A novel homozygous splicing mutation of CASC5 causes primary microcephaly in a large Pakistani family

Abstract

Primary microcephaly is a disorder characterized by a small head and brain associated with impaired cognitive capabilities. Mutations in 13 different genes encoding centrosomal proteins and cell cycle regulators have been reported to cause the disease. CASC5, a gene encoding a protein important for kinetochore formation and proper chromosome segregation during mitosis, has been suggested to be associated with primary microcephaly-4 (MCPH4). This was based on one mutation only and circumstantial functional evidence. By combining homozygosity mapping and whole-exome sequencing in an MCPH family from Pakistan, we identified a second mutation (NM_170589.4;c.6673-19T>A) in CASC5. This mutation induced skipping of exon 25 of CASC5 resulting in a frameshift and the introduction of a premature stop codon (p.Met2225Ilefs*7). The C-terminally truncated protein lacks 118 amino acids that encompass the region responsible for the interaction with the hMIS12 complex, which is essential for proper chromosome alignment and segregation. Furthermore, we showed a down-regulation of CASC5 mRNA and reduction of the amount of CASC5 protein by quantitative RT-PCR and western blot analysis, respectively. As a further sign of functional deficits, we observed dispersed dots of CASC5 immunoreactive material outside the metaphase plate of dividing patient fibroblasts. Normally, CASC5 is a component of the kinetochore of metaphase chromosomes. A higher mitotic index in patient cells indicated a mitotic arrest in the cells carrying the mutation. We also observed lobulated and fragmented nuclei as well as micronuclei in the patient cells. Moreover, we detected an altered DNA damage response with higher levels of γH2AX and 53BP1 in mutant as compared to control fibroblasts. Our findings substantiate the proposed role of CASC5 for primary microcephaly and suggest that it also might be relevant for genome stability.

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Gliosarcoma with neuroaxis metastases

Gliosarcomas are rare tumours of the central nervous system, with a well-known capacity for metastasis. When they metastasise, the dissemination occurs more frequently via the haematogenous route to extraneural sites. Metastasis-spread through the cerebrospinal fluid is extremely rare. We present the case of a 58-year-old man who underwent a gross total resection of a lesion in the left temporal lobe. The histological findings revealed a gliosarcoma and the patient received radiotherapy followed by chemotherapy. Seven months after surgery, while the patient remained neurologically intact, brain and spinal cord MRI revealed tumour recurrence and neuroaxis metastases through the traffic routes of the cerebrospinal fluid. The patient died 8 months after the diagnosis. A PubMed search regarding metastatic gliosarcoma up to June 2015 was also carried out. To the best of our knowledge, this is the first case report of gliosarcoma metastases to the brain and spinal cord leptomeninges.

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A cerebral abscess at first internist glance

A 73-year-old man was transferred to the neurosurgery ward, with a presumptive diagnosis of cerebral abscess. The case was also discussed with the internists as internal medicine consultants. The neurosurgeons pointed out a right temporal lobe abscedated lesion on CT, but we noticed that the hypodense attenuation that usually surrounds the abscess wall (vasogenic oedema) extended to a broader, well-delimitated area, suggesting medium cerebral artery territory. The patient had left-sided hemiplegia with a confusional state and low-grade fever. Considering possible haematogenous dissemination, an echocardiography was performed, confirming mitral endocarditis. Blood cultures and aspirated pus isolated Escherichia coli. Investigating the patient's medical history, we learned he had been submitted to bladder catheterisation 7 weeks before for acute urinary retention due to benign prostatic hyperplasia, and empirically medicated for urinary tract infection. E. coli had also been isolated in a urine specimen at the time. The clinical history of the patient cancelled the pathogenesis of cerebral abscess.

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Generic versus brand-name drugs used in cardiovascular diseases

Abstract

This meta-analysis aimed to compare the efficacy and adverse events, either serious or mild/moderate, of all generic versus brand-name cardiovascular medicines. We searched randomized trials in MEDLINE, Scopus, EMBASE, Cochrane Controlled Clinical Trial Register, and ClinicalTrials.gov (last update December 1, 2014). Attempts were made to contact the investigators of all potentially eligible trials. Two investigators independently extracted and analyzed soft (including systolic blood pressure, LDL cholesterol, and others) and hard efficacy outcomes (including major cardiovascular adverse events and death), minor/moderate and serious adverse events. We included 74 randomized trials; 53 reported ≥1 efficacy outcome (overall sample 3051), 32 measured mild/moderate adverse events (n = 2407), and 51 evaluated serious adverse events (n = 2892). We included trials assessing ACE inhibitors (n = 12), anticoagulants (n = 5), antiplatelet agents (n = 17), beta-blockers (n = 11), calcium channel blockers (n = 7); diuretics (n = 13); statins (n = 6); and others (n = 3). For both soft and hard efficacy outcomes, 100 % of the trials showed non-significant differences between generic and brand-name drugs. The aggregate effect size was 0.01 (95 % CI −0.05; 0.08) for soft outcomes; −0.06 (−0.71; 0.59) for hard outcomes. All but two trials showed non-significant differences in mild/moderate adverse events, and aggregate effect size was 0.07 (−0.06; 0.20). Comparable results were observed for each drug class and in each stratified meta-analysis. Overall, 8 serious possibly drug-related adverse events were reported: 5/2074 subjects on generics; 3/2076 subjects on brand-name drugs (OR 1.69; 95 % CI 0.40–7.20). This meta-analysis strengthens the evidence for clinical equivalence between brand-name and generic cardiovascular drugs. Physicians could be reassured about prescribing generic cardiovascular drugs, and health care organization about endorsing their wider use.

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Acute Pain Management/Regional Anesthesia

Publication date: December 2015
Source:Anesthesiology Clinics, Volume 33, Issue 4
Author(s): Tiffany Tedore, Roniel Weinberg, Lisa Witkin, Gregory P. Giambrone, Susan L. Faggiani, Peter M. Fleischut

Teaser

Effective and efficient acute pain management strategies have the potential to improve medical outcomes, enhance patient satisfaction, and reduce costs. Pain management records are having an increasing influence on patient choice of health care providers and will affect future financial reimbursement. Dedicated acute pain and regional anesthesia services are invaluable in improving acute pain management. In addition, nonpharmacologic and alternative therapies, as well as information technology, should be viewed as complimentary to traditional pharmacologic treatments commonly used in the management of acute pain. The use of innovative technologies to improve acute pain management may be worthwhile for health care institutions.


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Examining Health Care Costs

Publication date: December 2015
Source:Anesthesiology Clinics, Volume 33, Issue 4
Author(s): Beverly Chang, Javier Lorenzo, Alex Macario

Teaser

As health care costs threaten the economic stability of American society, increasing pressures to focus on value-based health care have led to the development of protocols for fast-track cardiac surgery and for delirium management. Critical care services can be led by anesthesiologists with the goal of improving ICU outcomes and at the same time decreasing the rising cost of ICU medicine.


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Ultrasound is at least as good as magnetic resonance imaging in predicting tumour size post-neoadjuvant chemotherapy in breast cancer

Publication date: January 2016
Source:European Journal of Cancer, Volume 52
Author(s): Birgit E.P.J. Vriens, Bart de Vries, Marc B.I. Lobbes, Saskia M. van Gastel, Franchette W.P.J. van den Berkmortel, Tineke J. Smilde, Laurence J.C. van Warmerdam, Maaike de Boer, Dick Johan van Spronsen, Marjolein L. Smidt, Petronella G.M. Peer, Maureen J. Aarts, Vivianne C.G. Tjan-Heijnen
BackgroundThe aim of this study was to evaluate the accuracy of clinical imaging of the primary breast tumour post-neoadjuvant chemotherapy (NAC) related to the post-neoadjuvant histological tumour size (gold standard) and whether this varies with breast cancer subtype. In this study, results of both magnetic resonance imaging (MRI) and ultrasound (US) were reported.MethodsPatients with invasive breast cancer were enrolled in the INTENS study between 2006 and 2009. We included 182 patients, of whom data were available for post-NAC MRI (n=155), US (n=123), and histopathological tumour size.ResultsMRI estimated residual tumour size with <10-mm discordance in 54% of patients, overestimated size in 28% and underestimated size in 18% of patients. With US, this was 63%, 20% and 17%, respectively. The negative predictive value in hormone receptor-positive tumours for both MRI and US was low, 26% and 33%, respectively. The median deviation in clinical tumour size as percentage of pathological tumour was 63% (P25=26, P75=100) and 49% (P25=22, P75=100) for MRI and US, respectively (P=0.06).ConclusionsIn this study, US was at least as good as breast MRI in providing information on residual tumour size post-neoadjuvant chemotherapy. However, both modalities suffered from a substantial percentage of over- and underestimation of tumour size and in addition both showed a low negative predictive value of pathologic complete remission (Gov nr: NCT00314977).



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Rationale for anti-OX40 cancer immunotherapy

Publication date: January 2016
Source:European Journal of Cancer, Volume 52
Author(s): Sandrine Aspeslagh, Sophie Postel-Vinay, Sylvie Rusakiewicz, Jean-Charles Soria, Laurence Zitvogel, Aurélien Marabelle
Immune checkpoint blockade with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) generate long lasting anti-tumour immune responses translating into clinical benefit across many cancer types. However, many patients are primarily resistant to immune checkpoint blockade –based monotherapy and many others will eventually relapse. Therefore, new immunostimulatory targets are needed to overcome primary and secondary resistance to immunotherapy. Besides the B7 co-inhibitory receptors, the tumour necrosis factor receptor superfamily contains many other immune checkpoints, which could become the next generation immunomodulators. Among them stands OX40 (CD134), a co-stimulatory molecule that can be expressed by activated immune cells. Several anti-OX40 agonistic monoclonal antibodies are currently tested in early phase cancer clinical trials. Accumulating preclinical evidence supports their clinical development. However, conflicting results and controversies between in vitro and in vivo data point to the need for comprehensive ancillary studies to be performed in upcoming clinical trials to better understand the mechanism of action of anti-OX40 mAbs-based therapy.



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Management of prostate cancer patients following radiation therapy after radical surgery referred from urology to radiation oncology departments in Spain

Abstract

Purpose

To define usual clinical management of prostate cancer (PCa) patients following postoperative radiation therapy (RT) (adjuvant or salvage) and its evolution over time in radiation oncology (RO) departments in Spain.

Methods

An epidemiological, cross-sectional, multicentre study was conducted. 567 PCa patients that had undergone radical prostatectomy (RP) and received postoperative RT between February and December of both 2006 and 2011 participated in the study. In patients from 2006, health-related quality of life (HRQoL) was assessed using the EPIC questionnaire. Investigators completed a specific survey on two clinical cases of adjuvant and salvage RT.

Results

70.6 % of patients received salvage RT versus 29.4 % who received adjuvant RT; no significant differences were found in terms of frequency for each procedure between both the years. Regarding the survey, a positive surgical margin was the main criteria used in adjuvant RT decision making. In terms of salvage RT scenario, 85.7 % of the investigators stated that adjuvant RT should have been offered instead, 81.4 % of the investigators agreed on a PSA score >0.2 ng/mL as the main criteria for identifying biochemical recurrence after RP, and 67.4 % of investigators did not consider any PSA score for ruling out salvage RT treatment.

Conclusions

Most patients are referred to RO departments to receive salvage RT. Despite the publication of three IA evidence level randomized clinical trials, the patterns for using adjuvant and salvage RT did not change from 2006 to 2011, although patients' profile did. A consensus regarding postoperative RT indications should be reached in order to correct this controversial situation.

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Perioperative Surgical Home

Publication date: December 2015
Source:Anesthesiology Clinics, Volume 33, Issue 4
Author(s): Thomas R. Vetter, Keith A. Jones

Teaser

Healthcare delivery and payment systems in the United States must continue to be reformed to address currently untenably increasing healthcare expenditures, while increasing the quality of care. The Perioperative Surgical Home is a highly patient-centered approach to care, focusing on the standardization, coordination, transitions, and value of care, throughout the perioperative continuum, including after hospital discharge. To increase the value of surgical care, any Perioperative Surgical Home model must translate, implement, and sustain improvements in quality, safety, and satisfaction, plus cost reduction strategies, throughout the perioperative continuum. Healthcare informatics, analytics, decision support, and practice change are central to this effort.


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The Pain Medical Home

Publication date: December 2015
Source:Anesthesiology Clinics, Volume 33, Issue 4
Author(s): Peter Pryzbylkowski, Michael A. Ashburn

Teaser

Chronic pain affects an estimated 100 million people a year in the United States and costs society anywhere from $560 to $635 billion annually. The patient-centered medical home and the patient-centered medical home-neighbor models of care have been advocated to improve patient outcomes. These models of care advocate improved coordination of care within the primary care and specialty care setting. The authors present the patient-centered medical home model of care and suggest how this model of care might be used to improve patient outcomes for patients with chronic pain.


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Racial and ethnic disparities in cost-related medication non-adherence among cancer survivors

Abstract

Purpose

Cancer survivors are delaying or avoiding necessary care due to costs, and medication non-adherence is an important aspect of deferred treatment. This study estimates the prevalence of cost-related medication non-adherence (CRN) by race and ethnicity and examines factors associated with CRN among cancer survivors.

Methods

Using the 2006–2013 National Health Interview Survey, we examine self-reported CRN among cancer survivors compared with cancer-free controls. Descriptive statistics and multiple logistic regression models were used to identify factors associated with CRN among cancer survivors.

Results

In a nationally representative sample of 472,542 adults, 10,998 participants reported a history of cancer and 461,544 did not. Among 10,998 cancer survivors, 1397 (12.70 %) reported CRN. Among older cancer survivors, African-Americans were 2.64 times more likely (95 % confidence interval (CI), 1.73 to 4.01) and Hispanics 2.07 times more likely (95 % CI, 1.32 to 3.24) than whites to report CRN. Among younger cancer survivors, Hispanics were 1.61 times more likely (95 % CI, 1.23 to 2.10) than whites to report CRN.

Conclusions

Significant racial and ethnic disparities in CRN were evident among cancer survivors. Older African-American and Hispanic overall survivors were more likely to report CRN in the past year compared with non-Hispanic whites.

Implications for Cancer Survivors

Given increasing prescription drug expenditure, it is important to closely monitor CRN in high-risk subgroups. Racial and ethnic minority groups at high risk for CRN should be counseled on the importance of medication adherence and offered support services to promote medication adherence. Further studies are warranted to establish effective policies and interventions in vulnerable populations.

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The Cognitive Symptom Checklist-Work in cancer patients is related with work functioning, fatigue and depressive symptoms: a validation study

Abstract

Purpose

The study objectives are to translate the 21-item Cognitive Symptom Checklist-Work (CSC-W21) to Dutch (CSC-W DV) and to validate the CSC-W DV in working cancer patients.

Methods

The CSC-W21 was cross-culturally translated and adapted to a Dutch version. In this 19-item version, the dichotomous response option was changed to an ordinal five-point scale. A validation study of the CSC-W DV was conducted among cancer patients who had returned to work during or following cancer treatment. Internal consistency (Cronbach's α), structural validity (exploratory factor analysis) and construct validity (hypothesis testing) were evaluated.

Results

In a cohort of 364 cancer patients, 341 (94 %) completed the CSC-W DV (aged 50.6 ± 8.6 years, 60 % women). Exploratory factor analysis revealed two subscales 'working memory' and 'executive function'. The internal consistency of the total scale and subscales was high (Cronbach's α = 0.93–0.95). Hypothesis testing showed that self-reported cognitive limitations at work were related to work functioning (P < 0.001), fatigue (P = 0.001) and depressive symptoms (P < 0.001), but not to self-rated health (P = 0.14).

Conclusions

The CSC-W DV showed high internal consistency and reasonable construct validity for measuring work-specific cognitive symptoms in cancer patients. The CSC-W DV was associated in expected ways with work functioning, fatigue and depressive symptoms.

Implications for Cancer Survivors

It is important to enhance knowledge about cognitive symptoms at work in cancer patients, to guide and support cancer patients as good as possible when they are back at work and to improve their work functioning over time.

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Surgical management of secondary hyperparathyroidism: how to effectively reduce recurrence at the time of primary surgery

Abstract

Background

Successful parathyroidectomy (PTX) often results in a dramatic drop in the parathyroid hormone (PTH) levels, relieves the patient from clinical symptoms, and reduces mortality. Although PTX is generally a successful treatment for progressive secondary hyperparathyroidism (SHPT) patients subjected to surgery, a significant proportion develops recurrent SHPT following PTX.

Key message

SHPT requiring PTX occurs more commonly in progressive chronic kidney disease and in long-term lithium therapy. Operative approaches include subtotal PTX, total PTX with or without autotransplantation, and possible thymectomy. Each approach has its proponents, advantages, and disadvantages. Although PTX offers the highest percentage cure for SHPT, compared to all other medical and surgical treatment, recurrent hyperparathyroidism can be observed in some patients dependent on follow-up time. A literature review and analysis of recent data regarding how to reduce recurrence of SHPT at the time of primary surgery was performed. The current literature and our own experience in the field have confirmed that pre-operative imaging, thymectomy, stereo magnifier, and surgical procedure may effectively reduce recurrence of SHPT at the time of primary surgery.

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Mild primary hyperparathyroidism as defined in the Italian Society of Endocrinology’s Consensus Statement: prevalence and clinical features

Abstract

Background

Mild primary hyperparathyroidism (PHPT) was recently clearly defined for the first time. Our study was thus aimed to pinpoint proportion and clinical characteristics of this kind of patients.

Design and patients

We retrospectively evaluated our series of 360 consecutive patients with PHPT, selecting those with all features allowing a correct classification (serum total and ionized calcium, phosphate, creatinine, PTH, 25OHD, urinary calcium, renal and neck ultrasound, MIBI scintiscan, and DEXA at lumbar spine, femoral neck, and distal third of radius). Patients were defined asymptomatic (aPHPT) when bone or kidney was not involved and no hypercalcemic symptom occurred; mild PHPT was defined as aPHPT not meeting updated surgical criteria.

Results

Seventy-five patients among 172 classified as aPHPT had all available data required for surgical evaluation and could be evaluated. Sixty/75 met surgical criteria and the remaining 15 were classified as mild. Mild PHPT patients had lower total and ionized calcium, urinary calcium, and PTH levels than aPHPT meeting surgical criteria, while vitamin D levels and BMD were similar.

Conclusions

Mild PHPT strictly defined according to the last consensus represents a small subgroup with a less active form of the disease.

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Improving the organisation of maternal health service delivery and optimising childbirth by increasing vaginal birth after caesarean section through enhanced women-centred care (OptiBIRTH trial): study protocol for a randomised controlled trial (ISRCTN10612254)

Background: The proportion of pregnant women who have a caesarean section shows a wide variation across Europe, and concern exists that these proportions are increasing. Much of the increase in caesarean sections in recent years is due to a cascade effect in which a woman who has had one caesarean section is much more likely to have one again if she has another baby. In some places, it has become common practice for a woman who has had a caesarean section to have this procedure again as a matter of routine. The alternative, vaginal birth after caesarean (VBAC), which has been widely recommended, results in fewer undesired results or complications and is the preferred option for most women. However, VBAC rates in some countries are much lower than in other countries.Methods/DesignThe OptiBIRTH trial uses a cluster randomised design to test a specially developed approach to try to improve the VBAC rate. It will attempt to increase VBAC rates from 25 % to 40 % through increased women-centred care and women's involvement in their care. Sixteen hospitals in Germany, Ireland and Italy agreed to join the study, and each hospital was randomly allocated to be either an intervention or a control site.DiscussionIf the OptiBIRTH intervention succeeds in increasing VBAC rates, its application across Europe might avoid the 160,000 unnecessary caesarean sections that occur every year at an extra direct annual cost of more than €150 million.Trial registrationCurrent Controlled Trials ISRCTN10612254, registered 3 April 2013.

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The small conductance potassium-activated calcium channel 3 (SK3) is a molecular target for Edelfosine to reduce the invasive potential of urothelial carcinoma cells

Abstract

Metastasis is the survival-determining factor in urothelial carcinoma (UC) of the urinary bladder. The small conductance calcium-activated potassium channel 3 (SK3) enhances tumor cell invasion in breast cancer and malignant melanoma. Since Edelfosine, a glycerophospholipid with antitumoral properties, effectively inhibits SK3 channel activity, our goal was to evaluate SK3 as a potential molecular target to inhibit the gain of an invasive phenotype in UC. SK3 protein expression was analyzed in 208 tissue samples and UC cell lines. Effects of Edelfosine on SK3 expression and intracellular calcium levels as well as on cell morphology, cell survival and proliferation were assessed using immunoblotting, potentiometric fluorescence microscopy, and clonogenic/cell survival assay; furthermore, we analyzed the effect of Edelfosine and SK3 RNAi knockdown on tumor cell migration and invasion in vitro and in vivo. We found that SK3 is strongly expressed in muscle-invasive UC and in the RT112 cellular tumor model. Higher concentrations of Edelfosine have a strong antitumoral effect on UC cells, while 1 μM effectively inhibits migration/invasion of UC cells in vitro and in vivo comparable to the SK3 knockdown phenotype. Taken together, our results show strong expression of SK3 in muscle-invasive UC, consistent with the postulated role of the protein in tumor cell invasion. Edelfosine is able to effectively inhibit migration and invasion of UC cells in vitro and in vivo in an SK3-dependent way, pointing towards a possible role for Edelfosine as an antiinvasive drug to effectively inhibit UC cell invasion and metastasis.

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Comparison of treatment outcomes of endoscope-guided pneumatic dilation and laparoscopic Heller myotomy

Publication date: Available online 30 November 2015
Source:The Kaohsiung Journal of Medical Sciences
Author(s): Hsin-Ming Wang, Wei-Chen Tai, Seng-Kee Chuah, Hung-I Lu, Lung-Sheng Lu, Chih-Ming Liang, Chung-Huang Kuo, Yi-Chun Chiu, Keng-Liang Wu, Chi-Sin Changchien
The debate on which is the better choice between laparoscopic Heller myotomy (LHM) and endoscopic pneumatic dilation (PD) for esophageal achalasia has been ongoing for decades. This study aims to compare the results of endoscope-guided PD and LHM in 42 patients with achalasia between May 1996 and August 2011. Twenty-one patients who had received PD and 21 who had received LHM were enrolled. The cumulative remission rate was analyzed using the Kaplan–Meier method with the assessment of symptom scores between grades before and after PD or LHM done at 6 weeks, 6 months, 1 year, and then every year thereafter. Possible confounding factors related to the remissions were analyzed by Cox's proportional hazard model. For PD, the cumulative remission rates were 81.0% (1 year), 76.2% (2), 66.7% (3), 61.9% (4), and 47.6% (5). For LHM, the cumulative remission rates were 90.5% every year from the 1^st to the 5^th. The LHM patients had significantly better remission rates than the PD patients (p = 0.033, by log-rank test). The LHM group had a longer hospital stay than the PD group [median (interquartile range): 8 (6.5–10) days vs. 3 (2–3) days, p < 0.001) and had more reflux complications (52.4% vs. 19.0%, p = 0.024). No perforation occurred in either group. In conclusion, the 5-year cumulative effectiveness of LHM is better than that of PD despite the association of LHM with more reflux events (52.4%).



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Are you ready for the winter?

The winter is coming you should be ready.. Take these steps for your home Many people prefer to remain indoors in the winter, but staying inside is no guarantee of safety. Take these steps to keep your home safe and warm during the winter months. •Winterize your home. ◦Install weather str...

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Closing the loop on an HIV escape mechanism

For the past three and a half years, a team of researchers from six universities, led by the University of Delaware and funded by the National Institutes of Health and the National Science Foundation, has been working to uncover new information about a protein that regulates HIV's capability to ...

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New and presumably tick-borne bacterium discovered in an Austrian fox

Adnan Hodzi from the Institute of Parasitology at the Vetmeduni Vienna is searching for pathogens transmitted by ticks. He is especially interested in wild carnivores (foxes and wolves) which could be a possible reservoir and source of infection for humans and other animals.

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Combined analysis of pri-miR-34b/c rs4938723 and TP53 Arg72Pro with cervical cancer risk

Abstract

miR-34 family members can form a p53-miR-34 positive feedback loop and induce apoptosis, DNA repair, angiogenesis, and cell cycle arrest. We conducted a case-control study to examine whether two polymorphisms (i.e., rs4938723 in the promoter of pri-miR-34b/c and TP53 Arg72Pro) were linked to the carcinogenesis of cervical cancer among Chinese Han women. Genotypes of the two polymorphisms in 328 cervical cancer patients and 568 control subjects were determined by using a polymerase chain reaction—restriction fragment length polymorphism assay. We found a significantly increased cervical cancer risk in the pri-miR-34b/c rs4938723 under dominant and overdominant model (CT/CC vs. TT: adjusted OR = 1.34, 95 % CI = 1.01–1.77; CT vs. TT/CC: adjusted OR = 1.37, 95 % CI = 1.05–1.80, respectively). Increased cervical cancer risks were also found in the TP53 Arg72Pro under a heterozygous comparison and overdominant model (CG vs. GG: adjusted OR = 1.44, 95 % CI = 1.06–1.95; CG vs. GG/CC: adjusted OR = 1.47, 95 % CI = 1.12–1.94, respectively). Stratification analysis showed that patients carrying the pri-miR-34b/c rs4938723 CT genotype had a significantly increased risk for developing poorly differential status and clinical stage I. Moreover, increased cancer risks were observed for the TP53 Arg72Pro polymorphism in patients with poorly differential status, clinical stage II, and without lymph node metastasis. Combined analysis revealed that the genotypes of rs4938723 CT/CC and TP53 Arg72Pro CG/CC had an increased cervical cancer risk (OR = 2.21, 95 % CI = 1.38–3.53). These findings suggest that the pri-miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms may contribute to the genesis of cervical cancer.

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Does the addition of drugs targeting the vascular endothelial growth factor pathway to first-line chemotherapy increase complete response? A meta-analysis of randomized clinical trials

Abstract

Drugs targeting the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling (anti-VEGF/VEGFR drugs) are the most validated anti-angiogenic strategies for cancer treatment. Complete response (CR) is a rare event in cancer patients receiving chemotherapy. A meta-analysis was conducted to determine whether adding anti-VEGF/VEGFR drugs to chemotherapy can further increase the chance of CR in the first-line therapy. Relevant databases were systematically searched for the period 2000–2015. Eligible studies were selected according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The incidence, relative risk (RR), and 95 % confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. A total of 12,453 patients from 28 randomized controlled trials were included. The overall incidence of CR in patients treated with anti-VEGF/VEGFR drugs plus chemotherapy was 1.5 % (95 % CI, 1.0–2.0 %) compared to 1.1 % (95 % CI, 0.7–1.4 %) in the chemotherapy-alone arm. Adding anti-VEGF/VEGFR drugs was associated with significant improvement of CR (RR, 1.52, 95 % CI, 1.18–1.95, P = 0.001). When stratified by drug type, adding VEGFR tyrosin kinase inhibitors (TKIs) did not increase the chance of CR (RR, 0.87, 95 % CI, 0.51–1.49; P = 0.614). The addition of bevacizumab with 7.5 mg/kg every 3 weeks, but not 15 mg/kg every 3 weeks, significantly improves the CR (7.5 mg, RR, 2.43, 95 % CI, 1.64–3.60, P = 0.000; 15 mg, RR, 1.07, 95 % CI, 0.63–1.81, P = 0.799). In subgroup analysis, a significant improvement of CR by the addition of anti-VEGF/VEGFR drugs was observed in patients with colorectal cancer (RR, 2.10, 95 % CI 1.21–3.63, P = 0.008), ovarian cancer (RR, 3.07; 95 % CI, 1.68–5.62, P = 0.000), and patients who are treated with platinum-based regimens (RR, 1.78, 95 % CI, 1.23–2.59, P = 0.002). Low-dose bevacizumab, rather than VEGFR TKIs or high-dose bevacizumab, can increase the chance of CR in patients receiving chemotherapy.

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The potential effect of patulin on mice bearing melanoma cells: an anti-tumour or carcinogenic effect?

Abstract

Mycotoxins are bioactive compounds that are noxious to human. Their effects on oncogenesis have been satisfactorily elucidated, and some of mycotoxins have been classified as carcinogenic to humans. Nevertheless, patulin (PAT) is considered by the International Agency of Research on Cancer as 'not carcinogenic to humans'. The present study was designed to understand the effect of this mycotoxin on melanoma cells (B16F10) by measuring cell proliferation and assessing the anti-tumour effect in vivo in Balb/c mice. Our results revealed that intraperitoneally administration of PAT for 20 days significantly induces tumour regression in B16F10 cell-implanted mice. This effect was evidenced by the activation of apoptosis which is supported by the increase in p53 and Bax expressions, the downregulation of the protein levels of Bcl2, and the increase in caspase-3 activity. Moreover, systemic toxicity analysis demonstrated that there is no potential toxicity following PAT treatment unlike untreated melanoma mice which suffer from anaemia, inflammation and liver dysfunction. Remarkably, this is the first published report demonstrating the therapeutic efficacy of PAT in vivo models.

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Anti-angiogenic alternatives to VEGF blockade

Abstract

Angiogenesis is a major requirement for tumour formation and development. Anti-angiogenic treatments aim to starve the tumour of nutrients and oxygen and also guard against metastasis. The main anti-angiogenic agents to date have focused on blocking the pro-angiogenic vascular endothelial growth factors (VEGFs). While this approach has seen some success and has provided a proof of principle that such anti-angiogenic agents can be used as treatment, the overall outcome of VEGF blockade has been somewhat disappointing. There is a current need for new strategies in inhibiting tumour angiogenesis; this article will review current and historical examples in blocking various membrane receptors and components of the extracellular matrix important in angiogenesis. Targeting these newly discovered pro-angiogenic proteins could provide novel strategies for cancer therapy.

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Panorama Dermatologische Praxis

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Reduced-dose abdominopelvic CT using hybrid iterative reconstruction in suspected left-sided colonic diverticulitis

Abstract

Objectives

To assess the effect of hybrid iterative reconstruction (HIR) and filtered back projection (FBP) on abdominopelvic CT with reduced-dose (RD-APCT) in the evaluation of acute left-sided colonic diverticulitis (ALCD).

Methods

Twenty-five consecutive patients with suspected ALCD who underwent RD-APCT (mean CTDIvol 11.2 ± 4.2 mGy) were enrolled in this study. Raw data were reconstructed using FBP and two increasing HIR levels, L4 & L6. Two radiologists assessed image quality, image noise and reviewer confidence in interpreting findings of ALCD, including wall thickening, pericolic fat inflammation, pericolic abscess, and contained or free extraluminal air. Objective image noise (OIN) was measured.

Results

OIN was reduced up to 54 % with HIR compared to FBP. Subjective image quality of HIR images was superior to FBP; subjective image noise was reduced. The detection rate of extraluminal air was higher with HIR L6. Reviewer confidence in interpreting CT findings of ALCD significantly improved with application of HIR.

Conclusions

RD-APCT with HIR offers superior image quality and lower image noise compared to FBP, allowing a high level of reviewer confidence in interpreting CT findings in ALCD. HIR facilitates detection of ALCD findings that may be missed with the FBP algorithm.

Key Points

• HIR significantly reduces objective image noise in comparison to conventional FBP

• HIR offers superior subjective image quality in comparison to conventional FBP

• HIR allows reduced-dose abdominopelvic CT with acceptable image quality

• Reviewer confidence in interpreting CT findings in ALCD significantly improves with HIR

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256-Slice coronary computed tomographic angiography in patients with atrial fibrillation: optimal reconstruction phase and image quality

ABSTRACT

Objectives

To assess the optimal reconstruction phase and the image quality of coronary computed tomographic angiography (CCTA) in patients with atrial fibrillation (AF).

Methods

We performed CCTA in 60 patients with AF and 60 controls with sinus rhythm. The images were reconstructed in multiple phases in all parts of the cardiac cycle, and the optimal reconstruction phase with the fewest motion artefacts was identified. The coronary artery segments were visually evaluated to investigate their assessability.

Results

In 46 (76.7 %) patients, the optimal reconstruction phase was end-diastole, whereas in 6 (10.0 %) patients it was end-systole or mid-diastole, and in 2 (3.3 %) patients it was another cardiac phase. In 53 (88.3 %) of the controls, the optimal reconstruction phase was mid-diastole, whereas it was end-systole in 4 (6.7 %), and in 3 (5.0 %) it was another cardiac phase. There was a significant difference between patients with AF and the controls in the optimal phase (p < 0.01) but not in the visual image quality score (p = 0.06).

Conclusions

The optimal reconstruction phase in most patients with AF was the end-diastolic phase. The end-systolic phase tended to be optimal in AF patients with higher average heart rates.

Key Points

• The optimal reconstruction phase in 76.7 % of patients with atrial fibrillation (AF) was end-diastole.

• The end-systolic phase was optimal in AF patients with higher heart rates.

• ECG and heart-rate control are necessary to obtain end-diastolic images with fewer motion artefacts.

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Ultrasound-guided core-needle biopsy in thyroid nodules. A study of 676 consecutive cases with surgical correlation

Abstract

Objectives

To analyze the diagnostic accuracy of ultrasound-guided core-needle biopsy (CNB) of thyroid nodules.

Methods

Of 3517 CNBs performed using an 18G spring-loaded device in one institution, we retrospectively reviewed 676 nodules in 629 consecutive patients who underwent surgery. CNB and pathological examination were compared. CNB diagnosis was standardized in four categories: insufficient (I), benign (B), follicular lesion (FOL), and malignant (M). Main outcome measures were predictive positive values (PPV), false positives (FP), and false negatives (FN).

Results

CNB showed a low rate of insufficient and FOL diagnoses (5.8 % and 4.5 %). On surgery, there were eight FNs in 374 benign CNBs and three FPs in 148 malignant CNBs. The 154 nodules classified as FOL in CNB included, at surgery, 122 neoplasms; 28 of them malignant. PPV for malignancy of a malignant CNB was 98 %, and for a CNB diagnosis of FOL 18.2 %. Sensitivity for malignancy if CNB of FOL and M are considered positive was 95.6. Only one major complication was observed.

Conclusions

CNB is reliable, safe, and accurate to evaluate thyroid nodules and can be an alternative technique to FNA. It has low rate of non-diagnostic and undetermined cases, with high sensitivity and PPV.

Key Points

• Thyroid core-needle biopsy (CNB) has high sensitivity and PPV.

• Pitfalls of CNB are rare.

• Pitfalls are due to cystic cancer, histological heterogeneity, and mistakes in analysis.

• CNB is a reliable, safe, and accurate method to approach thyroid nodules.

• CNB can be used primarily or after insufficient or indeterminate FNA.

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3D rotational angiography in the endovascular treatment of visceral aneurysms: preliminary experience in a single centre

Abstract

Objectives

Endovascular embolization is a valid option for the management of visceral artery aneurysms. Imaging is crucial for providing anatomical assessments, but preoperative non-invasive investigations may not be exhaustive. The aim of this work is to present preliminary experience with the use of three-dimensional rotational angiography (3DRA) in this particular theatre.

Methods

Seven patients were treated for eight visceral aneurysms (six splenic and two renal) by endovascular embolization. 3DRA was performed before the treatment using a standard protocol. Different parameters (location of the lesion, the afferent and efferent vessels, aneurysm neck, vascular diameters, working incidence) were analyzed.

Results

3DRA was successfully accomplished in all procedures. Mean aneurysm diameter was 23 mm and mean C-arm working incidence was 29° (R-L) and 9° (C-C). The sandwich technique was used in four lesions and the packing in the remaining four. Technical success was 100 %. The mean radiation dose per procedure was 291 600 mGy.cm². The mean procedural time was 2.25 hours. There were no immediate or short-term complications.

Conclusions

3DRA could be an interesting intraoperative tool to provide anatomical and technical assessments of the visceral arteries necessary for endovascular treatment, especially when information from preoperative imaging is not exhaustive.

Key Points

• Endovascular embolization is a valid alternative solution for visceral artery aneurysm treatment

• Imaging is crucial for anatomical assessments and treatment guidance

• 3DRA can contribute to endovascular treatment in lieu of preoperative imaging

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CT evaluation of sigmoid plate dehiscence causing pulsatile tinnitus

Abstract

Objectives

To evaluate the characteristics of sigmoid plate dehiscence (SPD) causing pulsatile tinnitus (PT) on CT arteriography and venography (CTA + V).

Methods

Thirty PT patients treated successfully with SPD reconstruction were enrolled. Sixty asymptomatic patients were matched. The location, extent, number of SPD cases and concomitant signs, including venous outflow dominance, transverse sinus stenosis, high jugular bulb, temporal bone pneumatization, height of pituitary gland and pituitary fossa, abnormal mastoid emissary vein, were detected and compared using CTA + V.

Results

More than one SPD was found on the symptomatic side in 13/30 PT patients (43.3 %). The upper segment of the sigmoid plate was involved in 29/44 SPDs in the vertical direction (65.9 %); the lateral wall was involved in 38/44 SPDs in the horizontal direction (86.4 %). Singular SPD was detected in 3/60 asymptomatic patients (1.67 ± 0.35 mm²), less so in PT patients (7.97 ± 5.17 mm²). Compared with the control group, ipsilateral venous outflow dominance, high jugular bulb and bilateral transverse sinus stenosis were more common in the PT group, together with deeper pituitary fossa and flatter pituitary glands.

Conclusion

SPD causing PT has characteristic CT findings. It may be generated by vascular or intracranial pressure abnormalities and act as a common key to triggering PT's perception.

Key Points

• Pulsatile tinnitus (PT) caused by sigmoid plate dehiscence (SPD) may be cured.

• SPD causing PT has some characteristic findings on CT.

• SPD may be a common key to triggering PT's perception.

• Thin-slice high resolution CT venography is recommended for SPD assessment.

• The relationship between intracranial pressure and SPD causing PT should be studied.

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Optimizing the MRI protocol of the sacroiliac joints in Spondyloarthritis: which para-axial sequence should be used?

Abstract

Introduction

To assess the diagnostic value of para-axial T2w-TSE (paT2) and fat-suppressed proton density (paPD-FS) MRI sequences for the evaluation of the sacroiliac joint (SIJ) of patients with axial Spondylarthritis (SpA).

Materials and methods

One hundred and six patients with clinical findings suggestive of SpA underwent an MR protocol of the SIJ with additional paPD-FS (41 patients) and paT2 (105 patients). Acute (bone marrow oedema [BME], enthesitis, capsulitis, synovitis) and chronic findings (erosions, ankylosis) were assessed by paPD-FS and compared with the gold standard post-contrast sequences, whereas chronic features (because of the lack of fat suppression) were evaluated on paT2 and compared with pcT1.

Results

paPD-FS demonstrated high sensitivity (98.9 %) and specificity (99.1 %) for BME; sensitivity and specificity for synovitis and enthesitis were 100 %; 85.7 % and 100 %, respectively, for capsulitis.

paPD-FS and paT2 showed 100 % sensitivity and specificity for ankylosis; for erosions, paT2 demonstrated 85.3 % sensitivity and 100 % specificity, whereas paPD-FS, respectively, 98 % and 100 %.

Discussion

PaT2 and paPD-FS provided precious information enabling an accurate interpretation of the heterogeneous findings of SpA. paPD-FS showed good results in detecting acute and chronic lesions and its inclusion in a routine MR examination of the SIJ could increase the diagnostic performance of a pre-contrast protocol.

Key Points

• Para-axial sequence should be included in a routine MRI protocol for SpA.

• Acute and chronic findings can be evaluated on para-axial PD-FS

• Para-axial PD-FS is superior to para-axial T2-W in SpA.

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Molecular MRI differentiation between primary central nervous system lymphomas and high-grade gliomas using endogenous protein-based amide proton transfer MR imaging at 3 Tesla

Abstract

Objectives

To show the ability of using the amide proton transfer-weighted (APTW) MRI signals as imaging biomarkers to differentiate primary central nervous system lymphomas (PCNSLs) from high-grade gliomas (HGGs).

Methods

Eleven patients with lymphomas and 21 patients with HGGs were examined. Magnetization-transfer (MT) spectra over an offset range of ±6 ppm and the conventional MT ratio (MTR) at 15.6 ppm were acquired. The APTW signals, total chemical-exchange-saturation-transfer signal (integral between 0 and 5 ppm, CEST_total), and MTR signal were obtained and compared between PCNSLs and HGGs. The diagnostic performance was assessed with the receiver operating characteristic (ROC) curve analysis.

Results

The PCNSLs usually showed more homogeneous APTW hyperintensity (spatially compared to normal brain tissue) than the HGGs. The APTW_max, APTW_max-min and CEST_total signal intensities were significantly lower (P < 0.05, 0.001 and 0.05, respectively), while the APTW_min and MTR were significantly higher (both P < 0.01) in PCNSL lesions than in HGG lesions. The APTW values in peritumoral oedema were significantly lower for PCNSLs than for HGGs (P < 0.01). APTW_max-min had the highest area under the ROC curve (0.963) and accuracy (94.1 %) in differentiating PCNSLs from HGGs.

Conclusions

The protein-based APTW signal would be a valuable MRI biomarker by which to identify PCNSLs and HGGs presurgically.

Key Points

• PCNSLs overall showed more homogeneous APTW hyperintensity than HGGs.

• Maximum APTW signals were lower in PCNSL lesions than in HGG lesions.

• MTR signals were higher in PCNSLs than in HGGs.

• APTW heterogeneity had the highest accuracy in differentiating PCNSLs from HGGs.

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Cystic form of paraduodenal pancreatitis (cystic dystrophy in heterotopic pancreas (CDHP)): a potential link with minor papilla abnormalities? A study in a large series

Abstract

Objectives

To analyze the association between cystic dystrophy in the heterotopic pancreas (CDHP) and minor papilla abnormalities.

Material and methods

Seventy-six patients with CDHP were retrospectively included over 14 years. Two radiologists searched for MDCT signs of CDHP (cysts and thickened intestinal wall, inflammatory changes), and minor papilla abnormalities (Santorini duct dilatation, luminal calcifications of the minor papilla). Other pancreatic abnormalities (parenchymal calcifications, main pancreatic duct dilatation) or bile duct dilatation were also analysed.

Results

CDHP was mostly located in the second part of the duodenum (71/76, 93.5 %). Median duodenal wall thickness was 20 mm (range 10–46). There were multiple cysts in 86 % (65/76, median = 3), measuring 2–60 mm. No cysts were identified in four patients (5 %). Inflammatory changes were found in 87 % (66/76). Minor papilla abnormalities were found in 37 % (28/76) and calcifications in the minor papilla without calcifications in the major papilla were only observed in three patients (4 %). Abnormalities of the pancreas and main bile duct dilatation were identified in 78 % (59/76) and 38 % (29/76).

Conclusion

Previously described CT features were seen in most patients with CDHP. However, minor papilla abnormalities were seen in a minority of patients and, therefore, do not seem to be a predisposing factor for CDHP.

Key Points

• Imaging features suggesting a CDHP diagnosis are confirmed in a large series.

• Minor papilla abnormalities do not seem to be a predisposing factor for CDHP.

• Most patients did not have any isolated minor papilla abnormalities.

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Impact of image denoising on image quality, quantitative parameters and sensitivity of ultra-low-dose volume perfusion CT imaging

Abstract

Objectives

To examine the impact of denoising on ultra-low-dose volume perfusion CT (ULD-VPCT) imaging in acute stroke.

Methods

Simulated ULD-VPCT data sets at 20 % dose rate were generated from perfusion data sets of 20 patients with suspected ischemic stroke acquired at 80 kVp/180 mAs. Four data sets were generated from each ULD-VPCT data set: not-denoised (ND); denoised using spatiotemporal filter (D1); denoised using quanta-stream diffusion technique (D2); combination of both methods (D1 + D2). Signal-to-noise ratio (SNR) was measured in the resulting 100 data sets. Image quality, presence/absence of ischemic lesions, CBV and CBF scores according to a modified ASPECTS score were assessed by two blinded readers.

Results

SNR and qualitative scores were highest for D1 + D2 and lowest for ND (all p ≤ 0.001). In 25 % of the patients, ND maps were not assessable and therefore excluded from further analyses. Compared to original data sets, in D2 and D1 + D2, readers correctly identified all patients with ischemic lesions (sensitivity 1.0, kappa 1.0). Lesion size was most accurately estimated for D1 + D2 with a sensitivity of 1.0 (CBV) and 0.94 (CBF) and an inter-rater agreement of 1.0 and 0.92, respectively.

Conclusion

An appropriate combination of denoising techniques applied in ULD-VPCT produces diagnostically sufficient perfusion maps at substantially reduced dose rates as low as 20 % of the normal scan.

Key Points

• Perfusion-CT is an accurate tool for the detection of brain ischemias.

• The high associated radiation doses are a major drawback of brain perfusion CT.

• Decreasing tube current in perfusion CT increases image noise and deteriorates image quality.

• Combination of different image-denoising techniques produces sufficient image quality from ultra-low-dose perfusion CT.

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Human AAT gene transfer to pig liver improved by using a perfusion isolated organ endovascular procedure

Abstract

Objective

The efficiency of endovascular liver gene transfer in pigs is evaluated by comparing two models of retrograde catheterization: single lobe catheterization with portal inflow (open procedure) versus whole liver isolation with portal and inferior vena cava blockage (close procedure).

Methods

Percutaneous endovascular catheterization was performed in pigs. Open procedure (n = 3): 8Fr balloon catheter placement in a suprahepatic branch through the jugular vein. Closed procedure (n = 3): simultaneous catheterization of the intrahepatic portal vein (transhepatic catheterization, 10Fr balloon catheter), the supra- and infrahepatic cava veins (8Fr balloon catheters through the jugular and femoral veins). In both models, 200 ml of hAAT DNA solution (20 μg/ml) were retrogradely injected at 20 ml/s. Tissue samples (8 per liver) were obtained 14 days later and the exogenous DNA, RNA and protein per cell were quantified. Blood samples were collected periodically for transaminase determination in all the animals.

Results

The open procedure achieved lower (approx. 1000-fold) DNA delivery, resulting in a significantly lower (p < 0.001) gene transcription (>100-fold). The closed model also achieved a higher translation index, although differences were smaller (p < 0.001).

Conclusions

Portal inflow blockage increased the delivery, transcription and translation indexes, significantly improving the final procedure efficacy when compared with an open procedure.

Key Points

• Endovascular hydrodynamic pig liver gene transfer: open procedure versus closed procedure

• Open procedure resulted in much lower DNA delivery than closed model

• Open procedure reached significantly lower gene transcription index

• Translation index with closed model was higher than with the open

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Imaging features of rosette-forming glioneuronal tumours (RGNTs): A Series of seven cases

Abstract

Objective

Rosette-forming glioneuronal tumours (RGNTs) are a recently described, rare, distinct nosological entity of the glioneuronal family. We describe imaging findings (CT and MRI) in seven patients with RGNTs.

Materials and methods

This retrospective study includes seven RGNT patients (4 male, 3 female; age range: 7-42 years; mean age: 25 years) diagnosed and treated at our institute. MR studies were performed on 3 T and 1.5-T clinical MR systems. All patients were reviewed by two experienced neuroradiologists and imaging findings were tabulated.

Results

Five tumours were located in the posterior fossa, and two were in the pineal region. One of the tumours demonstrated multiple satellite lesions, which involved the midbrain, pons, medulla as well as the cervical cord. Tumours located in the pineal region compressed the 3rd ventricle/aqueduct and extended below the tentorium cerebelli. All the tumours demonstrated enhancement, and susceptibility was evident in six of the seven patients. CSF dissemination was present in two patients.

Conclusion

RGNTs are usually solid-cystic tumours and frequently demonstrate peripheral/heterogeneous enhancement upon post-contrast study. Haemorrhage is a common feature which may not be evident on CT. Cerebrospinal fluid (CSF) dissemination is a feature and appropriate imaging should be performed whenever an RGNT is suspected.

Key Points

• CT and MRI findings of seven RGNT cases were retrospectively reviewed.

• RGNTs are predominantly posterior fossa tumours.

• RGNTs are typically T1 hypointense and T2 hyperintense.

• Haemorrhage and peripheral/heterogeneous enhancement are common features of RGNTs.

• CSF dissemination is a feature of RGNTs and requires appropriate imaging.

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mTOR-inhibitor treatment of metastatic renal cell carcinoma: contribution of Choi and modified Choi criteria assessed in 2D or 3D to evaluate tumor response

Abstract

Purpose

To determine whether 2D or 3D Choi and modified Choi (mChoi) criteria could assess the efficacy of everolimus against metastatic renal cell carcinoma (mRCC).

Methods

RECIST-1.1, Choi, and mChoi criteria were applied retrospectively to analyse baseline and 2-month contrast-enhanced computed tomography (CECT) images in 48 patients with mRCC enrolled in the everolimus arm of the French randomized double-blind multicentre phase III trial comparing everolimus versus placebo (RECORD-1). The primary endpoint was centrally reviewed progression-free survival (PFS) calculated from the initial RECORD-1 analysis. Mean attenuation was determined for 2D target lesion regions of interest drawn on CECT sections whose largest diameters had been measured, and for the 3D whole target lesion.

Results

The median PFS was 5.5 months. The median PFS for everolimus responders defined using 3D mChoi criteria was significantly longer than for non-responders (7.6 versus 5.4 months, respectively), corresponding to a hazard ratio for progression of 0.45 (95 % CI: 0.22–0.92), with respective 1-year survival rates of 31 % and 9 %. No other 2D or 3D imaging criteria at 2 months identified patients who would benefit from everolimus.

Conclusions

At 2 months, only 3D mChoi criteria were able to identify mRCC patients with a PFS benefit from everolimus.

Key points

• Choi criteria could not identify everolimus-treated patients with significantly prolonged PFS.

• mCHOI enabled identification of everolimus-treated mRCC patients with a PFS benefit.

• 3D attenuation measurement criteria appeared to perform better than single-slice measurement.

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Real-time eye lens dose monitoring during cerebral angiography procedures

Abstract

Objectives

To develop a real-time dose-monitoring system to measure the patient's eye lens dose during neuro-interventional procedures.

Methods

Radiation dose received at left outer canthus (LOC) and left eyelid (LE) were measured using Metal-Oxide-Semiconductor Field-Effect Transistor dosimeters on 35 patients who underwent diagnostic or cerebral embolization procedures.

Results

The radiation dose received at the LOC region was significantly higher than the dose received by the LE. The maximum eye lens dose of 1492 mGy was measured at LOC region for an AVM case, followed by 907 mGy for an aneurysm case and 665 mGy for a diagnostic angiography procedure. Strong correlations (shown as R²) were observed between kerma-area-product and measured eye doses (LOC: 0.78, LE: 0.68). Lateral and frontal air-kerma showed strong correlations with measured dose at LOC (AK_L: 0.93, AK_F: 0.78) and a weak correlation with measured dose at LE. A moderate correlation was observed between fluoroscopic time and dose measured at LE and LOC regions.

Conclusions

The MOSkin dose-monitoring system represents a new tool enabling real-time monitoring of eye lens dose during neuro-interventional procedures. This system can provide interventionalists with information needed to adjust the clinical procedure to control the patient's dose.

Key Points

• Real-time patient dose monitoring helps interventionalists to monitor doses.

• Strong correlation was observed between kerma-area-product and measured eye doses.

• Radiation dose at left outer canthus was higher than at left eyelid.

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CT fluoroscopy-guided preoperative short hook wire placement for small pulmonary lesions: evaluation of safety and identification of risk factors for pneumothorax

Abstract

Objectives

To retrospectively evaluate the safety of computed tomography (CT) fluoroscopy-guided short hook wire placement for video-assisted thoracoscopic surgery and the risk factors for pneumothorax associated with this procedure.

Methods

We analyzed 267 short hook wire placements for 267 pulmonary lesions (mean diameter, 9.9 mm). Multiple variables related to the patients, lesions, and procedures were assessed to determine the risk factors for pneumothorax.

Results

Complications (219 grade 1 and 4 grade 2 adverse events) occurred in 196 procedures. No grade 3 or above adverse events were observed.

Univariate analysis revealed increased vital capacity (odds ratio [OR], 1.518; P = 0.021), lower lobe lesion (OR, 2.343; P = 0.001), solid lesion (OR, 1.845; P = 0.014), prone positioning (OR, 1.793; P = 0.021), transfissural approach (OR, 11.941; P = 0.017), and longer procedure time (OR, 1.036; P = 0.038) were significant predictors of pneumothorax. Multivariate analysis revealed only the transfissural approach (OR, 12.171; P = 0.018) and a longer procedure time (OR, 1.048; P = 0.012) as significant independent predictors.

Conclusion

Complications related to CT fluoroscopy-guided preoperative short hook wire placement often occurred, but all complications were minor. A transfissural approach and longer procedure time were significant independent predictors of pneumothorax.

Key Points

• Complications related to CT fluoroscopy-guided preoperative short hook wire placement often occur.

• Complications are usually minor and asymptomatic.

• A transfissural approach and longer procedure time are significant independent predictors of pneumothorax.

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Extra-ocular muscle MRI in genetically-defined mitochondrial disease

Abstract

Objectives

Conventional and quantitative MRI was performed in patients with chronic progressive external ophthalmoplegia (CPEO), a common manifestation of mitochondrial disease, to characterise MRI findings in the extra-ocular muscles (EOMs) and investigate whether quantitative MRI provides clinically relevant measures of disease.

Methods

Patients with CPEO due to single mitochondrial DNA deletions were compared with controls. Range of eye movement (ROEM) measurements, peri-orbital 3 T MRI T1-weighted (T1w) and short-tau-inversion-recovery (STIR) images, and T2 relaxation time maps were obtained. Blinded observers graded muscle atrophy and T1w/STIR hyperintensity. Cross-sectional areas and EOM mean T2s were recorded and correlated with clinical parameters.

Results

Nine patients and nine healthy controls were examined. Patients had reduced ROEM (patients 13.3°, controls 49.3°, p < 0.001), greater mean atrophy score and increased T1w hyperintensities. EOM mean cross-sectional area was 43 % of controls and mean T2s were prolonged (patients 75.6 ± 7.0 ms, controls 55.2 ± 4.1 ms, p < 0.001). ROEM correlated negatively with EOM T2 (rho = −0.89, p < 0.01), whilst cross-sectional area failed to correlate with any clinical measures.

Conclusions

MRI demonstrates EOM atrophy, characteristic signal changes and prolonged T2 in CPEO. Correlation between elevated EOM T2 and ROEM impairment represents a potential measure of disease severity that warrants further evaluation.

Key Points

• Chronic progressive external ophthalmoplegia is a common clinical manifestation of mitochondrial disease.

• Existing extra-ocular muscle MRI data in CPEO reports variable radiological findings.

• MRI confirmed EOM atrophy and characteristic signal changes in CPEO.

• EOM T2 was significantly elevated in CPEO and correlated negatively with ocular movements.

• EOM T2 represents a potential quantitative measure of disease severity in CPEO.

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Parametric response mapping of dynamic CT for predicting intrahepatic recurrence of hepatocellular carcinoma after conventional transcatheter arterial chemoembolization

Abstract

Objectives

The aim of our study was to determine the diagnostic value of a novel image analysis method called parametric response mapping (PRM) for prediction of intrahepatic recurrence of hepatocellular carcinoma (HCC) treated with conventional transcatheter arterial chemoembolization (TACE).

Methods

This retrospective study was approved by the IRB. We recruited 55 HCC patients who achieved complete remission (CR) after TACE and received longitudinal multiphasic liver computed tomography (CT). The patients fell into two groups: the recurrent tumour group (n = 29) and the non-recurrent tumour group (n = 26). We applied the PRM analysis to see if this technique could distinguish between the two groups. The results of the PRM analysis were incorporated into a prediction algorithm. We retrospectively removed data from the last time point and attempted to predict the response to therapy of the removed data.

Results

The PRM analysis was able to distinguish between the non-recurrent and recurrent groups successfully. The prediction algorithm detected response to therapy with an area under the curve (AUC) of 0.76, while the manual approach had AUC 0.64.

Conclusions

Adopting PRM analysis can potentially distinguish between recurrent and non-recurrent HCCs and allow for prediction of response to therapy after TACE.

Key Points

• Parametric response mapping (PRM) could help assess patients with recurrent HCCs after TACE.

• Parametric response mapping could direct patients to individualized therapy.

• Longitudinal CT images were analyzed with advanced image analysis method.

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Gonadotropins facilitate potential differentiation of human bone marrow mesenchymal stem cells into Leydig cells in vitro

Publication date: Available online 30 November 2015
Source:The Kaohsiung Journal of Medical Sciences
Author(s): Lin Hou, Qiang Dong, Yun-jian Wu, Yuan-xing Sun, Yan-yu Guo, Yue-hong Huo
Infertility due to low testosterone levels has increased in recent years. This has impacted the social well-being of the patients. This study was undertaken to investigate the potential of gonadotropins in facilitating differentiation of human bone marrow mesenchymal stem cells (BMSCs) into Leydig cells in vitro. BMSCs were isolated, cultured, and their biological characteristics were observed. BMSCs were induced with gonadotropins in vitro and their ability to differentiate into Leydig cells was studied. The level of expression of 3-beta hydroxysteroid dehydrogenase (3β-HSD) and secretion of testosterone were determined using flow cytometry and enzyme-linked immunosorbent assay, respectively, and the results were compared between the experimental and control groups. The cultured BMSCs showed a typical morphology of the fibroblast-like colony. The growth curve of cells formed an S-shape. After inducing the cells for 8–13 days, the cells in the experimental group increased in size and showed typical characteristics of Leydig cells, and the growth occurred in spindle or stellate shapes. Cells from the experimental group highly expressed 3β-HSD, and there was a gradual increase in the number of Leydig cells. The control group did not express 3β-HSD. The level of testosterone in the experimental group was higher than the control group (p < 0.05). Additionally, the cells in the experimental group secreted higher levels of testosterone with increased culture time. The expression of Leydig cell-specific markers in the experimental group was significantly higher (p < 0.05). With these findings, BMSCs can be considered a new approach for the treatment of patients with low androgen levels.



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Association of HLA and cytokine gene polymorphisms with idiopathic pulmonary fibrosis

Publication date: Available online 30 November 2015
Source:The Kaohsiung Journal of Medical Sciences
Author(s): Hai-Ping Zhang, Jian Zou, Ping Xie, Fei Gao, Hui-Jun Mu
Idiopathic pulmonary fibrosis (IPF) is a rare, progressive, and lethal interstitial lung disease with unknown etiology. Divergent observations have suggested that genetic factors contribute to IPF susceptibility. This study investigated the relationship between human leukocyte antigen (HLA), cytokine gene polymorphisms, and IPF in a Chinese Han population. The gene polymorphisms of HLA-A, -B, -DRB1, tumor necrosis factor alpha [TNF-α (−308 A/G)], transforming growth factor beta [TGF-β1 (+869 T/C)], interleukin 10 [IL-10 (−592 C/A, −819 T/C, and −1082 G/A)], and interferon gamma [IFN-γ (+874 T/A)] were detected in 102 individuals with IPF and 266 unrelated normal controls using PCR with sequence-specific primers and a high-resolution melt (HRM) approach. The data showed that there was no difference in HLA allele frequencies between the IPF and control groups. However, the data showed the frequency of HLA-A*02-DRB1*04 haplotype in the IPF group was significantly higher than that in the control group [odds ratio (OR) = 4.69, 95% confidence interval (CI) = 1.82–12.08, p < 0.001]. In addition, no differences in the allele and genotype distributions of the cytokines were found between the IPF and control groups (p > 0.01). Our findings suggest that there is an association between specific HLA haplotype and IPF genetic susceptibility and that the genetic variability of some cytokines may not be involved in the pathogenesis of IPF.



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Guidelines for cytopathologic diagnosis of epithelioid and mixed type malignant mesothelioma. Complementary statement from the International Mesothelioma Interest Group, also endorsed by the International Academy of Cytology and the Papanicolaou Society of Cytopathology

Anders Hjerpe, Valeria Ascoli, Carlos Bedrossian, Mathilde Boon, Jenette Creaney, Ben Davidson, Annika Dejmek, Katalin Dobra, Ambrogio Fassina, Andrew Field, Pinar Firat, Toshiaki Kamei, Tadao Kobayashi, Claire W Michael, Sevgen Onder, Amanda Segal, Philippe Vielh

CytoJournal 2015 12(1):26-26

To provide practical guidelines for the cytopathologic diagnosis of malignant mesothelioma (MM). Cytopathologists involved in the International Mesothelioma Interest Group (IMIG) and the International Academy of Cytology (IAC), who have an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. This article is the result of discussions during and after the IMIG 2012 conference in Boston, followed by thorough discussions during the 2013 IAC meeting in Paris. Additional contributions have been obtained from cytopathologists and scientists, who could not attend these meetings, with final discussions and input during the IMIG 2014 conference in cape town. During the previous IMIG biennial meetings, thorough discussions have resulted in published guidelines for the pathologic diagnosis of MM. However, previous recommendations have stated that the diagnosis of MM should be based on histological material only. [1],[2] Accumulating evidence now indicates that the cytological diagnosis of MM supported by ancillary techniques is as reliable as that based on histopathology, although the sensitivity with cytology may be somewhat lower. [3],[4],[5] Recognizing that noninvasive diagnostic modalities benefit both the patient and the health system, future recommendations should include cytology as an accepted method for the diagnosis of this malignancy. [6],[7] The article describes the consensus of opinions of the authors on how cytology together with ancillary testing can be used to establish a reliable diagnosis of MM.

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Collagenous spherulosis: An interesting cytological finding in breast lesion

Shailja Puri, Shobha Mohindroo, Anchana Gulati

CytoJournal 2015 12(1):25-25

Collagenous spherulosis (CS) is a rare and interesting entity associated with benign breast lesions. CS is an incidental finding picked up only on 0.2% of cytology specimen. Typically cytologically of CS of breast consists of central spherical hyaline spherule surrounded by myoepithelial cells. The central hyaline spherule has been found to be basement membrane material histochemically and immunohistochemically. The importance of recognizing CS of breast lies in the fact that similar hyaline globules can occur in adenoid cystic carcinoma of the breast (ACCB). The two lesions need to be differentiated on cytology failing which inappropriate treatment can be given for either of the two lesions. We present here a case of CS associated with benign breast lesion and a case of ACCB to describe their cytological features and key points to differentiate them cytologically.

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Pitfall in immunohistochemical staining for thyroglobulin in case of thyroid metastasis from lung carcinoma

Napatt Kanjanahattakij, Palapong Chayangsu, Wasana Kanoksil, Sasiphat Chontong, Chutintorn Sriphrapradang

CytoJournal 2015 12(1):27-27



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Geomagnetic Field (Gmf) and Plant Evolution: Investigating the Effects of Gmf Reversal on Arabidopsis thaliana Development and Gene Expression

This protocol describes a method to test the hypothesis that the reversal of the effective geomagnetic field (GMF) induces differential gene expression and alters the morphology of Arabidopsis thaliana. A triaxial octagonal system of Helmholtz coil-pairs was used to artificially generate reversed GMF conditions in the plant growth chamber.

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Analysis of Zebrafish Larvae Skeletal Muscle Integrity with Evans Blue Dye

In this study, we describe a straightforward method to perform Evans Blue Dye (EBD) analysis on zebrafish larvae. This technique is a powerful tool for the characterization of skeletal muscle integrity and delineation of zebrafish models of muscular dystrophy, and is a valuable method for the development of novel therapeutics.

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Rapid Fractionation and Isolation of Whole Blood Components in Samples Obtained from a Community-based Setting

We outline a methodology for the processing of whole blood to obtain a variety of components for further analysis. We have optimized a streamlined protocol that enables rapid, high-throughput simultaneous processing of whole blood samples in a non-clinical setting.

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Microvascular decompression and MRI findings in trigeminal neuralgia and hemifacial spasm

. A single center experience

via Clinical Neurology and Neurosurgery

Publication date: December 2015
Source:Clinical Neurology and Neurosurgery, Volume 139
Author(s): Patrick W. Hitchon, Mario Zanaty, Toshio Moritani, Ergun Uc, Connie L. Pieper, Wenzhuan He, Jennifer Noeller
ObjectiveFor patients with medically unresponsive trigeminal neuralgia (TIC) and hemifacial spasm (HS), surgical microvascular decompression (MVD) is the procedure of choice. The authors of this report sought to review their outcomes with MVD in patients with TIC and HS, and the success of preoperative magnetic resonance imaging (MRI) in identifying the offending vascular compression.MethodsSince 2004, there were a total of 51 patients with TIC and 12 with HS with available MRI scans. All patients underwent preoperative MRI to rule out non-surgical etiologies for facial pain and facial spasm, and confirm vascular compression. Follow-up after surgery was 13±22 months for the patients with TIC and 33±27 months for the patients with HS.ResultsThere were 45 responders to MVD in the TIC cohort (88%), with a Visual Analog Score (VAS) of 1±3. All patients with HS responded to MVD between 25 and 100%, with a mean of 75±22%. Wound complications occurred in 10% of patients with MVD for TIC, and 1 patient reported hearing loss after MVD for HS, documented by audiogram. The congruence rate between the preoperative MRI and operative findings of vascular compression was 84% in TIC and 75% in HS.ConclusionMVD is an effective and safe modality of treatment for TIC and HS. In addition to ruling out structural lesions, MRI can offer additional information by highlighting vascular loops associated with compressions. On conventional scans as obtained here, the resolution of MRI was congruent with operative findings in 84% in TIC and 75% in HS. This review emphasizes that the decision to undertake MVD in TIC or HS should be based on clinical diagnosis and not visualization of a compressing vessel by MRI. Conversely, the presence of a compressing vessel by MRI demands perseverance by the surgeon until the nerve is decompressed.

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Autonomic symptoms in hypertensive patients with post-acute minor ischemic stroke

Autonomic symptoms in hypertensive patients with post-acute minor ischemic stroke

via Clinical Neurology and Neurosurgery

Publication date: December 2015
Source:Clinical Neurology and Neurosurgery, Volume 139
Author(s): Juan Idiaquez, Hector Farias, Francisco Torres, Jorge Vega, David A. Low
BackgroundMost studies regarding autonomic dysfunction in ischemic stroke are limited to heart rate and blood pressure changes during the acute phase. However, there are few data on quantitative assessment of autonomic symptoms. We sought to assess autonomic symptoms in hypertensive ischemic stroke patients.MethodsIn 100 hypertensive patients (45 with symptomatic ischemic stroke (6 months after stroke onset) and 55 without stroke), we assessed autonomic symptoms using the Scale for Outcomes in Parkinson disease-Autonomic (SCOPA-AUT).ResultsThe age (mean±standard deviation) for the stroke group was 66±12 and 63±15 for the without stroke group (P=0.8). Orthostatic hypotension occurred in 3.6% of the stroke group and 4.4% in the group without stroke. The total SCOPA-AUT score was higher in the stroke group compared with the group without stroke (P=0.001). Domain scores for gastrointestinal (P=0.001), urinary (P=0.005) and cardiovascular (P=0.001) were higher in the stroke group. No differences were found when comparing the total SCOPA-AUT scores for stroke subtypes (P=0.168) and for lateralization (P=0.6). SCOPA AUT scores were correlated with depression scores (P=0.001) but not with stroke severity (P=0.2).ConclusionAutonomic symptoms, especially, gastrointestinal, urinary and cardiovascular function, were significantly increased in hypertensive patients with minor ischemic stroke. Symptoms were associated with depression but not with the characteristic of the stroke.

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Festination in patients with Parkinson's disease

Festination in Chinese patients with Parkinson's disease

via Clinical Neurology and Neurosurgery

Publication date: December 2015
Source:Clinical Neurology and Neurosurgery, Volume 139
Author(s): Ruwei Ou, Xiaoyan Guo, Qianqian Wei, Bei Cao, Jing Yang, Wei Song, Na Shao, Bi Zhao, Xueping Chen, Huifang Shang
ObjectiveTo investigate the occurrence and clinical associations of festination in Chinese patients with Parkinson's disease (PD).MethodsA total of 480 PD patients were recruited in this cross-sectional study. Assessments scales included the Unified PD Rating Scale (UPDRS) part III, PD Questionnaire-39 (PDQ-39), Non-Motor Symptoms Scale (NMSS), Mini-Mental State Examination (MMSE), frontal assessment battery (FAB), Montreal Cognitive Assessment (MoCA), Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA).ResultsOne hundred and forty PD patients (29.2%) reported festination. Festination occurred more frequently in patients with lower limbs as the site of onset and patients with longer disease duration or higher Hoehn and Yahr (H&Y) stage (P<0.05). The mean age, levodopa and entacapone use, incidences of motor complications, falls and freezing of gait, and the scores for the UPDRS part III, NMSS, HAMD and HAMA were higher in patients with festination than those without festination (P<0.05). There were no differences in the scores for the PDQ-39, MMSE, FAB and MoCA between the patients with and without festination. The binary logistic regression model indicated that UPDRS part III, lower limbs as the site of onset, freezing of gait and falls were associated with festination.ConclusionsFestination is a relatively common disabling symptom in Chinese PD patients. Patients with lower limbs as the site of onset and more severe disability were more likely to experience festination. Festination in PD is not related to non-motor symptoms and cognitive dysfunction.

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BacterioFiles 240 - Water Worms Make (carbon) Monoxide Meals

This episode: Marine worms and their microbial symbionts can live on the toxic gas carbon monoxide!

Reminder: this is the last episode for at least a few weeks while I am wrapping up my PhD. See you again when I'm done!

(11.1 MB, 12.1 minutes)

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Pre-operative image-based segmentation of the cranial nerves and blood vessels in microvascular decompression

: Can we prevent unnecessary explorations?

via Clinical Neurology and Neurosurgery

Publication date: December 2015
Source:Clinical Neurology and Neurosurgery, Volume 139
Author(s): Parviz Dolati, Alexandra Golby, Daniel Eichberg, Mohamad Abolfotoh, Ian F. Dunn, Srinivasan Mukundan, Mohamed M. Hulou, Ossama Al-Mefty
ObjectivesThis study was conducted to validate the accuracy of image-based pre-operative segmentation using the gold standard endoscopic and microscopic findings for localization and pre-operative diagnosis of the offensive vessel.Patients and methodsFourteen TN and 6 HS cases were randomly selected. All patients had 3T MRI, which included thin-sectioned 3D space T2, 3D Time of Flight and MPRAGE Sequences. Imaging sequences were loaded in BrainLab iPlanNet and fused. Individual segmentation of the affected cranial nerves and the compressing vascular structure was performed by a neurosurgeon, and the results were compared with the microscopic and endoscopic findings by two blinded neurosurgeons. For each case, at least three neurovascular landmarks were targeted. Each segmented neurovascular element was validated by manual placement of the navigation probe over each target, and errors of localization were measured in mm.ResultsAll patients underwent retro-sigmoid craniotomy and MVD using both microscope and endoscope. Based on image segmentation, the compressing vessel was identified in all cases except one, which was also negative intraoperatively. Perfect correspondence was found between image-based segmentation and endoscopic and microscopic images and videos (Dice coefficient of 1). Measurement accuracy was 0.45±0.21mm (mean±SD).ConclusionImage-based segmentation is a promising method for pre-operative identification and localization of offending blood vessels causing HFS and TN. Using this method may prevent some unnecessary explorations on especially atypical cases with no vascular contacts. However, negative pre-operative image segmentation may not preclude one from exploration in classic cases of TN or HFS. A multicenter study with larger number of cases is recommended.

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