e-ULTRASONOGRAPHY 10-2017

Perspective
287	Thyroid disease in children and adolescents Hyun Sook Hong, Ji Ye Lee, Sun Hye Jeong Ultrasonography. 2017;36(4):287-291.   Published online May 28, 2017   DOI: https://doi.org/10.14366/usg.17031
Review Articles
292	Updated guidelines on the preoperative staging of thyroid cancer Hye Jung Kim Ultrasonography. 2017;36(4):292-299.   Published online April 9, 2017   DOI: https://doi.org/10.14366/usg.17023
300	Shear-wave elastography in breast ultrasonography: the state of the art Ji Hyun Youk, Hye Mi Gweon, Eun Ju Son Ultrasonography. 2017;36(4):300-309.   Published online April 5, 2017   DOI: https://doi.org/10.14366/usg.17024
310	Ultrasonographic evaluation of women with pathologic nipple discharge Jung Hyun Yoon, Haesung Yoon, Eun-Kyung Kim, Hee Jung Moon, Youngjean Vivian Park, Min Jung Kim Ultrasonography. 2017;36(4):310-320.   Published online April 9, 2017   DOI: https://doi.org/10.14366/usg.17013
321	Ultrasonography of the ankle joint Jung Won Park, Sun Joo Lee, Hye Jung Choo, Sung Kwan Kim, Heui-Chul Gwak, Sung-Moon Lee Ultrasonography. 2017;36(4):321-335.   Published online April 5, 2017   DOI: https://doi.org/10.14366/usg.17008
336	Ultrasound-guided genitourinary interventions: principles and techniques Byung Kwan Park Ultrasonography. 2017;36(4):336-348.   Published online May 29, 2017   DOI: https://doi.org/10.14366/usg.17026
Original Articles
349	Korean Thyroid Imaging Reporting and Data System features of follicular thyroid adenoma and carcinoma: a single-center study Jung Won Park, Dong Wook Kim, Donghyun Kim, Jin Wook Baek, Yoo Jin Lee, Hye Jin Baek Ultrasonography. 2017;36(4):349-354.   Published online April 13, 2017   DOI: https://doi.org/10.14366/usg.17020
355	Clinical features of recently diagnosed papillary thyroid carcinoma in elderly patients aged 65 and older based on 10 years of sonographic experience at a single institution in Korea Eun Sil Kim, Younghen Lee, Hyungsuk Seo, Gil Soo Son, Soon Young Kwon, Young-Sik Kim, Ji-A Seo, Nan Hee Kim, Sang-il Suh, Inseon Ryoo, Sung-Hye You Ultrasonography. 2017;36(4):355-362.   Published online April 13, 2017   DOI: https://doi.org/10.14366/usg.17010
363	Ultrasonographic findings of posterior interosseous nerve syndrome Youdong Kim, Doo Hoe Ha, Sang Min Lee Ultrasonography. 2017;36(4):363-369.   Published online April 5, 2017   DOI: https://doi.org/10.14366/usg.17007
370	Ultrasound contrast-enhanced study as an imaging biomarker for anti-cancer drug treatment: preliminary study with paclitaxel in a xenograft mouse tumor model (secondary publication) Hak Jong Lee, Sung Il Hwang, Jonghoe Byun, Hoon Young Kong, Hyun Sook Jung, Mira Kang Ultrasonography. 2017;36(4):370-377.   Published online February 14, 2017   DOI: https://doi.org/10.14366/usg.17015
378	Synthesis of ultrasound contrast agents: characteristics and size distribution analysis (secondary publication) Hak Jong Lee, Tae-Jong Yoon, Young Il Yoon Ultrasonography. 2017;36(4):378-384.   Published online February 14, 2017   DOI: https://doi.org/10.14366/usg.17014
Letter
385	Factors related to the efficacy of radiofrequency ablation for benign thyroid nodules Jung Hwan Baek Ultrasonography. 2017;36(4):385-386.   Published online May 17, 2017   DOI: https://doi.org/10.14366/usg.17034

3D/4D TPS for fetal progression in labor and maternal pelvic dimension

US Guided Drug Delivery in Cancer: Sonoporation Effects

In addition to diagnostic purposes, ultrasound is increasingly being used for therapeutic applications including imaging-guided drug and gene delivery to various tissue types [1-3]. Ultrasound-guided delivery of therapeutics has gained special attention since it allows spatially confined delivery of drugs into a target areas, such as a tumor, while minimizing systemic dose and toxicity [4,5]. Since ultrasound is widely available, relatively inexpensive and portable, along with the ability to focus it onto a target area non-invasively with high precision, ultrasound-guided drug delivery is a promising approach to efficiently treat certain cancer types that are anatomically accessible for ultrasound (for example liver tumors) [4,5].

Through a process called sonoporation, ultrasound and microbubble (USMB) mediated cavitation generates transient or permanent pores in the walls of blood vessels and can significantly enhance extravascular delivery of therapeutics in the region of interest (Fig. 1) [6]. USMB mediated drug delivery can be triggered through both stable and inertial cavitation of microbubbles. Cavitation is defined as the growing and shrinking response of microbubbles when subjected to the alternating low and high-pressure portions of the ultrasound wave [7]. Stable cavitation occurs when microbubbles stably oscillate without collapsing in an acoustic field (Fig. 2). In contrast, when microbubbles violently grow and collapse, this process is called inertial cavitation (Fig. 2). While both stable and inertial cavitation exert mechanical forces on adjacent tissues, microbubble collapse (inertial cavitation) can result in additional secondary mechanical effects such as shockwaves and liquid jetting that further enhance the effects of sonoporation.

Fig. 1.

Principle of ultrasound and microbubble mediated nanoparticle delivery in vivo.

Microbubbles and nanoparticles are injected intravenously (IV) and therapeutic ultrasound is focused at the region of interest to induce microbubble cavitation and subsequent opening of the vasculature to allow penetration of therapeutic payload in nanoparticles into the extravascular space. Modified from Delalande et al. Gene 2013;525:191-199, with permission from Elsevier through RightsLink [6]

Fig. 2.

Schematic drawing of the principles of stable and inertial cavitation.

The type of cavitation strongly depends on pressure intensity. When relatively low pressure intensities are applied, the negative and positive pressure phases of the ultrasound (US) waves cause respective growth and shrinkage of microbubbles, which can repeat stably for many cycles. Such stable oscillation of microbubbles which depends on their resonance frequency, is known as stable cavitation. In contrast, when relatively high pressure intensities are applied, microbubbles violently grow to a much larger size followed by energetic collapse, a phenomenon known as inertial cavitation.

Fig. 3.

Visualizing inertial cavitation.

Optical frame images (A-G) and corresponding streak image (H) shows oscillation and inertial cavitation of a microbubble over a 5-microsecond period in response to ultrasound. Initially, the microbubble had a diameter of ~3 μm. The microbubble then underwent expansion and contraction and finally fragmentation due to inertial cavitation. Optical data was captured with a combined frame and streak camera (Imacon 468, DRS Hadland). Modified from Chomas et al. Appl Phys Lett 2000;77:1056-1058, with permission from AIP Publishing through RightsLink [21].

Fig. 4.

Ultrasound and microbubble (USMB) mediated sonoporation and drug delivery.

A. Representative contrast-enhanced ultrasound (US) images of a subcutaneous cancer xenograft during a 2-minute USMB treatment cycle. Image signal increased as microbubbles entered into the tumor (up to 60 seconds), and then substantially decreased during sonoporation (70-120 seconds), indicating inertial cavitation of the microbubbles. B, C. Quantitative reverse transcription polymerase chain reaction shows that USMB mediated delivery substantially enhances intratumoral delivery of therapeutics such as microRNAs (miRNA) compared to untreated and no-US controls. 

Fig. 5.

Therapeutic effects of ultrasound and microbubble (USMB) mediated drug delivery.

A. Summary of terminal deoxynucleotidyl transferase dUTP nick end labeling assay data for quantification of apoptosis shows USMB mediated delivery of miRNAs resulted in increased therapeutic effects compared to control conditions in both doxorubicin (DOX)-resistant and non-resistant human hepatocellular carcinoma (HCC) xenografts in mice. 

Fig. 6.

First clinical ultrasound (US) and microbubble (MB) mediated drug delivery study.

Comparison of patients treated with US, MB, and gemcitabine versus gemcitabine alone indicates that survival improved in the combined treatment group compared to treatment with gemcitabine alone. Median survival was found to improve from 8.9 to 17.6 months (P=0.011, log-rank test) with the use of sonoporation. Patients treated with sonoporation also showed a statistically significant increase in number of treatment cycles (P=0.082, unpaired t test) indicating less toxicity to the patients. CI, confidence interval. Adapted from Dimsevski et al. J Control Release 2016;243:172-181, according to Creative Common license [9].

ACR updates LI-RADS for Ultrasound

By AuntMinnie.com staff writers

September 7, 2017 -- The American College of Radiology (ACR) is updating its standardized system for liver cancer screening and surveillance ultrasound imaging exams.

The refinements to the Liver Imaging Reporting and Data System (LI-RADS) focus on technique, interpretation, reporting, and data collection to improve patient care, education, research, and communication with referring clinicians.

The 24-page document includes screening and surveillance categories, a visualization scoring system, and technical recommendations for performing a screening or surveillance ultrasound exam.

CEUS LI-RADS^® v2017

The documents were created by the Contract Enhanced Ultrasound or CEUS LI-RADS Working Group and approved by the LI-RADS Steering Committee.

 The Core is a 25-page hyperlinked document that covers everything needed to apply CEUS LI-RADS v2017. It includes an updated diagnostic algorithm, basic management guidance, basic reporting guidance, key definitions, core supporting material, and FAQs.

View the LI-RADS® v2017 Core document »

PORTAL HYPERTENSION in CIRRHOSIS and ELASTO ULTRASOUND

TWINKLING ARTIFACT and LITTLE STONE: US PERFORMANCE IMPROVEMENT

NAFLD and NASH and ElastoUS

In the latter years in hepatology, due to new, very potent antiviral drugs that can eradicate or control viral replication in chronic hepatitis C and B patients, witnessed a change in focus has been witnessed: from chronic viral hepatitis  to  fatty  liver  disease. NAFLD  (non-alcoholic fatty  liver  disease)  affects  approximately  one  quarter of  the population  in developed  countries, while NASH (non-alcoholic  steato-hepatitis)  is  present  in  approximatively 2-4% [1,2]. Despite the fact that the course of NASH is quite long, the patients can develop liver cirrhosis and later hepatocellular carcinoma. In the last years, hepatologists  have  focused  on  how  to find  the  patients at risk for NAFLD and NASH, how to predict their evolution and maybe  to stratify  the  risk, considering  that a huge cohort of asymptomatic subjects (millions of people in an area) are dealt with at any one time.

The answer to the first question – how to find them? – is to evaluate the patients at risk for NAFLD and NASH: firstly the  overweight  and  obese  patients;  secondly  patients with type 2 diabetes: thirdly patients with metabolic syndrome and, of course, dyslipidemic subjects (many of them having all these risk factors) [3,4]. The second question is how to identify the subjects at risk to progress toward advanced liver disease. The general practitioner (GP) is the first gate of this strategy, being in direct contact with these patients, then the diabetologist who has most patients at risk under surveillance, usually for a long time (type 2 diabetes patients and dyslipidemic subjects), also the cardiologist  who  is  following-up  patients  with  metabolic syndrome.  Finally, the hepatologist/gastroenterologist  – whose duty  is  to establish  the disease severity,  the prognosis and the best treatment approach for these patients.

The first step in screening the population at risk is to find liver steatosis; the second – to find if this fatty infiltration has a significant  impact on  the  liver; and finally – for prognosis, to find if fibrosis is present. The first aim –  to discover steatosis and  to estimate its  severity  –  can  be  easily  and  inexpensively  reached by  using  liver  ultrasonography  (US). No  expensive  ultrasound machines  and  no  large  ultrasound  experience are required. The sensitivity of liver US for discovering and quantifying steatosis ranges between 60-80%, even higher  for severe steatosis  [5],  influenced by  the physician’s experience.  In centers where a FibroScan device is available, a more objective evaluation of steatosis can be performed using CAP (Controlled Attenuation Parameter). For CAP, cut-off values were calculated for different degrees of steatosis, with accuracy ranging from 80 to 85% [6,7]. In patients undergoing CT or MRI for other purposes, both techniques can give valuable information concerning  the  severity of  fatty  infiltration of  the  liver, but none of them are screening tools.

Considering  the  availability,  the  low  cost,  and  the relatively good sensitivity of US, it seems to be the best method to screen for steatosis in the general population. US can be performed by specialists or by a GP. The criticism for US can be that its accuracy is at its best only if fatty infiltration exceeds 20%. But considering carefully the increased echogenicity of the liver with posterior attenuation and the liver/right kidney gradient, the method is quite sensitive, at least for experienced people [8].

The next question  is how can  inflammation, and especially fibrosis, be assessed in patients with risk factors for NAFLD. A surrogate for inflammation can be the level of  aminotransferases  (ASAT/ALAT  ratio), useful  for general  practice  and  especially  for GP’s  screening. We must  advise  the GP,  the  diabetologist  and  cardiologist, that any small increase of aminotransferases in risk subjects must be evaluated by the hepatologist. Other more sophisticated  biological  tests  can  be  used,  such  as  the NAFLD test or FibroMax. Some of them are expensive (FibroMax) and not widely available. Cytokeratin 18 was proposed as a  surrogate  test  for  infammation detection and NASH [9].

 But let’s focus our discussion on liver fibrosis! This is the most important aspect, since it gives the prognosis. Liver fibrosis can be assessed by liver biopsy or non-invasively. But how can we speak about liver biopsy when NAFLD is an epidemic disease, with millions of cases?

This method  is  too  invasive  for  daily  practice  and  can lead to complications [10]. What about liver elastography? Lately it has became a  fashion! During  ILC Amsterdam  2017, many  papers and discussion were focused on this topic. More than 10 years  ago, Transient  Elastography  (TE)  arrived  on  the market,  performed  with  a  FibroScan  device.  It  evaluates  liver stiffness as a marker of fibrosis. Many papers demonstrated  its good value of  initially  in chronic viral hepatitis  and  later  also  in  NAFLD  [11].  The  new  XL probe (for obese subjects), that completed the M probe, improved the method’s feasibility to more than 90% [12]. Thus,  the vast majority of patients can be evaluated for fbrosis severity by TE. Cut-off values for various stages of fibrosis were calculated for different etiologies, so that TE became a “a must  to have”  in clinical hepatological practice.

During the last 5 years, other US based elastographic techniques were developed: point shear wave elastography (pSWE) or real time elastography (2D-SWE), all integrated into ultrasound machines, can provide liver steatosis  and  liver  stiffness  evaluation  in  the  same  session.

Very recently, an update on the EFSUMB Guidelines and recommendations on  liver elastography have been published [13]. We expect  that  in  the next few years, ultrasound systems with stiffness evaluation will be common in daily practice. The cost of such a system is still high (despite  the  fact  that  some  companies  have  introduced the  elastographic module  in  their mid-class  ultrasound machines),  but  many  hepatologists  (and  maybe  GPs) would  like  to have  such a  system  to evaluate a pathology that is increasing annually. The maintenance cost for such a system  is very  low and  thus  it can be used for a long time, without supplementary costs. One of the companies released very recently an ultrasound system able to perform both 2D-SWE and TE. Another company tried to combine pSWE and 2D-SWE in the same ultrasound machine.

Thus, very soon, the hepatologist (radiologist, diabetologist, maybe  the cardiologist, or GP) will be able  to start screening people at risk, in order to find significant liver  steatosis  and  significant  liver  fibrosis  using  ultrasound machines  and  liver  elastography.  In some  areas, such as the USA, where a lot of energy has been invested in Magnetic Resonance Elastography (MRE), this method can be a competitor. But it is still very expensive and probably not suitable  for screening purposes. The competition will be between the FibroScan with CAP (that quantifies steatosis and fibrosis severity) and ultrasound machines with elastography modules. Probably the analysis of the acquisition and maintenance costs will be the decisive factor. Of course, there  is a place also  for biological tests, but maybe decreasing the cost for complex tests (such as FibroMax) should be recommended.

In centers where systems are able to evaluate the severity of  liver steatosis and  liver fibrosis,  I believe  that it  is  the moment  to  start  screening  for  the  presence  of fatty liver and fibrosis in patients with risk factors (type 2  diabetes,  obese,  dyslipidemia,  metabolic  syndrome) [14]. Early diagnosis of significant disease is the best moment to start therapy (life style changes or drug therapy).

NAFLD is the more prevalent disease in hepatology now, in the developed world, and now is the time to start the fight against this disease!

3D Tumor Measurements on US Spot Thyroid Cancer Growth

By Erik L. Ridley, AuntMinnie staff writer

August 31, 2017 -- Using 3D ultrasound measurements of tumor volume rather than 2D measurements of diameter could be a better way to determine the aggressiveness of small papillary thyroid cancers (PTCs) -- and to guide active surveillance of tumors, according to an August 31 study in JAMA Otolaryngology -- Head & Neck Surgery.

In a study involving nearly 300 patients with papillary thyroid cancers, researchers from Memorial Sloan Kettering Cancer Center (MSKCC) in New York City found that 3D measurements of tumor volume identified tumor growth a median of 8.2 months before the tumor showed an increase in diameter. What's more, the tumors that grew in volume demonstrated a classic exponential growth pattern, with a median doubling time of 2.2 years, according to the authors.

"As the number of small, incidentally detected PTCs continues to increase, new approaches are needed to avoid overtreatment of tumors that would otherwise remain indolent and asymptomatic while identifying the small percentage of such tumors that will continue to grow," wrote the team led by Dr. Michael Tuttle. "Because PTCs appear to follow predictable growth kinetics under active surveillance, serial measurements of tumor volume hold significant promise in triaging patients to observation versus surgery."

Low-risk cancers

Thyroid cancer has been increasingly diagnosed in the U.S. and other countries due to more widespread use of imaging technologies. However, many of these cancers are small, low-risk, asymptomatic papillary thyroid cancers; up to 90% of these indolent cancers will never go on to cause symptoms or death, according to the group.

Recent research in Japan found that active surveillance is safe for PTCs smaller than 1 cm in diameter. Of the patients with these small PTCs, 10% to 15% experienced tumor growth, usually within five years. The threshold for surgical intervention was growth of 3 mm in diameter on 2D ultrasound -- the smallest difference that could be reliably measured with the modality, the authors noted.

However, the kinetics -- probability, rate, and magnitude -- of PTC growth during active surveillance haven't been well-defined, according to the MSKCC researchers.

"A more dynamic characterization of tumor growth based on 3D volume measurements may allow for earlier determination of whether a PTC is stable or growing," they wrote. "Such information would be of value in more precise tailoring of surveillance imaging and, if needed, intervention, in patients undergoing active surveillance."

Tumor growth kinetics

As a result, the researchers set out to describe the kinetics of papillary thyroid cancer growth in 291 patients at their institution who were receiving active surveillance with serial ultrasound exams for low-risk, intrathyroidal tumors 1.5 cm or smaller in size. The 291 patients had a mean age of 52 years; 219 (75.3%) were women and 72 (24.7%) were men.

Ultrasound exams were performed by radiologists every six months for two years, and then yearly after that. For the purposes of the study, an increase in tumor volume of more than 50% from baseline was judged to be a meaningful increase.

Over a median active surveillance period of 25 months (range, 6-166 months), only 11 (3.8%) of the 291 patients had tumor diameter growth of 3 mm or more. The cumulative incidence of this growth was 2.5% at two years of active surveillance and 12.1% at five years. There were no regional or distant metastases reported during active surveillance, according to the researchers.

For all 11 of these cases, 3D measurements of tumor volume on serial ultrasound studies identified growth before the tumor showed an increase in diameter -- at a median of 8.2 months sooner (range, 3-46 months). In addition, tumors that increased in volume showed a classic exponential growth pattern afterward, with a median doubling time of 2.2 years (range, 0.5-4.8 years). This indicates that growth can be accurately modeled, according to the researchers.

As a result, a meaningful increase in 3D tumor volume could potentially justify discontinuing active surveillance and proceeding to surgery. In addition, changes in 3D tumor volume over time could help in determining how often patients should receive surveillance imaging.

Delving further into the results, after performing multivariable analysis the researchers found that younger age at diagnosis was independently associated with the likelihood of more than 3 mm of tumor growth (hazard ratio per year, 0.92; p = 0.006); patients younger than 50 had a nearly fivefold likelihood of experiencing tumor growth within five years, compared with patients 50 and older (27.3% vs. 4.6%, p = 0.03). The patient's risk category at presentation was also independently associated with the likelihood of tumor growth (hazard ratio for inappropriate for observation, 55.17; p < 0.001).

Skilled radiologists are key

The researchers emphasized that the success of their institution's active surveillance management program depends on the availability of specialized and highly skilled radiologists. Before the patient is released from the suite, a senior radiologist reviews all images prepared by the sonographer and compares them with the patient's prior ultrasound images.

"This approach minimizes the expected variation between examiners and examinations, and also allows us to be confident that the serial 3D measurements used to calculate the tumor value fall within the ± 3-mm range of variation that we expected," they wrote. "With experience, expertise, and careful attention to detail, we are confident that these types of ultrasonographic examinations can be done outside of major medical centers."

Looking ahead, the group noted that additional studies will help determine the clinical significance of mild growth in PTC diameter and volume and further refine the thresholds for intervention.

Support for active surveillance

The study offers "invaluable and much-needed support" for implementing active surveillance protocols in the U.S., said Dr. Joseph Scharpf of the Cleveland Clinic Foundation in an invited commentary also published online August 31 in JAMA Otolaryngology -- Head & Neck Surgery.

"This study contributes to the body of knowledge regarding thyroid cancer, and the authors are to be commended for this excellent work that will benefit so many patients diagnosed with a cancer characterized as an epidemic of diagnosis rather than an epidemic of disease," Scharpf wrote. "The financial, physical, and emotional costs of thyroid cancer care associated with this increased incidence are significant and will continue to demand these careful and thoughtful approaches to care."