Executive functioning, academic skills, and quality of life in pediatric patients with brain tumors post-proton radiation therapy

Abstract

Radiation therapy (RT) is integral in the treatment of pediatric brain tumors; however, photon RT (XRT) often results in intellectual decline, executive functioning (EF) deficits, academic underachievement/failure, and lower health-related quality of life (HRQoL). Proton RT (PRT) provides more targeted therapy, minimizing damage to the developing brain, yet few studies have examined its neuropsychological effects. This study investigated the role of EF in academic skills and HRQoL in a sample of children treated with PRT. A mediation model was proposed in which academic skills mediated relations between aspects of EF and school-based HRQoL (sHRQoL). Sixty-five children (x̅_age = 12.4; 43.9% male) treated with PRT completed follow-up neuropsychological testing as part of routine care. Measures included assessment of intellectual functioning, EF, attention, and academic skills (reading, math, spelling). Parents reported on children's EF and attention problems. sHRQoL was assessed via child self-report. Children who underwent PRT demonstrated relatively intact intelligence, academics, attention, EF, and sHRQoL, but were at risk for reduced processing speed. Poorer working memory and processing speed were related to lower sHRQoL. Better EF and faster processing speed were associated with better academic skills, which were linked to higher sHRQoL. Better working memory was associated with better math performance, which was linked to higher sHRQoL; this relationship did not hold for reading or spelling. Results highlight the importance of EF skills in academic performance and sHRQoL, and the need for routine screening of EF deficits and proactive supports. Supports may include cognitive rehabilitation and in-class accommodations. Overall, results compare favorably to XRT outcomes reported in the literature.

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Executive functioning, academic skills, and quality of life in pediatric patients with brain tumors post-proton radiation therapy

Abstract

Radiation therapy (RT) is integral in the treatment of pediatric brain tumors; however, photon RT (XRT) often results in intellectual decline, executive functioning (EF) deficits, academic underachievement/failure, and lower health-related quality of life (HRQoL). Proton RT (PRT) provides more targeted therapy, minimizing damage to the developing brain, yet few studies have examined its neuropsychological effects. This study investigated the role of EF in academic skills and HRQoL in a sample of children treated with PRT. A mediation model was proposed in which academic skills mediated relations between aspects of EF and school-based HRQoL (sHRQoL). Sixty-five children (x̅_age = 12.4; 43.9% male) treated with PRT completed follow-up neuropsychological testing as part of routine care. Measures included assessment of intellectual functioning, EF, attention, and academic skills (reading, math, spelling). Parents reported on children's EF and attention problems. sHRQoL was assessed via child self-report. Children who underwent PRT demonstrated relatively intact intelligence, academics, attention, EF, and sHRQoL, but were at risk for reduced processing speed. Poorer working memory and processing speed were related to lower sHRQoL. Better EF and faster processing speed were associated with better academic skills, which were linked to higher sHRQoL. Better working memory was associated with better math performance, which was linked to higher sHRQoL; this relationship did not hold for reading or spelling. Results highlight the importance of EF skills in academic performance and sHRQoL, and the need for routine screening of EF deficits and proactive supports. Supports may include cognitive rehabilitation and in-class accommodations. Overall, results compare favorably to XRT outcomes reported in the literature.

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A multi-center pragmatic, randomized, feasibility trial comparing standard of care schedules of filgrastim administration for primary febrile neutropenia prophylaxis in early-stage breast cancer

Abstract

Introduction

The most effective duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer (EBC) patients is unknown. Despite significant differences in cost and toxicity, no prospective trial has been performed to optimize practice. We assessed the feasibility of using a novel pragmatic trial model to compare the most commonly used schedules of filgrastim.

Methods

Early breast cancer patients receiving chemotherapy were randomized to 5, 7, or 10 days of filgrastim as primary FN prophylaxis. The trial methodology integrated broad eligibility criteria, simply defined endpoints, an integrated consent model incorporating oral consent, and web-based randomization in the clinic. Feasibility was reflected through a combination of primary endpoints including patient and physician engagement (if > 50% of appropriate patients approached agree to participate, and if > 50% of physicians approached patients for the study). Secondary endpoints included the first occurrence rates of FN, treatment-related hospital admission, or chemotherapy dose reductions/delays/discontinuation.

Results

From May 2015 to August 2016, 142/149 (95.3%) patients approached agreed to participate and were randomized. Seventeen of 24 (70.8%) medical oncologists approached and randomized patients. The 142 patients received a total of 495 cycles of chemotherapy. Aggregate incidences of a first event by patient were FN (8/142, 5.6%), treatment-related hospitalization (6/142, 4.2%), chemotherapy discontinuation (7/142, 4.9%), chemotherapy delays (5/142, 3.5%), and chemotherapy dose reduction (18/142, 12.7%). Overall, 31.7% (45/142) of patients and 9.0% (45/495) of chemotherapy cycles were associated with one of these first events.

Conclusion

This study met its feasibility endpoints. This novel pragmatic trial approach offers a means of comparing standard of care treatments in a practical and cost-effective manner. The trial will now be expanded to compare rates of FN between the three filgrastim schedules.

Trial registration

ClinicalTrials.gov: NCT02428114.

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Acquired haemophilia A complicating alemtuzumab therapy for multiple sclerosis

Alemtuzumab is a highly efficacious therapy used in the treatment of multiple sclerosis (MS), but uncoupling of T and B cell repopulation during immune reconstitution associates with an increasing range of secondary B cell-mediated autoimmune complications. A 34-year-old woman developed Graves' disease 11 months following an initial course of alemtuzumab treatment for MS. Nine months following the second treatment with alemtuzumab, the patient presented with spontaneous intramuscular and subcutaneous haemorrhage due to development of an inhibitory autoantibody to coagulation factor VIII. Acquired haemophilia A (AHA) is an extremely rare complication in patients treated with alemtuzumab. Treatment with rituximab may induce a rapid remission of AHA; however, the patient's high John Cunningham virus (JCV) antibody index and alemtuzumab-induced T cell lymphopenia may lead to an increased risk of progressive multifocal leucoencephalopathy, a potential complication which was unacceptable to the patient.

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Parotid gland: an unusual site of breast cancer metastasis

Parotid gland metastases from breast cancer are an extremely rare and unusual event with a limited number of cases recorded in the literature. A 71-year-old woman with a history of ductal adenocarcinoma of the left breast presented to the maxillofacial clinic with an asymptomatic swelling of the left parotid gland. The presentation occurred 21 years after she underwent treatment for recurrent breast cancer. Investigations led to the diagnosis of a breast cancer metastasis which was oestrogen receptor and progesterone receptor positive and negative. Positron emission tomography scan confirmed this as a solitary metastasis. She was treated with aromatase inhibitors and a stable clinical response was observed on follow-up. Surgical intervention was avoided with its potential complications such as facial nerve injury. Metastasis from breast cancer to the parotid gland is a very rare phenomenon. However, in a patient with previous breast cancer, it should be considered as a possible differential diagnosis.

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Nerve abscess in pure neural leprosy mistaken for peripheral nerve sheath tumour with disastrous consequence: what can we learn?

A 34-year-old Indian man presented to an orthopaedician with gradually progressive hypoesthesia affecting his right lower limb and an ipsilateral common peroneal nerve swelling around the knee. The nerve swelling was diagnosed as a peripheral nerve sheath tumour based on MRI findings and was excised, only to be revealed as leprous nerve abscess on histopathology later. The patient developed right foot drop as a result of common peroneal nerve biopsy. This case presents several learning points in the diagnosis of pure neural leprosy.

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Gastric liposarcoma resected by laparoscopic total gastrectomy to achieve a wide surgical margin

Gastric liposarcoma is an extremely rare tumour that usually affects the extremities and retroperitoneum. Preoperative diagnosis is difficult, and operative procedures are not well standardised. A 61-year-old woman presented with melaena, epigastric discomfort and palpitations. Upper endoscopy revealed a submucosal tumour at the posterior gastric fundus with an actively bleeding ulcer on the top. Our preoperative diagnosis was lipoma, and we performed laparoscopic intragastric surgery. However, the histopathological diagnosis was liposarcoma. Laparoscopic total gastrectomy was performed to achieve a wide surgical margin. Several recent series have shown that a positive microscopic margin is associated with a higher rate of local recurrence than a negative margin. We have added a staged operation to obtain a wide margin in cases involving a positive surgical margin. Preoperative diagnosis of liposarcoma is still challenging. Gastric lipoma-like tumours should be resected with a wide margin because of their possibility of malignancy.

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Pathological ECG that seemed normal following electrode misplacement

We report the case of a 57-year-old woman found at home who received an ECG after having recovered from a seizure, without any clinical cardiac anomaly. The ECG revealed an elevation of the ST segment from the V1 to V5 leads and negative T waves from V1 to V5 leads. At her hospital admission, the emergency care unit (ECU) nurse performed another ECG. It no longer showed any repolarisation anomaly. However, the ECU nurse had put the precordial electrodes 3 cm too low, probably due to the patient's voluminous breasts. In the end, the pathological trace reappeared after we returned the electrodes to their initial positions. Malpositioning of the electrodes caused a seemingly normal ECG result with life-threatening consequences.

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Lentiform fork sign due to severe metabolic acidosis

Description

An 11-month-old, developmentally normal, female infant presented with acute-onset fever, vomiting, shallow breathing and gradually progressive lethargy for the past 2 days. There was no history of seizures, neck stiffness, focal motor deficits, cranial nerve palsies, tone changes, rash, diarrhoea, recurrent encephalopathies, abnormal body odour, recurrent infections or hospitalisations, drug or toxin ingestion. Her past and family history was not contributory. On examination, anthropometric parameters were normal for age. She had mild pallor, angular cheilitis, wrist widening, tachypnea (respiratory rate 58/min) with acidotic breathing. She was conscious with fluctuations in alertness (Glasgow Coma Scale (GCS) E4M5V2) and irritability with reduced spontaneous activity, mild hypotonia, preserved antigravity movements, brisk muscle stretch reflexes, bilateral extensor plantar response, absence of oculomotor abnormalities, cranial nerve palsies or bulbar signs and normal fundi. Rest of the systemic examination was unremarkable. A clinical diagnosis of acute febrile encephalopathy was considered.

Laboratory investigations showed...

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Dysphagia lusoria presenting as epigastric pain

Description

A 36-year-old African–American woman with medical history of systemic lupus erythematosus, lupus nephritis, protein S deficiency and recurrent deep venous thrombosis presented to outpatient clinic complaining of epigastric pain associated with nausea, vomiting and unintentional weight loss. Esophagogastroduodenoscopy (EGD) was performed; however, mucosal tear was noted following severe retching. Subsequently, the procedure was terminated. EGD was significant for distal oesophageal obstruction. CT of the chest with contrast was significant for pneumomediastinum. Moreover it demonstrated an aberrant right subclavian artery compressing on the posterior part of the oesophagus (figure 1). The patient was diagnosed with dysphagia lusoria. This patient's symptoms were moderate and managed with dietary modifications. Thus, surgical intervention was not recommended. There was no further progression of symptoms at 1-year follow-up.

Figure 1

Aberrant right subclavian artery compressing on the posterior part of the oesophagus.

Dysphagia lusoria is a condition...

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Painful testicular metastasis from prostate adenocarcinoma

A 60-year-old man presented with unilateral testicular pain and urinary frequency. His presenting prostate-specific antigen (PSA) was 100 ng/mL, and a biopsy revealed Gleason 4+4 prostate adenocarcinoma. The significance of his initial PSA was somewhat complicated by possible prostatitis and early initiation of bicalutamide. PSA rose on two occasions prior to radiotherapy but coincided with a flare of testicular pain on one of these. Whole-body staging diffusion-weighted MRI scan was negative. He was treated with 3 years of androgen deprivation therapy (ADT) and radical radiotherapy. PSA fell to undetectable levels on ADT. Twelve months following completion of ADT, PSA rose to 3.6 ng/mL. No disease recurrence was noted on restaging MRI pelvis. The patient was well, except for persistent testicular symptoms, which failed to resolve following multiple antibiotics. Testicular tumour markers were negative. Ultrasound findings were consistent with chronic epididymitis. A right orchidectomy was performed for symptomatic relief, confirming metastatic prostate adenocarcinoma.

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99m Tc-rituximab as a tracer for sentinel lymph node biopsy in breast cancer patients: a single-center analysis

Abstract

Purpose

This study aimed to determine the long-term prognosis of breast cancer patients with ^99mTc-rituximab for sentinel lymph node biopsy (SLNB).

Methods

A total of 2947 patients with negative sentinel lymph nodes (SLNs) omitting axillary lymph node dissection (ALND), treated between June 2005 and December 2013, were retrospectively analyzed. SLNB was performed prior to adjuvant therapy.

Results

After a median follow-up of 62 months, 22 cases of axillary recurrence (AR) were observed. The 5-year AR rate (ARR) was 0.7% [95% confidence interval (CI) 0.3–1.1%] and the 5-year relapse-free survival (RFS) was 95.2% (95% CI 94.4–96.0%). Multivariate analysis showed that abnormal axillary ultrasound with negative fine-needle aspiration (FNA) [hazard ratio (HR) 3.79, 95% CI 1.55–9.28; P = 0.004], not receiving radiotherapy (HR 4.38, 95% CI 1.47–13.05; P = 0.008), and age ≤ 40 years (HR 2.93, 95% CI 1.19–7.20; P = 0.020) were independent risk factors for AR.

Conclusions

ARR of SLNB-negative patients with ^99mTc-rituximab is low. Abnormal axillary ultrasound with negative FNA, not receiving radiotherapy, and age ≤ 40 years were prognostic factors for higher ARRs.

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Calpain-2 inhibitor treatment preferentially reduces tumor progression for human colon cancer cells expressing highest levels of this enzyme

Abstract

Calpain-2 levels are higher in colorectal tumors resistant to chemotherapy and previous work showed calpain-2 inhibitor therapy reduced inflammation-driven colorectal cancer, but direct effects of the inhibitor on colon cancer cells themselves were not demonstrated. In the present study, five human colon cancer cell lines were directly treated with a calpain-2 inhibitor and results showed increased cell death in 4 of 5 cell lines and decreased anchorage-independent growth for all cell five lines. When tested for levels of calpain-2, three cell lines exhibited increasing levels of this enzyme: HCT15 (low), HCC2998 (medium), and HCT116 (significantly higher). This was consistent with gel shift assays showing that calpain-2 inhibitor reduced of NF-κB nuclear translocation most effectively in HCT116 cells. Ability of calpain-2 inhibitor to impede tumor progression in vivo was evaluated using intrarectal transplant of luciferase-expressing cells for these three cell lines. Results showed that calpain-2 inhibitor therapy reduced tumor growth and increased survival only in mice injected with HCT116 cells. These data suggest calpain-2 inhibitor treatment may be most effective on colorectal tumors expressing highest levels of calpain-2.

Calpain-2 inhibitor therapy reduces inflammation in the colon, but its direct effects on colon cancer cells are unknown. This study shows in vitro and in vivo that calpain-2 inhibitor has the strongest therapeutic effects on colon cancer cells expressing the highest levels of calpain-2.

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Calpain-2 inhibitor treatment preferentially reduces tumor progression for human colon cancer cells expressing highest levels of this enzyme

Abstract

Calpain-2 levels are higher in colorectal tumors resistant to chemotherapy and previous work showed calpain-2 inhibitor therapy reduced inflammation-driven colorectal cancer, but direct effects of the inhibitor on colon cancer cells themselves were not demonstrated. In the present study, five human colon cancer cell lines were directly treated with a calpain-2 inhibitor and results showed increased cell death in 4 of 5 cell lines and decreased anchorage-independent growth for all cell five lines. When tested for levels of calpain-2, three cell lines exhibited increasing levels of this enzyme: HCT15 (low), HCC2998 (medium), and HCT116 (significantly higher). This was consistent with gel shift assays showing that calpain-2 inhibitor reduced of NF-κB nuclear translocation most effectively in HCT116 cells. Ability of calpain-2 inhibitor to impede tumor progression in vivo was evaluated using intrarectal transplant of luciferase-expressing cells for these three cell lines. Results showed that calpain-2 inhibitor therapy reduced tumor growth and increased survival only in mice injected with HCT116 cells. These data suggest calpain-2 inhibitor treatment may be most effective on colorectal tumors expressing highest levels of calpain-2.

Calpain-2 inhibitor therapy reduces inflammation in the colon, but its direct effects on colon cancer cells are unknown. This study shows in vitro and in vivo that calpain-2 inhibitor has the strongest therapeutic effects on colon cancer cells expressing the highest levels of calpain-2.

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[ 18 F]-BMS-747158-02PET imaging for evaluating hepatic mitochondrial complex 1dysfunction in a mouse model of non-alcoholic fatty liver disease

Abstract

Background

Mitochondrial dysfunction is one of the main causes of non-alcohol fatty liver disease (NAFLD). [¹⁸F]-BMS-747158-02 (¹⁸F-BMS) which was originally developed as a myocardial perfusion imaging agent was reported to bind mitochondrial complex-1 (MC-1). The aim of this study was to investigate the potential use of ¹⁸F-BMS for evaluating hepatic MC-1 activity in mice fed a methionine- and choline-deficient (MCD) diet.

Male C57BL/6J mice were fed a MCD diet for up to 2 weeks. PET scans with ¹⁸F-BMS were performed after 1 and 2 weeks of the MCD diet. ¹⁸F-BMS was intravenously injected into mice, and the uptake (standardized uptake value (SUV)) in the liver was determined. The binding specificity for MC-1 was assessed by pre-administration of rotenone, a specific MC-1 inhibitor. Hepatic MC-1 activity was measured using liver homogenates generated after each positron emission tomography (PET) scan. Blood biochemistry and histopathology were also assessed.

Results

In control mice, hepatic ¹⁸F-BMS uptake was significantly inhibited by the pre-injection of rotenone. The uptake of ¹⁸F-BMS was significantly decreased after 2 weeks of the MCD diet. The SUV at 30–60 min was well correlated with hepatic MC-1 activity (r = 0.73, p < 0.05). Increases in plasma ALT and AST levels were also noted at 1 and 2 weeks. Mild hepatic steatosis with or without minimal inflammation was histopathologically observed at 1 and 2 weeks in mice liver on the MCD diet. However, inflammation was observed only at 2 weeks in mice on the MCD diet.

Conclusions

The present study demonstrated that ¹⁸F-BMS is a potential PET probe for quantitative imaging of hepatic MC-1 activity and its mitochondrial dysfunction induced by steatosis and inflammation, such as in NAFLD.

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[ 18 F]-BMS-747158-02PET imaging for evaluating hepatic mitochondrial complex 1dysfunction in a mouse model of non-alcoholic fatty liver disease

Abstract

Background

Mitochondrial dysfunction is one of the main causes of non-alcohol fatty liver disease (NAFLD). [¹⁸F]-BMS-747158-02 (¹⁸F-BMS) which was originally developed as a myocardial perfusion imaging agent was reported to bind mitochondrial complex-1 (MC-1). The aim of this study was to investigate the potential use of ¹⁸F-BMS for evaluating hepatic MC-1 activity in mice fed a methionine- and choline-deficient (MCD) diet.

Male C57BL/6J mice were fed a MCD diet for up to 2 weeks. PET scans with ¹⁸F-BMS were performed after 1 and 2 weeks of the MCD diet. ¹⁸F-BMS was intravenously injected into mice, and the uptake (standardized uptake value (SUV)) in the liver was determined. The binding specificity for MC-1 was assessed by pre-administration of rotenone, a specific MC-1 inhibitor. Hepatic MC-1 activity was measured using liver homogenates generated after each positron emission tomography (PET) scan. Blood biochemistry and histopathology were also assessed.

Results

In control mice, hepatic ¹⁸F-BMS uptake was significantly inhibited by the pre-injection of rotenone. The uptake of ¹⁸F-BMS was significantly decreased after 2 weeks of the MCD diet. The SUV at 30–60 min was well correlated with hepatic MC-1 activity (r = 0.73, p < 0.05). Increases in plasma ALT and AST levels were also noted at 1 and 2 weeks. Mild hepatic steatosis with or without minimal inflammation was histopathologically observed at 1 and 2 weeks in mice liver on the MCD diet. However, inflammation was observed only at 2 weeks in mice on the MCD diet.

Conclusions

The present study demonstrated that ¹⁸F-BMS is a potential PET probe for quantitative imaging of hepatic MC-1 activity and its mitochondrial dysfunction induced by steatosis and inflammation, such as in NAFLD.

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Radiomics based analysis to predict local control and survival in hepatocellular carcinoma patients treated with volumetric modulated arc therapy

Abstract

Background

To appraise the ability of a radiomics based analysis to predict local response and overall survival for patients with hepatocellular carcinoma.

Methods

A set of 138 consecutive patients (112 males and 26 females, median age 66 years) presented with Barcelona Clinic Liver Cancer (BCLC) stage A to C were retrospectively studied. For a subset of these patients (106) complete information about treatment outcome, namely local control, was available. Radiomic features were computed for the clinical target volume. A total of 35 features were extracted and analyzed. Univariate analysis was used to identify clinical and radiomics significant features. Multivariate models by Cox-regression hazards model were built for local control and survival outcome. Models were evaluated by area under the curve (AUC) of receiver operating characteristic (ROC) curve. For the LC analysis, two models selecting two groups of uncorrelated features were analyzes while one single model was built for the OS analysis.

Results

The univariate analysis lead to the identification of 15 significant radiomics features but the analysis of cross correlation showed several cross related covariates. The un-correlated variables were used to build two separate models; both resulted into a single significant radiomic covariate: model-1: energy p < 0.05, AUC of ROC 0.6659, C.I.: 0.5585–0.7732; model-2: GLNU p < 0.05, AUC 0.6396, C.I.:0.5266–0.7526.

The univariate analysis for covariates significant with respect to local control resulted in 9 clinical and 13 radiomics features with multiple and complex cross-correlations. After elastic net regularization, the most significant covariates were compacity and BCLC stage, with only compacity significant to Cox model fitting (Cox model likelihood ratio test p < 0.0001, compacity p < 0.00001; AUC of the model is 0.8014 (C.I. = 0.7232–0.8797)).

Conclusion

A robust radiomic signature, made by one single feature was finally identified. A validation phases, based on independent set of patients is scheduled to be performed to confirm the results.

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Concordance of FDG PET/CT metabolic tumour volume versus DW-MRI functional tumour volume with T2-weighted anatomical tumour volume in cervical cancer

Abstract

Background

¹⁸F–fluoro-deoxyglucose positron emission tomography with computed tomography (FDG PET/CT) has been employed to define radiotherapy targets using a threshold based on the standardised uptake value (SUV), and has been described for use in cervical cancer. The aim of this study was to evaluate the concordance between the metabolic tumour volume (MTV) measured on FDG PET/CT and the anatomical tumour volume (ATV) measured on T2-weighted magnetic resonance imaging (T2W-MRI); and compared with the functional tumour volume (FTV) measured on diffusion-weighted MRI (DW-MRI) in cervical cancer, taking the T2W-ATV as gold standard.

Methods

Consecutive newly diagnosed cervical cancer patients who underwent FDG PET/CT and DW-MRI were retrospectively reviewed from June 2013 to July 2017.

Volumes of interest was inserted to the focal hypermetabolic activity corresponding to the cervical tumour on FDG PET/CT with automated tumour contouring and manual adjustment, based on SUV 20%–80% thresholds of the maximum SUV (SUVmax) to define the MTV_20–80, with intervals of 5%.

Tumour areas were manually delineated on T2W-MRI and multiplied by slice thickness to calculate the ATV.

FTV were derived by manually delineating tumour area on ADC map, multiplied by the slice thickness to determine the FTV_(manual). Diffusion restricted areas was extracted from b0 and ADC map using K-means clustering to determine the FTV_{(semi-automated)}.

The ATVs, FTVs and the MTVs at different thresholds were compared using the mean and correlated using Pearson's product-moment correlation.

Results

Twenty-nine patients were evaluated (median age 52 years). Paired difference of mean between ATV and MTV was the closest and not statistically significant at MTV₃₀ (−2.9cm³, −5.2%, p = 0.301). This was less than the differences between ATV and FTV_{(semi-automated)} (25.0cm³, 45.1%, p < 0.001) and FTV_(manual) (11.2cm³, 20.1%, p = 0.001). The correlation of MTV₃₀ with ATV was excellent (r = 0.968, p < 0.001) and better than that of the FTVs.

Conclusions

Our study demonstrated that MTV₃₀ was the only parameter investigated with no statistically significant difference with ATV, had the least absolute difference from ATV, and showed excellent positive correlation with ATV, suggesting its superiority as a functional imaging modality when compared with DW-MRI and supporting its use as a surrogate for ATV for radiotherapy tumour contouring.

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Overexpression of Cullin7 is associated with hepatocellular carcinoma progression and pathogenesis

Abstract

Background

Overexpression of Cullin7 is associated with some types of malignancies. However, the part of Cullin7 in hepatocellular carcinoma remains unclear. The aim of this study was to investigate the role of Cullin7 in pathogenesis and the progression of hepatocellular carcinoma.

Methods

In the present study, the expression of Cullin7 in hepatocellular carcinoma cell lines and five surgical hepatocellular carcinoma specimens was detected with quantitative reverse transcription PCR and western blotting. In addition, the protein expression of Cullin7 was examined in 162 cases of archived hepatocellular carcinoma using immunohistochemistry.

Results

We found elevated expression of both mRNA and protein levels of Cullin7 in hepatocellular carcinoma cell lines, and Cullin7 protein was significantly upregulated in hepatocellular carcinoma compared with paired normal hepatic tissues. The immunohistochemistry analysis revealed that overexpression of Cullin7 occurred in 69.1% of hepatocellular carcinoma samples, which was a significantly higher rate than that in adjacent normal hepatic tissue (P < 0.01). Statistical analysis found that overexpression of Cullin7 was significantly associated with lymph node metastasis, tumor thrombus of the portal vein and advanced clinical stage (P < 0.05). Furthermore, by overexpressing Cullin7 in hepatocellular carcinoma HepG2 cells, we revealed that Cullin7 could significantly enhance cell proliferation, growth, migration and invasion. Conversely, knocking down Cullin7 expression with short hairpin RNAi in hepatocellular carcinoma HepG2 cells inhibited cell proliferation, growth, migration and invasion.

Conclusion

Our studies provide evidence that overexpression of Cullin7 plays an important role in the pathogenesis and progression of hepatocellular carcinoma and may be a valuable marker for hepatocellular carcinoma management.

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Study protocol for a cluster-randomized trial to compare human papillomavirus based cervical cancer screening in community-health campaigns versus health facilities in western Kenya

Abstract

Background

Despite guidelines for cervical cancer prevention in low-resource countries, a very small proportion of women in these settings undergo screening, and even fewer women are successfully treated. Using pilot data from western Kenya and World Health Organization recommendations, we developed a protocol to implement evidence-based cervical cancer screening and linkage to treatment strategies to the rural communities. We describe the protocol for a cluster-randomized trial to compare two implementation strategies for human-papillomavirus (HPV)-based cervical cancer screening program using metrics described in the RE-AIM (reach, efficacy, adaption, implementation and maintenance) framework.

Methods

The study is a three-year, two-phase cluster-randomized trial in 18 communities in western Kenya. During Phase 1, six control communities were offered screening in health facilities; and six intervention communities were offered screening in community health campaigns. Screening was done with human-papillomavirus testing through self-collected specimens. Phase 1 ended and we are working in partnership with communities to further contextualize the implementation strategy for screening, and develop an enhanced linkage to treatment plan. This plan will be tested in an additional six communities in Phase 2 (enhanced intervention). We will compare the reach, efficacy, cost-effectiveness and adaptability of the implementation strategies.

Discussion

Effective low-cost cervical cancer prevention technologies are becoming more widely available in low- and middle-income countries. Despite increasing government support for cervical cancer prevention, there remains a sizeable gap in service availability. We will use implementation science to identify the most effective strategies to fill this gap through development of context-specific evidence-based solutions. This protocol design and results can help guide implementation of cervical cancer screening in similar settings, where women are most underserved and at highest risk for disease.

Trial registration

This trial is registered at ClinicalTrials.gov, NCT02124252.

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Decreased expression of the β 2 integrin on tumor cells is associated with a reduction in liver metastasis of colorectal cancer in mice

Abstract

Background

Lymphocyte Function-Associated Antigen-1 (LFA-1; CD18/CD11a) is one of the main adhesion molecules used by immune cells to infiltrate the liver under inflammatory conditions. Recently, the expression of this integrin has also been reported on several solid tumors, including colorectal cancer. However, its functional role in the metastatic progression to the liver remains unknown. Using in vitro assays and an experimental orthotopic in vivo model of liver metastasis, we aimed to elucidate the role of tumor LFA-1 in the metastatic progression by means of the partial depletion of the β₂ subunit of LFA-1, required for integrin activation, firm adhesion and signaling.

Methods

To do so, we evaluated the effects of β₂ reduction on the murine colon carcinoma C26 cell line on their pro-metastatic features in vitro and their metastatic potential in vivo in a mouse model of colon carcinoma metastasis to the liver.

Results

The reduction in β₂ integrin expression correlated with a slower proliferation, and a reduced adhesion and migration of C26 cells in an in vitro setting. Additionally, tumor cells with a reduced in β₂ integrin expression were unable to activate the liver sinusoidal endothelial cells (LSECs). This resulted in a recovery of the cytotoxic potential of liver lymphocytes which is compromised by LSECs activated by C26 cells. This was related to the abrogation of RNA expression of inflammatory and angiogenic cytokines by C26 cells after their activation with sICAM-1, the main ligand of β₂α_L. Furthermore, in vivo tumor cell retention and metastasis were profoundly reduced, along with a decrease in the recruitment and infiltration of myeloid derived suppressor cells (MDSCs) and lymphocytes to the liver.

Conclusion

Taken together, our findings uncovered the modulatory role for the tumor β₂ subunit of the LFA-1 integrin in the metastatic progression of colorectal cancer to the liver by impairing activation of liver endothelium and thus, the local immune response in the liver. Besides, this integrin also showed to be critical in vivo for tumor cell retention, cytokine release, leukocyte recruitment and metastasis development. These data support a therapeutical potential of the integrin LFA-1 as a target for the treatment of colorectal liver metastasis.

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Uterine rupture in a primigravid patient, an uncommon but severe obstetrical event: a case report

A spontaneous rupture of the unscarred uterus in a primigravid patient is extremely rare and is associated with high perinatal and maternal morbidity and mortality.

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Radiomics based analysis to predict local control and survival in hepatocellular carcinoma patients treated with volumetric modulated arc therapy

Abstract

Background

To appraise the ability of a radiomics based analysis to predict local response and overall survival for patients with hepatocellular carcinoma.

Methods

A set of 138 consecutive patients (112 males and 26 females, median age 66 years) presented with Barcelona Clinic Liver Cancer (BCLC) stage A to C were retrospectively studied. For a subset of these patients (106) complete information about treatment outcome, namely local control, was available. Radiomic features were computed for the clinical target volume. A total of 35 features were extracted and analyzed. Univariate analysis was used to identify clinical and radiomics significant features. Multivariate models by Cox-regression hazards model were built for local control and survival outcome. Models were evaluated by area under the curve (AUC) of receiver operating characteristic (ROC) curve. For the LC analysis, two models selecting two groups of uncorrelated features were analyzes while one single model was built for the OS analysis.

Results

The univariate analysis lead to the identification of 15 significant radiomics features but the analysis of cross correlation showed several cross related covariates. The un-correlated variables were used to build two separate models; both resulted into a single significant radiomic covariate: model-1: energy p < 0.05, AUC of ROC 0.6659, C.I.: 0.5585–0.7732; model-2: GLNU p < 0.05, AUC 0.6396, C.I.:0.5266–0.7526.

The univariate analysis for covariates significant with respect to local control resulted in 9 clinical and 13 radiomics features with multiple and complex cross-correlations. After elastic net regularization, the most significant covariates were compacity and BCLC stage, with only compacity significant to Cox model fitting (Cox model likelihood ratio test p < 0.0001, compacity p < 0.00001; AUC of the model is 0.8014 (C.I. = 0.7232–0.8797)).

Conclusion

A robust radiomic signature, made by one single feature was finally identified. A validation phases, based on independent set of patients is scheduled to be performed to confirm the results.

http://ift.tt/2B49Zj1

Concordance of FDG PET/CT metabolic tumour volume versus DW-MRI functional tumour volume with T2-weighted anatomical tumour volume in cervical cancer

Abstract

Background

¹⁸F–fluoro-deoxyglucose positron emission tomography with computed tomography (FDG PET/CT) has been employed to define radiotherapy targets using a threshold based on the standardised uptake value (SUV), and has been described for use in cervical cancer. The aim of this study was to evaluate the concordance between the metabolic tumour volume (MTV) measured on FDG PET/CT and the anatomical tumour volume (ATV) measured on T2-weighted magnetic resonance imaging (T2W-MRI); and compared with the functional tumour volume (FTV) measured on diffusion-weighted MRI (DW-MRI) in cervical cancer, taking the T2W-ATV as gold standard.

Methods

Consecutive newly diagnosed cervical cancer patients who underwent FDG PET/CT and DW-MRI were retrospectively reviewed from June 2013 to July 2017.

Volumes of interest was inserted to the focal hypermetabolic activity corresponding to the cervical tumour on FDG PET/CT with automated tumour contouring and manual adjustment, based on SUV 20%–80% thresholds of the maximum SUV (SUVmax) to define the MTV_20–80, with intervals of 5%.

Tumour areas were manually delineated on T2W-MRI and multiplied by slice thickness to calculate the ATV.

FTV were derived by manually delineating tumour area on ADC map, multiplied by the slice thickness to determine the FTV_(manual). Diffusion restricted areas was extracted from b0 and ADC map using K-means clustering to determine the FTV_{(semi-automated)}.

The ATVs, FTVs and the MTVs at different thresholds were compared using the mean and correlated using Pearson's product-moment correlation.

Results

Twenty-nine patients were evaluated (median age 52 years). Paired difference of mean between ATV and MTV was the closest and not statistically significant at MTV₃₀ (−2.9cm³, −5.2%, p = 0.301). This was less than the differences between ATV and FTV_{(semi-automated)} (25.0cm³, 45.1%, p < 0.001) and FTV_(manual) (11.2cm³, 20.1%, p = 0.001). The correlation of MTV₃₀ with ATV was excellent (r = 0.968, p < 0.001) and better than that of the FTVs.

Conclusions

Our study demonstrated that MTV₃₀ was the only parameter investigated with no statistically significant difference with ATV, had the least absolute difference from ATV, and showed excellent positive correlation with ATV, suggesting its superiority as a functional imaging modality when compared with DW-MRI and supporting its use as a surrogate for ATV for radiotherapy tumour contouring.

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Overexpression of Cullin7 is associated with hepatocellular carcinoma progression and pathogenesis

Abstract

Background

Overexpression of Cullin7 is associated with some types of malignancies. However, the part of Cullin7 in hepatocellular carcinoma remains unclear. The aim of this study was to investigate the role of Cullin7 in pathogenesis and the progression of hepatocellular carcinoma.

Methods

In the present study, the expression of Cullin7 in hepatocellular carcinoma cell lines and five surgical hepatocellular carcinoma specimens was detected with quantitative reverse transcription PCR and western blotting. In addition, the protein expression of Cullin7 was examined in 162 cases of archived hepatocellular carcinoma using immunohistochemistry.

Results

We found elevated expression of both mRNA and protein levels of Cullin7 in hepatocellular carcinoma cell lines, and Cullin7 protein was significantly upregulated in hepatocellular carcinoma compared with paired normal hepatic tissues. The immunohistochemistry analysis revealed that overexpression of Cullin7 occurred in 69.1% of hepatocellular carcinoma samples, which was a significantly higher rate than that in adjacent normal hepatic tissue (P < 0.01). Statistical analysis found that overexpression of Cullin7 was significantly associated with lymph node metastasis, tumor thrombus of the portal vein and advanced clinical stage (P < 0.05). Furthermore, by overexpressing Cullin7 in hepatocellular carcinoma HepG2 cells, we revealed that Cullin7 could significantly enhance cell proliferation, growth, migration and invasion. Conversely, knocking down Cullin7 expression with short hairpin RNAi in hepatocellular carcinoma HepG2 cells inhibited cell proliferation, growth, migration and invasion.

Conclusion

Our studies provide evidence that overexpression of Cullin7 plays an important role in the pathogenesis and progression of hepatocellular carcinoma and may be a valuable marker for hepatocellular carcinoma management.

http://ift.tt/2B3i5YO

Study protocol for a cluster-randomized trial to compare human papillomavirus based cervical cancer screening in community-health campaigns versus health facilities in western Kenya

Abstract

Background

Despite guidelines for cervical cancer prevention in low-resource countries, a very small proportion of women in these settings undergo screening, and even fewer women are successfully treated. Using pilot data from western Kenya and World Health Organization recommendations, we developed a protocol to implement evidence-based cervical cancer screening and linkage to treatment strategies to the rural communities. We describe the protocol for a cluster-randomized trial to compare two implementation strategies for human-papillomavirus (HPV)-based cervical cancer screening program using metrics described in the RE-AIM (reach, efficacy, adaption, implementation and maintenance) framework.

Methods

The study is a three-year, two-phase cluster-randomized trial in 18 communities in western Kenya. During Phase 1, six control communities were offered screening in health facilities; and six intervention communities were offered screening in community health campaigns. Screening was done with human-papillomavirus testing through self-collected specimens. Phase 1 ended and we are working in partnership with communities to further contextualize the implementation strategy for screening, and develop an enhanced linkage to treatment plan. This plan will be tested in an additional six communities in Phase 2 (enhanced intervention). We will compare the reach, efficacy, cost-effectiveness and adaptability of the implementation strategies.

Discussion

Effective low-cost cervical cancer prevention technologies are becoming more widely available in low- and middle-income countries. Despite increasing government support for cervical cancer prevention, there remains a sizeable gap in service availability. We will use implementation science to identify the most effective strategies to fill this gap through development of context-specific evidence-based solutions. This protocol design and results can help guide implementation of cervical cancer screening in similar settings, where women are most underserved and at highest risk for disease.

Trial registration

This trial is registered at ClinicalTrials.gov, NCT02124252.

http://ift.tt/2ntQgTE

Decreased expression of the β 2 integrin on tumor cells is associated with a reduction in liver metastasis of colorectal cancer in mice

Abstract

Background

Lymphocyte Function-Associated Antigen-1 (LFA-1; CD18/CD11a) is one of the main adhesion molecules used by immune cells to infiltrate the liver under inflammatory conditions. Recently, the expression of this integrin has also been reported on several solid tumors, including colorectal cancer. However, its functional role in the metastatic progression to the liver remains unknown. Using in vitro assays and an experimental orthotopic in vivo model of liver metastasis, we aimed to elucidate the role of tumor LFA-1 in the metastatic progression by means of the partial depletion of the β₂ subunit of LFA-1, required for integrin activation, firm adhesion and signaling.

Methods

To do so, we evaluated the effects of β₂ reduction on the murine colon carcinoma C26 cell line on their pro-metastatic features in vitro and their metastatic potential in vivo in a mouse model of colon carcinoma metastasis to the liver.

Results

The reduction in β₂ integrin expression correlated with a slower proliferation, and a reduced adhesion and migration of C26 cells in an in vitro setting. Additionally, tumor cells with a reduced in β₂ integrin expression were unable to activate the liver sinusoidal endothelial cells (LSECs). This resulted in a recovery of the cytotoxic potential of liver lymphocytes which is compromised by LSECs activated by C26 cells. This was related to the abrogation of RNA expression of inflammatory and angiogenic cytokines by C26 cells after their activation with sICAM-1, the main ligand of β₂α_L. Furthermore, in vivo tumor cell retention and metastasis were profoundly reduced, along with a decrease in the recruitment and infiltration of myeloid derived suppressor cells (MDSCs) and lymphocytes to the liver.

Conclusion

Taken together, our findings uncovered the modulatory role for the tumor β₂ subunit of the LFA-1 integrin in the metastatic progression of colorectal cancer to the liver by impairing activation of liver endothelium and thus, the local immune response in the liver. Besides, this integrin also showed to be critical in vivo for tumor cell retention, cytokine release, leukocyte recruitment and metastasis development. These data support a therapeutical potential of the integrin LFA-1 as a target for the treatment of colorectal liver metastasis.

http://ift.tt/2zQ0Dmr

JCAR015 in ALL: A Root-Cause Investigation [News in Brief]

Early CAR T-cell expansion, inflammatory cytokine surge among factors linked with fatal cerebral edema.

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FOXA1 inhibits hepatocellular carcinoma progression by suppressing PIK3R1 expression in male patients

Abstract

Background

Forkhead box A1 (FOXA1) expression is associated with various types of tumors; however, the function and underlying mechanism of FOXA1 in the development of hepatocellular carcinoma (HCC) remains obscure.

Methods

Here, we investigated the role of FOXA1 in the development of HCC by applying gene function gain and loss analysis to HepG2 and Hep3B cell lines, and comparing outcomes with those of clinical HCC samples.

Results

Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), which encodes protein PI3Kp85 (p85), was identified as a FOXA1 target gene. Analyses of the mechanism and function revealed that FOXA1 suppresses hepatocellular carcinoma cell viability and motility by inhibiting PI3K/Akt signaling through direct inhibition of PIK3R1 transcription. Moreover, in clinical samples from male HCC patients, FOXA1 expression was much lower, whereas PI3Kp85 levels were much higher in tumor than in non-tumor tissues. Elevated PI3Kp85 is an unfavorable factor in HCC.

Conclusions

As a tumor suppressor, FOXA1 targets PIK3R1 directly to inhibit PI3K/Akt signaling pathway, thus exerting a negative regulatory effect on proliferation, migration, and invasion of HCC in male patients.

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Identification and validation of a 44-gene expression signature for the classification of renal cell carcinomas

Abstract

Background

Renal cancers account for more than 3% of all adult malignancies and cause more than 23,400 deaths per year in China alone. The four most common types of kidney tumours include clear cell, papillary, chromophobe and benign oncocytoma. These histological subtypes vary in their clinical course and prognosis, and different clinical strategies have been developed for their management. Some kidney tumours can be very difficult to distinguish based on the pathological assessment of morphology and immunohistochemistry.

Methods

Six renal cell carcinoma microarray data sets, including 106 clear cell, 66 papillary, 42 chromophobe, 46 oncocytoma and 35 adjacent normal tissue samples, were subjected to integrative analysis. These data were combined and used as a training set for candidate gene expression signature identification. In addition, two independent cohorts of 1020 RNA-Seq samples from The Cancer Genome Atlas database and 129 qRT-PCR samples from Fudan University Shanghai Cancer Center (FUSCC) were analysed to validate the selected gene expression signature.

Results

A 44-gene expression signature derived from microarray analysis was strongly associated with the histological differentiation of renal tumours and could be used for tumour subtype classification. The signature performance was further validated in 1020 RNA-Seq samples and 129 qRT-PCR samples with overall accuracies of 93.4 and 93.0%, respectively.

Conclusions

A 44-gene expression signature that could accurately discriminate renal tumour subtypes was identified in this study. Our results may prompt further development of this gene expression signature into a molecular assay amenable to routine clinical practice.

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FOXA1 inhibits hepatocellular carcinoma progression by suppressing PIK3R1 expression in male patients

Abstract

Background

Forkhead box A1 (FOXA1) expression is associated with various types of tumors; however, the function and underlying mechanism of FOXA1 in the development of hepatocellular carcinoma (HCC) remains obscure.

Methods

Here, we investigated the role of FOXA1 in the development of HCC by applying gene function gain and loss analysis to HepG2 and Hep3B cell lines, and comparing outcomes with those of clinical HCC samples.

Results

Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), which encodes protein PI3Kp85 (p85), was identified as a FOXA1 target gene. Analyses of the mechanism and function revealed that FOXA1 suppresses hepatocellular carcinoma cell viability and motility by inhibiting PI3K/Akt signaling through direct inhibition of PIK3R1 transcription. Moreover, in clinical samples from male HCC patients, FOXA1 expression was much lower, whereas PI3Kp85 levels were much higher in tumor than in non-tumor tissues. Elevated PI3Kp85 is an unfavorable factor in HCC.

Conclusions

As a tumor suppressor, FOXA1 targets PIK3R1 directly to inhibit PI3K/Akt signaling pathway, thus exerting a negative regulatory effect on proliferation, migration, and invasion of HCC in male patients.

http://ift.tt/2BLGC21

Identification and validation of a 44-gene expression signature for the classification of renal cell carcinomas

Abstract

Background

Renal cancers account for more than 3% of all adult malignancies and cause more than 23,400 deaths per year in China alone. The four most common types of kidney tumours include clear cell, papillary, chromophobe and benign oncocytoma. These histological subtypes vary in their clinical course and prognosis, and different clinical strategies have been developed for their management. Some kidney tumours can be very difficult to distinguish based on the pathological assessment of morphology and immunohistochemistry.

Methods

Six renal cell carcinoma microarray data sets, including 106 clear cell, 66 papillary, 42 chromophobe, 46 oncocytoma and 35 adjacent normal tissue samples, were subjected to integrative analysis. These data were combined and used as a training set for candidate gene expression signature identification. In addition, two independent cohorts of 1020 RNA-Seq samples from The Cancer Genome Atlas database and 129 qRT-PCR samples from Fudan University Shanghai Cancer Center (FUSCC) were analysed to validate the selected gene expression signature.

Results

A 44-gene expression signature derived from microarray analysis was strongly associated with the histological differentiation of renal tumours and could be used for tumour subtype classification. The signature performance was further validated in 1020 RNA-Seq samples and 129 qRT-PCR samples with overall accuracies of 93.4 and 93.0%, respectively.

Conclusions

A 44-gene expression signature that could accurately discriminate renal tumour subtypes was identified in this study. Our results may prompt further development of this gene expression signature into a molecular assay amenable to routine clinical practice.

http://ift.tt/2kqVCy0

A polymorphism within the vitamin D transporter gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab

Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab (bev). Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bev were included in this study. 278 patients receiving FOLFIRI and cetuximab (cet) (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed. Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D binding protein, and treated with FOLFIRI/bev had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable P=0.001) and multivariable analyses P=0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR 1.83, P=0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR 0.50, P=0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab +/- irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P=0.033) and multivariable analyses (P=0.046). Conclusions:  GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bev or FOLFIRI/cet. Whereas AA carriers derive a survival benefit with FOLFIRI/cet, treatment with FOLFIRI/bev is associated with a worse outcome.

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CXCR4 is a potential target for diagnostic PET/CT imaging in Barrett's dysplasia and esophageal adenocarcinoma

Introduction: Barrett's Esophagus (BE) represents an early stage in carcinogenesis leading to esophageal adenocarcinoma (EAC). Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of BE and EAC. Methods: Here we utilized a IL-1b transgenic mouse model of BE and EAC and human patient imaging to analyse the importance of CXCR4 expressing cells during esophageal carcinogenesis. Results: IL-1b overexpression induces chronic esophageal inflammation and recapitulates the progression to BE and EAC. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1b mice, and also elevated in EAC patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4+) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4+ columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in ex vivo fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in esophageal cancer patients demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer. Discussion: In conclusion, the recruitment of CXCR4+ immune cells and expansion of CXCR4+ epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in EAC. 

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Inhibition of ID1-BMPR2 intrinsic signaling sensitizes glioma stem cells to differentiation therapy

Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear. Experimental Design: We performed in silico screening and in vitro validation studies through western blotting, q-RT-PCR for treatment of WNT and SHH signaling inhibitors and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice. Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through microRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacological blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice. Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation.

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CD271 Confers an Invasive and Metastatic Phenotype of Head and Neck Squamous Cell Carcinoma Through the Upregulation of Slug

Purpose: Head and neck squamous cell carcinoma (HNSCC) is comprised of heterogeneous populations of cells, and CD271 (NGFR; p75NTR) has been associated with a tumor-initiating cell subpopulation. This study assessed the role of CD271 in modulating metastatic behavior in HNSCC. Experimental Design: CD271 was overexpressed in murine and human oral squamous cell carcinoma cells to assess the impact of CD271 activation on the invasive and metastatic phenotype of these cells, using in vitro and orthotopic in vivo modeling. Treatment with human nerve growth factor (NGF) to activate CD271, as well as shRNA knockdown of the CD271-upregulated Snai2 expression, was used to assess the mechanism of the CD271-induced invasive phenotype. Relevance of CD271 expression in human HNSCC was evaluated in patient derived xenografts (PDXs) and primary human oral cancers, annotated with clinical behavior characteristics and survival data. Results: Forced expression of CD271 resulted in a more invasive and metastatic phenotype. Slug, an epithelial-to-mesenchymal transition (EMT)-related transcription factor, encoded by Snai2, was highly expressed in MOC2-CD271 and HSC3-CD271, compared to respective parental cells. CD271 activation by NGF conferred enhanced invasiveness in CD271-overexpressing cells, which was abrogated by Snai2 knockdown. In PDXs and primary human HNSCC, CD271 expression correlated with higher Snai2 expression, greater nodal metastasis, and shorter disease-free survival. Conclusions: Activation of CD271 results in upregulation of Snai2/Slug, which, in turn, results in a more invasive phenotype and an enhanced capacity for metastasis to regional lymph nodes. These findings point to CD271 as a promising, therapeutic target for oral cancer metastasis.

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Biomarkers of primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients: the AMNESIA case-control study

Purpose: Refining the selection of HER2 positive metastatic gastric cancer patients candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways. Experimental design: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed. Results: AMNESIA panel alterations were significantly more frequent in resistant (11 out of 20, 55%) as compared to sensitive (0% of 17) patients (p<0.001), and in HER2 IHC 2+ (7 out of 13, 53.8%) than 3+ (4 out of 24, 16.7%) tumors (p=0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free (5.2 versus 2.6 months, HR: 0.34 [95%CI: 0.07-0.48]; p=0.001) and overall survival (16.1 versus 7.6 months, HR: 0.38 [95%CI: 0.09-0.75], p=0.015). The predictive accuracy of AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of AMNESIA panel and HER2 IHC was 84%. Conclusions: Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients, and should be further validated with the aim of molecularly stratifying HER2 addicted cancers for the development of novel treatment strategies.

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Vimentin is required for lung adenocarcinoma metastasis via heterotypic tumor cell-cancer-associated fibroblast interactions during collective invasion

Purpose: Vimentin is an epithelial to mesenchymal transition (EMT) biomarker and intermediate filament protein that functions during cell migration to maintain structure and motility. Despite the abundance of clinical data linking vimentin to poor patient outcome, it is unclear if vimentin is required for metastasis or is a correlative biomarker. We developed a novel genetically engineered mouse model (GEMM) to probe vimentin in lung adenocarcinoma metastasis. Experimental Design: We used the LSL-Kras G12D/Lkb1 fl/fl/Vim-/-model (KLV-/-), which incorporates a whole-body knockout of vimentin and is derived from the Cre-dependent LSL-Kras G12D/Lkb1 fl/fl model (KLV+/+). We compared the metastatic phenotypes of the GEMMs and analyzed primary tumors from the KLV models and lung adenocarcinoma patients to assess vimentin expression and function. Results: Characterization of KLV^+/+ and KLV-/- mice, show that vimentin is not required for primary lung tumor growth but is required for metastasis and vimentin loss generates lower grade primary tumors. Interestingly, in the KLV+/+ mice, vimentin was not expressed in tumor cells but in cancer-associated fibroblasts (CAFs) surrounding collective invasion packs (CIPs) of epithelial tumor cells, with significantly less CIPs in KLV-/- mice. CIPs correlate with tumor grade, and are vimentin-negative and E-cadherin-positive, indicating a lack of cancer cell EMT. Similar heterotypic staining pattern was observed in human lung adenocarcinoma samples. In vitro studies show that vimentin is required for CAF-led tumor cell invasion, supporting a vimentin-dependent model of collective invasion. Conclusions: These data show that vimentin is required for lung adenocarcinoma metastasis by maintaining heterotypic tumor cell-CAF interactions during collective invasion.

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Etk interaction with PFKFB4 modulates chemoresistance of small cell lung cancer by regulating autophagy

Purpose: Epithelial and endothelial tyrosine kinase (Etk), also known as bone marrow X kinase (Bmx), was found to be critical in modulating the chemoresistance of small cell lung cancer (SCLC) in our preliminary study. However, the molecular mechanisms of Etk in SCLC chemoresistance remain poorly understood. The present study investigated the downstream factor and pathway involved. Experimental Design: We demonstrated first that knockdown of Etk by siRNAs suppressed autophagy in chemoresistant SCLC cells, and that direct inhibition of autophagy sensitized cells to chemotherapy. Our subsequent microarray, co-immunoprecipitation (co-IP) and GST-pull down experiments identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a downstream target of Etk and an Etk-interacting protein. We demonstrated knockdown of PFKFB4 suppressed autophagy in SCLC cells. Our in vitro and in vivo gain or loss-of-function analyses of PFKFB4 revealed PFKFB4 plays a critical role in SCLC chemoresistance. Our analysis of PFKFB4 expression in SCLC specimens demonstrated that high levels of PFKFB4 are associated with poor therapeutic response and prognosis. Furthermore, as Etk shares conserved domains with Btk (Bruton's tyrosine kinase) family, we explored the potential of Ibrutinib, a Btk inhibitor clinically effective in treating leukemia, in targeting Etk and found that Ibrutinib exhibited a synergistic anti-tumor effect with chemotherapy in SCLC preclinical models including a PDX model. Results: Described above Conclusions:Our results demonstrated for the first time that Etk interacts with PFKFB4 to promote SCLC chemoresistance through regulation of autophagy. Aberrant Etk and PFKFB4 can be predictive factors for the chemotherapy response as well as potential therapeutic targets in SCLC.

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A polymorphism within the vitamin D transporter gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab

Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab (bev). Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bev were included in this study. 278 patients receiving FOLFIRI and cetuximab (cet) (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed. Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D binding protein, and treated with FOLFIRI/bev had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable P=0.001) and multivariable analyses P=0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR 1.83, P=0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR 0.50, P=0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab +/- irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P=0.033) and multivariable analyses (P=0.046). Conclusions:  GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bev or FOLFIRI/cet. Whereas AA carriers derive a survival benefit with FOLFIRI/cet, treatment with FOLFIRI/bev is associated with a worse outcome.

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CXCR4 is a potential target for diagnostic PET/CT imaging in Barrett's dysplasia and esophageal adenocarcinoma

Introduction: Barrett's Esophagus (BE) represents an early stage in carcinogenesis leading to esophageal adenocarcinoma (EAC). Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of BE and EAC. Methods: Here we utilized a IL-1b transgenic mouse model of BE and EAC and human patient imaging to analyse the importance of CXCR4 expressing cells during esophageal carcinogenesis. Results: IL-1b overexpression induces chronic esophageal inflammation and recapitulates the progression to BE and EAC. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1b mice, and also elevated in EAC patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4+) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4+ columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in ex vivo fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in esophageal cancer patients demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer. Discussion: In conclusion, the recruitment of CXCR4+ immune cells and expansion of CXCR4+ epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in EAC. 

http://ift.tt/2AtPbjG

Inhibition of ID1-BMPR2 intrinsic signaling sensitizes glioma stem cells to differentiation therapy

Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear. Experimental Design: We performed in silico screening and in vitro validation studies through western blotting, q-RT-PCR for treatment of WNT and SHH signaling inhibitors and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice. Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through microRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacological blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice. Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation.

http://ift.tt/2AyFqPd

CD271 Confers an Invasive and Metastatic Phenotype of Head and Neck Squamous Cell Carcinoma Through the Upregulation of Slug

Purpose: Head and neck squamous cell carcinoma (HNSCC) is comprised of heterogeneous populations of cells, and CD271 (NGFR; p75NTR) has been associated with a tumor-initiating cell subpopulation. This study assessed the role of CD271 in modulating metastatic behavior in HNSCC. Experimental Design: CD271 was overexpressed in murine and human oral squamous cell carcinoma cells to assess the impact of CD271 activation on the invasive and metastatic phenotype of these cells, using in vitro and orthotopic in vivo modeling. Treatment with human nerve growth factor (NGF) to activate CD271, as well as shRNA knockdown of the CD271-upregulated Snai2 expression, was used to assess the mechanism of the CD271-induced invasive phenotype. Relevance of CD271 expression in human HNSCC was evaluated in patient derived xenografts (PDXs) and primary human oral cancers, annotated with clinical behavior characteristics and survival data. Results: Forced expression of CD271 resulted in a more invasive and metastatic phenotype. Slug, an epithelial-to-mesenchymal transition (EMT)-related transcription factor, encoded by Snai2, was highly expressed in MOC2-CD271 and HSC3-CD271, compared to respective parental cells. CD271 activation by NGF conferred enhanced invasiveness in CD271-overexpressing cells, which was abrogated by Snai2 knockdown. In PDXs and primary human HNSCC, CD271 expression correlated with higher Snai2 expression, greater nodal metastasis, and shorter disease-free survival. Conclusions: Activation of CD271 results in upregulation of Snai2/Slug, which, in turn, results in a more invasive phenotype and an enhanced capacity for metastasis to regional lymph nodes. These findings point to CD271 as a promising, therapeutic target for oral cancer metastasis.

http://ift.tt/2Aw1KL9

Biomarkers of primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients: the AMNESIA case-control study

Purpose: Refining the selection of HER2 positive metastatic gastric cancer patients candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways. Experimental design: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed. Results: AMNESIA panel alterations were significantly more frequent in resistant (11 out of 20, 55%) as compared to sensitive (0% of 17) patients (p<0.001), and in HER2 IHC 2+ (7 out of 13, 53.8%) than 3+ (4 out of 24, 16.7%) tumors (p=0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free (5.2 versus 2.6 months, HR: 0.34 [95%CI: 0.07-0.48]; p=0.001) and overall survival (16.1 versus 7.6 months, HR: 0.38 [95%CI: 0.09-0.75], p=0.015). The predictive accuracy of AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of AMNESIA panel and HER2 IHC was 84%. Conclusions: Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients, and should be further validated with the aim of molecularly stratifying HER2 addicted cancers for the development of novel treatment strategies.

http://ift.tt/2AyFgHB

Vimentin is required for lung adenocarcinoma metastasis via heterotypic tumor cell-cancer-associated fibroblast interactions during collective invasion

Purpose: Vimentin is an epithelial to mesenchymal transition (EMT) biomarker and intermediate filament protein that functions during cell migration to maintain structure and motility. Despite the abundance of clinical data linking vimentin to poor patient outcome, it is unclear if vimentin is required for metastasis or is a correlative biomarker. We developed a novel genetically engineered mouse model (GEMM) to probe vimentin in lung adenocarcinoma metastasis. Experimental Design: We used the LSL-Kras G12D/Lkb1 fl/fl/Vim-/-model (KLV-/-), which incorporates a whole-body knockout of vimentin and is derived from the Cre-dependent LSL-Kras G12D/Lkb1 fl/fl model (KLV+/+). We compared the metastatic phenotypes of the GEMMs and analyzed primary tumors from the KLV models and lung adenocarcinoma patients to assess vimentin expression and function. Results: Characterization of KLV^+/+ and KLV-/- mice, show that vimentin is not required for primary lung tumor growth but is required for metastasis and vimentin loss generates lower grade primary tumors. Interestingly, in the KLV+/+ mice, vimentin was not expressed in tumor cells but in cancer-associated fibroblasts (CAFs) surrounding collective invasion packs (CIPs) of epithelial tumor cells, with significantly less CIPs in KLV-/- mice. CIPs correlate with tumor grade, and are vimentin-negative and E-cadherin-positive, indicating a lack of cancer cell EMT. Similar heterotypic staining pattern was observed in human lung adenocarcinoma samples. In vitro studies show that vimentin is required for CAF-led tumor cell invasion, supporting a vimentin-dependent model of collective invasion. Conclusions: These data show that vimentin is required for lung adenocarcinoma metastasis by maintaining heterotypic tumor cell-CAF interactions during collective invasion.

http://ift.tt/2AurI1F

Etk interaction with PFKFB4 modulates chemoresistance of small cell lung cancer by regulating autophagy

Purpose: Epithelial and endothelial tyrosine kinase (Etk), also known as bone marrow X kinase (Bmx), was found to be critical in modulating the chemoresistance of small cell lung cancer (SCLC) in our preliminary study. However, the molecular mechanisms of Etk in SCLC chemoresistance remain poorly understood. The present study investigated the downstream factor and pathway involved. Experimental Design: We demonstrated first that knockdown of Etk by siRNAs suppressed autophagy in chemoresistant SCLC cells, and that direct inhibition of autophagy sensitized cells to chemotherapy. Our subsequent microarray, co-immunoprecipitation (co-IP) and GST-pull down experiments identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a downstream target of Etk and an Etk-interacting protein. We demonstrated knockdown of PFKFB4 suppressed autophagy in SCLC cells. Our in vitro and in vivo gain or loss-of-function analyses of PFKFB4 revealed PFKFB4 plays a critical role in SCLC chemoresistance. Our analysis of PFKFB4 expression in SCLC specimens demonstrated that high levels of PFKFB4 are associated with poor therapeutic response and prognosis. Furthermore, as Etk shares conserved domains with Btk (Bruton's tyrosine kinase) family, we explored the potential of Ibrutinib, a Btk inhibitor clinically effective in treating leukemia, in targeting Etk and found that Ibrutinib exhibited a synergistic anti-tumor effect with chemotherapy in SCLC preclinical models including a PDX model. Results: Described above Conclusions:Our results demonstrated for the first time that Etk interacts with PFKFB4 to promote SCLC chemoresistance through regulation of autophagy. Aberrant Etk and PFKFB4 can be predictive factors for the chemotherapy response as well as potential therapeutic targets in SCLC.

http://ift.tt/2AyF7Uz

Emerging Role of CRISPR/Cas9 Technology for MicroRNAs Editing in Cancer Research

MicroRNAs (miRNA) are small, noncoding RNA molecules with a master role in the regulation of important tasks in different critical processes of cancer pathogenesis. Because there are different miRNAs implicated in all the stages of cancer, for example, functioning as oncogenes, this makes these small molecules suitable targets for cancer diagnosis and therapy. RNA-mediated interference has been one major approach for sequence-specific regulation of gene expression in eukaryotic organisms. Recently, the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 system, first identified in bacteria and archaea as an adaptive immune response to invading genetic material, has been explored as a sequence-specific molecular tool for editing genomic sequences for basic research in life sciences and for therapeutic purposes. There is growing evidence that small noncoding RNAs, including miRNAs, can be targeted by the CRISPR/Cas9 system despite their lacking an open reading frame to evaluate functional loss. Thus, CRISPR/Cas9 technology represents a novel gene-editing strategy with compelling robustness, specificity, and stability for the modification of miRNA expression. Here, I summarize key features of current knowledge of genomic editing by CRISPR/Cas9 technology as a feasible strategy for globally interrogating miRNA gene function and miRNA-based therapeutic intervention. Alternative emerging strategies for nonviral delivery of CRISPR/Cas9 core components into human cells in a clinical context are also analyzed critically. Cancer Res; 77(24); 1–6. ©2017 AACR.

http://ift.tt/2BDpx9E

Emerging Role of CRISPR/Cas9 Technology for MicroRNAs Editing in Cancer Research

MicroRNAs (miRNA) are small, noncoding RNA molecules with a master role in the regulation of important tasks in different critical processes of cancer pathogenesis. Because there are different miRNAs implicated in all the stages of cancer, for example, functioning as oncogenes, this makes these small molecules suitable targets for cancer diagnosis and therapy. RNA-mediated interference has been one major approach for sequence-specific regulation of gene expression in eukaryotic organisms. Recently, the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 system, first identified in bacteria and archaea as an adaptive immune response to invading genetic material, has been explored as a sequence-specific molecular tool for editing genomic sequences for basic research in life sciences and for therapeutic purposes. There is growing evidence that small noncoding RNAs, including miRNAs, can be targeted by the CRISPR/Cas9 system despite their lacking an open reading frame to evaluate functional loss. Thus, CRISPR/Cas9 technology represents a novel gene-editing strategy with compelling robustness, specificity, and stability for the modification of miRNA expression. Here, I summarize key features of current knowledge of genomic editing by CRISPR/Cas9 technology as a feasible strategy for globally interrogating miRNA gene function and miRNA-based therapeutic intervention. Alternative emerging strategies for nonviral delivery of CRISPR/Cas9 core components into human cells in a clinical context are also analyzed critically. Cancer Res; 77(24); 1–6. ©2017 AACR.

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Benefit of using motion compensated reconstructions for reducing inter-observer and intra-observer contouring variation for organs at risk in lung cancer patients

In lung cancer patients, accuracy in contouring is hampered by image artefacts introduced by respiratory motion. With the widespread introduction of 4DCT there is additional uncertainty caused by the use of different reconstruction techniques which will influence contour definition. This work aims to assess both inter- and intra-observer contour variation on average and motion compensated (mid-position) reconstructions.

http://ift.tt/2inO1Ml

Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

Abstract

Background

Folate-dependent one-carbon metabolism provides one-carbon units for several biological processes. This pathway is highly compartmentalized in eukaryotes, with the mitochondrial pathway producing formate for use in cytoplasmic processes. The mitochondrial enzyme MTHFD2 has been reported to use NAD⁺ as a cofactor while the isozyme MTHFD2L utilizes NAD⁺ or NADP⁺ at physiologically relevant conditions. Because MTHFD2 is highly expressed in many cancer types, we sought to determine the cofactor preference of this enzyme.

Results

Kinetic analysis shows that purified human MTHFD2 exhibits dual redox cofactor specificity, utilizing either NADP⁺ or NAD⁺ with the more physiologically relevant pentaglutamate folate substrate.

Conclusion

These results show that the mitochondrial folate pathway isozymes MTHFD2 and MTHFD2L both exhibit dual redox cofactor specificity. Our kinetic analysis clearly supports a role for MTHFD2 in mitochondrial NADPH production, indicating that this enzyme is likely responsible for mitochondrial production of both NADH and NADPH in rapidly proliferating cells.

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Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

Abstract

Background

Folate-dependent one-carbon metabolism provides one-carbon units for several biological processes. This pathway is highly compartmentalized in eukaryotes, with the mitochondrial pathway producing formate for use in cytoplasmic processes. The mitochondrial enzyme MTHFD2 has been reported to use NAD⁺ as a cofactor while the isozyme MTHFD2L utilizes NAD⁺ or NADP⁺ at physiologically relevant conditions. Because MTHFD2 is highly expressed in many cancer types, we sought to determine the cofactor preference of this enzyme.

Results

Kinetic analysis shows that purified human MTHFD2 exhibits dual redox cofactor specificity, utilizing either NADP⁺ or NAD⁺ with the more physiologically relevant pentaglutamate folate substrate.

Conclusion

These results show that the mitochondrial folate pathway isozymes MTHFD2 and MTHFD2L both exhibit dual redox cofactor specificity. Our kinetic analysis clearly supports a role for MTHFD2 in mitochondrial NADPH production, indicating that this enzyme is likely responsible for mitochondrial production of both NADH and NADPH in rapidly proliferating cells.

http://ift.tt/2isaBDL

Treatment of sporadic Burkitt lymphoma in adults, a retrospective comparison of four treatment regimens

Abstract

Burkitt lymphoma is an aggressive B cell malignancy accounting for 1–2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14–74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.

http://ift.tt/2AylcoI

BRAF -Oncogene-Induced Senescence and the Role of Thyroid-Stimulating Hormone Signaling in the Progression of Papillary Thyroid Carcinoma

Abstract

Oncogene-induced senescence (OIS) explains the phenomenon of cellular senescence triggered by the action of oncogenes. It is a mechanism adopted by a cell to inhibit progression of benign tumors into malignancy, occurs in premalignant lesions, and is almost never present in malignant lesions. BRAF mutations occur in about 40–45% of all papillary thyroid carcinomas (PTCs) and of which 99.7% is the BRAFV600E mutation. A unique phenotype of the BRAFV600E mutation is the upregulation of the thyroid-stimulating hormone receptor (TSHR) on thyrocyte membranes. Despite the overexpression of the receptor, BRAFV600E cells undergo cell cycle arrest leading to OIS via a negative feedback signaling mechanism. A simultaneous increase in serum thyroid-stimulating hormone (TSH) in response to hypothyroidism (common in autoimmune diseases such as Hashimoto's thyroiditis) would cause senescent tumor cells to overcome OIS and proceed towards malignancy, hence showing the importance of TSH/TSHR signaling in the development of PTCs. Increase in TSH/TSHR signaling triggers an increase in levels of downstream enzymes such as manganese superoxide dismutase (MnSOD) and dual-specific phosphatase 6 (DUSP6) which eventually results in the production of oncogenic proteins such as c-Myc. Therefore, the detection of these genetic alterations as effective biomarkers for premalignant lesions of PTC is important in clinical settings and techniques such as polymerase chain reaction-mediated restriction fragment length polymorphism (PCR-RFLP) and real-time PCR can be used to detect the BRAFV600E point mutation and overexpression of TSHR, MnSOD, and DUSP6, respectively.

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BRAF -Oncogene-Induced Senescence and the Role of Thyroid-Stimulating Hormone Signaling in the Progression of Papillary Thyroid Carcinoma

Abstract

Oncogene-induced senescence (OIS) explains the phenomenon of cellular senescence triggered by the action of oncogenes. It is a mechanism adopted by a cell to inhibit progression of benign tumors into malignancy, occurs in premalignant lesions, and is almost never present in malignant lesions. BRAF mutations occur in about 40–45% of all papillary thyroid carcinomas (PTCs) and of which 99.7% is the BRAFV600E mutation. A unique phenotype of the BRAFV600E mutation is the upregulation of the thyroid-stimulating hormone receptor (TSHR) on thyrocyte membranes. Despite the overexpression of the receptor, BRAFV600E cells undergo cell cycle arrest leading to OIS via a negative feedback signaling mechanism. A simultaneous increase in serum thyroid-stimulating hormone (TSH) in response to hypothyroidism (common in autoimmune diseases such as Hashimoto's thyroiditis) would cause senescent tumor cells to overcome OIS and proceed towards malignancy, hence showing the importance of TSH/TSHR signaling in the development of PTCs. Increase in TSH/TSHR signaling triggers an increase in levels of downstream enzymes such as manganese superoxide dismutase (MnSOD) and dual-specific phosphatase 6 (DUSP6) which eventually results in the production of oncogenic proteins such as c-Myc. Therefore, the detection of these genetic alterations as effective biomarkers for premalignant lesions of PTC is important in clinical settings and techniques such as polymerase chain reaction-mediated restriction fragment length polymorphism (PCR-RFLP) and real-time PCR can be used to detect the BRAFV600E point mutation and overexpression of TSHR, MnSOD, and DUSP6, respectively.

http://ift.tt/2kpxUlE

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer, Published online: 05 December 2017; doi:10.1038/bjc.2017.420

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

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Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer, Published online: 05 December 2017; doi:10.1038/bjc.2017.420

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

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Aprotinin and coronary artery bypass surgery

No abstract available

http://ift.tt/2BM2JoQ

Procedural sedation and analgesia for adults in Europe: Safety first

No abstract available

http://ift.tt/2kmh3jB

Predictive models for acute kidney injury after cardiac surgery

No abstract available

http://ift.tt/2BLj7WM

European Society of Anaesthesiology and European Board of Anaesthesiology guidelines for procedural sedation and analgesia in adults

No abstract available

http://ift.tt/2BNNpbu

Safety and quality of procedural sedation and analgesia practice for adult patients throughout Europe: A step forward

No abstract available

http://ift.tt/2koKBNC

Fibrinogen on Admission in Trauma score: Early prediction of low plasma fibrinogen concentrations in trauma patients

BACKGROUND Early recognition of low fibrinogen concentrations in trauma patients is crucial for timely haemostatic treatment and laboratory testing is too slow to inform decision-making. OBJECTIVE To develop a simple clinical tool to predict low fibrinogen concentrations in trauma patients on arrival. DESIGN Retrospective cohort study. SETTING Three designated level 1 trauma centres in the Paris Region, from January 2011 to December 2013. PATIENTS Patients admitted in accordance with national triage guidelines for major trauma and plasma fibrinogen concentration testing on admission. INTERVENTION Construction of a clinical score [Fibrinogen on Admission in Trauma (FibAT) score] in a derivation cohort to predict fibrinogen plasma concentration 1.5 g l−1 or less after multiple regressions. One point was given for each predictive factor. The score was the sum of all. Validation was performed in a separate validation cohort. MAIN OUTCOME MEASURE Predictive accuracy of FibAT score. RESULTS In total, 2936 patients were included, 2124 in the derivation cohort and 812 in the validation cohort. In the derivation cohort, a multivariate logistic model identified the following predictive factors for plasma fibrinogen concentrations 1.5 g l−1 or less: age less than 33 years, prehospital heart rate more than 100 beats per minute, prehospital SBP less than 100 mmHg, blood lactate concentration on admission more than 2.5 mmol l−1, free intraabdominal fluid on sonography, decrease in haemoglobin concentration from prehospital to admission of more than 2 g dl−1, capillary haemoglobin concentration on admission less than 12 g dl−1 and temperature on admission less than 36°C. The FibAT score had an area under the receiver operating characteristic curve of 0.87 [95% confidence interval (0.86 to 0.91)] in the derivation cohort and of 0.82 (95% confidence interval (0.86 to 0.91)] in the validation cohort to predict a low plasma fibrinogen. CONCLUSION The FibAT score accurately predicts plasma fibrinogen levels 1.5 g l−1 or less on admission in trauma patients. This easy-to-use score could allow early, goal-directed therapy to trauma patients.

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High versus low PEEP for abdominal surgery

No abstract available

http://ift.tt/2BL6aw1

Blood glucose concentrations in prehospital trauma patients with traumatic shock: A retrospective analysis

BACKGROUND Deranged glucose metabolism after moderate to severe trauma with either high or low concentrations of blood glucose is associated with poorer outcome. Data on prehospital blood glucose concentrations and trauma are scarce. OBJECTIVES The primary aim was to describe the relationship between traumatic shock and prehospital blood glucose concentrations. The secondary aim was to determine the additional predictive value of prehospital blood glucose concentration for traumatic shock when compared with vital parameters alone. DESIGN Retrospective analysis of the predefined, observational database of a nationwide Helicopter Emergency Medical Service (34 bases). SETTING Emergency trauma patients treated by Helicopter Emergency Medical Service between 2005 and 2013 were investigated. PATIENTS All adult trauma patients (≥18 years) with recorded blood glucose concentrations were enrolled. OUTCOMES Primary outcome: upper and lower thresholds of blood glucose concentration more commonly associated with traumatic shock. Secondary outcome: additional predictive value of prehospital blood glucose concentrations when compared with vital parameters alone. RESULTS Of 51 936 trauma patients, 20 177 were included. In total, 220 (1.1%) patients died on scene. Hypoglycaemia (blood glucose concentration 2.8 mmol l−1 or less) was observed in 132 (0.7%) patients, hyperglycaemia (blood glucose concentration exceeding 15 mmol l−1) was observed in 265 patients (1.3%). Blood glucose concentrations more than 10 mmol l−1 (n = 1308 (6.5%)) and 2.8 mmol l−1 or less were more common in patients with traumatic shock (P 

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Dobutamine and its haemodynamic effects in pleural effusion

No abstract available

http://ift.tt/2ksZZc0

Median effective dose of intranasal dexmedetomidine sedation for transthoracic echocardiography examination in postcardiac surgery and normal children: An up-and-down sequential allocation trial

BACKGROUND Dexmedetomidine (DEX) has been used for sedation in young infants and children undergoing transthoracic echocardiography (TTE). The median effective dose of intranasal DEX has not been described for postcardiac surgery children. Postcardiac surgery children could require more DEX to achieve satisfactory sedation for TTE examination than children suspected of congenital heart disease. OBJECTIVES To study whether postcardiac surgery children need a larger dose of DEX for TTE than normal children. DESIGN A double-blind sequential allocation trial with doses determined by the Dixon and Massey up-and-down method. SETTING A tertiary care teaching hospital from 25 October to 30 November 2016. PATIENTS Children under the age of 3 years requiring intranasal DEX for TTE. INTERVENTIONS Children were allocated to a postcardiac surgery group (n = 20) or a normal group (n = 19). The first patient in both groups received intranasal DEX (2 μg kg−1): using the up-and-down method of Dixon and Massey, the next dose was dependent on the previous patient's response. MAIN OUTCOME MEASURES Median effective dose was estimated from the up-and-down method of Dixon and Massey and probit regression. A second objective was to study haemodynamic stability and adverse events with these doses. RESULTS The median effective dose (95% confidence interval) of intranasal DEX was higher in postcardiac surgery children than in normal children, 3.3 (2.72 to 3.78) μg kg−1 versus 1.8 (1.71 to 2.04) (μg kg-1), respectively (P 

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Reply to: alveolar recruitment manoeuvres after cardiac surgery

No abstract available

http://ift.tt/2nvWCC9

Clinical signs and electroencephalographic patterns of emergence from sevoflurane anaesthesia in children: An observational study

BACKGROUND Few studies have systematically described relationships between clinical–behavioural signs, electroencephalographic (EEG) patterns and age during emergence from anaesthesia in young children. OBJECTIVE To identify the relationships between end-tidal sevoflurane (ETsevoflurane) concentration, age and frontal EEG spectral properties in predicting recovery of clinical–behavioural signs during emergence from sevoflurane in children 0 to 3 years of age, with and without exposure to nitrous oxide. The hypothesis was that clinical signs occur sequentially during emergence, and that for infants aged more than 3 months, changes in alpha EEG power are correlated with clinical–behavioural signs. DESIGN An observational study. SETTING A tertiary paediatric teaching hospital from December 2012 to August 2016. PATIENTS Ninety-five children aged 0 to 3 years who required surgery below the neck. OUTCOME MEASURES Time–course of, and ETsevoflurane concentrations at first gross body movement, first cough, first grimace, dysconjugate eye gaze, frontal (F7/F8) alpha EEG power (8 to 12 Hz), frontal beta EEG power (13 to 30 Hz), surgery-end. RESULTS Clinical signs of emergence followed an orderly sequence of events across all ages. Clinical signs occurred over a narrow ETsevoflurane, independent of age [movement: 0.4% (95% confidence interval (CI), 0.3 to 0.4), cough 0.3% (95% CI, 0.3 to 0.4), grimace 0.2% (95% CI, 0 to 0.3); P > 0.5 for age vs. ETsevoflurane]. Dysconjugate eye gaze was observed between ETsevoflurane 1 to 0%. In children more than 3 months old, frontal alpha EEG oscillations were present at ETsevoflurane 2.0% and disappeared at 0.5%. Movement occurred within 5 min of alpha oscillation disappearance in 99% of patients. Nitrous oxide had no effect on the time course or ETsevoflurane at which children showed body movement, grimace or cough. CONCLUSION Several clinical signs occur sequentially during emergence, and are independent of exposure to nitrous oxide. Eye position is poorly correlated with other clinical signs or ETsevoflurane. EEG spectral characteristics may aid prediction of clinical–behavioural signs in children more than 3 months.

http://ift.tt/2nxvtPe