Medicine by Alexandros G.Sfakianakis: 12/07/17

Πέμπτη 7 Δεκεμβρίου 2017

A High-Performing Direct Carbon Fuel Cell with a 3D Architectured Anode Operated Below 600 °C

Abstract

Direct carbon fuel cells (DCFCs) are highly efficient power generators fueled by abundant and cheap solid carbons. However, the limited triple-phase boundaries (TPBs) in the fuel electrode, due to the lack of direct contact among carbon, electrode, and electrolyte, inhibit the performance and result in poor fuel utilization. To address the challenges of low carbon oxidation activity and low carbon utilization, a highly efficient, 3D solid-state architected anode is developed to enhance the performance of DCFCs below 600 °C. The cell with the 3D textile anode framework, Gd:CeO₂–Li/Na₂CO₃ composite electrolyte, and Sm_0.5Sr_0.5CoO₃ cathode demonstrates excellent performance with maximum power densities of 143, 196, and 325 mW cm⁻² at 500, 550, and 600 °C, respectively. At 500 °C, the cells can be operated steadily with a rated power density of ≈0.13 W cm⁻² at a constant current density of 0.15 A cm⁻² with a carbon utilization over 85.5%. These results, for the first time, demonstrate the feasibility of directly electrochemical oxidation of solid carbon at 500–600 °C, representing a promising strategy in developing high-performing fuel cells and other electrochemical systems via the integration of 3D architected electrodes.

A 3D architectured framework is fabricated and applied as anode for high-performing direct carbon fuel cells. The fuel cells demonstrate remarkable power densities below 600 °C, attributed to highly improved mass transfer and increased triple-phase boundaries within the 3D anode. This approach provides a promising strategy in developing 3D functional electrodes for fuel cells and other electrochemical devices.

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Achieving Nearly 30% External Quantum Efficiency for Orange–Red Organic Light Emitting Diodes by Employing Thermally Activated Delayed Fluorescence Emitters Composed of 1,8-Naphthalimide-Acridine Hybrids

Abstract

The combination of rigid acridine donor and 1,8-naphthalimide acceptor has afforded two orange–red emitters of NAI-DMAC and NAI-DPAC with high rigidity in molecular structure and strongly pretwisted charge transfer state. Endowed with high photoluminescence quantum yields (Φ_PL), distinct thermally activated delayed fluorescence (TADF) characteristics, and preferentially horizontal emitting dipole orientations, these emitters afford record-high orange–red TADF organic light-emitting diodes (OLEDs) with external quantum efficiencies of up to 21–29.2%, significantly surpassing all previously reported orange-to-red TADF OLEDs. Notably, the influence of microcavity effect is verified to support the record-high efficiency. This finding relaxes the usually stringent material requirements for effective TADF emitters by comprising smaller radiative transition rates and less than ideal Φ_PLs.

Orange–red organic light-emitting diodes with external quantum efficiencies of up to 29.2% are achieved using excellent thermally activated delayed fluorescence (TADF) emission of 1,8-naphthalimide-acridine hybrid. The relatively high photoluminescence quantum yield and horizontally oriented emitting dipoles of TADF emitters combined with the influence of microcavity effects are verified to support the record-high efficiency.

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Lymphoepithelioma-like Carcinoma of the Uterine Cervix: Cytomorphologic Features and Diagnostic Pitfalls by Liquid-Based Cytology

Lymphoepithelioma-like carcinoma (LELC) is a rare variant of cervical squamous cell carcinoma with unclear HPV and EBV association. Due to the accompanying and often obscuring lymphocytic inflammation, malignant cells may be difficult to recognize on cytologic samples and can mimic several more common benign and atypical cervical lesions. In this case report, we describe the cytomorphologic findings of LELC by liquid-based cytology in a 59-year-old Caucasian woman who was positive for high risk HPV but had no visible cervical lesions. We also discuss the differential diagnosis, diagnostic pitfalls, and practical considerations for diagnosis.

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Anti-diabetic potential of Sapium ellipticum (Hochst) Pax leaf extract in Streptozotocin(STZ)-induced diabetic Wistar rats

Ethnobatanical survey associates Sapium ellipticum (SE) with antidiabetic usage among other medicinal functions in different parts of Africa. More importantly, previous studies on the plant extract in our laborat...

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Food borne illness amongst health care workers, at a Central Hospital, Harare, Zimbabwe, 2016: a retrospective cohort study

Health care workers (HCW) at a Central Hospital, were served lunch at the hospital canteen on 12 December 2016. On 12 December 2016 at 1700 h, there was a sudden onset of symptoms suggestive of gastrointestina...

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Evaluation of clinical practice guidelines using the AGREE instrument: comparison between data obtained from AGREE I and AGREE II

The Appraisal of Guidelines for Research and Evaluation (AGREE) is a representative, quantitative evaluation tool for evidence-based clinical practice guidelines (CPGs). Recently, AGREE was revised (AGREE II)....

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Perceived causes of stress among a group of western Canadian dental students

The demanding nature of dental education, both academically and clinically, results in higher levels of perceived stress among its students. The aim of this study was to determine how dental students at the Co...

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Detection of metallo-β-lactamases-encoding genes among clinical isolates of Pseudomonas aeruginosa in a tertiary care hospital, Kathmandu, Nepal

This study was carried out to determine the prevalence of metallo-β-lactamases (MBLs) producing Pseudomonas aeruginosa in imipenem-nonsusceptible isolates and to detect MBL-encoding genes among MBLs-positive isol...

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Effects of a culturally tailored parenting support programme in Somali-born parents mental health and sense of competence in parenting: a randomised controlled trial

Objectives

To evaluate the effectiveness of a culturally tailored parenting support programme on Somali-born parents' mental health and sense of competence in parenting.

Design

Randomised controlled trial.

Setting

A city in the middle of Sweden.

Participants

Somali-born parents (n=120) with children aged 11–16 years and self-perceived stress in their parenting were randomised to an intervention group (n=60) or a waiting-list control group (n=60).

Intervention

Parents in the intervention group received culturally tailored societal information combined with the Connect parenting programme during 12 weeks for 1–2 hours per week. The intervention consisted of a standardised training programme delivered by nine group leaders of Somali background.

Outcome

The General Health Questionnaire 12 was used to measure parents' mental health and the Parenting Sense of Competence scale to measure parent satisfaction and efficacy in the parent role. Analysis was conducted using intention-to-treat principles.

Results

The results indicated that parents in the intervention group showed significant improvement in mental health compared with the parents in the control group at a 2-month follow-up: B=3.62, 95% CI 2.01 to 5.18, p<0.001. Further, significant improvement was found for efficacy (B=–6.72, 95% CI –8.15 to –5.28, p<0.001) and satisfaction (B=–4.48, 95% CI –6.27 to –2.69, p<0.001) for parents in the intervention group. Parents' satisfaction mediated the intervention effect on parental mental health (β=–0.88, 95% CI –1.84 to –0.16, p=0.047).

Conclusion

The culturally tailored parenting support programme led to improved mental health of Somali-born parents and their sense of competence in parenting 2 months after the intervention. The study underlines the importance of acknowledging immigrant parents' need for societal information in parent support programmes and the importance of delivering these programmes in a culturally sensitive manner.

Clinical trial registration

NCT02114593.

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Benefits of probiotics in preterm neonates in low-income and medium-income countries: a systematic review of randomised controlled trials

Objective

Although there is an overall reduction in underfive mortality rate, the progress in reducing neonatal mortality rate has been very slow. Over the last 20 years, preterm births have steadily increased in low-income and medium-income countries (LMICs) particularly in sub-Saharan Africa and South Asia. Preterm birth is associated with increased mortality and morbidity, particularly in LMICs. Based on systematic reviews of randomised controlled trials (RCTs), many neonatal units in high-income countries have adopted probiotics as standard of care for preterm neonates. We aimed to systematically review the safety and efficacy of probiotics in reducing mortality and morbidity in preterm neonates in LMICs.

Design

Systematic review and meta-analysis of RCTs.

Data sources

Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and E-abstracts from Pediatric Academic Society meetings and other paediatric and neonatal conference proceedings were searched in January 2017.

Eligibility criteria

RCTs comparing probiotics versus placebo/no probiotic in preterm neonates (gestation<37 weeks) conducted in LMICs.

Results

Total 23 (n=4783) RCTs from 4 continents and 10 LMICs were eligible for inclusion in the meta-analysis using fixed effect model. The risk of necrotising enterocolitis (NEC greater than or equal to stage II) (risk ratio (RR) 0.46 (95% CI 0.34 to 0.61), P<0.00001, numbers needed to treat (NNT) 25 (95% CI 20 to 50)), late-onset sepsis (LOS) (RR 0.80 (95% CI 0.71 to 0.91), P=0.0009, NNT 25 (95% CI 17 to 100)) and all-cause mortality (RR 0.73 (95% CI 0.59 to 0.90), P=0.003, NNT 50 (95% CI 25 to 100)) were significantly lower in probiotic supplemented neonates. The results were significant on random effects model analysis and after excluding studies with high risk of bias. No significant adverse effects were reported.

Conclusion

Probiotics have significant potential to reduce mortality and morbidity (eg, NEC, LOS) in preterm neonates in LMICs.

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Trastuzumab emtansine: determining its role in management of HER2+ breast cancer

Future Oncology, Ahead of Print.

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A clinical tool to predict Plasmodium vivax recurrence in Malaysia

Recurrence rates of Plasmodium vivax infections differ across various geographic regions. Interestingly, South-East Asia and the Asia-Pacific region are documented to exhibit the most frequent recurrence incidenc...

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Hypersomatotropism induced secondary polycythaemia leading to spontaneous pituitary apoplexy resulting in cure of acromegaly and remission of polycythaemia: 'The virtuous circle

A young man with subtle clinical features suggestive of hypersomatotropism presented with acute-onset severe headache. Relevant investigations confirmed polycythaemia and growth hormone (GH)-secreting pituitary macroadenoma with apoplexy. Secondary polycythaemia and myeloproliferative disorders were ruled out. At follow-up after 3 months, resolution of polycythaemia and acromegaly was observed, evident on normal haemoglobin levels, a normocellular marrow, and normal insulin-like growth factor-1 (IGF-1) with glucose-suppressed GH levels. Direct mitogenic properties of GH-IGF-1 axis on bone marrow progenitor cells may very rarely lead to erythroid hyperplasia and subsequent polycythaemia, reversible with successful therapy of acromegaly. In this case, polycythaemia secondary to hypersomatotropism likely resulted in pituitary apoplexy with subsequent remission of both acromegaly and resultant polycythaemia.

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Inguinoscrotal herniation of a caecal adenocarcinoma

An 84-year-old man with multiple comorbidities presented from a residential care home with a 1-month history of asthenia and moderate abdominal pain. On examination, he was found to have an irreducible right-sided inguinoscrotal hernia. Subsequent blood tests revealed a significant anaemia (haemoglobin 48 g/L), for which he was transfused. A CT scan of the abdomen and pelvis revealed a large caecal tumour, herniating through the right inguinal canal into the scrotum. The patient underwent an elective open right hemicolectomy with inguinal hernia defect repair, from which he recovered well. He was discharged from the ward 12 days postoperatively and is awaiting outpatient follow-up.

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Double duodenal perforation following foreign body ingestion

Intentional ingestion of a foreign body in adults is a rare clinical presentation. This case is one of a 27-year-old Sudanese man who presented having swallowed a ballpoint pen intentionally. Clinical examination and plain chest radiograph exhibited no signs indicative of perforation with only a raised C reactive protein identified on blood tests. Subsequent gastroscopy revealed that the pen had simultaneously perforated the duodenum at both D1 and D3 requiring removal via a laparotomy. The patient fully recovered and was discharged 2 weeks postoperatively following psychiatric input.

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One long umbilical cord, four nuchal cord loops and a true knot

Description

A 43-year-old woman G4 P2101 at 36 weeks of gestation presented to the labour floor with non-reactive fetal heart tracing and decreased fetal movement. She had a second-trimester ultrasound showing intrauterine growth retardation (IUGR). Patient had a history of hypothyroidism, two fetal demises at term and a planned preterm delivery at 34 weeks of gestation via caesarean section. Workup was negative for thrombophilia (lupus anticoagulant, anticardiolipin, anti-b2-glycoprotein, factor V Leiden, protein S, protein C, G20210 mutation, antithrombin III, antinuclear antibodies) and infectious diseases. Placental pathology following her second fetal demise revealed chorioamnionitis and necrotising funisitis with negative amniotic fluid cultures. There was no information regarding umbilical cord (UC) length or entanglements in previous pregnancies.

Given her history and the current non-reactive fetal heart tracing, the patient was taken for emergency caesarean delivery. A female infant was born with four loops of nuchal cord and a true knot (

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Catastrophic catheter-induced coronary artery vasospasm successfully rescued using intravascular ultrasound imaging guidance

A 46-year-old man underwent coronary angiography for stable angina. He developed inferior ST-segment myocardial infarction during the angiography. Intravascular ultrasound (IVUS) findings suggested coronary vasospasm. Intracoronary administration of isosorbide dinitrate restored the coronary flow. This case illustrates the essential role IVUS imaging played in establishing the diagnosis of catheter-induced coronary vasospasm.

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Treating patients with brain metastases has evolved: scalp-sparing, hippocampal avoidance whole brain radiotherapy with simultaneous integrated boost

Description

A 43-year-old male with a history of receiving treatment for squamous cell carcinoma (SqCC) of lung 2 years back presented with a complaint of a single episode of self-resolving generalised tonic–clonic seizure 1 day prior. General physical and neurological examinations were unremarkable. An MRI of the brain revealed a well-defined, enhancing, space-occupying lesion (SOL) in the right temporal lobe (figure 1). He was started on oral dexamethasone, oral phenytoin (after an intravenous loading dose) and underwent a whole body ¹⁸flourodeoxyglucose positron emission tomography CT (¹⁸FDG PET-CT), which revealed increased FDG uptake in the SOL without evidence of metastatic disease elsewhere (figure 1). A diagnosis of oligometastatic SqCC lung (cTx, cNx and cM1b) was made, and the options for management were discussed with the patient.

Figure 1

Pretreatment MRI and positron emission tomography CT (PET-CT) images. (A) T1-weighted contrast-enhanced axial image reveals a well-defined space occupying lesion in...

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Clinical examination and X-ray: an old approach to a current problem

Description

Ingesting a foreign body is not an uncommon occurrence. Most pass through the gastrointestinal tract uneventfully, and perforation is rare.1 The preoperative diagnosis, in these cases, is always very difficult and the radiological examinations are not always able to resolve the diagnostic. The mortality and the morbidity remain still high first of all for the delay in the diagnosis and the advanced age of patients.2

A 50-year-old man without relevant medical history was admitted to the emergency department with 4 days evolution of abdominal pain. The patient presented continuous abdominal pain at the left lower quadrant. There was no nausea, vomiting, alterations of bowel habits or fever.

On examination, the patient was in painful distress. Vital signs revealed tachycardia at 110 bpm, blood pressure of 120/64 mm Hg but no fever (36.8°C). Abdominal examination revealed diffuse tenderness and pain more intense at the left lower abdomen,...

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Necrotising pneumonia caused by non-PVL Staphylococcus aureus with 2-year follow-up

Necrotising pneumonia (NP) is a rare but life-threatening complication of pulmonary infection. It is characterised by progressive necrosis of lung parenchyma with cavitating foci evident upon radiological investigation. This article reports the case of a 52-year-old woman, immunocompetent healthcare professional presenting to Accident and Emergency with NP and Staphylococcus aureus septicaemia. The cavitating lesion was not identified on initial chest X-ray leading to a delay in antimicrobial optimisation. However, the patient went on to achieve a full symptomatic recovery in 1 month and complete radiological recovery at 2-year follow-up. Long-term prognosis for adult cases of NP currently remains undocumented. This case serves as the first piece of published evidence documenting full physiological and radiological recovery following appropriate treatment of NP in an immunocompetent adult patient.

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Interhemispheric subdural and subarachnoid haemorrhage in a patient with amphetamine-induced vasculitis

Description

A 27-year-old woman with a history of pulmonary embolism presented with confusion and depressed arousal after a night of alcohol and drug use. On examination, she was found to have lack of motivation and right leg weakness but had no other significant neurological findings. Trauma survey did not detect any signs of injury. CT scan of the head revealed interhemispheric subdural and subarachnoid haemorrhage with the highest volume in left frontoparietal region (figure 1). Urine toxicology showed presence of tetrahydrocannabinol and amphetamines. CT angiography demonstrated a small, incidental left supraclinoid internal carotid artery aneurysm but no other significant findings (figure 1). MRI was remarkable only for the haemorrhage and MR venogram confirmed patent venous sinuses (figure 1). Given the patient's history of drug use and the presence of amphetamines in her urine, conventional cerebral angiography was obtained to evaluate for vasculopathy. Cerebral...

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Fat embolism: a rare cause of perioperative renal transplant dysfunction

Fat embolism is a recognised complication of bony injury and orthopaedic surgery, commonly involving the long bones and pelvis. We report on the case of a 68-year-old renal transplant recipient who developed acute kidney injury following surgical stabilisation of metastatic carcinoma of the acetabulum and replacement of the proximal femur. A CT renal angiogram demonstrated a large fat embolus in the inferior vena cava (IVC) and left iliac veins below the level of IVC filter, with impaired renal perfusion. The risks of open or endovascular lipothrombectomy were felt to outweigh the potential benefits. The patient was managed with systemic anticoagulation and prepared for transplant failure. Subsequently, there was spontaneous improvement in urine output and 4 months postoperatively her transplant function had returned to her baseline level and this has remained stable at 1 year postsurgery.

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Perineal aggressive angiomyxoma in a menopausal woman

Aggressive angiomyxoma (AA) is an uncommon mesenchymal tumour that is principally located in the soft tissues of the pelvis and perineum of young women. The primary features of this benign tumour are a local invasion, a high local recurrence rate and non-specific local clinical signs. We describe the case of a 58-year-old woman, initially treated for a Bartholin's cyst. Histological examination indicated the presence of an AA. The MRI showed a 7 cm soft tissue mass extending from the lateral wall of the vagina, into the left buttock and down into the subcutaneous tissue. We performed a radical excision with wide resection, which is considered the standard gold treatment.

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An uncommon diagnosis for a recurrent erythematous patch in a paediatric patient

A 14-year-old girl presented with a circular erythematous patch over the left buttock for approximately 10 years, with ongoing ulceration and papules developing over the last 4 years. Punch biopsies were taken within and above the patch for diagnosis. Both revealed marked inflammatory infiltrates with atypical, irregular lymphocytes and increased mitosis. Immunostaining revealed CD8 positivity and a pan T helper cell phenotype. T cell receptor gene rearrangement analysis showed T cell clonality in both biopsies. These findings were consistent with mycosisfungoides and associated lymphomatoid papulosis. Both are rare conditions but have been associated in 5%–20% of cases. A definitive association has not yet been established; however, T cell monoclonality shows 50%–60% share a common origin. Management options are extensive with no one treatment showing superiority. Our patient received low-dose radiotherapy with good outcomes, but subsequently required further radiotherapy.

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Factors necessary for independent walking in patients with thalamic hemorrhage

Thalamic hemorrhages cause motor paralysis, sensory impairment, and cognitive dysfunctions, all of which may significantly affect walking independence. We examined the factors related to independent walking in...

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Anterior sacral meningocele infected with Fusobacterium in a patient with recently diagnosed colorectal carcinoma – a case report

Anterior sacral meningoceles are rare, and usually occur with other malformations of the posterior lower spine. While these are more frequently reported in pediatric cohorts, we report a case in an elderly woman.

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Cross sectional study of serum selenium concentration and esophageal squamous dysplasia in western Kenya

Abstract

Background

Low serum selenium status has been associated with increased risk of esophageal squamous cell carcinoma (ESCC). East Africa is a region of high ESCC incidence and is known to have low soil selenium levels, but this association has not previously been evaluated. In this study we assessed the association of serum selenium concentration and the prevalence of esophageal squamous dysplasia (ESD), the precursor lesion of ESCC, in a cross-sectional study of subjects from Bomet, Kenya.

Methods

294 asymptomatic adult residents of Bomet, Kenya completed questionnaires and underwent endoscopy with Lugol's iodine staining and biopsy for detection of ESD. Serum selenium concentrations were measured by instrumental neutron activation analysis. Odds ratios (OR) and confidence intervals (95% CI) for associations between serum selenium and ESD were calculated using unconditional logistic regression.

Results

The mean serum selenium concentration was 85.5 (±28.3) μg/L. Forty-two ESD cases were identified (14% of those screened), including 5 (12%) in selenium quartile 1 (Q1), 5 (12%) in Q2, 15 (36%) in Q3, and 17 (40%) in Q4. Higher serum selenium was associated with prevalence of ESD (Q4 vs Q1: OR: 3.03; 95% CI: 1.05–8.74) and this association remained after adjusting for potential confounders (Q4 vs Q1: OR: 3.87; 95% CI: 1.06–14.19).

Conclusion

This is the first study to evaluate the association of serum selenium concentration and esophageal squamous dysplasia in an African population at high risk for ESCC. We found a positive association between higher serum selenium concentration and prevalence of ESD, an association contrary to our original hypothesis. Further work is needed to better understand the role of selenium in the etiology of ESCC in this region, and to develop effective ESCC prevention and control strategies.

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A prospective, multi-center study assessing early loading with short implants in posterior regions. A 3-year post-loading follow-up study

Abstract

Background

Few prospective studies about early loading of short implant have been available and very little evidence exists on the outcomes longer than 3 years.

Purpose

To assess clinical and radiographic outcomes of 6 mm-short implants placed in the posterior maxilla and mandible applying an early loading protocol.

Materials and methods

Ninety-five short implants (6 mm-short, Ø 4 mm) were placed in 45 subjects at 3 study sites, 2 or 3 implants per subject, using a one-stage surgical procedure and loaded with a screw-retained splinted fixed prosthesis 6 weeks later. Follow-up took place at 6, 12, 24, and 36 months after loading. Marginal bone level changes, implant survival, clinical variables, and adverse events were assessed.

Results

The survival rate for all implants placed was 95.8%. From implant loading to 3 years follow-up, mean marginal bone level changes were minimal (0.07 ± 0.49 mm) and the peri-implant soft tissue status was healthy. No major technical or biological complications occurred except for the 4 early implant losses.

Conclusion

Three-year data indicates that the use of splinted 6 mm-short implants is a viable treatment in posterior regions with low marginal bone resorption. Early loading after 6 weeks should be taken cautiously in patients with known risk factors.

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We found that the co-expression of uPAR and FPR1 confers to A375 and M14 melanoma cells a clear-cut capability to move towards chemotactic gradients, to cross extracellular matrix and endothelial monolayers. FPR1 activity is required, as cell migration and invasion were abrogated by receptor desensitization. Finally, melanoma cell ability to move toward chemotactic gradients, invade matrigel or fibroblast-embedded collagen matrices and cross endothelial monolayers are prevented by anti-uPAR_84–95 antibodies or by the RI-3 peptide which we have previously shown to inhibit the uPAR_84–95/FPR1 interaction.

Conclusions

Collectively, our findings identify uPAR and FPR1 as relevant effectors of melanoma cell invasiveness and suggest that inhibitors of the uPAR_84–95/FPR1 cross-talk may be useful for the treatment of metastatic melanoma.

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FAM198B is Associated with Prolonged Survival and Inhibits Metastasis in Lung Adenocarcinoma via Blockage of ERK-Mediated MMP-1 Expression

Purpose: The comprehensive understanding of mechanisms involved in the tumor metastasis is urgently needed for discovering novel metastasis-related genes for developing effective diagnoses and treatments for lung cancer. Experimental Design: FAM198B was identified from an isogenic lung cancer metastasis cell model by microarray analysis. To investigate the clinical relevance of FAM198B, the FAMB198B expression of 95 Taiwan lung adenocarcinoma patients was analyzed by quantitative real-time PCR and correlated to patients' survivals. The impact of FAM198B on cell invasion, metastasis and tumor growth was examined by in vitro cellular assays and in vivo mouse models. Additionally, the N-glycosylation-defective FAM198B mutants generated by site-directed mutagenesis was used to study protein stability and subcellular localization of FAM198B. Finally, the microarray and pathway analysis were used to elucidate the underlying mechanisms of FAM198B-mediated tumor suppression. Results: We found that the high expression of FAM198B was associated with favorable survival in Taiwan lung adenocarcinoma patients and in a lung cancer public database. Enforced expression of FAM198B inhibited cell invasion, migration, mobility, proliferation and anchorage-independent growth and FAM198B silencing exhibited opposite activities in vitro. FAM198B also attenuated tumor growth and metastasis in vivo. We further identified MMP-1 as a critical downstream target of FAM198B. The FAM198B-mediated MMP-1 downregulation was via inhibition of the phosphorylation of extracellular signal-regulated kinase (ERK). Interestingly Deglycosylation nearly eliminated the metastasis suppression activity of FAM198B due to a decrease of protein stability. Conclusions: Our results implicate FAM198B as a potential tumor suppressor and to be a prognostic marker in lung adenocarcinoma.

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T cells expressing checkpoint receptor TIGIT are enriched in follicular lymphoma tumors and characterized by reversible suppression of T-cell receptor signaling

Purpose: T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing co-inhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets. Experimental Design: Surface expression of 9 co-inhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of TIGIT ligands were detected by immunohistochemistry. Results: TIGIT was a frequently expressed co-inhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly co-expressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFN-, while TCR proximal signaling (p-CD3, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells, and could be fully restored upon in vitro culture. The co-stimulatory receptor CD226 was downregulated in TIGIT+ compared to TIGIT-CD8 FL T cells, further skewing the balance towards immunosuppression. Conclusions: TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between co-inhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients.

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First-in-human phase I study of single-agent vanucizumab, a first-in-class bi-specific anti-Ang-2/anti-VEGF antibody, in adult patients with advanced solid tumors

Purpose: Vanucizumab is an investigational anti-angiogenic, first-in-class, bi-specific monoclonal antibody targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Experimental Design: Patients received escalating bi-weekly (q2w; 3-30 mg/kg) or weekly (qw; 10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally-located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg q2w dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related Grade ≥3 toxicities. Toxicity was generally higher with qw than q2w dosing. A maximum tolerated dose of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in K^TRANS (measured by dynamic contrast-enhanced-MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2000 mg q2w dose (phamacokinetically equivalent to 30 mg/kg q2w) was recommended for further investigation. Conclusion: Bi-weekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging anti-tumor activity in this heterogeneous population.

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Merkel cell carcinoma in the age of immunotherapy: Facts and hopes

Merkel cell carcinoma (MCC) is a rare (~2,000 US cases/year) but aggressive neuroendocrine tumor of the skin. For advanced MCC, cytotoxic chemotherapy only infrequently (<10% of cases) offers durable clinical responses (>1 year) suggesting a great need for improved therapeutic options. In 2008, the Merkel cell polyomavirus (MCPyV) was discovered and is clonally integrated in ~80% of MCC tumors. The remaining 20% of MCC tumors have large numbers of UV-associated mutations. Importantly, both the UV-induced-neoantigens in virus-negative tumors and the MCPyV T antigen oncogenes that are required for virus-positive tumor growth are immunogenic. Indeed, antigen-specific T cells detected in patients are frequently dysfunctional/'exhausted' and the inhibitory ligand, PD-L1, is often present in MCC tumors. These findings led to recent clinical trials involving PD-1 pathway blockade in advanced MCC. The combined data from these trials, involving three PD-1 pathway blocking agents (avelumab, pembrolizumab, and nivolumab) indicated a high frequency of durable responses in treated patients. Of note, prior treatment with chemotherapy was associated with decreased response rates to PD-1 checkpoint blockade. Over the past year, these striking data led to major changes in advanced MCC therapy, including the first-ever FDA drug approval for this disease. Despite these successes, ~50% of MCC patients do not persistently benefit from PD-1 pathway blockade, underscoring the need for novel strategies to broaden anti-tumor immune responses in these patients. Here we highlight recent progress in MCC including the underlying mechanisms of immune evasion and emerging approaches to augment the efficacy of PD-1 pathway blockade.

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CCL5-CCR5 interactions modulate metabolic events during tumor onset to promote tumorigenesis

Abstract

Background

In earlier studies we have shown that CCL5 activation of CCR5 induces the proliferation and survival of breast cancer cells in a mechanistic target of rapamycin (mTOR)-dependent manner and that this is in part due to CCR5-mediated increases in glycolytic metabolism.

Methods

Using the MDA-MB-231 triple negative human breast cancer cell line and mouse mammary tumor virus – polyomavirus middle T-antigen (MMTV-PyMT) mouse primary breast cancer cells, we conducted in vivo tumor transplant experiments to examine the effects of CCL5-CCR5 interactions in the context of regulating tumor metabolism. Additionally, we employed Matrix-Assisted Laser Desorption/Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry imaging (MALDI-FTICR-MSI) to evaluate tumor utilization of cellular metabolites.

Results

We provide evidence that, in the absence of CCR5, the early events associated with rapid tumor growth in the MMTV-PyMT mouse model of spontaneous breast cancer development, are diminished, as demonstrated by a delay in tumor onset. In tumor transplant studies into immunocompromised mice we identify a direct correlation between reduced tumor proliferation and decreased metabolic activity, specifically associated with tumor expression of CCR5. The reduction in tumorigenesis is accompanied by decreases in glucose uptake, glucose transporter-1 (GLUT-1) cell surface expression, intracellular ATP and lactate levels, as well as reduced CCL5 production. Using MALDI-FTICR-MS, we show that the rapid early tumor growth of CCR5^+/+ triple negative breast cancer cells in vivo is attributable to increased levels of glycolytic intermediates required for anabolic processes, in contrast to the slower growth rate of their corresponding CCR5^−/− cells, that exhibit reduced glycolytic metabolism.

Conclusions

These findings suggest that CCL5-CCR5 interactions in the tumor microenvironment modulate metabolic events during tumor onset to promote tumorigenesis.

http://ift.tt/2j4zysA

Improved Tumor Penetration and Single-Cell Targeting of Antibody Drug Conjugates Increases Anticancer Efficacy and Host Survival

Current antibody-drug conjugates (ADC) have made advances in engineering the antibody, linker, conjugation site, small molecule payload and drug-to-antibody ratio (DAR). However, the relationship between heterogeneous intratumoral distribution and efficacy of ADC is poorly understood. Here we compared trastuzumab and ado-trastuzumab emtansine (T-DM1) to study the impact of ADC tumor distribution on efficacy. In a mouse xenograft model insensitive to trastuzumab, co-administration of trastuzumab with a fixed dose of T-DM1 at 3:1 and 8:1 ratios dramatically improved ADC tumor penetration and resulted in twice the improvement in median survival compared to T-DM1 alone. In this setting, the effective DAR was lowered, decreasing the amount of payload delivered to each targeted cell but increasing the number of cells that received payload. This result is counterintuitive because trastuzumab acts as an antagonist in vitro and has no single-agent efficacy in vivo, yet improves the effectiveness of T-DM1 in vivo. Novel dual-channel fluorescence ratios quantified single-cell ADC uptake and metabolism and confirmed that the in vivo cellular dose of T-DM1 alone exceeded the minimum required for efficacy in this model. Additionally, this technique characterized cellular pharmacokinetics with heterogeneous delivery after one day, degradation and payload release by two days, and in vitro cell killing and in vivo tumor shrinkage 2-3 days later. This work demonstrates that the intratumoral distribution of ADC - independent of payload dose or plasma clearance - plays a major role in ADC efficacy.

http://ift.tt/2Amtbs0

Radiotherapy-activated cancer-associated fibroblasts promote tumor progression through paracrine IGF-1R activation

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer (RC), a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAF are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer (CRC) cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell cycle arrest, and secretion of paracrine mediators including insulin-like growth factor-1 (IGF-1). Subsequently, RT-activated CAF promoted survival of CRC cells as well as a metabolic switch favoring glutamine consumption through IGF-1 receptor (IGF-1R) activation. RT followed by IGF-1R neutralization in orthotopic CRC models reduced the number of mice with organ metastases. Activation of the downstream IGF-1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from RC patients after neoadjuvant chemoRT. Taken together, our data support the notion that paracrine IGF-1/IGF-1R signaling initiated by RT-activated CAF worsen CRC progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival.

http://ift.tt/2BgrJYs

SIRT6 is a target of regulation by UBE3A that contributes to liver tumorigenesis in an ANXA2-dependent manner

UBE3A is an E3 ubiquitin ligase well known for its role in the proteasomal degradation of p53 in human papillomavirus (HPV)-associated cancers. Here we report that UBE3A ubiquitylates and triggers degradation of the tumor suppressive sirtuin SIRT6 in hepatocellular carcinoma. UBE3A ubiquitylated the highly conserved Lys160 residue on SIRT6. FOXO1-mediated transcriptional repression of UBE3A was sufficient to stabilize SIRT6 and epigenetically repress ANXA2, a key mediator of UBE3A oncogenic function. Thus, UBE3A-mediated SIRT6 degradation promoted the proliferative capacity, migration potential and invasiveness of cells. In mouse models of hepatocellular carcinoma, SIRT6 downregulation and consequent induction of ANXA2 were critical for UBE3A-mediated tumorigenesis. Furthermore, in clinical specimens, increased UBE3A levels correlated with reduced SIRT6 levels and elevated ANXA2 levels in increasing tumor grades. Overall, our findings show how the tumor suppressor SIRT6 is regulated in hepatocellular carcinoma and establish the mechanism underlying UBE3A-mediated tumorigenesis in this disease.

http://ift.tt/2AkgkXn

Aptamer-conjugated extracellular nanovesicles for targeted drug delivery

Extracellular nanovesicles (ENV) released by many cells contain lipids, proteins and nucleic acids that contribute to intercellular communication. ENV have emerged as biomarkers and therapeutic targets but they have also been explored as drug delivery vehicles. However, for the latter application clinical translation has been limited by low yield and inadequate targeting effects. ENV vectors with desired targeting properties can be produced from parental cells engineered to express membrane-bound targeting ligands, or they can be generated by fusion with targeting liposomes, however, neither approach has met clinical requirements. In this study, we demonstrate that mechanical extrusion of ~107 cells grafted with lipidated ligands can generate cancer cell-targeting ENV and can be prepared in ~1 hour. This rapid and economic approach could pave the way for clinical implementation in the future.

http://ift.tt/2BgrD32

Tumor-associated fatigue in cancer patients develops independently of interleukin-1 signaling

Fatigue is the most common symptom of cancer at diagnosis, yet causes and effective treatments remain elusive. As tumors can be highly inflammatory, it is generally accepted that inflammation mediates cancer-related fatigue. However, evidence to support this assertion is mostly correlational. In this study, we directly tested the hypothesis that fatigue results from propagation of tumor-induced inflammation to the brain and activation of the central pro-inflammatory cytokine, interleukin-1 (IL-1). The heterotopic syngeneic murine head and neck cancer model (mEER) caused systemic inflammation and increased expression of Il1b in the brain while inducing fatigue-like behaviors characterized by decreased voluntary wheel running and exploratory activity. Expression of Il1b in the brain was not associated with any alterations in motivation, measured by responding in a progressive ratio schedule of food reinforcement, depressive-like behaviors, or energy balance. Decreased wheel running occurred prior to Il1b detection in the brain, when systemic inflammation was minimal. Further, mice null for two components of IL-1β signaling, the type 1 interleukin-1 receptor or the receptor adapter protein MyD88, were not protected from tumor-induced decreases in wheel running, despite attenuated cytokine action and expression. Behavioral and inflammatory analysis of 4 additional syngeneic tumor models revealed that tumors can induce fatigue regardless of their systemic or central nervous system inflammatory potential. Together our results show that brain IL-1 signaling is not necessary for tumor-related fatigue, dissociating this type of cancer sequela from systemic cytokine expression.

http://ift.tt/2AlGlph

Intensity modulated radiation therapy and surgery for Management of Retroperitoneal Sarcomas: a single-institution experience

Abstract

Background

Peri-operative radiation of retroperitoneal sarcomas (RPS) is an important component of multidisciplinary treatment. All retrospective series thus far included patients treated with older radiation therapy (RT) techniques including 2D and 3DRT. Intensity modulated radiation therapy (IMRT) allows for selective dose escalation while sparing adjacent organs. We therefore report the first series of patients with RPS treated solely with IMRT, surgery and chemotherapy. We hypothesized that IMRT would permit safe dose escalation and superior rates of local control (LC) in this high-risk patient population.

Methods

Thirty patients with RPS treated with curative intent between 2006 and 2015 were included in this retrospective study. RT was administered either pre- or post-operatively and IMRT was used in all patients. Statistical comparisons, LC, distant metastasis (DM), and overall survival (OS) were calculated by Kaplan-Meier analysis and univariate Cox regression.

Results

Median follow-up time after completion of RT was 36 months (range 1.4-112). Median tumor size was 14 cm (range 3.6 - 28 cm). The most prevalent histologies were liposarcoma in 10 (33%) patients and leiomyosarcoma in 10 (33%) with 21 patients (70%) having high-grade disease. Twenty-eight (93%) patients had surgical resection with 47% having positive margins. Chemotherapy was administered in 9 (30%) patients. RT was delivered pre-operatively in 11 (37%) patients, and post-operatively in 19 (63%) with 60% of patients receiving a simultaneous integrated boost. Pre-operative median RT dose to the high-risk area was 55 Gy (range, 43–66 Gy) while median post-operative dose was 60.4 Gy (range, 45-66.6 Gy). There was one acute grade 3 and one late grade 3 toxicity and no grade 4 or 5 toxicities. Three year actuarial LC, freedom from DM, and OS rates were 84%, 64%, and 68% respectively. Positive surgical margins were associated with a higher risk of local recurrence (p = 0.02) and decreased OS (p = 0.04). Pre-operative RT was associated with improved LC (p = 0.1) with a 5-year actuarial LC of 100%. Administration of chemotherapy, timing of RT, histology or grade was not predictive of OS.

Conclusions

Patients with RPS treated with peri-operative IMRT at our institution had excellent local control and low incidences of toxicity.

http://ift.tt/2zZB0zL

First-Line Osimertinib Beneficial in Advanced NSCLC [News in Brief]

In the FLAURA trial, drug improves survival for a subset of patients with higher incidence of EGFR-mutated disease.

http://ift.tt/2kxnDUt

Evaluation of lipid-lowering effect of Cynara scolymus extract-loaded mesoporous silica nanoparticles on ultra-lipid-fed mice

Abstract

In current investigation, twenty mice were divided into 4 different equal groups as follows: group CS which received 0.1 ml Cynara scolymus extract (diluted in distilled water) at dose of 600 mg kg⁻¹ daily for 3 weeks, group A which received 0.1 ml Atorvastatin 40 (diluted in distilled water) at dose of 20 mg kg⁻¹ daily for 21 days, group T which received 0.1 ml of Cynara scolymus extract at dose of 600 mg kg⁻¹ daily in nonporous (diluted in distilled water) during experimental period, and control group (group C) which received the same volume of normal saline. The supplements were gavaged in all animals, during experiment period, and blood samples were obtained after 21 days. Results showed that total cholesterol and triglyceride decreased significantly in the treatment group compared with the control and CS groups (p < 0.05). It seems that mesoporous silica nanoparticles improve drug delivery and therefore Cynara scolymus extract-loaded mesoporous silica nanoparticles has more effective lipid-lowering action than Cynara scolymus extract.

http://ift.tt/2j4DIkq

A longitudinal cohort study on the impact of the clobazam shortage on patients with epilepsy

Summary

Objective

Drug shortages are occurring at an increasing rate. From May to October 2016, there was a shortage of a level I critical antiepileptic drug, clobazam. We aimed to study the impact of this shortage on patients with epilepsy.

Methods

Adult patients from Calgary's Comprehensive Epilepsy Program who were taking clobazam were approached to participate in the study. Baseline data from the clinic prospective registry included clinical variables and presurvey patient-reported outcomes (PROs) such as the Global Assessment of Severity of Epilepsy, the Global Assessment of Disability Associated with Seizures, and the Quality of Life in Epilepsy questionnaire. We used a mixed-methods cross-sectional questionnaire via telephone. We analyzed quantitative data using descriptive methods and qualitative data using a phenomenological approach.

Results

Of the 85 eligible patients, 84% (n = 71) agreed to participate. Participants ranged from 18 to 78 years old, and 59.2% of participants were female. Overall, 80% of participants experienced some form of medication change due to the shortage. No significant differences were found in the pre- and during-shortage PRO data. However, 6 important themes emerged regarding the impact of the antiepileptic drug shortage on patients: (1) communication and awareness, (2) burden on patients and caregivers, (3) physical impact, (4) psychological impact, (5) health care provider assistance in navigating the shortage, and (6) policy change.

Significance

We examined the impact of the clobazam shortage on patients with epilepsy from the patient's perspective and identified 6 important themes. As a result, we were able to gain insight into what patients need to cope with drug shortages and make recommendations that can help mitigate the impact of shortages on patients in the future. Further research is needed to better understand drug shortages from the patient's perspective in various settings and conditions.

http://ift.tt/2iDadSD

Deep brain stimulation for drug-resistant epilepsy

Summary

Objectives

To review clinical evidence on the antiepileptic effects of deep brain stimulation (DBS) for drug-resistant epilepsy, its safety, and the factors influencing individual outcomes.

Methods

A comprehensive search of the medical literature (PubMed, Medline) was conducted to identify relevant articles investigating DBS therapy for drug-resistant epilepsy. Reference lists of these articles were used to source further articles.

Results

Stimulation of the anterior nucleus of the thalamus (ANT) and hippocampus (HC) has been shown to decrease the frequency of refractory seizures. Half of all patients from clinical studies experienced a 46%-90% seizure reduction with ANT-DBS, and a 48%-95% seizure reduction with HC-DBS. The efficacy of stimulating other targets remains inconclusive due to lack of evidence. Approximately three-fourths of patients receiving ANT, HC, or centromedian nucleus of the thalamus (CMT) stimulation are responders—experiencing a seizure reduction of at least 50%. The time course of clinical benefit varies dramatically, with both an initial lesional effect and ongoing stimulation effect at play. Improved quality of life and changes to cognition or mood may also occur. Side effects are similar in nature to those reported from DBS therapy for movement disorders. Several factors are potentially associated with stimulation efficacy, including an absence of structural abnormality on imaging for ANT and HC stimulation, and electrode position relative to the target. Certain seizure types or syndromes may respond more favorably to specific targets, including ANT stimulation for deep temporal or limbic seizures, and CMT stimulation for generalized seizures and Lennox-Gastaut syndrome.

Significance

We have identified several patient, disease, and stimulation factors that potentially predict seizure outcome following DBS. More large-scale clinical trials are needed to explore different stimulation parameters, reevaluate the indications for DBS, and identify robust predictors of patient response.

http://ift.tt/2BLfqPV

111In-DTPA-Octreotide SPECT (OctreoScan) Uptake in Metastatic Renal Cell Carcinoma to the Pancreas

Abstract We report a case of late presentation of metastatic renal cell carcinoma (RCC) demonstrating intense 111In-DTPA-octreotide uptake in pancreas without recurrence at the primary site. Immunohistochemistry study revealed somatostatin receptor subtype 2 of metastatic RCC preferentially expressed on tumor endothelial cells. The typical hypervascular features of RCC with intense homogeneous contrast enhancement in the arterial phase on CT should raise the possibility of metastatic RCC. This case illustrates that RCC can demonstrate high octreotide uptake in abdominal metastases.

http://ift.tt/2nH6clC

223Ra Therapy in Patients With Advanced Castration-Resistant Prostate Cancer With Bone Metastases: Lessons from Daily Practice

Purpose To identify pre-therapeutic variables associated with overall survival (OS) in patients treated with 223Ra. Methods Data from 45 CRPC patients treated with 223Ra were retrospectively analyzed. All patients who received at least one 223Ra injection were included in the study. Cox proportional hazard regression models were used to estimate hazard ratio's (HR) and to test for association. Results Twenty-one patients (47%) received six 223Ra injections and 24 patients (53%) received one to five 223Ra injections. Median OS since start of 223Ra was 13.0 months (95% confidence interval (CI) 8.2–17.8). Patients who completed 223Ra therapy had a median OS of 19.7 months (95% CI 14.9–24.6), while patients who received one to five 223Ra injections had a median OS of 5.9 months (95% CI 3.8–8.1; P

http://ift.tt/2nFba2m

High-Energy Collimator Is Preferable to Medium-Energy Collimator for Evaluating 223Ra Uptake in Bone Metastasis at 2 Weeks Postinjection

Abstract An 80-year-old man with castration-resistant prostate cancer received 223Ra injection to treat bone metastases. Two weeks after the injection, the patient underwent static 223Ra scan of the chest with medium-energy and high-energy collimators for 30 minutes each. Images obtained with the 2 collimators showed that uptake in metastatic lesions was visually clearer and semiquantitatively higher with the high-energy collimator. The use of HE collimator for 223Ra imaging in the early phase has been reported, and the present case suggests that in the late phase HE collimator would also be preferable to medium-energy collimator in terms of lesion-based evaluation.

http://ift.tt/2nHwFPQ

Quality and Safety in Health Care, Part XXXI: Selected Risk Factors for Transcatheter Aortic Valve Replacement

Abstract The Transcatheter Valve Therapy Registry has been very helpful in providing data to better understand patient risk factors for transcatheter aortic valve replacement (TAVR). The outcome of TAVR depends on many patient indicators, some of which are given in this article, including the age, dependence on oxygen, classification of pulmonary disease, gender, and the speed of walking. Patient characteristics also help determine which approach will be used to place the device. There are models for the outcome of the TAVR procedure now and more being developed.

http://ift.tt/2zYUJQ5

68Ga–Prostate-Specific Membrane Antigen Uptake in Gastrointestinal Stromal Tumor

Abstract A 62-year-old man with recently diagnosed prostatic adenocarcinoma was referred for a whole-body 68Ga-prostate-specific membrane antigen (PSMA) PET/CT scan for staging. Although the scan did not reveal metastatic disease, it did reveal a PSMA-avid lesion in the upper abdomen located between the liver and the stomach. Histopathologic examination demonstrated a gastrointestinal stromal tumor. The lesion demonstrated increased uptake in the margins of the tumor with a central photopenic area, which we consider to be the typical pattern on PSMA images of a gastrointestinal stromal tumor, based on theoretical PSMA distribution in such a tumor and other reported cases.

http://ift.tt/2A0lXWF

Solitary Orbital Metastasis in Carcinoma Esophagus: Findings on Serial 18F-FDG PET/CT Scans

Abstract Orbital metastasis is an uncommon and atypical presentation of recurrent esophageal cancer that has been only seldom reported in literature. 18F-FDG PET/CT is routinely performed for staging and response assessment in patients with esophageal carcinoma. This case demonstrates use of follow-up FDG PET/CT scans in characterizing solitary metastatic disease in orbit and in evaluating response to therapy. It also highlights a key teaching point that postradiation-related inflammatory/infective changes may interfere in accurate assessment of PET/CT scan; however, frequently used clinical and radiological correlation may not be entirely sufficient to rule out pathological involvement.

http://ift.tt/2zZrg8I

Role of Various Metabolic Parameters Derived From Baseline 18F-FDG PET/CT as Prognostic Markers in Non–Small Cell Lung Cancer Patients Undergoing Platinum-Based Chemotherapy

Purpose The aim of this study was to prospectively evaluate the role of various quantitative and semiquantitative metabolic parameters derived from dynamic and static baseline 18F-FDG PET/CT in prediction of overall survival (OS) in non–small cell lung cancer (NSCLC) patients who were planned to undergo platinum-based chemotherapy. Methods Sixty patients (51 male and 9 female patients) with biopsy-proven NSCLC and mean age 59.55 ± 10.06 years who were planned to undergo platinum-based chemotherapy were enrolled in the study. Each patient underwent a baseline regional dynamic and a static whole-body 18F-FDG PET/CT after injecting 0.21 mCi/kg (5.18–7.77 MBq/kg) of 18F-FDG intravenously. Two dynamic PET/CT parameters, that is, net influx rate constant and glucose metabolic rate at 30 and 60 minutes, were evaluated. In addition, whole-body PET/CT parameters, that is, SUVmax, average SUV, tumor-to-background ratio, metabolic tumor volume (MTV), total lesion glycolysis (TLG) of the primary tumor, and MTV and TLG of whole-body tumor lesions, were evaluated. Best possible cutoffs for all parameters were calculated using receiver operating characteristic curve analysis. Survival analysis was performed using log-rank test, Kaplan-Meier curves, and Cox proportional hazards model to determine the prognostic markers for OS. Results The median follow-up period was 4.4 months (range, 8 days to 15.9 months). In univariate analysis, the 4 static whole-body PET/CT parameters, that is, MTV, TLG, and MTV and TLG of whole-body tumor lesions, were found to be significantly associated with OS with cutoff values of 120, 800, 160, and 1350 cm3 and hazard ratios of 3.64 (P = 0.001), 3.35 (P = 0.002), 2.51 (P = 0.019), and 2.69 (P = 0.008), respectively. In multivariate survival analysis, MTV was found to be an independent prognostic marker for OS. Conclusions Baseline MTV and TLG evaluated from primary tumor as well as the whole-body tumor lesions are reliable prognostic markers of OS in NSCLC patients undergoing platinum-based chemotherapy. However, other baseline whole-body PET/CT parameters (SUVmax, average SUV, and tumor-to-background ratio) and dynamic PET/CT parameters (net influx rate constant, glucose metabolic rate) have no prognostic value in these patients.

http://ift.tt/2A1DE85

18F-FDG PET/CT Imaging of Hidradenocarcinoma Arising From Preexisting Hidradenoma of the Knee

Abstract Malignant tumors of the sweat glands are exceedingly rare and aggressive tumors. We present here a case of a 60-year-old man with a malignant hidradenocarcinoma that developed in a background of preexisting benign hidradenoma on the lateral aspect of the knee that was initially resected, but rapidly recurred with associated inguinal lymphadenopathy. 18F-FDG PET/CT was performed as part of preoperative staging, which demonstrated abnormal inguinal lymph nodes and metastatic disease to the lungs. FDG PET/CT can play an invaluable role in the initial staging and follow-up of this rare malignancy.

http://ift.tt/2A1M27w

Incidental Case of Relapsing Polychondritis Detected by 18F-FDG PET/CT

Abstract A 78-year-old man had fever, persistent wheezing, and serum C-reactive protein elevation. Malignant lymphoma was suspected because of mediastinal lymph nodes swelling on CT and soluble interleukin 2 receptor elevation. Symmetric 18F-FDG uptake in the tracheobronchial tree and bilateral auricles was observed on PET/CT. He was finally diagnosed as having relapsing polychondritis by auricular cartilage biopsy. 18F-FDG PET/CT may have crucial role in evaluating the extent of inflammation and deciding the biopsy site of relapsing polychondritis.

http://ift.tt/2A1uDft

Simultaneous Brain and Lung Histiocytic Sarcoma Revealed on 18F-FDG PET/CT

Abstract A 52-year-old man with intermittent head motor tics, aphasia and right upper extremity weakness had an 18F-FDG avid left front lobe brain lesion, and a left upper lobe lung lesion on PET/CT. The brain lesion was surgically resected, and was diagnosed pathologically as a histiocytic sarcoma (HS). The lung lesion was also a HS via bronchial biopsy. HS is rare and generally involves nodes as shown on PET/CT in a few case reports. The current case with simultaneous brain and lung HS lesions adds new imaging pattern information of the disease to the literature.

http://ift.tt/2A0lBiN

Intracardiac Metastases Detected by 18F-FSPG PET/CT

Abstract PET/CT imaging is frequently used for cancer diagnosis and restaging as metabolically active cells, including cancer, utilize glucose for proliferation. 18F-FDG is the most commonly utilized radiopharmaceutical in PET/CT imaging. Limitations of 18F-FDG imaging include intense physiologic uptake in benign tissues such as the brain and myocardium. We present a case of non–small cell lung cancer with myocardial and pericardial metastases obscured by physiologic 18F-FDG cardiac uptake but detected with the investigational PET radiotracer (4S)-4-(3-18F-fluoropropyl)-L-glutamate (18F-FSPG), which targets a pathway associated with glutathione biosynthesis. This case demonstrates the added value of 18F-FSPG PET/CT imaging.

http://ift.tt/2zZbJ8J

Re: 18F-Fluorocholine PET/CT of Incidental Male Breast Cancer

No abstract available

http://ift.tt/2A0iIya

Potential Visualization of Sorafenib-Induced Acidosis Using 11C-Acetate PET/CT in Patients With Hepatocellular Carcinoma

Abstract 11C-acetate uptake could be increased in physiologic or inflammatory conditions without evidence of cancer. We report a hepatocellular carcinoma patient with sorafenib-induced metabolic acidosis, who showed increased hepatic uptake of 11C-acetate. 11C-acetate PET/CT might be a potentially useful surrogate marker to monitor these adverse effects via the changes in 11C-acetate uptake patterns from before to after drug withdrawal.

http://ift.tt/2zZbFpv

Ectopic Adrenocorticotropic Hormone–Secreting Pituitary Adenoma Localized by 18F-Choline PET/CT

Abstract The criterion standard of treatment of an adrenocorticotropic hormone (ACTH)–secreting pituitary adenoma is complete surgical excision. However, ectopic location of these adenomas is an extremely rare condition, which may affect the diagnosis and treatment success. We report a case of a 49-year-old man who was referred to our institution with persistent hypercortisolemia after an unsuccessful attempt of surgical resection. 18F-choline PET/CT revealed increased radiopharmaceutical uptake in a nodule localized in the left maxillary sinus, which was proved at histology to be an ectopic ACTH-secreting pituitary adenoma staining positive for ACTH. Imaging with 18F-FDG PET/CT and 68Ga-DOTA-NOC PET/CT was not diagnostic.

http://ift.tt/2zYIpPN

Focal Pulmonary Uptake on 99mTc-Sestamibi Parathyroid Scintigraphy Due to Iatrogenic Microembolism

Abstract A middle-aged woman underwent 99mTc-sestamibi parathyroid scintigraphy because of parathyroid disease, and a focal pulmonary uptake of 99mTc-sestamibi was incidentally found on both planar and SPECT/CT images without corresponding pulmonary abnormality on the CT images. After 10 days, a subsequent parathyroid scintigraphy revealed no pulmonary accumulation. Therefore, the pulmonary intense 99mTc-sestamibi focus that once appeared in the first scan might be an artifact of iatrogenic microembolism from injection site.

http://ift.tt/2zYI8wf

Comparison Between Different PET and CT-Based Imaging Interpretation Criteria at Interim Imaging in Patients With Diffuse Large B-Cell Lymphoma

Objective To evaluate the predictive value of interim PET (iPET) in diffuse large B-cell lymphoma (DLBCL) using 5 different imaging interpretation criteria: Deauville 5-point scale criteria, International Harmonization Project (IHP) criteria, Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, European Organization for Research and Treatment of Cancer, and PET Response Criteria in Solid Tumors (PERCIST) 1.0. Methods We retrospectively reviewed records from 38 patients with DLBCL who underwent baseline and iPET at our institution. Imaging was interpreted according to the previously mentioned criteria. Results were correlated with end-of-treatment response, based on reports at the end of treatment radiological examinations, overall survival (OS), and progression-free survival (PFS) to assess and compare the predictive value of iPET according to each criterion. We also evaluated the concordance between different criteria. Results The Deauville and PERCIST criteria were the most reliable for predicting end-of-treatment response, reporting an accuracy of 81.6%. They also correlated with OS and PFS (P = 0.0004 and P = 0.0001, and P = 0.0007 and P = 0.0002, for Deauville and PERCIST, respectively). Interim PET according to European Organization for Research and Treatment of Cancer also predicted the end-of-treatment response with an accuracy of 73.7% and had a significant correlation with OS (P = 0.007) and PFS (P = 0.007). In contrast, the IHP criteria and RECIST did not predict outcomes: the accuracy for end-of-treatment response was 34.2% and 36.8%, respectively, with no significant correlation with OS or PFS (P = 0.182 and P = 0.357, and P = 0.341 and P = 0.215, for OS and PFS, respectively). Conclusions The predictive value of iPET in DLBCL patients is most reliable using the Deauville and PERCIST criteria. Criteria that rely on anatomical characteristics, namely, RECIST and IHP criteria, are less accurate in predicting patient outcomes in DLBCL.

http://ift.tt/2A1uqZJ

H Syndrome: A Rare Genodermatosis Imaged With 18F-FDG PET/CT

Abstract H syndrome (OMIM 612391) is an extremely rare autosomal recessive genodermatosis, characterized by extensive skin infiltration. We report a case imaged with 18F-FDG PET/CT.

http://ift.tt/2A2UnIh

Infliximab for the Treatment of Refractory Kawasaki Disease: A Nationwide Survey in Japan

To assess the safety and efficacy of infliximab (IFX) for the treatment of patients with Kawasaki disease (KD).

http://ift.tt/2ABfYKZ

Gut Transit in Duchenne Muscular Dystrophy Is Not Impaired: A Study Utilizing Wireless Motility Capsules

We examined gut transit in 7 young adults (18-24 years of age) with Duchenne muscular dystrophy using wireless motility capsules. Total and segmental gut transit times were normal in essentially all patients. Our study using a validated tool suggests normal transit constipation as the pathophysiologic basis for constipation in Duchenne muscular dystrophy.

http://ift.tt/2jrl8j4

Subclinical Atherosclerosis in Pediatric Liver Transplant Recipients: Carotid and Aorta Intima-Media Thickness and Their Predictors

To investigate prevalence and predictors of cardiovascular risk in pediatric liver transplant recipients using noninvasive markers of subclinical atherosclerosis: carotid intima-media thickness (cIMT) and aorta intima-media thickness (aIMT).

http://ift.tt/2jrl5DU

Bilateral Pulmonary Sequestration in a Preterm Infant

A female infant was born at gestational age of 30 weeks by cesarean delivery with a birth weight of 1250 g. Postnatal echocardiography showed multiple, small muscular ventricular septal defects as well as mild tubular aortic coarctation while arterial duct was still patent (patent ductus arteriosus [PDA]). During Doppler evaluation of the celiac trunk to examine hemodynamic relevance of the PDA, we found an additional vessel originating from the abdominal aorta just above the celiac trunk. This artery was feeding a bilateral, echogenic mass (Figure 1; available at www.jpeds.com).

http://ift.tt/2AD3jXP

Stuck in a Bind With Phosphate Binders

Scores of observational studies demonstrate that lower high-density lipoprotein cholesterol (HDL-C) concentrations are associated with cardiovascular risk. These associations are supported by mechanistic work in animal models. However, the New England Journal of Medicine recently published the disappointing results of a large clinical trial of evacetrapib, a cholesteryl ester transfer protein inhibitor.1 This medication increased HDL-C concentrations by a remarkable 133%, while reducing low-density lipoprotein cholesterol concentrations by 31%.

http://ift.tt/2nHe1Ys

Renal Involvement in Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) Syndrome: A Case Report

We report a case of a patient who had the mitochondrial cytopathy complex of neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome diagnosed at age 11 years with a biopsy-proven kidney involvement that progressed to end-stage renal disease at age 21 years. Mutations of mitochondrial DNA (mtDNA) are maternally inherited and lead to mitochondrial cytopathies with predominant neurologic manifestations: psychomotor retardation, epilepsy, ataxia, neuropathy, and myopathy. Given the ubiquitous nature of mitochondria, cellular dysfunction can also appear in tissues with high metabolic turnover; thus, there can be cardiac, digestive, ophthalmologic, and kidney complications.

http://ift.tt/2A1YqV1

In vivo Functional Analysis of Drosophila Robo1 Fibronectin Type III Repeats

The repellant ligand Slit and its Roundabout (Robo) family receptors regulate midline crossing of axons during development of the embryonic CNS. Slit proteins are produced at the midline and signal through Robo receptors to repel axons from the midline. Disruption of Slit-Robo signaling causes ectopic midline crossing phenotypes in the CNS of a broad range of animals, including insects and vertebrates. While previous studies have investigated the roles of Drosophila melanogaster Robo1's five Immunoglobulin-like (Ig) domains, little is known about the importance of the three evolutionarily conserved Fibronectin (Fn) type-III repeats. We have individually deleted each of Drosophila Robo1's three Fn repeats, and then tested these Robo1 variants in vitro to determine their ability to bind Slit in cultured Drosophila cells and in vivo to investigate the requirement for each domain in regulating Robo1's embryonic expression pattern, axonal localization, midline repulsive function, and sensitivity to Commissureless (Comm) downregulation. We demonstrate that the Fn repeats are not required for Robo1 to bind Slit or for proper expression of Robo1 in Drosophila embryonic neurons. When expressed in a robo1 mutant background, these variants are able to restore midline repulsion to an extent equivalent to full-length Robo1. We identify a novel requirement for Fn3 in the exclusion of Robo1 from commissures and downregulation of Robo1 by Comm. Our results indicate that each of the Drosophila Robo1 Fn repeats are individually dispensable for the protein's role in midline repulsion, despite the evolutionarily conserved "5+3" protein structure.

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Genome-Wide Analysis of Grain Yield Stability and Environmental Interactions in a Multiparental Soybean Population

Genetic improvement towards optimized and stable agronomic performance of soybean genotypes is desirable for food security. Understanding how genotypes perform in different environmental conditions helps breeders develop sustainable cultivars adapted to target regions. Complex traits of importance are known to be controlled by a large number of genomic regions with small effects whose magnitude and direction are modulated by environmental factors. Knowledge of the constraints and undesirable effects resulting from genotype by environmental interactions is a key objective in improving selection procedures in soybean breeding programs. In this study, the genetic basis of soybean grain yield responsiveness to environmental factors was examined in a large soybean nested association population. For this, a genome-wide association to performance stability estimates generated from a Finlay-Wilkinson analysis and the inclusion of the interaction between marker genotypes and environmental factors was implemented. Genomic footprints were investigated by analysis and meta-analysis using a recently published multi-parent model. Results indicated that specific soybean genomic regions were associated with stability, and that multiplicative interactions were present between environments and genetic background. Seven genomic regions in six chromosomes were identified as being associated with genotype-by-environment interactions. This study provides insight into genomic assisted breeding aimed at achieving a more stable agronomic performance of soybean, and documented opportunities to exploit genomic regions that were specifically associated with interactions involving environments and subpopulations.

http://ift.tt/2ABkdWV

Serum protein electrophoresis reference values in the gyrfalcon ( Falco rusticolus )

Abstract

Blood samples were collected as part of routine clinical examination procedures from 120 clinically normal gyrfalcons (Falco rusticolus) during a 4-year period between the months of September and February. Serum protein electrophoresis (SPE) was carried out to establish reference values for the species and to characterize species-specific electrophoretic patterns. The SPE analyses included measurements of pre-albumin, albumin, alpha-1, alpha-2, beta-1, beta-2, gamma globulins, and the albumin/globulin ratio. Reference intervals were determined using a quantile approach with 90% confidence intervals. Female gyrfalcons were found to have significantly lower median albumin and gamma concentrations than males. Juvenile gyrfalcons were found to have significantly lower median total protein, alpha-1, alpha-2, and beta-globulins than adults. Results of this study provide SPE values for gyrfalcons that may contribute to the medical management of this species commonly used in the sport of falconry in the Middle East.

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An unfortunate soul: a rare presentation of an uncommon pathology for upper gastrointestinal bleeding

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How to do liver transplantation using renoportal bypass

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Patient compliance with surveillance colonoscopy: patient factors and the use of a graded recall system

Background

Surveillance colonoscopy allows for the early detection and improved treatment outcomes in colorectal neoplasms but compliance rates and factors require further investigation.

Methods

This is a retrospective cohort study examining 816 patients recalled for surveillance colonoscopy at an Australian colorectal practice over a 6-month period. Primary outcome was compliance with colonoscopy within 12 months of recall. The secondary outcome of this study was to identify factors affecting compliance including patient factors and the practices' graded recall system.

Results

A total of 715 patients (87.6%) were compliant with recall requests for repeat colonoscopy. Significantly higher compliance rates were noted with a personal history of adenomatous polyps (90.9% versus 85.6%, P = 0.025). Those with private insurance or Department of Veterans Affairs were more likely to be compliant than those publicly funded (89.0% versus 93.3% versus 79.0%, P = 0.007). No statistically significant difference in compliance was shown with a personal history of colorectal cancer, diverticular disease, perianal disease, National Health and Medical Research Council risk category, gender, time associated with the practice or the clinician. There was a significant positive correlation between the number of letters sent and compliance with recall, with 61.8% being compliant after a single letter, and a final cumulative compliance after five letters of 87.6% (R = 0.882, P = 0.048).

Conclusion

A graded recall system can achieve compliance rates as high as 87.6% compared to a single letter only achieving 61.8% compliance. A history of adenomatous polyps and insurance status were the only factors shown to result in higher recall compliance.

http://ift.tt/2nGZaxa

Rapid Response Events in Hospitalized Patients: Patient Symptoms and Clinician Communication

Patients triggering Rapid Response Team (RRT) intervention are at high risk for adverse outcomes. Data on symptom burden of these patients does not currently exist and current symptom management and communication practices of RRT clinicians are unknown.

http://ift.tt/2ACYZFX

Enteral nutrition and quality of life in patients undergoing chemoradiotherapy for esophageal carcinoma: a comparison of nasogastric tube, esophageal stent, and ostomy tube feeding

This study prospectively recruited esophageal squamous-cell carcinoma patients who received esophageal stent, nasogastric tube (NG) or jejunostomy/gastrostomy feeding to compare the changes in nutritional status and quality of life during chemoradiation therapy (CRT).

http://ift.tt/2Bfd6on

Computer-aided diagnosis for identifying and delineating early gastric cancers in magnifying narrow-band images

Magnifying narrow-band imaging (M-NBI) is important in the diagnosis of early gastric cancers (EGCs), but requires expertise to master. We developed a computer-aided diagnosis (CADx) system to assist endoscopists in identifying and delineating EGCs.

http://ift.tt/2AkNk1L

Comparison of EUS with magnetic resonance cholangiopancreatography in idiopathic acute pancreatitis: a systematic review and meta-analysis

/Aims: Idiopathic acute pancreatitis (IAP) poses a diagnostic challenge for gastroenterologists, as confirmation of the disease etiology has important implications for the selection of the best possible treatment and the prevention of possible recurrence or the development of chronic pancreatitis. ERCP, EUS, and magnetic resonance cholangiopancreatography (MRCP) are typically used to diagnose IAP when conventional radiological methods fail. However, their exact role in the diagnosis of IAP has not yet been determined.

http://ift.tt/2Bg2c1y

Buprenorphine for Medication-Assisted Treatment of Opioid Use Disorder in Pregnancy: Relationship to Neonatal Opioid Withdrawal Syndrome

AJP Rep 2017; 07: e215-e222
DOI: 10.1055/s-0037-1608783

Objective To examine the relationship between antepartum buprenorphine dose for medication-assisted treatment (MAT) of opioid use disorder (OUD) and incident neonatal opioid withdrawal syndrome (NOWS). Study Design We performed a prospective cohort study of pregnant women with a singleton gestation diagnosed with OUD and receiving buprenorphine for MAT at a tertiary care academic institution from July 2015 to January 2017. We divided the study cohort into two groups—pregnancies with versus without NOWS. Substance abuse patterns in pregnancy, maternal, and neonatal clinical outcomes were compared. Results The incidence of NOWS was 31.11% (n = 28/90) in our study cohort. Pregnancies with NOWS had a significantly higher rate of benzodiazepine positive urine tests and number of positive urine drug screen (UDS) results for illicit opioids. The group without NOWS had significantly higher number of patients with an appropriate UDS result at delivery through postpartum. Rates of neonatal intensive care unit (NICU) admission, length of NICU stay, and maximum Finnegan score were significantly higher in the group with NOWS. Neither the initial (10.6 ± 5.2 versus 10.3 ± 4.8 mg, p = 0.80) nor the final buprenorphine doses (13.3 ± 5.1 versus 13.0 ± 4.6 mg, p = 0.81) were significantly different between study groups. Conclusion The occurrence of NOWS was not related to buprenorphine dose used for MAT.
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Article in Thieme eJournals:
Table of contents | Abstract | open access Full text

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Motivation for Launching a Cancer Metastasis Inhibition (CMI) Program

Abstract

Metastatic cancers impose significant burdens on patients, affecting quality of life, morbidity, and mortality. Even during remission, microscopic metastases can lurk, but few therapies directly target tumor cell metastasis. Agents that interfere with this process would represent a new paradigm in cancer management, changing the 'waiting game' into a time of active prevention. These therapies could take multiple forms based on the pathways involved in the metastatic process. For example, a phenome-wide association study showed that a single nucleotide polymorphism in the gene TBXA2R is associated with increased metastasis in multiple primary cancers (P = 0.003), suggesting clinical applicability of TBXA2R antagonists. Emerging data related to the role of platelets in metastasis are concordant with our sense that these pathways present significant opportunities for therapeutic development. However, before real progress can be made toward clinical targeting of the metastatic process, foundational work is needed to define informative measures of critical elements such as circulating tumor cells and tumor DNA, and circulatory vs. lymphatic spread. These challenges require an expansion of team science and composition to obtain competitive funding. At our academic medical center, we have implemented a Cancer Metastasis Inhibition (CMI) program investigating this approach across multiple cancers.

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Early Metabolic Change after Induction Chemotherapy Predicts Histologic Response and Prognosis in Patients with Esophageal Cancer: Secondary Analysis of a Randomized Trial

Abstract

Background

Early metabolic response after preoperative induction chemotherapy (IC) appears to predict histologic response and prognosis in esophageal cancer (EC), but the usefulness of this approach needs further development.

Objective

We evaluated metabolic response after one cycle of IC using positron emission tomography (PET) to correlate PET response and outcomes.

Patients and Methods

We retrospectively analyzed PET data from a randomized phase 2 trial (NCT00525915) of chemoradiation and surgery with or without IC for the treatment of EC. PET was performed at baseline, after one cycle of IC, and 5–7 weeks after chemoradiation. The relationship between PET response (≥35% reduction in standardized uptake value [SUV]) after IC and treatment response was analyzed.

Results

In 63 patients who received IC, the mean initial SUV_max prior to treatment was 11.9 ± 8.04 and mean SUV_max after one cycle of IC was 6.47 ± 4.45. The mean SUV reduction after IC was 39.3%. Eleven of 37 PET responders achieved a pathologic complete response (pCR), but only two of 22 PET non-responders did (univariate logistic regression; odds ratio: 4.25, 95% confidence interval: 0.83–21.77; p = 0.08). PET responders to IC had significantly longer overall survival (OS) than PET nonresponders (log-rank p = 0.009). PET response after chemoradiation was not correlated with OS (log-rank p = 0.15).

Conclusion

Early PET response after IC is prognostic, but subsequent PET changes (for example, after chemoradiation) are not prognostic. Early PET response might have the potential of predicting pCR.

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Diagnosis of EML4-ALK Translocation With FISH, Immunohistochemistry, and Real-time Polymerase Chain Reaction in Patients With Non–Small Cell Lung Cancer

Objective: To assess anaplastic lymphoma kinase (ALK) rearrangement detection with immunohistochemistry (IHC) and real-time polymerase chain reaction (RT-qPCR) in comparison with fluorescence in situ hybridization (FISH). Methods: Tumor tissue samples from 230 patients with advanced non–small cell lung cancer (NSCLC) were analyzed by FISH to detect ALK rearrangements. Additional IHC tests using 5A4 clone and RT-qPCR (variants 1 to 5) were performed in 63 and 48 patients, respectively. Results: Thirteen percent of FISH tests were not evaluable. From the remaining tests (n=200), 18 (9.0%) were ALK positive (ALK+). ALK+ patients were significantly younger at the time of diagnosis (below 55 y, 14.3% vs. 5.5%, P=0.035), were light smokers (tobacco index

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Potential Role of Single Nucleotide Polymorphisms of XRCC1, XRCC3, and RAD51 in Predicting Acute Toxicity in Rectal Cancer Patients Treated With Preoperative Radiochemotherapy

Objectives: To investigate the association between polymorphisms of DNA repair genes and xenobiotic with acute adverse effects in locally advanced rectal cancer patients treated with neoadjuvant radiochemotherapy. Methods: Sixty-seven patients were analyzed for the current study. Genotypes in DNA repair genes XRCC1 (G28152A), XRCC3 (A4541G), XRCC3 (C18067T), RAD51 (G315C), and GSTP1 (A313G) were determined by pyrosequencing technology. Results: The observed grade ≥3 acute toxicity rates were 23.8%. Chemotherapy and radiotherapy were interrupted for 46 and 14 days, respectively, due to critical complications. Four patients were hospitalized, 6 patients had been admitted to the ER, and 5 patients received invasive procedures (2 bladder catheters, 2 blood transfusions, and 1 growth factor therapy). RAD51 correlated with acute severe gastrointestinal toxicity in heterozygosity (Aa) and homozygosity (AA) (P=0.036). Grade ≥3 abdominal/pelvis pain toxicity was higher in the Aa group (P=0.017) and in the Aa+AA group (P=0.027) compared with homozygous (aa) patients. Acute skin toxicity of any grade occurred in 55.6% of the mutated patients versus 22.8% in the wild-type group (P=0.04) for RAD51. XRCC1 correlated with skin toxicity of any grade in the Aa+AA group (P=0.03) and in the Aa group alone (P=0.044). Grade ≥3 urinary frequency/urgency was significantly higher in patients with AA (P=0.01), Aa (P=0.022), and Aa+AA (P=0.031) for XRCC3 compared with aa group. Conclusions: Our study suggested that RAD51, XRCC1, and XRCC3 polymorphisms may be predictive factors for radiation-induced acute toxicity in rectal cancer patients treated with preoperative combined therapy.

http://ift.tt/2j1zSIN

Do Prostate Cancer Patients With Markedly Elevated PSA Benefit From Radiation Therapy?: A Population-based Study

Objectives: Patients with clinically localized prostate cancer but markedly elevated prostate-specific antigen (PSA) are often treated with systemic agents alone. We hypothesized that they would benefit from radiation therapy. Methods: We utilized the Survival, Epidemiology and End Results (SEER) Database for patients diagnosed with nonmetastatic prostate cancer from 2004 to 2008. Patients treated surgically or with brachytherapy were excluded. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. Propensity score was used to adjust for the nonrandomized assignment of local therapies. Results: A total of 75,539 nonmetastatic prostate cancer patients were identified who received either radiotherapy or no local treatment. Median age was 70 years. Median follow-up of alive subjects was 60 months, with an interquartile range of 47 to 77 months. Estimated 4-year overall survival of entire population was 88%. Significant prognostic variables for overall survival on multivariate analysis included age, grade, PSA level, T stage, and use of radiation therapy. Use of radiation therapy was the most powerful predictor of both cause-specific and overall survival (HR=0.41 and 0.46, respectively, P

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The Prognostic Significance of c-MET and EGFR Overexpression in Resected Gastric Adenocarcinomas

Objectives: Epidermal growth factor receptor (EGFR) and c-MET are tyrosine kinase growth factor receptors implicated in gastric cancer (GC), and their pathways appear to be interdependent. The aim of this study was to investigate the prognostic value of EGFR and c-MET protein overexpression by immunohistochemistry in Canadian patients with resected GC and correlate it with clinicopathologic characteristics and overall survival (OS). Materials and Methods: Tissue microarray blocks were constructed from 120 resected GCs stained with EGFR and c-MET and scored semiquantitatively (0 to 3+). Each receptor's expression was compared with clinicopathologic characteristics and survival. Descriptive statistics, Kaplan–Meyer, and Cox regression were used for statistical analyses. Results: Of the 113 interpretable cases, overexpression of EGFR and c-MET was noted in 17 (15%) and 65 (57%), respectively; coexpression of EGFR and c-MET was observed in 12 (10%) of GC. EGFR and c-MET overexpression correlated with poor OS: median 13 versus 30 months in EGFR positive versus negative GC (hazard ratio [HR]=1.67, P=0.11); 27 versus 49 months in c-MET positive versus negative GC (HR=1.17, P=0.49), respectively. GC coexpressing EGFR and c-MET was significantly correlated with poor survival: 12 versus 29 months in double-positive versus rest of tumors both in univariate (HR=2.62, P=0.003) and multivariate analyses (HR=2.58, P=0.01). Conclusions: This study describes the prevalence and prognostic value of EGFR and c-MET in a Canadian population of patients undergoing curative intent resection for GC. Both c-MET and EGFR overexpression trended toward poor OS, but only the group with EGFR+/c-MET+ GC reached statistical significance on multivariate analysis.

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c-Met Overexpression in Cervical Cancer, a Prognostic Factor and a Potential Molecular Therapeutic Target

Purpose: This study aimed to assess the association between pretreatment c-Met overexpression in local-regional advanced cervical cancer patients treated definitively with concurrent chemoradiation therapy (CRT) and treatment outcomes including overall survival (OS), progression-free survival (PFS), distant metastases (DM) control, and local-regional control (LC). Patients and Methods: This Institutional Review Board–approved study included cervical cancer patients treated definitively and consecutively with CRT. Evaluation of cytoplasmic immunoreactivity for c-Met was performed and scored semiquantitatively by 3 pathologists, blinded to the treatment outcomes, and incorporated both the intensity and percentage of immunoreactivity in invasive carcinoma (H score). Treatment outcomes were reviewed and reported. Outcomes were stratified by c-Met overexpression and tumor characteristics. OS, PFS, LC, and DC rates were obtained via the Kaplan-Meier method and differences between groups were evaluated by the log-rank test. Hazard ratios were obtained via Cox regression for both univariate and multivariate analyses. Results: The 5-year OS, PFS, LC, and DC were 57.18%, 48.07%, 72.11%, and 62.85%, respectively. Ten (35.7%) and 18 patients (64.3%) had c-Met H index >30 and

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Πέμπτη 7 Δεκεμβρίου 2017

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