, Dr. Ho and colleagues turn our attention to an understudied phenomenon- inattentional blindness [1]. This is defined as the failure to note events or actions that are in plain view, especially when that event is unexpected [2]. In this study, practicing academic anesthesiologists and medical students were asked to report on any abnormal vital signs or activities in a video of a simulated patient.

http://ift.tt/2oJydHM

The effect of dexmedetomidine on renal function in patients undergoing cardiac valve replacement under cardiopulmonary bypass: A double-blind randomized controlled trial

We attempted to explore the effect of Dex on renal function in patients with cardiac valve replacement under cardiopulmonary bypass (CPB).

http://ift.tt/2pPJYdl

Pediatric sleep-disordered breathing: an update on diagnostic testing.

Purpose of review: Recent advances in diagnostic testing for obstructive sleep apnea in children have refined the standard tests while identifying several new tools that hold promise to radically change how we diagnose sleep apnea. Recent findings: Studies have demonstrated that the polysomnogram may be modified to permit home assessment of sleep disturbed breathing in children to ensure more widespread access to the test. Alternately, questionnaires, nocturnal oximetry, and diagnostic urinary biomarkers have shown great promise as both sensitive and specific tools to diagnose sleep apnea in children as well as track the severity of the disease. Summary: The gold standard polysomnogram has been refined to permit its application in a modified form at home and for brief examinations in children. This standard has been challenged on several fronts, including questionnaires, nocturnal oximetry, drug-induced sleep endoscopy, and noninvasive urinary biomarkers that may ultimately supplant polysomnography as the gold standard to diagnose obstructive sleep apnea syndrome in children. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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The implications of immunization in the daily practice of pediatric anesthesia.

Purpose of review: Vaccination is an important prevention measure, but requires an intact immune system. Surgery and anesthesia suppress the immune system and may interfere with the benefits of immunization. Moreover, common vaccine side-effects may be misinterpreted as postsurgical complications. This review summarizes the essential basis of immunization and its potential interactions with anesthesia. Recent findings: Vaccines have mild side-effects, such as fever, but may lead to serious complications in immunocompromised patients. Surgery and anesthesia may decrease the efficacy of a vaccine, or promote vaccine-related complications. It, therefore, reasonable to schedule surgery and anesthesia with a delay either before or after vaccine administration, but there is no consensus among anesthesiologists and pediatricians regarding this timing. Summary: Inactive vaccines are generally well tolerated. Live vaccines provide an effective and long-lasting immunization, but may carry more serious complications. Elective operations should be postponed 1 week after an inactive vaccine and 3 weeks after immunization with a live vaccine. To avoid misinterpretation of vaccine-related side-effects, vaccination should be also delayed after surgery. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2oKODhp

Mentor Spotlight: Elva M. Arredondo, PhD

Lilian G. Perez, MPH, a fifth-year PhD Candidate, shares how being mentored by Elva M. Arredondo, PhD, a Professor in the Division of Health Promotion and Behavioral Science at San Diego State University, has positively influenced her career development.

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Concurrent Chemoradiotherapy in the Adjuvant Treatment of High-risk Primary Salivary Gland Malignancies.

Objectives: Adjuvant radiation therapy (RT) is indicated for patients with salivary gland malignancies with risk factors for recurrence following resection. We analyzed patients treated with adjuvant RT with or without concurrent chemotherapy to determine the impact of prognostic and treatment factors. Materials and Methods: Retrospective analysis was performed of 128 patients treated with surgical resection followed by intensity-modulated radiotherapy. In total, 31 (24.2%) patients were treated with concurrent chemoradiotherapy. The Kaplan-Meier method was used to estimate rates of progression-free survival (PFS), local-regional control, distant control, overall survival. Multivariable Cox regression was performed to evaluate factors significant on univariate analysis. Results: The 5-year rates of PFS, local-regional control, freedom-from distant metastasis, and overall survival were 61.2%, 85.8%, 76.5%, and 73.7%, respectively. Predictors of decreased PFS on univariate analyses were age, tumor stage, nodal stage, positive surgical margins, histology, high grade, perineural invasion, lymphovascular space invasion, extranodal extension, and use of chemoradiotherapy. On multivariable analysis, elevated T-stage, positive surgical margins, and presence of extranodal extension were predictive of decreased PFS. The acute toxicity rates were 30.3% grade 1, 51.5% grade 2, 11.4% grade 3, and 0.8% grade 4. There was no difference in rates of grade 3 or higher acute toxicity with use of RT alone versus chemoradiotherapy (P=0.183). Conclusions: Use of chemoradiotherapy for adjuvant treatment of salivary gland malignancies was well-tolerated, but no improvement in survival was seen with the use of chemoradiotherapy in both the overall study population and a subset with high-risk features. Caution should be used when using this modality until randomized evidence becomes available. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment

Abstract

Background

Through high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify SNPs associated with the response to imatinib administered for first-line treatment of patients with chronic myeloid leukemia.

Methods

In silico analysis using publicly available databases was done to select the SLC and ABC genes and their promoters for the next-generation sequencing. SNPs associated with the imatinib response were identified using Fisher's exact probability tests and subjected to the linkage disequilibrium analyses with regulatory loci of concerned genes. We analyzed cumulative achievement of major molecular response and probability of event free survival in relation to identified SNP genotypes in 129 CML patients and performed multivariate analysis for determination of genotypes as independent predictors of outcome. Gene expression analysis of eight cell lines naturally carrying different genotypes was performed to outline an impact of genotypes on the gene expression.

Results

We observed significant differences in the frequencies of the rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers that were associated with optimal and non-optimal responses, respectively. Loci rs460089 and rs2631365 were in highly significant linkage disequilibrium with 12 regulatory loci in introns of SLC22A4 and SLC22A5 encoding imatinib transporters. Genotype association analysis with the response to imatinib indicated that rs460089-GC carriers had a significantly higher probability of achieving a stable major molecular response (BCR-ABL1 transcript level below or equal to 0.1% in the international scale). In contrast, the rs460089-GG represented a risk factor for imatinib failure, which was significantly higher in rs460089-GG_rs2631365-TC carriers.

Conclusions

This exploratory study depicted potentially important genetic markers predicting outcome of imatinib treatment, which may be helpful for tailoring therapy in clinical practice.

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Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels

Abstract

Background

Grb2-associated binder 2 (Gab2) is a scaffolding protein that serves as a critical signaling amplifier downstream of tyrosine kinase receptors. Our previous study has shown that Gab2 induces epithelial-to-mesenchymal transition (EMT) and promotes metastasis in colorectal cancer (CRC). However, the role of Gab2 in CRC growth and angiogenesis remains unclear.

Methods

The expression of vascular endothelial growth factor (VEGF) in different colorectal tissues was detected by immunohistochemistry and qRT-PCR to evaluate its correlation with Gab2. Lentiviral vectors bearing Gab2 gene and its small interfering RNAs were constructed and transfected into CRC cell lines. The effects of Gab2 on the cell proliferation in vitro and tumorigenesis in vivo, were examined via CCK‑8 assay, colony formation assay as well as tumorigenicity assay respectively. Moreover, to assess its potential role in tumor growth and angiogenesis, the expression of Ki67, CD34 and vascular endothelial growth factor receptor-2 (VEGFR2) were detected by immunohistochemistry in CRC cells tumors. Finally, we evaluated the impact of Gab2 on the expression of c-Myc and VEGF, and the probable effect of mechanistic targeted extracellular signal-regulated kinase (ERK) pathway in suppressing tumor growth and angiogenesis.

Results

Up-regulation of Gab2 expression was found to be positively correlated with VEGF in CRC tissues. Exogenous expression of Gab2 obviously promoted, whereas silencing of Gab2 inhibited, proliferation and clone formation of human CRC cells in vitro. Of note, Gab2 enhanced tumorigenesis and tumor growth in mouse xenografts with high Ki67 expression, and led to an increased vessel density with strong CD34 and VEGFR2 activity. In addition, elevated Gab2 expression obviously up-regulated the expression of VEGF, and stimulated the activation of its downstream genes, ERK1/2 and c-Myc in CRC cells. Instead, down-regulated Gab2 expression significantly reduced the levels of VEGF, and inhibited the transduction of ERK/c-Myc pathway. Finally, we revealed that mechanistic target of mitogen-activated protein kinase (MEK) could attenuate Gab2-induced tumor growth and angiogenesis via altering VEGF and c-Myc levels.

Conclusions

The results from our study suggest that Gab2 promotes intestinal tumor growth and angiogenesis through upregulation of VEGF expression mediated by the MEK/ERK/c-Myc pathway.

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Predictive detection areas for identifying additional MRI-detected breast lesions on second-look ultrasonography

Abstract

Purpose

Identifying an additional MRI-detected breast lesion on second-look ultrasonography (US) is technically challenging because of lesion displacement with the patient's position change. The aim of this study is to help identify MRI-detected lesions on second-look US by developing a probing area, called "the predictive detection area" (PDA), and by assessing the PDA.

Methods

We measured the nipple-to-lesion distances (NLDs) for 16 breast lesions on prone- and supine-position MRI sets and calculated the difference and angle between the two NLD vectors, representing the lesion displacement. The minimum and maximum differences and angles were chosen to form the PDA. Another 22 breast lesions, detected in the prone MRI, were identified on US by probing the PDA to evaluate the probability of existence.

Results

The width between the minimum and maximum differences in two NLDs and the angle to form the PDA for the upper-inner, upper-outer, and lower-outer quadrants were 23.0 mm and 95.0°, 29.0 mm and 41.0°, and 18.0 mm and 17.0°, respectively. The respective probabilities of existence were 100, 80, and 100%.

Conclusions

The PDA had a high probability of existence and was acceptably accurate; therefore, the PDA in a second-look US has the potential to help operators to quickly identify additional MRI-detected lesions.

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Characteristics and prognosis of rectal gastrointestinal stromal tumors: an analysis of registry data

Abstract

Purpose

Rectal gastrointestinal stromal tumors (GISTs) are rare. Accordingly, their clinical features are not well-documented and optimal treatment has not been established. The objective of this study is to clarify the rates and patterns of recurrence after surgical resection of rectal GISTs, with a focus on outcomes and therapeutic modalities.

Methods

The registry was designed to collect data on rectal GISTs recorded between January, 2003 and December, 2007 at 40 participating institutions of the Kinki GIST Study Group. The principal variables were the rates and patterns of recurrence of rectal GISTs. Other study variables were age, sex, tumor size, mitotic count, distance from the anal verge, tumor location, surgical procedures, surgical margins, and recurrence-free survival.

Results

Twenty-four cases were registered, 11 (45.8%) of which were classified as high-risk by the modified NIH criteria. Locoregional recurrence (7/23, 30.4%) was the predominant recurrence pattern after curative resection, with rates that did not differ after local excision (33.3%; 3/9) vs. extended resection (28.6%; 4/14). The recurrence rates were high (25.0%) even for patients with low-risk disease. There was only one case of recurrence among patients who received perioperative treatment with imatinib.

Conclusions

Rectal GISTs showed high rates of local recurrence regardless of the surgical procedure. Perioperative treatment with imatinib may improve outcomes.

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TU-100 exerts a protective effect against bacterial translocation by maintaining the tight junction

Abstract

Purpose

We previously reported that TU-100 suppresses irinotecan hydrochloride (CPT-11)-induced inflammatory cytokines and apoptosis. However, the mechanism underlying this effect has not been fully elucidated. The aim of this study was to further clarify the mechanism of CPT-11-induced bacterial translocation (BT) and the effect of TU-100 on BT.

Methods

Cell cytotoxicity was assessed in vitro by a WST-8 assay. For the in vivo experiments, rats were randomly divided into 3 groups: the control group, the CPT-11 group (250 mg/kg i.p. for 2 days), and the CPT-11 and TU-100 co-treated group (1000 mg/kg, p.o. for 5 days). All of the rats were sacrificed on day 6 and their tissues were collected.

Results

CPT-11 and TU-100 co-treatment improved CPT-11 the related cytotoxicity in vitro. All CPT-11-treated rats developed different grades of diarrhea and BT was observed in 80% of the rats. CPT-11 caused a significant increase in the expression of TLR4, IL-6, TNF-α, IL-1β and caspase-3 mRNAs in the large intestine. The expression of tight junction (TJ) marker mRNAs (occludin, claudin-1 and 4, and ZO-1) was significantly decreased in comparison to the control group. TU-100 co-treatment significantly reversed diarrhea, BT, and the expression of TLR2, IL-6, TNF-α, IL-1β and caspase-3, and improved the expression of occludin, claudin-4 and ZO-1.

Conclusions

TU-100 can suppress the adverse effects associated with CPT-11 and improve the function of the TJ. It is possible that this occurs through the TLR pathway.

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The basal nutritional state of PDAC patients is the dominant factor for completing adjuvant chemotherapy

Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and several clinical trials have shown that adjuvant chemotherapy after curative resection can improve the prognosis of these patients. However, the adjuvant chemotherapy completion rate is less than satisfactory. If this rate could be increased then the overall prognosis of PDAC might be improved; however, reports addressing this problem are insufficient. To elucidate the factors, we retrospectively investigated PDAC patients.

Methods

Various factors of 121 PDAC patients undergoing R0 resection, including preoperatively treated patients, were investigated. Univariate and multivariate analyses were performed to investigate the factors that were associated with the completion of adjuvant chemotherapy.

Results

The analysis identified age and the prognostic nutritional index (PNI) as significant independent factors. A receiver operating characteristic curve analysis of age yielded a cutoff value of 67 years (sensitivity, 64%; specificity, 78%). Univariate and multivariate analyses of the 61 patients who were over 67 years of age revealed that the PNI (odds ratio, 0.85; P = 0.048) and Evans grade (odds ratio, 0.041; P = 0.0010) were significant factors for the completion of chemotherapy.

Conclusions

The results of our investigation suggest that nutrition should be controlled in older PDAC patients to facilitate the completion of adjuvant chemotherapy.

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