Double whammy: a tale of two malignancies

Description

A 61-year-old woman was referred to the dermatology clinic with multiple skin lesions on her scalp and central back. They were relatively asymptomatic but had increased in size over the previous few months. Her medical history was significant as she had a cerebellar medulloblastoma when she was 19 years old that was treated with a 6-month course of radiotherapy on her scalp and along the spinal cord.

On examination, she had multiple erythematous scaly plaques on the right occipital scalp and lower back, consistent with superficial basal cell carcinomas (BCC) and a nodular BCC in the left occipital scalp. They were present within the areas previously treated with radiotherapy, arising from the skin that showed poikilodermatous (atrophic) changes (figures 1 and 2). Scarring alopecia from the previous radiotherapy was also prominent in the occipital scalp. A diagnosis of postradiotherapy BCCs was made. In...

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Acquired capillary haemangioma of the eyelid in a 10-year-old boy

A 10-year-old boy presented with painless, gradually increasing mass in right upper lid without preceding trauma for the past 2 months. On examination, the mass was bluish red, soft to firm in consistency which bleeds on touch. Contrast-enhanced CT showed a well-defined heterogeneously enhancing mass lesion without any continuity with the underlying bone or the orbital cavity. Complete excision of the mass was performed under general anaesthesia, subsequent histopathological examination showed findings consistent with an acquired variant of capillary haemangioma. At the end of 1 year, patient is cosmetically fine without any recurrence/morbidity.

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Large chordoma of the sacrum

Description

A 53-year-old man presented to our service with a 1-month history of subacute bowel obstruction. Clinical examination was unremarkable with normal power and sensation in the lower limbs. This patient had no medical or surgical history. MRI of the pelvis identified a well-defined presacral midline lesion of 9.9 cm diameter, which appeared to arise from the S2 nerve root and below (figure 1A,B). These nerve roots control anal sphincter tone and prohibit faecal incontinence. Whole spine MRI and CT-thorax abdomen pelvis CT-TAP) out ruled metastasis. A biopsy confirmed diagnosis of chordoma. This patient was discussed by a multidisciplinary team consisting of orthopaedics, colorectal, vascular and plastic surgeons. Anterior mobilisation of the lesion, with ileostomy due to expected loss of anal tone and supporting vessel ligation, was undertaken. A wide sacral en-masse resection at the level of S1 disc and inferior nerve roots, incorporating partial gluteus...

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Carotid dissection presenting as a prolonged cluster-like headache in a patient with episodic cluster headache

We present a patient with known episodic cluster headache, who presented with cluster-like headache in the course of internal carotid artery dissection (ICAD) and discuss possible pathophysiological links between the two diseases. It is well known that cluster-like headache could be the presenting symptom of ICAD. However, ICAD occurring in a patient with a known episodic cluster headache was only once previously described. In the end of the manuscript, we propose red flags to help clinicians differentiate between primary cluster headache and cluster-like attacks masking underlying ICAD. Finally, we raise the question whether at least some proportion of those patients with cluster headache and Horner syndrome previously classified as a primary headache disorder might have been secondary cases to ICAD.

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Turbulent tackle: a novel surgical approach to a rugby-related jejunal perforation

Viscus perforation in the context of blunt-force abdominal trauma is a rarity. Within a sporting context, it is especially rare. However, the increasing physicality observed in rugby union, both in the amateur and professional setting, has resulted in a higher rate of serious injury. We report a novel laparoscopic surgical approach to the management of a traumatic jejunal perforation sustained on the playing field in a previously fit and healthy 28-year-old.

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The non-resolving lung cavity: a case of pulmonary cystic echinococcosis

The authors report a case of a 20-year-old woman who was diagnosed with pulmonary cystic echinococcosis. She was admitted to hospital with a 1-week history of unresolving cough, coloured sputum with occasional haemoptysis and fever despite oral antibiotics. Radiology revealed a cavitating right lower lobe lung abscess. After 4 weeks of treatment, follow-up radiology showed incomplete resolution. Bronchoscopy revealed a white, avascular cystic lesion in the right lower lobe and serology testing for Echinococcus granulosus was positive. Repeat imaging eventually confirmed the cystic lesion with the 'air bubble'sign. A thorough travel history, a high index of clinical suspicion and close follow-up are essential in making a diagnosis of pulmonary cystic echinococcosis.

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Early intracardiac thrombus and pulmonary embolus after trauma

Here, we present the case of a patient with the findings of an early intracardiac thrombus and a pulmonary embolus after major trauma. A large clot was identified extending from the inferior vena cava into the right atrium and ventricle in the setting of preserved right ventricular function. Post-traumatic intracardiac thrombus is extremely rare and no comparable cases have previously been described in the absence of a congenital heart defect and obvious myocardial injury. Best practice afterpost-traumatic intracardiac thrombus is not well established but we found that early inferior vena cava filter placement and treatment with therapeutic coagulation resulted in clinical improvement, resolution of the thrombus and no further emboli. The successful use of rivaroxaban, a direct-acting oral anticoagulant, to treat a right heart thrombus has, to our knowledge, not previously been reported. Early acute traumatic coagulopathy has received much attention but the hypercoagulable state that often follows is less well appreciated.

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Incidental finding of persistent left superior vena cava after 'bubble study verification of central venous catheter

We report a case of a patient with septic shock who underwent central venous catheter placement in the left internal jugular vein, and a bedside ultrasound 'bubble study' revealed venous cannulation. A chest X-ray postprocedure revealed concern for arterial system catheterisation. However, the possibility of a persistent left superior vena cava was discussed and confirmed with a formal transthoracic echocardiogram and CT. This case demonstrates the importance of ultrasound-guided visualisation of anatomical structures in real time during central venous catheterisation. Other similar cases from the literature are briefly described.

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Valacyclovir-associated neurotoxicity treated with intensification of peritoneal dialysis

We report a 57-year-old woman with end-stage renal disease (ESRD) on maintenance peritoneal dialysis (PD), who presented to the emergency room (ER) by ambulance with complaints of confusion and altered sensorium for 48 hours. She had been reviewed in a walk-in clinic 72 hours earlier and had been prescribed the standard 1000 mg three times per day of valacyclovir for an acute attack of shingles instead of 500 mg once a day on ESRD. In the ER, she received further 500 mg of intravenous acyclovir as herpes encephalitis was clinically suspected. CT of the brain and lumbar puncture were non-contributory to the diagnosis. Valacyclovir and acyclovir were discontinued when the diagnosis of valacyclovir-associated neurotoxicity became clinically evident. As the patient's Glasgow Coma Scale declined, we intensified her PD regimen from one to six exchanges per day and 24 hours later there was a significant neurological improvement.

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Huge cardiac myxoma in pregnancy

A 28-year-old pregnant woman presented at 28 weeks of gestation. She was diagnosed to have a left atrial myxoma 2 years earlier, but was lost to follow-up. During this pregnancy, the transthoracic echocardiography showed a 9 cm mass in the left atrium obstructing mitral valve inflow, interfering with mitral valve closure, causing severe mitral regurgitation and severe pulmonary hypertension. However, there were no clinical signs of pulmonary and systemic congestion or obstruction. Based on the clinical symptoms of the patient, the echocardiographic findings and the term of her pregnancy, the patient decided to schedule for a vaginal delivery with surgical correction after delivery. She gave birth at 32 weeks of gestation. During labour, pulmonary oedema developed but was detected early and it responded to therapy. Two weeks after delivery, a right anterior thoracotomy was performed to facilitate the removal of the left atrial myxoma and repair of the mitral valve.

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Peripheral hepatojejunostomy: a last resort palliative solution in Greece during the economic crisis

The geographical distribution of Greece and the growing proportion of uninsured patients make imperative the need for effective and efficient palliative solutions regarding obstructive jaundice due to hepatic malignancy, while repeated endoscopic interventions and all associated materials are either not accessible to the whole population or not even available on a daily basis due to the economic crisis and the difficulties on the hospital supply. On this basis, palliative hepatojejunostomy, introduced more than 50 years ago, could be revisited in the Greek reality in very selected cases and under these special circumstances. We report on two patients with locally advanced hilar cholangiocarcinoma and intrahepatic cholangiocarcinoma, respectively, who were treated with a combination of double hepaticojejunostomy with peripheral hepatojejunostomy or peripheral hepatoejunostomy alone, respectively. Both patients experienced an adequate decompression of the biliary tract over more than a year. Palliative hepatojejunostomy could be an ultimate solution for selected patients and circumstances in Greece during the economic crisis.

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Embryonal carcinoma presenting as a calcified solitary testicular mass on ultrasound

A 24-year-old man presented with a 2-week history of a painless right testicular mass; ultrasound demonstrated a dense, solitary calcified mass. The patient elected observation after further workup showed no evidence of metastasis.

A repeat ultrasound 3 months later showed interval growth and the patient underwent right radical orchiectomy. Pathology was consistent with pure embryonal carcinoma of the testis. Calcified testicular masses are typically benign but do carry a differential of spermatic granuloma, large-cell calcifying Sertoli cell tumour, trauma, tuberculosis, filariasis, calcified Leydig cell tumour and burned-out testicular tumour.

To our knowledge, this is the first case report of pure embryonal carcinoma presenting as a solitary calcified testicular mass.

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Wernickea{euro}™s encephalopathy associated with liver abscess

Wernicke's encephalopathy is a rare neurological disorder caused by thiamine deficiency, characterised by ocular motor dysfunction, ataxia and impairment in consciousness. It predominantly affects brain regions with a high metabolic rate such as mammillary bodies, medial thalamic nuclei, the tectal region and the cerebellum. Although chronic alcoholism is the most common cause of Wernicke's encephalopathy, various other conditions not related to alcohol consumption such as bariatric surgery, acute pancreatitis, hyperemesis gravidarum, prolonged fasting and gastrointestinal surgery have been implicated in its aetiology. We report the case of a patient who underwent surgery for liver abscess and subsequently developed Wernicke's encephalopathy; he showed a positive response to thiamine supplementation. This is the first report describing liver abscess as the cause of Wernicke's encephalopathy.

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Pseudo retinitis pigmentosa in a case of missed intraocular foreign body

A 35-year-old man presented with history of painless, progressive loss of vision in the left eye for the past 7 years. There was history of trauma to the same eye with an iron object 7 years prior. Fundus examination revealed pigmentary retinopathy (unilateral advanced retinitis pigmentosa (RP)-like picture). X-ray orbits were suspicious of retained intraocular foreign body (IOFB). CT orbits confirmed the presence of IOFB. Electroretinogram revealed depressed responses. Right eye examination was within normal limits. A diagnosis of siderosis bulbi with unilateral pseudo RP-like fundus was made. No surgical intervention was planned for IOFB in view of poor visual prognosis.

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Triggering of the abductor pollicis longus in association with deQuervain's tenosynovitis

DeQuervain's tenosynovitis is a common cause of radial-sided wrist pain. Symptoms result from a narrow first dorsal compartment and associated tendinosis of the enclosed extensor pollicis brevis and/or abductor pollicis longus (APL). Surgical intervention, offered when conservative measures fail to adequately relieve symptoms, requires a detailed understanding of potentially aberrant anatomy in order to avoid persistence or recurrence of symptoms. We describe a case whereby the patient presented with complaints of thumb triggering in extension and associated disabling first dorsal compartment tendinosis. Intraoperatively, after supernumerary tendons were identified and addressed, the APL was at risk for subluxation over a prominent fibroosseous ridge. Routine first dorsal compartment release alone may have failed to address all of this patient's pathology.

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Tuberculosis presenting as broncho-oesophageal fistula in a young healthy man

A 21-year-old Saudi man presented with a history of dysphagia and choking. CT scan of the chest showed clear evidence of chronic recurrent aspiration pneumonia in the left lung. It also showed a fistula connecting the left main bronchus to the oesophagus. Endoscopy showed clear opening on the oesophageal side. Bronchoscopy also confirmed the presence of a broncho-oesophageal fistula on the left bronchial side with the presence of secretions on swallowing. Bronchoalveolar lavage (BAL) was done and sent for mycobacterial tuberculosis culture. The fistula was closed with clips under endoscopic guidance, which alleviated his symptoms of dysphagia and choking. The BAL culture grew mycobacterial tubercle bacilli. The patient showed marked improvement after starting antitubercular therapy and was discharged to be followed up in the clinic.

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High proportion of PD-1-expressing CD4+ T cells in adipose tissue constitutes an immunomodulatory microenvironment that may support HIV persistence

We and others have demonstrated that adipose tissue is a reservoir for HIV. Evaluation of the mechanisms responsible for viral persistence may lead to ways of reducing these reservoirs. Here, we evaluated the immune characteristics of adipose tissue in HIV-infected patients receiving antiretroviral therapy (ART) and in non-HIV-infected patients. We notably sought to determine whether adipose tissue's intrinsic properties and/or HIV induced alteration of the tissue environment may favour viral persistence. ART-controlled HIV infection was associated with a difference in the CD4/CD8 T-cell ratio and an elevated proportion of Treg cells in subcutaneous adipose tissue. No changes in Th1, Th2 and Th17 cell proportions or activation markers expression on T cell (Ki-67, HLA-DR) could be detected, and the percentage of CD69-expressing resident memory CD4⁺ T cells was not affected. Overall, our results indicate that adipose-tissue-resident CD4⁺ T cells are not extensively activated during HIV infection. PD-1 was expressed by a high proportion of tissue-resident memory CD4⁺ T cells in both HIV-infected patients and non-HIV-infected patients. Our findings suggest that adipose tissue's intrinsic immunomodulatory properties may limit immune activation and thus may strongly contribute to viral persistence.

This article is protected by copyright. All rights reserved

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Absence of Notch1 in murine myeloid cells attenuates the development of experimental autoimmune encephalomyelitis by affecting Th1 and Th17 priming

Inhibition of Notch signalling in T cells attenuates the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Growing evidence indicates that myeloid cells are also key players in autoimmune processes. Thus, the present study evaluates the role of the Notch1 receptor in myeloid cells on the progression of myelin oligodendrocyte glycoprotein (MOG)_35-55-induced EAE, using mice with a myeloid-specific deletion of the Notch1 gene (MyeNotch1KO). We found that EAE progression was less severe in the absence of Notch1 in myeloid cells. Thus, histopathological analysis revealed reduced pathology in the spinal cord of MyeNotch1KO mice, with decreased microglia/astrocyte activation, demyelination and infiltration of CD4⁺ T cells. Moreover, these mice showed lower Th1 and Th17 cell infiltration and expression of IFN-γ and IL-17 mRNA in the spinal cord. Accordingly, splenocytes from MyeNotch1KO mice reactivated in vitro presented reduced Th1 and Th17 activation, and lower expression of IL-12, IL-23, TNF-α, IL-6, and CD86. Moreover, reactivated wild-type splenocytes showed increased Notch1 expression, arguing for a specific involvement of this receptor in autoimmune T cell activation in secondary lymphoid tissues. In summary, our results reveal a key role of the Notch1 receptor in myeloid cells for the initiation and progression of EAE.

This article is protected by copyright. All rights reserved

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Promoting Effect of Ni(OH)2 on Palladium Nanocrystals Leads to Greatly Improved Operation Durability for Electrocatalytic Ethanol Oxidation in Alkaline Solution

Most electrocatalysts for the ethanol oxidation reaction suffer from extremely limited operational durability and poor selectivity toward the CC bond cleavage. In spite of tremendous efforts over the past several decades, little progress has been made in this regard. This study reports the remarkable promoting effect of Ni(OH)₂ on Pd nanocrystals for electrocatalytic ethanol oxidation reaction in alkaline solution. A hybrid electrocatalyst consisting of intimately mixed nanosized Pd particles, defective Ni(OH)₂ nanoflakes, and a graphene support is prepared via a two-step solution method. The optimal product exhibits a high mass-specific peak current of >1500 mA mg⁻¹_Pd, and excellent operational durability forms both cycling and chronoamperometric measurements in alkaline solution. Most impressively, this hybrid catalyst retains a mass-specific current of 440 mA mg⁻¹ even after 20 000 s of chronoamperometric testing, and its original activity can be regenerated via simple cyclic voltammetry cycles in clean KOH. This great catalyst durability is understood based on both CO stripping and in situ attenuated total reflection infrared experiments suggesting that the presence of Ni(OH)₂ alleviates the poisoning of Pd nanocrystals by carbonaceous intermediates. The incorporation of Ni(OH)₂ also markedly shifts the reaction selectivity from the originally predominant C2 pathway toward the more desirable C1 pathway, even at room temperature.

A hybrid electrocatalyst material is reported here, which features small Pd nanoparticles abundantly interfaced with Ni(OH)₂ and uniformly supported on graphene nanosheets. The synergy between Pd and Ni(OH)₂ leads to dramatically improved electrocatalytic performance of the precious metal for ethanol oxidation reaction and markedly shifts its selectivity toward the C1 pathway in alkaline solution.

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Behavioral and fMRI responses to fearful faces are altered in benign childhood epilepsy with centrotemporal spikes (BCECTS)

Summary

Objective

We hypothesized that children with benign childhood epilepsy with centrotemporal spikes (BCECTS) might have altered social cognitive skills and underlying neural networks.

Methods

We studied 13 patients with BCECTS and 11 age-matched controls using event-related functional magnetic resonance imaging (fMRI) with an emotional discrimination task consisting of viewing happy, fearful, scrambled, and neutral faces. Behavioral performance measured during the task was correlated with clinical variables and behavioral ratings.

Results

In comparison with age-matched controls, children with BCECTS performing a fearful faces detection task showed significantly reduced bilateral fMRI activation in the insular cortex, caudate, and lentiform nuclei, as well as increased response time. The percentage of errors made by children with BCECTS correlated negatively with age, a finding not observed in controls. In patients, accuracy positively correlated with time since the last seizure. The above abnormalities were not observed during happy faces detection task, except for a slower response in children with BCECTS as compared to controls.

Significance

Our study suggests that BCECTS is associated with altered social cognition network and function, particularly for the identification of fearful faces. The age dependency of some of these findings supports the view that a delayed maturation of spiking cortical regions might underlie the cognitive dysfunction observed in BCECTS.

http://ift.tt/2vd4GKo

Reply to “Axonal hyperexcitability due to Schwann cell involvement in chronic progressive external ophthalmoplegia”

We thank Drs. Finsterer and Zarrouk-Mahjoub (Finsterer and Zarrouk-Mahjoub, 2017) for their interest in our paper on chronic progressive external ophthalmoplegia (CPEO) (Gueguen et al., 2017).

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A double determination of central motor conduction time in the assessment of Hirayama disease

Hirayama disease (HD) is a benign neurological disease associated with unilateral or asymmetric weakness and/or amyotrophy in the muscles supplied by the C7-T1 myotomes, without significant sensory involvement and myelopathy (Hirayama, 2000; Zhou et al., 2010; Wang et al., 2012).

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Fine motor skills predict performance in the Jebsen Taylor Hand Function Test after stroke

In our daily life, we are highly dependent on the functionality of our hands. Fine motor skills are essential for holding, grasping and manipulating objects. They require an interplay between multiple sensorimotor systems. Visual, haptic, auditory and sensory information has to be integrated with sensorimotor predictions based on mechanical properties of objects being manipulated, such as weight and surface. Additionally, reactive adaptions to changing loads (Nowak et al., 2013) also play an important role.

http://ift.tt/2vnpkbz

Prolongation of Terminal Latency of the Phrenic Nerve in Amyotrophic Lateral Sclerosis – Is it Clinically Useful, and what are the Mechanisms?

I read with interest the manuscript "The terminal latency of the phrenic nerve correlated with respiratory symptoms in amyotrophic lateral sclerosis" (this issue) by Park and Park, concluding that distal latency is the best parameter of phrenic nerve conduction to indicate early respiratory impairment in amyotrophic lateral sclerosis (ALS) patients. They investigated 23 ALS patients, split in 2 groups as defined by respiratory subscore of ALSFRS-R scale, each with a very small number of subjects (12 and 11).

http://ift.tt/2wgc6JT

Axonal hyperexcitability due to Schwann cell involvement in chronic progressive external ophthalmoplegia

With interest we read the article by Gueguen et al. about axonal hyperexcitability depended on the degree of muscle weakness in 13 patients with chronic progressive external ophthalmoplegia (CPEO) (Gueguen et al. 2017). We have the following comments and concerns.

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Applying a pelvic corrective force induces forced use of the paretic leg and improves paretic leg EMG activities of individuals post-stroke during treadmill walking

Walking dysfunction is one of the commonly reported physical limitations after stroke (Perry et al., 1995). Individuals with post-stroke hemiparesis typically demonstrate slow gait velocity, reduced stride and step length, and both decreased period of stance and increased period of swing of the paretic leg (Balaban and Tok, 2014; Patterson et al., 2010a). As walking dysfunction can increase the risk of falls (Hausdorff et al., 2001), restrict functional mobility and negatively affect quality of life (Maclean et al., 2000; Perry et al., 1995; Schmid et al., 2007), an important goal of stroke rehabilitation is to improve symmetrical gait patterns.

http://ift.tt/2wfXXMH

EEG-arousal regulation as predictor of treatment response in patients suffering from obsessive compulsive disorder

Obsessive Compulsive Disorder (OCD) is a neuropsychiatric disease characterized by recurrent intrusive thoughts as the obsessive part and/or repetitive ritualistic behavior as the compulsive component (American Psychiatric Association, 2013). OCD affects between 0,8 and 4% as lifetime prevalence (Angst et al, 2004; Baldwin et al, 2005; Karno et al, 1988; Robins et al, 1984) and the often chronic course is associated with high impairment in quality of life (Fontenelle et al, 2010; Hollander et al, 1996; Moritz, 2008).

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Reply to “Prolongation of Terminal Latency of the Phrenic Nerve in Amyotrophic Lateral Sclerosis – Is it Clinically Useful, and what are the Mechanisms?”

We appreciate de Carvalho's interest and constructive comments (de Carvalho, 2017) on our recent article (Park et al. 2017). He raised an important point on the possible mechanisms concerning the significantly prolonged terminal latency of the phrenic nerves in amyotrophic lateral sclerosis (ALS) in our recent study.

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PRODIGE: PRediction models in prOstate cancer for personalized meDIcine challenGE

Future Oncology, Ahead of Print.


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Ribociclib for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer

Future Oncology, Ahead of Print.


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Title: Local control outcomes using stereotactic body radiation therapy for liver metastases from colorectal cancer

The optimal stereotactic body radiation therapy (SBRT) dose and fractionation schedule for hepatic metastases from colorectal cancer has not yet been determined. Thus, we evaluated the effective dose by reviewing treatment results of 103 lesions. When compared with biological equivalent dose (BED), longer local control was expected if higher doses were used, with optimal BED greater than 132 Gy.

http://ift.tt/2wgckAE

Development and internal validation of a clinical risk score to predict pain response after palliative radiotherapy in patients with bone metastases

Radiotherapy is effective in reducing pain in about 60% of patients with bone metastases. We developed a prediction model to help identify patients who are unlikely to respond to palliative radiotherapy. Primary tumor site, performance status, and baseline pain score were associated with pain response, and were modestly able to discriminate good and poor responders.

http://ift.tt/2vnW6sO

Lack of Benefit from the Addition of External Beam Radiotherapy to Brachytherapy for Intermediate- and High-Risk Prostate Cancer

The efficacy of brachytherapy monotherapy for unfavorable-risk prostate cancer is unknown. Using a cohort of 5836 patients with intermediate- or high-risk disease treated with brachytherapy, we found the addition of external beam radiotherapy to not improve prostate cancer-specific mortality. This lack of benefit was observed for favorable intermediate-, unfavorable intermediate-, and high-risk subgroups. These results suggest that certain patients with unfavorable-risk disease treated with brachytherapy may not benefit from the addition of external beam radiotherapy.

http://ift.tt/2wg3naF

68 Ga-DOTATATE PET/CT in recurrent medullary thyroid carcinoma: a lesion-by-lesion comparison with 111 In-octreotide SPECT/CT and conventional imaging

Abstract

Purpose

The aim of this study was to prospectively compare the detection rate of ⁶⁸Ga-DOTATATE PET-CT with ¹¹¹In-octreotide SPECT-CT and conventional imaging (CI) in medullary thyroid carcinoma (MTC) patients with increased calcitonin (Ctn) levels but negative CI after thyroidectomy.

Methods

Fifteen patients with raised Ctn levels and/or CI evidence of recurrence underwent ⁶⁸Ga-DOTATATE PET-CT, ¹¹¹In-octreotide SPECT-CT and CI. Histopathology, CI and biochemical/clinical/imaging follow-up were used as the reference standard. PET/CT, SPECT/CT and CI were compared in a lesion-based and organ-based analysis.

Results

PET/CT evidenced recurrence in 14 of 15 patients. There were 13 true positive (TP), 1 true negative (TN), 1 false positive (FP) and no false negative (FN) cases, resulting in a sensitivity and accuracy of 100% and 93%. SPECT/CT was positive in 6 of 15 cases. There were 6 TP, 2 TN, 7 FN and no FP cases, resulting in a sensitivity of 46% and accuracy of 53%. CI procedures detected tumor lesions in 14 of 15 patients. There were 13 TP, 1TN, 1 FP and no FN cases with a sensitivity of 100% and accuracy of 93%.

A significantly higher number of lesions was detected by PET/CT (112 lesions, p = 0.005) and CI (109 lesions, p = 0.005) in comparison to SPECT/CT (16 lesions). There was no significant difference between PET/CT and CI for the total number of detected lesions (p = 0.734). PET/CT detected more lesions than SPECT/CT regardless of the organ. PET/CT detected more bone lesions but missed some neck nodal metastases evidenced by CI. The number of lesions per region demonstrated by PET/CT and CI were similar in the other sites.

Conclusion

⁶⁸Ga-DOTATATE PET/CT is superior to ¹¹¹In-octreotide SPECT/CT for the detection of recurrent MTC demonstrating a significantly higher number of lesions. ⁶⁸Ga-DOTATATE PET/CT showed a superior detection rate compared to CI in demonstrating bone metastases.

http://ift.tt/2f3kucd

Imaging children suffering from lymphoma: an evaluation of different 18 F-FDG PET/MRI protocols compared to whole-body DW-MRI

Abstract

Objectives

The objectives of this study were to evaluate and compare the diagnostic potential of different PET/MRI reading protocols, entailing non-enhanced / contrast-enhanced and diffusion-weighted ¹⁸F–FDG PET/MR imaging and whole-body diffusion-weighted MRI for lesion detection and determination of the tumor stage in pediatric lymphoma patients.

Methods

A total of 28 ¹⁸F–FDG PET/MRI datasets were included for analysis of four different reading protocols: (1) PET/MRI utilizing sole unenhanced T2w and T1w imaging, (2) PET/MRI utilizing additional contrast enhanced sequences, (3) PET/MR imaging utilizing unenhanced, contrast enhanced and DW imaging or (4) WB-DW-MRI. Statistical analyses were performed on a per-patient and a per-lesion basis. Follow-up and prior examinations as well as histopathology served as reference standards.

Results

PET/MRI correctly identified all 17 examinations with active lymphoma disease, while WB-DW-MRI correctly identified 15/17 examinations. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were 96%, 96.5%, 97%, 95%, and 96% for PET/MRI₁; 97%, 96.5%, 97%, 96.5%, and 97% for PET/MRI₂; 97%, 96.5%, 97%, 96.5%, and 97% for PET/MRI₃ and 77%, 96%, 96%, 78.5% and 86% for MRI-DWI.

Conclusion

¹⁸F–FDG PET/MRI is superior to WB-DW-MRI in staging pediatric lymphoma patients. Neither application of contrast media nor DWI leads to a noticeable improvement of the diagnostic accuracy of PET/MRI. Thus, unenhanced PET/MRI may play a crucial role for the diagnostic work-up of pediatric lymphoma patients in the future.

http://ift.tt/2hiEuZp

Development of standardized image interpretation for 68Ga-PSMA PET/CT to detect prostate cancer recurrent lesions

Abstract

Methods

After primary treatment, biochemical relapse (BCR) occurs in a substantial number of patients with prostate cancer (PCa). PET/CT imaging with prostate-specific membrane antigen based tracers (68Ga-PSMA) has shown promising results for BCR patients. However, a standardized image interpretation methodology has yet to be properly agreed. The aim of this study, which was promoted and funded by European Association of Nuclear Medicine (EANM), is to define standardized image interpretation criteria for 68Ga-PSMA PET/CT to detect recurrent PCa lesions in patients treated with primary curative intent therapy (radical prostatectomy or radiotherapy) who presented a biochemical recurrence. In the first phase inter-rater agreement between seven readers from seven international centers was calculated on the reading of 68Ga-PSMA PET/CT images of 49 patients with BCR. Each reader evaluated findings in five different sites of recurrence (local, loco-regional lymph nodes, distant lymph nodes, bone, and other). In the second phase the re-analysis was limited to cases with poor, slight, fair, or moderate agreement [Krippendorff's (K) alpha<0.61]. Finally, on the basis of the consensus readings, we sought to define a list of revised consensus criteria for 68Ga-PSMA PET/CT interpretation.

Results

Between-reader agreement for the presence of anomalous findings in any of the five sites was only moderate (K's alpha: 0.47). The agreement improved and became substantial when readers had to judge whether the anomalous findings were suggestive for a pathologic, uncertain, or non-pathologic image (K's alpha: 0.64). K's alpha calculations for each of the five sites of recurrence were also performed and evaluated. First Delphi round was thus conducted. A more detailed definition of the criteria was proposed by the project coordinator, which was then discussed and finally agreed by the seven readers. After the second Delphi round only four cases of disagreement still remained. These were evaluated for a final round, allowing a final agreement table to be written.

Conclusion

We hope that by developing these consensus guidelines on the interpretation of 68Ga-PSMA PET/CT, clinicians reporting these studies will be able to provide more consistent clinical reports and that within clinical trials, abnormality classifications will be harmonized, allowing more robust assessment of its diagnostic performance.

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Reply to: Predicting the outcome of peptide receptor radionuclide therapy in neuroendocrine tumors: the importance of dual-tracer imaging

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Patterns of failure after radical prostatectomy in prostate cancer – implications for radiation therapy planning after 68 Ga-PSMA-PET imaging

Abstract

Background

Salvage radiotherapy (SRT) after radical prostatectomy (RPE) and lymphadenectomy (LAE) is the appropriate radiotherapy option for patients with persistent/ recurrent prostate cancer (PC). ⁶⁸Ga-PSMA-PET imaging has been shown to accurately detect PC lesions in a primary setting as well as for local recurrence or for lymph node (LN) metastases.

Objective

In this study we evaluated the patterns of recurrence after RPE in patients with PC, putting a highlight on the differentiation between sites that would have been covered by a standard radiation therapy (RT) field in consensus after the RTOG consensus and others that would have not.

Methods and materials

Thirty-one out of 83 patients (37%) with high-risk PC were the subject of our study. Information from ⁶⁸Ga-PSMA-PET imaging was used to individualize treatment plans to include suspicious lesions as well as possibly boost sites with tracer uptake in LN or the prostate bed. For evaluation, ⁶⁸Ga-PSMA-PET-positive LN were contoured in a patient dataset with a standard lymph drainage (RTOG consensus on CTV definition of pelvic lymph nodes) radiation field depicting color-coded nodes that would have been infield or outfield of that standard lymph drainage field and thereby visualizing typical patterns of failure of a "blind" radiation therapy after RPE and LAE.

Results

Compared to negative conventional imaging (CT/MRI), lesions suspicious for PC were detected in 27/31 cases (87.1%) by ⁶⁸Ga-PSMA-PET imaging, which resulted in changes to the radiation concept. There were 16/31 patients (51.6%) that received a simultaneous integrated boost (SIB) to a subarea of the prostate bed (in only three cases this dose escalation would have been planned without the additional knowledge of ⁶⁸Ga-PSMA-PET imaging) and 18/31 (58.1%) to uncommon (namely presacral, paravesical, pararectal, preacetabular and obturatoric) LN sites. Furthermore, 14 patients (45.2%) had a changed TNM staging result by means of ⁶⁸Ga-PSMA-PET imaging.

Conclusion

Compared to conventional CT or MRI staging, ⁶⁸Ga-PSMA-PET imaging detects more PC lesions and, thus, significantly influences radiation planning in recurrent prostate cancer patients enabling individually tailored treatment.

http://ift.tt/2f3qEcx

Monitoring early response to chemoradiotherapy with 18 F-FMISO dynamic PET in head and neck cancer

Abstract

Purpose

There is growing recognition that biologic features of the tumor microenvironment affect the response to cancer therapies and the outcome of cancer patients. In head and neck cancer (HNC) one such feature is hypoxia. We investigated the utility of ¹⁸F-fluoromisonidazole (FMISO) dynamic positron emission tomography (dPET) for monitoring the early microenvironmental response to chemoradiotherapy in HNC.

Experimental design

Seventy-two HNC patients underwent FMISO dPET scans in a customized immobilization mask (0–30 min dynamic acquisition, followed by 10 min static acquisitions starting at ∼95 min and ∼160 min post-injection) at baseline and early into treatment where patients have already received one cycle of chemotherapy and anywhere from five to ten fractions of 2 Gy per fraction radiation therapy. Voxelwise pharmacokinetic modeling was conducted using an irreversible one-plasma two-tissue compartment model to calculate surrogate biomarkers of tumor hypoxia (k ₃ and Tumor-to-Blood Ratio (TBR)), perfusion (K ₁ ) and FMISO distribution volume (DV). Additionally, Tumor-to-Muscle Ratios (TMR) were derived by visual inspection by an experienced nuclear medicine physician, with TMR > 1.2 defining hypoxia.

Results

One hundred and thirty-five lesions in total were analyzed. TBR, k ₃ and DV decreased on early response scans, while no significant change was observed for K ₁ . The k ₃ -TBR correlation decreased substantially from baseline scans (Pearson's r = 0.72 and 0.76 for mean intratumor and pooled voxelwise values, respectively) to early response scans (Pearson's r = 0.39 and 0.40, respectively). Both concordant and discordant examples of changes in intratumor k ₃ and TBR were identified; the latter partially mediated by the change in DV. In 13 normoxic patients according to visual analysis (all having lesions with TMR = 1.2), subvolumes were identified where k ₃ indicated the presence of hypoxia.

Conclusion

Pharmacokinetic modeling of FMISO dynamic PET reveals a more detailed characterization of the tumor microenvironment and assessment of response to chemoradiotherapy in HNC patients than a single static image does. In a clinical trial where absence of hypoxia in primary tumor and lymph nodes would lead to de-escalation of therapy, the observed disagreement between visual analysis and pharmacokinetic modeling results would have affected patient management in <20% cases. While simple static PET imaging is easily implemented for clinical trials, the clinical applicability of pharmacokinetic modeling remains to be investigated.

http://ift.tt/2hiEbhd

Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer

Abstract

Purpose

Radium Ra 223 dichloride (radium-223, Xofigo®) is the first targeted alpha therapy for patients with castration-resistant prostate cancer and symptomatic bone metastases. Radium-223 provides a new treatment option for this setting, but also necessitates a new treatment management approach. We provide straightforward and practical recommendations for European nuclear medicine centres to optimize radium-223 service provision.

Methods

An independent research consultancy agency observed radium-223 procedures and conducted interviews with all key staff members involved in radium-223 treatment delivery in 11 nuclear medicine centres across six countries (Germany, Italy, the Netherlands, Spain, Switzerland and the UK) experienced in administering radium-223. The findings were collated and discussed at a meeting of experts from these centres, during which key consensus recommendations were defined.

Results

The recommendations cover centre organization and preparation; patient referral; radium-223 ordering, preparation and disposal; radium-223 treatment delivery/administration; and patient experience. Guidance includes structured coordination and communication within centres and multidisciplinary teams, focusing on sharing best practice to provide high-quality, patient-centred care throughout the treatment pathway.

Conclusions

These expert recommendations are intended to complement existing management guidelines. Sharing best practice and experience will help nuclear medicine centres to optimize radium-223 service provision and improve patient care.

http://ift.tt/2f3b4h2

SPECT/CT and PET/CT molecular imaging in medullary thyroid carcinoma. Are we running in the right direction?

http://ift.tt/2hiSXVb

The role of 18 F-FDG PET/CT in the detection of osteosarcoma recurrence

Abstract

Aim

The aim of this study was to investigate the diagnostic accuracy of ¹⁸F-FDG-PET/CT in osteosarcoma patients suspicious for disease recurrence after adequate surgical therapy.

Methods

Inclusion criteria were: a) adequate surgical treatment for proven osteosarcoma and documented complete remission after therapy; b) ¹⁸F-FDG-PET/CT performed during follow-up for clinical/diagnostic suspicion of relapse; c) new surgical treatment with excision of the suspected lesions; d) histological validation of ¹⁸F-FDG-PET/CT findings. Thirty-seven patients matching all inclusion criteria were retrospectively enrolled (20 men and 17 female). Primary surgical treatment consists of resection (31 cases) or amputation (six cases). ¹⁸F-FDG-PET/CT performance was assessed with a per-patient and per-site evaluation of sensitivity, specificity, accuracy, positive predicting value (PPV), and negative predicting value (NPV). The sites of relapse were classified as local, lung, lymphnodes (LNs), and distant (other skeletal segments and/or distant soft tissue). The disease-free survival (DFS) and the overall survival (OS) after 18F-FDG PET/CT were evaluated.

Results

¹⁸F-FDG-PET/CT was positive in 89.2% (33/37) of patients. Local uptake only was observed in 35.1% patients (13/37); lung uptake only in 18.9% (7/37); distant uptake only in 2.7% (1/37) case; multiple sites of uptake in 32.4% (12/37). Histology resulted positive in 92% (34/37) of patients. A total of 51 pathologic lesions were evaluated (22 local relapse, 11 lung metastasis, 10 metastatic LNs, eight distant metastatic lesions). On a per-patient analysis ¹⁸F-FDG-PET/CT showed a sensitivity, specificity, accuracy, PPV, and NPV of 91%, 75%, 89%, 97%, 50%. On a per-site analysis the performance for local relapse was 96%, 100%, 97%, 100%, 93%, while for lung relapse detection was 80%, 100%, 92%, 100%, 88%. The mean follow-up after ¹⁸F-FDG-PET/CT was 21.5 months. At the last follow-up, 19% (7/37) of patients were death with disease, 38% (14/37) were alive with disease, and 43% (16/37) had no evidence of disease. Overall survival was 90% and 75% at 24 and 60 months, respectively.

Conclusion

¹⁸F-FDG-PET/CT showed valuable results for detecting recurrence(s) in osteosarcoma patients with suspicious of relapse after treatment, particularly in the detection of local relapse and lung metastasis.

http://ift.tt/2f31nzd

Early PET imaging with [68]Ga-PSMA-11 increases the detection rate of local recurrence in prostate cancer patients with biochemical recurrence

Abstract

Purpose

PET/CT using ⁶⁸Ga-labelled prostate-specific membrane antigen PSMA-11 (HBEDD-CC) has emerged as a promising imaging method in the diagnostic evaluation of prostate cancer (PC) patients with biochemical recurrence. However, assessment of local recurrence (LR) may be limited by intense physiologic tracer accumulation in the urinary bladder on whole-body scans, normally conducted 60 min post-tracer injection (p.i.). It could be shown on early dynamic imaging studies that ⁶⁸Ga-PSMA-11 uptake in PC lesions occurs earlier than tracer accumulation in the urinary bladder. This study aims to investigate whether early static PET acquisition increases detection rate of local recurrence on ⁶⁸Ga-PSMA-11 PET/CT in comparison to PET imaging 60 min p.i..

Methods

203 consecutive PC patients with biochemical failure referred to ⁶⁸Ga-PSMA-11 PET/CT were analysed retrospectively (median prostate specific antigen (PSA) value: 1.44 ng/ml). In addition to whole-body PET/CT scans 60 min p.i., early static imaging of the pelvis was performed, starting at a median time of 283 s p.i. (range: 243–491 s). Assessment was based on visual analysis and calculation of maximum standardized uptake value (SUV_max) of pathologic lesions present in the pelvic area found on early PET imaging and on 60 min-PET scans.

Results

26 patients (12.8%) were judged positive for LR on PET scans 60 min p.i. (median SUV_max: 10.8; range: 4.7–40.9), whereas 50 patients (24.6%) revealed a lesion suggestive of LR on early PET imaging (median SUV_max: 5.9; range: 2.9–17.6), resulting in a significant rise in detection rate (p < 0.001). Equivocal findings on PET scans 60 min p.i. decreased significantly with the help of early imaging (15.8% vs. 4.5% of patients; p < 0.001). Tracer activity in the urinary bladder with a median SUV_max of 8.2 was present in 63 patients on early PET scans (31.0%). However, acquisition starting time of early PET scans differed significantly in the patient groups with and without urinary bladder activity (median starting time of 321 vs. 275 s p.i.; range: 281–491 vs. 243–311 s p.i.; p < 0.001). Median SUV_max value of lesions suggestive of LR on early images was significantly higher in comparison to gluteal muscle, inguinal vessels and seminal vesicle/anastomosis (median SUV_max: 5.9 vs. 1.9, 4.0 and 2.4, respectively).

Conclusions

Performance of early imaging in ⁶⁸Ga-PSMA-11 PET/CT in addition to whole-body scans 60 min p.i. increases the detection rate of local recurrence in PC patients with biochemical recurrence. Acquisition of early PET images should be started as early as 5 min p.i. in order to avoid disturbing tracer activity in the urinary bladder occuring at a later time point.

http://ift.tt/2hi9sk5

Players of ‘hypoxia orchestra’ – what is the role of FMISO?

http://ift.tt/2f3hBIw

PET and PET/CT with radiolabeled choline in prostate cancer: a critical reappraisal of 20 years of clinical studies

Abstract

We here aim to provide a comprehensive and critical review of the literature concerning the clinical applications of positron emission tomography/computed tomography (PET/CT) with radiolabeled choline in patients with prostate cancer (PCa). We will initially briefly summarize the historical context that brought to the synthesis of [¹¹C]choline, which occurred exactly 20 years ago. We have arbitrarily grouped the clinical studies in three different periods, according to the year in which they were published and according to their relation with their applications in urology, radiotherapy and oncology. Studies at initial staging and, more extensively, studies in patients with biochemical failure, as well as factors predicting positive PET/CT will be reviewed. The capability of PET/CT with radiolabeled choline to provide prognostic information on PCa-specific survival will also be examined. The last sections will be devoted to the use of radiolabeled choline for monitoring the response to androgen deprivation therapy, radiotherapy, and chemotherapy. The accuracy and the limits of the technique will be discussed according to the information available from standard validation processes, including biopsy or histology. The clinical impact of the technique will be discussed on the basis of changes induced in the management of patients and in the evaluation of the response to therapy. Current indications to PET/CT, as officially endorsed by guidelines, or as routinely performed in the clinical practice will be illustrated. Emphasis will be made on methodological factors that might have influenced the results of the studies or their interpretation. Finally, we will briefly highlight the potential role of positron emission tomography/magnetic resonance and of new radiotracers for PCa imaging.

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A new perspective for nuclear medicine: expanding the indications for PSMA targeted imaging and therapy

http://ift.tt/2hj7osq

The link between exercise and titin passive stiffness

New Findings

• What is the topic of this review?

  This review focuses on how in vivo and molecular measurements of cardiac passive stiffness can predict exercise tolerance and how exercise training can reduce cardiac passive stiffness.

• What advances does it highlight?

  This review highlights advances in understanding the relationship between molecular (titin-based) and in vivo (left ventricular) passive stiffness, how passive stiffness modifies exercise tolerance, and how exercise training may be therapeutic for cardiac diseases with increased passive stiffness.

Exercise can help alleviate the negative effects of cardiovascular disease and cardiovascular co-morbidities associated with sedentary behaviour; this may be especially true in diseases that are associated with increased left ventricular passive stiffness. In this review, we discuss the inverse relationship between exercise tolerance and cardiac passive stiffness. Passive stiffness is the physical property of cardiac muscle to produce a resistive force when stretched, which, in vivo, is measured using the left ventricular end diastolic pressure–volume relationship or is estimated using echocardiography. The giant elastic protein titin is the major contributor to passive stiffness at physiological muscle (sarcomere) lengths. Passive stiffness can be modified by altering titin isoform size or by post-translational modifications. In both human and animal models, increased left ventricular passive stiffness is associated with reduced exercise tolerance due to impaired diastolic filling, suggesting that increased passive stiffness predicts reduced exercise tolerance. At the same time, exercise training itself may induce both short- and long-term changes in titin-based passive stiffness, suggesting that exercise may be a treatment for diseases associated with increased passive stiffness. Direct modification of passive stiffness to improve exercise tolerance is a potential therapeutic approach. Titin passive stiffness itself may be a treatment target based on the recent discovery of RNA binding motif 20, which modifies titin isoform size and passive stiffness. Translating these discoveries that link exercise and left ventricular passive stiffness may provide new methods to enhance exercise tolerance and treat patients with cardiovascular disease.

http://ift.tt/2hhTtCL

Mechanisms of action of vitamin D as supplemental therapy for Pneumocystis pneumonia [PublishAheadOfPrint]

The combination of trimethoprim and sulfamethoxazole (TMP-SMX) is the most effective regimen for therapy of Pneumocystis pneumonia (PcP). As many patients with PcP are allergic or do not respond to it, efforts have been devoted to develop alternative therapies for PcP. We have found that the combination of vitamin D3 (VitD3; 300 IU/kg/day) and PMQ (5 mg/kg/day) was as effective as TMP-SMX for therapy of PcP. In this study, we investigated the mechanisms by which vitamin D enhances the efficacy of PMQ. C57BL/6 mice were immunosuppressed by CD4⁺ cell depletion, infected with P. murina for eight weeks, and then treated for 9 days with the combination of VitD3 and PMQ (VitD3-PMQ) or with TMP-SMX or PMQ to serve as controls. Results showed that vitamin D supplementation increased the number of CD11c⁺ cells; suppressed the production of pro-inflammatory cytokines (TNF-α, IFN, and IL-6) and iNOS; and enhanced the expression of genes related to anti-oxidation (glutathione reductase and glutamate-cysteine ligase modifier subunit), anti-microbial peptides (cathelicidin), and autophagy (ATG5 and Beclin-1). These results suggest that the main action of vitamin D is enhancing the ability of the host to defend Pneumocystis infection.

http://ift.tt/2f3L1WS

Caspofungin-Mediated Growth Inhibition and Paradoxical Growth in Aspergillus fumigatus involve Fungicidal Hyphal Tip Lysis Coupled with Regenerative Intrahyphal Growth and Dynamic Changes in {beta}-1,3-Glucan Synthase Localization [PublishAheadOfPrint]

Caspofungin targets cell wall β-1,3-glucan synthesis and is guideline-recommended to treat invasive aspergillosis as salvage therapy. Although caspofungin is inhibitory at low concentrations, it exhibits a 'paradoxical effect' (reversal of growth inhibition) at high concentrations by an undetermined mechanism. Treatment with either growth inhibitory (0.5 μg/ml) or paradoxical growth-inducing (4 μg/ml) caspofungin concentrations for 24 h caused similar abnormalities, including wider, hyperbranched hyphae, increased septation, and repeated hyphal tip lysis followed by regenerative intrahyphal growth. By 48 h, only hyphae at the colony periphery treated with the high caspofungin concentration displayed paradoxical growth. Similar high concentrations of caspofungin also induced paradoxical growth of Aspergillus fumigatus during human A549 alveolar cell invasion. Localization of the β-1,3-glucan synthase complex (Fks1 and Rho1) revealed significant differences between cells exposed to growth inhibitory and paradoxical growth inducing concentrations of caspofungin. At both concentrations, Fks1 initially mislocalized from hyphal tips to vacuoles. However, only continuous exposure to 4 μg/ml of caspofungin for 48 h led to recovery of normal hyphal morphology with renewed localization of Fks1 to hyphal tips. Rho1 remained at the hyphal tip under both caspofungin concentrations but was required for paradoxical growth. Farnesol blocked paradoxical growth and relocalized Fks1 and Rho1 to vacuoles. Our results highlight the importance of regenerative intrahyphal growth as a rapid adaptation to the fungicidal lytic effects of caspofungin on hyphal tips and the dynamic localization of Fks1 as part of the mechanism for the caspofungin-mediated paradoxical response in A. fumigatus.

http://ift.tt/2hinimF

A 2-hydroxyisoquinoline-1,3-dione active site RNase H inhibitor binds in multiple modes to HIV-1 reverse transcriptase [PublishAheadOfPrint]

The ribonuclease H (RNH) function of HIV-1 reverse transcriptase (RT) plays an essential part in the viral life cycle. We report the characterization of YLC2-155, a 2-hydroxyisoquinoline-1,3-dione-(HID)-based active site RNH inhibitor. YLC2-155 inhibits both polymerase (IC₅₀ = 2.6 μM) and RNH functions (IC₅₀ = 0.65 μM) of RT, but is more effective against RNH. X-ray crystallography, NMR, and molecular modeling were used to show that YLC2-155 binds at the RNH active site in multiple conformations.

http://ift.tt/2f2VZfy

Susceptibility of Mycobacterium tuberculosis cytochrome bd oxidase mutants to compounds targeting the terminal respiratory oxidase, cytochrome c [PublishAheadOfPrint]

We deleted subunits I (cydA) and II (cydB) of the Mycobacterium tuberculosis cytochrome bd menaquinol oxidase. The resulting cydA and cydAB mutants were hypersusceptible to compounds targeting the mycobacterial bc₁ menaquinol-cytochrome c oxidoreductase, and exhibited bioenergetic profiles indistinguishable from strains deficient in the ABC-type transporter, CydDC, predicted to be essential for cytochrome bd assembly. These results confirm CydAB and CydDC as potential targets for drugs aimed at inhibiting a terminal respiratory oxidase implicated in pathogenesis.

http://ift.tt/2hiF8Wy

In-vitro evaluation of biofilm dispersal as a therapeutic strategy to restore antimicrobial efficacy [PublishAheadOfPrint]

As a proof-of-concept study, the direct impact of biofilm dispersal on the in-vitro efficacy of imipenem and tobramycin was evaluated against three-day-old biofilms of Pseudomonas aeruginosa. Arabinose induction of biofilm dispersal via activation of the phosphodiesterase yhjH in P. aeruginosa engineering strain PAO1/p_BAD-yhjH resulted in an increased antimicrobial efficacy and synergy of the imipenem-tobramycin combination. These results support the use of biofilm dispersal to enhance antimicrobial efficacy in the treatment of biofilm-associated infections, representing a promising therapeutic strategy.

http://ift.tt/2f2VVMQ

Molecular characterization of fluoroquinolone-resistant Moraxella catarrhalis variants generated in vitro by stepwise selection [PublishAheadOfPrint]

Moraxella catarrhalis causes respiratory infections. In this study, fluoroquinolone-resistant strains were selected in vitro to evaluate the mechanism of fluoroquinolone resistance. Strains with reduced fluoroquinolone susceptibility were obtained by stepwise selection in levofloxacin, and fluoroquinolone targets, gyr and par, were sequenced. Six novel mutations in GyrA (D84Y, T594dup, and A722dup), GyrB (E479K and D439N), and ParE (Q395R) involved in M. catarrhalis resistance to fluoroquinolones were revealed.

http://ift.tt/2hj5jwe

In vitro isolation and characterization of oxazolidinone resistant Mycobacterium tuberculosis [PublishAheadOfPrint]

Oxazolidinones are promising candidates for the treatment of Mycobacterium tuberculosis infections. We isolated linezolid resistant strains from H37Rv (Euro-American) and HN878 (East-Asian) strains; resistance frequency was similar in both strains. Mutations were identified in ribosomal protein L3 (RplC) and the 23S rRNA (rrl). All mutant strains were cross resistant to sutezolid; a subset were cross-resistant to chloramphenicol. Mutations in rrl led to growth impairment and decreased fitness that could limit spread in clinical settings.

http://ift.tt/2f2VQZy

Tetrazole-Based trans-Translation Inhibitors Kill Bacillus anthracis Spores to Protect Host Cells [PublishAheadOfPrint]

Bacillus anthracis, the causative agent of anthrax, remains a significant threat to humans, including potential use in bioterrorism and biowarfare. The capacity to engineer strains with increased pathogenicity coupled with the ease of disseminating lethal doses of B. anthracis spores makes it necessary to identify chemical agents that target and kill spores. Here, we demonstrate that a tetrazole-based trans-translation inhibitor, KKL-55, is bactericidal against vegetative cells of B. anthracis in culture. Using a fluorescent analog, we show that this class of compounds co-localizes with developing endospores and bind purified spores in vitro. KKL-55 was effective against spores at concentrations close to its MIC for vegetative cells. Spore germination was inhibited at 1.2X MIC and spores were killed at 2X MIC. In contrast, ciprofloxacin killed germinants at concentrations close to its MIC but did not prevent germination even at 32X MIC. Because toxins are released by germinants, macrophages infected by B. anthracis spores are killed early in the germination process. At ≥ 2X MIC KKL-55 protected macrophages from death after infection with B. anthracis spores. Ciprofloxacin required concentrations ≥ 8X MIC to exhibit a similar effect. Taken together, these data indicate that KKL-55 and related tetrazoles are good lead candidates for therapeutics targeting B. anthracis spores, and suggest that there is an early requirement for trans-translation in germinating spores.

http://ift.tt/2hiQfyI

Molecular Epidemiology and Phylogenomics of Staphylococcus aureus Bacteremia in Latin-America: A Prospective Cohort Multicenter Study in Nine Countries [PublishAheadOfPrint]

Staphylococcus aureus are important pathogens causing a spectrum of diseases ranging from mild skin and soft tissue infections to life-threatening conditions. Bloodstream infections are particularly important and the treatment approach is complicated by the presence of methicillin resistance among S. aureus isolates (MRSA). Emergence of new genetic lineages of MRSA has occurred in Latin America (LA) with the rise and dissemination of the community-associated USA300 Latin American Variant (USA300-LV). Here, we prospectively characterized bloodstream MRSA recovered from selected hospitals in 9 Latin American countries. All isolates were typed by pulsed field gel electrophoresis (PFGE) and subjected to antibiotic susceptibility testing. Whole genome sequencing was performed in 96 MRSA representatives. MRSA represented 45% of all isolates (out of 1,185 S. aureus). The majority of MRSA isolates belonged to clonal cluster (CC) 5. In Colombia and Ecuador, most isolates (≥ 72%) belonged to the USA300-LV lineage (CC8). Phylogenetic reconstructions indicated that MRSA isolates from participating hospitals belonged to three major clades. Clade A grouped isolates with ST5, ST105, and ST1011 (mostly SCCmec I and II). Clade B included ST8, ST88, ST97, and ST72 strains (SCCmec IV, subtypes a, b, and c/E) and clade C grouped mostly Argentinian MRSA belonging to ST30. In summary, CC5 MRSA was prevalent in bloodstream infections in LA with the exception of Colombia and Ecuador where USA300-LV is now the dominant lineage. Clonal replacement appears to be a common phenomenon and continuous surveillance is crucial to identify changes in the molecular epidemiology of MRSA.

http://ift.tt/2f3bCnh

Fluconazole Pharmacokinetics in the Galleria mellonella Larvae and performance evaluation of a Bioassay compared to LC-MS/MS for haemolymph specimens. [PublishAheadOfPrint]

The invertebrate model Galleria mellonella can be used to assess treatment efficacy of fungal infection. The fluconazole dose best mimicking human exposure during licensed dosing is unknown. We validated a bioassay for fluconazole detection in haemolymph and determined the fluconazole pharmacokinetics and pharmacodynamics in larvae haemolymph in order to estimate a humanized dose for future experiments.

A bioassay using 4 mm agar-wells, 20 μl haemolymph and the hyper-susceptible Candida albicans DSY2621 was established and compared to a validated LC-MS/MS. Galleria mellonella larvae were injected with fluconazole (5, 10 and 20 mg/kg) and haemolymph harvested for 24 h for pharmacokinetics calculations. The exposure was compared to the human exposure during standard licensed dosing.

The bioassay had a linear standard-curve between 1-20 mg/L. Accuracy and coefficients of variation (%) values were below 10%. The Spearman coefficient between assays was 0.94. Fluconazole larval pharmacokinetic followed one-compartment linear kinetics, with AUC_24h being 93, 173 and 406 mg*h/L for the three doses compared to 400 mg*h/L in humans under licensed treatment.

In conclusion, a bioassay was validated for fluconazole determination in haemolymph. The pharmacokinetics was linear. An exposure comparable to the human exposure during standard licensed dosing is obtained with 20 mg/kg.

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First Detailed Genetic Characterization of the Structural Organization of Type III Arginine Catabolic Mobile Elements (ACMEs) Harbored by Staphylococcus epidermidis using Whole Genome Sequencing [PublishAheadOfPrint]

The type III arginine catabolic mobile element (ACME) was detected in three Staphylococcus epidermidis oral isolates recovered from separate patients (one healthy, one healthy with dental implants and one with periodontal disease) based on ACME-arc operon and -opp3 operon directed PCR. These isolates were subjected to whole genome sequencing to characterize the precise structural organization of ACME III for the first time and also revealed that all three isolates were the same sequence type, ST329.

http://ift.tt/2f2UYE0

Mycobacterium abscessus L,D-transpeptidases are susceptible to inactivation by carbapenems and cephalosporins but not penicillins [PublishAheadOfPrint]

As a growing number of clinical isolates of Mycobacterium abscessus are resistant to most antibiotics, new treatment options that are effective against these drug-resistant strains are desperately needed. The majority of the linkages in the cell wall peptidoglycan of M. abscessus are synthesized by non-classical transpeptidases, namely the L,D-transpeptidases. Emerging evidence suggests that these enzymes represent a new molecular vulnerability in this pathogen. Recent studies have demonstrated that inhibition of these enzymes by the carbapenem class of β-lactams determines their activity against M. tuberculosis. Here, we studied the interactions of β-lactams with two L,D-transpeptidases in M. abscessus, namely Ldt_Mab1 and Ldt_Mab2, and found both the carbapenem and cephalosporin—-but not penicillin—sub-class of β-lactams inhibit these enzymes. Contrary to the commonly held belief that combination therapy with β-lactams is redundant, doripenem and cefdinir exhibit synergy against both pan-susceptible M. abscessus and clinical isolates that are resistant to most antibiotics, which suggests that dual-β-lactam therapy holds potential for treatment of M. abscessus. Lastly, we solved the first crystal structure of an M. abscessus L,D-transpeptidase, Ldt_Mab2, and using substitutions of critical amino acids in the catalytic site and computational simulations, we describe the key molecular interactions between this enzyme and β-lactams, which provide an insight into the molecular basis for the relative efficacy of different β-lactams against M. abscessus.

http://ift.tt/2hi7CQm

Evaluation of Posaconazole Serum Concentrations from Delayed-Release Tablets in Patients at High-Risk for Fungal Infections [PublishAheadOfPrint]

Purpose: To determine the frequency of patients who achieved a therapeutic drug level after receiving posaconazole (PCZ) delayed release tablets (DRT) for prophylaxis or treatment of invasive fungal infections (IFIs), and to examine the effect of demographic traits and treatment characteristics on PCZ serum levels

Methods: A retrospective single-center study was conducted on high-risk inpatients at the University of Washington Medical Center (UWMC) that obtained PCZ for either treatment or prophylaxis from August 1^st 2014 and August 31^st, 2015. High-risk patients were defined as those undergoing chemotherapy for a primary hematologic malignancy and those undergoing hematopoietic cell (HCT) or solid organ transplantation. Serum trough concentrations of ≥700 mcg/L and ≥1,000 mcg/L were considered appropriate for prophylaxis and treatment respectively.

Results: The most frequent underlying medical condition was a hematological malignancy (43/53, 81%). 26/53 (49%) received PCZ for prophylaxis, the rest for treatment. A total of 37/53 (70%) had PCZ serum levels ≥700 mcg/L regardless of indication, including 22/26 (85%) that received PCZ for prophylaxis. Of the patients that received PCZ for treatment, only 12/27 (44%) had PCZ serum levels ≥1,000 mcg/L. The odds of having therapeutic PCZ serum levels were not statistically different in patients with a weight ≥90kg, diarrhea grade ≥2, mucositis grade ≥2, or poor dietary intake. However, the odds of having therapeutic PCZ serum levels was 5.85 times higher in patients without graft-versus-host disease (GVHD) treatment compared to those with GVHD treatment. Four patients on prophylaxis (15%) developed breakthrough invasive fungal infections, one of which had a subtherapeutic level.

Conclusion: Use of PCZ DRT provides adequate concentrations in only 70% of our patients and recommended dosing may lead to insufficient levels in patients treated for IFIs. Lower concentrations noted among high-risk patients with GVHD suggest a need for prospective studies evaluating therapeutic drug monitoring and/or dose adjustments among these patients.

http://ift.tt/2f3KSmi

Synthetic porcine hepcidin exerts opposite roles in Escherichia coli and Salmonella infections [PublishAheadOfPrint]

Hepcidin, an antimicrobial peptide, was discovered to integrate diverse signals from iron status and infection threat and orchestrate a series of host protective responses. There have been several studies investigating the antimicrobial role of hepcidin but controversial. Here, we aim to examine the role of hepcidin in bacterial adherence and invasion in vitro. We found that porcine hepcidin could decrease the amount of extracellular pathogen enterotoxigenic Escherichia coli (ETEC) K88 that adhered to cells by aggregating bacteria. However, additing hepcidin to infected macrophages with intracellular pathogen Salmonella typhimurium enhanced the intracellular growth of pathogens by degradation of ferroportin, an iron export protein, and then sequestering intracellular iron. It was consisted with iron chelator deferiprone (DFO), which reduced intracellular bacterial growth. These results demonstrated hepcidin exhibited different functions on extracellular and intracellular bacterial infection, which suggested that different defense strateges should be taken to prevent bacterial infection.

http://ift.tt/2hiSfap

Population Pharmacokinetics of High Dose Continuous Infusion Meropenem and Considerations for the Use in the Treatment of Infections due to KPC-Producing Klebsiella pneumoniae [PublishAheadOfPrint]

We assessed the population pharmacokinetics of high-dose continuous infusion (HDCI) meropenem in a cohort of patients with KPC-producing Klebsiella pneumoniae (KPC-Kp) infections. Monte Carlo simulations were used to define the permissible HDCI meropenem regimens that could be safely considered for the treatment of KPC-Kp infections due to meropenem-resistant strains. Permissible doses were arbitrarily defined as those associated with ≤10-15% likelihood of meropenem steady-state concentrations (C_ss) >100 mg/L. Probabilities of target attainment (PTA) of four incremental pharmacodynamic determinants for meropenem efficacy (100%T_>1xMIC, 100%T_>2xMIC, 100%T_>3xMIC, 100%T_>4xMIC) in relation to different classes of renal function were calculated. The cumulative fractions of response (CFR) for the permissible HDCI meropenem regimens were calculated against the MIC distribution of the KPC-Kp clinical isolates that were collected routinely at our University Hospital between 2013 and 2016 (n=169). Ninety-seven meropenem C_ss were included in the analysis. The final model included creatinine clearance (CrCL) as covariate, and explained 94% of the population variability. Monte Carlo simulations based on licensed dosages up to 6g/day predicted acceptable PTA (>80%) of 100%T_>1xMIC against KPC-Kp with an MIC for meropenem ≤32 mg/L in patients with CrCL <130 mL/min. Dosages of 8g/day were needed for achieving the same target in patients with CrCL 130-200 mL/min. When dealing with pathogens with an MIC for meropenem of 64mg/L, higher than licensed HDCI meropenem regimens should be considered. In these cases, real time therapeutic drug monitoring could be a useful adjunct for optimized care. The predicted CFR were >75% in all of the classes of renal function.

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Tools for the Individualized Therapy of Teicoplanin for Neonates and Children [PublishAheadOfPrint]

The aim of the study was to develop a population PK model for teicoplanin across childhood age ranges to be used as Bayesian prior information in the constructed software for individualized therapy. We developed a non-parametric population model fitted to PK data from neonates, infants and older children. We then implemented it in the BestDose multiple-model Bayesian adaptive control algorithm to show its clinical utility. It was used to predict the required dosages to achieve teicoplanin optimal pre-dose targets (15 mg/L) from day 3 of therapy. We performed individual simulations in an infant and a child from the original population, who provided early first dosing interval concentration time-data. An allometric model that linked weight to clearance and volume of distribution (Ke and V) and incorporating renal function as a power function of estimated glomerular filtration rate (eGFR) or Post-natal age (PNA)/serum creatinine(SCr) for infants < 3 months, best described the data. The median population PK parameters were as follows: Ke= 0.03*(wt/70)^-0.25 * Renal (h^-1); V=19.5*(wt/70) (L), being Renal= eGFR^0.07 (ml/min/1.73m²) or PNA/SCr (μmol/L). Increased teicoplanin dosages and alternative administration techniques (extended infusions and fractionated multiple dosing) were required in order to achieve the targets safely by day 3 in simulated cases. The software was able to predict individual measured concentrations and the required dosages and administration techniques to achieve the desired target concentrations early in therapy. Prospective evaluation is now needed in order to ensure that this teicoplanin individualized therapy approach is applicable in the clinical setting.

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Influence of beta-lactam infusion strategy on acute kidney injury [PublishAheadOfPrint]

Background. Limited literature is available assessing nephrotoxicity with prolonged beta-lactam infusions. This study compared the incidence of acute kidney injury (AKI) associated with a prolonged beta-lactam infusion (PI) or an intermittent infusion.

Methods. This was a retrospective, matched cohort study at an academic medical center from July 2006 to September 2015. Adult patients who received piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) for at least 48 hours were evaluated. Patients were excluded for pre-existing renal dysfunction or pregnancy. The primary outcome was difference in incidence of AKI evaluated using the RIFLE criteria. Patients in the intermittent group were matched three-to-one to patients in the PI group based on the following: beta-lactam agent, age, gender, Charlson Comorbidity Index, baseline creatinine clearance, hypotension, receipt of vancomycin, and treatment in an intensive care unit.

Key Results. A total of 2,390 were included in the matched analysis with 1,700 receiving intermittent infusions and 690 receiving PI. The incidence of AKI was similar in the PI group compared to intermittent (21.6% vs 18.6%, p = 0.1). After multivariate regression, PI was not associated with increased odds of AKI [OR of 1.07 (95% CI 0.83-1.39)]. Independent predictors of AKI included: TZP therapy, concomitant nephrotoxins, hypotension, and heart failure.

Conclusions. Although AKI was numerically more common in patients receiving prolonged beta-lactam infusions than those receiving intermittent infusions, prolonged infusion was not an independent risk factor for AKI.

http://ift.tt/2f3b6pl

Advances in Aging Research Vol.6,No.4 (July 2017)

The Relationship of Serum Calcium, Phosphorus, and Parathyroid Hormone with Renal Function in Elderly Osteoporotic Patients with No History of Chronic Kidney Disease
Calcium, Phosphorus, Parathyroid Hormone, Renal Function, Elderly Osteoporotic Patients
Paper Information Full Paper: PDF (Size:878KB)
DOI: 10.4236/aar.2017.64006

Development and Preliminary Validation of the Older Adult Service Usage Assessment
Older Adult, Home and Community-Based Services, Rural Aging
Paper Information Full Paper: PDF (Size:378KB)
DOI: 10.4236/aar.2017.64007

http://ift.tt/11MQ3FG

MAIT cells in infectious diseases

Marion Salou | Katarzyna Franciszkiewicz | Olivier Lantz

http://ift.tt/2f35gUM

Vaccines targeting helper T cells for cancer immunotherapy

Marit Melssen | Craig L Slingluff

http://ift.tt/2hiKgu1

Towards an evidence based approach for the development of adjuvanted vaccines

Derek T O'Hagan | Leonard R Friedland | Emmanuel Hanon | Arnaud M Didierlaurent

http://ift.tt/2f39Vpy

Tuberculosis vaccines — perspectives from the NIH/NIAID Mycobacteria vaccine testing program

Angelo A Izzo

http://ift.tt/2hiK6CV

TNF-receptor superfamily agonists as molecular adjuvants for cancer vaccines

Timothy NJ Bullock

http://ift.tt/2f39Ou8

Four pathways of CD1 antigen presentation to T cells

D Branch Moody | Rachel N Cotton

http://ift.tt/2hivPGo

Circulating tumor DNA reveals clinically-actionable somatic genome of metastatic bladder cancer

Purpose: Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer (BCa), but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally-invasive tool to profile the tumor genome in real-time, but is critically under-explored in BCa. <p>Experimental Design: We applied a combination of whole exome sequencing and targeted sequencing across 50 BCa driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive BCa, including 37 with metastatic disease.</p> <p>Results: The majority of metastatic patients, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9 - 72.6%). 12% of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic BCa with 95% of patients harboring deleterious alterations to TP53, RB1 or MDM2, and 70% harbouring a mutation or disrupting rearrangement affecting chromatin modifiers such as ARID1A. Targetable alterations in MAPK/ERK or PI3K/AKT/mTOR pathways were robustly detected, including amplification of ERBB2 (20% of patients) and activating hotspot mutations in PIK3CA (20%), with the latter mutually exclusive to truncating mutations in TSC1. A novel FGFR3 gene fusion was identified in consecutive samples from one patient.</p> <p>Conclusions: Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic BCa. The identification of a wide spectrum of clinically-informative somatic alterations nominates ctDNA as a tool to dissect disease pathogenesis and guide therapy selection in metastatic BCa.

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Epacadostat Shows Value in Two SCCHN Trials [News in Brief]

IDO1 inhibitor, combined with a checkpoint inhibitor, improved treatment responses in patients with head and neck cancer, other solid tumors.

http://ift.tt/2w0kDRJ

Normal and malignant cells exhibit differential responses to calcium electroporation

Calcium electroporation may offer a simple general tool for anticancer therapy. Transient permeabilization of cancer cell membranes created by applying short, high-voltage pulses in tumors enables high calcium influxes that trigger cell death. In this study, we compared the relative sensitivity of different human tumor models and normal tissues to calcium electroporation. Plasma membrane Ca2+-ATPase (PMCA) protein expression was confirmed in vitro in all cancer cell lines and normal primary dermal fibroblasts studied. In all tumor types tested in vivo, calcium electroporation effectively induced necrosis, with a range of sensitivities observed (36-88%) 2 days after treatment. Necrosis was induced using calcium concentrations of 100-500 mM and injection volumes 20-80% of tumor volume. Notably, only limited effects were seen in normal tissue. Calcium content increased >7-fold in tumor and skin tissue after calcium electroporation but decreased in skin tissue 4 hr after treatment to levels comparable to untreated controls, whereas calcium content endured at high levels in tumor tissue. Mechanistic experiments in vitro indicated that calcium influx was similar in fibroblasts and cancer cells. However, we observed decreased PMCA expression in cancer cells compared to fibroblasts offering a potential explanation for the different calcium content in tumor cells versus normal tissues. Overall, our results suggest that calcium electroporation can elicit a rapid and selective necrosis of solid tumors, with limited deleterious effects on surrounding normal tissues.

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FBW7 loss promotes chromosomal instability and tumorigenesis via Cyclin E1/CDK2-mediated phosphorylation of CENP-A

The centromere regulates proper chromosome segregation and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here we define the consequences of phosphorylation by Cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to chromosomal instability (CIN). This event on CENP-A reduced its centromeric localization, increased CIN and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that Cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A-mediated centromere dysfunction.

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Dual Targeting of Insulin Receptor and KIT in Imatinib-Resistant Gastrointestinal Stromal Tumors

Oncogenic KIT or PDGFRA receptor tyrosine kinase (RTK) mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GIST. Most GIST eventually acquire imatinib resistance due to secondary mutations in the KIT kinase domain, but it is unclear whether these genomic resistance mechanisms require other cellular adaptations to create a clinically meaningful imatinib-resistant state. Using phospho-RTK and immunoblot assays, we demonstrate activation of KIT and insulin receptor (IR) in imatinib-resistant GIST cell lines (GIST430 and GIST48) and biopsies with acquisition of KIT secondary mutations, but not in imatinib-sensitive GIST cells (GIST882 and GIST-T1). Treatment with linsitinib, a specific IR inhibitor, inhibited IR and downstream intermediates AKT, MAPK, and S6 in GIST430 and GIST48, but not in GIST882, exerting minimal effect on KIT phosphorylation in these cell lines. Additive effects showing increased apoptosis, anti-proliferative effects, cell cycle arrest, and decreased pAKT and pS6 expression, tumor growth, migration, and invasiveness were observed in imatinib-resistant GIST cells with IR activation after coordinated inhibition of IR and KIT by linsitinib (or IR shRNA) and imatinib, respectively, compared to either intervention alone. IGF2 overexpression was responsible for IR activation in imatinib-resistant GIST cells, whereas IR activation did not result from IR amplification, IR mutation, or KIT phosphorylation. Our findings suggest that combinatorial inhibition of IR and KIT warrants clinical evaluation as a novel therapeutic strategy in imatinib-resistant GISTs.

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Oncogenic KRAS and p53 loss drive gastric tumorigenesis in mice that can be attenuated by E-cadherin expression

Gastric adenocarcinoma (GA) is the third leading cause of cancer-related death worldwide, but no models exist to readily investigate distant metastases which are mainly responsible for mortality in this disease. Here we report the development of a genetically engineered mouse model of GA tumorigenesis based on KrasG12D expression plus inactivation of E-cadherin (Cdh1) and p53 in the gastric parietal cell lineage. Intestinal and diffuse gastric tumors arise rapidly in this model, which displays a median survival of 76 days. Tumors occur throughout the stomach with metastases documented in lymph nodes, lung and liver. Mice otherwise identical but retaining one wild-type Cdh1 allele exhibited longer survival with only 20% penetrance of invasive tumors and no apparent lung or liver metastases. Notably, increased RAS activity and downstream MAPK signaling was observed in stomachs only when E-cadherin was absent. This model offers a valuable tool to investigate GA subtypes where RAS/MAPK pathway activation and E-cadherin attenuation are common.

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Survival of head and neck cancer cells relies upon LZK kinase-mediated stabilization of mutant p53

Head and neck squamous cell carcinoma (HNSCC) includes epithelial cancers of the oral and nasal cavity, larynx, and pharynx and accounts for ~350,000 deaths/year worldwide. Smoking-related HNSCC is associated with few targetable mutations but is defined by frequent copy number alteration, the most common of which is gain at 3q. Critical 3q target genes have not been conclusively determined for HNSCC. Here we present data indicating that MAP3K13 (encoding LZK) is an amplified driver gene in HNSCC. Copy number gain at 3q resulted in increased MAP3K13 mRNA in HNSCC tumor samples and cell lines. Silencing LZK reduced cell viability and proliferation of HNSCC cells with 3q gain but not control cell lines. Inducible silencing of LZK caused near complete loss of colony-forming ability in cells harboring 3q gain. These results were validated in vivo by evidence that LZK silencing was sufficient to reduce tumor growth in a xenograft model of HNSCC. Our results establish LZK as critical for maintaining expression of mutant stabilized p53.

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Evaluation of Mineral Concentrations in Maternal Serum Before and After Birth and in Newborn Cord Blood Postpartum—Preliminary Study

Abstract

The mineral levels in maternal serum change during pregnancy and may be correlated with those of newborn cord blood. The aim of this study was to evaluate the concentrations of calcium (Ca), magnesium (Mg), zinc (Zn), iron (Fe), and copper (Cu) in maternal blood before and after delivery and in umbilical cord vein and artery serum. The study was carried out in 64 Caucasian pregnant women who delivered in a district hospital in Greater Poland region, aged 28.1 ± 5.4 years, with a mean gestational age of 39.2 ± 1.3 weeks. Blood samples were taken from women 2–8 h before delivery and immediately after childbirth. The umbilical cord artery and vein blood of newborns was obtained immediately after childbirth. The levels of minerals in serum were determined by flame atomic absorption spectrometry. A significant drop in the concentrations of Mg (17.71 ± 1.51 vs 17.07 ± 1.61 μg/ml; p < 0.007), Fe (1.08 ± 0.46 vs 0.82 ± 0.35 μg/ml; p < 0.0004), and Zn (0.63 ± 0.17 vs 0.46 ± 0.16; p < 0.0001) in maternal serum was found after delivery. Moreover, higher levels of Ca, Fe, and Zn and lower levels of Cu were observed in the umbilical vein (Ca: 102.80 ± 7.80 μg/ml; p < 0.0001, Fe: 1.96 ± 0.43 μg/ml; p < 0.0001, Zn: 0.65 ± 0.16 μg/ml; p < 0.0001, Cu: 0.36 ± 0.09 μg/ml; p < 0.0001) and in the umbilical artery cord blood (Ca: 98.07 ± 8.18 μg/ml; p < 0.0001, Fe: 1.63 ± 0.30 μg/ml; p < 0.0001, Zn: 0.65 ± 0.15 μg/ml; p < 0.0001, and Cu: 0.36 ± 0.10 μg/ml; p < 0.0001) compared to the maternal serum (Ca: 85.05 ± 10.76 μg/ml, Fe: 0.82 ± 0.35 μg/ml, Zn: 0.46 ± 0.16 μg/ml, and Cu: 1.90 ± 0.35 μg/ml). Fe levels in the cord artery serum negatively correlated with blood loss during delivery (R = −0.48; p = 0.01), while the Ca concentration in the maternal serum after birth decreased with the age of the women (R = −0.25; p = 0.03). In conclusion, it seems that the process of birth alters the mineral levels in pregnant women's blood. Moreover, it was found that blood loss and the age of the mother are associated with mineral concentrations in the maternal serum and cord artery blood.

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Decision support during electronic prescription to stem antibiotic overuse for acute respiratory infections: a long-term, quasi-experimental study

Interventions to support decision-making can reduce inappropriate antibiotic use for acute respiratory infections (ARI), but they may not be sustainable. The objective of the study is to evaluate the long-term...

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Paediatric surgical services in remote northern Australia: an integrated model of care

Background

Surgical services for children in the Northern Territory of Australia are routinely performed by general surgeons with specific paediatric training, supported by paediatric surgeons. In Australasia, indications for appropriate transfer of elective routine surgery in children to tertiary paediatric surgical centres have been contentious. To transfer all elective paediatric cases from rural locations would have significant social and financial consequences for families and the health system. This study reviews clinical outcomes for elective surgery for two common conditions managed by an integrated service of general surgeons and visiting paediatric surgeons, and compares them with published outcomes from paediatric centres.

Method

A retrospective audit of children undergoing orchidopexy under the age of 5 years or inguinal herniotomy under the age of 1 year at the Royal Darwin Hospital and Darwin Private Hospital between January 2005 and 2016 was conducted.

Results

During the study period, 66 boys underwent 80 orchidopexies at a mean age of 22.3 months (±20.4 SD). A recurrence rate of 5.5%, severe atrophy rate of 1.3% and total atrophy rate of 5.5% were achieved. Sixty-three children underwent 65 inguinal herniotomies at a mean age of 2.5 months (±4.2). A testicular maldescention and atrophy rate of 1.8% and recurrence rate of 0% was achieved.

Conclusion

Children managed with this model of care had complication rates equivalent to or slightly higher than published gold standards. Considering the family disruption, cultural, financial implications and threat to compliance that transfer across vast distances entails, this model provides acceptable outcomes.

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Impact of health utility after thrombotic complications following total hip and knee arthroplasty

Background

Medical complications and preexisting conditions frequently place the surgeon in the unenviable position of choosing between the serious and potentially life-threatening effects of thrombosis, or the issue of bleeding and surgical site complications. The aim of this research was to determine if health utility could be a consideration before choosing to therapeutically anticoagulate in the hip and knee arthroplasty patient.

Methods

The quantitative risks and effectiveness of treatment options for venous thromboembolism, atrial fibrillation, acute coronary syndromes, ischaemic stroke and mechanical heart valves were evaluated from previously published data. Previously calculated health utility values were obtained from published studies for both thrombotic events and anticoagulant-related complications at the site of arthroplasty. An impact score was generated through a multiplication of 1 − utility with the rate of the event occurring.

Results

Impact scores associated with revision surgery and deep infection at the arthroplasty site following anticoagulation are higher compared to impact scores in subsets of non-treated venous thromboembolism, low CHADS2 (congestive heart failure, hypertension, age >75, diabetes (1 point each), stroke/transient ischaemic attack (2 points)) atrial fibrillation and potentially some acute coronary syndrome patients. Some anticoagulation strategies in mechanical heart valves are of definite overall patient value due to the significant complications otherwise.

Conclusion

Objective calculation of both the benefit and risks of anticoagulation in the post-operative patient is significantly altered by including the effect on patient's quality of life utility value. Therapeutic anticoagulation in some common situations is probable to be of more detriment than benefit when considering health utility.

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Matern et During Pregnancy and Lactation has Opposite Effects on Gonadal Expression of Leptin and Leptin Receptor in Rat Dams and Their Offspring

Horm Metab Res
DOI: 10.1055/s-0043-115394

This study investigated the effect of a high-fat (HF) diet on protein expression of leptin and its receptor in the gonads of dams and their offspring. Female Wistar rats were fed a HF diet (30% fat) or a standard breeding (BD) diet (5% fat) during pregnancy and lactation. At 21 days of lactation, mothers and both sexes of prepubertal offspring were killed by decapitation. The protein expression of leptin and its receptor was assayed by Western blot and immunohistochemistry in gonadal, periovarian, and epididymal white adipose tissue (WAT). We demonstrated that leptin protein expression in ovary, and both leptin and ObRb expression in periovarian WAT was decreased in HF dams compared with BD animals. Immunohistochemistry showed lower leptin expression in growing antral follicles and corpora lutea of HF dams. Conversely, in both gonads and epididymal WAT of HF offspring, leptin and its receptor were significantly higher expressed compared with BD. Immunolocalization of leptin system in HF offspring gonads showed higher expression in growing and antral follicles of the ovary, seminiferous tubules, and interstitial tissue of testes. In conclusion, high gonadal and gonadal-WAT expression of leptin system was observed in the offspring of dams fed a HF diet during pregnancy and lactation.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Irisin and Testosterone in Men with Metabolic Syndrome

Horm Metab Res
DOI: 10.1055/s-0043-115227

The beneficial effects of testosterone on the metabolism and body composition of men are well established but the exact mechanisms of these effects are not clearly understood. A potential explanation might lie in the hormones, secreted from skeletal muscles, named "myokines". One such myokine, irisin, has been shown to also have potential beneficial metabolic effects. The aim of this pilot study was to evaluate the association of serum testosterone with circulating serum irisin levels in men with metabolic syndrome. A total 128 men with metabolic syndrome (MS) based on the IDF criteria participated in the study. Irisin serum concentration was determined by means of ELISA. Mean age±SD of the study participants was 51.8±8.3 years. Seventy percent of the subjects had type 2 diabetes mellitus. Circulating irisin was inversely associated with serum testosterone (r=−0.279, p<0.01) and was significantly higher in subjects with hypogonadism – mean±SD 252.0±147.1 vs.172.9±92.2 ng/ml (p=0.002). ROC analysis of serum irisin value was determined for distinguishing subjects with hypogonadism (AUC=0.670). In a multiple linear regression model with BMI, FPG, age, and irisin, only BMI (β=−0.228, p=0.004) and irisin (β=−0.170, p=0.045) were variables independently associated with testosterone concentrations. Irisin is negatively associated with serum testosterone in our population sample of men with MS. This might suggest a possible involvement of myokines and testosterone with regards to the human metabolism. As no such data on this association has been reported in the literature thus far, further prospective studies are required to elucidate this correlation.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Impact of Aldosterone Synthase Inhibitor FAD286 on Steroid Hormone Profile in Human Adrenocortical Cells

Horm Metab Res
DOI: 10.1055/s-0043-113829

Inhibition of aldosterone synthase (CYP11B2) is an alternative treatment option to mineralocorticoid receptor antagonism to prevent harmful aldosterone effects. FAD286 is the best characterized aldosterone synthase inhibitor. However, to date, no study has used sensitive liquid chromatography-tandem mass spectrometry to characterize in detail the effect of FAD286 on the secreted steroid hormone profile of adrenocortical cells. Basal aldosterone production in NCI-H295R cells was detectable and 9-fold elevated after stimulation with angiotensin II. FAD286 inhibited this increase, showing a maximal effect at 10 nmol/l. Higher concentrations of FAD286 did not further reduce aldosterone concentrations, but showed a parallel reduction in corticosterone, cortisol and cortisone levels, reflecting additional inhibition of steroid-11β-hydroxylase (CYP11B1). Pregnenolone, progesterone and 17-OH-progesterone levels remained unaffected. In conclusion, the aldosterone synthase inhibitor FAD286 lowers angiotensin II-induced aldosterone concentrations in adrenocortical cells but the relative lack of selectivity over CYP11B1 is evident at higher FAD286 concentrations.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Prevalence, Clinical Features, and Natural History of Incidental Clinically Non-Functioning Pituitary Adenomas

Horm Metab Res
DOI: 10.1055/s-0043-115645

The objective of the study was to assess the prevalence and clinical features of incidentally discovered clinically non-functioning pituitary adenoma (CNFPA) and to analyze its natural history. A multicenter retrospective study in patients diagnosed with incidental CNFPA periodically followed-up in 3 specialized neuroendocrinology units from 1992 to 2015 was performed. Out of a total of 189 CNFPA patients, 57 cases (30.1%; 29 women; age at diagnosis 55.8±16.7 years) were incidental. Most patients (n=55, 96.5%) were diagnosed by magnetic resonance imaging (MRI). A sum of 71.9% (n=41) were macroadenomas; 2 of them (3.5%) were giant adenomas (≥4 cm). Patients with macroadenomas were older than those with microadenomas (59.5±16.7 vs. 46.4±18.1 years, p=0.007). Macroadenomas were more common in men (85.7% vs. 58.6%, p=0.023). Twenty-eight patients (49.1%) showed suprasellar extension; of these, 19 were accompanied by chiasmatic compression. Hypopituitarism was present in 14 (24.6%) patients; which was partial in 13 patients (22.8%) and complete in one patient (1.8%). The gonadal axis was the most frequently affected (n=13, 22.8%). Twenty four patients (42.1%) underwent surgery. Of the non-operated patients, 26 patients could be evaluated morphologically after a median follow-up of 15.5 months (interquartile range, 5.7–32.7 months). No significant changes were found in the maximum tumor diameter at the end of follow-up (1.2±0.6 vs 1.2±0.7 cm). The majority of CNFPAs evaluated (n=23, 88.5%) did not show any changes in size. In 2 cases (7.7%) tumor size decreased, and in one patient (3.8%) increased. In our series of CNFPA patients, approximately one-third were incidental. These tumors were diagnosed by MRI preferably from the 5th decade of life without sex predilection. Most of them were macroadenomas, more commonly diagnosed in men and at an older age, compared to microadenomas. The suprasellar extension with chiasmatic compression and hypopituitarism were frequent at diagnosis. Most of the non-operated incidental CNFPAs remain with stable tumor size over time, growth being an unusual event.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Effects of a Low-Calorie, Low-Carbohydrate Soy Containing Diet on Systemic Inflammation Among Patients with Nonalcoholic Fatty Liver Disease: A Parallel Randomized Clinical Trial

Horm Metab Res
DOI: 10.1055/s-0042-118707

Few studies have focused on the effects of a soy containing diet on inflammation and serum leptin level among patients with nonalcoholic fatty liver disease (NAFLD). Therefore, we aimed to determine the effects of such a diet in patients with NAFLD. Forty-five patients with NAFLD participated in this parallel randomized clinical trial for 8 weeks. Patients were randomly allocated to these 3 groups: 1) a low-calorie diet, 2) low-calorie low-carbohydrate diet, and 3) low-calorie low-carbohydrate soy containing diet. Low-calorie low-carbohydrate soy containing diet reduced fasting blood sugar (FBS) and serum insulin level significantly compared to other 2 groups (−11.6±2.8 vs. −6.3±1.7 and −3.1±1.0 mg/dl for FBS; and −5.1±1.2  vs. −1.2±0.3 and −1.7±0.5 mg/dl for serum insulin level). Serum hs-CRP level was also reduced significantly following low-calorie low-carbohydrate soy containing diet (−0.8±0.1 vs. −0.1±0.06 and −0.1±0.06 mg/dl). Both systolic and diastolic blood pressures were reduced significantly. Changes in leptin level tended to be different among 3 groups. After trial, 5 patients in each intervention group did not have NAFLD. From 6 patients in grade 2 at the beginning only 1 patient remained and others moved to grade 1. Low-calorie low-carbohydrate soy containing diet could reduce glycemic indices, hs CRP, systolic and diastolic blood pressure in a significant level in patients with NAFLD. However, these effects were dependent on baseline weight and further studies are needed to clarify the effect of such interventions in subjects with different BMI categories.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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11-Keto-β-Boswellic Acid Inhibits Lymphocyte (CD3) Infiltration into Pancreatic Islets of Young None Obese Diabetic (NOD) Mice

Horm Metab Res
DOI: 10.1055/s-0043-112761

11-Keto-β-Boswellic acid (KBA) has been shown to prevent infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by injection of Multiple Low Doses of Streptozotocin (MLD-STZ), which is a chemical compound belonging to the class of nitrososureas. The aim of this work was to study whether or not KBA can also prevent/attenuate infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by genetic dysfunction resembling human type 1 diabetes in several important features. Four weeks old female NOD mice received daily i.p. injections of 7.5 mg/kg of KBA over a period of 3 weeks. Compared to 4 weeks old animals there was significant infiltration of lymphocytes (CD3) into pancreatic islets and appearance of peri-insular apoptotic cells in the period between 4 and 7 weeks. During this time plasma glucose dropped significantly and body weight did not increase. As far as pro-inflammatory cytokines are concerned, except a small increase of IFN-γ, there was no change in the blood. In mice that had been treated with KBA between 4 and 7 weeks after birth no significant infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells was observed, when compared to 4 weeks old mice. Moreover, there was no drop of blood glucose and the animals gained body weight. It is concluded that – similar to the model of MLD-STZ-diabetes – also in the NOD mouse model KBA is able to attenuate or even prevent development of insulitis, suggesting that KBA protects islets from autoimmune reaction regardless whether the signal is provided by a chemical compound or by genetic dysfunction. Whether this also holds for human type 1 diabetes remains to be established.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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