Chronic lesser tuberosity avulsion in an adolescent with an associated biceps pulley injury

Abstract

We report a case of a 15-year-old boy with chronic intermittent left shoulder pain due to an undiagnosed lesser tuberosity avulsion fracture, an associated biceps pulley injury and intra-articular dislocation of the long head of the biceps tendon. Lesser tuberosity avulsion fractures are rare injuries that are difficult to detect on clinical exam and radiographically, which may lead to delayed diagnosis and chronic shoulder instability. Few reports describe dislocations or subluxations of the biceps tendon in association with lesser tuberosity avulsions in children. We utilize this case to emphasize the importance of MR not only in detecting lesser tuberosity avulsions, but also in evaluating biceps pulley injuries, which are a rarely reported, but clinically important, association.

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Chronic lesser tuberosity avulsion in an adolescent with an associated biceps pulley injury

Abstract

We report a case of a 15-year-old boy with chronic intermittent left shoulder pain due to an undiagnosed lesser tuberosity avulsion fracture, an associated biceps pulley injury and intra-articular dislocation of the long head of the biceps tendon. Lesser tuberosity avulsion fractures are rare injuries that are difficult to detect on clinical exam and radiographically, which may lead to delayed diagnosis and chronic shoulder instability. Few reports describe dislocations or subluxations of the biceps tendon in association with lesser tuberosity avulsions in children. We utilize this case to emphasize the importance of MR not only in detecting lesser tuberosity avulsions, but also in evaluating biceps pulley injuries, which are a rarely reported, but clinically important, association.

http://ift.tt/2h4qMGm

Sensitivity of a prompt-gamma slit-camera to detect range shifts for proton treatment verification

A prompt-gamma imaging (PGI) slit-camera was recently applied successfully in clinical proton treatments using pencil beam scanning (PBS) and double scattering (DS). However, its full capability under clinical conditions has still to be systematically evaluated. Here, the performance of the slit-camera is systematically assessed in well-defined error scenarios using realistic treatment deliveries to an anthropomorphic head phantom.

http://ift.tt/2A7iPYI

Invitro Evaluation of Torin2 and 2, 6-Dihydroxyacetophenone in Colorectal Cancer Therapy

Abstract

Colorectal cancer (CRC) is one of the most prevalent cancers diagnosed worldwide. Despite recent advances, resistance to cytotoxic and targeted therapy remains one of the greatest challenges in long-term management of colorectal cancer therapy. Recently established role of mTOR signaling in proliferation of CRC has incited for evaluation of mTOR kinase specific inhibitors in CRC therapy. Second generation mTOR kinase inhibitors including Torin2 has demonstrated efficient anticancer properties against variety of cancers and are in various stages of drug development. The time and financial constraints concomitant from discovery to development of efficient chemical inhibitors has redirected attention towards investigation of wide spread naturally occurring largely inexpensive compounds for their therapeutic potential. One such naturally occurring compound acetophenone derivative polyphenolic compound 2, 6-Dihydroxyacetophenone (DHAP) inhibits cell growth in different conditions. We investigated anticancer properties of both Torin2 and DHAP against colorectal cancer in HCT8 cell lines. Both Torin2 and DHAP inhibited growth of CRC cells at different concentrations by restricting multiple cellular functions e.g., cell cycle progression, cell migration and induced apoptosis. Treatment of HCT8 cells with natural compound DHAP resulted in reduced expression of mTOR pathway specific genes p70S6K1 and AKT1. In silico docking studies showed affinity of DHAP to mTOR kinase like Torin2. Taken together, our result vouches for role of Torin2 in CRC therapy and recommends DHAP an mTOR inhibitor, as a potential lead in the development of new therapeutic regimes against colorectal cancer.

http://ift.tt/2lPBgyy

Invitro Evaluation of Torin2 and 2, 6-Dihydroxyacetophenone in Colorectal Cancer Therapy

Abstract

Colorectal cancer (CRC) is one of the most prevalent cancers diagnosed worldwide. Despite recent advances, resistance to cytotoxic and targeted therapy remains one of the greatest challenges in long-term management of colorectal cancer therapy. Recently established role of mTOR signaling in proliferation of CRC has incited for evaluation of mTOR kinase specific inhibitors in CRC therapy. Second generation mTOR kinase inhibitors including Torin2 has demonstrated efficient anticancer properties against variety of cancers and are in various stages of drug development. The time and financial constraints concomitant from discovery to development of efficient chemical inhibitors has redirected attention towards investigation of wide spread naturally occurring largely inexpensive compounds for their therapeutic potential. One such naturally occurring compound acetophenone derivative polyphenolic compound 2, 6-Dihydroxyacetophenone (DHAP) inhibits cell growth in different conditions. We investigated anticancer properties of both Torin2 and DHAP against colorectal cancer in HCT8 cell lines. Both Torin2 and DHAP inhibited growth of CRC cells at different concentrations by restricting multiple cellular functions e.g., cell cycle progression, cell migration and induced apoptosis. Treatment of HCT8 cells with natural compound DHAP resulted in reduced expression of mTOR pathway specific genes p70S6K1 and AKT1. In silico docking studies showed affinity of DHAP to mTOR kinase like Torin2. Taken together, our result vouches for role of Torin2 in CRC therapy and recommends DHAP an mTOR inhibitor, as a potential lead in the development of new therapeutic regimes against colorectal cancer.

http://ift.tt/2lPBgyy

Isolated right ventricular thrombus in an adult patient with nephrotic syndrome: a case report

Venous thrombosis in nephrotic syndrome is a well-described phenomenon. We report a case of an adult patient with an isolated thrombus in the right ventricle due to nephrotic syndrome, which was initially susp...

http://ift.tt/2y29ikR

Model-based optimization of G-CSF treatment during cytotoxic chemotherapy

Abstract

Purpose

Although G-CSF is widely used to prevent or ameliorate leukopenia during cytotoxic chemotherapies, its optimal use is still under debate and depends on many therapy parameters such as dosing and timing of cytotoxic drugs and G-CSF, G-CSF pharmaceuticals used and individual risk factors of patients.

Methods

We integrate available biological knowledge and clinical data regarding cell kinetics of bone marrow granulopoiesis, the cytotoxic effects of chemotherapy and pharmacokinetics and pharmacodynamics of G-CSF applications (filgrastim or pegfilgrastim) into a comprehensive model. The model explains leukocyte time courses of more than 70 therapy scenarios comprising 10 different cytotoxic drugs. It is applied to develop optimized G-CSF schedules for a variety of clinical scenarios.

Results

Clinical trial results showed validity of model predictions regarding alternative G-CSF schedules. We propose modifications of G-CSF treatment for the chemotherapies 'BEACOPP escalated' (Hodgkin's disease), 'ETC' (breast cancer), and risk-adapted schedules for 'CHOP-14' (aggressive non-Hodgkin's lymphoma in elderly patients).

Conclusions

We conclude that we established a model of human granulopoiesis under chemotherapy which allows predictions of yet untested G-CSF schedules, comparisons between them, and optimization of filgrastim and pegfilgrastim treatment. As a general rule of thumb, G-CSF treatment should not be started too early and patients could profit from filgrastim treatment continued until the end of the chemotherapy cycle.

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Model-based optimization of G-CSF treatment during cytotoxic chemotherapy

Abstract

Purpose

Although G-CSF is widely used to prevent or ameliorate leukopenia during cytotoxic chemotherapies, its optimal use is still under debate and depends on many therapy parameters such as dosing and timing of cytotoxic drugs and G-CSF, G-CSF pharmaceuticals used and individual risk factors of patients.

Methods

We integrate available biological knowledge and clinical data regarding cell kinetics of bone marrow granulopoiesis, the cytotoxic effects of chemotherapy and pharmacokinetics and pharmacodynamics of G-CSF applications (filgrastim or pegfilgrastim) into a comprehensive model. The model explains leukocyte time courses of more than 70 therapy scenarios comprising 10 different cytotoxic drugs. It is applied to develop optimized G-CSF schedules for a variety of clinical scenarios.

Results

Clinical trial results showed validity of model predictions regarding alternative G-CSF schedules. We propose modifications of G-CSF treatment for the chemotherapies 'BEACOPP escalated' (Hodgkin's disease), 'ETC' (breast cancer), and risk-adapted schedules for 'CHOP-14' (aggressive non-Hodgkin's lymphoma in elderly patients).

Conclusions

We conclude that we established a model of human granulopoiesis under chemotherapy which allows predictions of yet untested G-CSF schedules, comparisons between them, and optimization of filgrastim and pegfilgrastim treatment. As a general rule of thumb, G-CSF treatment should not be started too early and patients could profit from filgrastim treatment continued until the end of the chemotherapy cycle.

http://ift.tt/2y3B2Wb

Monitoring the estimated glomerular filtration rate (eGFR) in patients with small-cell lung cancer during chemotherapy: equations based on serum creatinine or cystatin C?

Abstract

Background

This study compared the differences between the estimated glomerular filtration rate (eGFR) calculated by several equations based on serum creatinine (Scr) and cystatin C (CysC) concentrations for monitoring renal function in patients with small-cell lung cancer (SCLC) during chemotherapy.

Methods

Seventy-one patients with SCLC were retrospectively analyzed. The eGFR before and after each chemotherapy cycle was calculated by the following equations: the chronic kidney disease epidemiology collaboration (CKD-EPI) equation, the modification of diet in renal disease (MDRD) equation, the Cockcroft–Gault (CG) equation, and five CysC-based equations. The patients were compared among the different eGFR groups.

Results

The mean decreases in eGFR_CKD-EPI (−2.25 ± 9.89 ml/min/1.73 m²) between each treatment cycle were more significant than the decreases in eGFR_CG (−0.46 ± 10.17 ml/min/1.73 m²), eGFR_MDRD (−0.48 ± 9.79 ml/min/1.73 m²), and five calculated eGFR_CysC (p < 0.05). Single-/multiparameter analyses showed that patients with a higher body mass index (BMI >23) and receiving more treatment cycles (>3) were at increased risk for developing renal impairment with an eGFR less than 60 ml/min/1.73 m² during chemotherapy.

Conclusions

The eGFR calculated by the CKD-EPI equation changed more significantly between each chemotherapy cycle than did the eGFR from the other equations based on Scr or CysC in patients with SCLC. Oncologists should pay more attention to the renal function of specific patient groups during treatment.

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Monitoring the estimated glomerular filtration rate (eGFR) in patients with small-cell lung cancer during chemotherapy: equations based on serum creatinine or cystatin C?

Abstract

Background

This study compared the differences between the estimated glomerular filtration rate (eGFR) calculated by several equations based on serum creatinine (Scr) and cystatin C (CysC) concentrations for monitoring renal function in patients with small-cell lung cancer (SCLC) during chemotherapy.

Methods

Seventy-one patients with SCLC were retrospectively analyzed. The eGFR before and after each chemotherapy cycle was calculated by the following equations: the chronic kidney disease epidemiology collaboration (CKD-EPI) equation, the modification of diet in renal disease (MDRD) equation, the Cockcroft–Gault (CG) equation, and five CysC-based equations. The patients were compared among the different eGFR groups.

Results

The mean decreases in eGFR_CKD-EPI (−2.25 ± 9.89 ml/min/1.73 m²) between each treatment cycle were more significant than the decreases in eGFR_CG (−0.46 ± 10.17 ml/min/1.73 m²), eGFR_MDRD (−0.48 ± 9.79 ml/min/1.73 m²), and five calculated eGFR_CysC (p < 0.05). Single-/multiparameter analyses showed that patients with a higher body mass index (BMI >23) and receiving more treatment cycles (>3) were at increased risk for developing renal impairment with an eGFR less than 60 ml/min/1.73 m² during chemotherapy.

Conclusions

The eGFR calculated by the CKD-EPI equation changed more significantly between each chemotherapy cycle than did the eGFR from the other equations based on Scr or CysC in patients with SCLC. Oncologists should pay more attention to the renal function of specific patient groups during treatment.

http://ift.tt/2zxPJ8A

Preoperative pulmonary function tests before low-risk surgery in Japan: a retrospective cohort study using a claims database

Abstract

Purpose

Routine preoperative pulmonary function tests (PFTs) are not recommended prior to low-risk surgery because their prognostic value is limited. However, only a few studies have assessed the utilization of healthcare resources regarding preoperative PFTs in a real-world setting. Here, we aimed to assess the prevalence and determinant factors of preoperative PFTs before low-risk surgery in Japan.

Methods

In this retrospective cohort study, we used the nationwide insurance claims databases. Patients who underwent low-risk surgeries under general anesthesia between April 1, 2012, and March 31, 2016, were included. The primary outcome was the receipt of PFTs within 60 days before an index surgery. We performed descriptive analyses to estimate the rates of preoperative PFTs annually starting in 2012, and examined the associations between patient- and institutional-level factors and preoperative PFTs using multilevel logistic regression analyses.

Results

The cohort included 9495 procedures (8866 patients) at 1487 institutions. Preoperative PFTs were conducted before 71.8% of the procedures. The temporal trend of preoperative PFTs remained constant from 72.4% in 2012 to 72.2% in 2015. Multilevel regression analysis revealed that preoperative PFTs were associated with older age, number of beds at a medical facility, and inpatient procedures. The median institutional-specific proportion of PFTs was 75.0% (interquartile range, 14.3–100%) with wide inter-institutional variation.

Conclusions

Our analysis found that preoperative PFTs were performed before 72% of low-risk surgeries under general anesthesia. Apart from age, preoperative PFTs were determined primarily by non-medical factors. Additionally, we observed substantial institutional variation in the use of preoperative PFTs.

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Chemotherapy-related anemia

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Cancer-Specific Survival Stratification Derived from Tumor Expression of Tissue Inhibitor of Metalloproteinase-2 in Non-Metastatic Renal Cell Carcinoma

Abstract

Degradation of the extracellular matrix is a prerequisite for the processes of cancer cell invasion and metastasis. The purpose of our study was to assess the association of matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9) and their inhibitors (TIMP-1 and TIMP-2) with renal cell carcinoma (RCC) progression and cancer-specific survival (CSS), using immunohistochemical analysis of 60 formalin-fixed, paraffin-embedded sections of tumor tissue and normal tissue near the tumor from surgical T1-3bN0 M0 RCC specimens. Significant overexpression of MMP-2 in tumor and normal tissue was correlated with advanced stages, tumor size, sarcomatous differentiation and clinical symptoms. Overall survival was 31.7% (55.2% M0, 9.7% M1) and CSS 56.7% (100% M0, 16.1% M1) with a follow-up of 76 (5–230) months. Fuhrman grade [HR 2.87 (95% CI: 1.28–6.45); p = 0.01], tumor size [HR 1.13 (95% CI: 1.03–1.26); p = 0.009] and low TIMP-2 expression [HR 0.35 (95% CI: 0.16–0.78); p = 0.01] were independent predictive factors of CSS and stratified the patients into three groups with different rates of 10-year CSS; [100%, 73.9% and 20.5% for the good, intermediate and poor prognosis group respectively (p = 0.000006)] . This study offers strong evidence that TIMP-2 expression in tumor tissue may play a crucial role in progression and poor prognosis in human localized and locally advanced RCC.

http://ift.tt/2y1qh6O

Cancer-Specific Survival Stratification Derived from Tumor Expression of Tissue Inhibitor of Metalloproteinase-2 in Non-Metastatic Renal Cell Carcinoma

Abstract

Degradation of the extracellular matrix is a prerequisite for the processes of cancer cell invasion and metastasis. The purpose of our study was to assess the association of matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9) and their inhibitors (TIMP-1 and TIMP-2) with renal cell carcinoma (RCC) progression and cancer-specific survival (CSS), using immunohistochemical analysis of 60 formalin-fixed, paraffin-embedded sections of tumor tissue and normal tissue near the tumor from surgical T1-3bN0 M0 RCC specimens. Significant overexpression of MMP-2 in tumor and normal tissue was correlated with advanced stages, tumor size, sarcomatous differentiation and clinical symptoms. Overall survival was 31.7% (55.2% M0, 9.7% M1) and CSS 56.7% (100% M0, 16.1% M1) with a follow-up of 76 (5–230) months. Fuhrman grade [HR 2.87 (95% CI: 1.28–6.45); p = 0.01], tumor size [HR 1.13 (95% CI: 1.03–1.26); p = 0.009] and low TIMP-2 expression [HR 0.35 (95% CI: 0.16–0.78); p = 0.01] were independent predictive factors of CSS and stratified the patients into three groups with different rates of 10-year CSS; [100%, 73.9% and 20.5% for the good, intermediate and poor prognosis group respectively (p = 0.000006)] . This study offers strong evidence that TIMP-2 expression in tumor tissue may play a crucial role in progression and poor prognosis in human localized and locally advanced RCC.

http://ift.tt/2y1qh6O

Stain-free Histopathology of Basal Cell Carcinoma by Dual Vibration Resonance Frequency CARS Microscopy

Abstract

Basal cell carcinoma (BCC) is the most common malignancy in Caucasians. Nonlinear microscopy has been previously utilized for the imaging of BCC, but the captured images do not correlate with H&E staining. Recently, Freudiger et al. introduced a novel method to visualize tissue morphology analogous to H&E staining, using coherent anti-Stokes Raman scattering (CARS) technique. In our present work, we introduce a novel algorithm to post-process images obtained from dual vibration resonance frequency (DVRF) CARS measurements to acquire high-quality pseudo H&E images of BCC samples. We adapted our CARS setup to utilize the distinct vibrational properties of CH₃ (mainly in proteins) and CH₂ bonds (primarily in lipids). In a narrowband setup, the central wavelength of the pump laser is set to 791 nm and 796 nm to obtain optimal excitation. Due to the partial overlap of the excitation spectra and the 5–10 nm FWHM spectral bandwidth of our lasers, we set the wavelengths to 790 nm (proteins) and 800 nm (lipids). Nonresonant background from water molecules also reduces the chemical selectivity which can be significantly improved if we subtract the DVRF images from each other. As a result, we acquired two images: one for "lipids" and one for" proteins" when we properly set a multiplication factor to minimize the non-specific background. By merging these images, we obtained high contrast H&E "stained" images of BBC's. Nonlinear microscope systems upgraded for real time DVRF CARS measurements, providing pseudo H&E images can be suitable for in vivo assessment of BCC in the future.

http://ift.tt/2xZSlHJ

Possible Predictive Markers of Response to Therapy in Esophageal Squamous Cell Cancer

Abstract

The aim of the present study was to investigate the relationship between the intensity of biomarker expression and the response to radiochemotherapy in patients with advanced esophageal squamous cell cancer (ESCC). Ninety-two patients with locally advanced ESCC were examined retrospectively. Pre-treatment tumor samples were stained for proteins SOUL, Hsp 16.2, Growth Hormone-Releasing Hormone Receptor (GHRH-R) and p-Akt using immunhistochemistry methods. Kaplan-Meier curves were used to show the relationship between intensity of expression of biomarkers and clinical parameters and 3-year OS. A significant correlation was found between high intensity staining for Hsp 16.2, p-Akt and SOUL and poor response to NRCT. Application of a higher dose of radiation and higher dose of cisplatin resulted in better clinical and histopathological responses, respectively. Among the clinical parameters, the localization of the tumor in the upper-third of the esophagus and less than 10% weight loss were independent prognostic factors for increased 3-year OS. Hsp16.2, p-Akt and SOUL are predictors of negative response to NRCT, therefore these biomarkers may become promising targets for therapy. Furthermore, level of expression of p-Akt, weight loss and the localization of the tumor are significant factors in the prediction of OS in ESCC.

http://ift.tt/2zcRTr1

Efficacy and safety in older patient subsets in studies of endocrine monotherapy versus combination therapy in patients with HR+/HER2− advanced breast cancer: a review

Abstract

Purpose

Prospective information regarding the tolerability and efficacy of endocrine therapy (ET) alone and in combination with targeted agents in older patients in the metastatic setting is limited. This review summarizes available trial data in this population.

Methods

We searched PubMed for Phase 2 or 3 trials with age-stratified patient cohorts (≥ 65 vs. < 65 years in most studies) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer treated with ET ± targeted agents.

Results

We identified 19 studies reporting 10 clinical trials. Efficacy was similar in age-stratified subsets. There was a reduced disease progression risk for ET + everolimus, palbociclib, or ribociclib versus ET alone. In the first-line setting, median progression-free survival (mPFS) in older patients was 8.5, 26.2 months, and not reached with letrozole + temsirolimus, palbociclib, and ribociclib, respectively, and in younger patients was 9.0, 18.8 months, and not reached, respectively. In the second-line setting, older patients had mPFS of 6.8 and 9.9 months with everolimus + exemestane and palbociclib + fulvestrant, respectively, and younger patients had mPFS of 8.1 and 9.5 months, respectively. Tolerability was worse for combination therapy versus monotherapy. No age-related differences in discontinuations were observed for CDK4/6 inhibitors, although a higher rate of treatment discontinuation was observed for patients ≥ 70 years receiving everolimus + exemestane. Adverse event rates were similar in age-stratified subsets.

Conclusions

ET + CDK4/6 or mTOR inhibitors are likely safe and effective in older patients with HR+, HER2− advanced breast cancer.

http://ift.tt/2A6jmtN

Real-world treatment patterns and effectiveness among patients with metastatic colorectal cancer treated with ziv-aflibercept in community oncology practices in the USA

Abstract

Routine clinical practice data often differ from clinical trials. This study describes real-world treatment patterns and effectiveness among patients with metastatic colorectal cancer (mCRC) receiving ziv-aflibercept in non-academic, community oncology practices in the USA. De-identified electronic medical records from Vector Oncology and Altos Solutions databases were analysed. We identified 218 patients diagnosed with mCRC who had received prior oxaliplatin therapy and initiated ziv-aflibercept as part of second-line or later-line therapy. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan–Meier analysis. Mean age was 62.8 years at ziv-aflibercept initiation. Most patients (91.7%) received bevacizumab before ziv-aflibercept, 95.4% initiated ziv-aflibercept with FOLFIRI or another irinotecan-based regimen, and 59.6% had received prior irinotecan. Overall, 24.8% of patients initiated ziv-aflibercept in second line, 31.7% in third line, 21.6% in fourth line and 22.0% in later lines of therapy. Mean duration of ziv-aflibercept treatment was 5.3 months. For patients initiating ziv-aflibercept in second-, third- and fourth-line therapy, median OS was 11.9 (95% confidence interval 5.1–16.2), 11.1 (6.9–16.7) and 8.1 (5.2–11.4) months, respectively, and median PFS was 4.4 (2.8–6.5), 4.3 (2.9–6.3) and 3.4 (2.2–5.2) months, respectively. Common adverse events (AEs) (any grade) included gastrointestinal disorders (64.7%) and asthenia/fatigue (63.3%). In routine clinical practice, ziv-aflibercept was frequently initiated in third line or later lines of therapy. Although patients receiving ziv-aflibercept were more heavily pretreated and potentially less robust compared with the VELOUR trial, median OS for patients receiving second-line ziv-aflibercept was comparable. AE rates were similar to or lower than the VELOUR trial.

http://ift.tt/2lS0Z9U

Real-world treatment patterns and effectiveness among patients with metastatic colorectal cancer treated with ziv-aflibercept in community oncology practices in the USA

Abstract

Routine clinical practice data often differ from clinical trials. This study describes real-world treatment patterns and effectiveness among patients with metastatic colorectal cancer (mCRC) receiving ziv-aflibercept in non-academic, community oncology practices in the USA. De-identified electronic medical records from Vector Oncology and Altos Solutions databases were analysed. We identified 218 patients diagnosed with mCRC who had received prior oxaliplatin therapy and initiated ziv-aflibercept as part of second-line or later-line therapy. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan–Meier analysis. Mean age was 62.8 years at ziv-aflibercept initiation. Most patients (91.7%) received bevacizumab before ziv-aflibercept, 95.4% initiated ziv-aflibercept with FOLFIRI or another irinotecan-based regimen, and 59.6% had received prior irinotecan. Overall, 24.8% of patients initiated ziv-aflibercept in second line, 31.7% in third line, 21.6% in fourth line and 22.0% in later lines of therapy. Mean duration of ziv-aflibercept treatment was 5.3 months. For patients initiating ziv-aflibercept in second-, third- and fourth-line therapy, median OS was 11.9 (95% confidence interval 5.1–16.2), 11.1 (6.9–16.7) and 8.1 (5.2–11.4) months, respectively, and median PFS was 4.4 (2.8–6.5), 4.3 (2.9–6.3) and 3.4 (2.2–5.2) months, respectively. Common adverse events (AEs) (any grade) included gastrointestinal disorders (64.7%) and asthenia/fatigue (63.3%). In routine clinical practice, ziv-aflibercept was frequently initiated in third line or later lines of therapy. Although patients receiving ziv-aflibercept were more heavily pretreated and potentially less robust compared with the VELOUR trial, median OS for patients receiving second-line ziv-aflibercept was comparable. AE rates were similar to or lower than the VELOUR trial.

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Title page

Publication date: December 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1868, Issue 2





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Cerebrovascular CO 2 reactivity during isoflurane-nitrous oxide anesthesia in patients with chronic renal failure

Abstract

Purpose

We assessed the cerebrovascular CO₂ reactivity (CO₂R) in chronic renal failure (CRF) patients without diabetes mellitus (DM), uncontrolled hypertension, peripheral vascular disease, or neurological disease under isoflurane-nitrous oxide anesthesia.

Methods

Forty-nine patients undergoing surgery, including 36 CRF patients (30 receiving dialysis and six pre-dialysis patients) and 13 patients without CRF (controls). Middle cerebral artery flow velocity (VMCA) was measured by transcranial Doppler ultrasonography at an end-tidal CO₂ of 35 to 45 mmHg. CO₂R was calculated as an absolute value (change in VMCA per mmHg PaCO₂) and a relative value (absolute CO₂R/baseline VMCA × 100). Factors associated with CO₂R were evaluated simultaneously.

Results

Despite no significant differences in the absolute and relative values of CO₂R between the CRF (mean 2.5 cm/s/mmHg; median 5.0%/mmHg) and control (2.4 cm/s/mmHg; 5.0%/mmHg) groups, blood urea nitrogen (BUN) concentrations in the CRF group correlated inversely with both absolute and relative CO₂R. BUN concentration was higher (mean 72 versus 53 mg/dl, p = 0.006) and relative CO₂R was lower (mean 2.6 versus 5.7%/mmHg, p = 0.011) in patients with pre-dialysis CRF (n = 6) versus CRF patients receiving dialysis (n = 30).

Conclusions

CO₂R in CRF patients was not significantly different from that in controls. However, in CRF patients with high BUN concentrations, CO₂R might be impaired, leading to reduced cerebrovascular reserve capacity. Because DM is a major cause of CRF and we excluded DM patients, our results might not be applicable to patients with DM-induced CRF.

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Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma.

Related Articles

Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma.

Cancer Biol Ther. 2017 Nov 03;:1-11

Authors: May CD, Landers SM, Bolshakov S, Ma X, Ingram DR, Kivlin CM, Watson KL, Sannaa GAA, Bhalla AD, Wang WL, Lazar AJ, Torres KE

Abstract
Undifferentiated pleomorphic sarcomas (UPSs) are aggressive mesenchymal malignancies with no definitive cell of origin or specific recurrent genetic hallmarks. These tumors are largely chemoresistant; thus, identification of potential therapeutic targets is necessary to improve patient outcome. Previous studies demonstrated that high expression of activated protein kinase B (AKT) in patients with UPS corresponds to poor disease-specific survival. Here, we demonstrate that inhibiting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling using a small molecule inhibitor reduced UPS cell proliferation and motility and xenograft growth; however, increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) indicated the potential for adaptive resistance following treatment through compensatory receptor activation. Co-treatment with a dual PI3K/mTOR inhibitor and an anti-IGF1R kinase inhibitor reduced in vivo tumor growth rates despite a lack of antiproliferative effects in vitro. Moreover, this combination treatment significantly decreased UPS cell migration and invasion, which is linked to changes in p27 subcellular localization. Our results demonstrate that targeted inhibition of multiple components of the IGF1R/PI3K/mTOR pathway was more efficacious than single-agent therapy and suggest that co-targeting this pathway could be a beneficial therapeutic strategy for patients with UPS.

PMID: 29099264 [PubMed - as supplied by publisher]

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Stain-free Histopathology of Basal Cell Carcinoma by Dual Vibration Resonance Frequency CARS Microscopy

Abstract

Basal cell carcinoma (BCC) is the most common malignancy in Caucasians. Nonlinear microscopy has been previously utilized for the imaging of BCC, but the captured images do not correlate with H&E staining. Recently, Freudiger et al. introduced a novel method to visualize tissue morphology analogous to H&E staining, using coherent anti-Stokes Raman scattering (CARS) technique. In our present work, we introduce a novel algorithm to post-process images obtained from dual vibration resonance frequency (DVRF) CARS measurements to acquire high-quality pseudo H&E images of BCC samples. We adapted our CARS setup to utilize the distinct vibrational properties of CH₃ (mainly in proteins) and CH₂ bonds (primarily in lipids). In a narrowband setup, the central wavelength of the pump laser is set to 791 nm and 796 nm to obtain optimal excitation. Due to the partial overlap of the excitation spectra and the 5–10 nm FWHM spectral bandwidth of our lasers, we set the wavelengths to 790 nm (proteins) and 800 nm (lipids). Nonresonant background from water molecules also reduces the chemical selectivity which can be significantly improved if we subtract the DVRF images from each other. As a result, we acquired two images: one for "lipids" and one for" proteins" when we properly set a multiplication factor to minimize the non-specific background. By merging these images, we obtained high contrast H&E "stained" images of BBC's. Nonlinear microscope systems upgraded for real time DVRF CARS measurements, providing pseudo H&E images can be suitable for in vivo assessment of BCC in the future.

http://ift.tt/2xZSlHJ

Possible Predictive Markers of Response to Therapy in Esophageal Squamous Cell Cancer

Abstract

The aim of the present study was to investigate the relationship between the intensity of biomarker expression and the response to radiochemotherapy in patients with advanced esophageal squamous cell cancer (ESCC). Ninety-two patients with locally advanced ESCC were examined retrospectively. Pre-treatment tumor samples were stained for proteins SOUL, Hsp 16.2, Growth Hormone-Releasing Hormone Receptor (GHRH-R) and p-Akt using immunhistochemistry methods. Kaplan-Meier curves were used to show the relationship between intensity of expression of biomarkers and clinical parameters and 3-year OS. A significant correlation was found between high intensity staining for Hsp 16.2, p-Akt and SOUL and poor response to NRCT. Application of a higher dose of radiation and higher dose of cisplatin resulted in better clinical and histopathological responses, respectively. Among the clinical parameters, the localization of the tumor in the upper-third of the esophagus and less than 10% weight loss were independent prognostic factors for increased 3-year OS. Hsp16.2, p-Akt and SOUL are predictors of negative response to NRCT, therefore these biomarkers may become promising targets for therapy. Furthermore, level of expression of p-Akt, weight loss and the localization of the tumor are significant factors in the prediction of OS in ESCC.

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Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma.

Related Articles

Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma.

Cancer Biol Ther. 2017 Nov 03;:1-11

Authors: May CD, Landers SM, Bolshakov S, Ma X, Ingram DR, Kivlin CM, Watson KL, Sannaa GAA, Bhalla AD, Wang WL, Lazar AJ, Torres KE

Abstract
Undifferentiated pleomorphic sarcomas (UPSs) are aggressive mesenchymal malignancies with no definitive cell of origin or specific recurrent genetic hallmarks. These tumors are largely chemoresistant; thus, identification of potential therapeutic targets is necessary to improve patient outcome. Previous studies demonstrated that high expression of activated protein kinase B (AKT) in patients with UPS corresponds to poor disease-specific survival. Here, we demonstrate that inhibiting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling using a small molecule inhibitor reduced UPS cell proliferation and motility and xenograft growth; however, increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) indicated the potential for adaptive resistance following treatment through compensatory receptor activation. Co-treatment with a dual PI3K/mTOR inhibitor and an anti-IGF1R kinase inhibitor reduced in vivo tumor growth rates despite a lack of antiproliferative effects in vitro. Moreover, this combination treatment significantly decreased UPS cell migration and invasion, which is linked to changes in p27 subcellular localization. Our results demonstrate that targeted inhibition of multiple components of the IGF1R/PI3K/mTOR pathway was more efficacious than single-agent therapy and suggest that co-targeting this pathway could be a beneficial therapeutic strategy for patients with UPS.

PMID: 29099264 [PubMed - as supplied by publisher]

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Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma.

Related Articles

Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma.

Cancer Biol Ther. 2017 Nov 03;:1-11

Authors: May CD, Landers SM, Bolshakov S, Ma X, Ingram DR, Kivlin CM, Watson KL, Sannaa GAA, Bhalla AD, Wang WL, Lazar AJ, Torres KE

Abstract
Undifferentiated pleomorphic sarcomas (UPSs) are aggressive mesenchymal malignancies with no definitive cell of origin or specific recurrent genetic hallmarks. These tumors are largely chemoresistant; thus, identification of potential therapeutic targets is necessary to improve patient outcome. Previous studies demonstrated that high expression of activated protein kinase B (AKT) in patients with UPS corresponds to poor disease-specific survival. Here, we demonstrate that inhibiting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling using a small molecule inhibitor reduced UPS cell proliferation and motility and xenograft growth; however, increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) indicated the potential for adaptive resistance following treatment through compensatory receptor activation. Co-treatment with a dual PI3K/mTOR inhibitor and an anti-IGF1R kinase inhibitor reduced in vivo tumor growth rates despite a lack of antiproliferative effects in vitro. Moreover, this combination treatment significantly decreased UPS cell migration and invasion, which is linked to changes in p27 subcellular localization. Our results demonstrate that targeted inhibition of multiple components of the IGF1R/PI3K/mTOR pathway was more efficacious than single-agent therapy and suggest that co-targeting this pathway could be a beneficial therapeutic strategy for patients with UPS.

PMID: 29099264 [PubMed - as supplied by publisher]

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Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma.

Related Articles

Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma.

Cancer Biol Ther. 2017 Nov 03;:1-11

Authors: May CD, Landers SM, Bolshakov S, Ma X, Ingram DR, Kivlin CM, Watson KL, Sannaa GAA, Bhalla AD, Wang WL, Lazar AJ, Torres KE

Abstract
Undifferentiated pleomorphic sarcomas (UPSs) are aggressive mesenchymal malignancies with no definitive cell of origin or specific recurrent genetic hallmarks. These tumors are largely chemoresistant; thus, identification of potential therapeutic targets is necessary to improve patient outcome. Previous studies demonstrated that high expression of activated protein kinase B (AKT) in patients with UPS corresponds to poor disease-specific survival. Here, we demonstrate that inhibiting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling using a small molecule inhibitor reduced UPS cell proliferation and motility and xenograft growth; however, increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) indicated the potential for adaptive resistance following treatment through compensatory receptor activation. Co-treatment with a dual PI3K/mTOR inhibitor and an anti-IGF1R kinase inhibitor reduced in vivo tumor growth rates despite a lack of antiproliferative effects in vitro. Moreover, this combination treatment significantly decreased UPS cell migration and invasion, which is linked to changes in p27 subcellular localization. Our results demonstrate that targeted inhibition of multiple components of the IGF1R/PI3K/mTOR pathway was more efficacious than single-agent therapy and suggest that co-targeting this pathway could be a beneficial therapeutic strategy for patients with UPS.

PMID: 29099264 [PubMed - as supplied by publisher]

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Seizure Triggered by Sick Sinus Syndrome

Sick sinus syndrome (SSS) is a dysfunction of sinoatrial node resulting in symptomatic bradycardia or sinus pauses causing decreased cardiac output with cerebral hypoperfusion and usually presents as syncope, presyncope or fatigue. The occurrence of a seizure is very rare. A 69-year-old man suffered two episodes of generalised tonic–clonic seizures. MRI and electroencephalogram failed to reveal the cause of seizures. In the emergency room, he experienced presyncope simultaneous to bradycardia and sinus pauses. He was stabilised with atropine and dopamine infusion and underwent definitive therapy with a permanent dual-chamber pacemaker with complete symptom resolution. Diagnostic confounders include convulsive syncope and ictal bradycardia. Syncope may be accompanied by myoclonic jerks (convulsive syncope), but postictal confusion is absent. Bradycardia may be seen during the postictal period (ictal bradycardia syndrome), but protracted sinus dysfunction is not present. Hypoperfusion due to significant SSS triggered seizures in this patient who may have an underlying predisposition.

http://ift.tt/2zholuC

Metastatic melanoma: a rare cause of central airway obstruction

A middle-aged woman with recurrent malignant melanoma presented initially with massive left pleural effusion. There was a complete obliteration of the left main bronchus on flexible bronchoscopy caused by a mass. Serial cryo-debulking of the tumour was done under rigid bronchoscopy; however, the outcome was not favourable due to the aggressive tumour growth. Vemurafenib was planned after thoracic radiation. She was not keen for the biologics treatment due to financial constraints. We report a case of central airway obstruction due to recurrent aggressive melanoma. More evaluations are needed on the role of interventional pulmonologist for bronchoscopic debulking of this rapidly growing tumour as well as the role of biological agents in treating such cases.

http://ift.tt/2zvGmWV

A rare localised nasal CD30+ primary cutaneous T-cell lymphoma following liver transplantation

Cutaneous T-cell post-transplant lymphoproliferative disorder (PTLD) is a rare clinical presentation that can potentially turn aggressive in solid-organ transplant recipients if not detected and intervened on early. We encountered a rare case of rapidly worsening primary cutaneous CD30-positive, Epstein-Barr virus-negative anaplastic large cell lymphoma (ALCL) of T-cell origin, manifesting as an isolated nasal tip lesion in a 71-year-old man 4 years after orthotopic liver transplantation. Excisional biopsy with partial rhinectomy showed subepithelial diffuse infiltration of medium-to-large lymphoid cells having round-to-irregular nuclei, partially condensed chromatin and prominent nucleoli. Immunophenotypic studies revealed CD30-positive primary cutaneous ALCL. Positron emission tomography/CT imaging revealed a locally active disease, and radiation therapy was initiated with complete response. A high index of suspicion for PTLD when evaluating skin lesions in a post-transplant patient is paramount for its early recognition, prompt diagnosis and timely intervention while the window for curative therapy remains possible.

http://ift.tt/2zhXgaC

Palm atheroma infection caused by Raoultella planticola

Description

A 74-year-old man presented to the emergency department with pain in the left hand. He had a history of lung carcinoma and was treated with chemotherapy for 2 years. On physical examination, his left hand was found to exhibit swelling and redness. There was an atheroma at the base of his middle finger, which was the most painful area (figure 1-A,B). He was prescribed cephalexin 2 g daily and ordered to see an orthopaedic surgeon the next day. However, the next day, his left hand became worse. There was increased swelling, redness, pain and pus (figure 1-C,D). The patient was treated with surgical drainage and intravenous cefazolin 2 g daily to control the infection (figure 2). A week later, bacterial isolation analysis revealed that the causative agent was Raoultella planticola. He was switched to ceftriaxone based on sensitivities and prior literature on the...

http://ift.tt/2zvPw5M

Anti-LGI1 encephalitis causing faciobrachial dystonic seizures

Anti-leucine-richglioma inactivated protein 1 (LGI1) encephalitis has an autoimmune origin and can be reversed with immunotherapy. It is obvious that identifying and treating this condition early is of paramount importance. We present the case of a 69-year-old man who was admitted to hospital with faciobrachial dystonic seizures and was found to have antibodies to LGI1. His symptoms started approximately 3 months prior admission to the hospital. There had also been some subtle cognitive impairment. He was treated with two courses of intravenous immunoglobulin and commenced on prednisolone 50 mg daily and clonazepam 500 µg at night. Despite these treatments, his seizures were becoming progressively more frequent and severe. He then underwent treatment with a course of plasma exchange followed by an intravenous infusion of methylprednisolone and returned to his previous baseline function.

http://ift.tt/2ziYF0K

Intestinal spirochaetosis mimicking acute appendicitis with review of the literature

Human intestinal spirochaetosis is a well-established micro-organism existing in the colon. It is less commonly seen in the appendix, and rarely presents as acute appendicitis. We present a case of a man presenting with symptoms consistent with acute appendicitis. The literature on spirochaetosis presenting as acute appendicitis is also reviewed.

http://ift.tt/2zvPjzw

Global health challenges in treating an elderly institutionalised patient: an oral medicine perspective

A 64-year-old institutionalised woman presented to our clinic for the management of black hairy tongue. Despite the predictable outcome in treating this disease, this case presents multiple challenges such as the patients' cognitive impairment, her family dynamics, social factors and the health system as a whole, that makes it difficult to treat.

http://ift.tt/2zky574

Frequent neck massage leading to bilateral anterior cerebral artery infarction

Description

The anterior cerebral artery (ACA) is a major vessel responsible for the blood supply to the interhemispheric regions. Infarction of the ACA territory accounts for only 0.3% to 4.4% of cerebral infarctions reported.1 The usual causes are aneurysmal rupture of the anterior communicating artery or thrombosis of the precommunal anterior cerebral artery.2 We are describing here a patient with bilateral ACA infarction due to dual pathology and frequent neck massage being the cause of this young stroke.

A 45-year-old man was admitted with sudden onset aphasia and weakness of both lower limbs with bowel–bladder incontinence. There was no history of loss of consciousness, headache, nausea or vomiting and convulsions. He had no significant medical history and no vascular risk factors. There is history of frequent neck massages from a chiropractor for relaxation purposes with visits amounting to two to four per week. There...

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Giant calvarial haemangioma with classical radiological features

Description

A 12-year-old girl presented with a large painless hard swelling in the left parietal region, gradually increasing in size for 6 years. No complaint of headache or visual disturbance was present. Radiographs showed a large expansile lytic lesion with prominent bony trabeculae radiating centrifugally from the centre of the mass. On CT scan, the lytic area showed areas of rarefaction traversed by radiating bony spicules. On MRI, the lesion was isointense to hyperintense on T1-weighted images (T1WI), hyperintense on T2WI, indenting over underlying brain parenchyma, causing mass effect and midline shift. Avid enhancement was noted on postcontrast scans (figure 1). Based on typical clinical presentation and classical radiological findings, a diagnosis of giant calvarial haemangioma was made.

Figure 1

(A) Clinical photograph showing large left parietal swelling. (B and C) Skull radiograph in frontal and lateral projections showing lytic lesion with centrifugally radiating bony trabeculae...

http://ift.tt/2zhMOQt

The effects of microduplication 1q21.1 and in-utero isotretinoin exposure

The impact of in-utero isotretinoin exposure has been widely reported, with many affected pregnancies failing to reach term.^{1 2} Due to the low numbers of in-utero isotretinoin exposed pregnancies, the interactions between this drug and rare genetic defects such as microduplication 1q21.1 are unclear, particularly how they might manifest phenotypically. We present this case of in-utero isotretinoin exposure occurring in a child with microduplication 1q21.1. The child was born with congenital abnormalities which did not fit into a single syndrome. Regrettably in-utero exposure to isotretinoin continues to occur. We hope this case will trigger further discussion on the dangers of dispensing Isotretinoin without ensuring stringent pregnancy testing and its potential interaction with genetic abnormalities, in particular with microduplication 1q21.1.

http://ift.tt/2zvOZRk

Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma

.


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Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma

.


http://ift.tt/2iuTlx8

Progression-free survival of up to 8 months of an advanced intrahepatic cholangiocarcinoma patient treated with apatinib: a case report

http://ift.tt/2lRCJVo

MicroRNAs as a novel class of diagnostic biomarkers for the detection of osteosarcoma: a meta-analysis

http://ift.tt/2yvCYer

SIRT3 deacetylates and promotes degradation of P53 in PTEN-defective non-small cell lung cancer

Abstract

Purpose

In non-small cell lung cancer (NSCLC), success of targeted therapy has promoted researches explicitly orientated based on genetic background. Although PTEN deficiency is common in NSCLC, carcinogenesis about such genetic type has not been fully explored. Here, we have found that classical tumor suppressor P53 could be modulated by deacetylase sirtuin-3 (SIRT3) depending on the PTEN condition in NSCLC, which may be a novel breakpoint for handling PTEN deficiency NSCLC.

Methods

First, we examined SIRT3 and P53 expression files in PTEN-deficient NSCLC clinical samples and investigated their correlation. Second, we built SIRT3 high or low expression models in different PTEN conditions by plasmid overexpression or si-RNA interference in NSCLC cell lines and explored the effect of SIRT3 upon P53. Furthermore, we investigated the influence of SIRT3 upon the ubiquitin–proteasome dependent degradation pathway of P53 in PTEN-deficient NSCLC cell lines. Finally, we probed into the deacetylation modification of P53 via SIRT3.

Results

We found that SIRT3 expression was strongly positive and P53 expression was almost negative in PTEN-deficient NSCLC clinical samples. Further, we demonstrated that SIRT3 promoted degradation of P53 in PTEN-deficient NSCLC cell lines via the ubiquitin–proteasome pathway. Finally, we demonstrated that SIRT3 could deacetylate P53 at lysines 320 and 382, which may account for the observed degradation of P53 in PTEN-deficient tumor cells.

Conclusions

We have identified a novel mechanism by which P53 was inactivated via SIRT3 in PTEN-deficient cells. This may shed light on the mechanisms underlying the malignancy of PTEN-deficient NSCLC.

http://ift.tt/2hbQWdW

SIRT3 deacetylates and promotes degradation of P53 in PTEN-defective non-small cell lung cancer

Abstract

Purpose

In non-small cell lung cancer (NSCLC), success of targeted therapy has promoted researches explicitly orientated based on genetic background. Although PTEN deficiency is common in NSCLC, carcinogenesis about such genetic type has not been fully explored. Here, we have found that classical tumor suppressor P53 could be modulated by deacetylase sirtuin-3 (SIRT3) depending on the PTEN condition in NSCLC, which may be a novel breakpoint for handling PTEN deficiency NSCLC.

Methods

First, we examined SIRT3 and P53 expression files in PTEN-deficient NSCLC clinical samples and investigated their correlation. Second, we built SIRT3 high or low expression models in different PTEN conditions by plasmid overexpression or si-RNA interference in NSCLC cell lines and explored the effect of SIRT3 upon P53. Furthermore, we investigated the influence of SIRT3 upon the ubiquitin–proteasome dependent degradation pathway of P53 in PTEN-deficient NSCLC cell lines. Finally, we probed into the deacetylation modification of P53 via SIRT3.

Results

We found that SIRT3 expression was strongly positive and P53 expression was almost negative in PTEN-deficient NSCLC clinical samples. Further, we demonstrated that SIRT3 promoted degradation of P53 in PTEN-deficient NSCLC cell lines via the ubiquitin–proteasome pathway. Finally, we demonstrated that SIRT3 could deacetylate P53 at lysines 320 and 382, which may account for the observed degradation of P53 in PTEN-deficient tumor cells.

Conclusions

We have identified a novel mechanism by which P53 was inactivated via SIRT3 in PTEN-deficient cells. This may shed light on the mechanisms underlying the malignancy of PTEN-deficient NSCLC.

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DNA hypermethylation enhanced telomerase reverse transcriptase expression in human-induced pluripotent stem cells

Abstract

During reprogramming into human induced pluripotent stem cells (iPSCs), several stem cell marker genes are induced, such as OCT-4, NANOG, SALL4, and TERT. OCT-4, NANOG, and SALL4 gene expression can be regulated by DNA methylation. Their promoters become hypomethylated in iPSCs during reprogramming, leading to their induced expression. However, epigenetic regulation of the TERT gene remains unclear. In this study, we focused on epigenetic regulation of the human TERT gene and identified a differentially methylated region (DMR) at a distal region in the TERT promoter between human iPSCs and their parental somatic cells. Interestingly, the TERT-DMR was highly methylated in iPSCs, but low-level methylation was observed in their parental somatic cells. Region-specific, methylated-promoter assays showed that the methylated TERT-DMR up-regulated the promoter activity in iPSCs. In addition, Lamin B1 accumulated at the TERT-DMR in iPSCs, but not in their parent somatic cells. These results suggested that the TERT transcription was enhanced by DNA methylation at the TERT-DMR via binding to nuclear lamina during reprogramming. Our findings shed light on a new functional aspect of DNA methylation in gene expression.

http://ift.tt/2hDUgM9

DNA hypermethylation enhanced telomerase reverse transcriptase expression in human-induced pluripotent stem cells

Abstract

During reprogramming into human induced pluripotent stem cells (iPSCs), several stem cell marker genes are induced, such as OCT-4, NANOG, SALL4, and TERT. OCT-4, NANOG, and SALL4 gene expression can be regulated by DNA methylation. Their promoters become hypomethylated in iPSCs during reprogramming, leading to their induced expression. However, epigenetic regulation of the TERT gene remains unclear. In this study, we focused on epigenetic regulation of the human TERT gene and identified a differentially methylated region (DMR) at a distal region in the TERT promoter between human iPSCs and their parental somatic cells. Interestingly, the TERT-DMR was highly methylated in iPSCs, but low-level methylation was observed in their parental somatic cells. Region-specific, methylated-promoter assays showed that the methylated TERT-DMR up-regulated the promoter activity in iPSCs. In addition, Lamin B1 accumulated at the TERT-DMR in iPSCs, but not in their parent somatic cells. These results suggested that the TERT transcription was enhanced by DNA methylation at the TERT-DMR via binding to nuclear lamina during reprogramming. Our findings shed light on a new functional aspect of DNA methylation in gene expression.

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Cell cycle-dependent translocation and regulatory mechanism of CacyBP/SIP in gastric cancer cells.

Our previous results showed that calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) inhibits the proliferation and tumorigenicity of gastric cancer; however, the exact mechanism remains unclear, especially from the aspect of cell cycle. The subcellular localization of CacyBP/SIP, Siah-1, and Skp1 in SGC7901 gastric cancer cells was assessed by immunofluorescence after cell cycle synchronization. Levels of CacyBP/SIP, Siah-1, Skp1, [beta]-catenin, and p-ERK1/2 were analyzed by western blotting. CacyBP/SIP phosphorylation (p-CacyBP/SIP) and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP in nucleoprotein were determined by immunoprecipitation. CacyBP/SIP, Siah-1, and Skp1 were mainly in the cytoplasm in the G1 phase, but translocated to the nucleus during G2. Their expression in total protein was not altered, but elevated in the G2 phase in nucleoprotein. The CacyBP/SIP nucleus translocation of cells transfected with mutant CacyBP/SIP that does not bind S100 (CacyBP-[DELTA]S100) was significantly increased compared with wild-type CacyBP/SIP. In the G2 phase, p-CacyBP/SIP expression and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP were all increased, whereas levels of [beta]-catenin and p-ERK1/2 reduced, compared with the G1 phase. CacyBP/SIP or CacyBP-[DELTA]S100 overexpression was correlated with constitutively low [beta]-catenin expression and affected its level through cell cycle. CacyBP/SIP overexpression led to retarded proliferation, G1 arrest, and [beta]-catenin reduction, which could be abolished by lithium chloride, [beta]-catenin activator, and further enhanced by the Wnt inhibitor XAV-939. In addition, CacyBP-[DELTA]S100 further suppressed cell proliferation and induced G1 arrest compared with CacyBP/SIP. In conclusion, CacyBP/SIP nuclear localization, dependent on S100 protein, suppresses gastric cancer tumorigenesis through [beta]-catenin degradation and the dephosphorylation of ERK1/2 during the G2 phase. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2hCorTW

Autophagy and doxorubicin resistance in cancer.

Doxorubicin (DOX), also known as adriamycin, is a DNA topoisomerase II inhibitor and belongs to the family of anthracycline anticancer drugs. DOX is used for the treatment of a wide variety of cancer types. However, resistance among cancer cells has emerged as a major barrier to effective treatment using DOX. Currently, the role of autophagy in cancer resistance to DOX and the mechanisms involved have become one of the areas of intense investigation. More and more preclinical data are being obtained on reversing DOX resistance through modulation of autophagy as one of the promising therapeutic strategies. This review summarizes the recent advances in autophagy-targeting therapies that overcome DOX resistance from in-vitro studies to animal models for exploration of novel delivery systems. In-depth understanding of the mechanisms of autophagy regulation in relation to DOX resistance and development of molecularly targeted autophagy-modulating agents will provide a promising therapeutic strategy for overcoming DOX resistance in cancer treatment. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2A5DADY

Temozolomide treatment of a malignant pheochromocytoma and an unresectable MAX-related paraganglioma.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors with a strong genetic background. The mainstay of treatment for PCC/PGLs is surgery. However, for unresectable lesions, no curative treatment is currently available. Temozolomide (TMZ) has been shown to determine radiological and biochemical response in malignant PCC/PGLs. We report two cases of PCC/PGLs treated with TMZ. Case 1 is a 51-year-old man with local and distant recurrence (liver and bone metastases) of right adrenal PCC. Case 2 is a 54-year-old woman with a PCC/PGL syndrome caused by a mutation in MAX gene (c.171+1G>A), operated on for bilateral adrenal PCC and presenting with a large unresectable abdominal PGL. Both patients presented hypertension due to catecholamine hypersecretion. TMZ determined radiological response according to RECIST criteria, reduction of urinary catecholamine levels, and controlled hypertension in both patients. Furthermore, the current study demonstrates, for the first time, that MAX-related PGLs are responsive to TMZ. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2hC5e4I

Cell cycle-dependent translocation and regulatory mechanism of CacyBP/SIP in gastric cancer cells.

Our previous results showed that calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) inhibits the proliferation and tumorigenicity of gastric cancer; however, the exact mechanism remains unclear, especially from the aspect of cell cycle. The subcellular localization of CacyBP/SIP, Siah-1, and Skp1 in SGC7901 gastric cancer cells was assessed by immunofluorescence after cell cycle synchronization. Levels of CacyBP/SIP, Siah-1, Skp1, [beta]-catenin, and p-ERK1/2 were analyzed by western blotting. CacyBP/SIP phosphorylation (p-CacyBP/SIP) and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP in nucleoprotein were determined by immunoprecipitation. CacyBP/SIP, Siah-1, and Skp1 were mainly in the cytoplasm in the G1 phase, but translocated to the nucleus during G2. Their expression in total protein was not altered, but elevated in the G2 phase in nucleoprotein. The CacyBP/SIP nucleus translocation of cells transfected with mutant CacyBP/SIP that does not bind S100 (CacyBP-[DELTA]S100) was significantly increased compared with wild-type CacyBP/SIP. In the G2 phase, p-CacyBP/SIP expression and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP were all increased, whereas levels of [beta]-catenin and p-ERK1/2 reduced, compared with the G1 phase. CacyBP/SIP or CacyBP-[DELTA]S100 overexpression was correlated with constitutively low [beta]-catenin expression and affected its level through cell cycle. CacyBP/SIP overexpression led to retarded proliferation, G1 arrest, and [beta]-catenin reduction, which could be abolished by lithium chloride, [beta]-catenin activator, and further enhanced by the Wnt inhibitor XAV-939. In addition, CacyBP-[DELTA]S100 further suppressed cell proliferation and induced G1 arrest compared with CacyBP/SIP. In conclusion, CacyBP/SIP nuclear localization, dependent on S100 protein, suppresses gastric cancer tumorigenesis through [beta]-catenin degradation and the dephosphorylation of ERK1/2 during the G2 phase. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Autophagy and doxorubicin resistance in cancer.

Doxorubicin (DOX), also known as adriamycin, is a DNA topoisomerase II inhibitor and belongs to the family of anthracycline anticancer drugs. DOX is used for the treatment of a wide variety of cancer types. However, resistance among cancer cells has emerged as a major barrier to effective treatment using DOX. Currently, the role of autophagy in cancer resistance to DOX and the mechanisms involved have become one of the areas of intense investigation. More and more preclinical data are being obtained on reversing DOX resistance through modulation of autophagy as one of the promising therapeutic strategies. This review summarizes the recent advances in autophagy-targeting therapies that overcome DOX resistance from in-vitro studies to animal models for exploration of novel delivery systems. In-depth understanding of the mechanisms of autophagy regulation in relation to DOX resistance and development of molecularly targeted autophagy-modulating agents will provide a promising therapeutic strategy for overcoming DOX resistance in cancer treatment. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Temozolomide treatment of a malignant pheochromocytoma and an unresectable MAX-related paraganglioma.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors with a strong genetic background. The mainstay of treatment for PCC/PGLs is surgery. However, for unresectable lesions, no curative treatment is currently available. Temozolomide (TMZ) has been shown to determine radiological and biochemical response in malignant PCC/PGLs. We report two cases of PCC/PGLs treated with TMZ. Case 1 is a 51-year-old man with local and distant recurrence (liver and bone metastases) of right adrenal PCC. Case 2 is a 54-year-old woman with a PCC/PGL syndrome caused by a mutation in MAX gene (c.171+1G>A), operated on for bilateral adrenal PCC and presenting with a large unresectable abdominal PGL. Both patients presented hypertension due to catecholamine hypersecretion. TMZ determined radiological response according to RECIST criteria, reduction of urinary catecholamine levels, and controlled hypertension in both patients. Furthermore, the current study demonstrates, for the first time, that MAX-related PGLs are responsive to TMZ. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Parenchymal asbestosis due to primary asbestos exposure among ship-breaking workers: report of the first cases from Bangladesh

We report for the first time asbestosis among ship-breaking workers of Sitakunda in Bangladesh who were exposed to asbestos during ship-based and beach-based operations for at least 10 years. Asbestosis was present among 35% of workers. Years of work (>20) and forced vital capacity (<80% of predicted) were significantly associated with the disease. Currently, global ship-breaking operations are mainly concentrated in the Indian subcontinent, and Bangladesh has the majority share. Ninety per cent of domestic steel is produced in the ship-breaking operations in Bangladesh and is an important contributor to the economy. It also gives employment to more than 100 000 people. It is imperative to medically check up all the workers for benign and malignant diseases causally related to asbestos among these vulnerable population of workers.

http://ift.tt/2xYU7ZR

Postprandial angina: not always due to stenotic coronary artery disease

Description

A 68-year-old man presented with history of postprandial angina for 6 months. He was a diabetic and hypertensive for 10 years. He was also a reformed smoker with 20 pack-years history of smoking. He did not give any history of acute coronary syndrome or any cardiac catheterisation. Clinical examination was unremarkable. ECG and chest X-ray were normal. Echocardiography revealed normal left ventricular function with features of left ventricular hypertrophy.

Coronary angiography revealed abnormal spillage of contrast in the left ventricular apical region with each diastole from obtuse marginal (OM) branch of left circumflex coronary artery (LCx) and distal part of left anterior descending coronary artery (LAD) suggestive of coronary–cameral fistula (CCMF) (figure 1, figure 2, online ). Coronary angiography did not show any signs of atherosclerotic coronary artery disease. Absence of dilated communicative fistulous tracts between the coronary arteries and the drainage chamber was...

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Delayed ischemic stroke due to stent marker band occlusion after stent-assisted coiling

A middle-aged patient with an internal carotid-posterior communicating artery aneurysm and basilar artery tip aneurysm was treated by stent-assisted coiling. One ischemic infarction and two transient ischemic attacks occurred with the same symptoms (inability to walk unassisted and tendency to fall to the left) during the first 2 years post-treatment. The ischemic infarction was found in the right side of the pons, consistent with the vascular territory of the stent-containing vessel. The cause of the delayed ischemic stroke was investigated on DSA and cone beam CT, which revealed that the proximal end of the stent, one marker band, was just covering a small perforating artery of the basilar artery trunk. The present case suggests that marker band occlusion can induce delayed ischemic stroke. To prevent this complication, it is important to evaluate the perforating vessels preoperatively and carefully deploy a stent for the marker band to avoid occlusion of large perforating vessels. Post-treatment evaluation is also important because dual antiplatelet therapy will be required for a longer period if an artery is occluded by a marker band.

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Fatal delayed haemolytic transfusion reaction in a patient without previous transfusions but with an obstetric history of 13 pregnancies

Delayed haemolytic transfusion reaction is a rare, life-threatening complication of blood transfusion that has been typically described among patients with sickle cell disease (SCD) due to alloimmunisation induced by their exposure to red blood cell antigens through recurrent transfusions. We report the case of a patient who suffered from fatal delayed haemolytic transfusion reaction (DHTR) occurring 1 week after blood transfusion. Indirect antiglobulin testing confirmed the presence of anti-Kell antibodies that were absent in the pretransfusion sample. The patient did not receive blood transfusions in the past, but her obstetric history was remarkable for 13 pregnancies. Although DHTR occurs more commonly among patients with SCD, this type of reaction can occur in any patient who is able to mount an immune response. We would to like to draw the attention of physicians to this rare and potentially lethal complication of blood transfusion, especially in grand multiparous women.

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Hepatic epithelioid haemangioendothelioma (HEHE): a diagnostic dilemma between haemangioma and angiosarcoma

We present a case of a 77-year-old male patient with a liver tumour diagnosed as hepatic epithelioid haemangioendothelioma (HEHE), a potentially malignant tumour treated with liver resection. The patient is disease-free 3 years after resection. Imaging features using fludeoxyglucose F 18 positron emission tomography CT and MRI with gadoxic acid as well as histopathological findings are discussed.

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Urinary tract aspergillosis in a patient with chronic kidney disease

Invasive aspergillosis is a life-threatening fungal infection, especially in immunocompromised patients. Pulmonary aspergillosis is the most common type of the infection, while urinary tract infection is relatively rare. Here, we describe a case of a 46-year-old man with chronic renal disease presenting with intermittent abdominal pain. The diagnosis of aspergillosis was established by pathological findings of the fungal ball in the bladder. The patient underwent multiple antimicrobial treatments and surgical interventions and was finally cured by posaconazole.

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Cabergoline-induced fibrosis of prolactinomas: a neurosurgical perspective

Presently, the standard of care for prolactinomas, a type of pituitary adenoma, is dopaminergic agents such as bromocriptine and cabergoline. However, dopaminergic agents may induce fibrosis of cardiac valves leading to valvular insufficiency, necessitating surgical treatment of prolactinoma. Fibrosis of prolactinoma can be induced by prolonged medical treatment with bromocriptine, and this usually occurs after years of treatment. In comparison to bromocriptine, there have been no reports of cabergoline-induced fibrosis of prolactinoma. There is a potential for greater emphasis to be placed on assessing the tumour consistency from preoperative MRI scans, or even preoperative contrast-enhanced 3D Fast Imaging Employing Steady-state Acquisition imaging to allow better planning of the surgery. We report a rare case of fibrosis of prolactinoma after cabergoline treatment resulting in its subsequent difficult surgical removal. This patient had early MRI changes of fibrosis of prolactinoma after a short period of 6 months of cabergoline treatment.

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Inflammatory optic disc neovascularisation managed with oral steroids/immunosuppressants and intravitreal ranibizumab

Inflammatory optic disc neovascularisation (NVD) has been treated with periocular or systemic steroids, immunosuppressants, panretinal photocoagulation and bevacizumab. However, the role of intravitreal ranibizumab in inflammatory NVD has not been explored in the peer-reviewed indexed literature. In case 1, NVD and associated subhyaloid haemorrhage showed rapid and dramatic regression after intravitreal ranibizumab. Recurrence was noted 8 weeks after injection which was managed by oral steroids. In case 2, intravitreal ranibizumab led to partial resolution of NVD. The addition of steroids, azathioprine and panretinal photocoagulation led to further fibrosis of the neovascularisation. Ranibizumab may be an important adjunct to anti-inflammatory therapy in the management of inflammatory NVD.

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Delayed-onset heparin-induced skin necrosis: a rare complication of perioperative heparin therapy

An uncommon case of delayed-onset dalteparin-induced skin necrosis in an 83-year-old Caucasian female patient associated with heparin-induced thrombocytopaenia (HIT) presenting on day 30 following dalteparin therapy is reported. Investigations revealed mild thrombocytopaenia with normal protein C, protein S, coagulation screen and positive test for heparin–platelet factor-4 antibody. Clinical diagnosis of heparin-induced skin necrosis with HIT was made. Dalteparin injection was discontinued promptly and substituted with fondaparinux therapy. The patient achieved good recovery following cessation of dalteparin therapy and was subsequently discharged.

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Giant phaeochromocytoma presenting with an acute stroke: reappraising phaeochromocytoma surveillance for the neurofibromatosis type 1 phakomatosis

Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder associated with reduced lifespan attributed largely to malignancy and vascular causes. One of the tumours associated with NF1 is phaeochromocytoma. The phaeochromocytoma has earned the moniker, a 'great mimicker', due to its varied means of presentation. We present a patient with NF1 who was diagnosed with a giant 20 cm phaeochromocytoma after suffering from an ischaemic stroke. Current guidelines do not advocate surveillance of phaeochromocytoma in asymptomatic patients with NF1, unlike other genetic syndromes associated with phaeochromocytoma. However, there is increasing evidence that this approach may not help in the early detection and treatment of this potentially life-threatening disease. Our patient remained hypertensive after surgery despite achieving biochemical cure. The suggested chronicity of the underlying tumour in our patient is a reminder to practising clinicians to rethink our strategy in identifying phaeochromocytoma in adults with NF1.

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Spontaneous subdural haematoma in a paediatric patient on anticoagulant therapy

Description

A 5-year old girl with congenital mitral and subaortic stenosis on anticoagulant therapy since her mechanical mitral valve replacement, and a remote history of idiopathic intrahepatic cholestasis requiring liver transplantation presented with jaundice and pruritus. She was found to have elevated transaminases, and an echocardiogram revealed significantly increased right ventricular pressures concerning for pulmonary hypertension. Subsequently, the patient needed to be intubated for respiratory insufficiency and poor cardiac output. After several days in the intensive care unit (ICU), she was noted to be bradycardic and have a dilated right pupil. A stat CT of the head demonstrated a large mixed density right-sided subdural haematoma with mass effect, midline shift and early uncal and transtentorial herniation, as well as a small subdural haematoma on the left (figure 1). The mixed density of the haematoma on CT scan was likely a result of multiple haemorrhages over the...

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Missed opportunity to diagnose subungual melanoma: potential pitfalls!

Subungual melanoma, an uncommon form of acral melanoma that arises within the nail matrix, accounts for 1%–3% of all cutaneous melanoma in Caucasians. As subungual melanoma presents in a more disguised manner than cutaneous lesions, increased vigilance is required. It most commonly presents as a discolouration of the nail, nail splitting or nail-bed bleeding. Black pigmentation of the adjacent nail fold, termed Hutchinson's sign, may be a diagnostic clue. Treatment of subungual melanoma remains surgical with wide local excision and amputation primary modalities. We present the case of a 61-year-old man with an 18-month history of a left thumb nail-bed abnormality and a 6-week history of left axillary lymphadenopathy. One year earlier, he presented to the emergency department with a purulent discharge from his left thumb but declined nail-bed ablation. He was referred to the 'Hand and Plastic Injuries Clinic' by his general practitioner and diagnosed with a chronic traumatic-induced nail-bed injury. As his symptoms did not improve, he was referred to the 2-week wait Skin Cancer Clinic. The left thumb nail-bed was excised as a nail unit down to bone, and the diagnosis of melanoma was rendered. Left axillary lymphadenopathy was confirmed as metastatic melanoma. He underwent amputation of his left thumb at the interproximal phalangeal joint, and a left axillary node dissection was performed. No residual melanoma was identified in his thumb. Microscopically, his left axillary dissection confirmed 9 out of 36 positive nodes for metastatic melanoma with extracapsular spread. He was staged at IIIC disease. This case report demonstrates missed opportunities to diagnose subungual melanoma and acts as a cautionary tale in considering this pathology in the differential diagnosis of nail-bed lesions with prompt referral for further investigation.

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